Melanocytic proliferations in sundamaged

Atypical Spitzoid Tumor: What Does It Mean And How Should It Be Managed? Melanocytic proliferations in sundamaged skin Jane L. Messina, Jane L. Messina MD International Melanoma Pathology Working Group 4 th annual meeting Tampa, Florida November 14, 2011 Melanoma and Other Cutaneous Malignancies, Session 5 March 23, 2013 8:45-9:05 am #

Disclosures Durect Corporation-consultant Glaxo Smith Kline-consultant 2

Exhibit 1 19 y/o M with lesion on posterior neck 3 diagnoses proferred: severely atypical compound melanocytic lesion with Spitzoid features, favor melanoma favor peculiar nevus with Spitzoid and congenital features but cannot r/o melanoma markedly atypical compound Spitzoid melanocytic tumor WLE and SLNbx: both negative Four years after surgery: patient develops multiple brain and lung metastases 3

Basic conundrum Criteria don t always predict behavior (or even SLN involvement) Misdiagnosed melanoma major issue (#1 lawsuit for dermatopathologists) Underdiagnosis Recurrence or death Loss of opportunity for adjuvant treatment Medicolegal Overdiagnosis Surgical morbidity SLNB procedure not proven to increase OS Psychological trauma Insurability 4

Goals Historical perspective Pathologic criteria Sentinel node issues Molecular advances Treatment algorithm

?? Spitz S. Melanoma of childhood. Am J Pathol. 1948;24:591-609 Barnhill RL et al. Atypical Spitz nevi/tumor: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol. 1999;30:513-520. Allen AC. A reorientation of the histogenesis and clinical significance of cutaneous nevi and melanomas. Cancer. 1949; 2:28-56. Smith KH, Barrett TL, Skelton HG et al. Spindle cell and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am J Surg Pathol. 1989;13:931-939.

Atypical Spitz nevus 1969: We propose the term atypical Spitz s nevus in the same fashion as Helwig, who uses atypical for the pseudomalignant character of the atypical fibroxanthoma. 1975: Reed et al. first use term atypical Spitz nevus in American literature 1976: Helwig reports 23 young patients with metastatic melanoma and Spitz-like primary tumor, proposed better prognosis 1977: Weedon and Little put forth histologic characteristics to distinguish atypical Spitz s nevus from melanoma Helwig EB.Heath Memorial Award Lecture. Year Book Medical Publishers, Inc; 1975: 11-26. Reed RJ et al. Semin Oncol, 1975;2:119-47. Weedon D, Little JH. Cancer, 1977; 40:217-225. 7

Conventional Atypical Spitz Nevus Spitz Nevus/Tumor Spitzoid melanoma??

Atypical Spitz Tumor Distinct entity or IDK? Large size, generally > 1.0cm Deeper extension, often involving subcutis Asymmetry, ulceration, poor circumscription Prominent pagetoid melanocytosis High cellular density and/or confluence of melanocytes Absence of maturation Increased deep/marginal mitoses (>2-6/mm 2 ) Spitzoid cytomorphology Barnhill, RL. Modern Pathol 19: S21-S33;2006. Caraco et al. Eur J Surg Oncol Oct. 2012, 932-935

Conventional Atypical Atypical Conventional Spitz Nevus Spitz Spitz Nevus/Tumor Nevus/Tumor Spitz Nevus Spitzoid Spitzoid melanoma melanoma

Atypical Spitz tumor Relevant questions What is the outcome of the reported series of AST? What is the incidence and meaning of SLN involvement? Does AST have a distinct histologic, immunohistochemical, genetic or molecular profile? How do we find the Spitzoid melanomas?

Atypical Spitz tumor Relevant questions What is the outcome of the reported series of AST? What is the incidence and meaning of SLN involvement? Does AST have a distinct histologic, immunohistochemical, genetic or molecular profile? How do we find the Spitzoid melanomas?

