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 1
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 2
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 3
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 4
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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 7
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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 13
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Underdiagnosis of a nonpagetoid or subtle pagetoid pattern 15
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Overdiagnosis of a prominent pagetoid configuration Kiddo with a diagnosis of melanoma on the foot Parent-initiated second opinion 23
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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 spreading Spitz nevi 26
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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 30
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 31
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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. Molecularmicroscopical 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 35
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) 36
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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) 39
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) 40
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) 41
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ALK p16 43
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p16 NTRK1 46
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) 47
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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 49
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 50
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 51
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) 52
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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 55
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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 59
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Melan-A Melan-A CD34 62
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 63
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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) 66
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 67
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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 70
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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 ex melanocytic 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 73
22 year old, from Phoenix, with new pigmented lesion 74
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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 77
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Called a persistent Spitz and nothing more done 80
About 2 years later 81
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Now clearly melanoma of 2.5 mm in thickness; SLNB pursued 85
Diagnosis: Melanoma, with metastasis to lymph nodes History repeats itself: 25 year old with a thigh lesion, called an irritated Spitz 86
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Persistent and metastatic melanoma noted within 18 months; patient expired within 48 months 89
In addition to watching for mitotic figures, Ki-67 or phosphohistone can be used 90
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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 92
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 93
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Numbness ensued in 1988 and spread; facial palsy eventually developed years later 96
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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 100
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Ultimate diagnosis: Melanoma with unrecognized neurotropism, with margins involved; narrow excision was insufficient and thus persistence ensued 104
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 105