Vulva & vagina

Melanocytic lesions

Melanoma


Editorial Board Members: C. Blake Gilks, M.D., Kyle Devins, M.D.
Anna Sarah Erem, M.D.
Gulisa Turashvili, M.D., Ph.D.

Last author update: 15 December 2023
Last staff update: 10 April 2024

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PubMed Search: Melanoma

Anna Sarah Erem, M.D.
Gulisa Turashvili, M.D., Ph.D.
Page views in 2023: 6,530
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Cite this page: Erem AS, Turashvili G. Melanoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/vulvamelanoma.html. Accessed April 14th, 2024.
Definition / general
  • Primary malignant melanocytic tumor
Essential features
  • Malignant melanocytic tumor arising from melanocytes in mucosal or cutaneous areas of the lower genital tract
  • Tumor thickness is the most important prognostic factor
Terminology
  • Malignant melanoma (MM)
  • Primary malignant melanoma of vulva
  • Primary malignant melanoma of vagina
  • Primary malignant melanoma of lower genital tract
ICD coding
  • ICD-O
    • 8720/3 - malignant melanoma, NOS
      • C51.0 - labia majus / labia majora, NOS; Bartholin gland; skin of the labia
      • C51.1 - labia / minus / labia minora
      • C51.2 - clitoris
      • C51.8 - overlapping lesions of the vulva
      • C51.9 - vulva, NOS
  • ICD-10
    • C51 - malignant neoplasm of the vulva
      • 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
    • C52 - malignant neoplasm of vagina
    • C57 - malignant neoplasm of other and unspecified female genital organs
      • C57.7 - malignant neoplasm of other specified female genital organs
      • C57.8 - malignant neoplasm of overlapping sites of female genital organs
      • C57.9 - malignant neoplasm of overlapping sites of female genital organ, unspecified
  • ICD-11
    • 2C70 - malignant neoplasm of the vulva
      • 2C70.1 - melanoma of vulva
      • 2C70.Z - malignant neoplasm of vulva, unspecified
    • Specific anatomy (use additional code, if desired)
    • 2C71 - malignant neoplasms of vagina
      • 2C71.1 - melanoma of vagina
      • 2C71.Z - malignant neoplasm of vagina, unspecified
    • Specific anatomy (use additional code, if desired)
    • 2C7Y - other specified malignant neoplasms of female genital organs
    • 2C7Z - malignant neoplasms of female genital organs, unspecified
Epidemiology
Sites
  • Vulvar melanoma
    • Labia majora and labia minora > periclitoral / clitoris > midline structures (e.g., periurethral, introitus and posterior fourchette) (Ann Surg Oncol 2015;22:1959)
    • Most common: glabrous (hairless, mucosal) site in about 50% of cases, followed by hairy - glabrous skin junction (38%) and hairy skin (13%) (Acta Oncol 2004;43:421)
  • Vaginal melanoma
Pathophysiology
Etiology
Diagrams / tables

Contributed by Anna Sarah Erem, M.D.
Summary of vulvar melanoma management

Summary of vulvar melanoma management

Treatment strategies for vaginal melanoma

Treatment strategies for vaginal melanoma

Clinical features

Table 1: Clinical and histologic differences between atypical genital nevus and vulvar melanoma (adapted from Hoang: Melanocytic Lesions - A Case Based Approach, 2014)
Proposed diagnosis Atypical genital nevus of special anatomic site Vulvar melanoma
Age Premenopausal, young adult Postmenopausal
Size < 1 cm > 1 cm
Delineation Well circumscribed Infiltrative
Symmetry Present Absent
Lateral extension of junctional component Focal Present
Lentiginous junctional component Focal Present
Junctional nests Discohesive Confluent
Retraction artefact Present Absent
Ulceration Absent or due to trauma Often present
Pagetoid upward spread Focal, central, inconspicuous Prominent
Cytologic atypia Superficial, mild to moderate Deep, moderate to severe
Dermal mitoses Rare and superficial Conspicuous, atypical, deep
Dermal maturation Present Absent
Melanin pigmentation Coarse, uniform Fine, irregular
Dermal fibrosis Broad zone of superficial coarse dermal fibrosis Regression type


