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Skin melanocytic tumor

Melanoma

Invasive melanoma

Authors: Boulos Mansour, M.D., Michele Donati, M.D.

Editorial Board Member: Kiran Motaparthi, M.D.

Last author update: 22 June 2021

Last staff update: 20 December 2021

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: Invasive melanoma [TI] skin

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Table of Contents

Cite this page: Mansour B, Donati M. Invasive melanoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skintumormelanocyticmelanoma.html. Accessed April 23rd, 2024.

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.

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Reference: Invasive melanoma

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