Jane L. Messina, MD SeptemberMELANOMA VERSUS NEVUS: 16, 2017 STRATEGIES FOR THE DIFFICULT DECISION
Jane L., Messina, MD September 16, 2017 Conflicts
• I serve as a consultant to Castle Biosciences Objec.ves
• Review classic features of melanoma • AJCC update • Discuss commonly encountered diagnos Asymmetry Poor circumscrip • Primary tumor staging: – Breslow depth to nearest 0.1 mm – Ulcera TX Primary tumor thickness cannot be assessed (i.e. cureIage specimen) T0 Regressed melanoma or melanoma of unknown primary T1a 0-0.8 mm T1b >0.8 mm-1.0 mm or ulcera.on T2a/b 1.1-2.0 mm w/ or w/o ulcera.on T3a/b 2.1-4.0 mm w/ or w/o ulcera.on T4a/b >4.0 mm w/ or w/o ulcera.on N1 N2 N3 A-occult 1 2-3 >4 B-clinical 1 2-3, at least 1 clinical+ >4, at least 1 clinical+ C-microsatellites 0 nodes+ At least 1 node+ At least 2 nodes+ microsatellite microsatellite microsatellite Commonly encountered scenarios • Lack of compunc Melan-A MITF Melanoma in situ! Immunohistochemistry in sun-damaged skin • S-100 – Polyclonal: cross reacts with pigmented AK – Monoclonal: diminished sensi.vity in LM and ALM • HMB-45: patchy/par.al staining Mart-1 • Melan-A and Mart-1: overstaining a problem • Sox-10 or MITF: ideal MITF Quan.fica.on of melanocytes in sun- damaged skin (CSD)-what is normal? • Confluence >3 melanocytes found in 16% of SDS specimens on H&E, 4% on Mart-1 • Deep follicular melanocytes in 6%, nested melanocytes in 1 BCC specimen • Melanocyte density: LM >NMSC pa Barlow, Maize, and Lang. Dermatol Surg 2007;33:199–207 Madden, Forman, and Elston. J Am Acad Dermatol 2011;64:548-52.) *MANOVA •Density : number of melanocytes/200µm •Diameter : mode of nuclear diameter of shortest axis of 3 melanocytes 200µ •Densityxdiameter >80 is 85% sensi Am J Dermatopathol 2011;33:573–578 Minimal diagnos.c criteria for MIS (len.go maligna type) • H&E and Sox-10/MITF staining • High number of melanocytes: >10 per 200 µm, especially if present over a broad front • Nuclear enlargement >9µm diameter/pleomorphism • In absence of nes Am J Dermatopathology; 18(6), December 1996, pp 560-566 Residual melanoma vs melanocy.c hyperplasia? Look at requisi • 5-10% of all Spitz nevi • Largest series (12): all female, extremity predominant, median age 34 years • <5 mm diameter • Nests <1/3 overall cellularity; single cells confined to lower ½ of epidermis in 75% • Molecular/IHC analysis not extremely helpful Fernandez AP, Billings SD, Bergfeld WF, Ko JS, Piliang M. Pagetoid Spitz nevi: clinicopathologic characteriza • Described on thigh, below knee, and ankle • “Epithelioid cell melanocy Dona< P, Muscardin L, Cota C, Panera C, Paolino G. The melanocy FIGURE 2 The Melanocy.c Epithelioid Cell Nevus of the Thigh of Woman: A Simulator of Melanoma. Dona<, Pietro; Muscardin, Luca; Cota, Carlo; Panera, Chiara; Paolino, Giovanni American Journal of Dermatopathology. 34(8):853-855, December 2012. DOI: 10.1097/DAD.0b013e31824d4f86 FIGURE 2 . Intraepidermal melanocy © 2012 Lippincor Williams & Wilkins, Inc. Published by Lippincor Williams & Wilkins, Inc. 2 Every site is SPECIAL in its own way Ahn, C., Guerra, A., and Sangueza, OP. Am J Dermatopathol 2016; 38:867-881 Acral skin • Len Genitalia • Large (up to 1 cm) and well circumscribed • High cellularity of junc from Sangueza et al. Ear • Poor circumscrip from Sangueza et al. Scalp • Features overlap with dysplas Fisher K, Maize JC, and Maize JC. J Am Acad Dermatol 2013;68:466-72.) Flexural sites -milk line -antecubital/popliteal fossae -breast • Nests at sides/between rete • Dyscohesive nests and single cells, len from Sangueza et al. Nevoid melanoma, dysplas.c nevus, or both? Useful