Table 2: Clinical differences in mucosal melanoma of the vulva and vagina (adapted from Ann Surg Oncol 2015;22:1959 and Am J Cancer Res 2020;10:4017)
Proposed diagnosis Vulvar melanoma Vaginal melanoma
Frequency 3 - 10% of vulvar tumors 4 - 5% of vaginal tumors
Age Postmenopausal (50 - 70 years) Postmenopausal (50 - 70 years)
Location Labia majora and labia minora > periclitoral / clitoris > midline structures (e.g., periurethral, introitus and posterior fourchette)* Lower vagina
Presentation Bleeding, abnormal discharge, pruritis or visible exophytic mass to the patient Similar to vulvar melanoma; polypoid mass may be only seen on closer gynecologic examination
Prognosis Poor; 5 year survival of 25 - 60% Very poor; 5 year survival of < 20%
Histologic growth patterns Lentiginous (most common)
Superficial spreading (less common)
Nodular and pagetoid (rare)
Nodular (most common)
Differential diagnosis Poorly differentiated carcinoma
Metastatic melanoma
Melanocytic nevus
Lymphoma
Soft tissue neoplasm
Poorly differentiated carcinoma
Metastatic melanoma
Lymphoma
Soft tissue neoplasm
*Labia majora (34%) > labia minora (29%) > periclitoral / clitoris (24%) > midline structures (13%) (Ann Surg Oncol 2015;22:1959)
Diagnosis

Table 3: Differential diagnosis of vulvar melanocytic nevi, melanosis and melanoma (adapted from J Am Acad Dermatol 2014;71:1241)
Reassuring features suggestive of a benign process Concerning features for possible malignancy
Clinical
  • Age at diagnosis < 50 years
  • Symmetric, uniformly pigmented, macular or papular lesion with regular borders
  • Measures < 1 mm in diameter
  • Associated with genodermatoses
  • Age at diagnosis > 50 years
  • Asymmetric, nonuniformly pigmented, elevated lesion with irregular borders
  • Measures > 0.7 mm in diameter
  • Associated bleeding, pruritus or discharge
Dermoscopy
  • Variable appearance, including cobblestone, globular, ring-like, reticular-like, homogeneous, parallel or mixed
  • Variable color (gray, white, or blue) with structureless zones, irregular globules or dots and atypical vessels
Reflectance confocal microscopy
  • Draped or ringed polycyclic papillae
  • Hyper refractive cells around the papillae
  • Sparse dendritic cells
  • Increased cellularity with atypical cells and disordered architecture
Laboratory
Prognostic factors

Table 4: Revised 2017 AJCC TNM staging for melanoma
Primary tumor (T)
TX Primary tumor thickness cannot be assessed (i.e., diagnosis by curettage)
T0 No evidence of primary tumor (i.e., axillary metastases without known primary tumor)
Tis Intraepithelial (i.e., melanoma in situ)
T1 Tumor ≤ 1.0 mm thick, without or with ulceration
T1a ≤ 0.8 mm thick and Clark level II or III, without ulceration
T1b < 0.8 mm thick and Clark level IV or V or with ulceration
0.8 - 1.0 mm thick and Clark level IV or V, with or without ulceration
T2 Tumor 1.01 - 2.0 mm thick, without (T2a) or with ulceration (T2b)
T3 Tumor 2.01 - 4.0 mm thick, without (T3a) or with ulceration (T3b)
T4 Tumor > 4.0 mm thick without (T4a) or with (T4b) ulceration
Regional lymph node (N)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to 1 lymph node or in transit, satellite or microsatellite metastases with no tumor involved nodes
N1a Clinically occult (i.e., detected by SLNB)
N1b Clinically apparent (i.e., macroscopic)
N1c In transit, satellite or microsatellite metastases with no tumor involved nodes
N2 Metastasis to 2 or 3 regional lymph nodes or in transit, satellite or microsatellite metastases with no tumor involved nodes
N2a Clinically occult (i.e., detected by SLNB)
N2b Clinically apparent (i.e., macroscopic)
N2c In transit, satellite or microsatellite metastases combine with 1 clinically occult or apparent
N3 Metastasis to 4 or more regional lymph nodes, matted lymph nodes or combination of in transit metastasis or satellite(s) and metastatic regional lymph node(s)
N3a Clinically occult (i.e., detected by SLNB)
N3b Clinically apparent (i.e., macroscopic) or presence of matted nodes
N3c In transit, satellite or microsatellite metastases combine with 2 or more clinically occult or clinically detected or presence of matted nodes
Distant metastasis (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis, LDH status (designated as 0 for not elevated and I for elevated level; no suffix is used if LDH is not recorded or is unspecified)
M1a Distant skin, subcutaneous or lymph node
M1b Lung
M1c All other non-central nervous system (CNS) visceral sites
M1d CNS


