Skin melanocytic tumor

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Authors: Aadil Ahmed, M.D., Ali M. Alani, M.D., Said Albahra, M.D., Saba Anjum, M.B.B.S., Sepideh Nikki Asadbeigi, M.D., Aaminah Faheem Azhar, M.D., Marialessandra Capuzzolo, M.D., Gerardo Cazzato, M.D., Ph.D., Anila Chughtai, M.B.B.S., Chico J. Collie, M.B.B.S., Jennifer Crimmins, M.D., Mona Deerwester, M.D., M.Sc., Carina Dehner, M.D., Ph.D., Sabina Desar, M.D., Michele Donati, M.D., Hailey Fisher, B.S., Joseph Gillam, M.D., Sarah E. Gradecki, M.D., Christopher S. Hale, M.D., Jonathan D. Ho, M.B.B.S., D.Sc., Dean Holliday, M.D., Gregory A. Hosler, M.D., Ph.D. , Robert E. LeBlanc, M.D., Boulos Mansour, M.D., Jeffrey McBride, M.D., Ph.D., Mark Mochel, M.D., Khaled Sabry Mohamed, M.D., Cuong Nguyen, M.D., Reeba Annie Omman, M.D., Elnaz Panah, M.D., Nat Pernick, M.D., Thuy L. Phung, M.D., Ph.D., Nicholas Polster, M.D., Alison Potter, M.B.B.S. , Carlos N. Prieto-Granada, M.D. , Syeda Qasim, M.D., Shyam Raghavan, M.D., Bethany R. Rohr, M.D., Casey Schukow, D.O., Bruce R. Smoller, M.D., Jodi Speiser, M.D., Pranvera Sulejmani, M.S., Muhammad Tahir, M.D, M.S., Idy Tam, M.D., Carlos A. Torres-Cabala, M.D., Kaitlin Vanderbeck, M.D., Katharina Wiedemeyer, M.D.

Resident / Fellow Advisory Board: Caroline I.M. Underwood, M.D.

Board of reviewers: Carina Dehner, M.D., Ph.D.

Editorial Board Members: Jonathan D. Ho, M.B.B.S., D.Sc., Viktoryia Kozlouskaya, M.D., Ph.D., Robert E. LeBlanc, M.D., Kiran Motaparthi, M.D., Bethany R. Rohr, M.D., Brandon Umphress, M.D.

Deputy Editor-in-Chief: Jonathan D. Ho, M.B.B.S., D.Sc.

Editor-in-Chief: Debra L. Zynger, M.D.

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Related chapters: Skin nonmelanocytic tumor, Skin nontumor

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Superpage Topics

Acral melanoma Acral nevus Atypical Spitz tumor (Spitz melanocytoma) BAP1 inactivated nevus / melanocytoma Blue nevus / cellular blue nevus Café-au-lait spot Combined (clonal, blue, PEM, DPN, BAP1 and Spitz) Common acquired nevus Congenital nevus Cutaneous neurocristic hamartoma Dermal melanocytosis Desmoplastic melanoma Dysplastic nevus Ephelis Halo nevus Invasive melanoma Lentigo Lentigo maligna melanoma Malignant Spitz tumor (Spitz melanoma) Melanocytic hyperplasia Melanoma arising in giant congenital nevus Melanomas with unusual features (balloon cell, verrucous, signet ring cell, small cell, etc.) Melanotic macule Metastatic melanoma Meyerson nevus Mucosal melanoma (genital, oral, sinonasal) Nevi on the nail apparatus (pending) Nevi-general Nevoid melanoma Nevus spilus Nevus with features of recurrence and traumatized nevus (pending) Nodular melanoma Other pigmented lesions and disorders of pigmentation - General Pediatric melanoma Pigmented epithelioid melanocytoma Proliferative nodule (pending) Recurrent nevus (pending) Reed nevus Regressed melanoma (tumoral melanosis) Sentinel node biopsy Special site nevus Spitz nevus Staging Subungual melanoma (melanoma of the nail apparatus) Superficial spreading melanoma (low CSD melanoma) WHO classification WHO classification (pending) WHO classification for pediatric melanocytic neoplasms (pending) WNT activated deep penetrating / plexiform melanocytoma (nevus)

Acral melanoma

Table of Contents

Definition / general

Acral melanoma (AM): melanoma relating to or affecting the non-hair bearing / glabrous or volar skin of the soles, palms and digits as well as the nail apparatus

Essential features

Occurs in nail apparatus as well as on volar surfaces of feet and hands (Cancer 1980;46:2492)
Multiple histologic subtypes, including acral lentiginous melanoma (ALM) as well as other conventional histologic subtypes such as superficial spreading melanoma (SSM, also known as low cumulative sun damage [CSD] melanoma), nodular melanoma (NM) and desmoplastic melanoma

Terminology

Acral lentiginous melanoma
Nail apparatus melanoma

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified
ICD-11: 2C30.3 - acral lentiginous melanoma, primary

Epidemiology

> 50% of cutaneous melanoma cases in East Asian countries (JAMA Dermatol 2013;149:1272)
Most common type of melanoma in patients of Asian, Hispanic and African descent (BMC Cancer 2016;16:691, Arch Dermatol 2009;145:427, Mayo Clin Proc 2007;82:364)
Subungual melanomas represent ~30% of acral melanomas (Ann Dermatol 2021;33:228, Br J Dermatol 2018;178:443)
Rare; age adjusted incidence of 1.8 per million person years (Arch Dermatol 2009;145:427)
Incidence is increased in older patients (mean age of onset: 63 years) (J Dermatol 2017;44:932, Br J Dermatol 2000;143:275, Arch Dermatol 2009;145:427)

Sites

Palms, soles, digits, nail apparatus (Cancer 1980;46:2492)
Weight bearing areas are most likely affected; heel more common than palm (N Engl J Med 2016;374:2404, Ann Dermatol 2021;33:228)
Subungual melanoma: fingernails more common than toenails (Histopathology 2021;78:717, Ann Plast Surg 2013;71:346)

Pathophysiology

Tumor mutation burden is decreased compared to other subtypes of melanoma while other structural aberrations, such as gene amplifications, are more commonly seen (N Engl J Med 2005;353:2135, JAAD Int 2020;1:135, Nature 2017;545:175)
Documented amplifications include (J Natl Cancer Inst 2019;111:1068, Annu Rev Pathol 2014;9:239, Nature 2017;545:175, JAAD Int 2020;1:135)
- CCND1
- CDK4
- nTERT
- PAK1
- GAB2
- EP300
- YAP1
- MDM2 loci
Mitogen activating protein kinase pathway (MAPK pathway) aberrations can be seen in some cases, specifically in BRAF, NRAS, KIT, NF1
PTEN and CDKN2A deletions in ~25% of cases (Nature 2017;545:175)
SPRED1 rearrangements in subungual melanomas are more common versus other locations (Nat Commun 2020;11:5259)

Etiology

Trauma and physical stress play a potential role (Ann Dermatol 2021;33:228)
Other factors including family history and ultraviolet (UV) radiation exposure are minimally involved (Genome Res 2017;27:524, Br J Dermatol 2006;155:561)

Clinical features

Acral lentiginous melanoma is the most common subtype
Typically starts as a pigmented macule and progresses to invasive melanoma over several months to years
Subungual melanomas begin as a longitudinal discoloration referred to as longitudinal melanonychia, with progression to involve adjacent skin; clinical extension of pigmentation onto adjacent skin is called Hutchinson sign (Histopathology 2021;78:717, J Am Acad Dermatol 2015;73:213, J Natl Cancer Inst 2019;111:1068, N Engl J Med 2011;364:e38)
Often advanced at diagnosis because hyperkeratotic epidermis overlies and hides primary lesion (J Am Acad Dermatol 2003;48:183)
May evolve slowly over years; mean is 1 year to diagnosis (J Foot Ankle Res 2008;1:11)
Rarely multiple (Dermatol Surg 2007;33:1)
Median disease free survival is 10 years (Br J Dermatol 2006;155:561)
Dermoscopy
- May have parallel ridge pattern (band-like pigmentation on ridges of skin markings is specific)
- Irregular pigmentation with variable shades (J Dermatol 2011;38:25)

Diagnosis

Clinical presentation
Definitive diagnosis is made on biopsy or excisional specimen through histologic examination

Prognostic factors

Breslow thickness, ulceration, high mitotic rate, microsatellites (Br J Dermatol 2007;157:311)
Positive sentinel lymph nodes are the most important factor for recurrence (Am J Surg 2012;204:874)
Increased locoregional recurrence rate compared to other melanoma subtypes
Worse survival rate than other melanoma subtypes (J Natl Compr Canc Netw 2014;12:1706)

Case reports

42 year old woman with lesion initially treated as plantar wart (Dermatol Online J 2006;12:3)
61 year old man with an amelanotic melanoma (Mol Clin Oncol 2020;13:59)
67 year old man with acral amelanotic melanoma with appearance of ulcer (Cureus 2022;14:e26615)
73 year old woman with acral melanoma clinically suspected of being mycotic intertrigo (Int Wound J 2020;17:1532)
74 year old man with in situ ALM which progressed to invasion (Ann Dermatol 2009;21:185)
84 year old man with ALM with multiple metastases to bone (Pan Afr Med J 2023;45:141)

Clinical images

Images hosted on other servers:

Plantar surface

Erosive and macerated lesion

In situ

Invasive ALM

Microscopic (histologic) description

Prominent acanthosis of epidermis with elongated rete ridges can be seen
Pagetoid spread
Atypical nuclei
Increased N:C ratio
Proliferation of melanocytes downward along eccrine ducts
Consumption of epidermis present (attenuation of basal / suprabasal layers with rete ridge loss) (J Cutan Pathol 2012;39:577)
Early lesions may show proliferation of solitary melanocytes in the epidermal rete ridge (crista profunda intermedia) underlying the ridge of the skin marking (Am J Dermatopathol 2006;28:21)
Nail lesions show confluent stretches of solitary melanocytes, multinucleation, lichenoid inflammatory reaction and florid pagetoid spread (Am J Surg Pathol 2008;32:835)
Heterologous osseocartilaginous differentiation seen more commonly in acral melanoma
ALM is the most common histopathologic subtype, followed by NM and SSM (JAMA Dermatol 2013;149:1281, Sci Rep 2016;6:31432, Melanoma Res 2017;27:315)
ALM
- ALM in situ demonstrates an increased number of irregularly distributed melanocytes at basal epidermis
- Variable cytologic atypia of melanocytes with hyperchromatic nuclei
- Prominent dendrites and confluent distribution of melanocytes
- Later vertical growth phase develops with invasion into dermis
- Melanocytes comprising the vertical growth phase are spindled (NF1 mutations) to epithelioid (BRAF mutations) (J Invest Dermatol 2018;138:933)
Subungual melanoma: first demonstrates a mild proliferation of atypical melanocytes with hyperchromatic nuclei, increased N:C ratio and elongated dendrites (Am J Surg Pathol 2007;31:1902, J Dermatol 2008;35:695, J Cutan Pathol 2016;43:41)
- Important histologic features in subungual melanoma in situ include irregular and hyperchromatic nuclei and increased melanocyte count (Histopathology 2021;78:717)

Microscopic (histologic) images

Contributed by Carlos A. Torres-Cabala, M.D.

Atypical compound melanocytic proliferation

Atypical junctional component

Vertical growth phase

Atypical melanocytes

Pagetoid spread

Atypical epithelioid melanocytes

Confluence of atypical junctional melanocytes

Epithelioid to spindled cytology

SOX10

D2-40 / MITF double stain

HMB45

MelanA

SOX10 in invasive component

PRAME

Positive stains

HMB45 (sometimes focal in amelanotic AM), useful to highlight long dendrites (Int J Dermatol 2003;42:123, J Am Acad Dermatol 2013;69:700)
MelanA, SOX10, S100, MITF, PRAME (Hum Pathol 2022;120:9, J Cutan Pathol 2022;49:220, Am J Surg Pathol 2018;42:1456)
- Note: HMB45, MelanA are negative in desmoplastic melanoma subtype (S100, SOX10 positive)
Cyclin D1: if positive, it is supportive of melanoma
Immunohistochemistry is not always required for diagnosis

Negative stains

HMB45, MelanA are negative in desmoplastic melanoma subtype

Molecular / cytogenetics description

BRAF p. V600E mutations predominate in patients of European descent (Exp Dermatol 2017;26:883)
ALMs demonstrate frequent amplifications, deletions and structural rearrangement, yet mutational burden is low relative to other melanoma subtypes (N Engl J Med 2005;353:2135, Nature 2017;545:175)
ALMs often demonstrate triple negative (BRAF, NRAS, KIT negative) pattern; ALMs generally develop from genetic amplifications de novo (Cancer Res 2000;60:1968)
BRAF mutations are more common in low CSD / superficial spreading melanomas of acral sites; may be associated with pre-existing nevus (J Invest Dermatol 2018;138:933, JAMA Dermatol 2021;157:831)
NRAS mutations are more common in nodular melanomas of acral sites (J Invest Dermatol 2018;138:933)
Cyclin D1 protein expression, characterized via molecular studies (or immunohistochemistry) is associated with increased CCDN1 copy number in acral melanoma (Diagn Pathol 2021;16:60)

Sample pathology report

Skin, right toe, punch biopsy:
- Invasive melanoma, acral lentiginous type (see comment)
- Tumor thickness (Breslow): at least 0.9 mm
- Clark level: at least IV
- Ulceration: present (0.2 mm width)
- Regression: not identified
- Mitotic count: 1/mm²
- Tumor infiltrating lymphocytes: present, nonbrisk
- Lymphovascular invasion: not identified
- Perineural invasion: not identified
- Tissue edges: melanoma present at deep and peripheral tissue edges
- Comment: Sections show skin and subcutis with a cellular and atypical compound melanocytic proliferation that extends to deep and peripheral tissue edges. Confluence of atypical melanocytes is appreciated at the dermoepidermal junction. Pagetoid spread is also readily seen. Cytologically, the melanocytes are epithelioid to spindled with abundant intracytoplasmic melanin pigment. These melanocytes have atypical and enlarged nuclei with readily identifiable mitotic figures within the dermal component. By immunohistochemistry, the tumor cells are positive for MelanA, HMB45, S100, SOX10 and PRAME. Overall, the findings are supportive of the above interpretation. Correlation with the subsequent excisional specimen is recommended for further definite staging information and classification.

Differential diagnosis

Acral lentiginous melanocytic nevi:
- ALM and nevi with pagetoid scatter are difficult to differentiate
- Acral nevi:
  - Melanocytes have less hyperchromatic and irregular nuclei
  - Melanocytes appear smaller in acral nevi with mitotic activity rare or absent
  - Inflammation and confluence of melanocytes at dermoepidermal junction are less common with acral nevi
  - Patient demographics, including age, size, clinical appearance, dermoscopic impressions, are required for diagnosis
  - In compound nevi, maturation of melanocytes is seen with descent
  - Acral nevi tend to be negative for PRAME and, if compound, to show decreased expression of HMB45 and LEF1 with descent (Mod Pathol 2020;33:2067)
  - Acral melanoma is more likely to be positive for cyclin D1 than acral nevi (Diagn Pathol 2021;16:60)
- Acral lentiginous nevus:
  - Predominantly junctional growth pattern with melanocytes arranged in nests of single cells along basal layer of the epidermis, giving a lentiginous appearance
  - Mild to moderate cytologic atypia; this cytologic atypia is less than that seen with ALM
  - Some cases may demonstrate pagetoid spread (see MANIAC below); typically lack significant dermal involvement
- Compound acral nevus:
  - Junctional component demonstrates melanocytes in nests and single cells along the basal layer of the epidermis with mild to moderate cytologic atypia; this cytologic atypia is less that that seen in acral melanoma
  - Some cases may demonstrate pagetoid spread
  - Dermal component demonstrates melanocytes in nests that are surrounded by fibroblasts and collagen fibers, typically without sclerosis, desmoplasia or significant inflammatory reaction (as in melanoma)
  - Melanocytes demonstrate maturation with depth within the dermis
- Melanocytic acral nevus with intraepithelial ascent of cells, variant of acral nevus (MANIAC), also known as lentiginous nevus with upward migration of melanocytes:
  - Defining feature of the variant is the presence of upward migration of melanocytes from the basal layer into the overlying epithelium
  - Pagetoid spread is most often seen toward the center of the lesion
  - This nevus otherwise demonstrates a predominantly junctional growth pattern with mild to moderate cytologic atypia; the cytologic atypia is typically less than that expected with ALM
  - Dermal component can be seen in these nevi; if dermal component is present, maturation of melanocytes with depth is observed and mitotic activity is usually rare or absent (see compound acral nevus above)
Other clinically relevant diagnostic considerations include the following
- Fibroma:
  - Well circumscribed proliferation of spindled fibroblasts in collagenous stroma
  - There is an absence of a melanocytic proliferation
  - Fibroblasts are cytologically bland
- Subungual hematoma:
  - Often demonstrate pigmentation clinically; examination demonstrates hemorrhage, hemosiderin, hemosiderin laden macrophages
  - There is an absence of a melanocytic proliferation
- Verruca:
  - Hyperkeratosis, epidermal hyperplasia, papillomatosis and hypergranulosis
  - Koilocytic / viral cytopathic change appreciated within keratinocytes
  - Dilated capillaries may also be seen within superficial dermis
- Squamous cell carcinoma:
  - Atypical and invasive squamous proliferation with increased mitotic activity and cytologic atypia
- Pyogenic granuloma:
  - Relatively bland vascular proliferation with superficial vessels
  - Predominantly lobular configuration of vessels
  - Overlying epidermal hyperplasia
- Lentigo:
  - Increased (melanin) pigmentation within predominantly basal layer of epidermis without an increase in melanocytes
  - Melanocytic proliferation appears absent

Additional references

WHO Classification of Tumours Editorial Board: Skin Tumours, 5th Edition, 2023

Board review style question #1

A 60 year old man presented with a dark 7 mm nodule on his heel (see images above). What is the best diagnosis?

Acral melanoma
Acral nevus
Deep penetrating nevus / WNT activated deep penetrating / plexiform melanocytoma
Hemangioma

Board review style answer #1

A. Acral melanoma. The images demonstrate an atypical compound melanocytic proliferation with a confluence of atypical melanocytes apparent at the dermoepidermal junction. Answer B is incorrect as the images lack benign features. The confluence of melanocytes, atypia of melanocytes with hyperchromatic, irregular and enlarged nuclei, increased N:C ratio and apparent mitotic figures are more in keeping with melanoma. Answer C is incorrect as the images do not show a wedge shaped melanocytic proliferation that is predominantly dermal. The images demonstrate marked cytologic and nuclear atypia as described that are more in keeping with melanoma versus deep penetrating nevus. Answer D is incorrect as the images demonstrate a melanocytic lesion and not a vascular lesion.

Comment Here

Reference: Acral melanoma

Board review style question #2

What immunohistochemical profile would be expected in an acral lentiginous melanoma?

MelanA-, SOX10+, S100+, PRAME+, HMB45+, cyclin D1-
MelanA+, SOX10-, S100-, PRAME+, HMB45+, cyclin D1+
MelanA+, SOX10+, S100+, PRAME-, HMB45+, cyclin D1+
MelanA+, SOX10+, S100+, PRAME+, HMB45+, cyclin D1+

Board review style answer #2

D. MelanA+, SOX10+, S100+, PRAME+, HMB45+, cyclin D1+. Via immunohistochemistry, acral lentiginous melanomas are positive for conventional melanoma markers including MelanA, SOX10, S100, PRAME and HMB45 as well as cyclin D1. Answers A, B and C are incorrect because acral lentiginous melanoma (ALM) is typically positive for all markers listed.

Comment Here

Reference: Acral melanoma

Acral nevus

Table of Contents

Definition / general

Melanocytic nevi on the skin of soles and palms, nail matrix or bed, knees and elbows
Nevi on acral skin are rarely precursors of melanoma (Dermatopathology (Basel) 2022;9:292)

Essential features

Melanocytic nevi on the skin of soles and palms, nail matrix or bed, knees and elbows
Rarely, acral nevi are precursors of melanoma
Dermoscopy plays a central role in the diagnosis of acral nevi
Histological findings can be typical or atypical
Dysplastic is a term that should not be used on the acral skin

Terminology

Atypical or acral lentiginous nevus; nevus of special sites; nail matrix nevus

ICD coding

ICD-O: 8744/0 - acral nevus

Epidemiology

Relatively frequent lesions occurring in 4 - 9% of Caucasians (Arch Dermatol 2010;146:1085)
More common in individuals with higher constitutional pigmentation and many melanocytic nevi on the skin
Different distribution in the world (U.S. > Japan) (J Am Acad Dermatol 2009;60:767)
F > M (2 - 3:1) (J Am Acad Dermatol 2016;74:724)

Sites

Palms, soles, fingernails > toenails

Clinical features

Usually small, dark brown or black lesions, with irregular but sharp margins
Most are flat and rarely (particularly on the volar skin) elevated

Diagnosis

Dermoscopy plays a crucial role in the diagnosis
Array of thin, parallel dark brown lines (corresponding the acral furrows) in a light brown background (J Dermatol 2011;38:25)
Maturation with descent of dermal component is the most strong indicative parameter of a benign acral nevus

Prognostic factors

Benign; rare progression to melanoma (Dermatology 1993;186:88)

Case reports

4 year old boy with an acral pigmented spitz nevus that clinically mimicked acral lentiginous malignant melanoma (Ann Dermatol 2011;23:246)
23 year old woman with a Spitz nevus on acral volar skin (Indian J Dermatol Venereol Leprol 2019;85:629)
37 year old pregnant woman with acral superficial spreading melanoma arising on melanocytic nevus of the left palm (Indian J Dermatol 2015;60:609)

Treatment

Excision

Clinical images

Contributed by Lucia Lospalluti, M.D.

Small and dark brown lesion

Pigmented acral lesion

Pigmented acral nevus on a foot

Images hosted on other servers:

Various patterns

Transition pattern

Microscopic (histologic) description

About half of the cases are typical and without any peculiar aspects (so called typical features)
May be junctional, compound or intradermal
Small nests of epithelioid cells with inconspicuous nuclei at the junction and small, round melanocytes in the dermis
Atypical cells are possible (sometimes with large vesicular or hyperchromatic nuclei) but they are only occasional, scattered among typical, innocent looking melanocytes
Lentiginous junctional pattern is more common than in nevi of nonacral sites (so called acral nevi with atypical features) with spare of the crista profunda intermedia (prominent melanocytic hyperplasia worrisome for Acral Melanoma in situ)
Often (61%) low level pagetoid, single cell migration into stratum spinosum, summarized by the acronym MANIAC (melanocytic acral nevus with intraepithelial ascent of cells) (Am J Surg Pathol 1995;19:792, Am J Dermatopathol 2000;22:556)
Pagetoid cells should not be atypical and should not be present beyond the center of the lesion
Possible columns of pigment present in the cornified layer, among the corneocytes
Nevus cells mature to lesional base
May have architectural disorder with moderately large melanocytes, bridging fibroplasia (so called special site features) (J Cutan Pathol 2008;35:889)
Usually lesions do not seem well circumscribed (this phenomenon can also depend on the plane of the section)

Microscopic (histologic) images

Contributed by Gerardo Cazzato, M.D. and Angel Fernandez-Flores, M.D., Ph.D.

Poor circumscription

Nests of melanocytes

Pigmented nests of melanocytes

Acral nevus

Melanocytes of acral nevus

Pseudo dysplastic melanocytes

Positive stains

MelanA, HMB45 (Arch Dermatol Res 1998;290:167)
p16 (J Cutan Pathol 2022;49:220)
Possible PRAME positivity in a subset of acral nevi (J Cutan Pathol 2022;49:859)

Sample pathology report

Skin, excision:
- Acral nevus (see comment)
- Comment: Compound melanocytic cutaneous nevus of congenital type in acral type skin (acral type nevus). Lesion is composed by small nests of epithelioid cells with inconspicuous nuclei at the junction and small, round melanocytes in the dermis. Free margins.

Differential diagnosis

Acral lentiginous melanoma (Arch Pathol Lab Med 2011;135:847):
- Mostly single melanocytes
- Diffuse pigment thoroughout the stratum corneum
- Long and uneven dendrites
- Clear cytologic atypia
- Moderate / diffuse pagetoid spread
- Junctional lesion in older patients
- Diffuse 4+ PRAME positivity may suggest melanoma

Board review style question #1

What is the most important clinical aid in the dermatopathological diagnosis of an acral nevus?

Asymmetry
Borders
Color
Dermoscopy
Time of onset

Board review style answer #1

D. Dermoscopy is the most important clinical feature to help the dermatopathological diagnosis of acral nevi. A pattern with an array of thin, parallel, dark brown lines (corresponding to the acral furrows) in a light brown background are characteristic of the lesion. Asymmetry (answer A), borders (answer B), color (answer C) and time of onset (answer E) are also important but in the second instance.

Comment Here

Reference: Acral nevus

Board review style question #2

In an acral nevus showing lively junctional activity, what is the diagnostic clue of benignity of the lesion?

Asymmetry
Localization
Maturation with descent of dermal component
Small nests of melanocytes at the junction
Time of onset

Board review style answer #2

C. Maturation with descent of dermal component is the most histological parameter for the benignity of the lesion. Asymmetry (answer A) is a possibility for an acral nevus. Localization (answer B) is obvious but not an indicator of malignancy. Small nests of melanocytes at the junction (answer D) and time of onset (answer E) are common in an acral nevus without signs of malignancy.

Comment Here

Reference: Acral nevus

Atypical Spitz tumor (Spitz melanocytoma)

Table of Contents

Definition / general

Atypical Spitz tumor (AST) is a classification of Spitz tumors that shares genetic and morphological characteristics between Spitz nevi and Spitz melanoma; it has variable potential for malignant progression

Essential features

Nevus that consists of epithelioid and spindled melanocytes and contains sufficient morphological and genetic atypia to distinguish from Spitz nevus but is insufficient for a diagnosis of melanoma
Has a higher risk of sentinel lymph node involvement but typically has an indolent behavior (Arch Pathol Lab Med 2015;139:1263)
Potential for malignancy is difficult to discern
Often contains HRAS mutation or tyrosine kinase fusions involving ROS1, NTRK1, NTRK3, ALK, BRAF, RET, MET and MAP3K8

Terminology

Spindle and epithelioid cell nevus with atypia and metastasis
Spitzoid tumor of uncertain malignant potential
Benign juvenile melanoma (historical)
Atypical Spitzoid melanocytic tumor

ICD coding

ICD-O: 8770/1 - Spitz melanocytoma (atypical Spitz tumor)
ICD-11
- 2F20.Y - other specific types of melanocytic nevus
- XH9WF4 - Spitz nevus, atypical
- 2F72.1 - Spitzoid tumor of uncertain malignant potential

Epidemiology

Can occur at any age but the majority of cases occur in childhood and into the second decade of life (Cancer 1977;40:217, Cancer 2009;115:631)
Rare congenital cases have been reported (Cancer 2009;115:631)
More common in the White population (Br J Dermatol 2019;181:366)
May have slight predilection for women (Cancer 1977;40:217, Cancer 2009;115:631)

Sites

Can occur anywhere on the skin but is most common on the lower limbs (Cancer 2009;115:631)

Pathophysiology

Cell proliferation mediated by mutations in genes associated with Spitz tumor, such as kinase fusion or inactivation of CDKN2A

Clinical features

Often larger than Spitz nevus, often > 1 cm (Front Oncol 2022:12:889223, Arch Pathol Lab Med 2015;139:1263, Histopathology 2022;80:122)
Usually presents as a dome shaped papule or nodule; may be plaque or polyploid, with or without ulceration (J Am Acad Dermatol 2015;73:777, Arch Pathol Lab Med 2015;139:1263)
Variable pigmentation, from amelanotic to black or multicolored (Br J Dermatol 2019;181:366, Dermatopathology (Basel) 2022;9:136, Cancer 2009;115:631)
Variable symmetry and circumscription (Histopathology 2022;80:122)
- Asymmetry is more associated with AST than Spitz nevus (J Am Acad Dermatol 2015;72:37)
History of a rapid, recent growth in a lesion that was previously stable (Histopathology 2022;80:122)
Dermoscopy
- Nearly 20% showed a characteristic appearance of an amelanotic nodule with hypopigmentation, dotted vessels and white lines (J Am Acad Dermatol 2015;73:777)
- Overall, dermoscopic appearance may be nonspecific or consist of a combination of starburst, globular, homogenous or atypical vascular patterns (J Am Acad Dermatol 2015;73:777)
- Benign and malignant Spitzoid lesions show significant dermoscopy overlap (Lancet Child Adolesc Health 2019;3:646)

Diagnosis

Biopsy
Modified ABCD (asymmetry, border irregularity, color variegation, diameter > 6 mm) and dermoscopy are used for detection of Spitzoid lesions but biopsy is necessary to evaluate the degree of atypia (Lancet Child Adolesc Health 2019;3:646)
Any asymmetrical, raised or nodular lesion should be biopsied for evaluation of atypia (Br J Dermatol 2017;177:645)

Prognostic factors

Tends to be indolent
Presence of tumor deposits in sentinel lymph nodes tends not to alter prognosis (Hum Pathol 2013;44:87, Clin Exp Dermatol 2022;47:1464)
Increased risk for metastatic progression is associated with
- Homozygous 9p21 deletion
- TERT promoter mutations
- MAP3K8 kinase rearrangements (Front Oncol 2022:12:889223)
- Older age
- Lesion diameter exceeding 1 cm
- Ulceration
- Subcutaneous fat involvement
- Mitotic activity > 6/mm² (Histopathology 2022;80:122)
Intermediate risk of metastasis associated with (Front Oncol 2022:12:889223)
- 6p25 gain: intermediate risk
- 11q13 gain: intermediate risk
Favorable prognosis is associated with HRAS amplification (Arch Pathol Lab Med 2015;139:1263)
Recurrence is infrequent if excised completely but risk may increase with homozygous 9p21 deletion or MAP3K8 fusion (Histopathology 2022;80:122)

Case reports

2 year old girl with a lower lip mass, harboring ROS1 kinase mutation and ALK variant (JAMA Otolaryngol Head Neck Surg 2020;146:203)
7 year old girl with 12 mm ALK positive pedunculated pigmented nodule of the right ankle (J Cutan Pathol 2018;45:136)
9 year old boy with 14 mm ALK positive pedunculated pigmented nodule of the thigh (J Cutan Pathol 2018;45:136)
16 year old girl with AST with Homer Wright-like rosettes (Am J Dermatopathol 2018;40:903)
40 year old woman with enlarging red polypoid lesion on right forearm, with ALK fusion (Hum Pathol 2018:80:99)
Case series including 13 ASTs with MAP3K8 fusions (Mod Pathol 2020;33:846)

Treatment

Complete excision
Re-excision of the lesion regardless of the margin status of the biopsy (J Cutan Med Surg 2020;24:144)
Typically, without sentinel lymph node biopsy due to lack of prognostic value (JAMA Dermatol 2013;149:1348)

Microscopic (histologic) description

Can be junctional, compound or dermal but compound form is more common
Greater degree of atypia compared to benign Spitz nevus (cytological atypia or architectural overlap with dysplastic nevus) and involves 1+ features atypical for Spitz nevus; not enough atypia to be equivocal to melanoma
Overlap features with benign Spitz nevus
- Spitzoid cytomorphology
- Junctional component with vertically oriented nests and retraction artifact
- Intranuclear pseudoinclusion
- Eosinophilic nucleoli
- Epidermal hyperplasia
- Vertical junctional nests
Overlap features with melanoma
- Large size (> 10 mm)
- Asymmetry
- Poor circumcision
- Ulceration
- Deep dermal component
- Absence of maturation
- Increased dermal mitosis in deep or peripheral component
Primarily epithelioid, spindle or mixed melanocytes that may present with (Front Oncol 2022:12:889223)
- Large tumor consisting of cellular fascicles of melanocytes
- Expansile growth with compression of stroma
- Most commonly asymmetrical
- Lymphocytic infiltrate
- Fewer Kamino bodies
- Pagetoid spread (often peripheral)
- Junctional nests with vertical orientation of cells (Arch Pathol Lab Med 2015;139:1263)
- Average Breslow depth: 2.4 mm (Cancer 2009;115:631)
ASTs with ALK fusion (Am J Surg Pathol 2017;41:491)
- Wedge shaped with large diameter
- Plexiform growth of intersecting fusiform melanocytes
ASTs with NTRK1 fusion (Am J Surg Pathol 2017;41:491)
- Smaller nests
- Presence of Kamino bodies and rosette formation
ASTs with MAP3K8 fusion
- Epithelioid with higher grade features (J Cutan Pathol 2019;46:878)

Microscopic (histologic) images

Contributed by Sepideh Nikki Asadbeigi, M.D. and AFIP

ALK fusion

Infiltrative border

Atypical cytomorphology

Bulbous infiltrating base

Epidermal hyperplasia

Lack of maturation in deep portion

Large epithelioid cells with amphophilic <br>cytoplasm

Large epithelioid
cells with
amphophilic
cytoplasm

Positive stains

No single IHC result can be used for the definitive identification, though it is suggested that the combination of Ki67 proliferative index, HMB45 and p16 results may be useful in distinguishing Spitz neoplasms (Front Oncol 2022:12:889223)
Melanocytic markers such as SOX10, MITF, MelanA
Ki67 proliferative index: 2 - 10% (intermediate between Spitz nevus and Spitz melanoma) (Front Oncol 2022:12:889223, Arch Pathol Lab Med 2015;139:1263)
BAP1: distinct subtype of ASTs express BAP1 (Am J Surg Pathol 2012;36:818)
ALK1 in ASTs with ALK fusion

Negative stains

Infrequent or diffuse PRAME staining may be useful in distinguishing AST from melanoma (J Cutan Pathol 2020;47:1123, J Cutan Pathol 2022;49:709)
BRAF V600E
p16: variable due to homozygous or heterozygous loss of 9p21 (Front Oncol 2022:12:889223)
HMB45: variable or diminished in dermis (Front Oncol 2022:12:889223)

Molecular / cytogenetics description

Often demonstrates HRAS mutations, similar to approximately half of all Spitz neoplasms (Am J Dermatopathol 2009;31:107)
Tyrosine kinase fusions are common in all varieties of Spitz neoplasms: ROS1, NTRK1, NTRK3, ALK, BRAF, RET, MET and MAP3K8 (Front Oncol 2022:12:889223, Nat Commun 2014:5:3116)
- Present in ~56% of ASTs (Nat Commun 2014:5:3116)
- ALK present in ~15 - 20% of diagnosed ASTs (Front Oncol 2022:12:889223, Am J Dermatopathol 2017;39:181, Nat Commun 2014:5:3116)
- MAP3K8 translocation tends to be more common in AST and Spitz melanoma than Spitz nevus (Front Oncol 2022:12:889223)
- MET, RET and MAP3K8 considered less common than the other tyrosine kinase fusions (Front Oncol 2022:12:889223)
Deep deletion with limited additional copy number of CDKN2A and no additional mutations (Histopathology 2022;80:122)
Array comparative genomic hybridization tends to show 1+ chromosomal gains / losses (Front Oncol 2022:12:889223)
May have homozygous or heterozygous loss of 9p21 (Front Oncol 2022:12:889223)
Tumors with BRAF V600E and NRAS Q61 mutations are not classified in Spitz tumors anymore (Histopathology 2022;80:122)

Videos

Common histological features associated with Spitz nevus

Sample pathology report

Skin, left cheek, shave biopsy:
- Atypical Spitz tumor (see comment)
- Comment: The sections show nests of melanocytes involving the epidermis and upper dermis. The melanocytes are nested and show some pagetoid scatter. The melanocytes show pink-lavender cytoplasm with large nuclei. The nucleoli are conspicuous and eosinophilic. Mitotic figures are present in superficial dermis (2/10 high power fields). The nests show some maturation. Immunohistochemistry shows diffuse positivity with SOX10. HMB45 shows loss of staining with maturation. p16 shows preserved nuclear staining in majority of the melanocytes and PRAME is negative within the nevomelanocytes. BRAF V600E immunohistochemistry is negative. The overall histology is consistent with atypical Spitz tumor. The margins are involved and a complete excision is recommended.

Differential diagnosis

Benign Spitz nevus:
- Factors favoring AST over Spitz nevus (J Am Acad Dermatol 2015;72:37)
  - Asymmetry
  - Ulceration or epidermal consumption (Front Oncol 2022:12:889223)
  - Lack of cytological maturation
  - Expansile nests and pushing lower border
  - Increased cellularity
  - Nuclear pleomorphism
  - High N:C ratio
  - Atypical and deep mitoses
  - High mitotic rate
  - Fewer, smaller Kamino bodies (Front Oncol 2022:12:889223)
Spitzoid melanoma:
- Older patients
- Distinction can be very challenging with only light microscopy; all of the following features can be present in both AST and Spitz melanoma but are more common in melanoma (Arch Pathol Lab Med 2015;139:1263, Am J Dermatopathol 2012;34:478)
  - High grade cytologic atypia
  - Poor nesting and prominent pagetosis in junctional component
  - Deep, numerous, atypical and marginal mitosis
  - Intravascular invasion
  - High cellular density
  - Lack of maturation
  - Consumption of epidermis
  - Infiltrative pattern
  - Immunohistochemistry
    - Complete or extensive p16 loss
    - Strong and diffuse PRAME positivity
    - High Ki67 index
    - Deep HMB45 expression
  - Molecular findings
    - Presence of TERT, BRAF and CDKN2A alterations are supportive of Spitz melanoma diagnosis (Pediatr Dermatol 2022;39:409)
    - FISH: aberration in 9p21,6p25,11q13 and 8q24
    - Chromosomal microarray (comparative genomic hybridization): multiple (> 3) and complex chromosomal abnormalities
    - Lack of tyrosine kinase mutation
    - Lack of HRAS mutation
- Cellular neurothekeoma:
  - Positive S100 and MelanA staining in ASTs and negative in cellular neurothekeoma
- Epithelioid fibrous histiocytoma:
  - Negative melanocytic marker
  - Lack of junctional component
- Dysplastic Clark nevus:
  - Commonly in older population with sun damaged skin
  - Lack of distinct spindle and epithelioid morphology seen in Spitz neoplasms

Board review style question #1

A 17 year old patient with an ulcerated pink papule on the face underwent a shave biopsy, which showed a tumor with cells staining strongly positive for MelanA and HMB45. The tissue was sent for molecular study. The presence of which alteration is more indicative of a malignant process?

ALK
GNAQ
HRAS
TERT

Board review style answer #1

D. TERT. The sections show a melanocytic proliferation with Spitzoid cytomorphology. Atypical features such as frequent mitosis and pushing borders are present, which can be seen in both ASTs and Spitz melanomas. The presence of TERT is supportive of a Spitz melanoma diagnosis. Answers A and C are incorrect because ALK fusion and HRAS deletion are common in Spitz lesions and can be observed in benign, atypical and malignant lesions. Answer B is incorrect because GNAQ mutation is common in blue nevi.

Comment Here

Reference: Atypical Spitz tumor (Spitz melanocytoma)

Board review style question #2

Which immunohistochemical pattern is more indicative of an atypical Spitz tumor rather than a benign Spitz nevus?

HMB45 positivity in junctional melanocytic nests
Negative BRAF V600E in melanocytic nuclei
p16 positivity in 40% of melanocytes
Weak PRAME positivity in 5% of melanocytes

Board review style answer #2

C. p16 positivity in 40% of melanocytes. Complete or extensive loss of p16 is more supportive of an atypical or malignant Spitz neoplasm. CDKN2A homozygous deletion can lead to p16 loss, which is indicative of a higher grade or malignant lesion. Answer B is incorrect because BRAF V600E immunohistochemistry is generally negative in Spitzoid lesions and its positivity should raise suspicion of melanoma. Answer A is incorrect because HMB45 shows a loss of staining with descent and the positivity of the stain only in the junctional component is supportive of benignity. Answer D is incorrect because weak and focal PRAME positivity (1+) is not strongly supportive of an atypical lesion and can be observed in benign Spitz nevi.

Comment Here

Reference: Atypical Spitz tumor (Spitz melanocytoma)

BAP1 inactivated nevus / melanocytoma

Table of Contents

Definition / general

BAP1 inactivated nevi / melanocytomas are benign melanocytic tumors with distinctive epithelioid morphology
They are the result of germline or somatic inactivating mutations in the tumor suppressor gene BAP1

Essential features

Benign melanocytic tumors with distinctive epithelioid morphology
Result of biallelic inactivation of the BAP1 gene accompanied by an activating mutation, typically in BRAF
Germline mutations of BAP1 are also associated with additional malignancies such as malignant mesothelioma, uveal melanoma and cutaneous melanoma
BAP1 inactivated nevus refers to tumors with benign appearing histology, while melanocytoma refers to tumors with at least moderate cytologic atypia

Terminology

First described in 2011 by Wiesner et al. (Am J Surg Pathol 2012;36:818)
Synonyms: BAPoma, Wiesner nevus, atypical Spitz tumor with BAP1 loss, nevoid melanoma-like melanocytic proliferation (NEMMP) (J Cutan Pathol 2019;46:965)
WHO categorizes BAP1 inactivated nevus and BAP1 melanocytoma under BAP1 inactivated melanocytic tumor (BIMT) (Mod Pathol 2022;35:664)
Benign appearing BIMTs classified as BAP1 inactivated nevi and highly atypical appearing variants as BAP1 melanocytomas (Mod Pathol 2022;35:664)
Listed as combined nevus due to remnants of a conventional nevus with retained expression of BAP1 within nevi that are histologically and molecularly consistent with BIMTs (Mod Pathol 2022;35:664)
BAP1 is an acronym for BRCA1 associated protein 1 (J Cutan Pathol 2019;46:965)

ICD coding

ICD-O: 8720/1 - BAP1 inactivated melanocytoma
ICD-11: 2F20.1 - atypical melanocytic nevus

Epidemiology

Equal sex distribution
Occurs at any age but typically begins appearing in second decade of life
Carrier frequency for the BAP1 tumor predisposition syndrome in the general population is 1:26,837 (GeneReviews: BAP1 Tumor Predisposition Syndrome [Accessed 20 December 2023])

Sites

Anywhere on the skin
Greatest predilection for the head and neck, followed by the trunk and upper extremities
Less commonly occurs on lower extremities (J Am Acad Dermatol 2019;80:1585)

Pathophysiology

BAP1 is a tumor suppressor gene located on chromosome 3p21.1 (Nat Rev Cancer 2013;13:153)
Encoded BAP1 protein is a nuclear protein that is involved in many processes, including regulation of the cell cycle, cell growth and the DNA damage response (J Clin Oncol 2012;30:e337)

Etiology

Can be sporadic or inherited
Inherited form results from autosomal dominant inactivating mutation in BAP1 gene; the second wild type allele is subsequently lost by somatic mutation (Nat Genet 2011;43:1018)

Clinical features

Transformation risk of BAP1 inactivated melanocytic nevus into melanoma is low
Additional germline BAP1 mutation associations (Nat Rev Cancer 2013;13:153)
- Malignant mesothelioma (40.0%)
- Uveal melanoma (38.4%)
- Cutaneous melanoma (24.8%)
- Renal cell carcinoma (6.1%)
BIMTs most commonly develop in second decade of life (Nat Genet 2011;43:1018)
Typically solitary but multiple papules can be seen with germline mutation (J Cutan Pathol 2019;46:965)
Size usually between 2 and 10 mm, average of 5 mm (Nat Genet 2011;43:1018, Nat Rev Cancer 2013;13:153)
Papules are flesh colored to orange or red-brown (Nat Genet 2011;43:1018, J Am Acad Dermatol 2019;80:1585)
Dome shaped to pedunculated (Nat Genet 2011;43:1018)
Can clinically resemble fibromas or intradermal nevi (J Am Acad Dermatol 2019;80:1585)
Varied dermoscopic findings, most commonly presenting as irregular dots / globules located eccentrically (29.8%), structureless pink to tan (14.9%) and network with raised, structureless, pink to tan areas (14.9%) (J Am Acad Dermatol 2019;80:1585)

Diagnosis

Diagnosis of BAP1 inactivated tumors is typically rendered by observing loss of nuclear expression of BAP1 on immunohistochemical staining of specimens that histologically demonstrate the characteristic features of the entity on H&E (Am J Surg Pathol 2012;36:818)
Internal control is mandatory; strong nuclear expression of BAP1 should be present in nearby keratinocytes and nonlesional melanocytes
Recommend direct sequencing of saliva or blood to determine if germline mutation present

Prognostic factors

Not well studied
On rare occasion, has been seen to progress to melanoma (J Clin Oncol 2012;30:e337)
Germline BAP1 mutation associated with the development of cutaneous melanomas without progression from BAP1 inactivated nevi / melanocytomas

Case reports

15 year old girl with uveal melanoma found to have BAP1 tumor predisposition syndrome (JAAD Case Rep 2020;6:563)
35 year old woman with melanocytic lesion with 3 distinct melanocyte populations (Am J Dermatopathol 2023;45:117)
49 year old woman with dome shaped papule on digit of right foot (BMC Dermatol 2017;17:13)

Treatment

Complete excision is recommended; margins must be negative
Reflex screening for germline BAP1 mutations not usually recommended but can be performed in patients with a high clinical suspicion for BAP1 tumor predisposition such as in younger patients (under 40) and in patients with family history of BAP1 tumor predisposition syndrome related malignancies (Eur J Hum Genet 2023;31:1261)

Clinical images

Images hosted on other servers:

Flesh colored papule

Right dorsal third toe

Red-brown papule

Red-orange nodule

Erythematous pedunculated papule

Gross description

Typically a well circumscribed, dome shaped, flesh colored 3 - 10 mm papule

Microscopic (histologic) description

Predominately dermal based proliferation of large epithelioid melanocytes, typically minimal junctional component
Large vesicular nuclei and eosinophilic cytoplasm
Often polypoid profile
Lymphocytic infiltrate with associated regression can be seen
2 predominant growth patterns (J Cutan Pathol 2019;46:965)
- Sheet-like growth of uniformly large epithelioid cells with distinct cytoplasmic borders
- Large epithelioid cells admixed with small nevoid cells
BAP1 inactivated nevus
- Minimal atypia with rare to few mitotic figures
BAP1 inactivated melanocytoma
- Can have pronounced cytologic atypia with high mitotic rate

Microscopic (histologic) images

Contributed by Matthew J. Kuhar, M.D., Ahmed K. Alomari, M.D. and Carina Dehner, M.D., Ph.D.

Combined nevus

Epithelioid cell morphology

Distinct cell borders

Well circumscribed nodule

Atypical epithelioid melanocytes

Lymphocytic infiltrate

Negative BAP1 IHC staining

Virtual slides

Images hosted on other servers:

BAPoma

Cytology description

Cytology is not part of the work up for BAP1 inactivated tumors

Positive stains

Negative stains

BAP1
HMB45 with gradient (66%)
Reference: J Cutan Pathol 2023;50:349

Molecular / cytogenetics description

Characteristic biallelic inactivation of BAP1
Accompanied by a separate activating mutation, usually BRAF V600E but also rarely in RAS1 (Mod Pathol 2022;35:664)
In combined nevi, the BRAF V600E mutation is found in all lesional melanocytes while only the epithelioid melanocytes have loss of BAP1

Videos

BAPoma - BAP1 inactivated nevus / melanocytoma - mimic of nevoid melanoma

Sample pathology report

Skin, biopsy, right scalp:
- Intradermal melanocytic proliferation with BAP1 loss, consistent with BAP1 inactivated nevus (see comment)
- Complete excision is indicated
- Comment: The findings are those of a compound melanocytic proliferation with 2 distinct populations of cells. Toward the center of the biopsy specimen, there is sheet-like nodular proliferation of large epithelioid melanocytes with abundant cytoplasm, prominent nucleoli and no significant mitotic activity. Outside of this nodular proliferation, there is a compound proliferation of more conventional melanocytes. Immunohistochemical staining shows preferential BAP1 loss in the central sheet-like nodule with preserved expression in the background nevus. These findings are consistent with a BAP1 inactivated nevus.

