pitfalls in the diagnosis of melanocytic tumors · 1/18/2018 2 risks of an incorrect judgment (a...

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Pitfalls in the diagnosis of melanocytic tumors

Timothy McCalmont, MD

University of California,

San Francisco

Ways to get into trouble…

Melanoma or not?Melanocytic nevus or not?

• Common and routine determination made by pathologists

• Reasonably accurate (we trust!), much of the time

• Jncorrect judgment holds profound implications for both patient and physician

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Risks of an incorrect judgment (a misdiagnosis)

• Undertreatment of disease

• Overtreatment of disease

• Professional embarrassment

• Legal culpability

• All of the above

The mindset:

• There are many ways to get into trouble and we will illustrate a few

• The best way to stay out of trouble is to avoid it in the first place

• Ancillary testing can be used in directed fashion to detect trouble

Factors behind trouble

• Poor technical work• Non-standard fixatives• Misplay a pagetoid configuration

• Overdo it or underdo it• Overcall an interface configuration• Miscall a biphasic configuration

• Overdo it or underdo it

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Ways to get into trouble

• Misplay mitotic figures• Overdo it or underdo it

• Misplay neurotropism• Overcall pagetoid cells



• Overdo it or underdo it• Overcall an interface configuration• Overcall a biphasic configuration

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Diagnosis (ugh!):

The surface of a thin melanoma




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The best diagnosis:

Desmoplastic melanoma, 2.4 mm in thickness

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The pitfall

• Poor sectioning obscures findings• Poor staining obscures details• Poor fixation or non-formalin

fixation blurs perception (and may preclude molecular evaluation)




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4 year old male with small darkly pigmented lesion of the lower leg = “melanoma”

Parent-initiated second opinion

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Final diagnosis:

Compound pigmented spindle cell (Reed/Spitz) nevus

Am J Surg Pathol. 1995;19:1061-7.

Pagetoid Spitz nevus. Intraepidermal Spitz tumor with

prominent pagetoid spread.

Busam K, Barnhill R

.

What can be pagetoid?

• Acral melanocytic nevi

• Melanocytic nevi of the nail unit

• Irritated melanocytic nevi

• Pigmented spindle cell nevi, especially on the extremity

• Spitz nevi, especially on the extremity

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Superficial spreadingSpitz nevi

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SSSN

• N = 41; M:F = 12:29

• Mean age 35.7 years (3-80)

• Leg: 68%

• Lateral spread: 2.1 +/- 0.8 mm

• Pagetoid scatter: 85%; marked 32%

• Desmoplasia: 36%

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The pitfall

• Nested melanoma is common

• Melanoma can present without pagetoid spread

• Pagetoid melanocytic nevi are common

• Pagetoid ≠ melanoma, esp. if small




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33 year old man with a pigmented area of face

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Our diagnosis:

Worrisome for a regressing melanocytic neoplasm

Take 2 (new specimen):

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Melan-A

Melan-A

Melan-A

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The real diagnosis:

Interface dermatitis with melanocytic pseudonests, probably lichen planuspigmentosus

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Melan-A

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Melan-A

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HMB-45

The pitfall

• Phantom nests—they seem real but are actually fake

• Obscured nests—they are real but you can’t really tell

• Fickle stains—they seem like they work (or seem like they should work) but it’s more complicated than that

Diseases prone to pseudonestformation• Lichen planus

• LPLK

• LE, sometimes

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Judging melanocyte density

• May be obscured by inflammation

• May be obscured by pigmentation

• May be difficult to judge with certainty in conventional sections

Determinants“specific” for melanocytes

• S100• HMB-45• NKI/C3, sometimes• Melan-A and MART-1• Mel-5• Tyrosinase• MiTF• SOX-10

Determinants best for assessing density

• S100• HMB-45• NKI/C3, sometimes• Melan-A and MART-1• Mel-5• Tyrosinase• MiTF• SOX-10

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MiTF / Giemsa

MiTF / Giemsa

MiTF / Giemsa

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Are melanocytes increased?

