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1/18/2018 1 The Ascent of Spitz Nevi Timothy McCalmont, MD University of California, San Francisco The Ascent of Spitz Nevi Timothy McCalmont, MD University of California, San Francisco Our goals for this session • A brief history of Spitz nevi • A brief look into the recent events important to those of us who love Spitz nevi • A massive review of Spitz variants • A brief review of what is NOT a Spitz

The ascent of Spitz nevi final final final.ppt · BAPoma • A Spitz (or at least Spitz-like because of cytomegaly) with a successful first hit with tumor suppressor loss • Overlap

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Page 1: The ascent of Spitz nevi final final final.ppt · BAPoma • A Spitz (or at least Spitz-like because of cytomegaly) with a successful first hit with tumor suppressor loss • Overlap

1/18/2018

1

The Ascent of Spitz Nevi

Timothy McCalmont, MDUniversity of California, San Francisco

The Ascent of Spitz Nevi

Timothy McCalmont, MDUniversity of California, San Francisco

Our goals for this session

• A brief history of Spitz nevi

• A brief look into the recent events important to those of us who love Spitz nevi

• A massive review of Spitz variants

• A brief review of what is NOT a Spitz

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1. History

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2. Recent events

Normal

Malignancy(fully transformed)

Mutation 1

Tumors arise from accumulated alterations in the genome

Mutation 2

Mutation 3

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Nevus

Melanoma

Phenotype of melanocytic nevi varies dependent on the oncogenic change

BRAF Threonine kinaseNRAS Small GTPaseGNAQ Large GTPaseGNA11 Large GTPaseHRAS Small GTPaseALK Receptor tyrosine kinaseROS1 Receptor tyrosine kinaseRET Receptor tyrosine kinaseMET Receptor tyrosine kinaseNTRK1 Receptor tyrosine kinaseNTRK3 Receptor tyrosine kinasePRKCA  Threonine kinaseBRAF Threonine kinase

Point 

mutations

Rearrangements

Acquired nevi

Congenital nevi

Blue nevi

Spitz nevi

Partially-transformed tumors

• With genomic loss:

• With genomic gain:

• With gene fusion/translocation:

Partially-transformed tumors

• With genomic loss:

• example: BAPoma (BAP1 loss)

• With genomic gain:

• With gene fusion/translocation:

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Partially-transformed tumors

• With genomic loss:

• example: BAPoma (BAP1 loss)

• With genomic gain:

• example: HRAS-mutant Spitz

• With gene fusion/translocation:

Partially-transformed tumors

• With genomic loss:

• example: BAPoma (BAP1 loss)

• With genomic gain:

• example: HRAS-mutant Spitz

• With gene fusion/translocation:

• example: ALKoma

ALKoma (Spitz tumor with ALK gene fusion)

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ALK

p16

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ALKoma

• A partially transformed Spitz

• A potential setup for additional transformation

• Promiscuous; multiple fusion partners

BAPoma (Wiesner nevus; epithelioid nevus/tumor with

BAP-1 genomic loss)

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BAP1

p16

BAPoma

• A Spitz (or at least Spitz-like because of cytomegaly) with a successful first hit with tumor suppressor loss

• Overlap with a historical spectrum that has safely been called combined Spitz nevus

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HRAS-mutated Spitz

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HRAS-mutated Spitz nevus

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11p Spitz (HRAS-mutated)

• Large with marked desmoplasia

• Horizontal orientation, often

• Infiltrative, often

• Mitotic figures, often

• Young adults rather than young children, often

HRAS-mutated Spitz nevus

• A Spitz tumor driving down a molecular dead end

• Defined within a historical spectrum that has safely been called Spitz nevus

3. Variants galore

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Spitz subsets for today

• Standard or mainstream

• Elegant, with refined features

• Oddballs

• Tough diagnostic situations

• Contrived ones, to make a point

3a. Standard Spitz variants

• Conventional Spitz nevus

• Reed nevus (pigmented spindle cell nevus)