Differential diagnosis

Atypical Spitz nevus:
- Spindle shaped melanocytes, epidermal hyperplasia, Kamino bodies, clefting around junctional melanocytes (Am J Surg Pathol 2012;36:818)
- No loss of BAP1 in IHC / molecular
- Do not have BRAF V600E mutations, which BAP1 inactivated tumors almost always have (Am J Surg Pathol 2012;36:818)
Invasive melanoma:
- Typically does not have loss of BAP1 in IHC / molecular
- Some cutaneous melanomas are part of BAP1 tumor predisposition syndrome
- Melanomas typically larger, > 1 cm compared to BAP1 inactivated nevi average of 0.5 cm and typically present as irregular pigmented lesions compared to the circumscribed flesh colored papules of BAP1 inactivated nevi
- Can display marked atypia depending on subtype
- Certain subtypes of melanoma such as spitzoid and nevoid melanomas can have lesional epithelioid cells, which may make differential without BAP1 IHC / molecular challenging (Arch Pathol Lab Med 2020;144:500)

Board review style question #1

Which of the following describes BAP1 inactivated nevi?

Can be associated with malignant mesothelioma and uveal melanoma
Found almost exclusively on the legs of older men
Frequently undergo malignant transformation
Histologically present as large spindled cells with Kamino bodies
Typically present as large, ulcerative lesions

Board review style answer #1

A. Can be associated with malignant mesothelioma and uveal melanoma. Germline BAP1 mutations are associated with melanocytic nevi, malignant mesothelioma, uveal melanoma, cutaneous melanoma and renal cell carcinoma. Answer B is incorrect as BAP1 inactivated nevi have an equal sex distribution, can occur at any age but mostly are seen in the second decade of life and have a predilection for the head, neck and upper extremities. Answer C is incorrect as BAP1 inactivated nevi have only in very rare cases been seen to metastasize. Answer D is incorrect because it describes Spitz nevi. Histologically, BAP1 inactivated nevi present as large, epithelioid cells with defined cell borders and do not present with Kamino bodies. Answer E is incorrect because BAP1 inactivated nevi typically present as flesh to red-brown colored papules < 1 cm in diameter.

Comment Here

Reference: BAP1 inactivated nevus / melanocytoma

Board review style question #2

BAP1 inactivated melanocytic nevi are most often associated with activating mutation in which gene?

BRAF
EGFR
HRAS
KRAS
NRAS

Board review style answer #2

A. BRAF. While BAP1 inactivated melanocytic nevi are characterized by biallelic inactivation of BAP1, they are accompanied by a separate mutation in a mitotic driver, usually BRAF V600E. Answers B, C, D and E are incorrect because mutations in the other listed genes are not known to be involved with the development of BAP1 inactivated melanocytic nevi.

Comment Here

Reference: BAP1 inactivated nevus / melanocytoma

Blue nevus / cellular blue nevus

Table of Contents

Definition / general

Common blue nevus (BN) was first described in 1906 (Virchows Arch Pathol Anat 1906;186:212)
Typical clinical presentation is that of a blue to black macule, papule or nodule on the head, distal extremities or buttock
Blue nevus is characterized by a dermal proliferation of melanocytes
Common (dendritic) blue nevus:
- Dermal proliferation of melanocytes (dermal melanocytosis) presenting as a blue to black nodule; sometimes multiple; amelanotic lesions may occur (StatPearls: Blue Nevus [Accessed 30 August 2021])
- Mostly acquired but it can rarely be congenital
  - LAMB (lentigines, atrial myxomas and blue nevi) (J Am Acad Dermatol 1984;10:72)
  - NAME (nevi, atrial myxoma, myxoid neurofibromas and ephelides) (Adv Anat Pathol 2009;16:365, StatPearls: Blue Nevus [Accessed 30 August 2021], Br J Dermatol 1980;103:421)
  - Epithelioid blue nevus, a rare variant, may be associated with Carney complex (a multiple neoplasia syndrome) (J Cutan Pathol 2019;46:954, Semin Diagn Pathol 1998;15:216)
- Bluish black color due to the deep location and abundant melanin; it can be amelanotic (Am J Dermatopathol 1999;21:225)
Cellular blue nevus:
- Pigmented biphasic tumor with a component of classic blue nevus and distinct cellular areas of spindled to oval melanocytes with clear or finely pigmented cytoplasm (Arch Pathol Lab Med 2011;135:327, Adv Anat Pathol 2009;16:365)
- May be clinically and histologically confused with melanoma
- Benign metastasizing variant is critical to recognize to avoid aggressive treatment (Eur J Dermatol 2008;18:586, J Craniomaxillofac Surg 2010;38:601)
Atypical cellular blue nevus:
- Rare variant between cellular blue nevus and malignant blue nevus (melanoma arising in association to blue nevus or blue nevus-like melanoma) (Clin Lab Med 2017;37:401)
- May be associated with sentinel lymph node deposits, which generally does not indicate adverse biological behavior

Essential features

Blue nevi are not uncommon; more frequent in females (F:M = 2:1) and adults < 40 years
Common blue nevus is composed of bipolar spindle dendritic melanocytes associated with dense collagenous stroma
Cellular blue nevus is usually a biphasic lesion composed of fusiform to ovoid cells with clear cytoplasm, arranged in nests and surrounded by collagen, pigmented dendritic and bipolar cells and melanophages
Cellular and atypical cellular blue nevi lack high mitotic activity, atypical mitotic figures, necrosis and marked pleomorphism

Terminology

Dendritic blue nevus
Common blue nevus
Dermal dendritic melanocytic nevus
Nevus of Jadassohn
Tièche nevus
Jadassohn-Tièche blue nevus

ICD coding

ICD-O:
- 8780/0 - blue nevus, NOS
- 8790/0 - cellular blue nevus
ICD-10:
- D23.9 - other benign neoplasm of skin, unspecified
- D22.9 - melanocytic nevi, unspecified

Epidemiology

Common blue nevus:
- Young adults
- F:M = 2:1 (StatPearls: Blue Nevus [Accessed 30 August 2021])
Cellular blue nevus:
- Middle aged individuals
- F:M = 2:1 (Am J Dermatopathol 1988;10:289)
- Caucasians more than dark skinned races
- Benign but rarely recurs or involves regional lymph nodes (J Cutan Pathol 2010;37:102)
- Melanomas may arise from cellular blue nevus (J Cutan Pathol 2012;39:1094, Am J Dermatopathol 2020;42:313)
Atypical cellular blue nevus:
- Wide age of presentation: 4 - 78 years
- F > M

Sites

Common blue nevus:
- Predilection to extremities (dorsa of hands and feet), buttock, scalp and face (Am J Dermatopathol 1988;10:289)
- Extracutaneous can occur; conjunctiva oral mucosa, lymph nodes, vagina, prostate (Adv Anat Pathol 2009;16:365)
Cellular blue nevus:
- Buttock and sacrococcygeal more common (Am J Dermatopathol 1988;10:289)
- Also scalp, face, trunk and extremities with predilection to dorsal foot (Am J Dermatopathol 1988;10:289)
Atypical cellular blue nevus:
- Buttocks, head and neck and extremities

Pathophysiology

Common blue nevus:
- May be due to arrested melanocytic migration or from specific stem cells within the dermis (Arch Pathol Lab Med 2011;135:327)
- Blue color is a result of reflection, a phenomenon known as the Tyndall effect (StatPearls: Blue Nevus [Accessed 30 August 2021])

Clinical features

Common blue nevus:
- Well demarcated, dome shaped, blue-black
- Small (< 1 cm) (Adv Anat Pathol 2009;16:365)
Cellular blue nevus:
- Slowly growing, grayish blue-black nodules
- Large (> 1 cm); can be up to 10 cm (Clin Lab Med 2017;37:401)
Atypical cellular blue nevus:
- Bluish deep dermal nodules

Diagnosis

Clinical presentation
Dermoscopy shows homogenous, structureless pigment pattern, with variety of colors (blue, white-blue, black, brown and polychromatic) (J Cutan Pathol 2007;34:543, J Am Acad Dermatol 2012;67:199)
Definite diagnosis is made on excision specimen through histologic examination

Case reports

Common blue nevus:
- 14 year old girl with persistent blue nevus that presented with prominent extension beyond the scar of the original excision, mimicking melanoma (J Am Acad Dermatol 2004;50:S118)
- 15 year old girl with poliosis overlying a nevus with blue nevus features (Dermatol Online J 2008;14:20)
- 35 year old man with multiple pigmented lesions of the penis (J Cutan Pathol 2004;31:185)
- 38 year old woman with blue-black discoloration of the proximal lunula of her right thumbnail (Australas J Dermatol 2020;61:164)
- 40 year old woman with blue-gray pigmentation on the nail of her left fourth finger (J Am Acad Dermatol 2008;58:1021)
- 41 year old woman with a nodular swelling in left axilla (Am J Clin Pathol 1984;81:367)
- 47 year old man with blue macule under the right first toenail (Dermatol Online J 2017;23:13030)
- 52 year old man with elevated prostate specific antigen and mild obstructive lower urinary tract symptoms (Case Rep Urol 2018;2018:7820717)
- 53 year old woman with large plaque type blue nevus with subcutaneous cellular nodules (Am J Surg Pathol 2000;24:92)
- 68 year old man with discoloration of right thumbnail (J Cutan Pathol 2020;47:1111)
- 69 year old man with blue nevus with satellitosis mimicking malignant melanoma (J Eur Acad Dermatol Venereol 2001;15:570)
Cellular blue nevus:
- 14 year old boy with a giant, infiltrative facial tumor (J Clin Pathol 2007;60:82)
- 16 year old girl with tender right sided submandibular neck mass (Am J Otolaryngol 2021;42:103139)
- 19 year old man with 0.5 cm epidermal cyst (Case #7)
- 19 year old man with pilonidal sinus (J Cutan Pathol 2007;34:942)
- 28 year old woman with intracranial extension (J Clin Neurosci 2000;7:453)
- 29 year old man with a pigmented lesion of the perilimbal conjunctiva on the right eye since birth (Ann Clin Lab Sci 2017;47:477)
- 30 year old woman, 40 year old woman and 43 year old man with cellular blue nevi of the eyelid (J Am Acad Dermatol 2008;58:257)
- 31 year old man with xanthomatosis and diabetes mellitus (Indian J Dermatol Venereol Leprol 2001;67:200)
- 34 year old man with nevus cells in sentinel lymph node (Eur J Dermatol 2008;18:586)
- 37 year old woman with abnormal uterine bleeding (Int J Gynecol Pathol 2021;40:349)
- 58 year old woman with a blue spot on the lanula of the left thumb (Dermatol Ther 2020;33:e13763)
- 61 year old woman with a pigmented nodule on her right buttock (J Cutan Pathol 2005;32:385)
- 63 year old man with yellowish papular lesion of the upper eyelid (Ophthalmic Plast Reconstr Surg 2017;33:e122)
Atypical cellular blue nevus:
- 8 year old boy with pigmented lesion in the buttock since birth, with progressive growth in 2 years (An Bras Dermatol 2017;92:110)
- 28 year old woman with a black skin lesion on the dorsum of the right foot (Dermatopathology (Basel) 2019;6:20)
- 37 year old woman with pedunculated thigh mass (J Dermatol 2000;27:730)
- 43 year old man with a tender mass on his left anterior chest (Am J Dermatopathol 2021;43:e61)
- 46 year old white man with a mass on his right buccal mucosa (Head Neck Pathol 2013;7:171)

Treatment

Common and cellular blue nevus: excision
Atypical cellular blue nevus:
- Excision with at least 1 cm margins
- Close follow up
Reference: Ann Otol Rhinol Laryngol 2021;130:1407

Clinical images

Contributed by Mark R. Wick, M.D.

Cellular blue nevus

Images hosted on other servers:

Giant cellular blue nevus

Microscopic (histologic) description

Common blue nevus:
- Dermal proliferation of pigmented dendritic bipolar spindle melanocytes associated with fibroblastic and collagenous stroma (Adv Anat Pathol 2009;16:365)
- Admixed scattered heavily pigmented melanophages
- Melanocytes aggregate around blood vessels, nerves or cutaneous appendages (Clin Lab Med 2017;37:401)
- May present in the superficial dermis or extend into subcutis (Clin Lab Med 2017;37:401)
- No maturation
- No cytologic atypia, no mitotic figures (Clin Lab Med 2017;37:401)
- Nodal blue nevi, in perinodal fat, capsule and septa but not in parenchyma (Am J Surg Pathol 1984;8:907)
- Junctional activity present only in combined nevus (Clin Lab Med 2017;37:401)
Cellular blue nevus:
- Well circumscribed lesion, occupying superficial and mid dermis, sometimes extending to deep dermis and subcutis (Adv Anat Pathol 2009;16:365)
- Oval to plump spindle cells intermingled with dendritic melanocytic cells; usually not heavily pigmented (Adv Anat Pathol 2009;16:365)
- Variable numbers of melanophages
- Margin may be pushing and infiltrates adjacent nerve trunks (Clin Lab Med 2011;31:345)
- Alveolar pattern:
  - Nests of amelanotic cells with clear cytoplasm
  - Surrounded by collagen, dendritic melanocytes and melanophages in variable amounts
  - Neuronevoid or fascicular pattern (Clin Lab Med 2017;37:401)
- Mitotic activity is usually absent and should be low (< 1/mm²)
- No atypical findings (including cell crowding, nuclear atypia, hyperchromasia, necrosis or expansile growth)
- Junctional activity present in combined nevus
- Angiomatoid variant containing numerous dilated blood vessels has been described (J Cutan Pathol 2005;32:385)
- Nodal involvement:
  - Is rare and often takes the form of subcapsular sinus and occasionally parenchymal deposits (Eur J Dermatol 2008;18:586, Int J Surg Pathol 2014;22:570, J Cutan Pathol 2010;37:102)
  - Cells are histologically identical to the parent lesion, with no pleomorphism or mitotic activity
  - Not true metastasis and does not alter prognosis
Atypical cellular blue nevus:
- Like cellular blue nevus and a background of common blue nevus is invariably present
- Nests and fascicles of spindle and epithelioid cells
- Lower portion may show an infiltrative border (Arch Pathol Lab Med 2011;135:327, Histopathology 2004;45:433)
- Mild cytologic atypia, nuclear hyperchromasia and pleomorphism centered in the lower aspect of the nevus (Adv Anat Pathol 2009;16:365)
- Low mitotic activity of < 2/mm² (Adv Anat Pathol 2009;16:365)
- Abnormal mitosis or necrosis never present (J Cutan Pathol 1998;25:252, Arch Pathol Lab Med 2011;135:327)
- Perineural and periadnexal infiltration typically present (J Cutan Pathol 1998;25:252)
- Perivascular lymphocytic infiltrate is often seen at the edge of the lesion (J Cutan Pathol 1998;25:252)
- Presence of more cytologic atypia, cell crowding, greater mitotic activity, abnormal mitoses and necrosis are consistent with malignant blue nevus (melanoma mimicking blue nevus; melanoma arising in association with blue nevus) (Arch Pathol Lab Med 2011;135:327)

Microscopic (histologic) images

Contributed by Carlos A. Torres-Cabala, M.D.

Common blue nevus

Dendritic melanocytes and melanophages

Focal extension into subcutis

Dense collagen stroma

Pigmented dendritic melanocytes

Pigmented melanophages

Cellular blue nevus

Dermal spindle cells

Biphasic appearance

Biphenotypic cytology

Sharp demarcation between the 2 populations

Positive stains

Common blue nevus:
- SOX10 (Clin Lab Med 2017;37:401, Arch Pathol Lab Med 2011;135:327)
- HMB45 (diffuse and strong) (J Cutan Pathol 1991;18:261, Clin Lab Med 2017;37:401)
- MelanA / MART1
- S100 (may be negative)
- Preserved BAP1 (Clin Lab Med 2017;37:401)
- Preserved p16
Cellular blue nevus:
- SOX10
- HMB45 (diffuse) (Am J Surg Pathol 1990;14:748, Clin Lab Med 2017;37:401)
- MelanA / MART1
- S100
- Ki67 < 2 - 3%
- Preserved BAP1 (Clin Lab Med 2017;37:401, Am J Dermatopathol 2020;42:313)
- Preserved p16
Atypical cellular blue nevus:
- HMB45 (Clin Lab Med 2017;37:401)
- Increased Ki67 (Clin Lab Med 2017;37:401)

Molecular / cytogenetics description

Common blue nevus:
- GNAQ and GNA11 mutations (Clin Lab Med 2017;37:401, Nature 2009;457:599)
- No BRAF, NRAS or NF1 mutations (N Engl J Med 2010;363:2191)
Cellular blue nevus:
- GNAQ and GNA11 mutations (Nature 2009;457:599)
- No chromosomal aberrations (Am J Surg Pathol 2005;29:1214)
Atypical cellular blue nevus:
- Complex copy number aberrations involving 4 or more chromosomal regions are indicative of malignancy (Mod Pathol 2016;29:227)

Sample pathology report

Common blue nevus:
- Skin, hand, dorsum, right, punch biopsy:
  - Blue nevus, present at peripheral and deep tissue edges (see comment)
  - Comment: Histological sections reveal a proliferation of spindle shaped melanocytes admixed with abundant pigment laden macrophages in dense collagenous background. The spindle cells have bland cytologic features. These findings support the above diagnosis.
Cellular blue nevus:
- Skin, buttock, right, ellipse:
  - Skin and subcutis with scar and cellular blue nevus, margins of resection are free of cellular blue nevus (see comment)
  - Comment: Sections show a dermal scar and an adjacent proliferation of spindle and epithelioid melanocytes occupying the dermis. Dendritic melanocytes showing classic blue nevus appearance are present at the periphery of the lesion. No nuclear atypia, necrosis or mitosis are identified. Immunohistochemical studies reveal the lesion cells to be diffusely positive for SOX10 and HMB45 and to show preserved expression of BAP1 (nuclear) and p16 (nuclear and cytoplasmic). The MIB1 proliferative rate is < 1%. These findings support the above diagnosis.
Atypical blue nevus:
- Skin, forearm, right, ellipse:
  - Skin and subcutis with atypical blue nevus, present at peripheral margins of resection (see comment)
  - Comment: Sections show a proliferation of spindle and epithelioid melanocytes involving dermis and focally extending into subcutis. The melanocytes are arranged in nests and fascicles. The lower portion of the nevus shows infiltrative growth with mild cytologic atypia and minimal pleomorphism. Perineural invasion is present. Rare mitotic figures (1/mm²) are identified; however, abnormal mitosis or necrosis are not identified. Immunohistochemical studies were performed. The lesion cells are diffusely positive for HMB45. A double MART1 / Ki67 study reveals low proliferation rate. Preserved expression of BAP1 is noted, along with focal expression of p16. The lesion appears to be incompletely excised. Re-excision is recommended, if clinically indicated.

Differential diagnosis

Common blue nevus:
- Melanoma mimicking blue nevus, melanoma arising in association with blue nevus, atypical blue nevus
- Congenital dermal melanocytosis:
  - Formerly known as Mongolian spot
- Benign fibrous histiocytoma:
  - Hemosiderin pigment, no melanin
- Dermatofibrosarcoma protuberans:
  - More cellular, tight storiform pattern, infiltrative, has pigmented variant
- Nevus of Ito / nevus of Ota
- Desmoplastic nevus (Arch Pathol Lab Med 2011;135:327)
- Desmoplastic Spitz nevus
- Metastatic melanoma:
  - Blue nevus-like cutaneous melanoma metastasis
Cellular blue nevus:
- Atypical cellular blue nevus
- Cellular neurothekeoma (Histopathology 2004;45:433)
- Dermatofibroma (Histopathology 2004;45:433)
- Blue nevus-like melanoma (melanoma mimicking blue nevus, melanoma arising in association with blue nevus):
  - Scalp or heel lesion with marked nuclear atypia, numerous mitotic figures, some atypical and necrosis
  - Variable epithelioid tumor cells (Clin Lab Med 2011;31:345)
- Clear cell sarcoma:
  - EWSR1 rearrangement (Histopathology 2004;45:433)
Atypical cellular blue nevus (Arch Pathol Lab Med 2011;135:327):
- Cellular blue nevus
- Blue nevus-like melanoma (Histopathology 2004;45:433, Am J Surg Pathol 2008;32:36)
- Desmoplastic melanoma (Clin Lab Med 2011;31:345)
- Cellular neurothekeoma
- Clear cell sarcoma
- Dermatofibroma

Additional references

Elder: WHO Classification of Skin Tumours, 4th Edition, 2018

Board review style question #1

A 28 year old woman presented with slow growing, 3 cm gray to dark blue solitary patch on her sacral skin. A biopsy specimen is shown. The best diagnosis is

Cellular blue nevus
Deep penetrating nevus
Dermatofibroma
Desmoplastic melanoma
Mongolian blue spot

Board review style answer #1

A. Cellular blue nevus

Comment Here

Reference: Blue nevus / cellular blue nevus

Board review style question #2

Epithelioid blue nevus is associated with

Carney complex
Birt-Hogg-Dubé syndrome
Muir-Torre syndrome
Neurofibromatosis
Tuberous sclerosis

Board review style answer #2

A. Carney complex

Comment Here

Reference: Blue nevus / cellular blue nevus

Café-au-lait spot

Table of Contents

Definition / general

Pigmented macule 0.5 mm+, flat, round / oval, sharply demarcated with even pigmentation; long axis is along cutaneous nerve tract
May have irregular borders
Pigment histologically restricted to basal layer of epidermis
Usually present at birth (Wikipedia)

Terminology

Café au lait is French for "coffee with milk", referring to light brown color of lesions
Often abbreviated as "CALM"

Epidemiology

If solitary, usually nonsyndromic
In U.S. study of children under 5 years, 19% had one, 0.75% had > 2; more present in African Americans (Arch Dis Child 1966;41:316)
If solitary, usually nonsyndromic; multiple associated with neurofibromatosis type 1 - any person with 6+ lesions should be presumed to have neurofibromatosis until proven otherwise
Also associated with McCune-Albright syndrome and other syndromes (eMedicine)

Case reports

7 week old infant with McCune-Albright syndrome and multiple, bilateral lesions (Pediatr Dermatol 1991;8:35)

Clinical images

Images hosted on other servers:

Various images

Axillary freckling

Lesion of face

Neurofibromatosis type I patient

Microscopic (histologic) description

Basal hyperpigmentation of epidermis, no deeper pigmentation
Increased amount of pigment in melanocytes, some have giant pigment granules (Tohoku J Exp Med 1976;118:255)
Melanophages are rare
Adnexal epithelium has no increased pigment
Syndromic patients: more DOPA+ melanocytes in lesional skin contrasted to sporadic patients with decreased DOPA+ melanocytes within lesion (Arch Dermatol 1970;102:442)

Electron microscopy description

Macromelanosomes

Differential diagnosis

Becker melanosis: increased hair and smooth muscle in lesion
Ephelides (freckles)
Lentiginous nevus
Mongolian spot: blue pigmentation, larger
Pigmented nevus: deeper pigment clinically, melanocytes not restricted to basal epidermis

Combined (clonal, blue, PEM, DPN, BAP1 and Spitz)

Table of Contents

Definition / general

Uncommon; two types of melanocytic proliferation in same pigmented lesion (Am J Surg Pathol 1991;15:1111)
Usually common blue nevus of penetrating type and acquired nevus (Pathology 2004;36:419)
Rarely includes Spitz nevus, which are difficult to classify by dermoscopy (J Cutan Pathol 2004;31:600)

Terminology

Also called melanocytic nevus with phenotypic heterogeneity

Epidemiology

Mean age 30 years

Sites

Usually trunk, head and neck and upper extremity

Clinical features

May resemble melanoma, particularly at dermoscopy (Dermatology 2007;214:174, Dermatol Surg 2006;32:1176)

Clinical images

Images hosted on other servers:

Globular pattern
associated with a
central homogenous
pattern (darker area)

Case reports

Common blue nevus and pigmented epithelioid melanocytoma (J Am Acad Dermatol 2008;58:1021)
Compound nevus and spindle cell Spitz nevus (J Dermatol 2000;27:233)
Cellular blue nevus in reticular dermis, overlying compound melanocytic nevus with transition to melanoma in situ (Am J Dermatopathol 1991;13:169)

Microscopic (histologic) images

Images hosted on other servers:

Spitz nevus and common nevus

Positive stains

S100, MelanA and HMB45 may be variable (J Dermatol 2000;27:233)

Common acquired nevus

Table of Contents

Definition / general

Common acquired nevus is a benign proliferation of melanocytes which is classified by its location in the epidermis, the dermis or both
Common acquired nevi consist of junctional nevi, compound nevi and intradermal nevi (Clin Cosmet Investig Dermatol 2014;7:89)

Essential features

Common acquired nevi are typically diagnosed clinically
Histologically they may be characterized as junctional, compound or intradermal based on the location of melanocytes
Approximately 33% of melanomas are derived from benign melanocytic nevi; therefore, understanding of the common acquired nevus is necessary

Terminology

Acquired melanocytic nevus
Nevocellular nevus
Mole

ICD coding

ICD-O:
- 8740/0 - junctional nevus, NOS
- 8750/0 - intradermal nevus
- 8760/0 - compound nevus
ICD-10:
- I78.1 - nevus, nonneoplastic
- D22.9 - melanocytic nevi, unspecified

Epidemiology

Arises at 6 months of age and reaches peak incidence during the third decade of life
Exhibits a particularly rapid rate of development at puberty and may decrease in quantity with increasing age
More common in people of Caucasian descent or in those with Fitzpatrick skin phenotype I and II
Incidence is increased in association with sun exposure and sun burns
Associated with familial melanoma syndromes
Acral and conjunctival nevi are more common in African, African American and Asian populations (Arch Dermatol 1999;135:47, Pigment Cell Melanoma Res 2011;24:879, Clin Cosmet Investig Dermatol 2014;7:89, J Natl Cancer Inst 1986;77:329, Arch Dermatol 2005;141:579)
Eruptive melanocytic nevi can be associated with different conditions such as immunodeficiency or immune suppression and targeted therapies in malignancies (Expert Opin Drug Metab Toxicol 2017;13:293)

Sites

May occur on any site, including acral skin, mucosal surfaces, within the nail matrix or within lymph nodes
Most commonly occur on sun exposed sites
May favor the trunk in males and the lower extremities in females (Arch Dermatol 1999;135:47, Arch Dermatol 2010;146:1085)

Pathophysiology

During embryogenesis pluripotent neural crest cells migrate through paraspinal ganglia and undergo differentiation into melanocytes of the basal layer of the epidermis and dermis
Melanocytes organize into interspersed single cells in the basal layer
Single melanocytes then proliferate into a lentiginous proliferation of contiguous individual melanocytes
Subsequently, melanocytes undergo a morphological transition into epithelioid type melanocytes in nests of 3 or more melanocytes at the dermoepidermal junction (junctional nevus)
With further cellular proliferation and differentiation, junctional nests may follow the dropping off model (or Abtropfung phenomenon) and some nests migrate downward to the dermis (compound nevus)
When nests are completely within the dermis, they are considered intradermal nevi (Clin Cosmet Investig Dermatol 2014;7:89)

Etiology

Risk factors:
- Childhood UV radiation
- Male gender
- Genetic susceptibility / genetic syndromes (familial atypical mole and melanoma syndrome [associated with CDKN2A mutations], BAP1 cancer syndrome, Carney complex, Turner syndrome, Noonan syndrome, EEC syndrome [ectrodactyly, ectodermal dysplasia and cleft lip / palate syndrome], Goeminne syndrome, Kuskokwim syndrome, Mulvihill-Smith syndrome, Langer-Giedion syndrome, tricho-odonto-onychial dysplasia)
- Individuals with fair skin phenotypes (Fitzpatrick types I and II) (Dermatol Clin 1995;13:595, J Am Acad Dermatol 1993;29:373)

Clinical features

Junctional nevi are typically flat or macular, brown to dark brown in color, < 6 mm, with regular borders and an even pigment network under dermoscopy
Compound nevi are typically elevated or papular, light tan to dark brown in color, < 6 mm and occasionally with hairs egressing from within it
Intradermal nevi are often round, well defined, amelanotic, pink to reddish brown or flesh colored, soft and raised papules, some of which may appear warty, papillomatous, framebesiform, pedunculated or dome shaped
Approximately 33% of melanomas are derived from a benign melanocytic nevus, especially from the junctional melanocytes (Clin Cosmet Investig Dermatol 2014;7:89, Oncogene 2017;36:5771)
Favorable prognosis for malignant melanoma arising from acquired melanocytic nevi compared to de novo melanomas (Arch Dermatol 1983;119:455)

Diagnosis

Diagnosis can often be made clinically through characteristic features and age of onset
If there are concerning or suspicious features such as asymmetry, irregular or indistinct borders, color variegation, diameter > 6 mm or evolution of the lesion, it should be biopsied and examined by a dermatopathologist to rule out dysplasia or melanoma
Dermoscopy may be utilized to assess pigment network and vessels for benign patterns (J Am Acad Dermatol 2009;60:508)

Case reports

5 year old girl with acquired compound melanocytic nevus on the hard palate (J Oral Maxillofac Res 2022;13:e5)
24, 41 and 55 year old men with abrupt development of melanocytic nevi with different stages of disease (Dermatol Online J 2018;24:13030)
57 year old woman with melanocytic nevus in the external auditory canal with keratin build up presenting with hearing loss (Case Rep Otolaryngol 2021;2021:5539286)
59 year old woman with multiple eruptive melanocytic nevi and change in pre-existing nevi secondary to encorafenib (In Vivo 2020;34:441)

Treatment

No treatment is necessary
Excisions can be performed for cosmetic purposes or for definitive diagnosis
Shave biopsies may not result in complete removal if residual melanocytes are left within the skin
Laser removal is controversial, as one should confident it is a benign nevus being treated (Acta Derm Venereol 2006;86:44)

Clinical images

Images hosted on other servers:

Multiple 3 - 4 mm junctional nevi

Junctional melanocytic nevus

Compound melanocytic nevus

Gross description

Flat tan to dark brown skin ellipse, size is usually < 1 cm or well circumscribed, pink, dome shaped papule

Microscopic (histologic) description

Well nested melanocytic proliferation of round to oval nests or theques at the dermoepidermal junction; no pagetoid spread (exception: ~33% of benign acral nevi may show scattered pagetoid upward spread) (J Am Acad Dermatol 1994;31:740)
Symmetrical from right to left, asymmetrical from top to bottom
Junctional nests are located at the tips and sides of rete ridges with regular spacing
As migration downward occurs, melanocytes disperse to single units and melanocytes undergo normal maturation from epithelioid (type A) to lymphocyte-like (type B), then neurotized (type C) morphologies
Multinucleated melanocytes can be present
Deep mitoses and deep pigment in melanocytic nests are rare
No destruction of surrounding structures
No significant nuclear atypia or mitotic activity
Intradermal nevus: melanocytic nests within the dermis only
Compound nevus: melanocytic nests at the dermal - epidermal junction and within the dermis

Microscopic (histologic) images

Contributed by Jeffrey McBride, M.D.

Benign intradermal nevus

Benign nevomelanocytes

Maturation

Multinucleated melanocytes

Virtual slides

Images hosted on other servers:

Recurrence of a severely dysplastic nevus

Positive stains

MelanA / MART1
SOX10
S100
HMB45 (intraepidermal and superficial dermal components)
p16
MITF1
Tyrosinase (Int J Clin Exp Pathol 2015;8:9742, J Cutan Pathol 2008;35:433, Am J Surg Pathol 2018;42:1456)

Negative stains

Ki67 (low expression, usually < 5% staining of cells)
PRAME
- Scattered positive cells are possible
- Majority of melanocytes are completely negative
- Some benign nevi can have scattered positive melanocytes but are negative or only 1+ positive (e.g., 1 - 25% = 1+; 26 - 50% = 2+; 51 - 75% = 3+)
- Exceptions are rare
p53
BCL2
Cyclin D (Int J Clin Exp Pathol 2015;8:9742, J Cutan Pathol 2008;35:433, Am J Surg Pathol 2018;42:1456, J Cutan Pathol 2022;49:220, Surg Pathol Clin 2021;14:165)

Molecular / cytogenetics description

Estimates are that 70 - 80% of common acquired nevi harbor activating BRAF mutations (e.g., BRAF V600E)
NRAS mutations are less common but still present in a small minority of acquired melanocytic nevi (5.9 - 18.2%) (Pigment Cell Melanoma Res 2015;28:661)
Estimated overall frequency of activating KIT gene mutations is 15% (Mod Pathol 2009;22:1446)

Videos

Microscopic description of junctional, compound and intradermal melanocytic nevi

Microscopic differences between solar lentigines and junctional nevi

Comprehensive clinical and histopathologic review of benign pigmented and melanocytic lesions including common acquired nevi

Microscopic clues to the diagnosis of melanoma versus benign nevi

Sample pathology report

Skin, left upper back, shave biopsy:
- Compound nevus (see comment)
- Comment: Sections reveal junctional and dermal melanocytes arranged in nests at the dermoepidermal junction and reticular dermis. The lesion is well circumscribed and symmetrical from left to right. No mitotic activity or cytological atypia is noted.

Differential diagnosis

Melanoma:
- Cytological atypia: absence of maturation, abundant pagetoid upward migration of melanocytes, nuclear pleomorphism, dermal mitoses, prominent and eosinophilic nucleoli, variably dusty pigmented cytoplasm
- Architectural atypia: asymmetry, epidermal consumption, ill defined borders, confluent growth of junctional melanocytes, expansile dermal growth pattern, irregular nest distribution
- Stromal change: variable inflammatory reaction, dermal fibrosis
- Retention of HMB45 in dermal nests, strong and diffuse PRAME positivity (> 75% positive melanocytes = 4+ positive)
Dysplastic nevus:
- Cytological atypia: pleomorphism (pleomorphism is less than melanoma)
- Architectural atypia: shouldering, bridging, lentiginous hyperplasia, irregular nesting
- Stromal change: lamellar fibroplasia, possible epidermal change
- Minor architectural atypia can be present in benign nevus; cytological abnormality should not be present
Small congenital melanocytic nevus:
- Tends to involve reticular dermis and nevomelanocytes involve the lower dermis
- Extension of nevomelanocytes between collagen bundles and around the skin adnexa
Café noir macule:
- Hyperpigmentation of basal cells without nesting of melanocytes
Neurofibroma:
- Proliferation of nerve fibers in dermis with background mast cells
- Pigmentation might be present

Board review style question #1

In nevomelanocytes of common acquired nevi, what immunohistochemistry marker shows loss of staining that corresponds with maturation and descent into the dermis?

HMB45
MART1
PRAME
S100
SOX10

Board review style answer #1

A. HMB45

Comment Here

Reference: Common acquired nevus

Board review style question #2

What is the most common mutation in common acquired nevi?

BRAF V600E
GNAQ
RAS
TERT

Board review style answer #2

A. BRAF V600E

Comment Here

Reference: Common acquired nevus

Congenital nevus

Table of Contents

Definition / general

Nevi that are present at birth or that arise within the first few postnatal weeks (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022])
Benign lesion comprised of bland melanocytes in dermis

Essential features

Nevi that are present at birth or shortly thereafter (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022])
Characterized by bland melanocytic proliferation in the dermis; melanocytes prominently cluster around dermal appendages and show maturation in the depth
Excellent prognosis

Terminology

Congenital melanocytic nevus (CMN) / giant hairy nevus (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022])
Large / giant CMN has been described as bathing trunk / vest / shoulder sleeve / stocking / glove nevi, depending on the site

ICD coding

ICD-10: D22.30 - melanocytic nevi of unspecified part of face

Epidemiology

M = F
Found in 1 - 2% of newborns, 0.6 - 1.6% of the population
Incidence of malignant change has been reported more in females, large nevi and axial lesions
Lesion over vertebral column can have associations with leptomeningeal melanocytosis, hydrocephalus, spina bifida or meningomyelocele
Large lesions are commonly associated with neurocutaneous melanosis (3 - 15%), hypertrophy of affected limb and SCALP syndrome
References: An Bras Dermatol 2017;92:200, StatPearls: Congenital Nevus [Accessed 15 September 2022], StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022], Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Sites

Trunk and legs, followed by head and neck, feet and hands
Can be multiple
Can have satellite lesions with large / giant lesions

Pathophysiology

Believed to develop due to unregulated growth of melanoblasts during fifth to twenty fourth week of gestation (An Bras Dermatol 2017;92:200)
Occur as a result of in utero somatic mutations of genes that play a role in the mitogen activated protein kinase (MAPK) pathway (mainly NRAS); this leads to the overproliferation of melanocyte lineage cells and thus the formation of CMNs (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022], StatPearls: Congenital Nevus [Accessed 15 September 2022])

Etiology

No known etiology

Clinical features

Flat or raised lesion, heavily pigmented, hairy
Based on size classified as:
- Small (< 1.5 cm)
- Medium (1.5 - 20 cm)
- Large (> 20 - 40 cm)
- Giant (> 40 cm) (StatPearls: Congenital Nevus [Accessed 15 September 2022])
Clinical relevance relies on their association with increased risk of melanoma and central nervous system involvement (neurocutaneous melanosis) (StatPearls: Congenital Nevus [Accessed 15 September 2022])

Diagnosis

Clinical presentation and histological examination is diagnostic

Laboratory

Usually not required

Prognostic factors

Excellent prognosis
Increased size of the lesion is linked to the increased risk of melanoma (J Am Acad Dermatol 2013;68:441)

Case reports

Neonate boy presented with a giant congenital melanocytic nevus (Cureus 2021;13:e15210)
19 month old boy and 4 year old girl presented with neurocutaneous melanosis in association with large congenital melanocytic nevi (Front Neurol 2019;10:79)
2 year old girl presented with giant congenital melanocytic nevus (Indian Dermatol Online J 2020;11:79)
12 year old girl presented with giant congenital melanocytic nevus (J Med Case Rep 2018;12:175)
16 year old girl presented with oral congenital melanocytic tumor (Head Neck Pathol 2015;9:481)

Treatment

Surgical excision (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022])
Other treatment modalities include laser, radiotherapy, dermabrasion, cryotherapy, electrotherapy and chemical peels (StatPearls: Congenital Melanocytic Nevi [Accessed 15 September 2022])

Clinical images

Contributed by Mark R. Wick, M.D.

Breast skin

Images hosted on other servers:

10 year old girl

Dermoscopically typified by a globular pattern

Papillomatous surface

Verrucous surface and hair

Giant CMN covering 20% of the total body surface area

Newborn with giant hairy congenital nevus

Ulcerated nodule within scalp

Reticular pattern and regular globules

Globular pattern and patchy network

Haloed globules

Target network and target globules

Gross description

Flat or slightly raised pigmented lesion usually exhibiting hair (Dermatol Pract Concept 2020;10:e2020068)

Gross images

Contributed by Koteeswaran Govindaswamy, M.D. (Case #383)

Partial black discoloration

Microscopic (histologic) description

Diffuse melanocytic proliferation in dermis with extension into subcutaneous fat
Grenz zone is identified between epidermis and melanocytes
Nevus cells encircle and extend to walls of dermal appendages, perineural space and blood vessels, and can dissect through collagen bundles
Variable pigmentation and focal neurotization may be present
Sparse mitotic activity
Neonates / young children can have any of these worrisome features: cytological atypia, increased mitotic activity, large junctional nests and pagetoid spread
Proliferation nodules in CMN
- Large epithelioid melanocytes with mild nuclear pleomorphism
- Mitoses are typically rare and do not exceed 1 mitosis/mm²
- No abnormal mitosis or necrosis
- Remain stable for a prolonged period of time and may regress spontaneously
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Microscopic (histologic) images

Contributed by Anila Chughtai, M.B.B.S.

Dermal melanocytic proliferation

Grenz zone

Melanocytes dissecting collagen bands

Melanocytes centered on pilosebaceous units

Melanocytes involve arrector pili muscle

Melanocytes centered on eccrine duct

Variable pigmentation

Positive stains

S100
SOX10
MelanA / MART1
HMB45 (positive only in superficial part)
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Negative stains

Molecular / cytogenetics description

NRAS mutation (Front Med (Lausanne) 2021;8:637857, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014)
BRAF mutations are also reported in CMN; however, they are uncommon (Pigment Cell Melanoma Res 2015;28:661)

Sample pathology report

Pigmented skin lesion at scalp, excision:
- Congenital melanocytic nevus (see comment)
- Comment: Benign lesion with excellent prognosis.
- Microscopic description: A dermal based proliferation of melanocytes arranged in small nests and cords, dissecting through dermal collagen bundles. A grenz zone is identified between epidermis and melanocytes. The melanocytes are bland with variable amount of melanin granules. The melanocytes ensheath pilosebaceous units and extend into arrector pili muscle. The lesion shows maturation at depth of the lesion. No evidence of cellular atypia, frequent mitoses or necrosis is found. The margins are clear.

Differential diagnosis

Acquired melanocytic nevi:
- Present in adults
- Location can be variable
- Prominent nesting pattern, presence of epidermal / junctional component and prominent neurotization
- Can ensheath dermal appendages, however, no involvement of walls of dermal appendages or arrector pili muscle is seen
- Immunohistochemical profile is similar to CMN
- Commonly have BRAF mutations (Pigment Cell Melanoma Res 2015;28:661, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019)
Melanoma:
- Proliferation nodules in congenital melanocytic nevus can mimic melanoma
- Melanoma usually presents in older adults
- Location can be variable
- Melanoma usually has asymmetry, epidermal involvement, cellular pleomorphism, brisk / abnormal mitosis, pagetoid spread and necrosis
- PRAME stain is positive in melanoma
- HMB45 stains melanocytes in the superficial and deeper parts of the lesion in melanoma
- In addition to NRAS mutation, melanoma also harbors BRAF, KIT, PTEN, TERTp, CDKN2A and TP53 mutations (Cell 2015;161:1681, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019)

Board review style question #1

Congenital melanocytic nevi commonly harbor which of the following molecular alterations?

ALK
BRAF
KRAS
NRAS
p16

Board review style answer #1

D. NRAS

Comment Here

Reference: Congenital nevus

Board review style question #2

Which prominent histological feature of congenital melanocytic nevi is shown in the microscopic image above?

Involvement of dermal appendages
Junctional nests of melanocytes
Melanocytes dissecting through collagen bundle
Pagetoid spread of melanocytes to epidermis
Prominent nesting pattern

Board review style answer #2

A. Involvement of dermal appendages

Comment Here

Reference: Congenital nevus

Cutaneous neurocristic hamartoma

Table of Contents

Definition / general

Neurocristic hamartoma (NCH) is a rare, multinodular, slow growing, pigmented lesion that involves the skin and soft tissue
It is composed of melanocytes, Schwann cells and pigmented dendritic spindle cells
Congenital NCH is an uncommon condition that appears to be caused by the aberrant development of neural mesenchyme and has a high risk of developing into malignant melanoma

Essential features

First described by Tuthhill et al. in 1982 (Arch Dermatol 1982;118:592)
Typically occurs in the head and neck region
Composed of variable cellular components of neural crest origin
- Melanocytes
- Peripheral nerves
- Stroma
Malignant transformation is uncommon (Am J Surg Pathol 1996;20:665)

Terminology

Cutaneous neurocristic hamartoma

ICD coding

ICD-10: D23.9 - other benign neoplasm of skin, unspecified
ICD-11: 2F24 - benign cutaneous neoplasms of neural or nerve sheath origin

Epidemiology

Most frequent in children (Am J Surg Pathol 1996;20:665)
Acquired (all ages) or congenital (Am J Surg Pathol 1996;20:665)
M = F

Sites

Head and neck region
Most frequently involves the scalp in children and young adults

Pathophysiology

Aberrant development of neuromesenchyme (Am J Dermatopathol 2022;44:e54)

Etiology

Unknown

Clinical features

Slowly enlarging multinodular patch or plaque with variable pigmentation (Am J Dermatopathol 2021;43:284)
Often bluish hue
NCH can involve and metastasize to lymph node (Am J Dermatopathol 2015;37:e87)

Diagnosis

Light microscopy and immunohistochemistry play a vital role
Dermoscopy
- Blue-gray clouds with featureless areas, brown dots and streaks with multiple clustered dotted and linear vessels (Dermatol Pract Concept 2022;12:e2022138)

Radiology description

On MRI
- NCH appears as an extra axial soft tissue mass (J Pediatr Neurosci 2012;7:181)
- Extensive congenital scalp lesions may show an associated herniation of the occipital lobe and ventricles through the gap in the calvarium and cutaneous defect (BMJ Case Rep 2023;16:e253156)
CT scan: a well defined, contrast enhancing extracranial mass (J Pediatr Neurosci 2012;7:181)

Radiology images

Images hosted on other servers:

MRI of the brain

CT showing a scalp lesion

Prognostic factors

Overall favorable prognosis (BMJ Case Rep 2023;16:e253156)

Case reports

Newborn boy with cutaneous cephalic neurocristic hamartoma on the head (Am J Dermatopathol 2021;43:284)
Newborn boy with cutaneous neurocristic hamartoma of the scalp with disseminated melanocytic nevi (BMJ Case Rep 2023;16:e253156)
2 month old girl with cutaneous neurocristic hamartoma of the scalp (J Pediatr Neurosci 2012;7:181)
1 year old girl with cutaneous neurocristic hamartoma of the scalp (Ann Dermatol 2009;21:396)
6 year old girl with xeroderma pigmentosa and cutaneous neurocristic hamartoma mimicking basal cell carcinoma (Am J Dermatopathol 2022;44:e54)
6 year old boy with cutaneous neurocristic hamartoma with lymph node metastasis (Am J Dermatopathol 2015;37:e87)
7 year old boy with proliferating cutaneous neurocristic hamartoma arising in giant congenital nevus (Am J Dermatopathol 2019;41:438)
17 year old boy with cutaneous neurocristic hamartoma involving the bone marrow (Am J Dermatopathol 2010;32:486)
20 year old woman with cutaneous neurocristic hamartoma presenting as cutis verticis gyrata (Am J Dermatopathol 2014;36:e66)
22 and 37 year old women and 32 year old man with malignant neurocristic hamartoma, the former 2 of which were metastatic (Am J Surg Pathol 2011;35:1570)
57 year old woman with congenital cutaneous neurocristic hamartoma with poliosis (J Cutan Pathol 2017;44:974)
74 year old man with neurotropic melanoma arising from a neurocristic hamartoma (J Cutan Pathol 2023;50:197)

Treatment

There are no standard recommendations for treatment of NCH
Prognosis is predicted by many factors, including
- Patient age
- Tumor location
- Clinical size
- Tumor depth / extent
- Presence or absence of malignant transformation
Wherever possible, a wide local excision is ideal (J Pediatr Neurosci 2012;7:181)
No known guidelines for SLNB or lymph node dissection
Long term cancer surveillance is recommended for all NCH patients (Am J Surg Pathol 1996;20:665)
Reference: J Pediatr Neurosci 2012;7:181

Clinical images

Images hosted on other servers:

Gray-blue scalp lesion

Dark brown scalp lesion with ulceration

Multiple erythematous tan-brown papules and plaque on the scalp

Erythematous tan-brown papules and plaque on scalp

Cerebriform swelling with alopecia and multiple bluish firm nodules over the back

Cerebriform swelling with alopecia / bluish firm nodules

Bluish, ill defined lesion on the scalp

Gross description

Size varies; up to 20 cm in size (BMJ Case Rep 2023;16:e253156)
Gray-blue to purplish in color
Soft to hard in consistency
Exhibits smooth to variegated tan pale cut surfaces

Gross images

Images hosted on other servers:

Tan-white to yellow smooth cut surfaces

Microscopic (histologic) description

Dermal based spindle cell proliferation composed of different components of neural crest origin, including epithelioid to spindled melanocytes, stromal cells and peripheral nerve component (Ann Dermatol 2009;21:396)
Fascicles of spindled cells and heavily pigmented cells with dendritic morphology are seen at high magnification
Some areas may show a mixture of fibrous and peripheral nerve differentiation in the stromal component
Epithelioid cells can show nuclear atypia and even frankly malignant nuclear changes (DermNet: Neurocristic Hamartoma Pathology [Accessed 29 August 2023])

Microscopic (histologic) images

Contributed by Muhammad Tahir, M.D, M.S. and Thuy L. Phung, M.D., Ph.D.

