Melanocytic Nevi Pretending

to be Melanoma

Thomas Brenn – University of Calgary, Canada

Melanocytic Tumors
One of the most challenging and controversial areas in
diagnostic dermatopathology
One of the most frequent causes of litigation
Important to remember: Perspective
Majority of melanocytic lesions no diagnostic challenge
Majority of nevi are common acquired nevi
Majority of melanomas are conventional subtypes
Melanocytic Tumors - Problems
Clinical information (or lack thereof):
Age, site, size, clinical presentation and level of concern
Type of biopsy: Is it representative?
Wide morphological spectrum of melanocytic lesions,
both malignant and benign
Diagnostic pitfalls
So-called “borderline” tumors
Melanocytic Tumors

Type of biopsy:
Preferably excisional or large incisional biopsy
Important to visualize peripheral edges and deeper
aspects of the tumor to comment on circumscription
and maturation
If partial, is the biopsy representative?
S100
Melanocytic Nevi
-Morphological Spectrum-

May resemble melanoma

• Architecture (symmetry, circumscription,
maturation, junctional disorder, Pagetoid spread)
• Cytology (atypia, Spitzoid features)
• Mitotic activity
May resemble non-melanocytic tumors
Applications for IHC in Melanocytic Tumor
Pathology
Confirm melanocytic differentiation
S100; SOX10; Melan A; HMB45, (MITF)
Differentiate ‘benign’ form ‘malignant’
Ki67; p16; (p21); PRAME; HMB45; (cyclin D1)
Define underlying molecular drivers and direct treatment
BRAF; RAS; GNAQ/11; BAP1; ALK; NTRK; ROS; ß-catenin,
KIT
Distinction Nevus - Melanoma
Solution:
Use all available information
• Clinical data, levels, immunohistochemistry, genetics
Awareness of variants of nevi and melanoma
Index of suspicion
Ask for help
Ask for appropriate biopsy and call if things don’t add up
Melanocytic Tumors
-Diagnostic Issues-
DDx of Desmoplastic melanoma
Acral melanoma vs acral nevi
Genital melanoma vs genital nevi
Melanocytomas:
• Two-hit wonders: Bapoma and DPN
• Pigmented epithelioid melanocytoma
Desmoplastic Melanocytic Tumors
Desmoplastic Melanoma
Sun-damaged skin; head and neck

Elderly; 60 yrs

M>F

Large, ill-defined and variably

pigmented tumors
 Immunohistochemistry

S-100 SMA
Desmoplastic Melanoma
-Genetics-

Frequent NF1,NFKBI, TERT

promoter mutations
No mutations in BRAF, NRAS,
KIT, GNA11 or GNAQ

Kiuru M, Busam KJ. The NF1 gene in tumor syndromes and

melanoma. Lab Invest. 2017 Feb;97(2):146-157.

Shain AH, et al. Nat Genet. 2015 Oct;47(10):1194-9.

Wiesner T, et al. Am J Surg Pathol. 2015 Oct;39(10):1357-62.
Plaque-type Blue Nevus
Longstanding variably pigmented
plaque
Multiple cm
Predilection for scalp

Young adulthood

Brenn T. Histopathology. 2012;60(5):690-705.

Courtesy of Dr. Keith Miller, Bristol
 Melan A

S100 HMB-45
Plaque-type BN vs DMM
Similar clinical setting as plaque on scalp of adults
Significant histological overlap with deep extension
but
No cytological atypia and areas of conventional BN
Melan A and HMB-45 positivity and weak and focal
S100 expression
GNAQ and GNA11 mutations
 Sclerosing Nevus
Wide age range (young adults)
Wide anatomical distribution
Sun protected skin
Longstanding history with recent change
Benign behavior
No abnormalities by FISH
Kiuru M, Patel RM, Busam KJ. J Cutan Pathol. 2012;39(10):940-4.
30 yo M; longstanding, slowly enlarging lesion on the foot
 S100

S100 Melan A
16 yo F; longstanding, recent change in congenital nevus on chest S100
Sclerosing Nevi vs Desmoplastic Melanoma

Difficult distinction on histology

• Asymmetry
• Deep extent
• Marked dermal sclerosis
• Lymphoid aggregates
Sclerosing Nevi vs Desmoplastic Melanoma

