Vulva & vagina

• Acquired nevus in the genital area with architectural and cytologic atypia

• Nevus with architectural and cytologic atypia (acceptable by the 5th edition of World Health Organization [WHO] Classification of Female Genital Tumors)

• During obstetrics - gynecologic visit
  • Women rarely examine their vulva closely; consequently, duration and change of vulvar melanocytic lesions are often unclear (Dermatol Clin 2010;28:795)
  • Decision to biopsy is based on atypical appearance of pigmented lesion (Dermatol Clin 2010;28:795)
  • Genital pigmented lesions usually appear more atypical than nongenital lesions (Dermatol Clin 2010;28:795)
  • Punch or excisional biopsy is preferred over shave biopsy (Dermatol Clin 2010;28:795)
• Dysplastic melanocytic nevus
  • Commonly presents as macules or papules with irregular borders, pink in the center and tan to brown at the periphery (Dermatol Ther 2010;23:449)
  • Usually measures > 0.6 cm in size contrasting with common acquired nevi, which are typically < 0.6 cm
  • Difficult to distinguish clinically from atypical melanocytic nevus of genital type (Am J Surg Pathol 2008;32:51, Hum Pathol 1998;29:S1)

Table 1: Clinical - pathologic features of vulvar melanocytic lesions (adapted from Diagn Histopathol 2024;30:P15)

	Vulvar melanocytic nevus	Vulvar melanocytic nevus in association with lichen sclerosus	Atypical genital nevus of special anatomic site	Dysplastic melanocytic nevus	Vulvar melanoma
Age	Premenopausal	Premenopausal	Premenopausal, young adult	Premenopausal	Postmenopausal
Size	< 1 cm	< 1 cm	< 1 cm	0.5 - 1 cm*	> 1 cm
Delineation	Well circumscribed	Well circumscribed	Well circumscribed	Well circumscribed	Infiltrative
Symmetry	Present	Present	Present	Present	Absent
Lateral extension of junctional component	Absent	Absent	Focal	Present	Present
Pigmented junctional nests	Absent	Present	Absent	Absent	Absent
Junctional nests	Discrete	Coalescent	Mostly discrete	Discrete	Coalescent
Retraction artefact	Absent	Absent	Present	Usually absent	Absent
Ulceration	Absent	Absent	Absent or traumatic	Absent or traumatic	Often present
Pagetoid spread	Absent	Focal Central	Focal Central	Focal Central	Prominent
Cytologic atypia	None to mild	Moderate to severe	Mild to moderate Superficial	Mild to severe**	Severe Uniform Deep
Dermal mitosis	Rare in pregnancy	Rare	Rare Superficial	Rare	Conspicuous Atypical Deep
Dermal maturation	Present	Present	Present	Present	Absent
Dermal fibrosis	Absent	Dermal sclerosis	Broad zone of superficial coarse dermal fibrosis	Concentric or fibrolamellar fibrosis	Regression type

*5 mm suggested as the minimum size for diagnosing dysplastic melanocytic nevus
**See Table 3 for dysplasia grading per WHO 5th edition

• Dermoscopy for nonmodified mucous membranes is useful (Dermatol Ther 2010;23:449)
  • May show any of the dermoscopic patterns seen in benign nevi
  • Globular / cobblestone, homogenous, structureless or mixed patterns are most common (Dermatology 2011;222:157, Dermatology 2010;221:55)
• Histologic diagnosis is confirmatory
• For optimal diagnosis, lichen sclerosus should be controlled before excision of the nevus (J Am Acad Dermatol 2004;50:690, Arch Dermatol 2002;138:77)

Table 2: 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 Hyperrefractive cells around the papillae Sparse dendritic cells	Increased cellularity with atypical cells and disordered architecture

Contributed by José Alberto Fonseca Moutinho, M.D.