Well circumscribed, dermal based lesion

Epithelioid / spindled cells

Mild cytologic atypia

Lymph node metastasis

S100

Dual stain: MelanA and Ki67

MITF

SOX10

p63

AE1 / AE3

CK5/6

EMS

Virtual slides

Images hosted on other servers:

NCH looks like blue nevus

Positive stains

Melanocytic component is positive for HMB45, S100, MelanA, MITF and SOX10 (J Cutan Pathol 2017;44:974)
Spindle cell component is positive for CD34, S100 and SOX10 (Am J Dermatopathol 2022;44:e54)

Negative stains

Desmin, EMA and CD10, cytokeratin

Molecular / cytogenetics description

No known genetic disposition described in the literature so far (Ann Diagn Pathol 1998;2:213)

Sample pathology report

Skin, neck, excision:
- Dermal spindle cell neoplasm, consistent with cutaneous neurocristic hamartoma (see comment)
- Comment: This is a dermal based proliferation of benign appearing spindle and epithelioid cells of neurocrest derivation with intermittent benign melanocytes. The spindle cell component is positive for SOX10, S100 and CD34 while the epithelioid cell component is positive for MelanA, HMB45 and S100, consistent with melanocytic origin.

Differential diagnosis

Melanoma:
- Expansile growth and marked atypia in melanoma
- Increased dermal mitotic index
- Often BRAF mutation in melanoma (Pigment Cell Melanoma Res 2015;28:661)
- More aggressive behavior and growth
Congenital nevus:
- Grenz zone between epidermis and melanocytes
- Common in neonates and young adults
- Lack of mitoses and necrosis (Calonje: McKee's Pathology of the Skin, 5th Edition, 2019)
Blue nevus:
- Portions of cutaneous neurocristic hamartoma is usually positive for CD34 while blue nevus is negative
- Histologic features of blue nevus
  - Admixed scattered heavily pigmented melanophages
  - Melanocytes aggregate around blood vessels, nerves or cutaneous appendages (Clin Lab Med 2017;37:401)
  - May present in the superficial dermis or extend into subcutis (Clin Lab Med 2017;37:401)
  - No maturation
  - No cytologic atypia, no mitotic figures (Clin Lab Med 2017;37:401)
Spitz nevus:
- Usually young adults
- Common on the extremities
- Usually < 6 mm
- ALK, ROS1, NTRK1 / NTRK3, BRAF or RET fusion
- Histologic features of Spitz nevus
  - Conventional Spitz nevi are well circumscribed, symmetrical and show an overall wedge shaped silhouette
  - Consist of large junctional and dermal melanocytic nests formed by spindled or epithelioid cells
  - Melanocytes are large, spindled or epithelioid, contain abundant pale or ground glass cytoplasm and finely dispersed pigment (if present)
  - Mild nuclear pleomorphism may occur, mitoses are rare or absent

Board review style question #1

A 5 year old boy presents with a small grayish blue nodular plaque on the scalp. From which germ layer is this lesion derived?

Ectoderm
Endoderm
Mesoderm
Neural crest

Board review style answer #1

D. Neural crest. This pigmented lesion has melanocytic lineage that derives from the neural crest, which has its origin in the neural tube. Answer A is incorrect because ectoderm is the outermost layer of cells or tissues of an embryo in early development and the parts derived from ectoderm include epidermis and nerve tissues. Answer B is incorrect because endoderm is the innermost layer of cells or tissues of an embryo in early development. The parts derived from endoderm include the inner lining of the digestive and respiratory tracts. Answer C is incorrect because the mesoderm is the middle layer of the 3 germ layers that develops during gastrulation in the very early development of the embryo. The structures derived from mesoderm include mainly muscles, mesenteries and gonads.

Comment Here

Reference: Cutaneous neurocristic hamartoma

Board review style question #2

A 5 year old boy with no significant medical history presents to the primary care physician with a small nodular lesion on the scalp. The lesion is 5 - 6 cm in size, grayish blue in color and soft in consistency. What is the diagnosis?

Congenital nevus
Folliculitis
Melanoma
Neurocristic hamartoma
Spitz nevus

Board review style answer #2

D. Neurocristic hamartoma. Based on clinical presentation and histological characteristics, neurocristic hamartoma is the correct diagnosis. Answer A is incorrect because congenital nevus is a diffuse melanocytic proliferation in the dermis with possible extension into subcutaneous fat. A Grenz zone is identified between the epidermis and melanocytes and this is a characteristic histopathological finding that differentiates congenital nevus from NCH. Answer B is incorrect because folliculitis is inflammation of a hair follicle. Histologically, there will be a presence of inflammatory cells within the wall and ostia of the follicular unit that will create a follicular based pustule. Answer C is incorrect because melanoma is rare in this age group, though it is one of the possibilities. This is a bland appearing spindle cell lesion with no atypia, mitotic activity or necrosis, which makes a melanoma diagnosis highly unlikely in this case. Answer E is incorrect because histologically, Spitz nevus consists of epidermal hyperplasia and large junctional nests of spindled to epithelioid melanocytes with characteristic Kamino bodies and clefting of the junctional nests.

Comment Here

Reference: Cutaneous neurocristic hamartoma

Board review style question #3

Dual stain: MelanA and Ki67

SOX10

S100

MITF

Immunohistochemistry was performed on a skin lesion using multiple antibodies against S100, SOX10, MITF, MART1, Ki67, CD10, CD34 and pancytokeratin. S100 and SOX10 were diffusely positive. MITF and MART1 show focal positivity. Ki67 shows a high proliferative index. CD10 and CD34 show focal positivity in the spindled / epithelioid cells. Pancytokeratin was negative. Based on the immunohistochemical profile, what is the most likely diagnosis?

Blue cellular nevus
Congenital nevus
Melanoma
Neurocristic hamartoma
Spitz nevus

Board review style answer #3

D. Neurocristic hamartoma. Neurocristic hamartoma is the correct answer because the immunohistochemical profile is consistent with this entity. Answer A is incorrect because cellular blue nevus would show dermal based pigmented melanophages and pigmented dendritic melanocytes with dense collagenous stroma. Cytogenetically, cellular blue nevus has characteristic GNAQ and GNA11 mutations. Answer B is incorrect because histologically, congenital nevus has a characteristic Grenz zone and negative MITF immunostaining. Answer C is incorrect because melanoma is one of the top differential diagnoses for this entity and has similar histological characteristics. The immunohistochemical pattern is a very useful diagnostic tool for this differential diagnosis. This is a bland appearing spindle cell lesion with no atypia, mitotic activity or necrosis which makes melanoma diagnosis highly unlikely. Melanoma will be positive for SOX10, MART1, MITF and will have a high Ki67 index and is negative for CD34. Answer E is incorrect because Spitz nevus is negative for CD10 and CD34. Histologically, Spitz nevus will consist of epithelioid to spindle cell melanocytes nested along a hyperplastic epidermis with Kamino bodies.

Comment Here

Reference: Cutaneous neurocristic hamartoma

Board review style question #4

Immunohistochemistry of this skin lesion is diffusely positive for S100 and SOX10 and focally positive for MITF and MART1. Ki67 shows a high proliferative index while CD10 and CD34 show focal positivity in the spindled / epithelioid cells and pancytokeratin was negative. A few enlarged lymph nodes are identified and removed during lymph node dissection. One lymph node is positive (see image) for a tumor with a similar immunohistochemical profile as above. What is the most likely diagnosis?

Blue cellular nevus
Congenital nevus
Melanoma
Metastatic neurocristic hamartoma
Spitz nevus

Board review style answer #4

D. Metastatic neurocristic hamartoma. Metastatic neurocristic hamartoma is the correct answer because the lesion is composed of spindled to epithelioid benign appearing cells without any necrosis, mitotic activity and is consistent with metastatic NCH. Answer A is incorrect because blue cellular nevus is a benign highly pigmented lesion with low metastatic potential. Answer B is incorrect because congenital nevus is a benign lesion with low metastatic potential. Answer C is incorrect because the immunohistochemical profile is diagnostic for neurocristic hamartoma rather than melanoma. Answer E is incorrect because Spitz nevus is a benign entity with low metastatic potential, although rare exceptional cases of metastatic Spitz nevus case been reported in the literature.

Comment Here

Reference: Cutaneous neurocristic hamartoma

Dermal melanocytosis

Table of Contents

Ito's nevus | Nevus of Ota | Mongolian spot

Ito's nevus

Definition / general

First described by Minor Ito in 1954

Terminology

More accurately grouped with dermal melanocytoses (nevus of Ito, nevus of Ota, Hori nevus, so called "Mongolian" spot) (eMedicine: Nevi of Ota and Ito [Accessed 23 July 2021])
Although melanocytic, it is not a true nevus
Different entity from Hypomelanosis of Ito, a neurocutaneous disorder (J Child Neurol 2000;15:635)

Epidemiology

Usually individuals with pigmented skin, most commonly Asians; also Hispanics, blacks, Native Americans
More common in women
Often occurs with nevus of Ota in same patient but is much less common

Sites

By definition, found in shawl or cloak distribution

Clinical features

Macule with irregular blue-gray pigmentation
Similar to nevus of Ota except for location
Ito’s nevus is found in shoulder, side of neck and supraclavicular areas, within the distribution of the lateral (also called posterior) supraclavicular nerve and lateral cutaneous brachial nerves
Nevus of Ota is found around the eyes

Case reports

38 year old man with nevus of Ota (Indian J Dermatol Venereol Leprol 2004;70:112)
72 year old woman with late onset Ito's nevus (J Cutan Pathol 2007;34:640)
With transformation to melanoma (J Am Acad Dermatol 2010;62:869)

Treatment

Laser to lighten pigment (cosmetic purposes)
Cryotherapy, dermabrasion, chemical peeling and surgical excision may give variable results (Facial Plast Surg Clin North Am 2007;15:367)

Clinical images

Images hosted on other servers:

Nevus of Ota (face) and nevus of Ito (shoulder)

Microscopic (histologic) description

Deeply pigmented dendritic melanocytes and melanophages dissecting bundles of dermal collagen in reticular dermis
Overlying epidermis is normal

Nevus of Ota

Definition / general

First described by Ota in 1939
Uncommon hamartoma in periorbital and temporal skin (eMedicine: Nevi of Ota and Ito [Accessed 23 July 2021])
Types:
- Type IB: mild zygomatic type - pigmentation in infrapalpebral fold, nasolabial fold and zygomatic region
- Type IC: mild forehead type - involvement of forehead alone
- Type ID: involvement of ala nasi alone
- Type II: moderate type - distribution over upper and lower eyelids, periocular, zygomatic, cheek and temple regions
- Type III: involves scalp, forehead, eyebrow and nose
- Type IV: bilateral
- Hori’s nevus: acquired bilateral nevus of Ota-like macules (J Am Acad Dermatol 1984;10:961, Dermatol Online J 2005;11:1); usually Chinese women with family history, becomes more confluent and gray over time (Br J Dermatol 2006;154:50)
- Sun’s nevus: acquired unilateral nevus of Ota

Terminology

Also called oculodermal melanosis or nevus fuscoceruleus ophthalmomaxillaris
Similar to nevus of Ito except for location (Ito in shoulder, side of neck and supraclavicular areas, within the distribution of the lateral supraclavicular nerve and lateral cutaneous brachial nerves)

Epidemiology

Usually Asians; also Hispanics, blacks and Native Americans
60% have lesions at birth, 87% female, 60% have dermal and ocular involvement (Indian J Dermatol Venereol Leprol 2008;74:125)

Sites

Periorbital, temporal

Clinical features

Tends to persist and extend locally, becoming increasingly prominent with age, puberty and postmenopausal state
Associated with ipsilateral glaucoma, intracranial melanocytosis; rarely with cutaneous, ocular or intracranial melanoma and vascular nevus (Cutis 2008;82:25, J Am Acad Dermatol 2008;58:88)
Macule with irregular blue-gray pigmentation in distribution of 1st and 2nd division of trigeminal nerve
May coexist with nevus of Ito
Tanino classification system most common, others include Hirayama system and proposed Chan system (Lasers Surg Med 2001;28:267)

Case reports

30 year old woman with bilateral and oral mucosa involvement (Indian J Dermatol Venereol Leprol 2002;68:104)
41 year old woman with acquired bilateral nevus (Dermatol Online J 2005;11:1)
47 year old light-skinned non-Asian woman with bilateral manifestations (Dermatol Online J 2007;13:19)
50 year old man with coexisting iris melanoma (Surv Ophthalmol 2008;53:411)
Elderly Caucasian woman with acquired Ito's nevus (J Cutan Pathol 2007;34:640)

Treatment

Cosmetic coverup products
Multiple sessions of laser photothermolysis to avoid darkening and extension, beginning early after diagnosis (Dermatol Surg 2007;33:455)
Subtypes vary in response to laser therapy (Lasers Surg Med 2001;28:267)
Combined skin abrasion and carbon dioxide snow method (Plast Reconstr Surg 1996;97:544)
- Cryosurgery and microsurgery not recommended due to scarring; chemical bleaching not recommended due to depigmentation

Clinical images

Images hosted on other servers:

Flat blue-gray pigmentation

Acquired dark brown spots below eyes

Episcleral involvement

With nevus of Ito

Microscopic (histologic) description

Deeply pigmented dendritic melanocytes and melanophages dissecting bundles of dermal collagen in reticular dermis

Microscopic (histologic) images

Contributed by Asmaa Gaber Abdou, M.D.

Elongated dendritic melanocytes scattered with collagen bundles extending around hair follicles

Images hosted on other servers:

Bipolar dendritic
melanocytes in
papillary and
reticular dermis

Wavy dendritic
cells with evenly
dispersed
melanin granules

Differential diagnosis

Acquired bilateral nevus of Ota-like macule
Cafe-au-lait patch
Speckled lentiginous nevus

Mongolian spot

Definition / general

Ill defined area of blue discoloration, up to several centimeters and in lumbosacral region (eMedicine: Congenital Dermal Melanocytosis (Mongolian Spot) [Accessed 23 July 2021], Wikipedia: Mongolian spot [Accessed 23 July 2021])
May also occur at other sites
See also Ito’s nevus

Terminology

Also known as congenital dermal melanocytosis
Related to dermal melanocytoses (nevus of Ito, nevus of Ota, Hori nevus)
Although melanocytic, is not a true nevus

Epidemiology

Congenital disorder, present at birth in most neonates from Asia, East-Africa or Turkey; also Native Americans
Incidence of 60 - 70% in Iran, Nigeria and Taiwan (Pediatr Dermatol 2006;23:61, Niger J Med 2001;10:121, Chang Gung Med J 2007;30:220)
- Usually regresses over several years, almost always by puberty but may persist (Int J Dermatol 2005;44:43)
Usually not present in children with blond hair (Turk J Pediatr 2006;48:232)
Extensive Mongolian spots may be associated with inborn errors of metabolism (Pediatr Neurol 2006;34:143, Br J Dermatol 2003;148:1173)

Sites

Usually sacral region

Case reports

1 year old boy with facial lesion near mandibular area (J Dermatol 2007;34:381)
4 infants with darker pigmented Mongolian spot superimposed on another Mongolian spot (Pediatr Dermatol 2008;25:233)

Treatment

Wait for regression
Laser (Lasers Med Sci 2007;22:159)

Clinical images

Images hosted on other servers:

Mongolian spots

Microscopic (histologic) description

Normal at low power
High power shows occasional deep dendritic melanocytes, with melanin granules dissecting bundles of dermal collagen
No associated melanophages

Differential diagnosis

Bruises from child abuse

Desmoplastic melanoma

Table of Contents

Definition / general

Rare desmoplastic / fibrosing variant of spindle cell melanoma with > 90% stroma / collagen

Essential features

Often amelanotic and mistaken for nonmelanocytic lesion, such as scar
Prognosis variable, dependent on presence of conventional melanoma
Positive for SOX10 and S100 but often negative for other melanocytic markers
Nodular lymphoid aggregates are a useful clue

Terminology

Pure form: tumor predominantly / entirely desmoplastic (≥ 90%)
Mixed form: significant component of conventional melanoma (> 10%)

ICD coding

ICD-O: 8745/3 - desmoplastic melanoma, malignant
ICD-10: C43.9 - malignant melanoma of skin, unspecified

Epidemiology

< 1% of all melanomas
Mean age: 61 (Cancer 1998;83:1128)
M > F (2:1) (J Am Acad Dermatol 2013;68:825)

Sites

Head and neck region most common

Pathophysiology

Unclear
Many have NF1 loss of function mutations (Am J Surg Pathol 2015;39:1357)
NFKBIE promoter mutations common (Nat Genet 2015;47:1194)

Etiology

Unclear
Mostly arises in a background of severe sun damage

Clinical features

Often nonpigmented and misdiagnosed as scar
Usually advanced thickness at presentation (Br J Dermatol 2005;152:673)
Dermoscopy is difficult due to absence of pigmented network
- Can have features of regression and melanoma associated vascular patterns (Br J Dermatol 2008;159:360)

Diagnosis

Diagnosis can be made on biopsy but paucicellular variant is easily misdiagnosed

Prognostic factors

5 year disease free survival: 68% (J Am Acad Dermatol 1995;32:717)
- Lymph node metastasis: 12% (Cancer 2004;100:598)
Prognosis related to
- Neurotropism: presence linked to significantly reduced survival
- Histologic type
  - Pure form biologically behaves as sarcoma with frequent local recurrence and metastasis to lung
  - Mixed form akin to conventional melanoma with metastasis to lymph node

Case reports

46 year old man with collision tumor with squamous cell carcinoma on lip (J Cutan Pathol 2008;35:473)
59 year old and 66 year old women presented with small scalp lesions clinically suggestive of alopecia (J Cutan Pathol 2016;43:872)
75 year old man presented with an ulceroproliferative growth on the foot (J Cutan Aesthet Surg 2015;8:60)

Treatment

Wide local excision
Adjuvant radiotherapy can be considered for pure form with perineural invasion, Breslow thickness > 4 mm or positive surgical margins (Melanoma Res 2016;26:35)

Clinical images

Images hosted on other servers:

Forearm lesion

Dermoscopy

Mandible leasion

Gross description

Pigmented or scar-like skin surface with ill defined induration (JAMA Dermatol 2013;149:413)
Cross sections with white, poorly demarcated tumor

Microscopic (histologic) description

Poorly circumscribed with deep infiltration
Elongated spindle cell surrounded by collagen bundles (Hum Pathol 1983;14:1072)
- Can resemble fibroblasts
- Scattered cells show hyperchromasia and bizarre nuclei
- Multinucleated cells often present
Stromal component varies in different tumors (Mod Pathol 2014;27:524)
- Some tumors with scattered spindle cells and abundant collagen
- Others with high cellularity and little stroma (best classified as spindle cell melanoma)
Small foci of lymphoid aggregates is a useful clue to the diagnosis on scanning
May be pure or combined with classic melanoma
Desmoplastic neurotropic melanoma considered a variant (33% of all cases of desmoplastic melanoma) (Am J Dermatopathol 2008;30:207)

Microscopic (histologic) images

Contributed by Gregory A. Hosler, M.D., Ph.D.

Pure type

Atypia, pure type

Mixed type

Lymphoid aggregates

Neurotropism

Mitosis

S100

SOX10

Spindle cell melanoma

Virtual slides

Images hosted on other servers:

Desmoplastic melanoma

Cytology description

Clean background; aggregates of pleomorphic spindle cells mixed with fibrous stroma and single cells
Fine, wispy and delicate cytoplasm at nuclear poles; elongated and plump nuclei with irregular contours; deep grooves and folds and dark coarse chromatin with variably prominent nucleoli (Cytojournal 2007;4:18)
Less cellular with fewer intranuclear cytoplasmic inclusions and mitoses relative to conventional melanoma (Am J Clin Pathol 2008;130:715)

Positive stains

S100 and SOX10 (J Cutan Pathol 2016;43:313)
Ki67: usually high
WT1, p75
H3K27me3 retained
- May be helpful when differentiating from a malignant peripheral nerve sheath tumor (Am J Surg Pathol 2016;40:479)
p53 (95%) (Am J Surg Pathol 2018;42:372)
- Helpful when differentiating from neurofibroma

Negative stains

MelanA / MART1, tyrosinase, CD63, MITF
HMB45 (can stain small clusters of cells in up to 20% of nonpure type cases)
PRAME (approximately 30% positive) (Am J Surg Pathol 2018;42:1456)

Electron microscopy description

Shows only modest evidence of melanocytic origin
- Stage II melanosomes considered the hallmark of melanoma and melanin synthesis
- Some cases with nonmembrane bound melanin granules and premelanosomes (Hum Pathol 1983;14:1072)
Cells have abundant rough endoplasmic reticulum and sometimes intracytoplasmic collagen and macular desmosomes

Molecular / cytogenetics description

NF1 loss of function mutations common
Numerous point mutations
In contrast, other melanomas have genetic copy number alternations
NFKBIE (NFκB inhibitor, epsilon; 6p21.1) promoter mutations appear to play a role in development (Nat Genet 2015;47:1194)
BRAF mutations unusual
Sensitivity of FISH assay ~ 50% (using a 4 probe FISH assay targeting RREB1, MYB, CEP6 and CCND1 (J Cutan Pathol 2011;38:329)
Sensitivity of both single nucleotide polymorphism array and gene expression profiling 50 - 80% (Hum Pathol 2017;70:113)

Videos

Desmoplastic melanoma: 5 minute pathology pearls

Sample pathology report

Skin, scalp, shave biopsy:
- Desmoplastic melanoma (pure type), level IV, 1.3 mm tumor thickness, nonulcerated

Differential diagnosis

Scarring process:
- Horizontal orientation of fibroblasts with vertically oriented blood vessels and absence of adnexa
- S100 and SOX10 typically negative but may display positivity (Pathology 2016;48:626)
Malignant peripheral nerve sheath tumor:
- Uniform spindle cells with hyperchromatic, thin and wavy, buckled or comma shaped nuclei
- Often arranged in sweeping fascicles
- May be associated with precursor lesion, such as neurofibroma
- Patchy S100 and SOX10 expression with lower rate of immunoreactivity (Appl Immunohistochem Mol Morphol 2012;20:445)
Neurofibroma:
- No or very low mitotic activity
Spindled squamous cell carcinoma:
- Cytokeratin positive (may be weak or spotty)
Atypical fibroxanthoma:
- Diagnosis of exclusion (negative for cytokeratins, S100, desmin and vascular markers)
- CD10 and procollagen 1 positive
Dermatofibroma:
- Haphazard pattern of bland spindle cells with peripheral collagen trapping
- Often with overlying epidermal acanthosis and follicular induction
- Factor XIIIa positive in tumor cells
Fibromatosis:
- Bland spindle cells arranged in sweeping bundles in a highly collagenized background
Nodular fasciitis (superficial portion):
- Spindle stellate cells with a loose fascicular to storiform pattern (tissue culture-like growth)
- SMA positive
- Majority contain MYH9-USP6 fusion
Cutaneous angiosarcoma:
- Anastomosing vascular channels lined by spindled to epithelioid endothelial cells
- CD31, CD34, ERG positive
Cutaneous leiomyosarcoma:
- Fascicular growth pattern
- Desmin positive

Board review style question #1

A 65 year old man presents with a lesion on the scalp. Biopsy shows a spindle cell neoplasm centered in the dermis. The tumor cells express S100 and are negative for CD34, desmin, CD10 and cytokeratins. Regarding this entity, which of the following statements is true?

Frequently metastasizes to lymph node
MART1 is always positive
Nodular lymphoid aggregates are a useful clue to the diagnosis
Often clinically suspected at the time of biopsy
Site of predilection is the trunk

Board review style answer #1

C. Nodular lymphoid aggregates are a useful clue to the diagnosis. This is a desmoplastic melanoma.

Comment Here

Reference: Desmoplastic melanoma

Board review style question #2

Which of the following is most commonly expressed in desmoplastic melanoma?

CD34
HMB45
MART1
MITF
SOX10

Board review style answer #2

E. SOX10

Comment Here

Reference: Desmoplastic melanoma

Dysplastic nevus

Table of Contents

Definition / general

Controversial topic (J Am Acad Dermatol 2012;67:19.e1)
Pigmented lesions that share clinical and histological features of both common nevi and melanoma (J Am Acad Dermatol 2012;67:19.e1)

Essential features

First described by Clark and colleagues in 1978 (Arch Dermatol 1978;114:732)
Dysplastic nevi are characterized by histological, rather than clinical, criteria
Although many melanomas arise de novo (without an obvious or detectable precursor lesion), approximately 25% histologically demonstrate an associated melanocytic nevus (J Natl Cancer Inst 2016;108:djw121)

Terminology

Clark nevus
Nevus with architectural disorder
Nevus with architectural disorder and cytologic atypia
Atypical mole
B-K mole syndrome (Semin Cutan Med Surg 1999;18:4)
Dysplastic nevus syndrome (Am J Dermatopathol 1982;4:455)
Familial atypical multiple mole melanoma syndrome (Can Med Assoc J 1968;99:17l)

ICD coding

ICD-O: 8727/0 - dysplastic nevus
ICD-10: D22.9 - melanocytic nevi, unspecified

Epidemiology

Common in general population, with incidence of 2 - 18% (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
More common in younger patient populations (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
Usually becomes clinically apparent after puberty (J Am Acad Dermatol 2012;67:1.e1)
Higher incidence in patients with skin Fitzpatrick type I or II, compared to III and IV (Am Fam Physician 2015;91:762)
Predilection in sun exposed areas and in patients with histories of acute sunburn (Am Fam Physician 2015;91:762)
Higher incidence among patients with history of melanoma (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
Higher risk for melanoma development in patients with nevi demonstrating more severe atypia (Mod Pathol 2003;16:764)
Inherited in autosomal dominant pattern in families with dysplastic nevus syndrome (Melanoma Res 1993;3:15)

Sites

Skin of any body site can be involved
More common on trunk and sun exposed skin (Am Fam Physician 2015;91:762)

Pathophysiology

Pathophysiology is not well understood (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
Familial cases:
- Autosomal dominant with incomplete penetrance
- CDKN2A mutation but found less frequently than in melanoma (Melanoma Res 1993;3:15)
BRAF (most commonly V600E), p53 and p16 mutation (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])

Etiology

Etiology is not well characterized; it appears that multiple factors, such as genetics and environment, play roles in dysplastic nevus development (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
CDKN2A point mutations or deletions are not commonly found in dysplastic nevi (StatPearls: Dysplastic Nevi [Accessed 14 April 2022], Arch Dermatol 2005;141:177)

Clinical features

Dysplastic nevi are characterized by histologic features; clinically, dysplastic nevi may appear small and banal
Atypical nevi demonstrate the following clinical features:
- Usually > 5 mm
- Irregular borders
- Some with a pigmented and erythematous rim
- Variegated pigmentation with a mixture of pink, light and dark brown
Dermoscopy: reticular pattern, dots and clods at the periphery (J Dermatol 2019;46:e76, Dermatol Clin 2016;34:395)
Classic dysplastic nevus syndrome:
- Patients with 100 or more nevi with at least 1 nevus larger than 8 mm and at least 1 nevus with clinical atypical features
- National Institutes of Health revision: this term should only be used in patients with a positive family history for melanoma (Clinics (Sao Paulo) 2011;66:493)
Eruptive atypical nevus may develop after chemotherapy or immunotherapy (Pediatr Dermatol 2007;24:135)

Diagnosis

Diagnosis is heavily dependent on the histologic features and has a relatively poor interobserver correlation (J Am Acad Dermatol 2012;67:1.e1)
Initial diagnostic biopsy should sample entire lesion (Australas J Dermatol 2005;46:70)

Prognostic factors

Most dysplastic nevi never progress to melanomas even though they are associated with melanomas
Several studies suggest that patients with dysplastic nevi demonstrate an increased risk of melanoma, between 4 - 15 fold (J Am Acad Dermatol 2012;67:1.e1)
Patients with familial dysplastic nevus syndrome have an increased risk of developing other malignancies, particularly pancreatic cancer (Int J Cancer 2000;87:809)
Patients with dysplastic nevi and 2 or more family members with melanoma have a higher risk of melanoma but patients who have a family history of melanoma and no dysplastic nevi are only at an average risk for melanoma (Clinics (Sao Paulo) 2011;66:493)
Risk of melanoma increases as the number of dysplastic nevi increase (Melanoma Manag 2016;3:85)
Superficial spreading type melanoma is more commonly associated with dysplastic nevus compared with lentigo maligna type melanoma (Arch Dermatol 2003;139:1620)

Case reports

22 year old man with multiple eruptive dysplastic nevi and postchemotherapy in situ melanomas (Pediatr Dermatol 2007;24:135)
24 year old man with pointillist dysplastic nevus (Arch Dermatol 2005;141:763)
38 year old woman with dysplastic nevi and pancreatic cancer (Exp Ther Med 2022;23:31)
44 year old man with agminated dysplastic nevi and atypical mole syndrome (Arch Dermatol 2001;137:917)
49 and 55 year old women with dysplastic nevus and associated sebocyte-like melanocytes in nevi (Am J Dermatopathol 2007;29:566)

Treatment

Surveillance of skin and pigmented lesion through self skin check and clinical exam; frequency depends on age, sex, family history and activity of the lesion (StatPearls: Dysplastic Nevi [Accessed 14 April 2022])
Sun protection
Total body photography and dermoscopy to track the changes or evolution (Cancer Epidemiol Biomarkers Prev 2013;22:528)
Re-excision: decision to re-excise depends on the clinician's perception and risk assessment
Severely dysplastic lesions: complete excision due to poor inter-rater concordance in differentiating from melanoma in situ or invasion of superficial dermis (J Am Acad Dermatol 2012;67:1.e1)
Mildly atypical nevi are considered benign and no additional treatment is necessary
Lack of consensus on moderate atypia (J Am Acad Dermatol 2017;76:527, JAMA Dermatol 2016;152:1327, JAMA Dermatol 2015;151:212)

Clinical images

Images hosted on other servers:

Dysplastic,
pointillist
nevi with multiple
brown dots

Diffuse and patchy network pattern

Agminated atypical nevi

Agminated atypical nevi on right arm

Multiple melanocytic nevi (anterior chest and abdomen)

Dysplastic nevus syndrome

Minimal change in a clinically dysplastic nevus

Evolving and regressing clinical dysplastic nevus

Development of a clinically dysplastic nevus

Microscopic (histologic) description

Familial or sporadic dysplastic nevi show the same features
Architectural changes:
- Dysplastic nevus should not be diagnosed solely based on architectural atypia; cytologic atypia should also be present
  - Shouldering: the epidermal component extends at least 3 rete ridges beyond the lateral margin of the dermal component in compound nevi
  - Bridging: connection of the adjacent nests along elongated rete ridges
  - Lentiginous hyperplasia
  - Irregular nesting: nests show irregular sizes and shapes and are not confined to the tips of rete ridges
Cytological changes:
- Increased nuclear size and hyperchromatic nuclei
- Irregular nuclear membrane
- Prominent nucleoli
- Pleomorphism
- Multivacuolated melanocytes in the dermal component
Cytologic atypia classified into mild, moderate or severe or simplified to low or high grade
Stromal changes:
- Lamellar fibroplasia
- Meyerson phenomenon: a subacute spongiotic dermatitis
- Possible epidermal changes: acanthosis, focal parakeratosis, effacement of rete ridges, attenuation of the epidermis; however, the latter 2 features are typically absent in dysplastic nevus and are more characteristic of melanoma (Arch Dermatol Res 2022;314:159)
- Epidermolytic hyperkeratosis may be present but not specific (Am J Dermatopathol 2002;24:23)
Nevus of special site: flexural, breast, genital and acral nevi can be clinically and histologically atypical and simulate features of a dysplastic nevus or melanoma (Mod Pathol 2006;19:S4)
- The following criteria are not considered to be the typical features of special site nevi and dysplasia should be considered:
  - Nevus of genital skin:
    - Large and poorly circumscribed
    - Extensive shouldering
    - Significant epidermal pagetosis
    - Necrosis
    - Ulceration
    - Dermal mitosis
  - Nevus of flexural skin:
    - Cytologic atypia
    - Stromal alterations
  - Nevus of acral sites:
    - Acral nevi are often more cellular and are arranged in predominantly lentiginous pattern rather than nested patterns
    - Dysplastic nevi demonstrate uniform elongation and anastomosis of rete ridges

Microscopic (histologic) images

Contributed by Sepideh Nikki Asadbeigi, M.D., Aleodar Andea, M.D. and AFIP images

Focally severe atypia

Dermal - epidermal junctional nest bridging

Enlarged nevomelanocytes and dusty cytoplasm

Shouldering

Cytological atypia

Bridging and focal lentiginous spread of melanocytes

Bridging

Clark nevus

Positive stains

Positive IHC but not useful in separating melanoma and dysplastic nevus:
- SOX10, MART1 / MelanA, MITF
- HMB45: loss of staining with maturation in dysplastic nevus

Molecular / cytogenetics description

Mutation in BRAF is more common compared to benign nevus (62 - 81%)
RAS mutation is seen in congenital nevus and rarely in dysplastic nevus
Mutation / deletion of p16 tumor suppressor gene rarely in dysplastic nevus
Altered expression of p53
Increased microsatellite instability in dysplastic nevus; not seen in benign nevus
Some dysplastic nevi have deletion in p16 encoding chromosomal region 9p21
Usually diploid
24% have high risk mucosal HPV by PCR (Br J Dermatol 2005;152:909)
Microarray analysis of 4 markers (ING4, Cul1, BRG1 and Bim) may distinguish melanoma from dysplastic nevi (PLoS One 2012;7:e45037)

Videos

Dysplastic nevus by Dr. Jerad Gardner

Compound Clark nevus

Dr. Clay Cockerell's approach to dysplastic nevi

Sample pathology report

Skin, left arm, shave biopsy:
- Compound nevus with architectural disorder and severe cytologic atypia (see comment)
- Comment: The process extends to lateral margins. A complete excision is recommended.
- Microscopic description: Sections reveal junctional and dermal melanocytes arranged in irregular nests and single units. The lesion is poorly circumscribed and has some focal upward migration of melanocytes. The melanocytes show significant pleomorphism and hyperchromasia. Lamellar fibroplasia and a scattered lymphohistiocytic infiltrate are noted in the dermis.

Differential diagnosis

Banal nevus:
- Minor architectural abnormalities can be present but cytological atypia is absent
Lentigo maligna:
- Epidermal atrophy and effacement instead of epidermal hyperplasia
- Dermis shows significant solar elastosis in lentigo maligna
Melanoma in situ, superficial spreading type:
- Severely dysplastic nevi and early melanoma are difficult to distinguish and the diagnosis may be subjective
Recurrent nevus:
- Scar of the previous biopsy or excision is present
- Extension of the junctional component beyond the margins of scar may be a more concerning feature

Board review style question #1

Which of the following favors a diagnosis of melanoma rather than dysplastic nevus?

Bridging of the rete ridges
Focal pagetosis of melanocytes
Lamellar fibroplasia
Mitotic activity in dermal melanocytes

Board review style answer #1

D. Mitotic activity in dermal melanocytes

Comment Here

Reference: Dysplastic nevus

Board review style question #2

Which mutation is more common in congenital nevi and is rarely seen in dysplastic nevi?

BRAF V600E
GNAQ
P53
RAS

Board review style answer #2

D. RAS

Comment Here

Reference: Dysplastic nevus

Ephelis

Table of Contents

Definition / general | Terminology | Clinical images | Microscopic (histologic) description | Differential diagnosis

Definition / general

Benign lesion of sun exposed skin, associated with fair skin and red hair (Wikipedia)
Appears in early childhood; fades in winter, reappears in summer
Due to variations in melanocortin 1 receptor gene (Hum Mol Genet 2001;10:1701)
Risk factor for skin cancer (Int J Cancer 2010;127:2430)

Terminology

Plural is ephelides

Clinical images

Images hosted on other servers:

Face

Face and upper body

Microscopic (histologic) description

Mild hyperpigmentation of basal keratinocytes, normal architecture
No increase in number of melanocytes

Differential diagnosis

Halo nevus

Table of Contents

Definition / general

Nevus surrounded by zone of hypopigmented skin (eMedicine: Halo nevus)

Terminology

Also called leukoderma acquisitum centrifugum, Sutton nevus (Am J Dermatopathol 2003;25:349)

Epidemiology

1% of population before adulthood, no racial or gender predilection (J Am Acad Dermatol 2012;67:582)

Sites

Back, followed by head / neck are most common sites (J Am Acad Dermatol 2012;67:582)

Clinical features

Single or multiple
Usually due to regression caused by cell mediated immunity, or less commonly humoral immunity or granulomatous inflammation (Am J Dermatopathol 2008;30:233)
No fibrosis, in contrast to melanoma (J Cutan Pathol 2007;34:301)
Seen in 18% of Turner syndrome patients (J Am Acad Dermatol 2004;51:354)
May persist for decades (J Am Acad Dermatol 2012;67:582)
Note: classify based on nevus cell population because halo phenomenon occurs in various nevus types (J Cutan Pathol 1995;22:342)

Treatment

Observation, excision (for cosmetic reasons) or laser for facial lesions to induce repigmentation (J Cosmet Laser Ther 2007;9:245)

Clinical images

Images hosted on other servers:

Normal mole and halo nevus

Depigmentation around nevi on back

Microscopic (histologic) description

Residual melanocytes with heavy infiltration by lymphocytes and histiocytes that destroy pigment containing cells

Microscopic (histologic) images

Contributed by Angel Fernandez-Flores, M.D., Ph.D.

Various images

CD3 (T cells)

CD20 (B cells)

Melan A

Images hosted on other servers:

Early regression

CD8+ T cells

Differential diagnosis

Dermatitis
Lymphoma
Melanoma

Invasive melanoma

Table of Contents

Definition / general

Malignant melanocytic tumor arising from melanocytes in the skin, mucosa and autochthonous (indigenous) melanocytes from numerous internal organs (i.e. GI tract, CNS, etc.)

Essential features

Malignant melanocytic tumor arising from melanocytes
Accounts for majority of mortality due to skin cancer
Breslow depth is the most important prognostic factor
BRAF mutation testing is recommended for patients with stage III - IV melanoma

Terminology

Historically called melanose and fungoid disease (Melanoma Res 2012;22:114)

ICD coding

ICD-O:
- 8743/3 - Superficial spreading melanoma
- 8742/3 - Lentigo maligna melanoma
- 8745/3 - Desmoplastic melanoma, malignant
- 8770/3 - Mixed epithelioid and spindle cell melanoma
- 8720/3 - Malignant melanoma, NOS
- 8746/3 - Mucosal lentiginous melanoma
- 8721/3 - Nodular melanoma
- 8780/3 - Blue nevus, malignant
- 8761/3 - Malignant melanoma in giant pigmented nevus
- 8771/3 - Epithelioid cell melanoma
- 8773/3 - Spindle cell melanoma, type A
- 8774/3 - Spindle cell melanoma, type B
- 8720/6 - Malignant melanoma, metastatic
ICD-10: C43 - Malignant melanoma of skin

Epidemiology

Incidence: 3 - 7% (Europe), 2.6% (U.S.)
1% of skin cancer
Incidence has risen rapidly over the last 50 years
Higher incidence in periequatorial zone
M:F = 1.5:1
Risk factors
- Fair skinned populations (Fitzpatrick scale I - II)
- Family and personal history of melanoma
- Intense intermittent sun exposure (or artificial UV radiation sources)
- Increased mole count (> 50)
- Dysplastic nevus phenotype
- Germline mutation in CDKN2A, CDK4, MITF, TERT, ACD, TERF2IP, POT1, MC1R or BAP1 genes (J Cutan Pathol 2020;47:606)
- Immunosuppression

Sites

Cutaneous melanoma: anywhere on the skin's surface, including subungual location
Frequent sites
- Lower extremities (female)
- Trunk (male)
Extracutaneous
- Uvea
- Anorectal region
- Upper aerodigestive tract
- Sinonasal tract
- Leptomeninges

Pathophysiology

Multistep process that involves interaction of genomic, environmental and host factors
4 step model proposed (Pigment Cell Melanoma Res 2016;29:122):
- Mitogenic driver mutation (i.e. BRAF mutation)
- Escaping primary senescence (i.e. CDKN2A loss)
- Overcoming apoptosis (i.e. TP53 mutation)
- Immortalization (i.e. TERT-p mutation)
Main oncogenic signaling pathways
- Mitogen activated protein kinase (MAPK) pathway (RAS / RAF / MEK / ERK)
- PI3K / AKT / mTOR
- WNT / beta catenin signaling pathway (N Engl J Med 2015;373:1926)

Etiology

Melanoma can occur de novo or develop on a pre-existent nevus, known as melanoma arising in nevus
Ultraviolet exposure is the main etiological factor
2 main categories (Annu Rev Pathol 2014;9:239):
- Cumulative sun damage (CSD) (pathways I - III)
  - Low CSD (superficial spreading melanoma / L CSD nodular melanoma)
  - High CSD (lentigo maligna melanoma / H CSD nodular melanoma / desmoplastic melanoma)
- Not consistently associated with cumulative sun damage (pathways IV - IX)
  - Spitz melanoma, acral melanoma, mucosal melanoma, melanoma arising in congenital nevus, melanoma arising in blue nevus and uveal melanoma
Reference: Arch Pathol Lab Med 2020;144:500

Diagrams / tables

Images hosted on other servers:

AJCC staging 8th edition

Clinical features

Flat, slightly elevated, nodular, polypoid or verrucous pigmented lesion
May be achromic (amelanotic melanoma)
ABCDE rule (superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma)
1. Asymmetry
2. Irregular borders
3. Variation in color
4. Diameter (> 6 mm)
5. Evolution
Ugly duckling sign
Hutchinson sign
Blowfly sign (Donati: Clinical Dermatopathology - A Practical Guide to the Diagnosis of Skin Neoplasms, 1st Edition, 2019)
Associated conditions
- Dysplastic nevus syndrome (BK mole syndrome)
- BAP1 inactivated tumor syndrome
- Xeroderma pigmentosum
- Parkinson disease
Dermoscopic findings
- Atypical pigmented network
- Blue whitish veil
- Atypical vascular pattern
- Abrupt cutoff
- Atypical dots or globules
- Presence of pseudopods
- Radial steaming
- Milky red areas
- Shiny white structures
- Regression structures
- Scar-like depigmentation
- Multicomponent pattern
- More than 4 colors
- Dermoscopic scoring systems (J Am Acad Dermatol 2016;74:1093)

Diagnosis

Total body skin examination for the identification of clinically suspicious lesions
Histopathological diagnosis after wide surgical excision is the gold standard
Correlation with clinical parameters including age, gender, anatomical location and dermoscopic findings

Laboratory

Increased LDH level in advanced stage

Prognostic factors

Favorable prognostic factors
- Young age
- Female
- Low risk sites: extremities
- Early staged melanomas
- Brisk tumor infiltrating lymphocytes
Unfavorable prognostic factors
- Elderly patients
- Male
- High risk sites: back, upper arm, head and neck and acral sites
- High Breslow depth
- Positive sentinel lymph node biopsy
- High dermal mitotic rate
- Ulceration
- Absent or nonbrisk tumor infiltrating lymphocytes
- Presence of microsatellites
- Lymphatic invasion
- Neurotropism (local recurrence)
- Histologic subtype (pure desmoplastic melanoma and Spitz melanoma may have better prognosis) (Am J Surg Pathol 2004;28:1518, Ann Surg Oncol 2005;12:207, Mod Pathol 2020;33:1122, J Eur Acad Dermatol Venereol 2013;27:1214)
- Increasing angiogenesis
5 year relative survival rates
- Localized disease: 99%
- Regional lymph nodes involvement: 62.2%
- Metastatic disease: 27.3%
Recurrence rate within 2 years
- 13% (for high risk melanoma) (JAMA Dermatol 2019;155:688)

Case reports

21 year old woman with a cutaneous lesion arising from the scalp (Am J Dermatopathol 2020;42:854)
34 year old man with a giant congenital nevus of the axilla (J Cutan Pathol 2020;47:1164)
61 year old woman with productive cough and chest pain (Medicine (Baltimore) 2017;96:e8772)
67 year old Caucasian woman with a tender subungual nodule (Am J Dermatopathol 2020;42:283)
67 year old man with progressive dysphagia (Am J Case Rep 2015;16:491)
70 year old woman with shortness of breath and wheezing (N Engl J Med 2018;379:e36)
72 year old man presented with a cutaneous lesion on the scalp (BMJ Case Rep 2018;2018:bcr2018224263)
73 year old man presented with a rapidly growing nodule on his lower left lateral thigh (J Cutan Pathol 2020;47:541)
79 year old Caucasian woman with a persistent nodule on her posterior neck and a slowly enlarging mass on the posterior scalp (J Cutan Pathol 2018;45:355)
82 year old man with unusual histopathological presentation (Am J Dermatopathol 2020;42:677)
85 year old man with a grayish nodule on the forehead (Am J Dermatopathol 2021;43:221)

Treatment

Wide surgical excision with safety skin margins according to Breslow depth
- In situ: 0.5 cm safety skin margins
- Breslow depth up to 2 mm: 1 cm
- Breslow depth > 2 mm: 2 cm
Sentinel lymph node biopsy (staging procedure and prognostic value)
Adjuvant / systemic therapy starting from stage III melanomas
- Target therapy (BRAF and MEK inhibitors, KIT inhibitors)
- Checkpoint inhibitors (PD1 / PDL1 inhibitors, CTLA4 blockade)
Chemotherapy
Radiotherapy

Clinical images

Contributed by Michele Donati, M.D.

Superficial spreading melanoma

Nodular melanoma

Invasive acral lentiginous melanoma

Lentigo maligna melanoma

Desmoplastic melanoma

Achromic melanoma

Ugly duckling sign

Hutchinson sign

Blowfly sign

Images hosted on other servers:

Thickened plaques on the nipple

Superficial spreading melanoma

Melanoma in situ

Melanoma in situ: acral lesion with parallel ridge pattern (B)

Melanoma in situ: before and after Imiquimod cream (A, B)

Melanoma in situ

Gross description

Skin ellipse with a lesion on the surface of variable presentation according to the clinical aspect (see Clinical features)

Gross images

Contributed by Michele Donati, M.D.

