Challenging Melanocytic Lesions - aad.org F054... · Photo courtesy of Dr. Julie Schaffer Pedrosa AF et al Dermatol Pract Concept. 2016 Apr 30;6(2) ... 14 y/o female, right arm lesion

Challenging Melanocytic Lesions

Carlos N. Prieto-Granada M.D.Assistant Professor

University of Alabama at Birmingham (UAB) Department of Pathology

2018 AAD Annual Meeting2/17/18 – San Diego, CA

Conflicts of InterestNone

Objectives•  Case-based review of salient features

from related melanocytic lesions•  Quick review of molecular methods used

in diagnosis of melanocytic lesions

Acknowledgments•  Jane Messina M.D. and Vernon Sondak

M.D. – Moffitt Cancer Center•  Maria Auxiliadora Deschaine M.D. –

University of Oklahoma•  Julie V. Schaffer M.D. - Hackensack

University

Case #1

Case #1- Clinical Features10 y/o female, rapidly growing lesions

Pictures courtesy of Dr. Jane Messina and Dr. Vernon Sondak

Case #1- Histopathology

Case #1- Histopathology

Case #1 - DiagnosisA.  Juvenile XanthogranulomaB. Dysplastic NevusC. Spitz NevusD. Melanoma E. Benign Epithelioid Histiocytoma

Case #1 - DiagnosisA.  Juvenile XanthogranulomaB. Dysplastic NevusC.  Spitz NevusD. MelanomaE. Benign Epithelioid Histiocytoma

Classic Spitz Nevus•  AKA “Spindle and Epithelioid Cell

Nevus”•  First known description from Darier

and Civatte as early as1910 •  Characterized by Dr. Sophie Spitz in

1948 as “Melanomas of Childhood” in a series of 13 cases from patients aged 18 months to 12 years old

•  Only 1 patient died of widely metastatic disease from a primary lesion consisting of an acral spindle cell tumor associated to the fascia (Clear Cell Sarcoma?)

Spitz S. Am J Pathol. 1948;24:591-609.Barnhill RL. Mod Pathol. 2006;19 Suppl 2:S21-33. Picture courtesy of Dr. Martin C. Mihm

PhotoscourtesyofDr.JulieSchaffer

JXG-like PG-like

Pigmented

Architecture•  Usually compound -

predominantly junctional (Reed), dermal (desmoplastic) variants

•  Junctional component:–  Well-circumscribed large nests

of cells in a “raining down” pattern

–  Epidermal hyperplasia –  Kamino bodies

•  Dermal component: •  Symmetrical, imparting a

dome shape to the lesion •  Inverted triangle shape with

evident maturation (“zonation”)

Cytology•  Epithelioid and spindle cells

with: –  Pink/“hyalinized” cytoplasm–  Large, often pleomorphic

nuclei with vesicular chromatin and prominent nucleoli

–  Bizarre forms and giant cells can be seen

•  Pagetoid spread is common (Pagetoid variant)

•  Mitoses are commonly seen (rapid growth) (less than 6 per mm2)

Busam KJ, Barnhill RL. Am J Surg Pathol. 1995 Sep;19(9):1061-7 Barnhill RL. Mod Pathol. 2006;19 Suppl 2:S21-33.

Case #1 –Which of these stains will be helpful in problematic cases?

A. S100 and Sox10B. Tyrosinase and Mart-1C. HMB45 and p16D. Trichrome and PAS

Case #1 –Which of these stains will be helpful in problematic cases?

A. S100 and Sox10B. Tyrosinase and Mart-1C.  HMB45 and p16D. Trichrome and PAS

p16: product of the CDKN2A gene (9p21.3) HBM45: Melanosome associated antigen

Ki-67 and Mart-1 cocktail

Case #2

Case #2 – Clinical/Dermoscopic Features

Pedrosa AF et al Dermatol Pract Concept. 2016 Apr 30;6(2):37-41 PhotocourtesyofDr.JulieSchaffer

20 y/o female, lower leg pigmented lesion

Case #2 – Histopathology

Case #2 - DiagnosisA. Common Acquired NevusB. Dysplastic NevusC. Spindle Cell MelanomaD. Pigmented Spindle Cell Nevus of Reed E. Atypical Spitz Tumor

