Skin melanocytic tumor
Melanoma
Invasive melanoma


Minor changes: 29 March 2021

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PubMed Search: Invasive melanoma [TI] skin

Boulos Mansour, M.D.
Michele Donati, M.D.
Page views in 2020: 43,568
Page views in 2021 to date: 16,414
Cite this page: Mansour B, Donati M. Invasive melanoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skintumormelanocyticmelanoma.html. Accessed April 14th, 2021.
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
  • Most lethal skin cancer
  • Breslow depth is the most important predictive factor
  • BRAF mutation testing is recommended for patients with stage III - IV melanoma
Terminology
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
    • 8721/3 - Nodular melanoma
    • 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

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
  • 5 year relative survival rates
    • Localized disease: 99%
    • Regional lymph nodes involvement: 62.2%
    • Metastatic disease: 27.3%
  • Recurrence rate within 2 years
Case reports
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 Superficial spreading melanoma

Superficial spreading melanoma

Nodular melanoma

Nodular melanoma

Invasive acral lentiginous melanoma

Invasive acral lentiginous melanoma

Lentigo maligna melanoma

Lentigo maligna melanoma


Desmoplastic melanoma

Desmoplastic melanoma

Achromic melanoma

Achromic melanoma

Ugly duckling sign

Ugly duckling sign

Hutchinson sign

Hutchinson sign

Blowfly 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

Superficial spreading melanoma

Invasive acral lentiginous 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 dermal proliferation
      • Atypical lentiginous junctional melanocytic proliferation in ~50%
      • May have sarcomatous features
      • Prominent desmoplasia
      • Perivascular lymphocytic aggregates
      • Neurotropism
      • May be pure or mixed (associated with conventional melanoma)
      • 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

Asymmetry

Early vertical growth phase

Early vertical growth phase

Poorly differentiated melanoma

Poorly differentiated melanoma

Nodular melanoma

Nodular melanoma

Confluent nests

Confluent nests


Ulceration

Ulceration

Superficial spreading melanoma in situ

Superficial spreading melanoma in situ

Epidermal consumption

Epidermal consumption

Invasive superficial spreading melanoma

Invasive superficial spreading melanoma

Ill defined border

Ill defined border


Pagetoid spreading

Pagetoid spread

Lentigo maligna melanoma

Lentigo maligna melanoma

Atypical melanocytes

Atypical melanocytes

Hair follicle involvement

Hair follicle involvement

Acral lentiginous melanoma, vertical growth phase

Acral lentiginous melanoma, vertical growth phase


Acral lentiginous melanoma

Acral lentiginous melanoma

Desmoplastic melanoma

Desmoplastic melanoma

Perineural invasion in DM

Perineural invasion in DM

MelanA

MelanA

S100

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

May Grünwald Giemsa smear preparation

Positive stains
Negative stains
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)
  • 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

MYC amplification

CDKN2A loss

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
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?

  1. Acral lentiginous melanoma
  2. Desmoplastic melanoma
  3. Lentigo maligna melanoma
  4. Nodular melanoma
  5. 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.

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?

  1. CK and MelanA
  2. Desmin and ERG
  3. MelanA and SMA
  4. S100 and CK
  5. 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 undifferentiated squamous cell carcinoma, invasive 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?

  1. BRAF V600E
  2. KIT
  3. NF1
  4. NRAS
  5. 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?

  1. HMB45
  2. MelanA
  3. PRAME
  4. S100
  5. 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
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