Death in patients with AST >300 reported cases of AST, most treated with SLN mapping Seven total deaths Ages 12,13,14, 24, 43, 46, and 50 6 had no SLNB, 1 had +SLN Raskin L et al. Am J Surg Pathol 2011;35:243-52. Ludgate MW et al. Cancer 2009;115:631-41/Cerroni L et al. Am J Surg Pathol 2010;34:314-260/Barnhill RL et al. Hum Pathol 1999;30:513-20./ Gerami et al. Am J Surg Pathol Feb 2013;

AST SLN biopsy results Pts Mean age Mean depth mm 14 SLN+ rate Lohmann et al. 2002 10 21 3.9 50% 1/5 Su et al 2003 18 16 3.5 44% 1/8 Gamblin et al 2006 10 21 n/d 33% 1/3 Urso et al. 2006 12 23.2 2.9 33% 1/3 Murali et al 2008 21 31 2.1 25% 0/6 Ludgate et al. 2009 67 23.7 2.4 47% 1/27 Ghazi et al 2010 27 15.5 1.9 22% 0/4 Cerroni et al. 2010 35 21 3.5 71% n/d Raskin et al. 2011 15 17.5 3.0 53% 0/8 Sepehr et al 2011 6 23.5 n/d 17% 0/1 Mills et al 2012 10 13 2.2 20% 1/2 Caraco et al 2012 40 32 1.5 0% n/a Hung et al. 2012 23 27 2.0 26% 0/3 Pts w/+clnd Totals 294 -- -- 34% 6/70 (9%)

Features of SLN in AST Four series describe SLN deposits Largest series of 27: 85% had <1% nodal involvement, 62% <0.2 mm Remaining 3 series: 50% of patients had isolated parenchymal/subcapsular disease, all <2 mm Urso, Murali, Ludgate, Gamblin

Features of involved SLN in AST

Contrast: Capsular nevus cell aggregates

Contrast: Intratrabecular nevus cell aggregates

Melanoma micrometastasis 20

Features predictive of SLN involvement in AST Most series, including largest, have found no significant differences between SLN+ and SLNtumors Significant: Deep mitoses, less inflammation plasma cells 1 Mean tumor thickness 2 >6 mitoses/sq mm 3 1.Massi et al. J Am Acad Dermatol 2011;64:919-35 2. Murali et al. Annals of Surgical Oncology 15(1):302 309 3. Hung et al Human Pathology (2013) 44, 87 94

Outcome of AST patients with SLNB Patients Mean duration f/u in mo Recurrence beyond SLN Lohmann et al. 2002 10 33.7 0/10 0/10 Su et al 2003 18 9.8 0/18 0/18 Gamblin et al 2006 10 33.7 0/10 0/10 Urso et al. 2006 12 26.3 0/12 0/12 Murali et al 2008 21 25.8 0/21 0/21 Ludgate et al. 2009 57 43.8 0/57 0/57 Ghazi et al. 27 56 0/6 0/6 Cerroni et al. 2010 35 83.5 8/35 1/35 Raskin et al. 2011 15 NR 0/15 0/15 Sepehr et al 2011 6 64.6 0/6 0/6 Caraco et et 2012 40 39 0/40 0/40 Mills et al 2012 10 49 0/10 0/10 Hung et al. 2012 23 55.6 0/23 0/23 Totals 284 9-64 8/263 1/263 Death with metatasis

Meaning of SLN involvement Recurrence and death vanishingly rare in 13 series with followup ranging from 9-64 months Comparison with childhood melanoma 5 year o/s ~75% ~1/2 of recurrence/death occurs after 5 years AST could represent unique, less aggressive subtype of melanoma potentially cured by SLN removal

Pros and cons of SLN biopsy Diagnosis? Metastatic melanocytic tumor of uncertain malignant potential Pros Guides further therapy/monitoring May be saved more extensive surgery later Alleviates uncertainty, about 2/3 get good news May be therapeutic Cons Guides further therapy/monitoring May create unecessary anxiety

Case 2-HH-age 14 1997: presented to pediatrician with longstanding mole since birth, biopsied and told benign 1999: mother went to MCC presentation and noted similarities to daugher s mole, prompting rebiopsy: diagnosis of malignant melanoma of back, Clark IV, 3.4 mm in depth Underwent WLE and SLNB No residual tumor 0/3 +SLN right neck 1/11 +SLN right axilla

14 y/o F with 3.4 mm melanoma of back L axilla SLN 9

Same patient 10 years after CLND and adjuvant interferon

Atypical Spitz tumor Relevant questions What is the outcome of the reported series of AST? What is the incidence and meaning of SLN involvement? Does AST have a distinct histologic, immunohistochemical, genetic or molecular profile? How do we find the Spitzoid melanomas?