Superficial spreading melanoma

Invasive acral lentiginous melanoma

Microscopic (histologic) description

Histologic features
- Dimension > 6 mm
- Asymmetry (assessed at scanning magnification)
Epidermal findings / in situ melanoma
- Ill defined border
- Pagetoid melanocytes (single scattered melanocytes, especially in the upper layers of the epidermis)
- Epidermal consumption / ulceration
- Irregular distribution of junctional melanocytes
  - Confluent growth
  - Skip areas
  - Nests of different size
  - Nests of different shape
  - Irregular distribution of nests
  - Confluent nests
  - Discohesive arrangement of melanocytes
Dermal component
- Radial growth phase
  - Invasion of single cells or small nests in the papillary dermis
- Vertical growth phase
  - Early vertical growth phase: dominant nest within the papillary dermis (expansile nest larger than any junctional nests)
  - Complex and asymmetrical growth pattern (irregular nests / fascicles)
  - Expansile growth pattern (sheet-like)
  - Absence of maturation (lack of decreasing size of melanocytes / nests from the top to the base of the lesion)
  - Increased dermal mitotic activity (> 1/mm²)
  - Tumor necrosis
Cytologic features
- Epithelioid / spindle shaped cell
- Nuclear pleomorphism
  - Nuclear enlargement (> 1.5 basal keratinocytes)
  - Nuclear hyperchromasia
  - Coarse irregular chromatin pattern with peripheral condensation ("peppered moth" nuclei) (J Am Acad Dermatol 2016;75:1032)
  - Prominent eosinophilic nucleoli
- Dusty pigmented cytoplasm
Stromal changes
- Variable inflammatory infiltrate (brisk, nonbrisk, absent)
- Dermal fibrosis
- Irregular distribution of pigment
Histological classification
- Superficial spreading melanoma (SSM)
  - Most common subtype
  - Asymmetrical proliferation of atypical melanocytes
  - Predominant junctional single units of melanocytes rather than nests
  - Prominent pagetoid spread (area > 0.5 mm²)
  - BRAF V600E mutation
- Lentigo maligna melanoma (LMM)
  - Elderly patients on chronic sun damaged skin
  - Confluent growth of solitary units of melanocytes along the dermoepidermal junction forming small nests (lentiginous pattern)
  - Confluent horizontal arranged nests of variable size and shape (nevoid / dysplastic-like pattern)
  - Extension into the hair follicles
  - Prominent solar elastosis
  - Dermal invasion of atypical melanocytes
  - BRAF non-V600E, NRAS or KIT mutation
- Acral lentiginous melanoma (ALM)
  - Most common in African Caribbeans and Asians
  - Acral location (palms, soles and subungual)
  - Asymmetrical lentiginous proliferation > 7 mm
  - Melanocytes mainly at the tips of cristae profunda intermedia (Am J Dermatopathol 2011;33:468)
  - Eccrine duct involvement
  - KIT mutation
- Nodular melanoma (NM)
  - No ABCDE rule (see Clinical features)
  - No radial growth phase
  - Junctional component not beyond the dermal component
  - Nodular dermal proliferation of atypical melanocytes
Uncommon variants
- Desmoplastic melanoma (DM)
  - Elderly patients on chronic sun damaged skin
  - Subtle scar-like paucicelluar dermal proliferation of spindle cells
  - May be sarcoma-like pleomorphic spindle cell melanoma with only partial desmoplasia
  - Atypical lentiginous junctional melanocytic proliferation in ~50%
  - Perivascular lymphocytic aggregates
  - Neurotropism
  - May be pure or mixed (associated with conventional melanoma)
    - Pure: 90% or more desmoplastic type
    - Mixed: more than 10% conventional or spindle cell type
  - Pure DM has higher local recurrence but lower regional lymph node involvement (Ann Surg 2010;252:1052)
  - MelanA / MART1, tyrosinase, HMB45 negative
  - NF1, TP53 mutation in ~50%
- Nevoid melanoma
  - Verrucous or doom shaped silhouette
  - Subtle asymmetry
  - No radial growth phase
  - Long thin rete ridges due to stuffed papillae: puffy shirt sign (J Cutan Pathol 2019;46:805)
  - Pseudomaturation
  - High mitotic activity
- Melanoma arising in blue nevus
  - Presence of a pre-existing blue nevus at the periphery
  - High cellular density with no intervening stroma
  - Areas of necrosis
  - BAP1 nuclear loss
  - GNAQ, GNA11, CYSLTR2, EIF1AX mutation
  - BAP1, SF3B1 mutation (secondary event)

Microscopic (histologic) images

Contributed by Michele Donati, M.D.

Asymmetry

Early vertical growth phase

Poorly differentiated melanoma

Nodular melanoma

Confluent nests

Ulceration

Superficial spreading melanoma in situ

Epidermal consumption

Invasive superficial spreading melanoma

Ill defined border

Pagetoid spread

Lentigo maligna melanoma

Atypical melanocytes

Hair follicle involvement

Acral lentiginous melanoma, vertical growth phase

Acral lentiginous melanoma

Desmoplastic melanoma

Perineural invasion in DM

MelanA

S100

Contributed by Jijgee Munkhdelger, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Dermal nodule with prominent pigmentation

Nodular melanoma

Loss of rete ridges

Cutaneous melanoma, HMB45

Metastatic melanoma

Lymph node metastatic melanoma

Contributed anonymously

Regression in melanoma

Tumor infiltrating lymphocytes

Subcapsular lymph node metastasis

Lymphatic invasion

Spindle cell melanoma with mitotic figures

Contributed by Angel Fernandez-Flores, M.D., Ph.D.

Pagetoid extension

Follicular growth

Contributed by Epitomics

PMEL17

Virtual slides

Images hosted on other servers:

Invasive melanoma with regression, H&E

Invasive melanoma, H&E

Invasive melanoma, HMB45

Invasive melanoma, MelanA

Nodular melanoma, H&E

Desmoplastic melanoma, H&E

Desmoplastic melanoma, S100

Desmoplastic melanoma, SOX10

Cytology description

Limitations
- Great variability of cytological presentation
- Can mimic almost any malignant tumor
- Variability in cluster configuration
Cytological features
- Epithelioid, spindle cells or giant cells
- Dispersed and finely granular pigment (may be subtle or obscure other cytological details)
- Variable cell shape and size
- Large irregular nuclei
- Prominent eosinophilic nucleoli
- Nuclear pseudoinclusions
- Melanophages

Cytology images

Contributed by Michele Donati, M.D.

May Grünwald Giemsa smear preparation

Positive stains

S100 (nuclear and cytoplasmic)
SOX10 (nuclear)
MelanA / MART1 (cytoplasmic)
HMB45 (cytoplasmic)
Tyrosinase (cytoplasmic)
MiTF (nuclear)
PRAME (nuclear) (Am J Surg Pathol 2018;42:1456)
PNL2 (cytoplasmic) (Mod Pathol 2003;16:481)
KBA62 (cytoplasmic) (Am J Surg Pathol 2012;36:265)
Ki67 / MIB1 > 10% (benign melanocytic nevi < 2%)

Negative stains

p16 (nuclear loss in melanoma)
Cytokeratin
CD34
LCA marker (CD45)
CD68

Electron microscopy description

Intracytoplasmic melanosomes and premelanosomes
No longer used in clinical practice

Molecular / cytogenetics description

Molecular alterations do not constitute proof of malignancy per se and have to be interpreted in light of the clinical and histological findings
In contrast with benign nevi, melanomas harbor multiple chromosomal copy number aberrations
- Main chromosomal copy number aberrations (detected by FISH, comparative genomic hybridization [CGH], array CGH and single nucleotide polymorphism array)
  - Gain: 6p, 7q, 17q, 20q, 4q, 8q, 1q, 11q
  - Loss: 9p21, 10, 21q
Main genetic driver alterations (detected by PCR, Sanger and next generation sequencing)
- BRAF, NRAS, NF1, KIT (Cell 2015;161:1681)
- Telomerase reverse transcriptase promoter (TERT-p) (Sci Rep 2015;5:11200)
- CDKN2A, PTEN, TP53
Generally high tumor mutational burden (TMB > 10 mut/Mb)
Gene expression profile (GEP), mRNA expression level of uveal and cutaneous melanoma related genes (Cancer Res 2004;64:7205, Clin Cancer Res 2015;21:175):
- PRAME
- S100A9 component
- 8 immune related genes
- 9 housekeeping genes

Molecular / cytogenetics images

Contributed by Petr Šteiner, Ph.D.

MYC amplification

CDKN2A loss

Videos

Melanoma

Superficial spreading melanoma

Acral lentiginous melanoma

Desmoplastic melanoma

Immunohistochemistry

Melanoma in situ

Sample pathology report

Trunk, excisional biopsy:
- Invasive melanoma, superficial spreading melanoma subtype
- Macroscopic: Skin ellipse 1.3 x 0.7 x 0.4 cm. On the surface, elevated darkly pigmented lesion 0.7 x 0.5 cm. The entire lesion submitted.
- Growth phase: vertical
- Breslow depth: 1.6 mm
- Ulceration: absent
- Dermal mitotic rate (mitoses/mm²): 2
- Regression: absent
- Neurotropism: absent
- Lymphatic invasion: absent
- Microsatellites: absent
- Tumor infiltrating lymphocytes (TILs): present (nonbrisk)
- Margin: minimal distance to the nearest peripheral margin 4 mm
- TNM staging: pT2a; N: x; M: x

Differential diagnosis

Differential diagnosis of melanoma may be very broad
Changes according to the histological subtype
Invasive melanoma may mimic any undifferentiated malignancy (Am J Surg Pathol 2021;45:240)
Benign melanocytic nevus and its histological variants:
- Dysplastic nevus:
  - No asymmetry
  - No florid pagetoid spread (< mm² in an area of 0.5)
  - No confluence of expansile nests
  - No epidermal consumption / ulceration
  - Cytological maturation of dermal melanocytes
- Persistent / recurrent nevus:
  - Atypical junctional melanocytic proliferation does not extend beyond the dermal scar
- Melanocytic nevi of special sites:
  - Scalp, ear, skin folders, breast, genital area
  - Variable degree of cytological and architectural atypia (Am J Dermatopathol 2016;38:867)
- Mitotically active nevi (posttrauma, postbiopsy, during pregnancy, halo reaction):
  - Absence of an in situ component
  - No cytological atypia
  - Maturation of dermal melanocytes
  - No atypical mitotic figures
- Spitz tumor:
  - Younger patient
  - Extremities
  - < 6 mm
  - Dermal mitoses < 1/mm²
  - ALK, ROS1 or pan-TRK+
  - ALK, ROS1, NTRK1/3, BRAF or RET fusion
  - No further genomic aberrations
- BAP1 inactivated melanocytic tumor (BIMT):
  - No tumor necrosis
  - Dermal mitoses < 1/mm²
  - BAP1 nuclear loss in the epithelioid component
  - BRAF mutation and BAP1 mutation / loss
- Pigmented epithelioid melanocytoma (PEM):
  - No tumor necrosis
  - Mitoses < 1/mm²
  - BRAF or MAP2K1 mutation and PRKAR1a mutation (combined type)
  - PRKC fusion (pure type)
  - No further genomic aberrations
- Deep penetrating nevus (DPN):
  - No tumor necrosis
  - Mitoses < 1/mm²
  - Nuclear beta catenin+
  - BRAF or MAP2K1 mutation and beta catenin mutation / APC loss
  - No further genomic aberrations
- Cellular blue nevus:
  - No nuclear atypia
  - No tumor necrosis
  - No overlapping nuclei
  - Mitoses < 1/mm²
  - GNAQ, GNA11 or CYSLTR2 mutation
  - No further genomic aberrations
- Metastatic melanoma:
  - Positive personal history of melanoma
  - Absence of lymphocytic infiltrate
  - Absence of junctional component (exceptionally rare epidermotropic metastases)
Nonmelanocytic neoplasms:
- Bowen disease (squamous cell carcinoma in situ):
  - Full thickness epithelial atypia
  - Negative melanocytic markers in pagetoid cells
- Extramammary Paget disease (EMPD):
  - CK7+, CEA+, GCDFP-15+ (primary EMPD)
  - CK20+ (secondary EMPD)
- Merkel cell carcinoma:
  - Neuroendocrine markers (synaptophysin, chromogranin)+
  - CK20+
- Atypical fibroxanthoma / pleomorphic dermal sarcoma:
  - Absence of junctional component
  - SMA+
- Poorly differentiated squamous cell carcinoma:
  - Cytokeratin+, p63+
- Cutaneous leiomyosarcoma (atypical smooth muscle tumor):
  - Absence of junctional component
  - Smooth muscle markers (desmin, SMA, h-caldesmon)+
- Epithelioid angiosarcoma:
  - Subtle atypical vascular spaces form at the periphery
  - Vascular markers (ERG, CD31, CD34)+
- Anaplastic lymphoma:
  - LCA marker (CD45)+

Additional references

Am J Dermatopathol 2019;41:243, Am J Dermatopathol 2019;41:321, N Engl J Med 2017;376:2211, J Cutan Pathol 2009;36:425, BMJ 2017;357:j2813, Nat Rev Cancer 2016;16:345, Nat Genet 2019;51:1123, J Am Acad Dermatol 2019;80:1168, Elder: WHO Classification of Skin Tumours, 4th Edition, 2018

Board review style question #1

A 64 year old man presented with a 1.5 x 0.9 cm pigmented nodule on the trunk. Which is the corresponding histological subtype of melanoma?

Acral lentiginous melanoma
Desmoplastic melanoma
Lentigo maligna melanoma
Nodular melanoma
Superficial spreading melanoma

Board review style answer #1

E. Superficial spreading melanoma. The picture shows the scanning of an invasive superficial spreading melanoma, vertical growth phase. Note the asymmetrical silhouette with a broad junctional component. The broad junctional component allows distinction between superficial spreading melanoma with prominent vertical growth phase and nodular melanoma.

Comment Here

Reference: Invasive melanoma

Board review style question #2

An 82 year old man presented with a 1.2 x 0.7 cm nodular dichromic lesion on the scalp. The patient's personal medical history was unremarkable. Which positive immunostains would confirm the diagnosis of invasive melanoma?

CK and MelanA
Desmin and ERG
MelanA and SMA
S100 and CK
SOX10 and MelanA

Board review style answer #2

E. SOX10 and MelanA. The picture shows a nodular dermal proliferation of highly pleomorphic spindle cells; the main differential diagnosis includes poorly differentiated squamous cell carcinoma, spindle cell melanoma, atypical fibroxanthoma / pleomorphic dermal sarcoma (AFX / PDS), cutaneous leiomyosarcoma and angiosarcoma. Positive stain for SOX10 and MelanA confirms the diagnosis of invasive melanoma.

Comment Here

Reference: Invasive melanoma

Board review style question #3

Which of the following mutations is most commonly observed in acral lentiginous melanoma?

BRAF V600E
KIT
NF1
NRAS
TP53

Board review style answer #3

B. KIT. KIT mutation or amplification is the most common early genomic event observed in ALM. Secondary molecular events include loss of function mutation in key tumor suppressor genes (TP53 and CDKN2A).

Comment Here

Reference: Invasive melanoma

Board review style question #4

Which of the following stains is useful to distinguish melanoma cells from melanocytes?

HMB45
MelanA
PRAME
S100
SOX10

Board review style answer #4

C. PRAME. PRAME is a member of the cancer testis antigen family, normally expressed in testicular germ cells and occasionally placenta. It is present in a variety of cancers and is useful to support a diagnosis of melanoma, since positive stain is expected in melanoma but not in benign melanocytic nevi.

Comment Here

Reference: Invasive melanoma

Lentigo

Table of Contents

Definition / general

Benign melanocytic proliferation due to sun exposure (Br J Dermatol 2007;156:1214, eMedicine)
Multiple lesions, often poorly circumscribed

Terminology

Also called solar lentigines, age spots

Epidemiology

Sun exposed skin of elderly (90% of whites age 60+); also truck drivers on sun exposed face (J Dermatol 2008;35:146)
Multiple large solar lentigos on upper back and shoulders suggest prior severe sunburn, a risk factor for melanoma (Dermatology 2007;214:25)
PUVA (psoralen + ultraviolet A) treatment for psoriasis cause numerous solar lentigines with atypia; similar findings after severe radiation exposure (Arch Dermatol 1997;133:209)

Clinical features

Macular hyperpigmentation
Often > 1 cm
"Ink spot lentigo" variant: small, darkly pigmented, stellate

Treatment

Laser (J Am Acad Dermatol 2006;54(5 Suppl 2):S262)
Intense pulsed light (Dermatol Surg 2007;33:449)
Cryotherapy
Trichloroacetic acid (J Eur Acad Dermatol Venereol 2008;22:316)

Dermoscopy

Sharply demarcated border and fingerprint like structures

Clinical images

Images hosted on other servers:

Back lesions

Pre and post laser treatment

Microscopic (histologic) description

Elongation of rete ridges and increased pigmentation at tips of retes; pigmentation may be irregular
Also solar elastosis, telangiectasia, variable chronic inflammatory infiltrate in dermis

Differential diagnosis

Actinic keratosis
Lentigo maligna melanoma: clusters of MelanA+ cells at dermoepidermal junction, versus scattered for solar lentigo (J Cutan Pathol 2008;35:931)
Macular seborrheic keratosis: thicker lesion, horn cysts / pseudocytes and on continuum with solar lentigo

Lentigo maligna melanoma

Table of Contents

Definition / general

Subtype of melanoma arising on chronically sun damaged skin and appearing as an irregular pigmented macule, corresponding to an intraepidermal proliferation of atypical melanocytes; over time, may develop foci that are indurated, papular or nodular, indicating tumorigenic growth (Am J Pathol 1969;55:39)
Lentigo maligna (LM) typically refers to the in situ form of this disease, while lentigo maligna melanoma (LMM) designates invasive disease (JAMA Dermatol 2019;155:782)

Essential features

Presents as a flat, growing, irregularly pigmented lesion on chronically sun damaged skin, which may develop a raised, papular or nodular focus, indicating tumorigenic growth
Microscopically, a proliferation of intraepidermal melanocytes overlying solar elastosis and exhibiting crowded growth along the basal epidermis; irregular distribution of nests and effacement of epidermal rete with or without an underlying dermally invasive component
Immunohistochemistry for melanocytic markers (MelanA / MART1, SOX10, MITF, HMB45) may assist in identification of diagnostic architectural features and may distinguish the lesion from mimics
Prognosis is correlated with presence and depth of invasion, mitotic rate among invasive cells and presence / absence of ulceration
Prognosis is excellent if noninvasive and completely excised
Treatments: excision (gold standard), adjuvant topical therapies and radiation (adjuvant / unresectable setting)

Terminology

Chronic sun damage (CSD) associated melanoma
Hutchinson melanotic freckle

ICD coding

ICD-10:
- D03.9 - melanoma in situ, unspecified
- C43.9 - malignant melanoma of skin, unspecified

Epidemiology

Older patients, usually over 50 (Annu Rev Pathol 2014;9:239)
Develops at sites of chronic, continuous, cumulative sun exposure

Sites

Face, neck, ears, scalp (if not shielded by hair), forearms, dorsal hands

Pathophysiology

Acquisition of oncogenic genetic mutations by chronic ultraviolet light exposure (Annu Rev Pathol 2014;9:239)
Flat, spreading, pigmented radial growth phase eventually gives rise to invasive, tumorigenic vertical growth phase with metastatic potential

Etiology

Chronic ultraviolet light exposure

Clinical features

Growing, irregularly pigmented lesion on chronically sun damaged skin
Development of a raised, papular or nodular focus indicates tumorigenic / vertical growth phase
Reference: Am J Pathol 1969;55:39

Diagnosis

Skin exam revealing classic features, as described above
Dermoscopy
- Asymmetric hyperpigmented follicular openings, pigmented rhomboidal structures, annular granular pattern (J Am Acad Dermatol 2000;42:25, Br J Dermatol 2012;167:280)
- Pseudonetwork and homogeneous areas (Clin Cosmet Investig Dermatol 2019;12:403)
Biopsy with diagnostic histopathologic features, as described below

Prognostic factors

Lentigo maligna (melanoma in situ of lentigo maligna type)
- Excellent prognosis after excision if no invasive component (Br J Dermatol 2014;171:1605)
Lentigo maligna melanoma (malignant melanoma of lentigo maligna type)
- Controlling for other parameters (depth, ulceration, etc.); prognosis overlaps that of other melanoma subtypes
- Poor prognostic factors include greater Breslow depth (distance from granular zone to deepest invasive melanoma cell), presence of ulceration, high mitotic rate, presence of microsatellite, satellite or in transit metastases, positive sentinel node and distant metastases (e.g., lung, liver, brain) (CA Cancer J Clin 2017;67:472)

Case reports

70 year old woman with a gradually enlarging pigmented macule on her face (Dermatology 2016;232:24)
76 year old man with an evolving pigmented lesion on the occipital scalp (J Cutan Pathol 2020;47:1155)
85 year old man with a pigmented right malar lesion (An Bras Dermatol 2017;92:565)

Treatment

Complete excision, accomplished via wide local excision, staged surgical excision or Mohs micrographic surgery (Dermatol Surg 2011;37:1210)
Excisions may utilize staged Mohs micrographic surgery (slow Mohs) with rush processing, examination of surgical margins and closure upon report of negative margins
Mohs surgeons may also utilize frozen sections with melanocytic immunohistochemistry for margin assessment (J Am Acad Dermatol 2021;84:196)
For in situ disease, topical therapies (including imiquimod) may be useful in the adjuvant setting or as primary treatment if unresectable (J Am Acad Dermatol 2015;72:1047)
Radiotherapy (Radiat Oncol 2020;15:174)
Consideration of sentinel lymph node biopsy (CA Cancer J Clin 2017;67:472)

Clinical images

Contributed by Julia Nunley, M.D.

Lentigo maligna involving forearm

Images hosted on other servers:

Asymmetric
and irregularly
pigmented
macule

Microscopic (histologic) description

Proliferation of intraepidermal (single and nested) melanocytes overlying solar elastosis
Melanocytes demonstrate crowded growth along the basal epidermis
Associated epidermal alterations, including loss (effacement) of epidermal rete and associated irregular epidermal hyperplasia
Pagetoid scatter (melanocytes above the basal layer)
Involvement of adnexal epithelium
Melanocytic cytology is variable, ranging from small cells with dark nuclei and scant cytoplasm to epithelioid pigmented melanocytes, to spindled melanocytes
Invasive component, if present, consists of single or nested melanocytes in the dermis with similar cytologic features to those in the in situ component (Cancer Res 1969;29:705, Am J Pathol 1969;55:39)

Microscopic (histologic) images

Contributed by Joseph Gillam, M.D., Jennifer Crimmins, M.D. and Mark Mochel, M.D.

Broad intraepidermal proliferation of melanocytes

Crowded, atypical intraepidermal melanocytes

Atypical intraepidermal melanocytes

Broad compound proliferation of melanocytes

Dermal nests with fibrosis

SOX10 highlighting pagetoid growth

Positive stains

Immunohistochemistry for MelanA / MART1, SOX10 and MITF may assist in diagnosis by highlighting the arrangement of melanocytes in the epidermis and by assisting in identification of dermally invasive cells (Am J Dermatopathol 2014;36:387, Am J Dermatopathol 2014;36:124)

Negative stains

Cytokeratins and p63

Molecular / cytogenetics description

Activating BRAF mutations are less common than in superficial spreading (nonchronic sun damage) melanomas (N Engl J Med 2005;353:2135)
Of cases with BRAF mutations, many are non-V600E (e.g., V600K) (Clin Cancer Res 2012;18:3242)
High tumor mutation burden (Cells 2021;10:2320)
Genetic alterations identified (Annu Rev Pathol 2014;9:239):
- Inactivating mutations of NF1
- Activating mutations of NRAS
- Copy number increase of CCND1
- Activating mutations of KIT
- TP53 and TERT mutations

Sample pathology report

Skin, right temple, biopsy:
- Melanoma in situ, lentigo maligna type (see comment)
- Comment: Sections reveal a poorly circumscribed intraepidermal proliferation of atypical melanocytes with crowded growth along the basal epidermis, irregular distribution of nests and pagetoid scatter.

Differential diagnosis

Lentigo:
- While intraepidermal melanocytes within a lentigo are increased in number, these melanocytes will lack nesting, crowding at the basal layer (contiguity) and pagetoid ascent of melanocytes
Melanocytic hyperplasia of sun damaged skin:
- Lacks nesting, crowding at the basal layer (contiguity) and pagetoid ascent of melanocytes (Am J Dermatopathol 1996;18:560)
Dysplastic nevus:
- On skin with chronic sun damage (indicated by significant solar elastosis), this diagnosis should be made with extreme caution
- Lesions with features of atypical / dysplastic / Clark nevus in this setting have a high likelihood of representing melanoma or melanoma in situ (J Cutan Pathol 2005;32:405)
Squamous cell carcinoma in situ:
- Shares pagetoid ascent of atypical cells with melanoma in situ / lentigo maligna; in contrast to melanoma in situ, does not form rounded nests below the basal layer, is composed of polygonal cells with eosinophilic cytoplasm and tends to show suprabasilar confluence, leaving a residual distinctive layer of native basal epidermal keratinocytes (eyeliner sign) (J Cutan Pathol 2018;45:734, J Cutan Pathol 2016;43:24)
- Immunohistochemical stains can be utilized in challenging cases
  - p63+
  - MelanA / MART1-, SOX10-

Board review style question #1

A 76 year old retired chemist with light skin presents with a pigmented lesion on his right cheek. Physical examination reveals a 1.5 x 1.0 cm tan to brown macule with irregular borders. A biopsy is performed. What is the diagnosis?

Dysplastic nevus
Lentigo maligna
Solar lentigo
Squamous cell carcinoma in situ

Board review style answer #1

B. Lentigo maligna

Comment Here

Reference: Lentigo maligna melanoma

Board review style question #2

Which of the following behaviors represents the greatest risk factor for the development of this lesion, photographed above (H&E and MelanA)?

Decades of midday yardwork
Electronic cigarette use (vaping)
Rare ethanol consumption
Workplace exposures to organic chemicals

Board review style answer #2

A. Decades of midday yardwork

Comment Here

Reference: Lentigo maligna melanoma

Malignant Spitz tumor (Spitz melanoma)

Table of Contents

Definition / general

Spitz nevi are composed of epithelioid to spindled melanocytes with abundant homogeneous cytoplasm and large vesicular nuclei; they often display epidermal hyperplasia, clefts around and between melanocytes, Kamino bodies and maturation with descent
The current classification of Spitz tumor includes:
- Benign Spitz nevi (SN)
- Atypical Spitz nevus / tumor (AST) as tumor of intermediate malignant potential
- Spitz melanoma (SM)

Essential features

Spitz tumor refers to the spectrum of melanocytic tumors with histopathologic features of Spitz nevus that ranges from benign to malignant
They may be challenging to classify as benign or malignant because histopathologic features that are commonly taken as indicators of malignancy (e.g., nuclear atypia, scatter of melanocytes in the upper epidermis, poor maturation within the dermis, deep extension and deep dermal mitoses) are commonly seen in Spitz tumors with benign biologic behavior
WHO 2018 guideline differentiates Spitz versus spitzoid as follows: Spitz lesions are associated with at least a single specific genetic alteration (HRAS mutation, fusions in ROS1, ALK, NTRK1, NTRK3, MET and RET) and spitzoid lesions are lesions with morphological resemblance to Spitz nevi
First described by Sophie Spitz in 1948 as melanomas of childhood

Terminology

Spitzoid melanoma, malignant Spitz melanoma, spitzoid lesions

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified

Epidemiology

Though initially named as juvenile melanomas, Spitz tumors occur in individuals of all ages with the mean age of Spitz melanoma of 55 years in a 54 patient study (J Am Acad Dermatol 2014;71:1077)
A study on the yearly incidence of Spitz nevi, atypical Spitz tumor and Spitz melanoma in the Netherlands between 1999 - 2014 demonstrated that the yearly incidence of Spitz nevi increased from 525 to 751 cases during this period; atypical Spitz tumor from 9 to 153 cases; Spitz melanoma from 8 to 40 cases (Br J Dermatol 2020;183:1121)
Spitz melanoma occurs in all races, though the majority of Spitz melanoma cases have been reported in white patients (Pediatr Dermatol 2020;37:1073, Br J Dermatol 2019;181:366)
WHO 2018 classification mentions a higher prevalence in men for Spitz melanoma; however, in other studies Spitz melanoma appears to exhibit a relatively equal distribution between sexes, though this conclusion could be limited by sample size (J Am Acad Dermatol 2014;71:1077, Am J Dermatopathol 2017;39:181)

Sites

Almost all Spitz tumors occur in patients < 20 years old; older patients, particularly those > 20 or 30 years old, have a greater likelihood of malignancy (Clin Dermatol 2009;27:564)
Spitz tumors commonly affect the extremities and face but atypical Spitz tumors may also, less frequently, affect other areas such as the back (J Am Acad Dermatol 2011;65:1073)
Distribution of Spitz melanoma tends to be as follows: 50% located on the lower extremities, 22.2% located on the trunk, 20.4% the upper extremities and 7.4% the head and neck (J Am Acad Dermatol 2014;71:1077)

Pathophysiology

Pathogenesis and etiology of Spitz melanoma are unknown; discovery of kinase translocations and other mutations alludes to potential pathways involved in their pathogenesis
Kinase fusions lead to a loss of a 3’ regulatory domain resulting in a constant activation of the kinase domain portion of the fusion, which is likely responsible for cellular proliferation in these lesions (Am J Surg Pathol 2019;43:538)
Translocations include those involving ROS1, ALK, RET, BRAF, NTRK1, MET and NTRK3

Etiology

Unknown at this time

Diagnosis

Clinical and histopathologic characteristics are the gold standard in diagnosing Spitz lesions
Ancillary studies including immunohistochemistry (IHC), array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) may be helpful for borderline lesions, such as atypical Spitz tumor, where ancillary studies can contribute to assessing malignant potential (Mod Pathol 2020;33:1122)

Prognostic factors

Spitz melanoma has a poor prognosis compared with atypical Spitz tumor and Spitz nevi
Prognosis of Spitz melanoma compared with melanoma is unclear
Older age appears to correspond with negative outcomes
5 year survival rate for children < 10 years old is 88% and for children 11 - 17 years old is 49%
Spitz melanoma with MAP3K8 kinase rearrangements may present with more advanced disease than those without
References: JAMA Dermatol 2013;149:283, Hum Pathol 1998;29:1105, Cancer 2007;109:1579, Am J Surg Pathol 2019;43:1631

Case reports

4 year old girl presented with multiple recurrent papules and inguinal lymphadenopathy diagnosed as metastatic Spitz tumor (Australas J Dermatol 2018;59:e234)
7 year old girl presented with a 12 mm nodule on the anterior right ankle and a 9 year old boy presented with a 14 mm nodule on the anterior left thigh diagnosed as ALK positive Spitz tumor (J Cutan Pathol 2018;45:136)
13 year old boy, 26 year old woman and 72 year old woman presented with melanocytic neoplasms with a spitzoid cytomorphology, variable nuclear atypia and harboring undescribed fusions involving RASGRF1 (Am J Surg Pathol 2022;46:655)
42 year old woman presented with a 1 cm sized, small brown macule on her right temple diagnosed as Spitz melanoma after a primary diagnosis of breast cancer (Ann Dermatol 2022;34:76)

Treatment

No current consensus guidelines exist for the management of Spitz melanoma but given the resemblance to melanoma, the majority of clinicians perform a biopsy, especially in older patients (JAMA Dermatol 2013;149:1348)
Excision is typically recommended to avoid recurrence and common practice is to re-excise a lesion with positive margins
Sentinel lymph node biopsy may be recommended
With the advent of a defined Spitz melanoma as a molecularly separate entity from conventional melanoma and the low incidence of recurrence / relapse associated with Spitz melanoma, treatment of Spitz melanoma may not require the same aggressive treatment protocol currently utilized in melanoma management (Melanoma Manag 2015;2:121)
Ipilimumab, a monoclonal antibody to CTLA4 receptor and PD-1, is efficacious in treating advanced melanoma

Gross description

Clinically, Spitz melanomas are usually evolving amelanotic nodular lesions and can grow to a diameter of ≥ 1 cm; they can often go clinically undiagnosed because of their wide range of clinical appearances and a lack of pigmentation
Spitz melanoma is typically larger than atypical Spitz tumor, with a mean of 1.05 cm, however, Spitz melanoma < 6 mm can also be seen
Spitz melanoma tumors are more likely to be nodular than Spitz nevi but can also present as flat lesions
Spitz melanomas exhibit a wide range of color, with 80% containing red / pink, 53.3% containing dark brown, 35.7% containing gray and 33.3% containing light brown
References: J Am Acad Dermatol 2014;71:1077, J Am Acad Dermatol 2018;78:278, J Am Acad Dermatol 2015;72:47

Microscopic (histologic) description

According to WHO 2018 guidelines, compared with Spitz nevi, Spitz melanomas are much larger (> 1 cm) and like atypical Spitz tumor, they show asymmetry, irregular nesting patterns, lack of maturation, poor circumscription, ulceration, increased mitotic rate (> 6 mm²) and deep or atypical mitoses (Am J Dermatopathol 2012;34:478, Pathology 2002;34:6)
These lesions also display high rates of cytological atypia
Some Spitz melanomas retain histopathologic features of Spitz nevi, including loss of p16 in those with HRAS mutations, fascicular melanocyte nests and increased dermal mitoses in those with ALK fusions and dermal rosette-like structures in those with NTRK1 fusions (Mod Pathol 2020;33:1122)
Spitz melanomas with MAP3K8 fusions exhibit similar morphology to atypical Spitz tumor with MAP3K8 mutations, including epithelioid morphology, high grade cytologic atypia, multinucleated giant cells and p16 loss (Virchows Arch 2022;480:369)

Microscopic (histologic) images

Contributed by Shyam Raghavan, M.D.

Atypical melanocytic proliferation

Spindle and epithelioid melanocytes

Irregular nests

Mitotic figures

Positive stains

Compared with melanoma (where usually the Ki67 proliferation index is > 10% of melanocytes), Spitz melanoma tends to have a high and diffuse expression throughout the entire lesion and like other melanomas, tends to display a higher proliferative index (> 10% of melanocytes) (Front Med (Lausanne) 2018;5:344)
Staining pattern of HMB45 to distinguish Spitz nevus from Spitz melanoma, as Spitz nevus displays a progressively diminished HMB45 staining pattern; atypical Spitz tumor displays either diminished or variable staining in the dermis; deep staining of the dermis is common in Spitz melanoma
Combinations of different IHC stains may assist in algorithmically differentiating between Spitz nevi, atypical Spitz tumor and Spitz melanoma, and supplement histopathological differential diagnoses
It has been proposed that if IHC of a lesion displays deep dermal cell proliferation through Ki67 in association with complete loss of p16 or HMB45, the lesion is less likely a Spitz nevus and more likely Spitz melanoma / atypical Spitz tumor; this staining pattern should prompt additional molecular investigations (Mod Pathol 2016;29:656)

Molecular / cytogenetics description

HRAS mutations can be present in both Spitz nevi and Spitz tumors and are associated with a good clinical outcome (Am J Pathol 2000;157:967)
ROS1 translocations are present in up to 17% of Spitz nevi or atypical Spitz tumor; Spitz melanoma usually does not have this translocation
BRAF mutations exclude a diagnosis of Spitz tumor but these lesions can have a translocation in this gene as the driver oncogenic event
MAPK activating mutations identified in Spitz melanoma and spitzoid melanoma

Videos

Spitz nevi and spitzoid melanocytic lesions

Sample pathology report

Skin, right forehead, biopsy:
- Malignant Spitz tumor

Differential diagnosis

Spitz nevus:
- More common in children and young adults
- < 1 cm, symmetrical with sharply demarcated borders, no deep extension, rare mitoses, Kamino bodies
Atypical Spitz nevus:
- Mostly in adults
- > 1 cm, asymmetrical with irregular lateral borders, expansile nodule with deep extension, frequent mitoses, no Kamino bodies
- Low Ki67 nuclear staining

Additional references

Chan: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Front Oncol 2022;12:889223, J Case Rep Images Pathol 2020;6:100039Z11CJ2020

Board review style question #1

Which of the following is an important histological feature of Spitz melanoma that differentiates it from Spitz nevi?

Absence of cytological atypia
Asymmetry
Well circumscribed lesion
Well differentiated

Board review style answer #1

B. Asymmetry. Spitz melanomas are differentiated from Spitz nevi on the basis of asymmetry, lack of maturation, poor circumscription, ulceration, increased mitotic rate as well as high rates of cytological atypia.

Comment Here

Reference: Malignant Spitz tumor (Spitz melanoma)

Board review style question #2

Which of the following mutations is seen in Spitz melanoma but not in superficial spreading melanoma?

BRAF fusion
BRAF mutation
NF1 mutation
NRAS mutation

Board review style answer #2

A. BRAF fusion

Comment Here

Reference: Malignant Spitz tumor (Spitz melanoma)

Melanocytic hyperplasia

Table of Contents

Definition / general | Terminology | Case reports | Microscopic (histologic) description | Differential diagnosis

Definition / general

Controversial topic
May coexist with benign nevi (Mod Pathol 2000;13:857)
May occur on foot or on sun damaged skin (Arch Dermatol 1994;130:1042, J Dermatol 2007;34:56)
Chronic sun exposure leads to 2× increase in melanocyte density, often with aytpia (J Am Acad Dermatol 2011;65:1186)

Terminology

Also called atypical melanocytic proliferation or benign atypical junctional melanocytic hyperplasia

Case reports

64 year old woman with esophageal squamous cell carcinoma in situ (Virchows Arch 2000;437:203)

Microscopic (histologic) description

Atypical single unit melanocytes limited to epidermis, often seen at periphery of classic melanoma
In contrast to melanoma in situ, exhibits only focal confluence at dermoepidermal junction, has limited pagetoid spread and involves only upper hair follicle
Factors favoring atypical melanocytic hyperplasia over melanoma in situ (Mod Pathol 2000;13:857):
- No lateral spread
- No upward extension into epidermis
- No finely granular, "smoky" melanin
- No marked cytologic atypia
- No mitotic figures
- No host inflammatory fibrotic response

Differential diagnosis

Melanoma in situ (Am J Dermatopathol 1996;18:560)
Pseudomelanocytic nests in lichenoid reactions (Am J Dermatopathol 2009;31:305)

Melanoma arising in giant congenital nevus

Table of Contents

Definition / general

Malignant tumors arising from melanocytes in pre-existing, benign melanocytic nevi of skin (e.g., giant congenital melanocytic nevi) (Br J Dermatol 2017;176:1131)

Essential features

Malignant tumors arising from melanocytes in pre-existing congenital nevus (Br J Dermatol 2017;176:1131)
Presents in childhood or early adulthood (Br J Dermatol 2017;176:1131)
Identification of benign melanocytic nevus, which is clinically present since birth, in the background (StatPearls: Congenital Melanocytic Nevi [Accessed 8 May 2023])
Risk of development of melanoma depends largely on size of congenital nevus and is directly proportional to increase in size (StatPearls: Congenital Melanocytic Nevi [Accessed 8 May 2023], J Am Acad Dermatol 2013;68:441)
Aggressive tumor contributing to the majority of deaths due to skin cancers (Br J Dermatol 2017;176:1131, Int J Mol Sci 2022;23:5911)
Poor prognosis

Terminology

Malignant melanoma in congenital nevus
Historically called melanose and fungoid disease (Melanoma Res 2012;22:114)

ICD coding

ICD-O: 8761/3 - malignant melanoma in giant pigmented nevus
ICD-10: C43.9 - malignant melanoma of skin, unspecified

Epidemiology

Higher risk of malignant change is reported in women; F:M = 14.1:6.4
Incidence of malignant change in large congenital nevi is reported to range from 3.8 to 18%
Malignant change mostly occurs before puberty and has also been reported at birth
Giant congenital nevi are associated with neurocutaneous melanosis in 3 - 15% of cases; this is associated with significantly higher risk of primary CNS melanoma
Primary CNS melanoma accounts for ~33% of melanoma occurring in patients with giant congenital nevi (Br J Dermatol 2017;176:1131)
Risk of melanoma development is exceedingly low in small to medium sized congenital nevi
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Sites

Trunk and legs are the most common sites for congenital melanocytic nevi, followed by head and neck, feet and hands; melanoma can arise in any of these locations
Risk of malignant transformation is strikingly higher in axial lesions
Central nervous system (CNS) / leptomeningeal melanomas arise in settings of neurocutaneous melanosis / congenital nevus syndrome
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Pathophysiology

Somatic gene mutations involving mitogen activated protein kinase (MAPK) pathways (mainly NRAS) lead to the formation of congenital melanocytic nevi during in vitro period (StatPearls: Congenital Melanocytic Nevi [Accessed 8 May 2023], StatPearls: Congenital Nevus [Accessed 8 May 2023])
Additional mutations and copy number alterations lead to development of malignant change in congenital nevi (Br J Cancer 2017;116:990)

Etiology

Melanoma can occur de novo or develop on a pre-existing nevus, known as melanoma arising in nevus
Melanomas arise through either cumulative sun damage pathway or noncumulative sun damage pathway; melanomas arising in congenital nevi belong to the latter category (Annu Rev Pathol 2014;9:239, Arch Pathol Lab Med 2020;144:500)

Clinical features

Malignant change is usually associated with congenital nevi, which are giant / large or multiple; congenital nevi are present since birth and are usually heavily pigmented, hairy and cover significant surface area of skin (StatPearls: Congenital Nevus [Accessed 8 May 2023])
The following changes are possible indications of the malignant change in congenital nevi
- Appearance of new nodule in pre-existing congenital nevus (Br J Dermatol 2017;176:1131)
- Surface ulceration
- Variation in pigmentation
- Rapid increase in size of the lesion
Local lymphadenopathy due to metastasis (Br J Dermatol 2017;176:1131)
Signs of neurocutaneous melanosis include seizures, cranial nerve dysfunctions, hydrocephalus and endocrine abnormalities (StatPearls: Congenital Nevus [Accessed 8 May 2023])
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Diagnosis

Histopathological diagnosis following surgical excision is the gold standard (Br J Dermatol 2017;176:1131)
Molecular testing may aid in diagnosis (Br J Dermatol 2017;176:1131)

Radiology description

MRI is the modality of choice for CNS screening in settings of congenital nevus syndrome / neurocutaneous melanosis and is currently the best predictor of all adverse outcomes in children
Those with a normal scan are in a low risk group for all complications independent of the rest of their clinical phenotype (Br J Dermatol 2017;176:1131)
Abnormal MRI is an indicator of a higher burden of mutated cells in the body (Br J Dermatol 2017;176:1131)

Prognostic factors

Prognosis largely depends upon stage of tumor at the time of diagnosis (Int J Mol Sci 2022;23:5911)
Younger age, female gender, extremities as primary site, early tumor stage and brisk tumor infiltrating lymphocytes are linked with favorable prognosis (Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019)
Older age, male gender, high risk sites (head and neck, trunk and acral sites), high tumor stage, increased Breslow thickness, nodal metastasis, absent or nonbrisk tumor infiltrating lymphocytes, surface ulceration, neurotropism, microsatellite nodules and high mitotic rate are associated with poor prognosis (An Bras Dermatol 2018;93:19, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019)

Case reports

19 month old boy and 57 month old girl with neurocutaneous melanosis in association with large congenital nevi (Front Neurol 2019;10:79)
3 year old boy with melanoma arising in giant congenital nevus (J Craniofac Surg 2021;32:e342)
12 year old girl with melanoma arising in giant congenital melanocytic nevus (Diagn Cytopathol 2020;48:564)
34 year old man with a giant congenital nevus of the axilla (J Cutan Pathol 2020;47:1164)
46 year old man with multicentric melanoma in giant congenital melanocytic nevus (Dermatol Surg 2003;29:99)

Treatment

Surgical excision is the standard treatment approach for cutaneous disease; sentinel lymph node assessment for staging and prognostic purposes is usually carried out (Br J Dermatol 2017;176:1131)
Management of leptomeningeal melanoma involving the spine is mainly palliative as excision is not possible in these cases (Br J Dermatol 2017;176:1131)
- Chemotherapy
- Radiotherapy
- Targeted therapy includes BRAF inhibitors, MEK inhibitors, KIT inhibitors, PD-1 / PDL1 inhibitors and CTLA4 inhibitors
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Clinical images

Contributed by Anila Chughtai, M.B.B.S.

Nodular ulcerated mass in CMN

Multiple congenital melanocytic nevi

After excision of malignant growth

Gross description

Skin ellipse / excision specimens with pigmented lesion on the surface
Surface ulceration is usually present
Lesion can be of variable sizes
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Microscopic (histologic) description

Benign melanocytic nevus can be identified in background of malignant proliferation
Malignant proliferation / melanoma exhibits the following morphological features
- Epidermal ulceration is commonly present
- Architectural asymmetry is evident with either radial growth phase or vertical growth phase
  - Radial growth phase comprises growth predominantly along the dermoepidermal junction with lateral spread and only small nests or individual cells in superficial dermis
  - Vertical growth phase comprises growth predominantly occupying dermis in form of large dermal nest and expansile sheet-like areas
- Atypical melanocytes show irregular distribution at dermoepidermal junction (confluent growth alternating with skip area)
- Junctional melanocytic nests show significant variation in size
- Singly scattered melanocytes in the superficial part of the epidermis (pagetoid spread)
- Atypical melanocytes can be round, epithelioid or spindle shaped with prominent nuclear pleomorphism, nuclear hyperchromasia, prominent nucleoli and irregular distribution of melanin pigment
- Absence of maturation
- Increased dermal mitotic activity (> 1/mm²) with atypical mitotic figures
- Tumor necrosis might be present
- Tumor infiltrating lymphocytes can be seen (brisk / nonbrisk / absent)
Evidence of lymph node metastasis is usually present at the time of first clinical presentation
Primary CNS melanoma in settings of congenital melanocytic nevi (CMN) can present either as solid tumors within the brain parenchyma or as leptomeningeal lesions (Br J Dermatol 2017;176:1131)
Leptomeningeal melanosis shows diffuse proliferation of melanin producing cells in leptomeninges which exhibits minimal cellular atypia and usually no brain parenchymal invasion
- Transformation to leptomeningeal melanoma is documented on the basis of unequivocal brain parenchymal invasion or cytological atypia (Br J Dermatol 2017;176:1131)
References: Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Microscopic (histologic) images

Contributed by Anila Chughtai, M.B.B.S.

Dermal based proliferation of atypical melanocytes

Architectural arrangement of melanoma

Architectural arrangement of background nevus

Background nevus cell around sebaceous units

Cellular features of melanoma cells

Brisk mitotic activity

Tumor necrosis

Variable pigmentation

Epidermal consumption

Tumor infiltrating lymphocytes

Nonbrisk tumor infiltrating lymphocytes

Brisk tumor infiltrating lymphocytes

Melanoma metastasis to lymph node

S100 stain

HMB45 stain

MelanA stain

Cytology description

Clusters and individually scattered cells with nuclear pleomorphism, prominent nucleoli, nuclear pseudoinclusions and coarse cytoplasmic blackish brown pigment (variable, can be absent)
Limitation: cytological findings can be subtle and can mimic other malignant tumors
Reference: Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020

Cytology images

Contributed by Anila Chughtai, M.B.B.S.

Diff-Quik stained smear

Papanicolaou stained smear

Cytoplasmic melanin pigment

Cell block preparation

HMB45 stain on cell block

MelanA stain on cell block

Positive stains

S100
SOX10
MITF
MelanA / MART1
HMB45
Tyrosinase
PRAME
PD-1 / PDL1
Ki67 / MIB1 > 10% (benign melanocytic nevi < 2%)
References: Am J Surg Pathol 2018;42:1456, Int J Mol Sci 2022;23:5911, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Negative stains

H3K27me3 (nuclear loss in up to 50 - 80% of tumor cells)
p16 (nuclear loss in melanoma)
Cytokeratin
CD34
CD45
References: Int J Mol Sci 2022;23:5911, Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019

Electron microscopy description

Intracytoplasmic melanosomes (ORL J Otorhinolaryngol Relat Spec 1975;37:233)

Molecular / cytogenetics description

Melanoma harbors KIT, PTEN, TERT-p, CDKN2A, TP53 and NRAS mutations (Cell 2015;161:1681)
BRAF mutations have not been described in melanoma arising in congenital nevi (Br J Dermatol 2017;176:1131)
Copy number abnormalities (loss or gain of part of or whole chromosome) are commonly documented in melanoma arising in settings of congenital nevi (Br J Cancer 2017;116:990)

Videos

Melanocytic dermpath basics: melanoma

Sample pathology report

Lesion, right arm, excisional biopsy:
- Malignant melanoma arising in background of congenital nevus
- Macroscopic:
  - Received elliptical skin excision specimen (4.3 x 3.7 x 2.4 cm) with ulcerated pigmented nodular lesion (3.1 x 2.5 cm). Representative sections of the lesion are taken along with margins.
- Microscopy:
  - Sheet and confluent nests of atypical melanocytes with enlarged pleomorphic nuclei having prominent eosinophilic nucleoli, eosinophilic cytoplasm, brisk and abnormal mitotic activity. Cytoplasmic melanin pigment is identified. Necrosis and epidermal ulceration are seen. Pagetoid spread to epidermis is noted. Benign melanocytic nevus is seen at the periphery of malignant proliferation. Tumor infiltrating lymphocytes are noted and are brisk. Resection margins are free.
- Details of morphological prognostic parameters are as follows
  - Ulceration: present
  - Growth phase: vertical
  - Breslow depth: 3.8 mm
  - Dermal mitotic rate (mitoses/mm²): 3
  - Microsatellites: absent
  - Regression: absent
  - Neurotropism: absent
  - Lymphatic invasion: absent
  - Tumor infiltrating lymphocytes (TILs): present (brisk)
  - Margin: all margins are free with closest being free by 2.0 cm
  - TNM staging: pT3; pNx; pMx

Differential diagnosis

Proliferating nodule (Elder: Lever's Histopathology of the Skin, 11th Edition, 2014, Calonje: McKee's Pathology of the Skin, 5th Edition, 2019):
- Proliferating nodules can mimic melanoma arising in congenital melanocytic nevus
- Proliferating nodules exhibit large melanocytes with conspicuous nucleoli (however, nucleoli are not prominent), rare mitotic activity (< 1/mm²), no abnormal mitosis, no necrosis, no pagetoid spread, rare epidermal involvement
- Proliferating nodules merge with adjacent nevus cells while malignant melanoma usually exhibits sharp delineation
- Melanocytes in proliferation nodules retain nuclear expression of H3K27me3 stain while melanoma cells show nuclear loss
- PRAME stain is positive in melanoma
- Proliferating nodules exhibit HMB45 expression in only the superficial part of the lesion while melanoma shows its expression in the superficial as well as in the deeper part of the lesion
- Melanoma harbors BRAF, KIT, PTEN, TERT-p, CDKN2A, TP53 mutations in addition to the NRAS mutation, which is commonly seen in proliferating nodules (Cell 2015;161:1681)

Board review style question #1

A 21 year old man presented with a new lump that appeared in previously known congenital nevus. The histopathology features of the nodule are shown in the photograph. Which of the following immunohistochemical stains would help differentiate proliferating nodule from melanoma?