Case #2 - DiagnosisA. Common Acquired NevusB. Dysplastic NevusC. Spindle Cell MelanomaD.  Pigmented Spindle Cell Nevus of Reed E. Atypical Spitz Tumor

Pigmented Spindle Cell Nevus of Reed•  AKA “Pigmented Spindle Cell

Tumor of Reed”•  First described by Dr. Richard

J. Reed in 1975•  “Dark brown-black macular or

papular dome-shaped lesion appearing in the lower limbs of females in the first 4 decades of life”

Reed RJ et al. Semin Oncol. 1975 Jun;2(2):119-47

Picture courtesy of Dr. Martin C. Mihm

Pigmented Spindle Cell Nevus of Reed

PhotocourtesyofDr.JulieSchaffer

Pictures courtesy of Dr. Martin C. Mihm

Pigmented Spindle Cell Nevus of Reed

Case #2 – How would you treat these lesions (Classic Spitz and PSCN) (2 might be correct)

A. Observe and re-excise upon recurrenceB. Conservative (narrow margin) re-excisionC. Wide local excision with 5-10 mm margin D. Wide local excision with 10 mm margin

and sentinel lymph node biopsyE. Cryotherapy

Case #2 – How would you treat these lesions (Classic Spitz and PSCN) (2 might be correct)

A.  Observe and re-excise upon recurrenceB.  Conservative (narrow margin) re-excisionC. Wide local excision with 5-10 mm margin D. Wide local excision with 10 mm margin and

sentinel lymph node biopsyE.  Cryotherapy

Case #3

Case #3 – Clinical Features

Pictures courtesy of Dr. Ma. Auxiliadora Deschaine and Dr. Jane Messina

14 y/o female, right arm lesion





Case #3 - DiagnosisA.  Intradermal melanocytic nevus B. Classic Spitz NevusC. Spitzoid MelanomaD. Desmoplastic Spitz NevusE. Benign Epithelioid Histiocytoma

Case #3 - DiagnosisA.  Intradermal melanocytic nevus B. Classic Spitz NevusC. Spitzoid MelanomaD.  Desmoplastic Spitz NevusE. Benign Epithelioid Histiocytoma

Desmoplastic Spitz Nevus•  Uncommon Spitz variant,

usually presents in the extremities as scaly, erythematous, flesh-colored or occasionally pigmented papulonodule

•  Affected patients are usually in the third decade of life

•  The lesions usually show variable amount of fibrosis/hyalinization and are often dermal-based

Moscarella E et al Br J Dermatol. 2015 Apr;172(4):1045-51Bastian BC et al Am J Pathol. 2000 Sep;157(3):967-72.

Mart -1 negativeCD68 positiveCD163 positiveMart -1 positive

McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations Philadelphia Elsevier Mosby; 2005Glusac, Earl; McNiff, Jennifer American Journal of Dermatopathology. 21(1):1-7, February 1999.Cangelosi JJ Am J Dermatopathol. 2008 Aug;30(4):373-6.

Desmoplastic Spitz Nevus Benign Epithelioid Histiocytoma

Benign Epithelioid Histiocytoma

Case #3 – Clinical Features






Case #3 – Diagnosis of Background Lesion

A.  Lentigo maligna melanomaB. EphelidesC. Nevus spilus (Agminated Nevus)

(segmental variant)D. Nevoid MelanomaE. Nevus spilus (Agminated Nevus)

Case #3 – Diagnosis of Background Lesion

A.  Lentigo maligna melanomaB. EphelidesC.  Nevus spilus (Agminated Nevus)

(segmental variant)D. Nevoid MelanomaE. Nevus spilus (Agminated Nevus)

Haenssle HA et al J Am Acad Dermatol. 2009 Aug;61(2):337-41

Common Nevus Spilus

Nevus Spilus

Segmental Nevus Spilus

Case #3


Case #3 – Which genetic aberration characterizes this type of Spitz nevus (desmoplastic)?

A. BAP1 lossB. BRAF V600EC. HRAS amplificationsD. BRAF fusionsE. ALK1 fusions

Case #3 – Which genetic aberration characterizes this type of Spitz nevus (desmoplastic)?

