Vernon K. Sondak. Department of Cutaneous Oncology Moffitt Cancer Center Tampa, Florida

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1 Vernon K. Sondak Department of Cutaneous Oncology Moffitt Cancer Center Tampa, Florida Australasian Melanoma Conference 2016 Sydney, NSW, Australia October 29, 2016

2 Disclosures Dr. Sondak is a compensated consultant for Amgen, BMS, GSK, Merck, Novartis and Provectus. The content of this presentation has been entirely controlled and prepared by Dr. Sondak, who is not acting as an agent or spokesperson for any company. No company had the right of final approval of the content and/or edits of this presentation.

3 Atypical Melanoctyic Lesions The Elephant in the Living Room? Atypical melanocytic neoplasms (AMN) Melanocytic tumor of uncertain malignant potential (MELTUMP) Pigmented epithelioid melanocytoma Atypical Spitz tumors Melanocytic proliferation of uncertain biologic potential WTF?? Expert dermatopathologists frequently disagree about whether a lesion is benign, atypical or malignant even those with fatal outcomes! Gerami et al. Am J Surg Pathol 2014;38:934

4 Atypical Melanoctyic Lesions The Elephant in the Living Room? Atypical melanocytic neoplasms (AMN) Melanocytic tumor of uncertain malignant potential (MELTUMP) Pigmented epithelioid melanocytoma Atypical Spitz tumors Melanocytic proliferation of uncertain biologic potential WTF?? Because of the long natural history and the challenges of follow-up in pediatric patients, sometimes the same lesion is counted as an AMN in one series and as melanoma in another Gerami et al. Am J Surg Pathol 2014;38:934

5 What Are They? Many cutaneous neoplasms, particularly in children and young adults, have pathologic features reminiscent of but not diagnostic for the benign Spitz nevus Some of these are clearly melanoma, termed Spitzoid melanoma Lesions lacking unequivocal diagnostic criteria for either a benign Spitz nevus or a Spitzoid melanoma are termed atypical Spitz tumors but this covers a broad spectrum with diverse metastatic potential Sreeraman Kumar R, et al. Cancer Treat Res 2016;167:331-69

6 Known Genetic Abnormalities Incidence (%) 34% unknown BAP-1 loss HRAS NTRK ALK ROS-1 BRAF RET Unknown Van-Engen-van Grunsven et al. Am J Surg Pathol 2010;34: Wiesner et al. Nat Commun 2014;5:3116

7 Unique Chromosomal Abnormalities Detected by FISH Heterozygous 9p21 loss: significant sentinel node involvement but no spread beyond the regional nodes 6p25 and 8q11 were seen in 2 cases with spread beyond SLN but no deaths Spitzoid melanoma 6p25 gain or 11q13 gain North et al. Am J Surg Pathol 2014;38: Raskin et al. Am J Surg Pathol 2011;35:243-52

8 Comparative Genomic Hybridization Assesses copy number changes across tissue, but misses individual cell abnormalities 12-26% Spitz nevi have gain of 11p (67% have HRAS mutation), benign behavior 7/16 atypical Spitz nevi had abnormal CGH 3 cases had gain of 1p No difference in CGH in cases with +SLNB vs SLNB One AST that caused death had multiple aberrations No abnormal CGH involved chromosomes evaluated by FISH North et al. Am J Surg Pathol 2014;38: Raskin et al. Am J Surg Pathol 2011;35:243-52

9 Beware the Ivory Tower Some diagnostic uncertainty is inevitable in many cases of atypical melanocytic tumors, but it can and should be minimized by good communication between clinician and pathologist Diagnostic uncertainty in and of itself contributes to a disproportionate amount of anxiety among patients and families An integrated approach requires clear communication among the medical team and with the patient and family, and commitment to manage the worst case scenario

10 The Worst Case Scenario If there is a chance a lesion could be melanoma, we treat it the way we would treat a melanoma For kids, even the worst case scenario is not always really bad But how does the pathologist communicate the chance the lesion could be melanoma to other doctors?

