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Spitz Tumors

KJ Busam, MD, MSKCC

New York, NY

Savannah 2019

Sophie Spitz

“Melanomas of Childhood”; Am J Pathol 1948

• 13 children (18 mo - 12 yrs)

• 12/13 had a benign clinical course

1910 - 1956

S Spitz

Sophie Spitz

• Born 1910 in Nashville

• AFIP 1944/45: Atlas of

Pathology of Tropical

Diseases

• MSK 1939 – 1956

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Am J Pathol 1948

Sophie Spitz

“Melanomas of Childhood”; Am J Pathol 1948

• 13 children (18 mo - 12 yrs)

• 12/13 had a benign clinical course

1910 - 1956

S Spitz

JUVENILE MELANOMA -

different from adult tumors

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Sophie Spitz’s Melanomas

- Heterogeneous Group of Tumors Am J Pathol 1948

• 13 children (18 mo -12 yrs)

• All benign except for one:

– 12 yo girl

– Tumor on foot

– Deeply locate: plantar fascia

1910 - 1956

S Spitz

Probable correct diagnosis: Clear cell sarcoma

Juvenile Melanoma

A sheep in wolf’s clothes

Spitz Nevus

• Kernan JA, Ackerman LV. Spindle cell nevi and epithelioid cell nevi

(so-called juvenile melanomas) in children and adults: a

clinicopathological study of 27 cases. Cancer. 1960;13:612-25.

• Weedon D, Little J. Spindle and epithelioid cell nevi in children and

adults. A review of 211 cases of Spitz nevi. Cancer 1977; 40: 217-25.

• Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle

and/or epithelioid cells (Spitz's nevus). Arch Dermatol. 1978; 114:

1811-23

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Spitz Nevus

Melanoma

J Derm Surg 1975

Distinction by Microscopy

Spitz Nevus

• Architecture

– Symmetric

– Sharply circumscribed

• Cytology

– Maturation

– Spindle and/or epithelioid

• Other Features

– Kamino bodies

– Clefts

Melanoma

• Architecture

– Asymmetric

– Ill-defined

• Cytology

– No maturation

– “Pagetoid”, Pleomorphism

• Other Features

– No Kamino bodies

– Consumption of epidermis

Spitz Nevus

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Spitz

Nevus

Kamino

Bodies

Pigmented Spitz Nevus

The Spitz Family Grows

WHO Classification of

Skin Tumours. 2018.

Chapter 2. Spitz Naevus,

p111.

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Reported as “Spitz Nevus”

28 yo man with dark “mole” on chest – “Spitz’s nevus”

Junctional nests

of pigmented

spindle cells with

cleft

Maturation Mitotic figures

6 yrs later

Metastatic melanoma in LN6 yrs later: LN Metastasis

Spitzoid Melanoma

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Atypical Spitz Tumor or Spitz Nevus?

Spitz Nevus

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Spitz Nevus, AST or Melanoma?

“Nevoid Borderline Tumor”

Diagnosis: Combined

BAP1-Deficient Epithelioid

Melanocytic Nevus/Tumor

(aka Wiesner’s Nevus)BAP1

Surgery to the

Rescue

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J Am Acad Dermatol 2000;42:527-30

SLN Findings for Diagnosis

• “If any neoplasm made up of melanocytes

metastasizes, it is a melanoma”

• A “Spitz-like lesion that metastasizes is a

melanoma, pure and simple”

Mones & Ackerman Am J Dermatopathol 2004;26:310-33AB Ackerman

Dermal Solar Elastotic Material in SLN

Am J Surg Pathol 2010; 34:1492-7

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Mesothelial Cells in LN

Subcapsular Melanocytes –

What do they mean?

Axillary SLN from 44F with mammary adenocarcinoma

Mart1 Mart1

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The Brave New Spitz

The Molecular Revolution in

Dermatopathology

Molecular Classification of

Spitz Tumors

MAPK mutations

MET fusions

Spitz Nevus

SNP-array:

11p

33 F

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BAP1-Deficient Epithelioid Nevus/Tumor

(Wiesner’s Nevus)

Wiesner et al. Am J Surg Path 2012;36:818-30.

ALK-TPM3 Fusion

Am J Surg Pathol 2014;38:925-33

Spitz Tumors with Alk-Fusions

Yeh et al Am J Surg Pathol 2015;39:581-91

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Yeh at al Am J Surg Pathol 2019;43:737-46.