Table 5: 2017 eighth AJCC prognostic stage group for cutaneous melanoma
Stage T N M
0 Tis N0 M0
IA T1a N0 M0
IB T1b N0 M0
T2a
IIA T2b N0 M0
T3a
IIB T3b N0 M0
T4a
IIC T4b N0 M0
IIIA T1a, T1b N1, N2a M0
T2a
IIIB T0 N1b, N1c M0
T1a / b - T2a N1b / c, N2b
T2b / T3a N1a - N2b
IIIC T0 N2b / c, N3b / c M0
T1a - T3a N2c, N3
T3b / T4a Any N ≥ N1
T4b N1a - N2c
IIID T4b N3 M0
IV Any T, Tis Any N M1
Case reports
Treatment

Table 6: Clinicopathologic correlates of melanoma in the lower genital tract (adapted from Am J Cancer Res 2020;10:4017)
Subtype Sun protected cutaneous vulvar melanoma Mucosal melanoma (vulvar and vaginal)
Molecular alterations BRAF, NRAS, TERT, CDKN2A, PTEN KIT, NRAS, BRAF, NF1, CDKN2A, TERT, PTEN, SF3B1
Metastatic pattern Initially involving regional lymph nodes, distant metastases (lung, brain) at later stage More likely to develop distant metastases (lung, liver, brain)
Surgical modality Wide local excision with adequate margins Complete excision
Lymph node assessment Sentinel lymph node biopsy, regional lymphadenectomy if needed Sentinel lymph node biopsy or routine regional lymphadenectomy not recommended
Systemic therapy
Chemotherapy Interferon, dacarbazine, paclitaxel Cisplatin, vinblastine, dacarbazine, interferon
Radiotherapy Neoadjuvant or adjuvant Palliative treatment of local or metastatic disease
Targeted therapy BRAF and MEK inhibitors BRAF and c-KIT inhibitors
Immunotherapy Programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) checkpoint inhibitors
Palliative therapy Palliative surgery or radiotherapy
Prognosis factors AJCC staging, Breslow thickness, lymph node status, distant metastases Breslow thickness, depth of invasion, lymph node status, distant metastases
Clinical images

Contributed by Anna Sarah Erem, M.D., Gulisa Turashvili, M.D., Ph.D. and José Alberto Fonseca Moutinho, M.D.
Vulvar melanoma

Vulvar melanoma

Vulvovaginal melanoma

Vulvovaginal melanoma



Images hosted on other servers:

Nodule and ulcer

Large friable, gray-white growth

Large friable, gray-white growth

Vulvar melanoma

Missing Image

Nonpigmented primary lesion found in vagina

Gross description
Gross images

Contributed by Anna Sarah Erem, M.D. and Gulisa Turashvili, M.D., Ph.D.
Vulvectomy for melanoma Vulvectomy for melanoma

