Melanoma Update: 8th Edition of AJCC Staging System and …

1 Melanoma Update: 8thEdition of AJCC Staging System and MoreRosalie Elenitsas, of DermatologyDirector, DermatopathologyUniversity of PennsylvaniaDISCLOSURE OF RELATIONSHIPS WITH INDUSTRY None relevant to these talks Other: Royalties Lippincott Williams Wilkins Lever s Histopathology of the SkinDermatopathology, University of PennsylvaniaGuidelines of care Management of Primary Cutaneous Melanoma AJCC Melanoma Staging , 8th ed(2018) AAD Guidelines of Care (2019) 7thedition 2010 8thedition 2018 AJCC Staging System Designed for simplicity and easy use Attributes that can be determined by any pathologist Does not capture all that is known about Melanoma prognosisAJCC 8th Edition Melanoma 10 major global medical cancer centers USA, Europe, Australia 43,792 patients with Melanoma Stage I-III Initial diagnosis 1998 Eliminates patients from the pre-SLNB eraAJCC Melanoma Update For localized (stage I or II) Melanoma , the most powerful prognostic parameters include: 1.

2 Tumor thickness 2. UlcerationAJCC 8th Edition update T-category tumor thickness cutoffs maintained Except substratificationof T1: Melanomas < mm in thickness= T1a Melanomas mm mm = T1bSeveral published reports indicate thatsurvival T1 melanomas is related to thickness with a breakpoint around mmT1 Melanoma Positive SLNB in <5% of MM < mm Positive SLNB in 5-12% of MM Melanomas Definitions of T1a and T1b are revised: T1a, < mm without ulceration T1b, with or without ulceration T1b, < mm with ulceration * Mitotic rate no longer a T category criterionTumor Thickness Tumor thickness measurements to be recorded to nearest mm (not mm)Tumor Thickness ExampleT1b, with or without ulceration mm Breslow thickness tumors are reported as mm T1b tumorTumor Thickness ExampleT1b, with or without ulceration mm Breslow thickness tumors are reported as mm T1b tumorMitotic Rate Tumor mitotic rate was removed as a Staging criterion for T1 tumors Remains an overall important prognostic factor that should continue to be recorded for all patients with T1-T4 primary cutaneous melanomaMitotic Rate Refers to rate in the dermal component Mitotic rate in epidermis not prognostic No longer in the Staging for the 8thEdition, but should still be reportedMitotic Rate.

3 Methods Identify highest mitotically active area, hot spot Count mitoses in 1 mm2(about HPF) Report as # mitoses per mm2 No need to cut deeper levels just to find mitoses If no mitoses, report as 0/mm2 If rate is 0-1/mm2, just report as 1/mm2 PHH3 (phosphohistone3) may highlight mitoses, but not considered standard for AJCC stagingAJCC 8th edMelanoma StagingEpidermal ulceration Defined as full thickness absence of epidermis above any portion of the primary tumor with an associated host reaction (fibrinousand acute inflammatory exudate)UlcerationUlceration Associated host response (fibrin, crust, inflammation, epidermal hyperplasia) helps to distinguish from sectioning artifact Ulceration from prior biopsy should not be reported as ulceration Pitfalls: sectioning artifact; traumaUlceration If doubt remains if ulcer is traumatic or iatrogenic, then report as ulceration presentMicrosatellites, 8thEdition Microscopic metastasis completely discontinuous from primary Melanoma with unaffected stroma between them No minimum size threshold No minimum distance from the primary tumorAttributes not addressed by AJCC tumor stagingSex Women do better than menAnatomic Location Extremity Melanoma better than: Trunk Head Palms/solesAge Younger patients do betterPathology.

