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Pitfalls in the diagnosis of melanocytic tumors

Timothy McCalmont, MD

University of California,

San Francisco

Ways to get into trouble, ideas on avoiding trouble,

and diagnostic approaches to keep trouble at bay

Melanoma or not?Melanocytic nevus or not?

• Common and routine determination made by histopathologists

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

• An incorrect judgment holds implications for both patient and physician

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Risks of an incorrect judgment (a misdiagnosis)

• Undertreatment

• Overtreatment• Embarrassment• Legal culpability• All of the above

The mindset:

• There are many ways to get into trouble in the interpretation of melanocytic tumors

• We can’t talk about all of them, at least not today

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

Stephen Jay Gould

The world contains far more objects and subtleties than we have concepts, so we make mistakes all the time…

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Wallace Clark

• A pathology specimen represents little bits of a fellow human being; the pathologist will be bonded to that person for a lifetime and should never underestimate that bond

Wallace Clark

• Do not ever make the diagnosis of melanoma quickly, casually, or without vigilant forethought of the consequences; for the recipient, a life is changed forever…

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

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Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

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Dodging the pitfall

• Poor sectioning may obscure key findings, so don’t accept that

• Pale staining may hide cellular and tissue details, so don’t accept that

• Poor fixation or use of non-formalin fixatives may impede interpretation (including molecular evaluation)

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

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2 years later…

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Dodging the pitfall

• Maintain a system to be certain all unique tissue sections on a slide have been reviewed

• Work at a comfortable pace• Know your limits and don’t exceed

them

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

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Underdiagnosis of a non-pagetoid or subtle pagetoidpattern

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Overdiagnosis of a prominent pagetoid configuration

Kiddo with a diagnosis of melanoma on the foot

Parent-initiated second opinion

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Ultimate diagnosis:

Pagetoid pigmented spindle cell (Reed/Spitz) nevus

Pagetoid melanocytic nevi

• Pagetoid Spitz nevus

• Pagetoid Reed nevus• Acral melanocytic nevus• Irritated melanocytic nevi• Superficial spreading Spitz nevus

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%

Dodging the pitfall

• Nested configurations of melanoma are not uncommon: a pagetoid configuration is not required

• Watch for big nests (‘meganests’)• Variants of melanocytic nevi with a

pagetoid configuration are common: all that is pagetoid is not melanoma

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Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

Adolescent male:

• Clinical diagnosis: ? Spitz

• Pathologic diagnosis: STUMP or spitzoid melanoma with recommendation for SLNB

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HRAS-mutated Spitz nevus

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 Surg Pathol. 2010 Oct;34(10):1436-41.

• Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. 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)

• Often large with desmoplasia• Horizontal orientation, often• Infiltrative, commonly• Melanocytes in mitosis, often• In young adults rather than

young children, often

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The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

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The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz

• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

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The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz

• Gene fusion Spitz (ALKoma and NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

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The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

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ALK

p16

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p16

NTRK1

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Kinase fusion Spitz

• Induced by various kinase gene fusions, including ALK, NTRK1, NTRK3, ROS1

• Partially transformed tumors that may be large with mitotic figures

• p16 immunohistochem of value in screening for potential second hit

The full Spitz spectrum

• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

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BAP1

p16

BAP-1 and BAPoma

• BRCA-associated protein 1

• Tumor suppressor protein• Key element in ocular melanoma• Weak role in cutaneous melanoma• BAPomas are partially transformed

• May be marker for syndromic BAP-1 mutation

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The full Spitz spectrum• Conventional Spitz

• Superficial spreading Spitz• HRAS-mutant Spitz• Gene fusion Spitz (ALKoma and

NTRKoma

• BAPoma (epithelioid with BAP-1 genomic loss)

• Atypical Spitz / spitzoid melanoma

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p16

Dodging the pitfall

• Recognize that there has been an explosion of understanding in the Spitz spectrum

• Nomenclature is in flux• Mitotically-active, partially

transformed tumors can potentially be overcalled as melanoma

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Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

Desmoplastic melanoma

• M > F (13:10)

• Mean onset: >60 years

• Head or neck area: 70%• Pigmentation: 25-30%

• Visceral > Nodal: (2:1)