But
• Patient age, duration, location
• Circumscription
• Pre-existing naevus
• Melan A expresssion
Nevi with Perineurial Differentiation
Young to middle aged adults (26-48 years)
M=F
Wide anatomical distribution
Not chronically sun-damaged sites
Longstanding history with recent change
Benign behavior
McCalmont TH, et al. J Cutan Pathol. 2011;38(12):940-2.
McAfee JL,et al. J Cutan Pathol. 2021;48(10):1223-1230.
Ferreira I, et al. Histopathology. 2018;72(4):679-84.
S100
EMA
S100
EMA
S100
EMA
68 yo male with a nodule on the right cheek
S100 melan a
EMA Glut1
Perineuriomatous Nevi vs DM
Difficult distinction on histology
• Asymmetry
• Deep extent
• Marked dermal sclerosis
• Lymphoid aggregates
Perineuriomatous Nevi vs DM

But
• Patient age, duration, location
• Circumscription
• Pre-existing nevus
Acral Melanocytic Tumors
Acral Lentiginous Melanoma

Elderly, 70 yrs
M=F
Large, ill-defined and
variably pigmented tumors
Plantar surface
Atypical Acral Nevus

Young to middle adults

F>M
Macules/papules
<1cm
Acral Spitz Nevi
Adolescents and young
adults, median: 24 years
Wide age range (3-61 yrs)
F:M = 2:1
Foot : Hand = 2:1
<1 cm
Entirely benign
Wiedemeyer K, ey al. Am J Surg Pathol. 2018 Jun;42(6):821-827.
Melan a
Melan a
Acral Spitz Nevi vs ALM

Large with broad junctional component

Florid Pagetoid spread
Spitzoid cytology
Dermal mitoses
Dermal regression
Acral Spitz Nevi vs ALM

BUT:
Circumscribed +/-symmetrical
No nuclear pleomorphism
Maturation of dermal component
No deep dermal mitoses
 ALM Dx - Useful IHC markers

In situ component Invasive component

Melan A / HMB45 / PRAME
SOX10 P16/p21
PRAME (MIB1)

Wiedemeyer K, ey al. Am J Surg Pathol. 2018;42(6):821-827.

McBride JD, et al. J Cutan Pathol. 2022;49(3):220-230.
Hu J, et al. Hum Pathol. 2022;120:9-17.
 Acral Spitz Nevi

p16 p21
 Acral Spitz Nevi
P16 P21

P16+ P21+
P16- P16+ low P16+ intermediate P21- P21+ low P21+ intermediate
high high

Expression in % of dermal melanocytes 0% 1-25% 26-50% 51-75% 76-100% 0% 1-25% 26-50% 51-75% 76-100%

acral Spitz nevi (n=21) 0 1 1 0 19 1 0 1 0 19

acral lentiginous melanoma (n=10) 6 3 1 0 0 1 8 1 0 0

acral nevi (n=10) 0 0 0 0 10 10 0 0 0 0

Wiedemeyer K, ey al. Am J Surg Pathol. 2018;42(6):821-827.

Genital (Vulvar) Melanocytic
Tumors
Vulvar Melanoma
Postmenopausal women, 60-70yrs
20% before age 50
Large (2cm), ill-defined and
variably pigmented tumors
Mucosal surfaces
Aggressive behavior due to
advanced stage at presentation
Melan A
Atypical Genital-Type Nevi
-Clinical-
Adolescents and young adults
(median: 26 years)
Vulva (mucosa and skin)
Mons pubis, perineum
Strong female predilection
Clinically atypical
Calonje, et al 2012 McKees Pathology of the Skin

(large, hyperpigmented, irregular)

Mean size: 6 mm (range: 2-20mm) Clark WH Jr, et al. Hum Pathol. 1998;29(1 Suppl 1):S1-24.
Gleason BC, et al. Am J Surg Pathol. 2008;32(1):51-7.
Atypical Genital-Type Nevi
-Outcome-