Vulvectomy for melanoma

Microscopic (histologic) description

Table 7: AJCC versus CAP features recommended for histopathologic assessment of primary vulvar melanomas (adapted from CAP: Protocol for the Examination of Specimens From Patients With Melanoma of the Skin [Accessed 30 November 2023])
Histopathologic feature AJCC recommended CAP recommended
Histologic type Yes
Clarka / anatomicb level
Breslowa / tumorb thickness Yes Yes
Radial (nontumorigenic) growth phase
Vertical (tumorigenic) growth phase
Mitotic rate (number/mm2) Yes Yes
Ulceration Yes Yes
Regression
Lymphovascular invasion Yes
Perineural invasion
Microscopic satellitosis Yes Yes
Tumor infiltrating lymphocytes
Associated precursor melanocytic nevus
Predominant cytology
Margins Yes
a Used in evaluation of primary melanomas of cutaneous origin
b Used in evaluation of primary melanomas of mucosal origin

Table 8: Clark and Chung classifications comparative aspects (adapted from Biomedicines 2021;9:758, Ann Surg 1970;172:902, Cancer Res 1969;29:705, Obstet Gynecol 1975;45:638)
Level of invasion Clark classification
Level of invasion of cutaneous melanoma
Chung classification
Level of invasion of mucosal melanoma
I Lesions involving only the epidermis (in situ melanoma) Tumor confined to the epithelium (in situ melanoma)
II Invasion of the papillary dermis, does not reach the papillary - reticular dermal interface Invasion into the basement membrane to a depth of ≤ 1 mm
III Invasion fills and expands the papillary dermis, does not extend to reticular dermis Invasion to a depth of 1 - 2 mm
IV Invasion into the reticular dermis, does not extend to the subcutaneous tissue Invasion to a depth of > 2 mm, does not extend to the subcutaneous fat
V Invasion through the reticular dermis into the subcutaneous tissue Tumor penetrates the subcutaneous fat
Microscopic (histologic) images

Contributed by Anna Sarah Erem, M.D., Gulisa Turashvili, M.D., Ph.D. and Priya Nagarajan, M.D., Ph.D.
superficial growth pattern superficial growth pattern

Superficial growth pattern

Melanoma in situ

Melanoma in situ

Melanoma in situ, lentiginous pattern

Melanoma in situ, lentiginous pattern

Vaginal melanoma

Vaginal melanoma

HMB45

HMB45


Vulvovaginal melanoma

Vulvovaginal melanoma

Vulvar melanoma, recurrent

Vulvar melanoma, recurrent

S100

S100

Mucosal vulvar melanoma

Mucosal vulvar melanoma

MelanA / MART1

MelanA / MART1

Vaginal amelanotic melanoma

Vaginal amelanotic melanoma

Positive stains
Negative stains
  • p16: complete loss of expression is usually seen in melanomas
    • Its utility in differentiation between benign and malignant melanocytic lesions has been questioned
Molecular / cytogenetics description
  • Current studies have not consistently separated melanomas arising from glabrous / mucosal from hair bearing vulva; hence, their molecular distinction is challenging (J Low Genit Tract Dis 2023;27:40)
  • KIT mutations are the most common alterations in mucosal melanomas (J Clin Oncol 2006;24:4340, Melanoma Res 2014;24:360, J Low Genit Tract Dis 2023;27:40)
    • Vulvar melanoma > vaginal melanomas >> cutaneous melanomas
  • NRAS, NF1, TP53, TERT, CDKN2A, PTEN have also been identified
  • BRAF mutation in vulvovaginal melanomas (J Low Genit Tract Dis 2023;27:40)
    • Rare and identified in < 10% of cases by next generation sequencing
  • Fluorescence in situ hybridization (FISH) or comparative genomic hybridization to confirm or rule out melanoma
  • See table 6 for clinicopathologic correlates
Videos

Vulvovaginal melanoma
by Dr. Lewis Hassell

Vaginal melanoma radiology
by Dr. Ayushi Gupta

Vaginal melanoma

Sample pathology report
  • Vulva, right labium majus, excision:
    • Melanoma, superficial spreading growth pattern, with features of regression (Breslow thickness = 1.7 mm, Clark level = IV; pT2a)
    • Compound nevus
    • Dermal scar
    • All margins are free of melanoma (see comment and synoptic report)
    • Comment: Immunohistochemical stains for MelanA performed on blocks A3 - A7 highlight the invasive melanoma. A BRAF V600E stain performed on block A6 is positive in the tumor cells.