4 Growth Phase Radial (MIS and early level II) Vertical Regression Inconsistent definitions in literature Worse prognosis in most studies Not a factor in AJCC stagingRegression comments, 8thEdition If regression is present, measure to the deepest tumor cell, not to the base of the regression If all invasive component is regressed, report as Tis ( Melanoma in situ)AngiolymphaticInvasion Associated with poor survival Many studies, not an INDEPENDENT variableAngiolymphaticInvasion Tumor within vascular spaces, vessels and lymphatics Immunoperoxidasestains (CD34, CD31, D2-40) may assist in identification of vascular invasion, but not standard of care. LVI was associated with poor survival as an independent variable Double staining for S100/D2-40 utilizedClinCancer Res. 2012 January 1; 18(1): 229 237. (red) with D2-40 (brown)double stainT0, Tis, Tx T0 = No evidence of tumor/ completely regressed or unknown primary tumor Tis = Melanoma in situ Tx= tumor thickness cannot be determined/diagnosis by curettageThe N Category Documents metastatic disease both in regional lymph nodes and in non-nodal locoregionalsites (microsatellites, satellites, and in-transit metastases)

5 Regional LN metastases Number of LN involved remains the primary determinant of N stage N1 =1 Includes negative nodes + microsatellites/in-transits N2 = 2-3 N3 = 4 or more metastatic nodesMetastatic Disease microscopic = clinically occult nodal metastasis determined at SLN Bxand without clinical or radiographic node metastasis macroscopic = clinically apparent regional LN metsidentified by clinical, radiographic or US examinationProviding information to the PathologistEssential information for Pathology ReportEssential information for Pathology Report Specimen size Tumor thickness Ulceration Dermal mitotic rate (# per mm2) Margin assessment MicrosatellitesOptional information for Pathology Report Gross description of lesion Histologic subtype Lymphovascularinvasion Clark level Vertical growth phase Regression Tumor infiltrating lymphocytes Perineuralinvasion Tumor stageReporting Notes The working group discouraged reporting a measurement (mm) of distance between the tumor and surgical margin Recommended by CAP Treatment recommendations are based on clinical margin measurement, not by pathology Routine reporting could lead to unnecessary surgery Reporting with a measurement may be necessary if the clear margin is very narrowGenetic testingSynoptic Reporting Recommended by CAP (and TJC)

6 Recommended in AAD GuidelinesCAP August 2019 Protocols for Melanoma Biopsy Melanoma ExcisionMelanoma TemplateSurvival of patients with early invasive Melanoma down-staged under the new 8th AJCC Edition von Schuckmann LA, Celia B Hughes M, Lee R, Lorigan P, Khosrotehrani K, Smithers BM, Green ACJAAD(2018), doi: Survival of patients with early invasive Melanoma down-staged under the new 8th AJCC Edition Queensland, Australia Compared the outcomes of patients classified as T1b in AJCC 7thEd T< with mitoses Reclassified in 8theditionTotal 208 T1b patients (7th) Reclass to 8thedition criteria Removal of mitoses as criterion 111 (53%) remained T1b 97 (47%) became T1aStratified by mitotic rate (new T1a)Mitotic Rate 1-3 per mm2 >3 per mm2 Disease Free Survival 96% 80%Survival of patients with early invasive Melanoma down-staged under the new 8th AJCC Edition Reclassified T1b T1a patients Mitotic rate >3/mm2 80% survival Reinforces the importance of reporting mitotic rate 187 pathologists in the US Evaluated 116 invasive melanomaJAMA Network Open.

7 2018;1(1) Using AJCC8 in comparison to AJCC7: Greater concordance with consensus reference Greater interobserverreproducibilitySelected New LiteratureEpidermal Genetic Information Retrieval Stratum corneumstripping DermTech, Inc, Pigmented Lesion Assay Adhesive patch applied to lesion of concern Extracts RNAP igmented Lesion Assay 2 gene RNA molecular assay Gene expression by RT-PCR LIN00518(long intergenic protein coding RNA518) PRAME (preferentially expressed antigen in Melanoma )Pigmented Lesion Assay Tape stripping, instructions on website Patients 18 years and older Lesion size 5-16mm Not for: Palms, soles, nails, mucous membranes (cannot get enough RNA) Bleeding or ulcerated lesionsEpidermal Genetic Information Retrieval Largest study: 555 patients, validation sample of 398 Sensitivity 91% Specificity 69%GeramiP et al JAAD 2017.