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• Dysplastic melanocytic nevus is characterized by architectural and cytologic atypia
  • Architectural atypia
    • Bridging / fusion of junctional nests between adjacent rete ridges
    • Variation in the size, shape or position of junctional nests
    • Scattered mild to moderate cytologic atypia in the melanocytes
    • Pagetoid spread of melanocytes may be seen, which is typically central and confined to lower epidermal layer
    • Bland melanocytes may extend into the papillary dermis
    • Concentric, lamellar eosinophilic fibroplasia in the papillary dermis near the dermoepidermal junction
    • Presence of shouldering (junctional shoulders): a lentiginous junctional component (basilar proliferation of atypical melanocytes) at the periphery of the lesion, extending beyond the dermal component (> 3 rete ridges)
    • Inflammatory infiltrate is usually confined to the superficial dermis
    • Usually papillomatous appearance of the epidermis
  • Cytologic atypia
    • See Table 3 for grading
    • Nuclear features are evaluated based on nuclear size, shape and presence of prominent nucleoli
    • To estimate the nuclear size, the adjacent keratinocytes are typically referenced
    • Chromatin evaluation includes hyperchromasia, coarse versus clumping of chromatin and its condensation within the nucleus
    • Typically, absent or low mitotic activity (< 1/mm²)
• Stereotypical features of junctional nevi are usually seen, including a well circumscribed, symmetrical lesion with intradermal component demonstrating maturation (J Cutan Pathol 2008:35:24)
• Nevi in the background of lichen sclerosus may appear more atypical (Arch Dermatol 2002;138:77)
• See Table 1 for clinicopathologic correlations

Table 3: Grading of cytologic atypia (adapted from WHO Classification of Skin Tumors, 5th edition)

Grade	Previously	WHO grade, 4th edition	Nucleus		Presence of nucleoli	Chromatin
			Size	Shape variation
0	Mild	Not dysplastic nevus	1x	Minimal	Absent or small	Can be hyperchromatic
1	Moderate	Low grade dysplasia	1 - 1.5x	Random atypia*	Hyperchromatic or dispersed	Hyperchromatic or dispersed
2	Severe	High grade dysplasia	1.5x or more	More than random atypia but still in minority of cells**	Prominent, often lavender	Hyperchromatic Coarse granular Peripheral condensation

Note: architectural atypia is essential for the diagnosis; high grade (severe dysplasia) in the presence of low grade cytology should be considered if the following architectural features are present: pagetoid spread (typically central and not above the middle third of the epidermis), presence of rare mitoses (< 1/2 mm²) and focal continuous basal proliferation
*Random atypia is referred to prominent shape variation in the minority of cells
**Shape variation would be more than random atypia or in a larger minority of cells, hence, not diagnostic for melanoma

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

A 42 year old woman presented to the clinic with a 0.8 cm flat, dark brown lesion with an irregular border on the mons pubis. The histologic findings of the shave biopsy demonstrated a broad junctional atypical melanocytic proliferation with central dermal component, focal bridging of adjacent junctional nests, focal pagetoid spread, moderate cytologic atypia, rare dermal mitoses (2 mitoses/2 mm²) and dense lymphocytic infiltrate. The lesion is transected at the deep dermis. What is the most important histological finding that questions the diagnosis of a dysplastic nevus?

1. Cytologic atypia, grade 1
2. Dermal mitotic activity (2 mitoses/2 mm²)
3. Focal fused junctional nests
4. Focal pagetoid spread

B. Dermal mitotic activity (2 mitoses/2 mm²). When considering a dysplastic melanocytic nevus, any dermal mitotic figures, especially atypical mitosis, should warrant additional work up. Answer C is incorrect because unless there is confluent architectural atypia, the focal fusion of junctional nests is not a concerning feature by itself and part of the diagnostic criteria for dysplastic nevus. Answer D is incorrect because it is permissible for dysplastic nevus to demonstrate focal pagetoid spread that does not exceed the lower part of epidermis. The concerning features include extensive wide pagetoid spread of melanocytes, especially if it extends past the epidermis and laterally beyond the underlying junctional component. Answer A is incorrect because cytologic atypia, grade 1 (see Table 3) is the least concerning feature in this lesion and without the presence of architectural atypia would not be enough for diagnosis of dysplastic nevus.

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Reference: Dysplastic nevi

A 38 year old woman presented to the OBGYN clinic with a 0.9 cm, irregular, dome shaped, dark pigmented papule on the right labium majus. A biopsy demonstrated symmetric melanocytic proliferation, with maturation, adjacent bridges of rete ridges and focal pagetoid spread mostly confined to the lower level of the epidermis. What is the most likely molecular alteration in this lesion?

1. ALK fusion
2. BRAF V600E mutation
3. Homozygous deletion of CDKN2A
4. NRAS mutation

B. BRAF V600E mutation. Most dysplastic melanocytic nevi have a driver mutation in BRAF V600E. Answer A is incorrect as ALK fusion is more characteristic of Spitz nevus. Answers C and D are incorrect as those alterations are specific to superficial spreading melanoma.

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Reference: Dysplastic nevi