H3K27me3
HMB45
MelanA / MART1
S100
SOX10

Board review style answer #1

A. H3K27me3. The majority of melanoma cells show nuclear loss of H3Kme3 IHC stain while it is retained in proliferating nodule as well as in background nevus cells. Answers B, C, D and E are incorrect because HMB45, MelanA, S100 and SOX10 IHC stains will be positive in both benign proliferating nodules and melanoma; therefore, these will not help in differentiation.

Comment Here

Reference: Melanoma arising in giant congenital nevus

Board review style question #2

Which of the following morphological features is the most important in determining prognosis of malignant melanoma arising in congenital nevi?

Breslow thickness
Necrosis
Pagetoid spread to epidermis
Surface ulceration
Tumor regression

Board review style answer #2

A. Breslow thickness. Breslow thickness is the most important morphological parameter that helps determine pathological stage of the tumor and ultimately prognosis. Answers B, C, D and E are incorrect because while tumor necrosis, pagetoid spread, surface ulceration and tumor regression are all important parameters and add significant prognostic value, Breslow thickness is the most important parameter out of all others.

Comment Here

Reference: Melanoma arising in giant congenital nevus

Melanomas with unusual features (balloon cell, verrucous, signet ring cell, small cell, etc.)

Table of Contents

Definition / general

Rare forms of melanoma that account for < 1% of cases (Curr Opin Oncol 1993;5:364)

Essential features

Melanoma can present with rare and unusual histomorphological forms (variants) that account for < 1% of cases
Morphological peculiarities do not always translate to a worsening prognosis
Appropriate histological description and immunohistochemical markers allow us to reach a precise and detailed diagnosis of unusual forms of melanoma
It is essential to consider the differential diagnoses of particular forms of melanoma

Terminology

Balloon cell melanoma (Dermatopathology (Basel) 2022;9:100)
Rhabdoid melanoma (Int J Clin Exp Pathol 2014;7:840)
Verrucous melanoma (Open Access Maced J Med Sci 2017;5:547)
Signet ring cell melanoma (Pathol Int 2015;65:383)
Small cell melanoma (Dermatopathology (Basel) 2019;6:231)
Myxoid melanoma (Clin Exp Dermatol 2013;38:559)
Osteogenic melanoma (Skeletal Radiol 2018;47:711)
Dedifferentiated / undifferentiated melanoma (Dermatopathology (Basel) 2021;8:494)

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified
ICD-11
- 2C30.Y - other specified melanoma of skin
- 2C30.Z - melanoma of skin, unspecified

Epidemiology

Middle aged to elderly persons
No sex predilection (Int J Clin Exp Pathol 2014;7:840)

Sites

Balloon cell: choroid (14%) and other locations
Melanoma with rhabdomyosarcomatous differentiation: metastatic setting (lymph nodes, soft tissue, liver) more common than primary cutaneous (scalp, trunk, extremities) (Int J Clin Exp Pathol 2014;7:840)
Verrucous: more common in face and limbs
Signet ring cell: metastatic setting more common than primitive
Small cell, 2 forms
1. Develops in large congenital nevus
2. Develops in children, de novo, on the scalp
Myxoid: metastatic more common than primary mucocutaneous (skin, nasal sinuses, conjunctiva, gastrointestinal system)
Osteogenic: more common on acral skin and nail bed; occasional mucosal involvement

Clinical features

Balloon cell (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
- Usually pigmented lesion on the extremities
- Clinical features not different from common melanoma
- Nodular, polypoid, papillated lesions
- Clinical appearance not influenced by cytological alterations
Rhabdoid
- No distinctive clinical features for either primary cutaneous or metastatic lesions
Verrucous (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
- Resembles a keratotic epidermal tumor such as squamous cell carcinoma (SCC), seborrheic keratosis (SK), keratoacanthoma (KA) or others
Signet ring cell
- More frequent in metastatic setting
- No distinctive clinical findings
- Usually very thick (Pathol Int 2015;65:383)
Small cell (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
- First form: core of a large congenital nevus
- Second form: de novo, children, on the scalp, rapidly fatal
- Possible metastatic setting
Myxoid (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
- Myxoid variant of melanoma is more likely to be metastastic than primitive, although usually primitive melanoma is common
- Primitive forms are very rare
Osteogenic
- Some cases related to potential trauma (Mod Pathol 2006;19:S41)
Dedifferentiated / undifferentiated
- Nonspecific

Diagnosis

Excisional biopsy
Incisional biopsy
Shave or punch biopsy with adequate breadth and depth

Case reports

28 year old man with asymptomatic pink lesion on his arm (Dermatol Pract Concept 2017;7:59)
32 year old woman with a lesion in the left lumbar region (Case Rep Oncol 2016;9:262)
32 year old man with a right thumb lesion (Skeletal Radiol 2018;47:711)
57 year old man with enlarging nodule arising from a congenital nevus on the right flank (Pathol Int 2015;65:383)
64 year old man with metastatic rhabdoid melanoma (Indian J Cancer 2020;57:473)
79 year old woman with a pigmented, raised lesion (Dermatopathology (Basel) 2021;8:494)
Woman with a verrucous keratotic lesion on the right thigh (Open Access Maced J Med Sci 2017;5:547)

Microscopic (histologic) description

Balloon cell
- Melanocytes with abundant and finely vacuolated cytoplasm, scattered dusty melanin granules (Dermatopathology (Basel) 2022;9:100)
- Nuclei are pleomorphic with occasional prominent nucleoli
- Mitoses are rare, something found only in hot areas
- Frequent involvement of the dermis and subcutis
Rhabdoid
- Rhabdoid cells have plasmacytoid appearance, round to oval contour and large amounts of cytoplasm with refractive, deeply eosinophilic material (Int J Clin Exp Pathol 2014;7:840)
- Nuclei are crescent or round shaped, disposed polar to the cytoplasm against the cellular membrane
- Hyperchromatism, pleomorphism, high mitotic rate and single cell necrosis are frequent
Verrucous
- Striking epidermal and adnexal hyperplasia with thickened epidermis, dyskeratotic cells, squamous eddies and keratotic cysts (Cureus 2022;14:e29098)
- Strikingly atypical proliferation of melanocytes at the junction and in the dermis
- Rare pagetoid spread
Signet ring
- Large cells containing a big roundish cytoplasmic vacuole (Am J Dermatopathol 2014;36:985)
- Nuclei seem to be pushed against the cell membrane, with a crescent shaped silhouette
Small cell
- 2 variants: small cells, so called non-Merkel tumor-like cell variant and large cells, Merkel cell tumor-like variant (Dermatopathology (Basel) 2019;6:231)
- Small or barely visible cytoplasm with hyperchromatic nucleus with coarse chromatin
- Cells are atypical and mitoses are easily found
- No maturation as the lesion goes deeper
- Monotonous cells
- Pigment is usually rare and focal
Myxoid
- Dendritic or stellate melanocytes scattered in abundant mucinous material
- Large nuclei and irregularly clumped nuclear chromatin (J Am Acad Dermatol 2002;46:264)
- Rare mitoses in myxoid background
- Scarce melanin
Osteogenic (osseocartilaginous differentiation)
- Atypical melanocytes with chondroid or osteoid metaplasia (J Am Acad Dermatol 2002;46:264)
Dedifferentiated / undifferentiated
- Pleomorphic, atypical cells, with numerous mitotic figures; nuclei with thinned chromatin and numerous central and peripheral nucleoli (Am J Surg Pathol 2021;45:240)

Microscopic (histologic) images

Contributed by Gerardo Cazzato, M.D., Ph.D.

Melanocytes with clear / balloon cytoplasm

Balloon cell with atypia

Rhabdoid melanocytes within necrosis

Rhabdoid melanocytes with mitoses

Striking atypical melanocytic proliferation

Melanoma with pseudo-epitheliomatous hyperplasia

Images hosted on other servers:

Signet ring cell melanoma

Small cell melanoma

Myxoid melanoma

Positive stains

Balloon cell
- S100, HMB45: diffusely and strongly positive but also MelanA and SOX10 (Dermatopathology (Basel) 2022;9:100)
- MITF usually positive, also PRAME (Diagn Cytopathol 2017;45:828)
Rhabdoid
- S100, HMB45: diffusely and strongly positive (rare cases negative for both); consistent expression of vimentin and sometimes, desmin
- Sometimes aberrant expression of cytokeratin (CK), SMA and synaptophysin
- SOX10
- PRAME usually positive (Dermatopathology (Basel) 2022;9:148)
Verrucous
- Usually same as conventional melanoma
- SOX10
- Usually MITF and PRAME positive
Signet ring cell
- S100: diffusely and strongly positive (rare cases S100 negative), variable immunostaining with HMB45
- SOX10
- Sometimes MITF positive
Small cell
- Usually same as conventional melanoma
- SOX10
Myxoid
- S100, MelanA, vimentin positive in almost all cases, variable expression of HMB45
- SOX10
Osteogenic
- S100 almost always positive
- SOX10
- MITF positive

Negative stains

Rhabdoid
- MelanA usually negative
- Most cases negative for MITF
Dedifferentiated / undifferentiated
- Almost all negative (Am J Surg Pathol 2021;45:240)
- Usually MITF and PRAME negative

Molecular / cytogenetics description

Dedifferentiated / undifferentiated: detection of a melanoma compatible gene mutation, such as BRAF or NRAS, aids in diagnosis (Am J Surg Pathol 2021;45:240)

Videos

Rhabdoid melanoma

Small cell melanoma

Sample pathology report

Limb skin, excisional biopsy:
- Melanoma with rhabdoid cell features (see comment)
- Comment: Sections of skin and subcutis including a proliferation of cells with a plasmacytoid appearance, characterized by round / oval outlines and large amounts of cytoplasm containing eosinophilic material with a glassy hyaline but sometimes filamentous appearance. The cell nuclei (hyperchromatic, pleomorphic) are crescent shaped or round and arranged polar to the cytoplasm against the cellular membrane.

Differential diagnosis

Balloon cell
- Balloon cell nevus:
  - Symmetrical, usually papillated, small, round melanocytes and roundish, small, monomorphous nuclei
  - No mitosis, atypia
- Renal cell carcinoma (RCC):
  - Clear cells arranged in solid sheets with a delicate branching vasculature
  - Carbonic anhydrase IX, CD10 positive
- Clear cell sarcoma:
  - Much deeper and balloon cells are without the vacuoles
  - S100 positive such as balloon cell melanoma
- Xanthoma:
  - No atypia, histiocytes
- Liposarcoma:
  - Lipoblasts
- Eccrine acrospiroma:
  - Different cellular components
- Atypical fibroxanthoma (AFX):
  - Pleomorphic cells, negative for melanocytic markers
- Granular cell tumor (GCT)
  - Cells with abundant, granular cytoplasm with occasional neurotropism
Rhabdoid
- Rhabdomyosarcoma:
  - Cells with rhabdoid morphology, usually positive for skeletal muscle markers
- Rhabdoid renal tumor metastatic to the skin
- Rhabdoid ovarian tumor metastatic to the skin
- Malignant peripheral nerve sheath tumor (MPNST), epithelioid variant:
  - Positive for EMA and synaptophysin
  - Different clinical setting
  - S100 and vimentin can be positive
- Malignant form of primitive neuroectodermal tumor (PNET):
  - NSE and CD99 positive
  - S100 and vimentin can be weakly positive
  - Rhabdoid features only focal
- Rhabdoid appearance of carcinoma:
  - CK strongly expressed
Verrucous
- Carcinoma or other epithelial neoplasms:
  - Different immunohistochemistry
- Spitz nevus with pseudocarcinomatous hyperplasia:
  - More nests of melanocytes than sheets
  - No atypia
  - No mitotic figures
Signet ring cell
- Primitive cutaneous or metastatic signet ring carcinoma
- Liposarcoma:
  - Lipoblasts; absence of real signet ring cell
- Lymphoma:
  - Lymphoid cells, positive for CD45 LC and other lymphocytic markers
- Squamous cell carcinoma
- Basal cell carcinoma
- Epithelioid hemangioma
- Hemangioendothelioma
Small cell
- Lymphoma:
  - Lymphoid cells, positive for CD45 LC and other lymphocytic markers
- Merkel cell carcinoma
- MPNST
- Small cell metastatic carcinoma
- PNET
- Neuroblastoma
- Proliferative nodule in children
Myxoid
- Malignant
- Benign
  - Mucinosis:
    - Different background; no cells
  - Melanocytic nevi with mucinous change
  - Myxoid schwannoma
  - Neurofibroma
  - Chondroid syringoma
Osteogenic
- Nevi with metaplastic changes
- MPNST with osteochondroid metaplasia
Dedifferentiated / undifferentiated
- Carcinomas:
  - Different lineage of cells; variable positivity for epithelial markers
- High grade sarcomas:
  - Different lineage of cells; molecular biology necessary
Reference: Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014

Board review style question #1

A 61 year old man with a history of melanoma of the right preauricular region presents with right lateral cervical swelling. Which of the following statements is true regarding this entity?

Clinical features are pathognomonic
S100 and HMB45 are almost always positive
S100 is usually negative
This lesion is usually primary cutaneous

Board review style answer #1

B. S100 and HMB45 are almost always positive. Despite the morphological peculiarities of rhabdoid melanoma, immunohistochemical investigations for neuroectodermal markers, such as S100 protein and HMB45, are almost always invariably positive and help the pathologist in the correct differential diagnosis with other entities of striated muscle lineage. Rhabdoid melanoma can present with widespread and strong positivity for vimentin and sometimes for desmin, while usually MelanA is negative. Answer A is incorrect because rhabdoid melanoma doesn't have any clinical pathognomonic features. Answer C is incorrect because S100 is usually positive, not negative. Answer D is incorrect because the metastatic setting is more common than primary cutaneous setting in case of rhabdoid melanoma.

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Reference: Melanomas with unusual features

Board review style question #2

What are the characteristics that allow a differential diagnosis between balloon cell melanoma and balloon cell nevus?

Melanin
Mitoses, large nuclei, distinct and large nucleoli, architecture of the neoplasm and intraepidermal pagetoid scatter of balloon cells
Percentage of balloon cell component
Positivity for MelanA

Board review style answer #2

B. Mitoses, large nuclei, distinct and large nucleoli, architecture of the neoplasm and intraepidermal pagetoid scatter of balloon cells. It is important to remember that the parameters used in the differential diagnosis of common forms of melanoma are the same as with unusual and rare forms of melanoma; therefore, in differentiating a balloon cell melanoma from a balloon cell nevus, it is essential to rely on the criteria we know. Answer D is incorrect because positivity for MelanA is not useful for a differential diagnosis. Answer A is incorrect because presence of melanin is not a criterion. Answer C is incorrect because the percentage of melanocytes with balloon cell appearance is useful for the diagnosis of a balloon cell lesion but not in distinguishing a nevus from a melanoma.

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Reference: Melanomas with unusual features

Melanotic macule

Table of Contents

Definition / general

Melanotic macule is a benign hyperpigmented lesion predominantly involving the mucosa or acral (volar) skin
Due to basilar hyperpigmentation of the mucosa or the epidermis
Typically no increase in the number of melanocytes (mild melanocytic hyperplasia occasionally)
No relation to sun exposure (except for ink spot lentigo) (Oral Surg Oral Med Oral Pathol 1976;42:196)

Essential features

Prominent basal layer melanin hyperpigmentation without an increase / minimal increase in the number of melanocytes
Sporadic or rarely associated with syndromes or diseases

Terminology

Mucosal melanotic macule; mucosal lentigo
Based on location:
- Genital melanotic macule; vulvar melanosis; penile melanotic macule
- Oral melanotic macule; melanotic macule of oral mucosa; labial melanotic macule
- Volar melanotic macule (on the palms and soles)
- Ungual melanotic macule (nails)
Based on etiology:
- Ink spot lentigo with reticulated pattern on the skin due to sun exposure (Arch Dermatol 1992;128:934)
- PUVA (psoralen and UVA therapy) lentigines / melanotic macules on the skin as a side effect of PUVA treatment (J Am Acad Dermatol 1983;9:47)

ICD coding

ICD-10:
- L81.4 - other melanin hyperpigmentation
- L81.8 - other specified disorders of pigmentation

Epidemiology

Genital melanotic macule:
- 0.01% of dermatologic patients
- No racial predilection
- Both sexes (F:M = 3.1:1)
- May affect all ages
- Average age of onset (41 years) is younger than that for genital melanoma (J Am Acad Dermatol 2017;76:836)
Vulvar melanosis:
- 68% of pigmented vulvar lesions in the reproductive age group
- 67% of lesions occur in premenopausal women (J Am Acad Dermatol 1990;22:104, JAMA Dermatol 2020;156:1185)
Oral melanotic macule:
- 3% of the general population
- Second most common (30.8%) solitary pigmented lesion of the oral mucosa after amalgam tattoo
- 14% with family history; more common in the white population (60.9%); more common in females (74.1%) (Head Neck 2021;43:3775)
Congenital melanotic macule of the tongue: rare; might be more frequent in dark skinned patients (Pediatr Dermatol 2015;32:109, Ann Dermatol Venereol 2008;135:567)

Sites

Vulva:
- Mucosal surfaces more often than skin
- Labia minora is the most common vulvar site (Arch Dermatol 2008;144:1030, JAMA Dermatol 2020;156:1185)
Penis: the glans is the most common location (J Am Acad Dermatol 2000;42:640, J Cosmet Dermatol 2022;21:3308)
Oral mucosa: the vermilion border of the lower lip is the most common location, followed by gingiva, then buccal mucosa and palate (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112:e21)
Volar: found on palms, fingers, soles or toes in dark skinned individuals (Am J Dermatopathol 2008;30:612)
Congenital melanotic macule of the tongue:
- Rare
- Solitary or multiple dark macules present since birth with proportional growth
- On the dorsum of the tongue
- No family history or associated systemic conditions (Pediatr Dermatol 2015;32:109)

Pathophysiology

Unclear
Hypermelaninosis (increase in melanin pigmentation) without or occasionally slight increase in melanocyte number
May be due to increased melanocytic activity (Oral Dis 1999;5:80)

Etiology

Sporadic
Post sun exposure
- Ink spot lentigo: rete ridges appear less blunted and more tortuous (eMedicine: Lentigo Workup [Accessed 27 November 2022])
Postradiotherapy
- PUVA: increased melanocytes, atypia, elongated rete ridges with increased pigmentation in basal cell region (eMedicine: Lentigo Workup [Accessed 27 November 2022])
Syndromic
- Melanotic macules and multiple lentigines (systemic conditions)
  - Addison disease
    - Endocrinal disorder, most common cause is autoimmune and tuberculosis (Contemp Clin Dent 2012;3:484)
    - Generalized hyperpigmentation, hyperpigmentation of mucosa and skin, hyponatremia, hypokalemia, GI upset, anorexia, nausea, vomiting, diarrhea (J Assoc Physicians India 2001;49:523, The Open Dermatology Journal 2009;3:3, J Clin Endocrinol Metab 2001;86:2909)
  - Peutz-Jeghers syndrome
    - Inherited condition
    - Hamartomatous polyps in GI tract, increased risk of cancer and mucocutaneous hyperpigmentation (Cancer.Net: Peutz-Jeghers Syndrome [Accessed 20 November 2022])
  - Carney complex
    - Also known as NAME (nevi, atrial myxomas, ephelides) and LAMB (lentigines, atrial myxoma, blue nevi)
    - Most common skin lesions are lentigines, epithelioid type blue nevi, combined nevi, café au lait macules and depigmented lesions
    - Also associated with myxomas, thyroid cancer, acromegaly, psammomatous melanotic schwannoma, etc. (GeneReviews: Carney Complex [Accessed 28 November 2022])
  - LEOPARD syndrome or Noonan syndrome with multiple lentigines
    - Lentigines (flat brown macules), electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness
    - Autosomal dominant disorder, caused by missense mutation in PTPN11 gene (eMedicine: LEOPARD Syndrome [Accessed 20 November 2022])
  - Laugier-Hunziker syndrome (LHS)
    - Rare benign acquired condition occurs frequently among middle aged women
    - Manifests as single or multiple lenticular hyperpigmented macules (2 - 5 mm) and longitudinal melanonychia (50% of patients)
    - Most common sites of macules are labial (particularly the lower lip), oral (especially buccal mucosa), acral and genital (World J Clin Cases 2018;6:322)
    - Dermoscopy of labial lesions in LHS: parallel furrow pattern with multiple brown dots; multiple brown or blue-gray granular patterns (Arch Dermatol 2007;143:631, Dermatol Surg 2010;36:152)

Diagrams / tables

Images hosted on other servers:

Diseases and syndromic associations

Clinical features

Asymptomatic
Genital:
- Multifocal (> 50%)
- < 5 cm (> 50% are < 1.5 cm)
- Homogenous or irregular pigmentation (brown to black)
- One study (small sample size) showed 15% associated with a personal history of melanoma (Arch Dermatol 2008;144:1030, J Am Acad Dermatol 2017;76:836)
Oral: solitary; well circumscribed; 6 - 10 mm; brown to black (Head Neck 2021;43:3775)

Diagnosis

Clinical examination:
- Genital melanosis: a thorough total body skin examination to rule out occult melanoma (J Am Acad Dermatol 2017;76:836)
- Diffuse or multiple mucocutaneous pigmented macules: careful clinical examination and clinically relevant investigations to rule out associated syndromes
Dermoscopy:
- Labial lesions in LHS: parallel furrow pattern with multiple brown dots; multiple brown or blue-gray granular patterns (Arch Dermatol 2007;143:631, Dermatol Surg 2010;36:152)
- Vulvar melanosis: ring-like, structureless, globular-like, parallel, cobblestone-like and reticular-like or combined patterns (Arch Dermatol 2008;144:1030)
Biopsy:
- Oral melanotic macule: histological confirmation is necessary as any oral pigmented lesion is considered melanoma until proven otherwise

Laboratory

Laboratory tests typically not required; in patients with features suggestive of syndromic / systemic disease association, pertinent lab tests should be performed

Prognostic factors

Excellent with no malignant transformation

Case reports

Hispanic infant boy with a congenital hyperpigmented macule of the tongue (Cureus 2020;12:e11475)
28 year old woman with lingual melanotic macule (An Bras Dermatol 2018;93:310)
64 year old woman with a pigmented lesion of the marginal gingiva (Med Buccale Chir Buccale 2017;23:156)

Treatment

No treatment is required

Clinical images

Images hosted on other servers:

Labial melanotic macule

Congenital melanotic macules of the tongue

Labial melanotic macule in LHS

Dermoscopy in LHS

Microscopic (histologic) description

Increased basal keratinocyte pigmentation
Mostly restricted to tips of rete ridges
Dendrites are short and delicate
- Coarse dendrites reaching to the upper epidermis are worrisome for early melanoma in situ
Melanin pigment incontinence and melanophages in the lamina propria or upper dermis
No increase in the melanocyte number (occasionally a very mild increase in melanocytes at the dermoepidermal junction may occur but typically have no atypia and lack confluence)
- Rare cells above the DEJ can be seen but only with immunohistochemistry
- More epithelioid and somewhat atypical melanocytes may be seen in vulval and penile melanotic macules (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
Associated frequent acanthosis, hyperkeratosis, hyperparakeratosis, spongiosis and elongated rete ridges (in nonoral lesions) (World J Clin Cases 2018;6:322)

Microscopic (histologic) images

Contributed by Khaled Sabry Mohamed, M.D. and Priya Nagarajan, M.D., Ph.D.

Volar skin melanotic macule

Mucosal melanotic macule

Vulvar melanotic macule

Mucosal melanotic macule

Positive stains

SOX10 / S100 / HMB45 / MelanA / MART1 show normal / minimally increased melanocytic density
PRAME: false positive in rare subungal melanotic macules (Am J Dermatopathol 2022;44:499)

Videos

Labial melanotic macule
(brown spot on lip)

Sample pathology report

Lip, biopsy:
- Melanotic macule (see comment)
- Comment: Sections show increased basilar pigmentation at the tips of rete ridges. Mild acanthosis and dermal melanophages are present. No significant increase in melanocytes is noted.

Differential diagnosis

Melanoma in situ:
- Increase in irregularly scattered melanocytes restricted to the epidermis / mucosa
- Confluence of melanocytes or presence of pagetoid spread
- Melanocytes are atypical, epitheliod / spindled, pleomorphic, with eosinophilic or purple nucleoli (Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
- Coarse melanin granules may be seen
- Heavy lymphoplasmacytic infiltrate
Melanoma:
- Prominent atypical lentiginous melanocytes and often nested pattern of melanocytic hyperplasia with the atypical melanocytes invading the dermis
- Dermal mitosis present
- Pigment is not only restricted to basal layer but haphazardly distributed
Acquired mucosal nevus:
- Has junctional, compound and intramucosal nevi types (BMJ Case Rep 2013;2013:bcr2013010191)
- Presence of nested melanocytes without atypia
Lentiginous nevus:
- Also known as jentigo
- Rare melanocytic nests and melanocytic hyperplasia towards the edges
Lentigo simplex:
- Increased melanocytes at the basal layer and epithelial hyperplasia
- Pigmentation of the rete ridges
Solar lentigo:
- Solar elastosis and bulb-like elongation of the rete ridges
- Mild increase in melanocytes at the tips of rete ridges, giving dirty sock appearance
Ephelis:
- No increase in melanocytes, diagnosis is usually clinical, appears during summer and fades in winter
- Increased pigmentation (darkness of pigment increases with sun exposure)
Oral melanoacanthoma:
- Pigmented, spongiosis and interspersed dendritic melanocytes (J Med Case Rep 2009;3:11)
- Lack of melanocytic proliferation at the dermoepidermal junction but proliferation of dendritic melanocytes scattered throughout spinous layer present
Amalgam tattoo:
- Due to dental silver fillings that may be implanted into the mucosa during dental procedure (PLoS One 2018;13:e0207026)
- Dark brown to black or fine golden to dark brown granules deposited in the dermis
Smoker's melanosis:
- Benign pigmentation of the oral mucosa, on anterior mandibular gingiva and interdental papillae
- Adult onset and lesion continues to darken (J Periodontol 1991;62:524)
Racial pigmentation / physiologic pigmentation:
- Macular pigmented areas of varying shapes and sizes
- Shows increased melanin within the basal epithelial layer and melanin incontinence within the superficial lamina propria (Dermatol Ther 2010;23:220)
Drug induced pigmentation:
- Antineoplastic (imatinib); antimalarials (the second most common); antibiotic (minocycline); antifungal (ketoconazole); antiretroviral; antimycobacterial (clofazimine) (Patient Prefer Adherence 2020;14:1961)
  - Patterns of histologic abnormalities are drug specific
  - Features such as hyperpigmentation of the basal cell layer, pigment incontinence within the dermis and accumulation of pigment laden macrophages around blood vessels and eccrine glands often seen (eMedicine: Drug-Induced Pigmentation Workup [Accessed 20 November 2022])
Postinflammatory hyperpigmentation:
- Acquired excess of pigment in various conditions (infection, drugs, inflammatory diseases and others)
- Epidermal postinflammatory hyperpigmentation: increased melanin pigment in the basal cell layer of the epidermis
- Dermal postinflammatory hyperpigmentation: melanin pigment in the upper dermis, with pigment incontinence
  - Increased numbers of melanophages in the papillary dermis (eMedicine: Postinflammatory Hyperpigmentation Workup [Accessed 20 November 2022])

Additional references

eMedicine: Oral Nevi Workup [Accessed 10 August 2022]

Board review style question #1

A biopsy of the vulvar pigmented macule of a 42 year old patient shows basilar hyperpigmentation with no nest formation. SOX10 immunostain was performed and shows no increase in melanocytes. What is the best classification for this lesion?

Invasive melanoma
Melanoma in situ
Melanotic macule
Mucosal nevus

Board review style answer #1

C. Melanotic macule

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Reference: Melanotic macule

Board review style question #2

Which of the following syndromes has associated melanotic macules?

Brooke-Speigler syndrome
Laugier-Hunziker syndrome
Netherton syndrome
Nevoid basal cell carcinoma syndrome

Board review style answer #2

B. Laugier-Hunziker syndrome

Comment Here

Reference: Melanotic macule

Metastatic melanoma

Table of Contents

Definition / general

Metastatic melanoma is the spread of melanoma beyond the primary site of disease (cutaneous or noncutaneous primary melanoma)
Melanoma can metastasize to the skin or to sites beyond the skin / subcutaneous fat, including lymph nodes, soft tissue / bone compartments and visceral organs

Essential features

Presence of histologically confirmed deposit(s) of melanoma beyond the primary site of disease
Confirmation of diagnosis may require ancillary tests including immunohistochemistry and molecular studies
Clinical correlation is required to ascertain relationship to the culprit primary tumor (in the setting of in transit / satellite cutaneous metastases) or the possibility of a regressed primary tumor (metastatic melanoma of occult primary)

Terminology

In transit melanoma metastasis, epidermotropic melanoma, satellitosis / microsatellitosis

ICD coding

ICD-O: 8720/6 - melanoma metastatic to the skin / melanoma metastatic to other organs
ICD-11: 2E2Z & XH4846 - malignant neoplasm metastasis, unspecified & malignant melanoma, NOS

Epidemiology

Age and gender distributions reflect those of the primary melanoma site and type

Sites

Cutaneous sites of metastasis are commonly within the vicinity of a primary tumor on the scalp and limbs (Am J Dermatopathol 2010;32:129, J Surg Oncol 2019;119:232)
Common noncutaneous sites of melanoma metastasis are lymph nodes, lung, liver, central nervous system and bone (J Clin Oncol 1983;1:126)
Less frequent metastatic sites include intestines, pancreas, gallbladder, kidney, adrenals and thyroid gland
Primary uveal melanoma has a propensity to metastasize to liver (Arch Ophthalmol 2005;123:1639)

Pathophysiology

Arises as lymphatic, hematogenous or perineural spread from the primary site of disease (J Invest Dermatol 2002;119:705, Cancer Med 2018;7:583)
Driver mutations of oncogenesis at the cutaneous primary site of disease, including BRAF (40 - 50%), NRAS (20 - 30%) and NF1 (10%), are also present within the metastatic deposit, with additional genetic abnormalities that contribute to tumor progression (J Transl Med 2019;17:289, Pathology 2016;48:147, Cancer Metastasis Rev 2016;35:93)

Etiology

May develop in anyone with a primary invasive melanoma (of cutaneous or noncutaneous site)
More likely in patients with thick cutaneous melanoma (≥ 1.0 mm T2 - 4) than thin (< 1 mm T1) (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018, CA Cancer J Clin 2017;67:472)

Clinical features

Most commonly presents as a palpable lymph node in the draining nodal basin from the primary site of disease (CA Cancer J Clin 2017;67:472)
May arise as a solitary metastasis or multifocal disease
Can be diagnosed in patients who have no known prior melanoma and no clinically detected culprit primary lesion on thorough clinical examination (occult primary), due to complete regression of the primary melanoma (J Surg Oncol 2019;119:232)

Diagnosis

Clinical examination and radiological investigation of suspected sites of disease, including the use of modalities such as computed tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI) (J Surg Oncol 2019;119:232)
Histological assessment is required for definitive diagnosis, obtained through biopsy techniques or surgical excision (J Surg Oncol 2019;119:232)

Laboratory

Serum lactate dehydrogenase (LDH), S100B or melanoma inhibitory activity (MIA) protein testing is not required or recommended for screening or diagnosis of metastatic melanoma (Surg Oncol Clin N Am 2011;20:181)

Radiology description

Involved lymph nodes can have an irregular hypoechoic and lobulated appearance on ultrasound
When combined with computed tomography, positron emission tomography (PET / CT) is the most sensitive modality for detection of metastatic deposits (Clin Radiol 2011;66:224)
MRI is more sensitive for detection of cerebral metastases than CT alone (J Neurooncol 1999;44:275)

Radiology images

Images hosted on other servers:

Visceral organ masses

Pleural mass with effusion

Axial CT enhancing lesions

Prognostic factors

Prognosis is dependent on stage of disease, number of sites involved, disease burden and primary melanoma site (cutaneous versus noncutaneous) (CA Cancer J Clin 2017;67:472)
Metastasis to the regional lymph node basin (5 year survival stage III: 77%) has a better prognosis than visceral organ involvement (5 year survival stage IV: 27%)
Tumor biology, including driver mutations and the tumor inflammatory microenvironment, may alter outcomes and predict response to therapies (Front Immunol 2021;12:663495)

Case reports

39 year old man with metastatic melanoma to the parietal cortex (CA Cancer J Clin 2020;70:78)
46 year old man with multiorgan involvement by metastatic melanoma (World J Clin Cases 2022;10:10136)
55 and 57 year old women and 84 year old man with melanoma with divergent differentiation, presenting as sarcoma (Pathologica 2022;114:217)
57 year old man with solitary lung nodule (J Med Case Rep 2021;15:347)
67 and 69 year old men with metastatic melanoma to the gastrointestinal tract (Int J Surg Case Rep 2023;103:107907)

Treatment

Solitary metastases can be treated by complete surgical resection
Isolated limb perfusion / infusion with chemotherapeutic agents can be used for multiple in transit metastases (Ann Surg Oncol 2016;23:2330)
Macroscopic lymph node involvement may be managed with regional lymph node dissection, with longterm control in 50% of patients (Ann Surg Oncol 2014;21:292)
Patients with extensive stage III or IV disease may be treated with systemic therapies, including targeted therapy with BRAF / MEK inhibitors or immunotherapies that target PD1 and CTLA4 immune checkpoints (N Engl J Med 2014;371:1867, N Engl J Med 2015;373:23)
Unresectable cutaneous, subcutaneous or nodal metastases can be treated with intralesional talimogene laherperepvec (T-VEC), an engineered oncolytic herpesvirus that induces a local and systemic immunological antitumor response and can be used in combination with systemic therapies (Cancers (Basel) 2021;13:1383)

Clinical images

Images hosted on other servers:

Melanoma in transit metastases

Satellite metastasis melanoma

Gross description

Numerous and distinct dermal or subcuticular nodules, seen either within 2 cm (satellite) or beyond 2 cm (in transit) of the primary tumor without appreciable connection (needs to be confirmed microscopically) (Ann Surg Oncol 2018;25:2105)
Cutaneous, nodal or visceral deposits may be circumscribed, poorly defined or encapsulated and may show pigmentation (brown discoloration), hemorrhage or evidence of necrosis

Gross images

Contributed by Alison Potter, M.B.B.S.

Numerous cutaneous melanoma deposits

Microscopic (histologic) description

Within skin, are often well circumscribed nodules within the dermis or the subcutis
Display overt malignant melanocytic features, including cytological atypia, pleomorphism, sheet-like growth and proliferative activity
Cytomorphology is frequently similar to that seen in the primary tumor; however, there can be variation or dedifferentiation at the metastatic site (Histopathology 2012;61:889)
Presence of an intraepidermal component does not exclude a metastatic deposit, as up to 10% of cutaneous metastasis can show epidermotropism (Am J Dermatopathol 2010;32:129, Histopathology 2018;72:472, Am J Surg Pathol 1994;18:1140)
Microsatellites (0.05 - 0.1 mm) are confirmed microscopic foci of metastasis, which are most likely lymphovascular in nature (Histopathology 2012;61:889)
Satellites occur within 2 cm of the primary lesion and in transit melanoma > 2 cm from the primary tumor, often towards the draining nodal basin; cutaneous deposits at a distant site from a culprit primary are considered stage IV disease
Metastasis within the lymph node most frequently involves the nodal sinus and can extend into parenchyma, show extracapsular extension or complete node replacement (Eur J Cancer 2009;45:2736, J Clin Oncol 2004;22:3345)
Isolated tumor cells within a lymph node are classified as nodal disease, stage III (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018, CA Cancer J Clin 2017;67:472)
- SOX10 and S100 immunohistochemistry highlights nerve fibers, with S100 detecting interdigitating dendritic cells within normal lymph node
Metastases in visceral organs form solid expansile nodules or infiltrate in a nondestructive pattern around native structures; perivascular (peritheliomatous) accentuation of tumor growth can be noted, especially in intracranial metastases (Angiogenesis 2020;23:27, J Cutan Pathol 2019;46:570)
Dedifferentiated and undifferentiated melanoma can occur, whereby cytomorphological and immunohistochemical features of melanoma are lost
- Thorough sampling and immunohistochemical investigation is required
- Identification of a transition between conventional and undifferentiated components can aid in establishing the correct diagnosis (Am J Surg Pathol 2021;45:240)

Microscopic (histologic) images

Contributed by Alison Potter, M.B.B.S.

Intracranial metastasis, peritheliomatous pattern

Small bowel submucosal deposit

Splenic metastasis

Gallbladder polyp

Cutaneous metastasis

Epidermotropism in cutaneous metastasis

Lymph node metastasis, pigmented melanoma

Metastatic melanoma and tumoral melanosis

In transit metastasis within skin

In transit metastasis in lymphatics

Dedifferentiated melanoma axilla

Dedifferentiated component

Conventional melanoma transition to dedifferentiated

Dedifferentiated melanoma with SOX10

Dedifferentiated melanoma with HMB45

Dedifferentiated melanoma with MelanA

Dedifferentiated melanoma with BRAF V600E

Virtual slides

Images hosted on other servers:

Metastatic melanoma and capsular nevus

Metastatic melanoma to ovary

Cytology description

Preparations are usually highly cellular, with loosely cohesive and singly dispersed malignant cells with overt features of malignancy, including pleomorphism, nuclear membrane irregularities, coarse chromatin, prominent nucleoli and mitotic activity (Semin Diagn Pathol 2016;33:198)
Binucleation and multinucleation is a common feature, as are intranuclear pseudoinclusions
Melanin pigment can be sparse at metastatic sites but when present is of a blue-black (petroleum blue) quality on Romanowsky based stains and brown-black on Papanicolaou stain
Presence of numerous pigmented histiocytes may provide a clue to the diagnosis
Limitations
- Broad spectrum of morphologies from epithelioid to spindled to bizarre forms
- Morphological overlap with many primary and metastatic malignancies, especially in nodal and visceral sites

Cytology images

Contributed by Alison Potter, M.B.B.S.

Hilar mass metastatic melanoma

Singly dispersed melanoma cells

Melanophages within melanoma

Pseudopapillary clusters on Pap stain

Pap stained melanoma and melanophages

Tumor aggregates in cell block

MelanA positive tumor

Positive stains

S100 protein, MelanA (MART1), SOX10, HMB45 (J Cutan Pathol 2008;35:433)
Tyrosinase and MITF are less sensitive, with MITF showing only moderate specificity
PRAME may be positive but should not be used as confirmation of melanocytic lineage, as expression can occur in other entities, including numerous carcinomas and sarcomas (Am J Surg Pathol 2022;46:1467)
Aberrant expression of markers of epithelial, mesenchymal and hematopoietic lineage may occur in dedifferentiated tumors (Am J Surg Pathol 2021;45:240)

Negative stains

Molecular / cytogenetics description

Melanoma driver mutations (most frequently seen in BRAF or NRAS) are carried through from the primary to the metastatic site of disease (J Transl Med 2019;17:289)
Identification of a common driver mutation can support the link between the metastatic tumor and the culprit primary site, in cases where numerous possible primary sites are clinically identified
New diagnosis of metastatic melanoma (stage III or IV disease) warrants characterization of melanoma associated targetable mutations, in order to facilitate systemic treatment strategies (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018, Pathology 2022;54:6)
BRAF V600E mutation or NRAS Q61R mutation can be identified by immunohistochemistry; alternative mutations can be detected on polymerase chain reaction (PCR) based sequencing modalities
Demonstration of a melanoma associated mutation (e.g., in BRAF and NRAS) may aid in the diagnosis of metastatic melanoma in cases where the morphology is dedifferentiated / undifferentiated (J Cutan Pathol 2023;50:223, Am J Surg Pathol 2016;40:181)

Sample pathology report

Skin, left proximal thigh, excision:
- Dermal melanoma, favor cutaneous / in transit metastasis (see comment)
- Comment: Sections of the left proximal thigh lesion show a dermal nodule of malignant epithelioid and spindled cells in keeping with melanoma. The tumor is located within the papillary dermis and attenuates an overlying epidermis, without evidence of a junctional melanocytic component. No significant surrounding inflammation or fibrosis is seen. Adjacent lymphatic spaces contain small tumor nests, in keeping with lymphovascular space invasion. Central tumor necrosis is present as well as numerous mitoses (6 per mm²). No background nevus component is appreciated. Margins are clear of tumor by 4 mm (both peripheral and deep). BRAF V600E immunohistochemistry is negative and tissue has been sent for formal molecular testing for melanoma associated targetable mutations; a separate molecular report will be issued.

Small bowel, excision:
- Metastatic melanoma (see comment)
- Comment: Sections show multiple deposits of metastatic melanoma, between 10 and 150 mm in size. Several deposits involve the mucosal surface with extension into lamina propria and secondary erosion of the overlying epithelium. There is evidence of patchy tumor necrosis and a sparse infiltrate of lymphocytes. Most tumor appears viable and is highlighted on immunohistochemistry for S100, SOX10, MelanA, HMB45 and BRAF V600E. 22 lymph nodes are identified, none of which show metastatic melanoma (0/22). The melanoma deposits appear completely excised. The closest margin is 2 mm (gastric margin).

Right axilla lymph node / mass, excision:
- Metastatic poorly differentiated / dedifferentiated melanoma (see comment)
- Comment: Sections of the left axillary mass show a poorly differentiated epithelioid malignancy with cohesive sheet-like growth and large areas of necrosis. There is no evidence of glandular or squamoid differentiation and no melanin pigment is seen. A large range of immunostains (performed on block A8) show the tumor is negative for a large range of melanocytic, epithelial and lymphoid markers. Due to the poorly differentiated morphology, additional stains were performed (on block A1) and these demonstrate a small focus of viable tumor with positivity for SOX10, S100, HMB45, MelanA, tyrosinase, MITF and PRAME. The tumor cells are also positive for BRAF V600E. Repeated staining for SMA, desmin, MNF116, p40, myogenin and MyoD1 are negative. Overall, despite being focal in nature, the expression of a panel of melanocytic markers would favor this nodal disease to represent poorly differentiated / dedifferentiated metastatic melanoma.

Differential diagnosis

Primary cutaneous melanoma (versus satellite melanoma metastasis):
- Multiple step sections are required to exclude contiguous soft tissue or periadnexal / perineural tracking from the primary tumor
Primary dermal melanoma (versus in transit melanoma metastasis):
- Presence of an inflammatory infiltrate, surrounding fibrosis, junctional activity or adjacent benign nevus are all features which favor a primary (dermal) nodular melanoma, over a metastatic deposit (Histopathology 2018;72:472)
Capsular nevus (versus lymph node metastatic melanoma):
- Seen in lymph nodes draining the skin, capsular nevi are commonly present within the fibrous capsule and trabeculae (rather than sinus and parenchyma)
- Nevus cells lack cytological atypia, pleomorphism and mitotic activity
- Immunohistochemistry for S100 and SOX10 are strongly positive but HMB45 shows negative to weak expression, compared to the strong diffuse expression of most melanomas
- Lack of PRAME expression may also support a benign nevus if a culprit primary melanoma is known to be PRAME positive
Primary tumor of the visceral site of disease (versus visceral metastatic melanoma):
- Melanoma can mimic tumors from a range of organs and cell lineages.
- Clinicopathological correlation and knowledge of primary tumors within the particular visceral site is required to aid in distinction
- Alterations and premalignant change in the adjacent organ may provide diagnostic clues
- Judicious use of a panel of immunohistochemical stains and molecular studies may assist in the correct diagnosis
Undifferentiated pleomorphic sarcoma (versus undifferentiated / dedifferentiated melanoma):
- Identification of transition between conventional and dedifferentiated / undifferentiated components can aid in the diagnosis of melanoma
- Factors favoring a dedifferentiated / undifferentiated melanoma include (Am J Surg Pathol 2021;45:240)
  - Previous history of melanoma
  - Metastatic disease in a regional nodal basin or site uncommon for sarcomas (including neck, axilla, inguinal, viscera)
  - Multifocal disease
  - Identification of a melanoma associated mutation or molecular signature concordant with that of a culprit primary tumor
  - Absence of a bona fide primary tumor at another site with alternative histogenesis
Clear cell sarcoma (versus dermal or soft tissue melanoma metastasis):
- These tumors show overlap in architecture, cytology, immunohistochemistry (S100, HMB45 and MelanA) and ultrastructure
- Presence of wreath-like multinucleated tumor cells would favor clear cell sarcoma, with definitive diagnosis by FISH or PCR to detect EWSR1 rearrangement, with common fusion partners ATF1 or CREB1
- Intraepidermal involvement can be seen in both melanoma metastasis and cutaneous clear cell sarcoma (Am J Surg Pathol 2020;44:21, Pathology 2022;54:369)
PEComa (versus soft tissue metastatic melanoma):
- Overlapping immunohistochemical profile (HMB45 and MelanA positive) but lack expression of S100
- Evidence of smooth muscle differentiation may also be seen (desmin, caldesmon, calponin, SMA)
Cellular blue nevus / malignant blue nevus (versus dermal metastasis):
- These tumors have distinct morphological features and demonstrate aberrations in GNAQ or GNA11
Cutaneous tumor with CRTC1::TRIM11 rearrangement (versus dermal melanoma metastasis)
- These tumors frequently show intersecting bundles and nests of tumor cells with cytological uniformity and expression of melanocytic markers (S100, HMB45)
- Definitive distinction can be made on molecular studies (Am J Surg Pathol 2022;46:1457)

Board review style question #1

This undifferentiated epithelioid malignancy is identified within the right groin of a 76 year old man. The patient was diagnosed with a 1.2 mm Breslow thickness superficial spreading melanoma on the right lateral ankle 3 years ago. A broad panel of immunohistochemical stains is negative. Which of the following modalities would be most helpful in establishing a diagnosis of metastatic dedifferentiated / undifferentiated melanoma?