11 Management Approach Any management approach must recognize the potential for the atypical diagnosis to be replaced by a malignant diagnosis at some point based on new clinical or pathologic information BIOPSY WIDE EXCISION SENTINEL NODE BIOPSY SUBSEQUENT FOLLOW-UP

12 Five Shades of Gray S1 Benign Spitz nevus HRAS mutation 6q23 loss S2 Atypical, favor benign S3 Atypical, uncertain biologic potential S4 Atypical, favor malignant S5 Spitzoid melanoma 6p25 gain 11q13 gain 9p21 deletion Combination of morphologic, IHC, genetic, and chromosomal features can convey the best assessment of risk Sreeraman Kumar et al. Clin Oncol AYA 2015;5:75-86

13 Management Approach Adequate excision of the primary in all cases, with pathology reevaluation and, if necessary, reclassification Goal of excision is a histologically negative margin S2: Reexcision with 0.5 to 1.0 cm margin similar to melanoma in situ S3-4: Reexcision with 1.0 cm margin similar to thin/intermediate thickness melanoma

14 Management Approach Sentinel lymph node biopsy is used in lesions considered to be S3 or S4 Goals of procedure are diagnostic, staging and therapeutic Finding of unequivocally malignant deposits in the sentinel node can upstage a lesion to S5 spitzoid melanoma in about 5% to 10% of cases

15 Management Approach Sentinel lymph node biopsy is used in lesions considered to be S3 or S4 Goals of procedure are diagnostic, staging and therapeutic The sentinel lymph nodes are negative in 60% to 70% of cases The patients can be reassured that everything possible has been done, even if the lesion is malignant, and that the overall prognosis is good

16 Management Approach Sentinel lymph node biopsy is used in lesions considered to be S3 or S4 Goals of procedure are diagnostic, staging and therapeutic The sentinel lymph nodes contain lesional cells that are NOT diagnostic of malignancy in the remaining 20% to 30% of cases Uncertainty remains, but at least those potentially malignant cells are OUT!

17 Sentinel Node Biopsy Impact Negative Sentinel Node REASSURANCE Atypical cells? significance Spitzoid melanoma TREAT

18 Management Approach Sentinel lymph node biopsy is used in lesions considered to be S3 or S4 Patients and their families need to be fully informed in advance that the sentinel node biopsy results may also be nondiagnostic The treatment philosophy is managing the worst case scenario, namely that these cells represent metastatic spitzoid melanoma

19 Management Options for Sentinel Node Positive AST Just as for patients with unequivocal melanoma of any histologic type, there are multiple management options to consider for patients with sentinel node positive atypical Spitz tumors or spitzoid melanomas Consideration 1: Completion lymph node dissection versus observation of the nodal basin with serial ultrasonography and physical examination

20 Management Options for Sentinel Node Positive AST Just as for patients with unequivocal melanoma of any histologic type, there are multiple management options to consider for patients with sentinel node positive atypical Spitz tumors or spitzoid melanomas Consideration 2: Adjuvant systemic therapy or observation after completion of surgery

21 Management Options for Sentinel Node Positive AST Just as for patients with unequivocal melanoma of any histologic type, there are multiple management options to consider for patients with sentinel node positive atypical Spitz tumors or spitzoid melanomas Consideration 3: Follow-up after completion of treatment how aggressive should we be with imaging procedures like PET-CT scans?

22 The Worst Case Scenario

23 An Integrated Approach Some degree of diagnostic uncertainty is inevitable and anxiety provoking, but it can and should be minimized by good communication between clinician and pathologist, and clinician and patient/family Since at least some cases of atypical Spitz tumors are associated with metastasis and death, and since we cannot currently predict with certainty which ones those are, an integrated approach managing the worst case scenario remains prudent and appropriate

24 So if it IS melanoma, and my child is fine right now, what does the future hold?

25

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