Benign behavior

Rare local recurrence after incomplete removal

No adverse outcome reported so far

Atypical Genital-Type Nevi
-Concerning features-
Clinical presentation Histological features
Size Size
Shape Cytological atypia (mod-severe in 80%)
Pigmentation Confluent atypia
Dermal atypia
Suprabasilar and rarely Pagetoid spread
Adnexal involvement
Dermal mitoses (up to 4)
Atypical Genital-Type Nevi
-Reassuring features-
Lesional circumscription and symmetry
No significant shoulder formation and radial growth
Cytological atypia confined to junctional / superficial dermal
component
Maturation with depth
Lack of expansile growth
No deep dermal or atypical mitoses
Genetically: BRAF mutations Yélamos O, et al. J Invest Dermatol. 2016;136(9):1858-1865.
Two Hit Wonders
BAP1-inactivated Melanocytic Tumor /
Melanocytoma (BAPoma)
Majority sporadic but may be autosomal-dominant
inherited cancer predisposition syndrome
Young adults (median: 30 years); F>M
Wide anatomic distribution: trunk, head and neck courtesy Dr Zlatko Marusic, Zagreb

Small flesh-colored dome-shaped papules

Mutations in BRAF and BAP1 genes
Wiesner T, et al. Nat Genet. 2011;43(10):1018-21.
Donati M, et al. Mod Pathol. 2021 PMID: 34857909. Wiesner T, et al. Am J Surg Pathol 2012;36(6):818-30. courtesy Dr Zlatko Marusic, Zagreb
BAP1 BRAF
BAP1 BAP1
BAP1
BAP1 BAP1
Melan A/Ki67
BAP1-inactivated Melanocytic Tumor /
Melanocytoma (BAPoma)

Benign clinical behavior in vast majority of tumors

Exceptional metastatic disease

Deep Penetrating Nevus / WNT-activated
Melanocytoma
Wide age range; adolescence and
early adulthood
Face, neck, extremities
Darkly pigmented to grayish
symmetrical papule/nodule <1cm
Mutations in ß-catenin and MAP-
kinase pathway
Yeh I, et al. Nat Commun. 2017;8(1):644.
Robson A, et al. Histopathology. 2003 Dec;43(6):529-37.
ß-catenin
Deep Penetrating Nevus
Concerning features:
Melanocyte atypia
Lack of maturation
Scattered mitotic activity
Deep pigmentation
Growth along neurovascular bundles
Extension into subcutis
Deep Penetrating Nevus
BUT:
Circumscription
Wedge-shaped architecture
No severe or confluent atypia
No atypical mitoses
No expansile growth
No necrosis
Case
18-year-old male
1-year history
Leg lesion with dark veil
On methotrexate for severe
bilateral pan-uveitis
mib-1
Case

Deep Penetrating Nevus-like

Melanoma in the setting of
immunosupression
ß-catenin
Case

Positive SLN biopsy and

clearance
Disseminated metastases and
Death form disease 2 years after
presentation
Case

30 yo F with a pigmented lesion on the right

labium majus
 Immunohistochemistry

Melan A

S100 HMB-45
Case

Pigmented epithelioid melanocytoma

Pigmented Epithelioid Melanocytoma

Unusual but distinctive melanocytic tumor

Reminiscent of melanomas in grey horses
“Animal- / Equine-type Melanoma”
Morphological overlap with epithelioid blue nevus in
Carney complex
Mutations in and loss of expression of PRKAR1A in
sporadic PEM and EBN in patients with Carney complex
Pigmented Epithelioid Melanocytoma
-Clinical-
Deeply pigmented tumors
Extremities, head & neck, trunk
Mucosa, genital sites
Young adults (20-30 yrs)
Wide age range including congenital onset
M=F
Pigmented Epithelioid Melanocytoma
-Histological Features-
Deeply pigmented tumors
Tumor thickness: 2-3 mm (range: 0.8
– 10 mm); level IV or V
Large ovoid to polygonal cells
Heavily pigmented cytoplasm and
vesicular nuclei with prominent
nucleoli
Low mitotic rate
No or minimal junctional component
Pigmented Epithelioid Melanocytoma
-Clinical Behavior-

Overall favourable prognosis

High rate of LN metastasis (30-50%)
Rare distant metastasis to liver
Rare documented mortality
Antony FC Histopathology 2006;48:754-762
Zembowicz A et al Am J Surg Pathol 2004;28:31–40
Mandal RV Am J Surg Pathol 2009;33:1778–1782
Heavily Pigmented Melanoma
Conventional Melanoma
Heavy cytoplasmic and stromal
melanin pigmentation
Clinical course predicatble by tumor
thickness
Often thick tumors at presentation
Poor prognosis
Morphological Variants of Nevi
Awareness of wide morphological spectrum and
diagnostic pitfalls
May closely resemble invasive melanoma
Attention to clinical presentation and
Histological, immunohistochemical and genetic clues
Expression of uncertainty