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S100

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Melan-A

Desmo MM IHC

• S100 / SOX10: highly effective

• HMB, Mel-A, MART: ineffective• p75: effective but unavailable• WT-1: cytoplasmic, effective• CD34: tends to be absent (often

present in neurofibroma)

70 year old VA patient with diagnosis of spindle cell carcinoma by conventional microscopy

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Everything desmoplastic is not desmoplastic melanoma• Desmoplastic carcinoma

• Desmoplastic AFX• Desmoplastic nevus• Desmoplastic Spitz nevus• Nevus with hybrid nerve sheath

differentiation

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Melan-A

Melan-A

CD34

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Dodging the pitfall

• Liberally utilize SOX10 or S100 in the evaluation of spindle cell tumors, especially if with elastosis

• Eschew Melan-A, MART1, HMB45• Remember desmoplastic nevi

• If you encounter desmo MM arising with a nevus, it’s probably not that

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

• Young woman new in clinic

• Reportedly with melanoma of 2 mm in thickness

• Diagnosis with concurrence by 2 pathologists

• Wide local excision, sentinel nodes already done and all negative

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Ultimate diagnosis: combined melanocytic nevus• ““““Inverted type A nevus””””• ““““Focal clonal hyperplasia”””” or ““““clonal nevus”

• (Deep penetrating nevus centrally in a congenital melanocytic nevus)

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Ultimate diagnosis: combined melanocytic nevus• ““““Inverted type A nevus””””• ““““Focal clonal hyperplasia”””” or ““““clonal nevus”

• (Deep penetrating nevus centrally in a congenital melanocytic nevus)

• The component of DPN is triggered by an activating beta catenin mutation

35 year old male

• Recently changing pigmented lesion of the arm

• Diagnosis of melanoma of 1 mm in thickness at an academic dermatopathology laboratory

• Patient-initiated second opinion

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Ultimate diagnosis, again: combined melanocytic nevus• Combined melanocytic nevi

• Conventional and blue

• Conventional and Spitz

• Blue and Spitz

• Dysplastic and Spitz

• Conventional and BAPoma

• Et cetera

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Dodging the pitfall

• When encountering two populations, consider combined nevus as well as melanoma ex nevus

• Most melanoma initiates along the junction; be cautious in the diagnosis of wholly dermal melanoma exmelanocytic nevus

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

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22 year old, from Phoenix, with new pigmented lesion

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Called a Spitz and nothing more done

No comment regarding:

• unconventional features

• mitotic figures• status of the margin• need for consideration of reexcision

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Called a persistent Spitz and nothing more done

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About 2 years later…

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Now clearly melanoma of 2.5 mm in thickness; SLNB pursued

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Diagnosis:

Melanoma, with metastasis to lymph nodes

History repeats itself: 25 year old with a thigh lesion, called an irritated Spitz

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

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In addition to watching for mitotic figures, Ki-67 or phosphohistone can be

used

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Dodging the pitfall

• Dermal mitotic figures do not equate with melanoma, but the finding of mitoses mandates caution

• Spitz nevi and other unconventional melanocytic tumors warrant consideration of molecular assessment and complete excision

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Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

History of melanoma of lip, resected in 1987

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Numbness ensued in 1988 and spread; facial palsy

eventually developed years later

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1987

1987

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1987

2003

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82 year old male presents with persistent neurotropic melanoma of the arm, S/P excision of melanoma of 1 mm in thickness

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Ultimate diagnosis:

Melanoma with unrecognized neurotropism, with margins involved; narrow excision was insufficient and thus persistence ensued

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Dodging the pitfall

• Intentionally screen for neurotropism when evaluating each and every melanoma

• Similarly, intentionally screen for other uncommon findings, including vascular invasion

• A checklist approach may be helpful

Ways to get into trouble• Poor technical work• Not paying attention• Misplay of a pagetoid configuration• Being too strong with a Spitz• Not knowing the full Spitz spectrum• Misplay of desmoplasia• Misplay of a biphasic configuration• Missing mitoses• Missing neurotropism

Copy of this talk:

• Through the meeting organizers

• If all else fails, go to dermpath.ucsf.edu and contact me