Investigations for melanoma associated mutations in BRAF or NRAS
Morphological comparison to the primary ankle melanoma
Performing immunohistochemistry for PRAME on multiple different regions of tumor
Performing special stains (e.g., Fontana-Masson / Schmorl stain) to identify intracytoplasmic pigmentation

Board review style answer #1

A. Investigations for melanoma associated mutations in BRAF or NRAS. A dedifferentiated tumor in a nodal basin in a patient with a history of melanoma is suspicious for metastatic melanoma. There may only be focal conventional melanocytic differentiation present within dedifferentiated melanoma and sampling of numerous areas of the tumor may be required to identify these foci. A broad panel of immunohistochemistry is required to exclude other lines of differentiation and may be able to identify small foci of tumor that retain immunohistochemical features of melanoma. Identification of a melanoma associated mutation such as BRAF or NRAS may assist in rendering the diagnosis, especially if the mutational status of the primary tumor is known. Answer D is incorrect because dedifferentiated melanomas lack the morphological features of melanoma and are likely to lack evidence of pigmentation, with special stains negative. Answer B is incorrect because primary melanomas are rarely dedifferentiated at their primary site and morphological overlap is insufficient to render a diagnosis in an undifferentiated tumor. Answer C is incorrect because PRAME immunohistochemistry is not specific for a melanocytic lineage and can be positive in a range of high grade mesenchymal tumors; therefore, it cannot be relied upon to establish a diagnosis of dedifferentiated melanoma.

Comment Here

Reference: Metastatic melanoma

Board review style question #2

Which of the following presentations of melanoma is considered metastatic in nature?

Dermal nodule of melanoma seen within the perineural space, which on deeper levels is identified to be in continuity with the primary tumor invasive front
Dermal nodule of melanoma with an adjacent dysplastic compound nevus
Solitary subcuticular nodule of melanoma with adjacent lymphovascular space invasion
Thin rim of bland melanocytes within the fibrous capsule of an axillary lymph node

Board review style answer #2

C. Solitary subcuticular nodule of melanoma with adjacent lymphovascular space invasion. Subcuticular deposits of melanoma without continuity to the dermis / epidermis and with evidence of nearby lymphovascular space invasion are classic for in transit metastasis. Answers A and B are incorrect because a focus of melanoma that remains in direct continuity with the primary tumor is not regarded as metastatic disease, nor are tumors that arise within an adjacent nevus (even if there is an absence of in situ component). Answer D is incorrect because lymph nodes draining the skin, which can contain capsular nevi, are located within the fibrous capsule and should not be regarded as metastatic melanoma. Care should be taken to ensure that no continuity exists with a nearby primary melanoma prior to establishing a diagnosis of metastatic melanoma.

Comment Here

Reference: Metastatic melanoma

Meyerson nevus

Table of Contents

Definition / general

First described in 1971 (Arch Dermatol 1971;103:510)
Solitary, pruritic, erythematous eruption encircling a pre-existing pigmented nevus

Terminology

Also called halo dermatitis (Br J Dermatol 1988;118:125)

Epidemiology

Young adults > children (Pediatr Dermatol 1992;9:275)
No apparent anatomic or gender predilection in children (Pediatr Dermatol 2009;26:292)

Sites

Usually trunk and proximal upper extremities

Case reports

12 year old boy with seven nevi on trunk (Dermatol Online J 2008;14:28)
25 year old man with two nevi on abdomen (An Bras Dermatol 2010;85:681)

Treatment

Wait (may regress) or excision
Does not recur or progress to melanoma (Australas J Dermatol 2008;49:191)
Possibly topical steroids (J Cutan Med Surg 2010;14:30)

Dermoscopy

Meyerson phenomenon does not modify dermatoscopic characteristics (An Bras Dermatol 2010;85:681)

Microscopic (histologic) description

Epidermal spongiosis and dermal inflammation (CD3+ lymphocytes) associated with a usual type junctional or compound nevus
At most mild atypia, no regression (by definition)

Differential diagnosis

Atypical nevi: may have eczematous halos: see J Am Acad Dermatol 1996;34:357

Mucosal melanoma (genital, oral, sinonasal)

Table of Contents

Definition / general

Malignant neoplasm of mucosal melanocytes
Rare melanoma subtype that originates from melanocytes within sun protected mucous membranes
Mucosal melanomas share many of the histologic characteristics of cutaneous melanomas and differ mainly in the underlying anatomic sites involved

Essential features

Mucosal melanoma represents a rare subtype of melanoma, accounting for ~0.8 - 3.7% of all melanomas in Caucasians (Cancer Treat Res 2016;167:295)
Can arise from any mucosal epithelium within the body, including epithelium from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%) and other (e.g., conjunctiva, 3%) (Cancer Treat Res 2016;167:295)
While the incidence of cutaneous melanomas has increased by ~1.4% every year, the incidence of mucosal melanoma has remained stable (Cancer Treat Res 2016;167:295)
Mucosal melanoma is one of the most aggressive subtypes of melanoma and carries a significantly worse prognosis than cutaneous melanoma with a 5 year overall survival of < 25%; 23% of patients have metastases at the time of diagnosis (Ann Oncol 2017;28:868)

ICD coding

ICD-10:
- C21.0 - malignant neoplasm of anus, unspecified
- C21.1 - malignant neoplasm of anal canal
- C43.0 - malignant melanoma of lip
- C43.11 - malignant melanoma of right eyelid, including canthus
- C43.12 - malignant melanoma of left eyelid, including canthus
- C43.51 - malignant melanoma of anal skin
- C51.0 - malignant neoplasm of labium majus
- C51.1 - malignant neoplasm of labium minus
- C51.2 - malignant neoplasm of clitoris
- C51.8 - malignant neoplasm of overlapping sites of vulva
- C51.9 - malignant neoplasm of vulva, unspecified
- C60.0 - malignant neoplasm of prepuce
- C60.1 - malignant neoplasm of glans penis
- C60.2 - malignant neoplasm of body of penis
- C60.8 - malignant neoplasm of overlapping sites of penis
- C60.9 - malignant neoplasm of penis, unspecified

Epidemiology

Unlike cutaneous melanoma, which is estimated to be the fifth most common cancer in the United States among men and the sixth among women, mucosal melanomas are rare
Mucosal melanomas represent only ~1.4% of all melanomas (all races / ethnicities); however, they have a worse prognosis when compared to cutaneous melanomas
Mucosal melanoma accounts for ~0.8 - 3.7% of all melanomas in Caucasians; the incidence of mucosal melanomas is higher in Caucasians than other racial groups (Cancer Treat Res 2016;167:295)
Mucosal melanoma differs by race / ethnicity with regard to the anatomic site
- Non-Hispanic whites have the highest proportion of genitourinary mucosal melanoma, while Asian / Pacific Islanders most commonly have anorectal mucosal melanoma; head and neck tumors are most frequently seen in Hispanics (J Am Acad Dermatol 2017;76:250)
Mucosal melanoma tends to present in older populations compared to cutaneous melanoma (median age of diagnosis: 70 versus 55 years old) (Cancer Treat Res 2016;167:295)
Gender disparities within mucosal melanoma exist with the incidence being 2 times higher in women, due to the development of the disease in the genital tract (Cancer Treat Res 2016;167:295)

Sites

Arises in the head and neck in the following decreasing order of prevalence: nasal cavity, paranasal sinuses and oral cavity
Larynx
Esophagus
Rectum and anal canal
Vagina
Cervix

Pathophysiology

Evolution of mucosal melanoma from precursor lesions is poorly understood but has been associated with some risk factors
Presence of melanocytes has been demonstrated in many mucosal membranes; however, their function in the mucosa is not well understood
Many mutations have been associated with mucosal melanomas (see Molecular section) (Front Oncol 2021;11:702287)

Etiology

Smoking, ill fitting dentures and ingested / inhaled carcinogens, such as tobacco and formaldehyde, are regarded as potential causative factors for oral and sinonasal mucosal melanoma (Front Oncol 2021;11:702287)
Chronic inflammatory disease, viral infections and chemical irritants are thought to be implicated in vulvar mucosal melanoma
Human immunodeficiency virus (HIV) is associated with anorectal mucosal melanoma

Head and neck mucosal melanoma staging

The AJCC TNM stages for mucosal melanoma of the head and neck are as follows (Amin: AJCC Cancer Staging Manual, 8th Edition, 2017):
- T1 and T2: omitted due to the poor prognosis of even small and superficial lesions
- T3: mucosal disease
- T4A: moderately advanced disease; tumor involves the cartilage, deep soft tissue or overlying skin
- T4B: very advanced disease; tumor involves one or more of the following:
  - Brain
  - Dura
  - Skull base
  - Lower cranial nerves (IX, X, XI, XII)
  - Masticator space
  - Carotid artery
  - Prevertebral space
  - Mediastinal structures

Genitourinary tract mucosal melanoma staging

Urinary tract, female and male genital tracts and anorectal melanomas are staged using the cutaneous melanoma staging system; there is no Union for International Cancer Control (UICC) staging criteria for these melanomas

Diagnosis

Biopsies should attempt to remove the entire lesion, including a depth adequate to determine an accurate Breslow depth; if limited by large size, representative samples should be obtained
CT or MRI to assess the primary site of disease (Clin Radiol 2011;66:224)
CT or PET scan to assess for metastases and lymph node involvement
MRI with contrast is the modality of choice to detect cerebral metastases with higher sensitivity and specificity than contrast enhanced CT (J Neurooncol 1999;44:275)
CT is the modality of choice for detecting distant metastases
- Lungs and pleura are most frequently affected, followed by the liver
- Lesions may be hypervascular on CT in the arterial phase and hypodense in the portal phase
- Rim enhancement and central necrosis is common
- High signal is often noted on noncontrast T1W liver MRI
PET CT is 98% sensitive and 94% specific for detecting metastatic melanoma (Radiology 2007;244:566)

Prognostic factors

Mucosal melanomas have a worse prognosis than cutaneous melanoma
5 year survival of mucosal melanoma patients is < 25%; 23% of patients have metastases at the time of diagnosis (Ann Oncol 2017;28:868)
Mucosal melanoma patients have a median survival of 9 months and the worst prognosis compared with other melanoma subgroups such as uveal, acral, nonacral cutaneous and unknown primary melanoma (Ann Oncol 2017;28:868)

Case reports

53 year old man with mucosal melanoma of eustachian tube (J Int Adv Otol 2022;18:455)
56 year old postmenopausal woman who presented with intermittent vaginal bleeding and passage of dark clots (Cureus 2020;12:e10536)
60 and 67 year old women with malignant amelanotic melanoma of the female genital tract (Melanoma Res 2009;19:267)
65 year old with mucosal melanoma of paranasal sinuses (Int J Surg Case Rep 2021;87:106450)
80 year old woman with oral mucosal melanoma (J Dent Sci 2020;15:556)
84 year old postmenopausal woman with a suspicious vaginal lesion (BMJ Case Rep 2020;13:e232200)

Clinical images

Images hosted on other servers:

Malignant oral melanoma

Vaginal melanoma lesion

Malignant melanoma of the minor labia

Frozen section description

Intraoperative consultation is not recommended

Microscopic (histologic) description

Arising upon the mucosal surfaces, the intraepithelial component demonstrates a proliferation of melanocytes as single cells and nests, beginning within the basal layer
Ulceration is frequently encountered
There is pagetoid involvement of the epidermis
Lesion is often asymmetric with lack of maturation and cytological atypia
Cells are often large and epithelioid, with abundant eosinophilic cytoplasm
Histologic features can vary widely from spindled, epithelioid and pleomorphic to rhabdoid, plasmacytoid and undifferentiated
Prominent nucleoli and mitotic figures are often seen
Approximately 50% of mucosal melanomas are amelanotic (or minimal pigmentation) leading to overlapping features and diagnostic challenges in differentiating mucosal melanomas from other small cell / undifferentiated sinonasal tumors (Head Neck Pathol 2017;11:110)
Reference: Dermatopathology (Basel) 2018;5:41

Microscopic (histologic) images

Contributed by Mona Deerwester, M.D. and Janira M. Navarro Sanchez, M.D.

Invasive mucosal melanoma

Melanoma in situ of the vulva

Malignant melanoma of the vulva

Malignant melanoma of the vagina

S100 stain

Cytology description

Limitations:
- Variability in cytological presentation
- Can mimic any malignant tumor
Cytologic features:
- Discohesive epithelioid, plasmacytoid, spindle cells or giant cells
- Can be multinucleated
- Sometimes microvacuolized cytoplasm
- Dispersed and finely granular pigment
- Variable cell shape and size
- Large irregular nuclei
- Prominent eosinophilic nucleoli
- Nuclear pseudoinclusions
- Melanophages
Reference: Cancer Cytopathol 2022;130:18

Cytology images

Contributed by Mona Deerwester, M.D.

Multinucleated cells

Discohesive cells

Multinucleated cells and melanophages

Images hosted on other servers:

Morphologic features of melanoma

Cytologic immunohistochemical stains of melanoma

Positive stains

Negative stains

Electron microscopy description

Melanosomes
Premelanosomes
No longer used in clinical practice

Electron microscopy images

Images hosted on other servers:

Melanoma cells
with melanosomes
and premelanosomes

Molecular / cytogenetics description

Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8 (Nat Commun 2019;10:3163)
SF3B1 mutations occur more commonly in female genital and anorectal melanomas
CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas (Nat Commun 2019;10:3163)
TERT aberrations and ATRX mutations are associated with alterations in telomere length (Nat Commun 2019;10:3163)
Oral mucosal melanomas have shown mutations as follows: KIT in 14.6%, BRAF in 7%, NRAS in 5.6% (J Stomatol Oral Maxillofac Surg 2022;123:e425)

Sample pathology report

Vulva, left, radial vulvectomy:
- Malignant melanoma (see comment)
- Comment:
  - Depth: 1.8 cm. (18 mm) (Breslow)
  - Level: IV (Clark)
  - Ulceration: present
  - Mitoses (per mm²): 5
  - Regression: not identified
  - Angioinvasion: not identified
  - Neural invasion: present
  - Lymphocytic infiltrate: absent
  - Microsatellites: not identified
  - Margins: negative
  - Lymph nodes: 2/2
  - Pathologic stage: pT4b N2

Differential diagnosis

Benign melanocytic nevus and its histological variants:
- Dysplastic nevus:
  - No asymmetry
  - No pagetoid spread
  - No confluence of expansile nests
  - No epidermal consumption / ulceration
  - Cytological maturation of dermal melanocytes
- Melanocytic nevi of special sites:
  - A small degree of cytological and architectural atypia is acceptable (Am J Dermatopathol 2016;38:867)
Metastatic melanoma:
- Personal history of melanoma
- Absence of lymphocytic infiltrate
- Absence of junctional component
Merkel cell carcinoma:
- Neuroendocrine markers (synaptophysin, chromogranin)+
- CK20+ (perinuclear dot-like positivity)
Anaplastic lymphoma (ALK positive / ALK negative):
- LCA marker (CD45)+

Additional references

WHO Classification of Tumours Editorial Board: Head and Neck Tumours, 5th Edition, 2024, WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022, WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

What is the most common location for mucosal melanoma of the head and neck?

Larynx
Nasal cavity
Oral cavity
Paranasal sinuses
Pharynx

Board review style answer #1

B. Nasal cavity, followed by paranasal sinuses and oral cavity. About 80% of head and neck mucosal melanomas involve the nasal cavity or septum and maxillary sinus. In the oral cavity, most cases arise in the maxillary gingiva and palate. Tumors arising in other paranasal sinuses, pharynx and larynx are rare.

Comment Here

Reference: Mucosal melanoma (genital, oral, sinonasal)

Board review style question #2

What is the recurrence rate of the disease of the vagina shown in the image above?

Board review style answer #2

D. 80%. The recurrence rate is 80% in vaginal melanomas and 60% in vulvar melanomas.

Comment Here

Reference: Mucosal melanoma (genital, oral, sinonasal)

Nevi on the nail apparatus (pending)

[Pending]

Nevi-general

Table of Contents

Nevi-general | Junctional nevus | Compound nevus | Dermal nevus | Lentiginous nevus

Nevi-general

Definition / general

Congenital or acquired benign melanocytic proliferation
Dermoscopy: nevus type varies by skin type in whites (Arch Dermatol 2007;143:351)
Color: due to Tyndall effect (scattering of light as it hits melanin granules); melanin in stratum corneum appears black, melanin in reticular dermis appears slate-gray or blue (Wikipedia: Tyndall Effect [Accessed 2 December 2021])
Nevi may regress due to lymphocytic infiltration (see halo nevus)

Terminology

Nevus (singular) also spelled naevus
Means birthmark in Latin
Also called melanocytic, nevocellular or pigmented lesion

Epidemiology

Most common melanocytic tumor
Usually clinically evident between ages 2 - 6 years
Most whites have 20 - 30 nevi; much less common in Asians and Afro-Caribbeans
Can estimate total body count in 13 - 14 year olds by examining lateral arms (Am J Epidemiol 2007;166:472)
2 theories of nevogenesis: Abtrofung versus Hochsteigerung (Arch Dermatol 2007;143:284)

Patterns associated with benign behavior

Small size, circumscription and symmetry
Nested proliferation with nests regularly distributed at tips of the rete ridges
Melanocyte nuclei smaller than in adjacent keratinocytes
Uniform cellular density throughout same level of lesion
Melanocytes decrease in size towards base of lesion (maturation)
Coalescent eosinophilic globules (Kamino bodies) are associated with Spitz nevi
Absence of mitotic activity (particularly at base of lesion), although rare mitoses may be seen in benign nevi (J Cutan Pathol 2007;34:713, Am J Dermatopathol 2010;32:643)
Lack of necrosis and cytologic atypia

Clinical features

Nevi common on head, neck and trunk in Caucasians, on acral sites in Asians and Afro-Caribbeans
Mostly occur in skin but also mucosal membranes covered by squamous epithelium
May be neoplastic since many are clonal
Existence of freckles, lentigines (small, pigmented, flat or slightly raised spots with a clearly defined edge but no nests of melanocytes) and melanocytic nevi increases chance of having melasma (BMC Dermatol 2008;8:3)
Often accompanied by keratinous cysts, abscess or folliculitis
Incidental microscopic aggregates of nevus cells occur in 1% of skin excisions (Am J Dermatopathol 2008;30:45); also occur in clusters in lymph node capsules (intracapsular nevus), particularly in axilla (see lymph nodes chapter)
Large numbers of nevi are risk factor for melanoma (Int J Cancer 2009;124:420)
Increasing numbers of nevi are associated with neonatal phototherapy, sun exposure on hot holidays and number of nevi in parents, although this does not necessarily mean that these factors are risk factors for melanoma (Arch Dermatol 2006;142:1599, J Invest Dermatol 2005;124:56, Cancer 2003;97:628)

Prognostic factors

May recur with incomplete excision (shave biopsy), usually within 3 months
Recurrent nevus (persistent nevus) may resemble melanoma (pseudomelanoma) due to irregular scarring, lentiginous melanocytic hyperplasia, basilar keratinocytic hyperpigmentation, nuclear enlargement and prominent nucleoli (J Cutan Pathol 2011;38:503)

Case reports

65 year old man with melanocytic intranuclear inclusions due to molluscum contagiosum (J Cutan Pathol 2008;35:782)
Nodal nevus cells associated with dermatopathic lymphadenopathy (Diagn Cytopathol 2004;31:180)

Treatment

Biopsy any clinically atypical melanocytic lesions in adults, such as nevi causing chronic mechanical irritation, itching, bleeding, ulceration or oozing of serum, nevi with rapid growth, deepening pigmentation, pigmentation beyond outline of lesion, flat areas of depigmentation or erythema
Pathologically confirmed banal nevi and mildly atypical nevi do not require additional treatment
Nevi with moderate and severe atypia usually are excised with negative margins

Gross description

Papule or macule, tan-brown, uniformly pigmented and small (≤ 0.6 cm)
Often erosion or ulceration if adjacent to a hair follicle, with a granulomatous response or scale crust

Microscopic (histologic) description

Intraepidermal component: junctional nests of melanocytes uniform in size, distributed at the tips of the rete ridges
Dermal component:
- Type A morphology:
  - In superficial dermis
  - Pigmented epithelioid cells with well defined cell boundaries
  - Abundant eosinophilic to amphophilic cytoplasm containing coarse melanin granules
  - Uniform round / oval nuclei slightly smaller than that of adjacent keratinocytes
  - Finely dispersed chromatin
  - Delicate nuclear membrane
  - No / small distinct eosinophilic nucleoli
- Type B morphology:
  - In intermediate dermis
  - Cells more lymphoid than epithelioid
  - Decreased cytoplasm with no melanin
  - Smaller and slightly hyperchromatic nuclei with dispersed chromatin and no nucleoli
- Type C morphology:
  - In deep dermis
  - Spindled, fibroblast-like or schwannian cells with oval nuclei and bland chromatin
  - Single cell infiltration of superficial reticular collagen
- Maturation:
  - Deeper portion of lesion has smaller cells with less pigment and less atypia
  - Deep cells grow in smaller sized nests or single cells
  - May resemble neural tissue
  - Terminal differentiation recapitulates some aspects of Schwann cell development (Am J Pathol 1999;155:549)
- Traumatized nevi:
  - Features include parakeratosis (92%), dermal telangiectasias (61%), ulceration (51%), dermal inflammation (49%), melanin within stratum corneum (24%), dermal fibrosis (25%), pagetoid spread of melanocytes limited to the site of trauma (20%) or away from areas of trauma (8%) (Am J Dermatopathol 2007;29:134)

Microscopic (histologic) images

Contributed by Yuri Tachibana, M.D.

Nests of melanocytes

Images hosted on other servers:

Clusters of nevus cells in neck node of patient with oral squamous cell carcinoma

Positive stains

MelanA in type A and B but not type C cells
S100, HMB45 in the intraepidermal and superficial dermal component

Molecular / cytogenetics description

BRAF mutations in 75% of congenital and acquired nevi, have clonal genetic changes (Hum Pathol 2002;33:191, Am J Dermatopathol 2007;29:534)

Junctional nevus

Definition / general

Melanocytic proliferation restricted to basal epidermis (junctional area)
Earliest stage of intraepidermal melanocytic proliferation

Terminology

Lentigo simplex:
- Also called lentigo, lentigines
- Often in acral sites
- Precursor lesion to nevi, with proliferation of melanocytes (but no nests) in epidermal basal layer along rete ridges (DermNet NZ: Lentigo Simplex [Accessed 2 December 2021])
Multiple lentigines:
- Associated with Peutz-Jeghers syndrome, centrofacial lentiginosis, Moynahan’s syndrome, LEOPARD syndrome, Carney’s syndrome and xeroderma pigmentosum

Epidemiology

Traditionally considered more common in children (possible sampling bias), may actually occur in all ages (J Am Acad Dermatol 2007;56:825)
Melanomas may arise from junctional nevi

Sites

Usually non sun exposed areas, such as palms and soles (J Am Acad Dermatol 2007;56:825)

Clinical features

Small, flat or slightly elevated; non hairy, deeply pigmented

Case reports

57 year old woman with coexisting mastocytoma (Am J Dermatopathol 2004;26:478)

Treatment

None needed; excision for cosmetic reasons, laser for flat lesions (Br J Dermatol 2003;148:80)

Dermoscopy

Regular pigmented network of brown and uniform color, more prominent in center with gradual fading to borders (reticular pattern)
May have black or brown globules and dots regularly distributed inside lesion (usually in central region)

Microscopic (histologic) description

Rounded nests of melanocytes / nevus cells on epidermal side of dermoepidermal junction, originating from tips of rete ridges
Variable lentiginous melanocytic hyperplasia

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Breast skin

Differential diagnosis

Lentigo
Melanoma

Compound nevus

Definition / general

Features of both junctional and intradermal nevi (i.e. epidermal and dermal components)

Terminology

Compound = junctional and intradermal components
Do not confuse with combined nevus

Epidemiology

Highest incidence in second decade, then decreases (Arch Dermatol 1962;86:310)

Clinical features

Elevated or dome shaped
Less pigmented than junctional nevi
Only rarely undergoes malignant transformation
Nevogenesis may be due to ultraviolet light (Am J Dermatopathol 2005;27:456)

Clinical images

Images hosted on other servers:

Eccentric
hyperpigmented
nevus suspicious
for melanoma

Case reports

17 year old girl with pigmented lesion on mons pubis (Arch Pathol Lab Med 2003;127:e391)
17 year old girl with compound nevus and spindle cell Spitz nevus (J Dermatol 2000;27:233)

Microscopic (histologic) description

Features of both junctional and intradermal nevi (i.e. epidermal and dermal components)
Junctional component is similar to junctional nevus, with nests regularly distributed at bases of rete ridges, occasional lentiginous pattern, no pagetoid spread, no atypia, symmetry diminishes with patient age
Dermal component consists of nests (may be very large) or linear pattern of melanocytes, cells are small with scant cytoplasm and regular nuclei and mature with depth by becoming more slender / spindled with less pigment
Dermal melanocytes or nests are separated by collagenous stroma
Often clusters of chronic inflammatory cells at base of nevus
Mucin in < 1% (Am J Dermatopathol 2008;30:236)
May have occasional mitoses (Am J Dermatopathol 2013;35:30)

Videos

Compound nevus with halo reaction

Differential diagnosis

Other melanocytic proliferations

Dermal nevus

Definition / general

Nevus with all melanocytes within the dermis

Terminology

Also called intradermal nevus

Epidemiology

Most common adult nevus
Represents final stage in progression from junctional to compound to dermal nevus
Seen mainly after adolescence

Clinical features

Flat, pedunculated or papillary, often hairy
Flesh colored or lightly pigmented (usually becomes lighter over time)
Pigmentation may be in flecks up to 1 cm
Melanomas only rarely arise from intradermal nevi (Dermatology 1998;196:425)
Rarely has cerebriform appearance; these nevi may be congenital (Cutis 2004;73:254)

Dermoscopy description

Nonpigmented lesions: brown pigment (78%), white areas (53%), comma shaped vessels (50%), hair (47%), hairpin vessels (22%), comedolike openings (22%) and dotted vessels (19%) (Dermatol Surg 2007;33:1120)

Case reports

46 year old woman with osseous metaplasia / osteonevus of Nanta in intradermal melanocytic nevus (Dermatol Online J 2007;13:16)
Intradermal melanocytic nevus with prominent Verocay-like bodies (Am J Dermatopathol 2002;24:39)

Clinical images

Contributed by Mark R. Wick, M.D.

Polypoid, breast skin

Images hosted on other servers:

Mole on the cheek below ear

Microscopic (histologic) description

Small nests of melanocytes in upper dermis, often around pilosebaceous units, with variable pigmentation and cellularity
May have multinucleated melanocytes; deeper portion is usually less pigmented and less cellular and may have Wagner-Meissner corpuscles (representing neural portion of nevus)
Mucin in 3% of stroma and within nests of nevus cells (Am J Dermatopathol 2008;30:236)
Rarely nevus giant cells, balloon cells, infiltration by fat cells or osseous metaplasia
No junctional component
Can also be classified as Unna’s pattern (purely adventitial lesion confined to expanded papillary dermis and often to perifollicular dermis, usually neck, trunk or limbs) or Miescher’s pattern (melanocytes diffusely infiltrate adventitial and reticular dermis in wedge shaped pattern, usually on face) (Am J Dermatopathol 2007;29:141)
Slit-like pseudovascular spaces may be seen through artifact of processing and biopsy procedure (Ultrastruct Pathol 1980;1:361, Am J Dermatopathol 1984;6 Suppl:25)

Microscopic (histologic) images

Contributed by Yuri Tachibana, M.D. and Angel Fernandez-Flores, M.D., Ph.D.

Nests of melanocytes

Unna pattern

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Intradermal nevus with osseous metaplasia

Lentiginous nevus

Definition / general

Common type of agminate (clustered) nevus with multiple pigmented macules or papules within a pigmented patch (Cutis 2007;80:465, eMedicine: Speckled Lentiginous Nevus)
May be congenital or acquired (Arch Dermatol 2001;137:172)

Terminology

Also called speckled lentiginous nevus or nevus spilus
Not related to acral lentiginous nevus (see acral nevi)

Epidemiology

Speckled lentiginous nevus syndrome: hyperhidrosis, muscular weakness, dysesthesia or other neurological abnormalities

Clinical features

Often benign mole with increase in size, formation of irregular borders or peripheral change in color
May be due to reactivation of radial proliferation
Usually ≤ 5 mm
Note: atypia often present in childhood acral lesions (Pediatr Dev Pathol 1998;1:388)

Case reports

42 year old man with speckled lentiginous nevus on trunk (Dermatology 2004;209:228)
45 year old man with melanoma (Int J Dermatol 2006;45:1362)

Treatment

Excision of speckles or entire lesion

Clinical images

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Macular
hyperpigmentation
and superimposed
darker macules

Speckled lentiginous nevus

Thick hypertrichotic inferolateral portion

Admixed type hypertrichotic hybrid nevus

Large unilateral speckled lentiginous nevus

Extensive speckled lentiginous nevus

Microscopic (histologic) description

Shoulder area of lentiginous junctional melanocytic proliferation beyond lateral border of underlying dermal nevus
Elongation of rete ridges with small nests of melanocytes at tips of rete
Individual unit melanocytes extending along sides of rete, often mild lymphohistiocytic infiltrate with pigment incontinence
No atypia, no pagetoid spread and no dermal fibrosis
Acral lesions: resemble dysplastic nevus due to elongation of rete ridges, continuous proliferation of melanocytes at dermoepidermal junction, single scattered melanocytes or less commonly small clusters within the upper epidermis; poor or absent lateral circumscription, melanocytes with abundant pale cytoplasm and round / oval, sometimes hyperchromatic nuclei and prominent nucleoli present at the dermoepidermal junction; however, unlike dysplastic nevi, they lack anastomosing rete ridges, cytological atypia and well formed lamellar fibroplasia (Histopathology 1995;27:549)
Variants:
- Macular variant: jentigo pattern (lentiginous pattern plus nests of melanocytes at dermal epidermal junction) in the darker speckles and by some nests of melanocytes at the dermoepidermal junction at the tips of the papillae but background pigmentation has microscopic features of lentigo; tan-brown background with dark flat speckles in relatively even distribution resembling polka dots; associated with phacomatosis pigmentovascularis
- Papular variant: dermal or compound melanocytic nevi; light-brown macule superimposed by multiple melanocytic nevi in the form of papules or nodules that show a more uneven distribution reminiscent of a star map; small dark macules may be present; associated with phacomatosis pigmentokeratotica or speckled lentiginous nevi syndrome (Dermatology 2006;212:53)

Microscopic (histologic) images

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Nests of small and
monomorphic
melanocytes at the
dermoepidermal junction

Elongated rete ridges and
lentiginous proliferation
of melanocytes at the
dermal epidermal junction

Prominent basal
layer pigmentation
similar to that seen
in lentigo simplex

Differential diagnosis

Dysplastic nevus
Lentigines:
- No nests, may be nevi if examine serial sections (Am J Dermatopathol 1985;7 Suppl:5)
Superficial spreading or lentiginous melanoma
- Pagetoid lateral spread, mitotic activity in deep dermis and no maturation (Mod Pathol 2005;18:1397)

Nevoid melanoma

Table of Contents

Definition / general

Rare variant characterized by morphologic features of nevus (Hum Pathol 1995;26:171, Arch Dermatol Res 1985;277:362, Mod Pathol 2006;19:S41)

Terminology

Synonym: "verrucous pseudonevoid melanoma"
Distinct from controversial term "minimal deviation melanoma"

Epidemiology

Adults in fifth decade
No clear gender preponderance (Clin Dermatol 2009;27:564, Mod Pathol 2006;19:S41)

Clinical features

Rare variant characterized by morphologic features of nevus
Behavior similar to other melanomas; may recur or metastasize causing death (Am J Dermatopathol 2001;23:167)
Key to diagnosis is high index of suspicion
Dome shaped papule, nodule or verrucous lesion
Tan nodule 1 cm or larger on trunk or proximal limbs of young adult

Case reports

4 year old girl with metastatic tumor to sentinel lymph node (J Cutan Pathol 2003;30:647)
Multiple primary nevoid melanomas in HIV / AIDS patient (J Am Acad Dermatol 2002;47:S172)

Microscopic (histologic) description

Resembles ordinary compound or dermal nevus at low power, with symmetrical dome shaped or verrucous and papillomatous features, sharp lateral demarcation, inconspicuous junctional component and no pagetoid growth
High power shows relatively bland and monomorphic cells resembling classic nevus or epithelioid cells in Spitz nevus
Focal sheetlike growth pattern, nucleoli in tumor cells at base of lesion
Multiple dermal mitoses with atypical mitoses
Subtle pleomorphism and impaired maturation with depth

Microscopic (histologic) images

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Lesion #1:

Various images

Lesion #2:

Various images

Lesion #3:

Various images

Atypical single cells

Mitotic figures

Positive stains

HMB45 (strong throughout) (J Cutan Pathol 1995;22:502)
Increased labeling index with Ki67
Diffuse staining with cyclin D1

Differential diagnosis

Melanoma arising in dermal nevus:
- Residual nevus present, often tumor extension into deep reticular dermis and fat
Metastatic melanoma
Minimal deviation melanoma:
- At most moderate atypia, at least level III due to dermal invasion, remnants of existing nevi usually present and usually few mitotic figures
Nodular melanoma:
- High grade atypia, intraepidermal atypia

Often only part of lesion is excised and pathologist report includes recommendation for complete excision (J Clin Pathol 2004;57:1121)

Patterns of Benign Behavior

Lentiginous hyperplasia (single cell melanocytic growth along dermoepidermal junction)
Nested proliferation
Melanocyte nuclei are smaller than adjacent keratinocytes
Pagetoid proliferation (discohesive single cell growth throughout entire epidermis) is nonspecific; present in Spitz nevi, acral nevi, melanoma (Am J Surg Pathol 1995;19:792)

Other Benign Features

Symmetric pattern of growth and involution
Lateral dimension of dermal component should roughly equal that of original epidermal component ("shoulder" = when epidermal component extends laterally beyond dermal)

Maturation

Deeper portion of lesion has smaller cells with less pigment, less atypia
Deep cells grow in smaller sized nests or single cells
May resemble neural tissue
Maturation is a morphologic term; does not truly reflective biologic maturation (Am J Dermatopathol 1988;10:20)

Case reports

7 month old girl with lentiginous hyperplasia associated with hamartoma (Am J Dermatopathol 2008;30:488)
Lentiginous melanocytic hyperplasia overyling dermatofibroma (J Dermatol 1996;23:840)

Pediatric melanoma

Table of Contents

Definition / general

Pediatric melanoma is defined as melanoma occurring in patients younger than or equal to 19 years of age (Pediatrics 2013;131:846)

Essential features

Pediatric melanoma is exceedingly rare with distinct biologic, clinical and histopathologic features compared to adult melanoma (J Eur Acad Dermatol Venereol 2023;37:1758)
Pediatric melanoma is classified into 3 main categories: conventional melanoma, melanoma arising in congenital melanocytic nevi and Spitz and spitzoid melanoma (J Eur Acad Dermatol Venereol 2023;37:1758)
Pediatric melanoma, particularly Spitz and spitzoid melanoma, is usually greater in thickness at initial presentation and has a higher occurrence of amelanotic lesions, higher frequency of positive sentinel nodes and an overall less aggressive clinical progression as compared to adult melanoma (J Eur Acad Dermatol Venereol 2023;37:1758, Cancers (Basel) 2023;15:1835)

Terminology

Juvenile melanoma (J Eur Acad Dermatol Venereol 2023;37:1758)
Childhood melanoma

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified
ICD-11
- 2C30.0 - superficial spreading melanoma, primary
- 2C30.Y - other specified melanoma of skin
- 2C30.Z - melanoma of skin, unspecified

Epidemiology

Pediatric melanoma is rare, accounting for 1 - 3% of all pediatric malignancies (J Eur Acad Dermatol Venereol 2023;37:1758)
- ~1 - 4% of all melanomas occur in pediatric patients
- Conventional melanomas (i.e., superficial spreading and nodular) are most common
  - 58.1% in children < 11 years and 86.7% in children 12 - 19 years
- Spitz and spitzoid melanomas are second most common
  - 35.5% in children < 11 years and 12.4% in children 12 - 19 years
- Melanoma arising in giant congenital nevi are least common
  - 6.5% in children < 11 years and 0.9% in children 12 - 19 years
Genetic factors including (J Eur Acad Dermatol Venereol 2023;37:1758)
- Inherited deoxyribonucleic acid (DNA) repair defects
- Family history of melanoma
- Light skinned individuals
- Increased total number of nevi
- Congenital melanocytic nevi with risks correlating with size (> 40 cm) and number
Cumulative sun damage (J Eur Acad Dermatol Venereol 2023;37:1758)
- Extensive sun exposure and sunburns
- Indoor tanning

Sites

Childhood melanomas are more common on the extremities and trunk (J Eur Acad Dermatol Venereol 2023;37:1758)
Adolescent melanomas are more common on the trunk (J Eur Acad Dermatol Venereol 2023;37:1758)

Pathophysiology

Biologically distinct from melanoma in adults
Conventional pediatric melanomas are histologically alike to adult melanoma with a majority demonstrating somatic single nucleotide mutations such as those seen with ultraviolet radiation (J Eur Acad Dermatol Venereol 2023;37:1758)
- Mutations
  - BRAF
  - TERT
  - CDKN2A
  - PTEN
  - TP53
  - RB1
Melanomas arising from congenital nevi are associated with NRAS mutation (J Eur Acad Dermatol Venereol 2023;37:1758)
Spitz and spitzoid melanomas are associated with kinase fusion mutations (J Eur Acad Dermatol Venereol 2023;37:1758)
- MAP3K8
- ALK
- NTRK1
- NTRK3
- MET
- RET
- ROS1
- BRAF

Etiology

Immunosuppression and immunodeficiency (J Eur Acad Dermatol Venereol 2023;37:1758)
History of retinoblastoma (J Eur Acad Dermatol Venereol 2023;37:1758)
History of certain genetic disorders such as xeroderma pigmentosum or Werner syndrome (J Eur Acad Dermatol Venereol 2023;37:1758)
Giant melanocytic nevi (> 40 cm) (N Engl J Med 1995;332:656)
Cumulative sun damage (N Engl J Med 1995;332:656)
Numerous nevi
Family history (N Engl J Med 1995;332:656)
- Dysplastic nevus syndrome
- Melanoma

Clinical features

Childhood melanomas, particularly in prepubertal cases, deviate from conventional ABCDE criteria (asymmetry, border irregularity, color variegation, diameter ≥ 6 mm, evolving lesion) (N Engl J Med 1995;332:656)
- Pink or reddish, dome shaped papule
- Amelanotic, nodular lesion
- Often mimics benign lesions (i.e., symmetric, pigmented lesions with regular borders)
- Modified ABCD criteria: amelanotic, bleeding / bump, color uniformity, de novo / any diameter (N Engl J Med 1995;332:656)
Melanoma arising in congenital melanocytic nevi features (Br J Dermatol 2006;155:1, J Eur Acad Dermatol Venereol 2023;37:32)
- Giant congenital melanocytic nevi (> 40 cm)
- Arising in deeper nevi
- Predominantly observed on the trunk region
- Giant congenital melanocytic nevi that extend across the midline of the spine
- Presence of satellite nevi
- Melanomas may also arise within the central nervous system

Diagnosis

Excisional biopsy deep to subcutaneous fat with surrounding 2 mm of normal appearing skin
Histopathologic diagnosis is gold standard (Ital J Dermatol Venerol 2021;156:300)
Conventional pediatric melanomas (NCCN: NCCN Guidelines - Melanoma: Cutaneous [Accessed 7 February 2024])
- Sentinel lymph node biopsy (SLNB) is recommended for lesions with Breslow depth of 1 mm or deeper
Indeterminate or spitzoid pediatric melanoma indications for sentinel lymph node biopsy have not been defined (J Pediatr Surg 2022;57:425)
- Sentinel lymph node biopsy should take into consideration patient's age, histopathologic and molecular diagnosis and anatomic location
- Prognosis of positive SNLB is unclear in spitzoid pediatric melanoma (J Am Acad Dermatol 2013;68:913)
Additional molecular testing with comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH) and alterations in TERT promoter to aid in accurate pathologic classification of pediatric melanoma (Pediatr Blood Cancer 2018;65:10.1002/pbc.26792, Sci Rep 2015;5:11200)

Prognostic factors

Adverse prognostic indicators (J Am Acad Dermatol 2023;88:609)
- Breslow thickness > 4 mm
- Presence of ulceration
- Localization on head and neck
- Diagnosis in adolescence
Spitz and spitzoid melanomas have a high risk of nodal progression but are associated with low mortality (J Eur Acad Dermatol Venereol 2023;37:1758)
Sentinel lymph node positivity does not predict prognosis or outcome (Ann Surg 2011;253:1211)

Case reports

Newborn girl with a giant congenital nodular melanoma (BMC Pediatr 2021;21:121)
7 year old boy with amelanotic conjunctival melanoma (Am J Ophthalmol Case Rep 2022;29:101735)
11 year old boy with Fitzpatrick type VI skin type with an ulcerated amelanotic melanoma of the ear (Pediatr Dermatol 2021;38:106)
14 year old Japanese girl with metastatic juvenile spitzoid melanoma on the buttock expressing PRAME (Case Rep Oncol 2020;13:1141)
15 year old boy with primary intracranial malignant melanoma (Pediatr Neurosurg 2023;58:223)

Treatment

First line treatment is wide local excision to the deep fascia
- Margins for excision specific to pediatric melanoma have not been defined but in most cases follow adult melanoma guidelines
  - Wide local excision 1 - 2 cm depending on the thickness of melanoma
SNLB should be individualized, considering factors such as the patient's age, clinical circumstances, melanoma subtype, diagnostic certainty, location on the body, lymph drainage pattern and desired prognostic information
SNLB for pediatric melanomas typically follows adult melanoma guidelines
- Consider SNLB if < 0.8 mm thick with ulceration or 0.8 - 1.0 mm thick with or without ulceration
Targeted adjuvant therapy
- BRAF and MEK inhibitors
Immunotherapy with checkpoint inhibitor
- PD-1 and CTLA4 inhibitors
Chemotherapy
Radiotherapy
Surveillance with regular total body skin and lymph node examinations
References: PDQ Cancer Information Summaries: Childhood Melanoma Treatment (PDQ®) - Health Professional Version [Accessed 7 February 2024], NCCN: NCCN Guidelines - Melanoma: Cutaneous [Accessed 7 February 2024], N Engl J Med 2017;377:1824, Lancet Oncol 2020;21:121, Target Oncol 2022;17:283

Clinical images

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Pediatric superficial spreading melanoma

Dermoscopy of melanoma in adolescent

Spitzoid melanoma in child

Microscopic (histologic) description

Conventional melanoma
- Superficial spreading (Arch Pathol Lab Med 2020;144:500)
  - Radial followed by horizontal growth phase
  - Pagetoid growth scattered in the epidermis
  - Nests vary in size, shape and distribution
    - Not evenly spaced and not confined to tips of rete
  - Asymmetrical
  - Fails to mature from superficial to deep
  - Cytological atypia and mitoses
  - Can have lymphoid infiltrate at the base
  - With or without ulceration
- Nodular (Arch Pathol Lab Med 2020;144:500, Ital J Dermatol Venerol 2021;156:300)
  - May be polypoid and exophytic
  - Lacks radial growth
  - Tumor size often > 10 mm
  - Cytologic atypia and mitoses
  - Necrosis
  - With or without ulceration
- Pathologic stage classification American Joint Committee on Cancer (AJCC) guidelines, eighth edition (2018) (Ital J Dermatol Venerol 2021;156:300)
  - Tumor (Breslow) depth is the strongest predictor of clinical outcome, used for staging
    - Measure vertically from the top of granular layer of the epidermis to the deepest invasive melanoma cell(s)
    - If ulcerated, measure from base of ulcer
    - Round to nearest 0.1 mm using ocular micrometer
    - Avoid measuring vascular invasion, microsatellites, involvement of skin appendages
Melanoma arising in congenital nevi (Am J Dermatopathol 2013;35:e16)
- Dermal lesions composed of epithelioid cells, spindle cells or round cells resembling a malignant small round blue cell tumor
- Proliferative nodules may be present
- Generally, little to no necrosis, cytological atypia or increased mitotic activity
Spitz and spitzoid melanoma (Pediatr Blood Cancer 2018;65:10.1002/pbc.26792, Diagnostics (Basel) 2023;13:2380)
- Presence of enlarged epithelioid or spindled cells
- Dome shaped configuration with epidermal hyperplasia
- Vertical disposition of melanocytes
- Asymmetry, absence of dermal maturation
- May reach Breslow > 10 mm without ulceration
- Frequent mitoses in the dermis
- High grade of cellular atypia
- High N:C ratio
- Absence of Kamino bodies

Microscopic (histologic) images

Contributed by Idy Tam, M.D. and Bethany R. Rohr, M.D.

Poorly circumscribed proliferation

Pagetoid melanocytes

Pleomorphic melanocytes

PRAME immunostain

SOX10 immunostain

Positive stains

SOX10 (nuclear)
MART1 (MelanA)
HMB45
S100
MITF
PRAME
Tyrosinase
Ki67 / MIB1 (elevated)
BRAF (J Cutan Pathol 2023;50:223)
References: Pediatr Blood Cancer 2018;65:10.1002/pbc.26792, Semin Diagn Pathol 2022;39:239

Negative stains

Loss of melanocytic markers is possible (Dermatopathology (Basel) 2021;8:359)
p16 (nuclear loss in melanoma) (J Cutan Pathol 2023;50:763)
Cytokeratins (Dermatopathology (Basel) 2021;8:359)
CD34, CD31 (Dermatopathology (Basel) 2021;8:359)

Molecular / cytogenetics description

Fluorescence in situ hybridization (FISH) to identify copy number alterations of chromosomes in melanoma and Spitz tumors (Am J Surg Pathol 2013;37:676)
- Interpret in context with clinical and histopathologic findings
  - 6p25
  - 6q23
  - 11q13
  - 9p21
  - 8q24
Next generation sequencing to identify melanoma related gene mutations (Am J Pathol 2002;161:1163)
- Interpret in context with clinical and histopathologic findings
  - BRAF
  - TERT
  - MAP3K8
  - RET
  - ALK
  - NTRK
  - ROS1
Comparative genomic hybridization can detect amplifications and deletions of smaller DNA regions along the chromosome (Am J Pathol 2002;161:1163, Pathology 2004;36:458)
- Can detect copy number variations of melanomas arising in giant congenital nevi
- Melanomas show frequent aberrations in chromosomes 6, 7, 9 and 10

Molecular / cytogenetics images

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Abnormal FISH with (6p25; red) gain; (6q23, yellow) loss

Sample pathology report

Skin, biopsy:
- Invasive malignant melanoma, superficial spreading subtype (Breslow depth to the nearest 0.1 mm) (see comment)
- Comment: The sections demonstrate a highly atypical compound melanocytic proliferation consisting of irregular epithelioid melanocytes. These melanocytes exhibit poor nesting along the dermal epidermal junction, showing both confluence and pagetoid scatter. In the dermis, melanocytes fail to mature and disperse with descent. Dermal mitotic activity is observed.

Differential diagnosis

Benign nevi:
- Well circumscribed and symmetric
- Well nested junctional component without significant pagetoid scatter or confluence
- Dermal component matures and disperses with descent
Dysplastic nevi:
- Can resemble melanoma clinically with asymmetry, border irregularity, color variegation and large diameters
- Generally, lacks severe cytologic and architectural atypia
- Dermal component matures and disperses with descent
- Lacks dermal cytologic atypia, pleomorphism and mitotic activity
- Histologically may resemble early melanoma, especially in severely dysplastic nevi
Spitz nevi:
- Often presents as pink papules that primarily affect pediatric patients
- Histologically lacks severe cytologic atypia and has rare mitotic figures
  - Should be well demarcated
  - Usually lacks deep dermal to subcutaneous extension
  - Presence of Kamino bodies
Blue nevi:
- Blue to dark gray homogenous macules or papules
- Histologically lacks cytologic atypia and mitotic figures
- Sclerotic stroma
- Various subtypes
Pyogenic granulomas:
- Red, friable, bleeding papule
- May clinically resemble Spitz or spitzoid melanoma and amelanotic melanoma
- Histologically, this is a vascular tumor with lobular thin capillaries with surrounding fibrous stroma
Deep penetrating nevus:
- Dark dome shaped papule
- Histologically, it is wedged shaped or plexiform growth pattern with melanin pigment
- Well circumscribed and symmetrical
- Can have occasional mitotic figure and cytologic atypia

Board review style question #1

A 7 year old child presents with a new, evolving, reddish, dome shaped papule that is symmetric with regular borders. What are the ABCD criteria of childhood melanoma?