  • Vagina, radical hysterectomy and bilateral salpingo-oophorectomy:
    • Vagina:
      • Multifocal melanoma, nodular type (largest focus: 4.7 x 1.7 x 1.0 cm)
      • Vaginal cuff margin involved by melanoma
    • Cervix:
      • Involved by melanoma (direct extension)
    • Uterus:
      • Endometrium: secretory
      • Myometrium: adenomyosis
      • Uterine serosa and cervix: benign
      • Fallopian tubes: benign, fimbriated
      • Ovaries: benign
Differential diagnosis
  • Atypical melanocytic nevus of genital type (AMNGT):
  • Pigmented epithelioid melanocytoma (PEM) of the vulva:
    • PEM family consists of multiple, usually slow growing, distinct histologic melanocytic entities with potential to metastasize but with a better prognosis than melanoma (WHO 5th edition)
    • Infiltrative deep dermal tumor that may involve subcutis
    • Hypercellular tumor with cells ranging from medium sized epithelioid cells to large epithelioid cells and spindled cells
    • Low mitotic activity
    • PRKAR1A loss in 67% of PEMs (Am J Surg Pathol 2017;41:1333, Am J Surg Pathol 2019;43:480)
  • Dysplastic nevus of vulva:
    • Differentiation requires clinical - pathologic correlates
    • Relative symmetry
    • Presence of junctional shoulders: extension of junctional component at least 3 rete ridges beyond the dermal component
    • Superficial nests are usually very similar and may show focal bridging or coalescence of the nests
    • Elongation and bridging of the rete ridges with nests
    • Melanocytes may scatter suprabasally (confined to the lower epidermal layer and centrally)
    • 2 tier grading of cytologic atypia is recommended by World Health Organization (WHO) classification and is largely based on nuclear features (WHO 5th edition) (Hum Pathol 1999;30:500)
Board review style question #1
A 67 year old woman was recently diagnosed with vulvar melanoma of the right labium majus. What is the most likely molecular alteration in this lesion?

  1. ALK fusion
  2. BRAF mutation
  3. KIT mutation
  4. NTRK 1/3
  5. PRKAR1A loss
Board review style answer #1
C. KIT mutation. KIT mutations are more common in vulvar melanomas compared with cutaneous melanomas. Answers A and D are incorrect as ALK fusions and NTRK rearrangements are common in Spitz nevi. Answer E is incorrect as PRKAR1A loss is characteristic of pigmented epithelioid melanocytoma. Answer B is incorrect as BRAF mutations are more common in cutaneous melanomas and are only rarely encountered (< 10%) in vulvovaginal melanomas; however, nevi in genital areas, including atypical melanocytic nevi of genital type, frequently have a driver mutation in BRAF.

Comment Here

Reference: Melanoma
Board review style question #2

A 69 year old woman presented to the OBGYN clinic with severe pruritis. Clinical exam showed a 12 x 15 mm asymmetric, dark brown patch on the right labia minora extending into the clitoral hood. Biopsy demonstrated a broad, asymmetric, junctional melanocytic proliferation with dense lichenoid infiltrate. What is most likely to be demonstrated by the immunohistochemical stains for this patient’s lesion?

  1. HMB45 showing diffuse nuclear expression
  2. Loss of PRAME expression
  3. MelanA highlighting invasive melanoma cells
  4. p16 demonstrating strong nuclear expression
  5. SOX10 highlighting increased number of melanocytes with focal pagetoid spread
Board review style answer #2
E. SOX10 highlighting increased number of melanocytes with focal pagetoid spread. The histologic features are consistent with melanoma in situ, lentiginous growth pattern. SOX10 and MelanA will highlight increased melanocytes and pagetoid growth in melanoma. Answer C is incorrect as there is no evidence of invasive melanoma on H&E section. Answers A, B and D are incorrect as HMB45 is a cytoplasmic stain, PRAME is usually diffusely positive in melanoma and p16 typically demonstrates loss of nuclear expression in melanoma.

Comment Here

Reference: Melanoma
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