Spitz Tumor with PWWP2A-ROS1 Fusion

ROS1

15M, Arm

Value of Molecular Findings

• Clarity of Terminology

• Adjunct Evidence for Diagnosis

• Possibly Useful for Prognosis and/or

Treatment

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Clarity of Terminology

• Spitzoid

– Resembles a Spitz Nevus

• Spitz/Spitzian

– Pathway of Spitz Nevus

Spitzoid Melanomas

Melanomas with BRAF and NRAS Mutations

Conventional melanomas with minor spitzoid features

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“Spitzoid” Neoplasm

Clinical and Molecular Findings

• Elderly woman

• New and growing lesion

NRASQ61R

Diagnosis: Melanoma

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Spitzoid vs Spitz Melanoma

• BRAF- or NRAS- mutated conventional

melanoma with Spitz nevus-like features

• Melanoma with genomic aberrations typical

of Spitz = malignant Spitz tumor or Spitz

melanoma

WHO

Classification

of Skin Tumors.

2018

Spitzoid Melanoma –

A Diagnostic Problem

- Modern ancillary methods

can reduce diagnostic errors

- Better clinical correlation

can reduce errors

Wolf in Sheep’s Clothing

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Spitz Nevus vs Melanoma

Role of Molecular Studies for

Diagnostic Accuracy

19 F, rt wrist

DiagnosisCompound Clear Cell Sarcoma

J Cutan Pathol 2013; 40: 950-4

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Nevi n=54Melanoma n=133

Cytogenetics for the Distinction of

Nevus from Melanoma

Bastian et al Am J Pathol 2003

Diagnosis?

14 F; rt cheek

Reported as “Spitzoid neoplasm with severe atypia”

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Diagnosis: Spitz Nevus

14 F, rt cheek

Gain of 11pSNP Array:

Atypical Spitz Tumor

SNP-

Array6q.22

15M, ArmROS1

Reported as “Spitz Nevus”

28 yo man with dark “mole” on chest – “Spitz’s nevus”

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FISH Results:

Gains in CCDN1 (11q13) and

RREB1 (6p25) in > 70% of cells

Spitzoid Melanoma6 yrs later

Metastatic melanoma in LN

Spitz Melanoma

Loss on chromosome 9

p16

2 yo girl

Homozygous

9p21 deletion Metastatic Melanoma

2F

Risk Assessment of AST

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Risk Assessment

8 yo M, rt arm

- Pos SLN and 4 pos NSLN

Am J Surg Pathol 2013;37

9p

Homozygous Deletions

of p16 are associated

with metastasis and death

Spitz Tumor

Ancillary Test result:

- Negative for PRAME

- FISH: Homozygous deletions of 9p

6F

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Spitz Melanoma

Cytogenetics:

- Homozygous deletions of 9p

- Addtl aberrations

IHC:

- Diffusely positive for PRAME

18M

Mutations for Risk Assessment

Spitz Tumors –

What have we learned?

• Genomic parameters have helped improve

terminology/classification

• Ancillary methods can improve diagnostic

accuracy and risk assessment

• “Atypical Spitz Tumors” (AST) are gray

zone and biologically intermediate tumors

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Use of “Atypical Spitz Tumor”

• Diagnostic Problem – Short Term

– Work-up incomplete

• Diagnostic Uncertainty – Long Term

– Work-up did not yield definitive evidence

Spitz Tumors –

Continued Challenges

• Ancillary methods have limitations

• Genomic parameters have limitations

• Prognosis and clinical management

Limitations to Molecular Methods

• Practical

– Insufficient tissue

– Technical or interpretative errors

• Biological

– Not all melanomas have expected aberrations

– Some nevi or indolent tumors have unexpected

aberrations

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CGH:

-Loss of 1p and 9p“Spitzoid Melanoma of

Childhood” in 2005

Limitations of Cytogenetic Analysis

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Limitations of Cytogenetic Analysis

CGH: 9p, 7q

8M, back

Limitations to Molecular

Classifications

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Anal Skin Melanoma with NTRK Fusion

NTRK2-TRAF2

Fusion

NTRK

Lezcano et al Primary and

Metastatic Melanoma with

NTRK Fusions

Am J Surg Pathol 2018

Prognosis of Spitz Tumors

• Accuracy of diagnosis important

• Most atypical Spitz tumors are indolent

• Risk assessment of Spitz or Spitzoid

melanoma difficult

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AST – Limitations for Prognosis

• SLN bx of no/limited value

• Clinico-pathologic assessment imperfect

• Molecular assessment imperfect

• Low incidence of adverse events and

limited follow-up

Pediatric Melanomas

• Melanoma death rates (2007, USA): 13.5%(www.cancer.org)

• MSKCC: Death rate of patients with melanoma diagnosed before age 18: 12%

Cancer 2013; 119: 3911

Is “Spitzoid Melanoma of Childhood”

a Malignant Melanoma?

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Acknowledgements

• Colleagues in Dermatology

• Members of Melanoma DMT

• Various colleagues at other institutions

• Members of the Dermpath team at MSKCC

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