Amelanotic, bleeding / bump, color uniformity, de novo / any diameter
Amelanotic, bleeding / bump, color variegation, diameter > 6 mm
Asymmetry, bleeding / bump, color uniformity, diameter > 6 mm, evolution over time
Asymmetry, irregular borders, color variegation, diameter > 6 mm, evolution over time

Board review style answer #1

A. Amelanotic, bleeding / bump, color uniformity, de novo / any diameter. Childhood melanomas often do not adhere to the conventional ABCDE criteria because often spitzoid melanomas occur. The deviation from the typical criteria includes lesions that are amelanotic, symmetric, pigmented or bleeding with color uniformity. Answers B - D are incorrect because these lesions tend to be de novo and can be of any size. In addition, the evolution of lesions over time is not a good indicator for pediatric melanoma because at this age group, new onset and evolution of common nevi is expected.

Comment Here

Reference: Pediatric melanoma

Board review style question #2

What is the recommended method for biopsy when there is clinical suspicion of melanoma in a child?

Excisional biopsy of entire lesion
Incisional biopsy of thickest portion of the lesion
Punch biopsy of thickest portion of the lesion
Superficial shave biopsy of the entire lesion

Board review style answer #2

A. Excisional biopsy of entire lesion. Excision biopsy is the preferred approach for suspected malignant melanoma. Answer B is incorrect because incision biopsy can be considered for large lesions in areas where cosmetic concerns are heightened, such as on the face or in cases of acral melanoma. In certain instances, incision biopsy may also be justified in regions undergoing recent changes within a giant congenital nevus. However, partial sampling of the lesion will be inadequate for accurate staging. Answers C and D are incorrect because other biopsy methods, including punch and superficial shave techniques, are not recommended as they lack the ability to provide comprehensive histological staging. At times, deeper scoop shave biopsies may be utilized to accurately sample melanoma and determine the lesion's true depth.

Comment Here

Reference: Pediatric melanoma

Board review style question #3

What is the role of fluorescence in situ hybridization (FISH) in the molecular characterization of pediatric melanoma?

Analysis of TERT promoter alterations
Assessment of chromosomal copy number variations
Detection of BRAF mutations
Sequencing of melanoma specific gene panels

Board review style answer #3

B. Assessment of chromosomal copy number variations. FISH is used to identify copy number variations of chromosomes in melanoma and spitz tumors. Answers A, C and D are incorrect because they do not support the purpose of FISH.

Comment Here

Reference: Pediatric melanoma

Pigmented epithelioid melanocytoma

Table of Contents

Definition / general

Melanocytic tumor with heavily pigmented epithelioid, spindled and dendritic melanocytes (Surg Pathol Clin 2021;14:285)

Essential features

Composed of pigmented epithelioid, spindled and dendritic melanocytes with large vesicular nuclei
Associated with Carney complex or can be sporadic

Terminology

Epithelioid blue nevus (EBN)
Animal type melanoma (not recommended based on WHO)
Benign melanocytoma
Melanocytoma

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified

Epidemiology

Median age of 20 - 27 years (Surg Pathol Clin 2021;14:285)
Infants and children
M = F (Am J Clin Dermatol 2018;19:15)
Affects all racial / ethnic groups
Associated with Carney complex or can be sporadic

Sites

Extremities (38.3%), head and neck (30.8%) and trunk (30.8%) (Surg Pathol Clin 2021;14:285)

Pathophysiology

Hypothesized that reduced expression of glutathione S transferase may play a role

Etiology

Unknown etiology

Clinical features

Pigmented epithelioid melanocytoma (PEM) has been divided into 2 general categories (histologically indistinguishable):
- PEM with benign outcome
  - PEM associated with Carney complex
  - PEM combined with other banal nevi
- PEM with low grade neoplasia
  - Sporadic PEM not associated with Carney complex or other banal nevi
Slow growing
Blue to blue-black papules or nodules (Surg Pathol Clin 2021;14:285)
Dermoscopy: displays large and centrally homogeneous or structureless blue areas, with the coexistence of black area and crystalline structures

Diagnosis

Biopsy

Prognostic factors

Overall, a benign to low grade neoplasm
Sentinel lymph node involvement (30 - 50% of cases) (Surg Pathol Clin 2021;14:285)
Rare distant metastasis (Surg Pathol Clin 2021;14:285)
Clinical meaning of lymph node or rare distant metastases remains uncertain; positive regional nodes in PEM do not imply systemic metastatic disease and death secondary to rare systemic metastases has not been reported
Does not appear to be related to sun exposure

Case reports

4 year old African American girl with an enlarging lesion on her right parietal scalp (J Cutan Pathol 2020;47:70)
60 year old Japanese man with a 20 year history of a black dome shaped nodule on the nose (Case Rep Oncol 2018;11:378)
63 year old man with a dermal based nodule on the scalp with blue pigmentation (Int J Mol Sci 2017;18:1769)

Treatment

Complete excision
As regional lymph nodes do not imply systemic metastatic disease, aggressive therapy is not recommended

Clinical images

Images hosted on other servers:

Pigmented nodule on scalp

Blue-black, dome shaped nodule on nose

Smooth, blue-black papule with protruding hairs

Verrucous lesion with uniform, gray-brown pigment

Gross description

Domed, papular or nodular lesion with dark blue or purple pigmentation
May be multifocal

Microscopic (histologic) description

Wedge shaped and relatively well circumscribed proliferation of melanocytes and melanophages, with the majority having overlying epidermal hyperplasia and dark, evenly distributed pigmentation
Junctional component generally consists of isolated dendritic melanocytes with upward spread into the spinous layer but some PEM are entirely intradermal or consist of large nests reminiscent of Spitz / spindle cell nevus of Reed
Dermal component consists of single cell or small nests of melanocytes that do not show maturation but can have periadnexal, perivascular and perineural extension
4 cell types described (most show mixed cell population):
- Small epithelioid cells
- Large epithelioid cells; can be multinucleated, similar to a Reed-Sternberg cell
- Spindle shaped melanocytes
- Melanophages
Vesicular nuclei with large, central nucleoli
Rare or absent mitoses and necrosis
Histologic features more concerning for PEM with low grade malignancy:
- Large size: extending to subcutis
- Cytologic atypia
- Solid sweeping fascicles with no intervening collagen fibers
- Poor circumscription
PEM with PRKCA fusion: solid sheets of pigmented epithelioid melanocytes, younger patients
PEM with PRKAR1A mutation: more cytologic heterogeneity, may have conventional nevus component with smaller nests, separated by fibrous bands of collagen
References: Calonje: McKee's Pathology of the Skin, 5th Edition, 2019, Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014, Busam: Pathology of Melanocytic Tumors, 1st Edition, 2018

Microscopic (histologic) images

Contributed by Elnaz Panah, M.D. and Jodi Speiser, M.D.

Intradermal melanocytic proliferation

Numerous melanophages

Melanocytes with vesicular nuclei

HMB45

MART1 / Ki67

Positive stains

Negative stains

Loss of cytoplasmic PRKAR1A in combined PEMs and in a subset of pure PEMs but PRKAR1A is retained in PEM associated with PRKCA fusion (Busam: Pathology of Melanocytic Tumors, 1st Edition, 2018)

Electron microscopy description

Large indented nuclei with abundant cytoplasm
Numerous single melanosomes varying in size
Melanosomes seen in the early stage of maturation, a pleomorphic appearance (Arch Dermatol 2009;145:55)

Molecular / cytogenetics description

Loss of cytoplasmic expression of PRKAR1A
Inactivating alterations in protein kinase A regulatory subunit R1 alpha gene (PRKAR1A) with a preceding mutation of BRAF (seen in combined PEM) or less frequently, NRAS (J Cutan Pathol 2019;46:878)
Fusions in protein kinase C alpha fusion (PRKCA) (J Cutan Pathol 2019;46:878)
Mutations of MAP2K1 associated with loss of expression of PRKAR1A
Recently, a subset of combined lesions PEM + spitzoid was described (Am J Dermatopathol 2022;44:568)
CD63::PRKCB fusion was also described (Pediatr Dermatol 2022;39:322)

Sample pathology report

Skin, biopsy / excision:
- Pigmented epithelioid melanocytoma
- Microscopic description: The sections show a symmetric, compound, wedge shaped mass spanning most of the dermis and comprised of predominantly melanophages and scattered melanocytes. There is epidermal hyperplasia overlying the lesion. The junctional component is relatively inconspicuous and composed of scattered, single dendritic melanocytes. The dermal component is composed of epithelioid and dendritic melanocytes with large, vesicular nuclei and large, central nucleoli.

Differential diagnosis

Animal type melanoma:
- Controversial diagnosis; some experts use the terms PEM and animal type melanoma interchangeably, some group them into pigment synthesizing melanocytic tumors and some consider them a malignant variant of PEM
- Asymmetric proliferation of deeply pigmented and large epithelioid cells
- Cells obliterate the collagen fibers and can involve the subcutis
- Widespread uniform cellular atypia and mitoses
Typically all of these entities lack the PRKAR1A changes of PEM (loss of cytoplasmic expression, molecular changes)
- Blue nevus-like melanoma (malignant blue nevus):
  - Pigment is irregularity distributed
  - Proliferation comprises atypical epithelioid cells
  - Lack of benign looking spindle cell component
  - Junctional component similar to melanoma in situ
- Blue nevus with epithelioid cells:
  - Dermal proliferation of monomorphic epithelioid polygonal cells
  - No dendritic cellular component, junctional component
  - GNAQ and GNA11 mutations are present
- Deep penetrating nevus:
  - Clear cut plexiform architecture (extension of melanocytes along the path of adnexal structures, blood vessels and nerve bundles)
  - Less pigmented
  - Consists of predominantly larger clear cells
- Common blue nevus:
  - No junctional component
  - Lack of epithelioid cells
  - GNAQ and GNA11 mutations are present
Pigmented spindle cell nevus of Reed:
- Predominantly epidermal lesion composed of large nests of spindle cells
- Pigment generally most prominent in epidermis, at dermal / epidermal junction and within the papillary dermis
- Nests can coalesce to form a long ribbon with an underlying inferior smooth border
- Nuclei are small, basophilic and inconspicuous
Psammomatous melanotic schwannoma:
- Asymmetric with variable pigmentation, psammoma bodies, focal nuclear palisading and mild cytologic atypia
- Lacks heterogenous combination of elongated dendritic cells, epithelioid dendritic cells and melanophages
Melanoma developing in a nevus:
- Asymmetric
- Most commonly has an epidermal component with upward spread
- Lacks heterogenous combination of elongated dendritic cells, epithelioid dendritic cells and melanophages
- Widespread cytologic atypia and frequent mitotic activity
Pigmented primary nodular melanoma and metastatic melanoma:
- Asymmetric
- Lacks heterogenous combination of elongated dendritic cells, epithelioid dendritic cells and melanophages
- Widespread cytologic atypia, frequent mitotic activity, necrosis

Additional references

Elder: WHO Classification of Skin Tumours, 4th Edition, 2018

Board review style question #1

Based on the pictures shown above, which of the following syndromes can be seen with the diagnosis?

Carney complex
Cowden syndrome
Gorlin syndrome
Muire-Torre syndrome

Board review style answer #1

A. Carney complex

Comment Here

Reference: Pigmented epithelioid melanocytoma

Board review style question #2

What are the histologic characteristics of pigmented epithelioid melanocytoma?

Asymmetric proliferation of deeply pigmented and large epithelioid cells, which obliterate the collagen fibers
Asymmetric proliferation with variable pigmentation, psammoma bodies, focal nuclear palisading and mild cytologic atypia
Proliferation comprised of atypical epithelioid cells with irregularly distributed pigmentation
Proliferation of larger clear cells with plexiform architecture
Wedge shaped and relatively well circumscribed proliferation of melanocytes and melanophages with the majority having overlying epidermal hyperplasia and dark, evenly distributed pigmentation

Board review style answer #2

E. Wedge shaped and relatively well circumscribed proliferation of melanocytes and melanophages with the majority having overlying epidermal hyperplasia and dark, evenly distributed pigmentation. Pigmented epithelioid, spindled and dendritic melanocytes with large vesicular nuclei.

Comment Here

Reference: Pigmented epithelioid melanocytoma

Proliferative nodule (pending)

[Pending]

Recurrent nevus (pending)

[Pending]

Reed nevus

Table of Contents

Definition / general

First described by Reed in 1975
Heavily pigmented nevus, often recent onset, widely considered a Spitz nevus variant (J Am Acad Dermatol 1993;28:565)
Clinically and histologically simulates melanoma

Terminology

Also called Reed's nevus

Epidemiology

Young adults, commonly women (Am J Surg Pathol 1984;8:645)
Median age 25 (Dermatol Online J 2004;10:5)

Sites

Proximal extremities or trunk (Am J Surg Pathol 1984;8:645)

Clinical features

< 1 cm, solitary, deeply pigmented and well circumscribed maculopapule
Clinically resembles melanoma

Case reports

23 year old woman with pigmented lesion since childhood on lower leg (Australas J Dermatol 2011;52:104)

Treatment

Conservative but complete excision
Does not recur

Dermoscopy

2 patterns reported:
1. Brown to blue pigmentation with peripheral rim of large brown globules (globular pattern)
2. Dark diffused pigmentation and pseudopods regularly distributed at periphery in stellate or radiate pattern (starbust pattern) (Dermatol Online J 2004;10:5)

Clinical images

AFIP images

Small and
symmetrical
lesion differs
from Spitz nevus

Images hosted on other servers:

Rim of brown globules around lesion

Pseudopods arranged regularly

Small multicolored lesion

Slightly raised dark lesion

Microscopic (histologic) description

Some similarity with Spitz nevi
Symmetric with cytologic maturation
Nests and fascicles of spindled melanocytes along dermoepidermal junction and within dermal papillae
May be junctional or compound
Expansive, not infiltrative growth pattern
Extends no deeper than reticular dermis
Nevus cells typically contain abundant melanin pigment, may be associated with melanophages
Nuclei are monotonous, resemble normal keratinocytes and may have small nucleoli
Often has architectural or cytologic atypia (Hum Pathol 1991;22:52)
Variable lymphocytic infiltrate at base of lesion
Variable transepidermal elimination of junctional nests
No / rare mitotic figures
Note: hypopigmented variant is similar but without abundant melanin (J Cutan Pathol 2008;35 Suppl 1:87)

Microscopic (histologic) images

AFIP images

Various images

Images hosted on other servers:

Symmetric pigmented tumors (figs 6 - 9)

Symmetric pigmented tumor

Pigmented spindle cell tumor

Positive stains

HMB45 highly expressed in intraepidermal component of pigmented spindle cell nevus (PSCN) and spindle cell melanoma but dermal component negative in PSCN, irregularly positive in spindle cell melanoma (Am J Surg Pathol 2011;35:1733)
Other melanocytic markers (S100, MelanA)

Molecular / cytogenetics description

FISH targeting 6p25 (RREB1), 11q13 (CCND1), 6q23 (MYB) and centromere 6 may differentiate from melanoma (Am J Surg Pathol 2011;35:1733, Adv Anat Pathol 2011;18:229)

Videos

Pigmented spindle cell nevus

Differential diagnosis

Spindle cell melanoma
Spitz nevus
Superficial spreading melanoma (Dermatol Online J 2004;10:5)

Regressed melanoma (tumoral melanosis)

Table of Contents

Definition / general

The definition and classification of histologic regression in melanoma can vary considerably among institutions and even among individual pathologists (Lab Invest 2017;97:657)
On histologic examination, regression can be characterized by the presence of a host response to melanoma consisting of dermal melanophages with associated fibrosis, chronic inflammation, telangiectasias, epidermal attenuation or apoptosis of keratinocytes / melanocytes

Essential features

Regression in melanoma can occur spontaneously or in response to treatment (Lab Invest 2017;97:657)
Histopathological examination reveals a dermal infiltrate comprised of melanophages, chronic inflammation, fibrosis and telangiectasias
Conflicting data have been reported on the prognosis of regressed melanoma; although it has been proposed that partial regression in < 50 - 75% of tumor cells has no effect on prognosis, whereas extensive regression > 75% of tumor tissue may be associated with metastatic disease (An Bras Dermatol 2021;96:797, Arch Dermatol 2002;138:603, World J Surg 1992;16:196, Arch Dermatol 1987;123:1326)

Terminology

Regressive melanoma / partial regression
Tumoral melanosis

ICD coding

ICD-O: 8723/3 - malignant melanoma, regressing
ICD-10: C43.9 - malignant melanoma of skin, unspecified

Epidemiology

Melanoma is the sixth most common fatal malignancy in the United States and the second most common cancer in women aged 20 - 29 years (Exp Ther Med 2020;20:87)
It is expected that ~1 million cases of melanoma are diagnosed yearly in the United States
Patients < 50 years of age have a lower incidence of melanoma but a higher rate of new, changed and regressed nevi than patients > age 50 (Arch Dermatol 2005;141:998)

Sites

Regression in melanoma can occur throughout the body
Although rare, fully regressive melanomas are most commonly found on the lower extremities and trunk in elderly patients (J Clin Aesthet Dermatol 2016;9:42)
~12% are located on the head or neck, while ~9% of regressive melanomas are located on the hands or feet (J Clin Aesthet Dermatol 2016;9:42)

Pathophysiology

Melanoma cells express proteins with strong immunogenic effects such that melanomas with increased expression of MelanA (MART1), gp100 or HLA-A-0201 show increased rates of spontaneous regression (EJC Suppl 2013;11:97)
Regression is a phenomenon in which the host's cytotoxic T lymphocytes attack the primary melanocytic tumor cells and leave behind a fibrotic scar (J Clin Aesthet Dermatol 2016;9:42)
Regression of melanoma clinically can demonstrate subtle hyperpigmentation, followed by depigmentation of parts of or the entirety of the lesion yielding blue, pink, white or gray areas (Lab Invest 2017;97:657)
Some authors postulate 3 levels of regression (Lab Invest 2017;97:657)
- Early stage: characterized by mononuclear inflammatory cell infiltrate with mature lymphocytes and keratinocytes and dermal layer disruption
- Intermediate stage: characterized by lack of melanocytes, the presence of macrophages, lymphohistiocytic infiltrate, fibroblastic proliferation, mild collagen deposition and increased vascular pattern in the superficial dermal layer
- Late stage: lesion with complete absence of melanocytes, fibrosis in the superficial / papillary dermis, ectatic capillaries, variable numbers of melanophages and a small number of inflammatory cells (Exp Ther Med 2020;20:87)

Etiology

Risk factors for melanoma include ultraviolet (UV) light radiation, prior history of sunburns, increased numbers of congenital or acquired nevi and family history of melanoma (i.e., genetic susceptibility) (Exp Ther Med 2020;20:87)
There are no specific factors that cause regression; however, the majority of the cases are described after metastasis (J Natl Cancer Inst 2001;93:1047)

Clinical features

~10 - 35% of cutaneous melanoma cases may completely or partially spontaneously regress (Histopathology 1992;20:315)
Histologic regression may not necessarily correlate with clinical regression (i.e., clinically looks like melanoma)
Management of regressed melanoma still determined by stage (dependent on Breslow depth and presence or lack of ulceration)

Diagnosis

Diagnosis of regressive melanoma is made in conjunction with clinical, dermatoscopic and pathologic findings (J Clin Aesthet Dermatol 2016;9:42)
Diagnosis depends on histologic examination
Dermatoscopic examination of fully regressed melanoma may reveal scar-like depigmentation, pink macules, linear / irregular vessels, globular vessel patterns, blue-gray peppered papular remnants and white transverse bands (Br J Dermatol 2008;158:1224)

Prognostic factors

According to a recent cohort study of 17,721 Dutch and 4,980 Australian patients with stage 1 or 2 melanoma, regression was significantly associated with improved overall survival (especially tumors with Breslow thickness ≤ 4.0 mm) (JAMA Dermatol 2021;157:166)
However, it is also known that the majority of regressive melanomas are discovered after the occurrence of metastasis, making it a potential negative prognostic factor in melanoma (Exp Ther Med 2020;20:87)

Case reports

40 year old man with metastasis to his brain, 45 year old woman with left sided axillary lymphadenopathy and 45 year old man with a primary lesion on his back (Rom J Morphol Embryol 2014;55:635)
62 year old man with completely regressed melanoma on his back without metastasis (J Clin Aesthet Dermatol 2016;9:42)
62 year old woman with multiple lymph nodes, brain and lung metastases (Exp Ther Med 2020;20:87)

Treatment

Mohs micrographic surgery may be appropriate in certain cases; if signs of regression are present at Mohs layer margins, removal of additional layers may be required (Clin Cosmet Investig Dermatol 2018;11:309)
Immunotherapies such as PD1 and CTLA4 blockers have shown efficacy in some patients, especially when combined with chemotherapy or radiotherapy (Radiol Case Rep 2018;13:580)

Clinical images

Images hosted on other servers:

Solitary bluish to black patch

Asymmetric, variegated, pigmented lesion

Gross description

Asymmetric, variegated or pigmented patch, plaque or nodule with variable black, gray and pink discolorations
Ulceration, crusting, active exsanguination or granulation may be present
Reference: J Clin Aesthet Dermatol 2016;9:42

Frozen section description

Frozen section diagnosis of regressed melanoma is difficult and should be deferred for paraffin sections (Cancer 1983;51:1168)

Microscopic (histologic) description

Variably decreased number of melanoma cells with varying degrees of the following
- Dermal fibrosis
- Inflammatory infiltrate
- Melanophages
- Ectatic blood vessels
- Epidermal attenuation
- Apoptosis of keratinocytes or melanocytes
Importantly, however, there remains a lack of well defined or agreed upon criteria (Lab Invest 2017;97:657)

Microscopic (histologic) images

Contributed by Aadil Ahmed, M.D.

In situ regressed melanoma

Dermal fibroplasia and melanophages

Melanophages with dark brown pigment

Regression with viable melanoma

Tumor melanosis with necrosis

Nodal regression

Positive stains

CD3, CD4, CD8 may be present in local T cells, suggesting active immune response (Exp Ther Med 2020;20:87)
CD68 can highlight melanophages (Lab Invest 2017;97:657)

Negative stains

Negative staining for MelanA, SOX10, S100, HMB45 (J Cutan Pathol 2015;42:388, Am J Dermatopathol 2007;29:22)

Molecular / cytogenetics description

Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) have been found to be helpful in distinguishing difficult cases of melanoma, including regressed melanomas
CEP6, 6p23, 6p25 and 11q13 are suggestive of malignancy (J Clin Aesthet Dermatol 2016;9:42)

Sample pathology report

Skin lesion, biopsy:
- Melanoma in situ with features of regression, extends to peripheral margins (see comment)
- Comment: SOX10 and MelanA immunostains highlight the intraepidermal melanocytic proliferation, demonstrating confluence of growth and pagetoid spread, supporting the above diagnosis. Additionally noted is the presence of superficial dermal fibrosis with associated melanophages, chronic inflammation and telangiectasias. On histologic grounds, these findings are most consistent with that of regression. In this regard, the possibility of a previously regressed invasive component cannot be entirely excluded.

Differential diagnosis

Epidermal nevi:
- Typically present as a linear tan patch or plaque along Blaschko lines that often evolve to become thicker, darker and more verrucous during puberty (Dermatol Clin 2022;40:61)
Pigmented actinic keratosis:
- A variant of actinic keratosis in which melanin may be present in keratinocytes of the lower epidermis, in melanocytes or in dermal melanophages (Am J Dermatopathol 2022;44:784)
- May show mild keratinocyte dysplasia involving only the basal epidermal layers which can be misdiagnosed as melanoma in situ
Pigmented basal cell carcinoma:
- A variant of basal cell carcinoma with pigmented nests of basaloid tumor cells
- Peripheral palisading and retraction clefting can commonly be seen on microscopy (J Clin Diagn Res 2013;7:3010)
Pigmented squamous cell carcinoma:
- A variant of squamous cell carcinoma with abundant pigmentation among intraepidermal / dermal aberrant keratinocytes
- Tumor cells may express both melanin positivity (e.g., MelanA) and cytokeratin (e.g., AE1 / AE3) (An Bras Dermatol 2018;93:96)
Macular seborrheic keratosis:
- Acanthosis, hyperkeratosis and pseudohorn cysts may be present (Open Access Maced J Med Sci 2018;6:2270)
Regressed lichenoid keratosis:
- More frequently have necrotic keratinocytes in the epidermis
- Less often have dense infiltrates of melanophages in papillary dermis

Board review style question #1

A 60 year old man presents with an 11 mm x 9 mm asymmetric, variegated pigmented lesion with gray and pink discoloration on his right leg diagnosed as regressed melanoma. Which of the following would be revealed by histopathology?

Dense, dermal melanophage infiltrate but no atypical melanocytes
Large basaloid lobules with peripheral nuclear palisade within fibromyxoid stroma
Lobules of capillary sized vascular channels, lined by single layer of flattened endothelial cells
Lymphocytes surrounding the entire melanocytic proliferation in a band-like pattern
Spindled banal appearing melanocytes in the dermis with pigment in the cytoplasm

Board review style answer #1

A. Dense, dermal melanophage infiltrate but no atypical melanocytes. Regressed melanoma can present clinically by initially subtle hyperpigmentation, followed by depigmentation of parts of or the entirety of the lesion yielding blue, pink, white or gray areas. Histopathology is characterized by dense, dermal melanophage infiltrate but no atypical melanocytes. Answer B is incorrect because it describes basal cell carcinoma. Answer C is incorrect because it describes lobular capillary hemangioma. Answer D is incorrect because it describes features of a halo nevus. Answer E is incorrect because it describes blue nevus.

Comment Here

Reference: Regressed melanoma (tumoral melanosis)

Board review style question #2

Which immunohistochemical stain is positive in completely regressed melanomas?

Fontana-Masson
HMB45
MelanA
S100
SOX10

Board review style answer #2

A. Fontana-Masson. Fontana-Masson stains the melanin pigment in melanophages. Answers B - E are incorrect because regressed melanoma is characterized by negative staining for MelanA, SOX10, S100 and HMB45.

Comment Here

Reference: Regressed melanoma (tumoral melanosis)

Sentinel node biopsy

Table of Contents

Definition / general

Sentinel lymph node is defined as first extracutaneous target of lymphogenous tumor cell spread and potential source of subsequent lymph node metastases and distant metastases (eMedicine)
Interval sentinel nodes: nodes receiving direct lymphatic drainage from primary site but lying between tumor and a recognized node field (Ann Surg Oncol 2011;18:3292)
Lymphatic mapping and sentinel lymph node biopsy are widely used for staging

Recommendations

Recommended for patients with intermediate thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site (J Clin Oncol 2012;30:2912)
Tumor in sentinel node by H&E predicts recurrence (Mod Pathol 2007;20:427), usually leads to dissection of lymph nodes in affected nodal basin (Ann Surg Oncol 2008;15:1566), which reduces recurrence (Curr Treat Options Oncol 2008;9:243)
Measuring antimony (originating from antimony sulfide colloid) can confirm sentinel nature of node (Mod Pathol 2004;17:1191)

Diagrams / tables

Images hosted on other servers:

Intraoperative lymphatic mapping and sentinel node

Prognostic factors

Predictors of positive sentinel nodes: Breslow thickness < 1 mm (Int J Surg 2008;6:205); lymphatic invasion using D2-40, ulceration (Arch Dermatol 2008;144:462), younger age (Ann Surg Oncol 2008;15:630), low density of tumor infiltrating lymphocytes (TILs, J Clin Oncol 2012;30:2678), absence of regression (Ann Surg Oncol 2011;18:3593)
Predictors of positive non sentinel nodes in sentinel node positive patients (occurs in 20 - 35%): amount of tumor in sentinel node, Breslow thickness of primary melanoma and density of dendritic WBCs in sentinel node paracortex (Mod Pathol 2004;17:747); also perinodal intralymphatic tumor (Ann Surg Oncol 2008;15:1723), depth of invasion in sentinel node (Ann Surg Oncol 2008;15:1202)
Intraoperative touch imprints may be accurate (Anticancer Res 2008;28:465)
Patients with triple negative (H&E, S100 / HMB45, RT-PCR) nodes have a markedly improved survival (Mod Pathol 2008;21:438)
Micrometastasis: single metastasis < 2 mm are NOT associated with metastases in non sentinel nodes (J Surg Oncol 2008;98:46)

Selected protocols for sentinel nodes:

3 levels at 250 micrometer intervals, each level has 1 section stained with H&E, S100 and HMB45 (Am J Surg Pathol 2005;29:305) OR
2 H&E sections, S100 and HMB45 (Am J Surg Pathol 2003;27:1197)
4 sequential sections of both halves of each sentinel node examined - first and fourth sections stained with H&E, second section stained for S100 and third section for HMB45 (Semin Diagn Pathol 2008;25:100)
Complete step sectioning of nodes with high gamma counts (Ann Surg Oncol 2008;15:1492)

Clinical images

Images hosted on other servers:

Lymphatic mapping

Intraoperative left
axillary node
seen after uptake
with blue dye

Microscopic (histologic) images

Images hosted on other servers:

D2-40+ lymphatic in tumor

Increased 11q13 (cyclin D1) by FISH

Tattoo pigment (not tumor)

Positive stains

S100 and NKI-C3 are most sensitive stains for nodal metastases but are nonspecific; MART1 is most specific (Am J Surg Pathol 2001;25:1039)
S100 and MART1 together are recommended (Hum Pathol 2004;35:217)
Pattern of reticulin staining may help distinguish positive node from nodal nevus (Am J Dermatopathol 2013;35:452)

Molecular / cytogenetics description

RT-PCR: prognostic significance of melanocytic mRNA in histologically negative nodes is controversial (significant - APMIS 2008;116:199, not significant - Mod Pathol 2007;20:427)
RT-PCR detects significant sentinel node metastases that are missed by histopathology but overestimates number of patients with clinically significant metastases (Melanoma Res 2003;13:313)
FISH detects chromosomal aberrations in 83% of nodal metastatic melanoma vs. 6% of nodal nevi (Am J Surg Pathol 2010;34:231)

Videos

Wide excision and sentinel node mapping

Differential diagnosis

Antigen presenting interdigitating dendritic cells
Benign nevus cells: usually in capsule, also parenchyma, no atypia, MART1+, S100+, HMB45- and Ki67- (Am J Surg Pathol 2002;26:1351, Am J Surg Pathol 2003;27:673)
Histiocytes: no atypia
Tattoo pigment, see Dermatol Online J 2005;11:14

Special site nevus

Table of Contents

Definition / general

Melanocytic nevi located on specific anatomical sites, such as the scalp, ear, breast, umbilicus, genital skin, acral skin, axilla and other flexural sites that may demonstrate atypical histologic features (Am J Dermatopathol 2016;38:867, Mod Pathol 2006;19:S4)

Essential features

Benign melanocytic tumors
May display atypical features, such as pagetoid spread, lentiginous growth and epidermal effacement
Lack of deep or atypical mitoses

Terminology

Melanocytic nevi with site related atypia, melanocytic nevi of special sites

ICD coding

ICD-10:
- D22.2 - melanocytic nevi of ear and external auricular canal
- D22.4 - melanocytic nevi of scalp and neck
- D22.6 - melanocytic nevi of upper limb, including shoulder
- D22.7 - melanocytic nevi of lower limb, including hip
ICD-11:
- 2F20.Y - other specific types of melanocytic nevus
- 2F20.Z - melanocytic nevus, unspecified

Epidemiology

Melanocytic nevi of the breast appear to be the most common special site (56%), followed by axilla (16%) and then scalp (12%) (J Cutan Pathol 2020;47:664)
Melanocytic nevi of the ear do not appear to have a predilection for age (5 - 86 years, mean: 42.4) and occur in a similar frequency between males and females (F:M = 1.1:1) (J Cutan Pathol 2005;32:40)
Scalp melanocytic nevi are more commonly found in adolescents with a slightly higher frequency of occurrence in males; adults and children are less commonly affected (Br J Dermatol 2011;165:137)
Breast melanocytic nevi more commonly present in younger females ages 30 - 40 but may occur in both men and women (J Am Acad Dermatol 2016;75:364, J Cutan Pathol 2004;31:137)
Genital melanocytic nevi most commonly present in premenopausal, reproductive age woman with a median age of 26 years but may occur in children and commonly involve mucosal sites (Am J Surg Pathol 2008;32:51)
Acral melanocytic nevi occur with a frequency of 10 - 30% in the population and are more common in patients of color (Arch Dermatol 2010;146:1085)

Pathophysiology

Melanocytic nevi can be either acquired or congenital
Acquired melanocytic nevi are thought to result from activation of oncogenes such as BRAF (usually BRAF V600E) or NRAS, resulting in clonal proliferation of melanocytes (J Invest Dermatol 2019;139:1762)
Congenital melanocytic nevi are thought to result from arrested migration of melanocyte precursor neural crest derived stem cells within the dermis

Etiology

Etiology of variation in histologic features of site specific melanocytic nevi is not known
Possible causes that determine these peculiar cytologic and architectural features are unknown; developmental factors or hormonal changes (e.g., those occurring in adolescence and pregnancy) have been suggested as contributing factors

Diagrams / tables

Nevi site	Atypical nevi features	Differentiating features from melanoma
Scalp	Lentiginous growth, pagetoid spread, loss of symmetry	Lack of severe atypia (uniform atypia), dermal maturation, lack of deep or atypical mitoses
Ear	Pagetoid spread, irregular nesting pattern, cytologic atypia, may induce host inflammatory response	Dermal maturation, lack of severe atypia (uniform atypia), symmetry, lack of deep or atypical mitoses
Breast	Dyshesive nests, cytologic atypia, rete effacement	Dermal maturation, symmetry, effacement of rete limited to center, lack of deep or atypical mitoses
Genital	Large dyshesive nests, lentiginous growth, asymmetry is common, pagetoid spread	Dermal maturation, lack of deep or atypical mitoses, limited pagetoid spread
Acral	Lentiginous growth, pagetoid spread	Lentiginous growth does not involve crista profunda intermedia, lack of deep or atypical mitoses, dermal maturation

Clinical features

Melanocytic nevi of the ear:
- May present as macules or papules
- Uniform coloration (light or dark brown) (Busam: Pathology of Melanocytic Tumors, 1st Edition, 2018)
Melanocytic nevi of acral skin:
- More common in patients of color (J Am Acad Dermatol 2016;74:724)
- Well circumscribed
- Parallel furrow dermoscopic patterns are common
Melanocytic nevi of the genitals:
- Predilection for premenopausal and reproductive age women (Am J Surg Pathol 2008;32:51)
- May affect hair bearing and mucosal sites
Melanocytic nevi of the breast:
- Predilection for premenopausal and reproductive age women (J Am Acad Dermatol 2016;75:364)
- Irregular borders
- Irregular pigment network and nonuniform dots and globules
Melanocytic nevi of the scalp:
- More common in adolescent males (Br J Dermatol 2011;165:137)
- Flat, papular or plaque-like
- Perifollicular hypopigmentation commonly seen on dermoscopy
Melanocytic nevi of the umbilicus:
- More common in women
- The umbilicus and periumbilical region are considered to be anatomically located in the milk line, an ectodermal ridge associated with mammary gland and breast development (Histopathology 2015;66:363)

Diagnosis

Clinical presentation and dermoscopic findings
Definitive diagnosis is made through histologic examination of excised specimen

Case reports

5 year old girl with an asymptomatic, brown, pigmented macule on the left nipple areolar complex (Breast J 2016;22:237)
18 year old woman with an asymptomatic raised, pigmented swelling over the scalp since birth, with initial focal hair loss followed by rapid enlargement of the lesion with hair growth (Int J Trichology 2019;11:253)
24 year old woman with pain, itching and discharge from left ear nevus, mimicking pyogenic granuloma (Otol Neurotol 2022;43:e137)
Man in his mid 30s with a pigmented lesion on the glans penis that quickly grew in size over a 10 month period, mimicking melanoma (JAAD Case Rep 2020;6:323)
43 year old woman with a large brown-yellow cerebriform plaque on the dorsum of the hand present since birth (Indian J Dermatol Venereol Leprol 2021;87:876)

Treatment

Complete excision

Microscopic (histologic) description

Many nevi from special sites have typical features that, when taken in conjunction with the unusual morphologic features that may be present and the patient’s clinical information, assist in deciding whether the lesion is an atypical melanocytic proliferation or a nevus with special site features
- A junctional melanocytic proliferation in a patient > 50 years without a bland dermal component should be regarded as suspicious, while a relatively atypical lesion in a younger patient is unlikely to be malignant
- Equally as important is the morphology of the melanocytes present, with vertically orientation and coarse melanosomes conveying higher risk of malignancy
Melanocytic nevi of the ear (Am J Dermatopathol 2005;27:111):
- Frequently display poor lateral circumscription
- Junctional nests may not be centered and can be placed within inter-rete spaces and along sides of rete
- May display pagetoid spread
- Irregular nesting pattern
- Cytologic atypia that is uniformly present may be seen
- May induce a host inflammatory response
Melanocytic nevi of the acral skin (Am J Dermatopathol 2016;38:867):
- May have unusually prominent pagetoid or lentiginous growth pattern
- Should not display high grade cytologic atypia
- Dermal component should display well formed nests and maturation with descent
- Cytologic atypia and mitotic activity should not be seen in dermal component
- There is an absence of lentiginous involvement of the crista profunda intermedia
- Banal appearing nests along eccrine apparatus are an acceptable feature in acral nevi
Melanocytic nevi of the genitals (Am J Surg Pathol 2008;32:51):
- May contain large dyshesive irregular nests in close proximity to one another
- May contain a prominent lentiginous component
- Deeper nests may evoke a stromal fibrotic host response
- Lesion should maintain symmetry, circumscription and maturation
- Pagetoid growth can be seen but typically does not extend into granular layer
- Junctional component may extend into adnexal structures
- Significant cytologic atypia can occur
Melanocytic nevi of the breast (Am J Dermatopathol 2016;38:867):
- May contain large irregular dyshesive nests in close proximity to one another
- Junctional nests may not be centered and can be placed within inter-rete spaces and along sides of rete
- Nests may have variable pigmentation (results in globules seen on dermoscopic exam)
- Nests may have prominent horizontal streaming resulting in rete blunting or epidermal effacement
- Cytologic atypia is common
- Maturation with melanocyte descent should be retained
Melanocytic nevi of the scalp (Am J Dermatopathol 2016;38:867):
- Melanocytes can be enlarged with irregular nuclei but atypia should be uniform throughout the nevus
- May contain large irregular nests in close proximity to one another
- Lentiginous growth may be prominent
- Pagetoid spread is a common feature
- Lesion can have broad junctional involvement and involve adnexa
- Single cell dispersion can be seen at lateral edges
- Lateral circumscription and maturation should be maintained, however symmetry may be lost (Am J Dermatopathol 2016;38:867)
- Prominent stromal fibrotic response can be seen
Melanocytic nevi of the umbilicus (Histopathology 2015;66:363):
- May have large variability in the size of junctional nests with a dyshesive pattern
- Junctional nests may not be centered and can be placed within inter-rete spaces and along sides of rete
- May have lamellar fibrosis that is confluent and extends into the reticular dermis, entrapping dermal melanocytes
- Maturation of entrapped cells may be impaired, however surrounding unentrapped melanocytes should continue to mature normally
- Shouldering, bridging and lentiginous growth pattern are common

Microscopic (histologic) images

Contributed by Dean Holliday, M.D. and Carlos N. Prieto-Granada, M.D.

Melanocytic nevus of the ear

Breast melanocytic nevus

Umbilicus melanocytic nevus

Genital melanocytic nevus

Acral melanocytic nevus

Positive stains

Melanocytic markers (HMB45, S100, MelanA, SOX10)

Molecular / cytogenetics description

Driver mutations in MAPK signaling pathway involving either BRAF V600E or NRAS Q61R / Q61L (J Invest Dermatol 2019;139:1762)

Sample pathology report

Skin, left breast, biopsy:
- Compound melanocytic nevus with architectural disorder consistent with nevus of special site (see comment)
Vulva, biopsy:
- Compound melanocytic nevus with features of nevi of special sites, present at peripheral tissue edge (see comment)
Comment: Histologic sections show a junctional / compound melanocytic proliferation with a junctional component exhibiting architectural disorder in the form of irregularly placed nests containing dyshesive pigmented melanocytes. These features have been associated with melanocytic nevi arising from so called special sites, which include the ear, milk line and genital areas, among others.

Differential diagnosis

Melanoma:
- May have atypical mitotic figures
- May have marked atypia
- Poor symmetry
- See Diagrams / tables
Dysplastic nevus:
- Large overlap in histopathologic features with special site nevi
- Poor maturation and occurrence at nonspecial site location

Additional references

Elder: WHO Classification of Skin Tumours, 4th Edition, 2018, Patterson: Weedon's Skin Pathology, 5th Edition, 2020

Board review style question #1

Which of the following anatomic locations is considered a special site for nevi?

Back
Ear
Forearm
Lymph node

Board review style answer #1

B. Ear

Comment Here

Reference: Special site nevus

Board review style question #2

Which of these features may be seen in melanoma but should not be observed in nevi from special sites?

Deep and atypical mitoses
Effacement of rete ridges
Lentiginous growth
Pagetoid spread

Board review style answer #2

A. Deep and atypical mitoses

Comment Here

Reference: Special site nevus

Spitz nevus

Table of Contents

Definition / general

Spitz nevi are benign neoplasms composed of large epithelioid or spindled melanocytes (Adv Anat Pathol 2010;17:73)

Essential features

Benign melanocytic tumors
Composed of large spindled and epithelioid melanocytes
Primarily affect children and young adults
Treatment options: observation or complete excision

Terminology

First described by Sophie Spitz in 1948 (Am J Pathol 1948;24:591)
Synonyms for Spitz nevus:
- Spindle cell nevus
- Spindle and epithelioid cell nevus

ICD coding

ICD-O: 8770/0 - epithelioid and spindle cell nevus

Epidemiology

Exact data about prevalence and incidence are lacking
Approximately 1 - 2% of all excised nevi are Spitz nevi
Predilection for children and young adults but may occur at any age
Females are affected more commonly than males
Congenital Spitz nevi are very rare
References: Cancer 1977;40:217, Am J Surg Pathol 2002;26:654

Sites

Anatomical distribution of Spitz nevi is wide
Lower extremities, the face (especially in children) and the trunk (preferably in adults) are most commonly affected
Reference: Adv Anat Pathol 2010;17:73

Pathophysiology

Generally arises de novo and lacks oncogenic mutations common to conventional and blue nevi
Congenital variants have been described

Etiology

Etiology of Spitz nevi is unknown
Spitzoid melanocytic neoplasms have significant morphologic and molecular differences from conventional melanocytic lesions

Clinical features

Prototypic or conventional Spitz nevi are solitary, well circumscribed, symmetrical, pink or pigmented, dome shaped papules several millimeters in size, typically < 6 mm
May appear verrucous and may ulcerate
Can resemble hemangioma or pyogenic granuloma
Rarely occur in multiples, either disseminated or in clusters (agminated Spitz nevi)
Show a risk of recurrence after incomplete excision
Behavior is entirely benign
Reference: Am J Dermatopathol 2009;31:107

Diagnosis

The diagnosis of conventional Spitz nevi is straightforward clinically and histopathologically
Spitz nevi need to be distinguished from atypical Spitz tumors and spitzoid melanomas including Spitz melanomas

Laboratory

Not applicable; no laboratory values exist to diagnose or monitor Spitz nevi

Prognostic factors

Conventional Spitz nevi are benign, the prognosis is good
Recurrences should be treated with re-excision

Case reports

Infant with a congenital Spitz nevus clinically mimicking melanoma (J Am Acad Dermatol 2002;47:441)
4 year old boy with acral pigmented Spitz nevus that clinically mimicked acral lentiginous malignant melanoma (Ann Dermatol 2011;23:246)
4 year old Caucasian boy with agminated Spitz nevus arising in normal skin with redundant HRAS mutation (Eur J Dermatol 2017;27:73)
8 year old girl with a pseudogranulomatous Spitz nevus mimicking a granulomatous dermatitis (J Cutan Pathol 2013;40:330)
9 year old boy with angiomatoid Spitz nevus (Pathology 2016;48:739)

Treatment

Complete excision with evaluation of margins

Clinical images

AFIP images

Small, symmetrical pinkish tan lesion

Images hosted on other servers:

On ear of child

Gross description

Well circumscribed, dome shaped pink or pigmented papule, size is several millimeters (usually < 1 cm)

Microscopic (histologic) description

Conventional Spitz nevi are well circumscribed, symmetrical and show an overall wedge shaped silhouette
Consist of large junctional and dermal melanocytic nests formed by spindled or epitheliod cells
Melanocytes are large, spindled or epitheliod, contain abundant pale or ground glass cytoplasm and finely dispersed pigment (if present)
Mild nuclear pleomorphism may occur, mitoses are rare or absent
Melanocytic nests may show maturation with depth and break up into single melanocytes at the dermal base of the lesion
Junctional nests often show separation artifacts (clefting) to the surrounding epidermis and are oriented perpendicularly to the epidermis
Mild pagetoid scatter of single melanocytes may be a feature but is usually confined to the lower half of the epidermis and found only in the center of the lesion
Transepidermal elimination of melanocytic nests may occur
A typical finding of classic Spitz nevi are PAS+, eosinophilic, hyaline globules, so called Kamino bodies, located at the dermoepidermal junction
Perivascular lymphocytic infiltrates are variably present
Histopathological variants of Spitz nevi:
- Pigmented spindle cell nevus (Reed nevus)
- Angiomatous Spitz nevus
- Desmoplastic Spitz nevus
- Plexiform Spitz nevus
- Polypoid Spitz nevus
- Agminated Spitz nevus
- Pseudogranulomatous Spitz nevus
- Myxoid Spitz nevus
- Combined Spitz nevus
Reference: J Am Acad Dermatol 2014;71:1077

Microscopic (histologic) images

Contributed by Katharina Wiedemeyer, M.D., Ph.D.

Symmetrical, sharply demarcated tumor

Nested spindled and epitheliod melanocytes

Epidermal hyperplasia and large junctional nests

Kamino bodies and clefting of junctional nests

Epithelioid cell morphology

No cell atypia within dermis

Spindle cell morphology

Cytology description

Cytology is not performed on Spitz nevi; for cell morphology please see Microscopic (histologic) description

Positive stains

S100
MART1 / MelanA
SOX10
HMB45 in junctional melanocytes and cells of papillary dermis
Ki67 proliferation index < 5%
p16
ALK, ROS, NTRK (in Spitz nevi with fusions involving ALK, ROS or NTRK)
Reference: Mod Pathol 2003;16:505

Negative stains

Electron microscopy description

No elecron miscroscopic studies of Spitz nevi exist

Molecular / cytogenetics description

Biologically distinct entity, unlike common aquired melanocytic nevi and melanoma no BRAF or NRAS mutations
Genomic rearrangements of ALK (ALK fusions), ROS1 and NTRK1 kinases can occur
HRAS mutation occurs, especially in desmoplastic Spitz nevi
References: Pathology 2016;48:113, Am J Surg Pathol 2014;38:925, Nat Commun 2014;5:3116

Sample pathology report

Skin, left arm (clinical nevus), excision:
- Spitz nevus, conventional (see comment)
- Comment: The gross specimen is a 0.5 cm, pink-brown, dome shaped papule of the right arm. Microscopically, the tumor is symmetrical and well demarcated with a wedge shaped growth pattern. There is epidermal hyperplasia with hypergranulosis and hyperkeratosis. The tumor consists of large melanocytic nests composed entirely of spindle and epithelioid cells containing abundant cytoplasm with varying amounts of melanin granules. Single Kamino bodies are found at the dermal-epidermal junction, with occasional upward scatter of single melanocytes confined to the center of the lesion. No atypia is noted. Dermal melanocytes show maturation with depth and are dispersed singly within the collagen bundles at the base of the tumor. No dermal mitoses are found. Immunohistochemical staining demonstrates strong positivity for S100 protein; HMB45 staining is partially positive within junctional and upper dermal nests. The margins are clear.