8 76(1): 114-120 Epidermal Genetic Information Retrieval When might it get used? Wound healing issues Diabetes, vascular compromise Patient preference Cosmetically sensitive areas (face) Patients who develop keloidsJ Am Acad Dermatol 2018;79 IntraepidermalMelanocytic Proliferation Proliferation of predominantly single melanocytes in the epidermis without a developed nevus or Melanoma Other names Atypical junctional melanocytic lesion Proliferation of solitary units of melanocytes Atypical melanocytic hyperplasia Lentiginous junctional melanocytic proliferationMohs for AIEMP, Etzkorn et al Retrospective review Single institution 223 such lesions of the head, neck, hand, foot, or pretibial Treated with Mohs surgery 42 ( )of all lesions upstaged to unequivocal Melanoma in situ or invasive melanomaMelanoma and Melanoma In-Situ Diagnosis after Excision of Atypical Intraepidermal Melanocytic Proliferation (AIMP)

9 Blank, NR et and Melanoma In-Situ Diagnosis after Excision of Atypical IntraepidermalMelanocytic Proliferation Retrospective 1127 biopsies reported as AIMP subsequently excised one academic institution Melanoma (in-situ, stage 1A) was diagnosed after excision in (92/1127) of AIMP samplesFactors associated with MIS diagnosis Age > 60 years Head and neck location Incomplete studies, limitations Retrospective Single institution No evaluation of AIMP that were NOT removed Issues Difficulty in defining AIEMP Difficulty in defining MISTake home message More work needed on AIEMP ?genetics Complete excision should be considered if incompletely removed A subset represent MIS/MMAm J Surg Pathol 2018;42:1456 1465 PRAME PReferentially expressed Antigen in Melanoma Antigen that was isolated from T cells in patient with metastatic melanomaPRAME Found in: Melanoma , Lung CA, non-small cell, breast CA, renal cell CA, ovarian CA, leukemia, synovial sarcoma, myxoid liposarcoma Not in normal tissue except: Testis, ovary, placenta, adrenals, endometrium Member of Cancer Testis Antigens PRAME Expression Immunohistochemistry 155 primary MM 100 metastatic MM 145 neviAm J Surg Pathol 2018.

10 42:1456 1465 PRAME Expression, Immunohistochemistry Diffuse positivity in Melanoma 87% of metastatic MM 83% of primary MM Desmoplastic MM lowest at 35% Nevi: positive 1/145 diffuse + (spitz nevus) 18/145 focal + (< 50% cells)PRAME in MelanomaAm J Surg Pathol 2018;42:1456 1465 Normal skin and lentigo Rare PRAME expression Potentially useful for margin assessment in MIS of chronically sundamagedskinPRAME for use in margin evaluationAm J Surg Pathol 2018;42:1456 1465 Nodular MM vs MetastasisPathology Report Nodular Malignant Melanoma Note: metastatic Melanoma cannot be excludedPrimary Nodular vs EpidermotropicMetastasisPrimary vs Metastasis 75 Primary Nodular Melanomas 74 EpidermotropicMetastatic MelanomasFeatures associated with Mets Diameter <2mm Absent TILs Absent infiltrating plasma cells Monomorphism Involvement of adnexal epitheliumFeatures associated with Primary Exophytic Prominent TILs Prominent Plasma cells Diameter >10mm Ulceration Epidermal collarette Hi mitotic count Necrosis Pleomorphism Multiple phenotypes Lichenoid inflammationMultivariate analysisFeatures predictive of Primary Tumor Large size Ulceration Prominent infiltrating plasma cells Lichenoid inflammation CollaretteModerately Dysplastic Nevi 9 academic centers Does Melanoma develop at the sites of moderately dysplastic nevi with + margins?