A. BAP1 lossB. BRAF V600EC.  HRAS amplificationsD. BRAF fusionsE. ALK1 fusions

Desmoplastic Spitz NevusThe majority of Spitz lesions with desmoplastic features will show an activation of HRAS (11p15.5), through either:

- Increased copy number of 11p (amplification) - Activating mutations of HRAS

Bastian BC et al Am J Pathol. 2000 Sep;157(3):967-72.

HRASp.G13R,p.A11Sandamplification

HRASp.G13R,p.A11Sandamplification

Porubsky C et al J Cutan Pathol. 2018 Feb;45(2):180-183.

Proline for Arginine in position 13Alanine for Serine in position 11

Sarin KY et al JAMA Dermatol. 2013 Sep;149(9):1077-81

Molecular Taxonomy of Melanocytic Lesions

Wiesner T et al Pathology. 2016 Feb;48(2):113-31.

BAP1 LossALK1

Case #3 – How would you treat/manage this patient (2 might be correct)

A. Observe and excise new lesionsB. Wide local excision with 5-10 mm margin C. Wide local excision with 10 mm margin

and sentinel lymph node biopsyD.  If amenable, re-excision with narrow

margins and plastic reconstruction

Case #3 – How would you treat/manage this patient (2 might be correct)

A.  Observe and excise new lesionsB. Wide local excision with 5-10 mm margin C. Wide local excision with 10 mm margin

and sentinel lymph node biopsyD.   If amenable, re-excision with narrow

margins and plastic reconstruction

Case #4

Case #4 – Clinical/Dermoscopic Features

Yoradjian A et al An Bras Dermatol. 2012 May-Jun;87(3):349-57

11 y/o male, chest lesion



Case #4 - DiagnosisA. Spitzoid MelanomaB. Spitz NevusC. Atypical Spitz Tumor/NevusD. Superficial Spreading MelanomaE. Granular Cell Tumor

Case #4 - DiagnosisA. Spitzoid MelanomaB. Spitz NevusC.  Atypical Spitz Tumor/NevusD. Superficial Spreading MelanomaE. Granular Cell Tumor

Atypical Spitz Nevus/Tumor




Benign Spitz Nevus et al

Atypical Spitz Tumor

SAMPUSMELTUMP

(Spitzoid) Melanoma

MELTUMP: MELanocytic Tumor of Undetermined Malignant PotentialSAMPUS: Superficial Atypical Melanocytic Proliferation of Undetermined Significance

CGH/FISH +Chromosomal Copy Number Aberrations

Elder DE, Xu X Pathology. 2004;36:428-434.

1.  6p25: RREB1 (Ras-responsive binding protein) > 2 copies

2.  6q23: MYB (myeloblastosis viral oncogene) loss*

3.  11q13: CCDN1 (cyclin-D1 protein) > 2 copies

4.  CEP6: centromere of 6 5.  8q24: MYC > 2 copies6.  9p21: CDKN2A (p16 protein) loss*7.  CEP9: centromere of 9 Pros: No limit in terms of cellularity, relatively easy to do, quick turnaround timeCons: Technical difficulties, required thresholds/ratios, narrow view of the potential aberrations, might be hampered by poly/aneuploidy or senescent changes

FISH Vs. CGHFISH CGH

Analysis of genomic material of tumor versus normal Pros: Panoramic, comprehensive view of the genomeCons: Special equipment is required, limit in thickness 0.4 mm., certain findings are still of undetermined significance

Modified from Dr. Timothy McCalmont’s ASDP board review lecture

FISH findings and prognosis in Atypical Spitzoid Lesions

•  9p21: CDKN2A (codes for p16Ink4A) homozygous deletion – associated with “high risk lesions”

•  6q23: MYB (codes for MYB protein) isolated loss – associated with “low risk lesions”

Tetzlaff MT et al , Clin Lab Med. 2017;37(3):431-448.