Differential diagnosis

Atypical Spitz tumor:
- Age usually > 10 years or postpubertal
- Atypical Spitz tumors are usually larger (> 5 - 10 mm) than Spitz nevi and show some worrisome histological features, such as asymmetry, pagetoid scatter in the periphery of the tumor, moderate nuclear pleomorphism and hyperchromatic nuclei
- Mitotic rate can be increased but no mitoses are found in the deep dermis
- There is no reliable immunohistochemical marker to distinguish atypical Spitz tumor from Spitz nevus or Spitz melanoma
Malignant Spitz tumor / Spitz melanoma:
- Age usually postpubertal
- Histopathological criteria of malignancy are size > 10 mm, an asymmetric outline with poor circumscription, infiltrative growth, consumption of the epidermis, ulceration, nuclear pleomorphism, increased mitotic activity within dermis including atypical mitoses, lack of maturation of cells with depth and lymphovascular invasion
References: Surg Pathol Clin 2017;10:281, Pathology 2016;48:113

Additional references

Pediatr Dermatol 2017;34:25, Elder: WHO Classification of Skin Tumours (Medicine), 4th Edition, 2018

Board review style question #1

Are benign melanocytic neoplasms affecting children and young adults
Behave biologically similar to melanoma
Frequently show BRAF mutations
Require wide excision and sentinel lymph node biopsy
Usually affect sun exposed skin of elderly adults

Board review style answer #1

A. Are benign melanocytic neoplasms affecting children and young adults

Comment Here

Reference: Spitz nevus

Board review style question #2

Are always unpigmented
Can show Kamino bodies at the epidermodermal junction
Exhibit marked cytological atypia
Often show atrophy of the epidermis
Show mitoses in the dermis

Board review style answer #2

B. Can show Kamino bodies at the epidermodermal junction

Comment Here

Reference: Spitz nevus

Staging

Table of Contents

Definition / general

All cutaneous melanomas are covered by this staging system
These topics are not covered:
- Melanoma of the conjunctiva
- Melanoma of the uvea
- Mucosal melanoma of the head and neck
- Mucosal melanoma of the urethra, vagina, rectum and anus
- Merkel cell carcinoma
- Squamous cell carcinoma

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the AJCC, 8th Edition, 2018 is mandatory

ICD coding

ICD-10: C43 - malignant melanoma of skin

Primary tumor (pT)

pTX: thickness cannot be assessed (e.g. curettage specimen)
pT0: no evidence of primary tumor (unidentified or completely regressed primary)
pTis: melanoma in situ
pT1a: < 0.8 mm thickness without ulceration
pT1b: < 0.8 mm thickness with ulceration or 0.8 - 1.0 mm thickness with or without ulceration
pT2a: > 1.0 - 2.0 mm thickness without ulceration
pT2b: > 1.0 - 2.0 mm thickness with ulceration
pT3a: > 2.0 - 4.0 mm thickness without ulceration
pT3b: > 2.0 - 4.0 mm thickness with ulceration
pT4a: > 4.0 mm thickness without ulceration
pT4b: > 4.0 mm thickness with ulceration

Notes:

Breslow depth: measure from the surface of the epidermal granular layer to the point of maximum tumor thickness at a right angle to adjacent epidermis
- Measured with a calibrated ocular micrometer
- Measurement is rounded to the nearest 0.1 mm
- Report as "at least _ mm" if the maximum tumor thickness cannot be determined, most commonly when invasive melanoma is present at the edge of a shave biopsy
Ulceration: full thickness epidermal defect including absence of stratum corneum and basement membrane, fibrin deposition and neutrophils and thinning, effacement or reactive hyperplasia of the adjacent epidermis in the absence of a trauma or recent surgical procedure

Regional lymph nodes (pN)

pNX: cannot be assessed (staging procedure not performed or previously removed)
pN0: no regional metastasis
pN1a: 1 nodal metastasis, clinically occult (no in transit / satellite / microsatellite metastasis)
pN1b: 1 nodal metastasis, clinically detected (no in transit / satellite / microsatellite metastasis)
pN1c: negative for nodal metastasis (positive in transit / satellite / microsatellite metastasis)
pN2a: 2 to 3 nodal metastases, clinically occult (no in transit / satellite / microsatellite metastasis)
pN2b: 2 to 3 nodal metastases, clinically detected (no in transit / satellite / microsatellite metastasis)
pN2c: 1 nodal metastasis, clinically occult or detected (positive for in transit / satellite / microsatellite metastasis)
pN3a: 4 or more nodal metastasis, clinically occult (no in transit / satellite / microsatellite metastasis)
pN3b: 4 or more nodal metastasis, clinically detected (no in transit / satellite / microsatellite metastasis)
pN3c: 2 or more nodal metastasis (positive for in transit / satellite / microsatellite metastasis)

Notes:

Regional lymph nodes / sentinel lymph nodes: sentinel node(s) receive direct lymphatic drainage from the primary tumor site as determined by lymphatic mapping
Clinically occult: nodal metastasis detectable only by microscopic evaluation
Clinically detected: lymph node enlarged or abnormal by physical or radiologic examination
Microsatellite metastasis: microscopic (no size cutoff) cutaneous or subcutaneous metastasis adjacent or deep to the primary melanoma; microsatellite cells are not contiguous with those of the primary melanoma (serial step level sections through the tissue block are often necessary for confirmation) and there is no intervening dermal inflammation, fibrosis or scarring
Satellite metastasis: intralymphatic metastasis within 2 cm of the primary melanoma
In transit metastasis: intralymphatic metastasis > 2 cm from primary melanoma but not beyond the regional lymph nodes

Distant metastasis (pM)

pM0: no evidence of distant metastasis
pM1a(0): distant metastasis to skin, soft tissue (including muscle) or nonregional lymph node; LDH level not elevated
pM1a(1): distant metastasis to skin, soft tissue (including muscle) or nonregional lymph node; LDH level elevated
pM1b(0): distant metastasis to lung; LDH level not elevated
pM1b(1): distant metastasis to lung; LDH level elevated
pM1c(0): distant metastasis to non CNS viscera; LDH level not elevated
pM1c(1): distant metastasis to non CNS viscera; LDH level elevated
pM1d(0): distant metastasis to CNS; LDH level not elevated
pM1d(1): distant metastasis to CNS; LDH level elevated

Prefixes

y: post therapy or post neoadjuvant radiotherapy or chemotherapy
r: recurrent tumor
a: autopsy classification

AJCC clinical prognostic stage groups (cTNM)

Completed following the biopsy

Incorporates histologic information from the biopsy with clinical (radiologic) staging data

Stage group 0:	Tis	N0	M0
Stage group IA:	T1a	N0	M0
Stage group IB:	T1b - T2a	N0	M0
Stage group IIA:	T2b - T3a	N0	M0
Stage group IIB:	T3b - T4a	N0	M0
Stage group III:	Any T	≥ N1	M0
Stage group IV:	Any T	Any N	M1

AJCC pathological prognostic stage groups (pTNM)

Generally reserved for patients with disease beyond cTNM stage IA
Completed following the wide surgical excision and staging biopsies (e.g. sentinel node)

Incorporates histologic information from the excision and staging specimens

Stage group 0:	Tis	N0	M0
Stage group IA:	T1a - T1b	N0	M0
Stage group IB:	T2a	N0	M0
Stage group IIA:	T2b - T3a	N0	M0
Stage group IIB:	T3b - T4a	N0	M0
Stage group IIC:	T4b	N0	M0
Stage group IIIA:	T1a - T2a	N1a - N2a	M0
Stage group IIIB:	T0	N1b - N1c	M0
	T1a - T2a	N1b - N2b	M0
	T2b - T3a	N1a - N2b	M0
Stage group IIIC:	T0	N2b - N3c	M0
	T1a - T3a	N2c - N3c	M0
	T3b - T4a	N1a - N3c	M0
	T4b	N1a - N2c	M0
Stage group IIID:	T4b	N3a - N3c	M0
Stage group IV:	Any T	Any N	M1

Registry data collection variables

Breslow tumor thickness (xx.x mm)
Ulceration (yes or no)
Mitotic rate (whole number per square mm²)
Microsatellites, not clinically detected (yes or no)
Tumor infiltrating lymphocytes (absent, non brisk or brisk)
Clark level of invasion (1 - 5)
Regression (yes or no)
Neurotropism (present or absent)
Lymphovascular invasion (present or absent)
In transit / satellite metastasis (in transit, satellite or both)
Regional lymph node clinical or radiological detection (yes or no)
Microscopic confirmation of metastasis in clinical or radiologically detected node (yes or no)
Sentinel lymph node biopsy performed (yes or no)
Number of nodes examined from sentinel node procedure (whole number)
Number of tumor involved nodes from sentinel node procedure (whole number)
Sentinel node tumor burden (cross section diameter of largest discrete deposit in mm)
Extranodal extension in in any lymph node or clinically detected (present or absent)
Completion or therapeutic lymph node dissection performed (yes or no)
Number of lymph nodes examined from completion or therapeutic dissection (whole number)
Number involved with tumor from completion or therapeutic dissection (whole number)
Matted nodes (yes or no)
Distant metastasis to skin, soft tissue or distant (nonregional) node (yes or no)
Distant metastasis to lung (yes or no)
Distant metastasis to non CNS viscera (yes or no)
Distant metastasis to CNS (yes or no)
Serum LDH level and serum LDH level upper limit of normal from laboratory reference range

Notes:

Tumor infiltrating lymphocytes: considered brisk when the inflammation diffusely infiltrates the tumor or is present around the entire base of the tumor
Clark level of invasion: superseded by Breslow depth but often still reported
- Level 1: melanoma in situ
- Level 2: invasion of the papillary dermis
- Level 3: filling but confined to the papillary dermis
- Level 4: invasion of the reticular dermis
- Level 5: invasion of subcutaneous fat
Regression: replacement of melanoma cells by lymphocytic inflammation; this commonly has the appearance of an attenuated epidermis with rete effacement, mild dermal fibrosis and vascular ectasia with perivascular lymphocytes and melanophages

Histologic grade (G)

Not used in melanoma staging

Histopathologic type

Modified World Health Organization classification (Elder: WHO Classification of Skin Tumours (Medicine), 4th Edition, 2018)
- Superficial spreading melanoma
- Acral lentiginous melanoma
- Lentigo malignant melanoma
- Desmoplastic melanoma
- Nodular melanoma
- Melanoma arising from blue nevus
- Melanoma arising in a giant congenital nevus
- Melanoma of childhood
- Nevoid melanoma
- Melanoma, not otherwise classified
- Other histologic type not listed

Microscopic (histologic) images

Contributed by Robert E. LeBlanc, M.D.

Nodal nevus

Nodal metastasis

Regression

Microsatellite

Breslow depth

Board review style question #1

Depth 1.1 mm, nonulcerated, three occult SLN metastases
Depth 1.9 mm, nonulcerated, one occult SLN metastasis, one nonregional lymph node metastasis
Depth 2.4 mm, nonulcerated, SLN negative for metastasis, one satellite metastasis
Depth 4.5 mm, ulcerated, SLN negative for metastasis

Board review style answer #1

B. Melanomas with nonregional lymph node metastases are categorized as pM1a. The presence of distant metastases, including nonregional lymph node involvement, places a melanoma in stage IV irrespective of the other tumor attributes. In contrast, sentinel node metastases, in transit metastases, satellite metastases and microsatellites are not considered distant metastases. These findings affect the pN category but not pM.

Comment Here

Reference: Skin melanocytic tumor - Staging

Subungual melanoma (melanoma of the nail apparatus)

Table of Contents

Definition / general

Melanoma arising in nail unit

Epidemiology

Uncommon; difficult to diagnose clinically and pathologically
Median age 66 years (Am J Surg 2008;195:244), range 24 to 83

Sites

Common sites are great toe and thumb

Clinical features

Often delay in diagnosis because lesion is attributed to trauma; most (73%) cases are AJCC stage II / III, acral lentiginous subtype (66%) and Clark level IV / V (79%, Am J Surg Pathol 2007;31:1902)
Sentinel node metastases in 24%

Case reports

86 year old man with posttraumatic amelanotic tumor (Dermatol Online J 2008;14:13)
Regressed tumors (Dermatol Surg 2006;32:577)
With osteocartilaginous differentiation (Skeletal Radiol 2003;32:724)
Amelanotic tumor resembling pyogenic granuloma (J R Coll Surg Edinb 2002;47:638)

Treatment

Wide local excision, may require amputation (Am J Surg 2008;195:244) although conservative approach for thumb lesions has been advocated (J Plast Reconstr Aesthet Surg 2007;60:635)

Dermoscopy

Useful for distinction from subungual hemorrhage
Features include: Hutchinson sign, longitudinal irregular lines, triangular shape of bands, vascular pattern and ulcerations (Br J Dermatol 2013;168:1224)

Clinical images

Images hosted on other servers:

Red, friable, broad based nodule

Ulcer on left middle finger

Microscopic (histologic) description

Usually not circumscribed
Have prominent lentiginous growth with more single cells than nests, moderate to severe atypia, haphazard and dense pagetoid intradermal spread
Also ulceration (33%), tumor infiltrating lymphocytes

Microscopic (histologic) images

Images hosted on other servers:

Tumor cells are isolated or in nests

Tumor cells are MelanA+

Differential diagnosis

Lentigo
Fungal melanonychia
Minocycline induced pigmentation
Subungual hemorrhage

Superficial spreading melanoma (low CSD melanoma)

Table of Contents

Definition / general

Superficial spreading melanoma (SSM) is the most common subtype of melanoma in the Western world (Arch Pathol Lab Med 2020;144:500)

Essential features

Develops on sun exposed sites with low cumulative sun damage (CSD) (Arch Pathol Lab Med 2020;144:500)
Has a radial growth phase (Arch Pathol Lab Med 2020;144:500)
Most common mutation in superficial spreading melanoma is BRAF^V600E (Arch Pathol Lab Med 2020;144:500)

Terminology

Pagetoid melanoma (Arch Pathol Lab Med 2020;144:500)

ICD coding

ICD-10: C43.9 - malignant melanoma of skin, unspecified
ICD-11
- 2C30.0 - superficial spreading melanoma, primary
- 2C30.Y - other specified melanoma of skin
- 2C30.Z - melanoma of skin, unspecified

Epidemiology

Superficial spreading melanoma accounts for up to 56% of cutaneous melanomas (Br J Dermatol 2021;185:700)
Low cumulative sun damage (Arch Pathol Lab Med 2020;144:500)
- Intermittent sun exposure throughout childhood
- Tanning bed use
Increased total number of melanocytic nevi (Arch Pathol Lab Med 2020;144:500)
Dysplastic nevi (Arch Pathol Lab Med 2020;144:500)
Increased size of nevi (Arch Pathol Lab Med 2020;144:500)

Sites

Back in men (Arch Pathol Lab Med 2020;144:500)
Legs, calves in women (Arch Pathol Lab Med 2020;144:500)

Pathophysiology

Mutation patterns overlap with other melanoma subtypes
Low CSD melanoma (Arch Pathol Lab Med 2020;144:500)
Mutations (Arch Pathol Lab Med 2020;144:500)
- BRAF most common
  - V600E most common amongst BRAF
- NRAS
- TERT
- Biallelic inactivation of CDKN2A
- PTEN, TP53 in advanced primary melanomas

Etiology

Low cumulative sun damage (Arch Pathol Lab Med 2020;144:500)
- Intermittent sun exposure and sunburns

Clinical features

Irregular red, brown or black macule, patch, papule or plaque (Arch Pathol Lab Med 2020;144:500)
ABCDE: asymmetry, border irregularity, color variation, diameter > 6 mm, other evolution history

Diagnosis

Excisional biopsy
Histopathologic diagnosis is gold standard
Sentinel lymph node biopsy (SLNB)
- For primary tumors with Breslow depth of 0.8 mm or deeper
  - Consider SLNB if < 0.8 mm with ulceration
- Breslow depth: measured from the top of the granular layer or base of ulceration to the deepest invasive melanoma cell
References: Ital J Dermatol Venerol 2021;156:300, NCCN: NCCN Guidelines - Melanoma: Cutaneous [Accessed 3 October 2023]

Prognostic factors

Adverse prognosis indicators (Ital J Dermatol Venerol 2021;156:300)
- Thicker (Breslow) depth: most important
- Presence of ulceration
- Dermal mitoses
- Deeper anatomic (Clark) level of invasion (I-V)
- Presence of lymphovascular invasion
- Presence of neurotropism
  - Increased risk of local recurrence
- Presence of sentinel lymph node biopsy (SLNB)
- Positive excision margins
  - Report proximity of melanoma in situ or invasive melanoma to excision margins when able

Case reports

32 year old man with primary superficial spreading melanoma recurring with desmoplastic melanoma features (Virchows Arch 2022;480:945)
47 year old woman with superficial spreading melanoma developing within a nevus spilus (J Osteopath Med 2023;123:223)
78 year old man with a history of superficial spreading melanoma developing a malignant peripheral nerve sheath tumor (World J Clin Cases 2021;9:6457)

Treatment

Treatment includes excision with or without sentinel lymph node biopsy; additional treatment based on stage (NIH: Melanoma Treatment (PDQ®) - Health Professional Version [Accessed 7 July 2023], NCCN: NCCN Guidelines - Melanoma: Cutaneous [Accessed 3 October 2023], American Cancer Society: Immunotherapy for Melanoma Skin Cancer [Accessed 3 October 2023])
- Wide local excision 1 - 2 cm
- SLNB for primary tumors with Breslow depth of 0.8 mm or deeper
  - Consider SLNB if < 0.8 mm with ulceration
  - No clinical or radiographic evidence of nodal disease
- Targeted or immunotherapy / checkpoint inhibitors
  - Targeted therapies include BRAF and MEK inhibitors
  - Immune checkpoint inhibitors include PD1, PDL1, CTLA4 and LAG3 inhibitors
- Talimogene laherparepvec (T-VEC) injections
- Interleukin 2
- Chemotherapy
- Radiation therapy
- Regular skin examination with a dermatologist

Clinical images

Images hosted on other servers:

Irregularly pigmented plaques

Dermoscopy

Microscopic (histologic) description

Radial growth phase with or without vertical growth phase (Arch Pathol Lab Med 2020;144:500)
- Large epithelioid melanocytes
- Prominent junctional and intraepidermal component
- Irregular and enlarged nests of melanocytes along dermal - epidermal junction
- Junctional melanocyte confluence
- Dermal component is composed of similar appearing melanocytes that fail to mature and disperse with descent; dermal mitoses are noted
- Pagetoid scatter
  - Presence of melanocytes above the basal layer
- If invasive
  - Failure of dermal melanocytes to mature (i.e., become smaller) and disperse (i.e., smaller nests, single unit melanocytes) with descent into the dermis
  - With or without dermal mitotic figures
With or without melanin pigmentation
Absent to moderate underlying solar elastosis
Lacks severe solar elastosis
Precursor or associated melanocytic nevus may be present (Arch Dermatol 2003;139:1620)
- Most frequent melanoma subtype to arise with a nevus
Pathologic stage classification AJCC guidelines, eighth edition (2018) (Ital J Dermatol Venerol 2021;156:300)
- Tumor (Breslow) depth is the strongest predictor of clinical outcome, used for staging
  - Measure vertically from the top of granular layer of the epidermis to the deepest invasive melanoma cells
  - If ulcerated, measure from base of ulcer
  - Round to nearest 0.1 mm using ocular micrometer
  - Avoid measuring vascular invasion, microsatellites, involvement of skin appendages

Microscopic (histologic) images

Contributed by Bethany R. Rohr, M.D.

Epithelioid melanocytes

Pagetoid melanocytes

Poorly nested melanocytes

Atypical melanocytes

SOX10 immunostain

HMB45 immunostain

Positive stains

SOX10 (nuclear)
MART1, also known as MelanA (cytoplasmic)
PRAME
HMB45
S100
MITF
Tyrosinase
BRAF variable
Reference: Semin Diagn Pathol 2022;39:239

Negative stains

Loss of melanocytic markers is possible (Dermatopathology (Basel) 2021;8:359)
Keratin immunostains
- CK, AE1 / AE3, OSCAR, CAM5.2
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)
Neuroendocrine markers
- Neurofilament, glial fibrillary acidic protein, synaptophysin, chromogranin, CD56
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)
Muscle specific markers
- SMA, desmin, myoglobin, calponin
- Rare positivity, particularly in melanoma with rhabdomyosarcomatous differentiation
Macrophage markers
- CD68, CD163
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)
Vascular markers
- CD31, CD34
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)
Hematopoietic markers
- CD4, CD20
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)
Miscellaneous
- FLI1, GATA3, CEA, calretinin, PAX8, PAX2
- Rare aberrant expression in melanoma (Dermatopathology (Basel) 2021;8:359)

Videos

Superficial spreading melanoma
by Dr. Jerad Gardner

Sample pathology report

Skin, biopsy:
- Invasive malignant melanoma, superficial spreading subtype, extending to a Breslow depth of ## (see comment)
- Comment: The sections reveal a severely atypical compound melanocytic proliferation composed of atypical epithelioid melanocytes. The melanocytes are poorly nested along the dermal - epidermal junction with confluence and pagetoid scatter. The dermal component is composed of similar appearing melanocytes that fail to mature and disperse with descent. Dermal mitoses are noted.

Differential diagnosis

Lentigo maligna melanoma:
- High cumulative sun damage
  - Significant dermal solar elastosis
- Pagetoid scatter is less prominent
- Radial growth phase
- More common on chronically sun exposed sites of elderly, light skinned adults
Acral lentiginous melanoma:
- Acral sites
- Noncumulative sun damage related
Nevoid melanoma (Ital J Dermatol Venerol 2021;156:300):
- Resembles intradermal nevus, 2 types
- Papillomatous type
  - NRAS mutation most common
  - Head, neck, limbs
  - Puffy shirt appearance: scanning magnification shows dense cellular aggregates surrounded by bent elongated rete ridges lined up side by side
- Maturing nevoid type: limbs, trunk
  - Heterogeneous mutations: BRAF, NRAS
Nodular melanoma:
- Low or high cumulative sun damage
- No radial growth phase
Cutaneous involvement of metastatic malignant melanoma:
- History of prior locoregional invasive melanoma
- Features that favor metastases (Arch Pathol Lab Med 2020;144:500)
  - Tumor size of < 2 mm
  - Absence of tumor infiltrating lymphocytes and plasma cells
  - Monomorphism
  - Involvement of adnexal epithelium

Additional references

Mod Pathol 2018;31:24

Board review style question #1

Superficial spreading melanoma is most commonly associated with which mutation?

BRAF
NRAS
PTEN
TERT
TP53

Board review style answer #1

A. BRAF is the most commonly mutated driver oncogene in low cumulative sun damage melanoma. The most common mutation is the p. V600E. Answers B - E are incorrect because NRAS, TERT, PTEN and TP53 are less commonly mutated in superficial spreading melanoma.

Comment Here

Reference: Superficial spreading melanoma (low CSD melanoma)

Board review style question #2

From which of the following pathways does superficial spreading melanoma develop?

Both high and low cumulative sun damage
High cumulative sun damage
Low cumulative sun damage
No association with cumulative sun damage

Board review style answer #2

C. Low cumulative sun damage. Superficial spreading melanoma arises on sun exposed skin sites with little underlying solar elastosis. Answer B is incorrect since high cumulative sun damage is associated with lentigo maligna melanoma. Answer D is incorrect since superficial melanoma is associated with low cumulative sun damage. Answer A is incorrect because nodular melanoma may be associated with both high and low cumulative sun damage.

Comment Here

Reference: Superficial spreading melanoma (low CSD melanoma)

Board review style question #3

Which subtype of melanoma is most likely to arise in association with a precursor melanocytic nevus?

Acral lentiginous
Lentigo maligna
Nodular
Primary dermal
Superficial spreading

Board review style answer #3

E. Superficial spreading melanoma is the most frequent histologic subtype of melanoma to be found arising in association with a melanocytic nevus. Other predictors of melanoma arising in association with a nevus include younger age and truncal location (Arch Dermatol 2003;139:1620). Answers A - D are incorrect because these other melanoma subtypes are less commonly documented to arise in association with a precursor melanocytic nevus.

Comment Here

Reference: Superficial spreading melanoma (low CSD melanoma)

WHO classification

Table of Contents

Definition / general

WHO classification of melanocytic skin tumors
Currently on 5th edition, published August 2022 (Epub ahead of print)

Major updates

Advanced knowledge of molecular pathomechanisms have led to definition changes (Annu Rev Pathol 2014;9:239)
- Nevi: single initiating mutation, bland cytology and benign biology
- Melanocytomas: neoplasms with > 1 driver mutation with a second mutation affecting specific pathways resulting in distinct atypical microscopic features and increased risk of local recurrence; melanocytomas occur on a spectrum between nevi and melanoma
Some nevi renamed as melanocytoma variants
- WNT activated deep penetrating / plexiform melanocytoma (previously deep penetrating nevus) (Clin Exp Dermatol 2023 Nov 23 [Epub ahead of print])
- Pigmented epithelioid melanocytoma (PEM, also known as PRKAR1A inactivated melanocytoma); previously epithelioid blue nevus (Surg Pathol Clin 2021;14:285)
- BAP1 inactivated melanocytoma (Pathol Res Pract 2024 Jan 24 [Epub ahead of print])
- Spitz melanocytoma (Front Oncol 2022:12:889223)
- Microphthalmia associated transcription factor (MITF) pathway activated melanocytic tumors (melanocytomas)
  - Clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation (CCTMAM) (Am J Surg Pathol 2021;45:962)
  - Clear cell tumor with melanocytic differentiation and MITF::CREM translocation (CCTMMC) (Virchows Arch 2021;479:841)

WHO (2022)

Melanocytic neoplasms	ICD-O	ICD-11
Melanocytic neoplasms in intermittently sun exposed skin
Nevi
Junctional, compound and dermal nevi	8740/0, 8760/0, 8750/0	2F36.Y & XH1M79, XH27A6, XH2MQ5
Simple lentigo and lentiginous melanocytic nevus	8742/0	2F20.0Y, 2F20.2Y
Dysplastic nevus	8727/0	2F20.1 & XH9035, 2F72.2
Nevus spilus	8720/0	2F20.Y & XH40S8
Special site nevus (of the breast, axilla, scalp and ear)		2F20.1, 2F20.Y
Halo nevus	8723/0	2F20.Y & XH5971
Meyerson nevus	8720/0	2F20.Y & XH8NP4
Recurrent nevus		2F20.Y
Combined nevus	8720/0	2F20.Y & XH0DU8
Melanocytomas
WNT activated deep penetrating / plexiform melanocytoma (nevus)	8720/1	2F20.Y & XH81Y1
Pigmented epithelioid melanocytoma	8780/1	2F20.1 & XH4VD0
BAP1 inactivated melanocytoma	8720/1	2F20.1
MITF pathway activated melanocytic tumors	8727/0	2F20.1
Melanoma intermittently sun exposed skin
Melanoma on skin with low cumulative sun damage (low CSD); includes superficial spreading melanoma	8743/3	2C30.0
Melanocytic neoplasms in chronically sun exposed skin
Lentigo maligna melanoma	8742/3	2C30.2
Desmoplastic melanoma	8745/3	2C30.Y & XH1Z15
Spitz tumors
Spitz nevi
Pigmented spindle cell nevus (Reed nevus)	8770/0	2F20.Y & XH2P88
Spitz nevus	8770/0	2F20.Y & XH2HG8
Spitz melanocytoma
Spitz melanocytoma (atypical Spitz tumor)	8770/1	2F20.Y & XH9WF4, 2F72.1
Spitz melanoma	8770/3	2C30.Y & XH8DS3
Melanocytic tumors in acral skin
Acral nevi	8744/0	2F20.Y & XH9DB2
Acral melanoma	8744/3	2C30.3
Genital and mucosal melanocytic tumors
Mucosal and genital nevus
Melanosis		ED61.Y
Genital nevus	8720/0	2F20.Y & XH5EL4
Mucosal melanomas	8720/3	2C70.1, 2C11.2 & XH4846
Blue nevi and related tumors
Blue nevus and melanocytoses
Nevus of Ito and nevus of Ota		LC10
Congenital dermal melanocytosis		LC10
Blue nevus	8780	2F20.Y & XH7QJ7, XH3X84
Melanoma arising in blue nevus	8780/3	2C30.Y & XH1G74
Congenital melanocytic tumors
Congenital nevi
Congenital melanocytic nevus	8761/0	2F20.2Z
Proliferative nodules in congenital melanocytic nevus	8762/1	2F20.2 & XH6AH3
Melanomas arising in congenital nevi
Melanoma arising in giant congenital nevus	8761/3	2C30.Y & XH5L25
Ocular and central nervous system (CNS) melanocytic tumors
Conjunctival melanocytic tumors
Conjunctival nevus	8740/0, 8760/0, 8750/0	2F36.Y & XH1M79, XH27A6, XH2MQ5
Conjunctival melanocytic intraepithelial lesions	8720/2	2E63.1
Conjunctival melanoma	8720/3	2D00.0
Uveal melanocytic tumors
Uveal melanocytoma	8726/0	2F36.0
Uveal melanoma	8770/3, 8771/3, 8772/3, 8773/3, 8774/3	2D07.2, 2D06.4, 2D05.0
CNS melanocytic tumors
Diffuse meningeal melanocytic neoplasms: melanocytosis and melanomatosis	8728/0, 8728/3	2A01.0Y & XH8974, XH1BP7
Circumscribed meningeal melanocytic neoplasms: melanocytoma and melanoma	8728/1, 8720/3	2A01.0Y & XH2RY7, XH3DN1
Nodular, nevoid and metastatic melanomas
Nodular and other melanomas
Nodular melanoma	8721/3	2C30.1
Nevoid melanoma	8720/3	2C30.Y & XH8681
Dermal melanoma	8780/3	2C30.Y
Metastatic melanomas
Melanoma metastatic to the skin	8720/6	2E08 & XH4846
Melanoma metastatic to other organs	8720/6	2E0Y & XH4846

Diagrams / tables

N/A

Microscopic (histologic) images

Contributed by Jonathan D. Ho, M.B.B.S., D.Sc.

Dermal nevus

Melanoma, high cumulative sun damage (CSD)

Spitz melanocytoma

Metastatic melanoma

Blue nevus

Melanoma cytomorphology

Acral lentiginous melanoma

Acral lentiginous melanoma in situ

Additional references

J Pathol Transl Med 2023;57:337, WHO Classification of Tumours Editorial Board: Skin Tumours, 5th Edition, 2022

Board review style question #1

What are melanocytic neoplasms with > 1 driver mutation with a second mutation affecting specific pathways resulting in distinct atypical microscopic features, increased risk of local recurrence and little risk of distant spread best defined as?

Melanocytic hyperplasia
Melanocytic tumors of uncertain metastatic potential
Melanocytomas
Melanomas
Nevi

Board review style answer #1

C. Melanocytomas. Melanocytomas are neoplasms with > 1 driver mutation with a second mutation affecting specific pathways resulting in distinct atypical microscopic features and increased risk of local recurrence. Melanocytomas occur on a spectrum between nevi and melanoma. Examples include WNT activated deep penetrating / plexiform melanocytoma (previously deep penetrating nevus), pigmented epithelioid melanocytoma (PEM, also known as PRKAR1A inactivated melanocytoma) and BAP1 inactivated melanocytoma.

Answer D is incorrect because melanomas are malignant neoplasms that have accumulated mutations allowing for unregulated growth and lack of response to tumor suppressor pathways. They have a risk of both local recurrence and distant metastasis. Answer E is incorrect because nevi are melanocytic tumors with a single initiating mutation, bland cytology and benign biology. Answer B is incorrect because melanocytic tumors of uncertain metastatic potential is reserved for neoplasms with atypical features that fall short of melanoma, yet do not exhibit typical histopathologic, immunohistochemical and molecular features of well described melanocytomas. These are lesions with a prominent dermal component whose biologic behavior is unclear and in which the vertical growth phase melanoma is the main diagnostic consideration. Answer A is incorrect because melanocytic hyperplasia is a general term for an increase in epidermal melanocytes which may be benign, atypical or frankly malignant.

Comment Here

Reference: Skin melanocytic tumor - WHO classification

WHO classification (pending)

[Pending]

WHO classification for pediatric melanocytic neoplasms (pending)

[Pending]

WNT activated deep penetrating / plexiform melanocytoma (nevus)

Table of Contents

Definition / general

Cellular melanocytic neoplasm with extension into deep dermis or subcutis (Arch Dermatol 1993;129:328)
Wedge shaped appearance (inverted triangle) (Am J Surg Pathol 1989;13:39, J Cutan Pathol 1992;19:172, Arch Dermatol 1993;129:328, Biology (Basel) 2022;11:460)

Essential features

Uncommon variant of acquired melanocytic nevus
Mostly indolent; some may exhibit atypical histologic features
Rare metastatic potential in lesions with atypical features (Eur J Dermatol 2014;24:594, Cancers (Basel) 2021;13:3066, J Cutan Pathol 2020;47:1150, Biology (Basel) 2022;11:460)
Wedge shaped appearance on microscopy (Am J Surg Pathol 1989;13:39, J Cutan Pathol 1992;19:172, Arch Dermatol 1993;129:328, Biology (Basel) 2022;11:460)
Cellular with deep extension into dermis and subcutis (Arch Dermatol 1993;129:328)
Typically with abundant pigment

Terminology

Deep penetrating nevus (DPN)
Plexiform spindle cell melanocytoma / nevus and inverted type A nevus considered variants of WNT activated deep penetrating / plexiform melanocytoma (J Cutan Pathol 2018;45:254, Histopathology 1991;18:243, J Am Acad Dermatol 1994;30:724)

ICD coding

ICD-10: D22.9 - melanocytic nevi, unspecified
ICD-11: XH81Y1 - deep penetrating nevus

Epidemiology

Uncommon lesion, first reported in 1989 (Am J Surg Pathol 1989;13:39)
Usually appears before age 50 (Arch Pathol Lab Med 2011;135:321)
Age range: 3 - 56 years (mean: 26 years) (Histopathology 2003;43:529)
F > M

Sites

Usually face, neck, upper back / trunk and proximal extremities (Arch Pathol Lab Med 2011;135:321)

Pathophysiology

Lesions demonstrate Wnt pathway activation via gain of function mutation in CTNNB1, which encodes beta catenin protein (Biology (Basel) 2022;11:460, Zhonghua Jie He He Hu Xi Za Zhi 1988;11:362)
Most arise from common acquired nevi and therefore may also exhibit mutations in the mitogen activated protein kinase (MAPK) pathway (BRAF [p.V600E], MEK1 / MAP2K1, HRAS) (Nat Commun 2017;8:644)
Mutations in beta catenin and BRAF result in activation of LEF1 (transcription factor), which leads to epithelial mesenchymal transition and tumor growth and development (Biology (Basel) 2022;11:460)
Rare cases may exhibit inactivation of APC (Biology (Basel) 2022;11:460)
Increased melanocyte size and pigmentation derived from Wnt pathway activation

Clinical features

< 1 cm in diameter
Dark dome shaped papule with regular borders (Biology (Basel) 2022;11:460, Massi: Histological Diagnosis of Nevi and Melanoma, 2nd Edition, 2014)
Often described as new or changing
May resemble melanoma (J Plast Reconstr Aesthet Surg 2007;60:1252)

Diagnosis

Clinical presentation
Dermoscopic criteria for DPN is not well established (J Am Acad Dermatol 2014;71:1234, Biology (Basel) 2022;11:460)
Definite diagnosis is made on excision specimen through histologic examination

Case reports

4 year old boy with unconventional deep penetrating melanocytic nevus with microscopic involvement of regional lymph nodes (J Cutan Pathol 2012;39:25)
25 year old man with linear arrangement of multiple deep penetrating nevi (Arch Dermatol 2003;139:1608)
46 year old woman with penetrating nevus of cheek skin (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:e49)
49 year old woman with multiple oral and facial deep penetrating nevi (J Oral Maxillofac Surg 2017;75:2579)
51 year old woman with deep penetrating nevus of the left anterior leg (Diagn Pathol 2006;1:31)

Treatment

Simple excision; only rarely recurs (Histopathology 2003;43:529, Cancers 2021;13:3066)

Clinical images

Images hosted on other servers:

Linear distribution of nevi behind ear

Microscopic (histologic) description

Melanocytic neoplasm that exhibits a wedge shaped or plexiform growth pattern with melanin pigmentation (Am J Surg Pathol 1989;13:39, J Cutan Pathol 1992;19:172, Arch Dermatol 1993;129:328)
Usually well circumscribed and symmetrical (Biology (Basel) 2022;11:460)
Extends into deep dermis or subcutis with no clear maturation with depth (Am J Surg Pathol 1989;13:39, J Cutan Pathol 1992;19:172, Arch Dermatol 1993;129:328, Arch Pathol Lab Med 2011;135:321)
Can have encircling of blood vessels, adnexal structures, nerves (Am J Surg Pathol 1989;13:39, J Cutan Pathol 1992;19:172, Arch Dermatol 1993;129:328)
Cellular, nested or fascicular with abundant pigment (Am J Surg Pathol 1989;13:39, Histopathology 2003;43:529)
Lesions may be entirely intradermal, have an inconspicuous junctional component or uncommonly exhibit prominent junctional nests (Am J Surg Pathol 1989;13:39, Arch Pathol Lab Med 2011;135:321)
Grenz zone may be present (Biology (Basel) 2022;11:460, Arch Pathol Lab Med 2011;135:321, J Am Acad Dermatol 2014;71:1234)
May be combined with other nevi
Melanocytes are epithelioid to spindled
Nuclei are typically round to fusiform
Cytoplasm may exhibit granular pigment and nuclear pseudoinclusions
C shaped melanocytes surrounding epithelioid nests can be seen
Occasional dermal mitotic figures (nonatypical, < 1 - 2/mm²) (J Cutan Pathol 1992;19:172, Arch Pathol Lab Med 2011;135:321, J Am Acad Dermatol 2014;71:1234)
Occasional mild cytologic atypia can be seen including mild pleomorphism and hyperchromasia, variation in size, small nucleoli (Am J Surg Pathol 1989;13:39, Biology (Basel) 2022;11:460, J Cutan Pathol 1992;19:172, J Am Acad Dermatol 2014;71:1234)
Atypical features in DPN include increased cytologic and architectural atypia
- 1 - 3 mitotic figures/mm², increased nuclear pleomorphism, increased N:C ratio; cherry red nucleoli (Biology (Basel) 2022;11:460, Eur J Dermatol 2014;24:594, Cancers (Basel) 2021;13:3066, J Cutan Pathol 2020;47:1150)
- Asymmetrical, hypercellular, infiltrative borders (Biology (Basel) 2022;11:460, Eur J Dermatol 2014;24:594, Cancers (Basel) 2021;13:3066, J Cutan Pathol 2020;47:1150)
- These lesions have been associated with lymph node metastasis (Eur J Dermatol 2014;24:594, Cancers (Basel) 2021;13:3066, J Cutan Pathol 2020;47:1150, Biology (Basel) 2022;11:460)
- Can have increased Ki67 proliferation index (Biology (Basel) 2022;11:460)

Microscopic (histologic) images

Contributed by Kaitlin Vanderbeck, M.D. and Carlos A. Torres-Cabala, M.D.

Pigmented
predominantly
dermal melanocytic
lesion

Pigmented epithelioid to spindled melanocytes

Combined nevus

HMB45

Ki67

Beta catenin

Beta catenin nuclear positivity

Cyclin D1

LEF1

Positive stains

HMB45 (diffuse), cyclin D1 (nuclear and cytoplasmic), beta catenin (nuclear, cytoplasmic and membranous) (Biology (Basel) 2022;11:460)
LEF1 (nuclear)
Ki67 proliferation index is typically low (Biology (Basel) 2022;11:460)
p16: mosaic / checkerboard (J Cutan Pathol 2020;47:815)

Negative stains

PRAME is typically negative (Am J Dermatopathol 2023;45:549)

Molecular / cytogenetics description

Wnt / beta catenin pathway activation (Biology (Basel) 2022;11:460)
Can demonstrate mitogen activated protein kinase (MAPK) mutations (i.e., BRAF, MAP2K1 / MEK1, HRAS) (Nat Commun 2017;8:644, Biology (Basel) 2022;11:460)
Typically no chromosomal aberrations via FISH or comparative genomic hybridization (CGH) even in DPN with atypical features (J Cutan Pathol 2020;47:1150, Eur J Dermatol 2014;24:594, Biology (Basel) 2022;11:460)
- This may be helpful with other diagnostic considerations such as melanoma
- Appropriate clinical correlation is encouraged

Sample pathology report

Skin, right arm, excisional biopsy:
- Deep penetrating nevus, margins appear free (see comment)
- Comment: Sections show skin and subcutis with a cellular melanocytic proliferation within dermis with extension into subcutis. Cytologically, the melanocytes are epithelioid to spindled with abundant melanin pigment appreciated. The melanocytes are arranged in a wedge shaped orientation with focal encircling on adnexal structures and nerves within predominantly deep dermis. Nuclear pleomorphism, conspicuous cherry red nucleoli, lymphovascular invasion and mitotic activity are not identified. By immunohistochemistry, the lesional cells of interest are positive for HMB45, cyclin D1 (nuclear and cytoplasmic), beta catenin (nuclear, cytoplasmic and membranous), LEF1 (nuclear) and p16. Ki67 proliferation index is relatively low. Overall, the findings are supportive of the above interpretation. Further clinical correlation and follow up are recommended as appropriate.

Differential diagnosis

Melanoma:
- May have atypical junctional components including pagetoid spread of melanocytes
- Obvious mitotic figures (including atypical), marked atypia, lymphovascular invasion, ulceration, necrosis
- Typically, increased Ki67 proliferation index
- Typically, PRAME positive, HMB45 positive
- Genetic aberrations common to melanoma can be identified
- References: Cancer Epidemiol Biomarkers Prev 2007;16:2486, Biology (Basel) 2022;11:460, Am J Surg Pathol 1989;13:39, J Am Acad Dermatol 2014;71:1234)
Cellular blue nevus:
- Spindled melanocytes (ovoid to plump) within dermis with inconspicuous nucleoli
- Well circumscribed and pigmented
- Predominantly within superficial and mid dermis
- Extension into deep dermis and subcutis can be seen
- Typically, pushing borders
- Cyclin D1 negative, beta catenin demonstrates cytoplasmic staining (no nuclear staining), LEF1 negative in most cases (Am J Dermatopathol 2023;45:549)
- HMB45 positive
- GNAQ and GNA11 mutations (Biology (Basel) 2022;11:460)
Inverted type A nevus:
- Considered a variant of DPN (J Cutan Pathol 2018;45:254)
- Melanocytic nevus with population of epithelioid melanocytes (type A nevus cells) with extension into dermis or subcutis
- More superficial than DPN (Biology (Basel) 2022;11:460)
- Mitoses absent to rare
- Often pigmented melanocytes
Spitz nevus:
- Raining down pattern of epithelioid and spindled melanocytes
- Typically, compound
- Kamino bodies
- Younger patients
- HMB45 is typically negative
- ALK, ROS, NTRK fusions can be seen (Mod Pathol 2003;16:505)
Plexiform spindle cell nevus:
- Considered a variant of DPN
- Fascicular plexiform architecture versus wedge shaped (Biology (Basel) 2022;11:460)
- Predominantly spindled cells splitting collagen fibers
- Typically, more superficial
Pigmented epithelioid melanocytoma (PEM):
- Can be associated with Carney complex
- Epidermal hyperplasia is commonly seen
- Heavily pigmented; usually 3 melanocyte cell types (most demonstrate a mixed population) including small, large and spindled melanocytes
- Typically, abundant melanophages are present
- Can demonstrate PRKCA fusion or PRKAR1A mutation

Additional references

WHO Classification of Tumours Editorial Board: Skin Tumours, 5th Edition, 2023

Board review style question #1

What immunohistochemical staining profile would you expect for the skin lesion pictured above?

HMB45 negative; beta catenin negative; cyclin D1 shows cytoplasmic staining
HMB45 negative; beta catenin shows nuclear, cytoplasmic and membranous staining; cyclin D1 negative
HMB45 positive; beta catenin shows cytoplasmic staining; cyclin D1 negative
HMB45 positive; beta catenin shows nuclear, cytoplasmic and membranous staining; cyclin D1 shows nuclear and cytoplasmic staining

Board review style answer #1

D. HMB45 positive; beta catenin shows nuclear, cytoplasmic and membranous staining; cyclin D1 shows nuclear and cytoplasmic staining. This is the expected staining profile for deep penetrating nevus / WNT activated deep penetrating / plexiform melanocytoma (DPN). DPN typically demonstrates positive staining for HMB45 and demonstrates nuclear, cytoplasmic and membranous staining for beta catenin and nuclear and cytoplasmic staining for cyclin D1. Of note, DPN typically demonstrates Wnt pathway activation via gain of function mutations of CTNNB1, which encodes beta catenin protein. Wnt activation results in the increased melanocyte size and pigmentation seen in DPN.

Answer B is incorrect because DPN is typically positive for HMB45 and demonstrates nuclear and cytoplasmic positivity for cyclin D1. DPN demonstrates nuclear, cytoplasmic and membranous staining for beta catenin. Answer C is incorrect because DPN typically demonstrates nuclear, cytoplasmic and membranous staining for beta catenin and nuclear and cytoplasmic staining for cyclin D1. DPN demonstrates positive staining for HMB45. Answer A is incorrect because DPN is typically positive for HMB45 and exhibits nuclear, cytoplasmic and membranous staining for beta catenin and nuclear and cytoplasmic staining for cyclin D1.

Comment Here

Reference: WNT activated deep penetrating / plexiform melanocytoma (nevus)

Board review style question #2

A 37 year old woman presented with a dark 5 mm papule on her forearm. An excisional biopsy is performed and is shown in the image above. What is the best diagnosis?

Cellular blue nevus
WNT activated deep penetrating / plexiform melanocytoma (deep penetrating nevus)
Melanoma
Spitz nevus

Board review style answer #2

B. WNT activated deep penetrating / plexiform melanocytoma (deep penetrating nevus). The image demonstrates a cellular wedge shaped melanocytic proliferation with abundant pigment and involvement of dermis and subcutis. A junctional component is not seen. These are hallmark features of deep penetrating nevus (DPN).

Answer D is incorrect. Typically compound, these nevi demonstrate a raining down appearance of melanocytes. Kamino bodies can be seen. These nevi are seen predominantly in younger / pediatric patients (see Spitz nevus). Answer A is incorrect because cellular blue nevus is usually more superficial and melanocytes are typically spindled in shape. Borders are typically pushing versus wedge shaped (see Blue nevus / cellular blue nevus). Answer C is incorrect because melanoma may have an atypical junctional component including pagetoid spread of melanocytes. Melanoma typically exhibits obvious mitotic figures (including atypical), marked atypia, lymphovascular invasion, ulceration, necrosis and other features of malignancy (see Melanoma).

Comment Here

Reference: WNT activated deep penetrating / plexiform melanocytoma (nevus)

Recent Skin melanocytic tumor Pathology books

Bhawan: 2022

Bolognia: 2017

Brenn: 2017

Busam: 2018

Calonje: 2019

Dadzie: 2016

Elder: 2022

Elder: 2020

Elston: 2018

Gardner: 2019

Gru: 2023

IARC: 2018

Johnston: 2023

Massi: 2013

Plaza: 2016

Rapini: 2021

Find related Pathology books: dermatopathology, hematopathology, IHC

Home > Skin melanocytic tumor

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