Fluorescence in situ hybridization Initial four-probe assay (6p25, Cep6, 6q23, 11q13) tested on unequivocal neoplasms: sensitivity 87%, specificity 95% Newer four-probe assay with 6p25, 8q24, 9p21, 11q13: sens. 94%, spec. 98% Polyploidy: 10% of typical Spitz have balanced gains in all four probe sets (3-4x) Isaac et al. Am J Dermatopathol 2010;32:144 148

FISHing for ASTs Original assay 25 typical and atypical Spitz with known outcome (4 deaths/advanced logoregional disease) 24% of cases FISH positive (3 had <5 year f/u) 100% sensitive, 57% specific 16 AST with long-term outcome (1 death) All negative (0% sensitive, 0% specific) Massi et al. J Am Acad Dermatol 2011;64:919-35 Raskin et al. Am J Surg Pathol 2011;35:243 252

FISHing for ASTs Newer assay Recently tested on 75 AST 64 uneventful 5 year f/u, 11 with advanced locoregional disease, distant metastasis or death All 11 patients with advanced disease had abnormality of at least one locus 9 showed deletions of 9p21-most significant and only feature predictive of death However, 24.3% of patients with uneventful follow up had a positive result Sensitivity 100%, specificity 74% Gerami et al, Am J Surg Pathol, Feb 2013

Comparative genomic hybridization 95% of melanomas harbor numerous chromosomal gains and losses Nevi rarely show aberrations 15% of Spitz nevi (esp. recurrent) have 11p or 7q gain 7/16 AST had abnormalities (esp. 1p, 9 loss or gain, none in chromosomes evaluated by FISH) Bastian BC et al. J Invest Dermatol. 1999;113:1065 1069. Bastian BC et al. Am J Pathol. 2003;163:1765 1770 Raskin et al. Am J Surg Pathol 2011;35:243 252

Molecular characteristics of AST BRAF: 0-75% found in 54 lesions tested in four series 0/7, 12/16, 1/16, 2/15 HRAS: 15% (4/26) in two series NRAS: 6% (2/31) in two series Raskin et al. Am J Surg Pathol 2011;35:243 252 Massi et al. J Am Acad Dermatol 2011;64:919-35 Takata et al. British Journal of Dermatology 2007 156, pp1287 1294 Fullen et al. Mod Pathol 2006;19:1324-32.

Immunohistochemical staining Ki-67 for proliferative activity: >10% favors melanoma, <10% does not exclude phh3 for mitoses HMB-45 for maturation BAP1 if multiple lesions P16 loss, BRAFv600E significance unclear Nasr MR, El-Zammar O. Am J Dermatopathol. Apr 2008;30(2):117-122 Ohsie et al. J Cutan Pathol 2008; 35:433-444

Ki-67: the good, the bad, and the ugly

Phosphohistone H3 stains cells in mitosis

p16 and malignant potential p16:multiple studies show loss in 50-98% of melanoma Loss of p16 in 6/6 childhood Spitzoid melanoma, but present in 18/18 Spitz nevi and 12/12 melanocytic nevi Recently, present in 15/19 (79%) Spitzoid melanoma and 83% Spitz Al Dhaybi R et al J Am Acad Dermatol. Aug 2011;65(2):357-363 Ohsie et al. J Cutan Pathol 2008; 35:433-444 Mason et al. J Cutan Pathol 2012; 39(12): 1062-74.

Loss of p16 in childhood melanoma

Loss of p16 in childhood melanoma

p16 stains childhood Spitz nevi

HMB-45 Diminished staining with dermal depth in most benign nevi including Spitz Stains entire dermal component of melanoma Ohsie et al. J Cutan Pathol 2008; 35:433-444

HMB-45 staining in nevus

Atypical Spitz tumor Relevant questions What is the outcome of the reported series of AST? What is the incidence and meaning of SLN involvement? Does AST have a distinct histologic, immunohistochemical, genetic or molecular profile? How do we find the Spitzoid melanomas?

Summary Atypical Spitz tumor: What does it mean and how is it managed? Increasingly recognized melanocytic neoplasm which deviates from typical benign Spitz but does not seem to have a distinctive molecular or genetic profile Most common in children and young adults Frequent but low-volume SLN metastasis Low recurrence rate with relatively long-term followup 44

Summary Atypical Spitz tumor: What does it mean and how is it managed? Workup should include expert consultation, molecular analysis by FISH and/or CGH Recommend wide excision and SLN biopsy until reliable test to exclude melanoma is available