Case #4 – How would you treat these lesions (Atypical Spitz nevus/tumor) (2 might be correct)

A.  Observe and re-excise upon recurrenceB.  Conservative (narrow margin) re-excisionC. Wide local excision with 5-10 mm margin D. Wide local excision with 10 mm margin and

clinical follow up of lymph node basin(s)E.  Cryotherapy

Case #4 – How would you treat these lesions (Atypical Spitz nevus/tumor) (2 might be correct)

A.  Observe and re-excise upon recurrenceB.  Conservative (narrow margin) re-excisionC.  Wide local excision with 5-10 mm margin D.  Wide local excision with 10 mm margin

and clinical follow up of lymph node basin(s)

E.  Cryotherapy

The End! Questions?Thank you very much for your

attention/endurance

References1.  Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, 'Spitzoid melanoma' and risk assessment. Mod Pathol. 2006;19 Suppl

2:S21-33.2.  Busam KJ, Barnhill RL. Pagetoid Spitz nevus. Intraepidermal Spitz tumor with prominent pagetoid spread. Am J Surg Pathol. 1995 Sep;19(9):1061-7.3.  McKee PH, Calonje E, Granter SR. Pathology of the skin : with clinical correlations / [edited by] Phillip H. McKee, Eduardo Calonje, Scott R. Granter.

Edinburgh: Philadelphia Elsevier Mosby; 2005.4.  Pedrosa AF, Lopes JM, Azevedo F, Mota A. Spitz/Reed nevi: a review of clinical-dermatoscopic and histological correlation. Dermatol Pract Concept.

2016 Apr 30;6(2):37-41.5.  Reed RJ, Ichinose H, Clark WH Jr, Mihm MC Jr. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol. 1975 Jun;2(2):

119-47.6.  Wiesner T, Kutzner H, Cerroni L, et al. Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and

therapy. Pathology. 2016;48:113-131.7.  Moscarella E, Al Jalbout S, Piana S, Argenziano G, Lallas A, Longo C, Hofmann-Wellenhof R, Zalaudek I. The stars within the melanocytic garden:

unusual variants of Spitz naevi. Br J Dermatol. 2015 Apr;172(4):1045-51.8.  Porubsky C(1), Teer JK(2)(3), Zhang Y(2), Deschaine M(3), Sondak VK(4), Messina JL(3)(4)Genomic analysis of a case of agminated Spitz nevi and

congenital-pattern nevi arising in extensive nevus spilus. J Cutan Pathol. 2018 Feb;45(2):180-183. 9.  Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol.

2000;157:967-972.10.  Sarin KY, Sun BK, Bangs CD, Cherry A, Swetter SM, Kim J, Khavari PA. Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus.

JAMA Dermatol. 2013 Sep;149(9):1077-81.11.  Luo S, Tsao H. Epidermal, sebaceous, and melanocytic nevoid proliferations are spectrums of mosaic RASopathies. J Invest Dermatol. 2014 Oct;

134(10):2493-6.12.  Glusac EJ(1), McNiff JM. Epithelioid cell histiocytoma: a simulant of vascular and melanocytic neoplasms. Am J Dermatopathol. 1999 Feb;21(1):1-7.13.  Cangelosi JJ(1), Prieto VG, Baker GF, Moore BA, Diwan AH. Unusual presentation of multiple epithelioid cell histiocytomas. Am J Dermatopathol.

2008 Aug;30(4):373-6.14.  Haenssle HA, Kaune KM, Buhl T, Thoms KM, Padeken M, Emmert S, Schön MP. Melanoma arising in segmental nevus spilus: detection by

sequential digital dermatoscopy. J Am Acad Dermatol. 2009 Aug;61(2):337-41.15.  Yoradjian A, Enokihara MM, Paschoal FM. Spitz nevus and Reed nevus. An Bras Dermatol. 2012 May-Jun;87(3):349-5716.  Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion. Pathology. 2004;36:428-434.17.  Tetzlaff MT, Reuben A, Billings SD, Prieto VG, Curry JL. Toward a Molecular-Genetic Classification of Spitzoid Neoplasms. Clin Lab Med. 2017;37(3):

431-448.18.  Theisen, A. (2008) Microarray-based Comparative Genomic Hybridization (aCGH). Nature Education 1(1):4519.  Gerami P, Cooper C, Bajaj S, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in

children. Am J Surg Pathol. 2013;37:1387-1394.20.  Gerami P, Busam K, Cochran A, et al. Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic

neoplasms with long-term follow-up. Am J Surg Pathol. 2014;38:934-940.

Documents

Challenging Melanocytic Lesions - aad.org F054... · Photo courtesy of Dr. Julie Schaffer Pedrosa AF et al Dermatol Pract Concept. 2016 Apr 30;6(2) ... 14 y/o female, right arm lesion