• They may or may not be

• MiTF or SOX-10 (with Giemsa or with red chromogen) is probably the current optimal detection method





Overdo it

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24 year old woman

• Referred with diagnosis of melanoma of 2 mm in thickness

• S/P wide excision and SLNB

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It’s a combined melanocytic nevus!• Combined conventional / deep

penetrating nevus

• AKA:

• “Inverted type A nevus”

• “Focal clonal hyperplasia”

• “Clonal nevus”

Combined DPN

• Initiates as a conventional melanocytic nevus, i.e. a BRAF-mutated melanocytic nevus

• An activating mutation in beta catenin represents the second step as a molecular dead end

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35 year old male

• Recently changing pigmented lesion of the arm

• Prior interpretation as melanoma of 1 mm in thickness

• Patient initiated a second opinion

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It’s a combined melanocytic nevus!• Combined melanocytic nevi

• Conventional and deep

• Conventional and blue

• Conventional and Spitz

• Blue and Spitz

• Dysplastic and Spitz

• Et cetera

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60 year old man

• Referred for evaluation of an ambiguous melanocytic proliferation

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Combined melanocytic nevus with a ‘BAPoma’ component• Melanocytic nevus with a second

clone with BAP-1 genomic loss

• Most are probably somatic (sporadic)

• A potential indicator of BAP-1 germline mutation if multiple

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Underdo it

46 year old woman

• Biopsy of a papule with recent change but little pigmentation

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Two years later

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The pitfall

• Assuming a second population is melanoma is an oversimplification--but don’t forget it might be so

• Most melanoma starts at the junction; wholly dermal melanoma ex melanocytic nevus often sits better as a combined melanocytic nevus

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HRAS-mutated Spitz nevus

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HRAS-mutation with 11p gain

11p Spitz (HRAS-mutated)

• van Engen-van Grunsven AC et al. HRAS-mutated Spitz tumors: A subtype of Spitz tumors with distinct features. Am J SurgPathol. 2010 Oct;34(10):1436-41.

• Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathologicalfeatures. Am J Pathol. 2000 Sep;157(3):967-72.

• McCalmont TH, Vemula S, Sands P, Bastian BC. Molecular-microscopical correlation in dermatopathology. J Cutan Pathol. 2011 Apr;38(4):324-6.

11p Spitz (HRAS-mutated)

• Large with lots of desmoplasia

• Horizontal orientation, often

• Infiltrative, often

• Mitotic figures, often

• Young adults rather than young children, often

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HRAS-mutated Spitz nevus

• A Spitz tumor driving down a molecular dead end

• Generally exists within a historical spectrum that has been safe as Spitz nevus




22 year old man with new pigmented lesion

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“Compound nevus with features of a Spitz”

No comment regarding:

• unconventional features

• mitotic figures

• status of the margin

• need for reexcision

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“Persistent nevus, edges not involved”

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About 2 years later…

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Obvious melanoma of 2.5 mm in thickness; referred

for SLNB

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Diagnosis:

Melanoma with metastasis to lymph nodes

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And again…

25 year old woman with a thigh lesion

“Spitz nevus with features of irritation”

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Persistent and metastatic melanoma noted within 18 months; patient expired within 48 months

The pitfall

• Mitotic figures can be found in nevi and melanoma

• Selected nevi, including pregnancy nevi and HRAS-mutant Spitz nevi, may have multiple mitoses and are at risk for overdiagnosis of melanoma

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The pitfall

• Tumors with an elevated mitotic index are potentially risky when underdiagnosed as nevi

• Nevoid melanoma often has a low mitotic index and can be diagnostically frustrating

The pitfall

• When evaluating Spitz nevi and other melanocytic nevi with unconventional features:

• think about reexcision

• think about molecular




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History of melanoma of lip, resected in 1987

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Clinical course

• After resection (1987), localized numbness of R chin

• Spreading numbness over chin, eventually reaching forehead

• Weakness in mastication

• S/P negative neuropathy workup

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1987

1987

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1987

2003

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82 year old male with persistent neurotropic

melanoma

S/P excised melanoma of 1 mm thick from 2000

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Revised final diagnosis:

Melanoma with unrecognized neurotropism, margins involved; S/P small (inadequate) reexcision

The pitfall

• The course of melanoma is variable• Neurotropism is an established

association• Neurotropism may be protracted in

the absence of metastasis• Keep neurotropism on your checklist

in the evaluation of every melanoma




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From the breast of a 39 year old; called melanoma

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Final diagnosis:

Special site nevus (flexural melanocytic nevus is equivalent)

What can have pagetoid cells?

• Melanoma, often

• Spitz nevi, occasionally

• Deep penetrating nevi, often

• Special site nevi, often

• Flexural melanocytic nevi, often

The pitfall

• Just as pagetoid scatter ≠ melanoma, big fluffy (pagetoid) melanocytes do not equate with melanoma

• Approaching the diagnosis of melanoma by cytology is often weak, while approaching it by architecture is generally strong

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pitfalls in the diagnosis of melanocytic tumors · 1/18/2018 2 risks of an incorrect judgment (a...

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