• Polypoid Spitz nevus

• Combined Spitz nevus

• Multiple Spitz nevi

• Agminated Spitz nevi

Conventional Spitz

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PSCN

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Fascicular PSCN

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Polypoid Spitz nevus

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p16

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Combined Spitz

• Conventional and Spitz

• Conventional and PSCN

• Conventional and desmo Spitz

• Blue and Spitz

• Et cetera

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Multiple Spitz

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Agminated Spitz

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3b. Elegant Spitz subtypes

• Desmoplastic Spitz

• Hyalinized Spitz

• Angiomatoid Spitz

• Myxoid Spitz

• Perineuriomatous Spitz

• Syringofibroadenomatous Spitz

• Superficial spreading Spitz

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Desmoplastic Spitz

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p16

p16

Hyalinized Spitz

• Probably best thought of as a subset of desmoplastic Spitz

• The degree of hyalinization varies and is occasionally extreme

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Angiomatoid Spitz

• A subtype of desmoplastic Spitz

• All angiomatoid Spitz nevi are desmoplastic, but not all desmoplastic Spitz nevi are angiomatoid

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Myxoid Spitz

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Perineuriomatous Spitz

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p16

EMA

SyringofibroadenomatousSpitz

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Syringeal Spitz

• In a recent analysis of 7 examples, 4/7 were induced by ROS1 gene fusion

Superficial spreading Spitz(SSSN)

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(superficial spread)

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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: 85%; marked: 32%

• Desmoplasia: 36%

SSSN

• A minimally transformed or non-transformed Spitz

• Falls within a spectrum that has safely been called Spitz nevus

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3c. Oddball Spitz subtypes

• Spitz with edema

• Spitz with rosettes

• Palisaded Spitz/Reed nevus

• Spitz with oncocytic metaplasia

• Spitzerson nevus

Edematous Spitz

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p16

p16

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p16

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Spitz with rosettes

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Spitz/Reed w/ palisading

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Oncocytic Spitz

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Mitochondrial Ag

Mitochondrial Ag

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Spitzerson nevus (Spitz with Meyerson-like inflammation)

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p16

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Spitzerson nevus

• A non-transformed or minimally transformed Spitz

• Strong overlap with a spectrum safely called Spitz or PSCN

3d. Practical Spitz subtypes reflecting unusual or tough diagnostic situations• Pagetoid Spitz

• Special site Spitz

• Spitz with consumption

• Bottom heavy Spitz

• Spitz with meganests

• Spitz with adnexal extension

• Spitz with intralymphatic extension

• Mitotically-active Spitz

Pagetoid Spitz

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Spitz of a ‘special site’

• Flexural Spitz nevus

• Spitz nevus of the breast

• Genital Spitz nevus

• Acral Spitz nevus

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Acral Spitz

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Spitz w/ consumption

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p16

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p16

NTRK1

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(FISH neg)

Spitz w/ meganests

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Spitz w/ adnexal extension

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Melan-A

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Spitz w/ intralymphatic

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Mitotically-active Spitz

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(NTRK3 fusion)

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Subtypes I completely made up to make a point • Spitz kneevus

• Spitz elbovis

• Spastic (hybrid) nevus

• Spitz with Kaminoettes

• Spitz with megamelanophages

Spitz kneevus

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p16

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p16

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Spitz elbovis

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SOX-10

SOX-10

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SOX-10

Spastic nevus

Spastic nevus

• Spitzoid dysplastic nevus

• Dysplastic Spitz nevus

• Spitzoid Clark nevus

• Spark nevus

• Et cetera

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p16

Hybrid Spitz

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Spitz w/ Kaminoettes

• (Tiny Kamino bodies)

• The guidelines of pink globules:

• Make sure it’s really a Kamino

• Kaminos favor the dx of Spitz

• Kaminos are rare in melanoma

• Large Kaminos = greatest impact

• Small Kaminos great if numerous

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Spitz with megamelanophages

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4. Even though the spectrum is broad, much is NOT a Spitz

Melanoma w/ meganests

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PSCN-like MISPSCN-like melanoma

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Melanomaw/ large pagetoid cells

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p16

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Conclusions

• History has oversimplified the categorization of melanocytic tumors. It’s broader that melanoma and nevus or melanoma and Spitz.

Conclusions

• There are categories that current nosology has not conceived of, including melanoma ex Spitz, low-grade melanoma, and partially-transformed but benign.

Conclusions

• In our existing paradigm, ancillary analysis provides additional insight into controversial tumors.

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Conclusions

• Morphologic analysis may be misleading, especially if imprecisely applied. In the context of melanocytic tumors, we may lump unrelated entities.

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Last thought

• While morphology earns us a living, morphologic arguments and morphologic categories may be deceptive and limiting

• That whale might be a hippo, or that hippo might be a whale


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