immunohistochemical tools • Prolifera • P16 OR ? Ki-67: the good, the bad, and the ugly Melan-A/Ki-67 (MelPro) in nevoid melanoma Nevi: <5% Melanoma: >10% MelPro in a nevus Phosphohistone H3 for mitoses • Compound nevus: MR 0.06/sq mm • Spitz nevus: mean MR 0.5 mitoses/10 HPF (range 0-2) or MR 0.325/sq mm • Melanoma: mean MR 24.7 (range 2-75) Nasr MR, El-Zammar O. Am J Dermatopathol. Apr 2008;30(2):117-122 Phadke et al. Am J Surg Pathol 2011; 35:656-699 Glatz et al. Am J Dermatopathol 2010 Oct; 32(7) 643-649. HMB-45 staining in nevus versus nevoid melanoma Nevus Melanoma Pixalls • Blue nevus, DPN, trauma Retained expression: favors benign Expression lost in 50-98% of melanomas 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 p16 caveats • Many melanomas s Gray-Schopfer VC et al. Br J Cancer 2006; 95:496-505 Yazdan et al. Am J Surg Pathol 2014; 38:638-645. “A melanocy • a/k/a/ minimal devia Diwan AH, Lazar AJ. Surg Pathol Clin 2009 Sep;2(3):521-33 Idriss et al. JAAD 2015 Nov; 73(5):836-42 Confluence at junc Melanoma! Pre- exis HMB-45 Sox10 Pagetoid melanocytes in dysplas.c nevi Am J Dermatopathol 2014;36:340–343) • 43 dysplas S-100 Sox-10 MiTF negative (usually) HMB-45 negative P75-NGFR63 Melan-A negative Desmoplas.c melanoma • Pure v mixed: > or < 90% paucicellular dermal growth – Hypercellular component may be spindle or epithelioid Pure Mixed Busam et al. Am J Surg Pathol 2004; 28:1518-1525. 64 Differen.al diagnosis • Scar: Sox-10 nega Desmoplastic nevus Neurofibroma DM 65 H3K27me3 expression can dis.nguish between MPNST and desmoplas.c melanoma • Loss of staining using C36B11 an Prieto-Granada C et al., Am J Surg Pathol 2016; 49(4): 479-48966 Retained expression of H3K27me3 in desmoplas.c/ spindle cell melanoma 67 Loss of H3K27me3 in MPNST arising in neurofibroma 68 Feeling blue Pigmented Epithelioid epithelioid blue nevus melanocytoma Animal-type melanoma Epithelioid blue nevus • Carney triad • Loss of PRKAR1α Pigmented epithelioid melanocytoma • Epidermal hyperplasia • Perinuclear pigment clearing • <<5% prolifera Yazdan, P., Haghighat, Z., Guitart, J., and Germai, P. Am J Surg Pathol 2013;37:81–88) Clonal nevus Clonal (“inverted type A”) nevus MBAIT (Melanocy BAP-1 loss 34% unknown HRAS NTRK ALK ROS-1 BRAF RET Unknown Van-Engen-van Grunsven et al. Am J Surg Pathol 2010;34:1436-41 Wiesner et al. Nat Commun 2014;5:3116 Significance of kinase fusions • Found in lesions across Spitzoid spectrum • Can be iden<fied by immunohistochemistry • Associated AST’s may have dis melanocyticRISK OF MALIGNANCY neoplasms 1 2 3 4 5 BENIGN ATYPICAL, UNCERTAIN ATYPICAL, MALIGNANT FAVOR MALIGNANT FAVOR BENIGN POTENTIAL MALIGNANT CATEGORY B-BLUE NEVUS LIKE • CLINICAL HISTORY AND APPEARANCE C-CONGENITAL • HISTOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS D-DYSPLASTIC • MOLECULAR TESTING IF NECESSARY S-SPITZOID Putting it all together S2 S3 S5 S1 S4 Atypical, Atypical, Spitzoid Benign Spitz favor benign uncertain Atypical, melanoma nevus biologic favor poten.al malignant HRAS 6p25 gain amplifica.on 11q13 gain 11p or 7 p gain 9p21 dele.on or abn. CGH 6q23 gain Customizing treatment S2 S3 S5 S1 S4 Atypical, Atypical, Spitzoid Benign Spitz favor benign uncertain Atypical, melanoma nevus biologic favor poten.al malignant Re- excision Re-excision 1 cm with SLNB 0.5-1 cm Let’s do the numbers…. 541 pa 5 (4%) REGIONAL SLNB No SLNB 11 (5%) REGIONAL RECURRENCE 303 (56%) 238 (44%) RECURRENCE 1 DEATH 5 (1%) DEATHS +SLN -SLN 119 (39%) 184 (61%) CLND 97 No CLND 22 • 24 studies, 2002-2013 (82%) (18%) • Average age: 24 years • Median f/u: 59.3 months +CLND 18 (19%) Lallas et al. Lancet Oncol 2014;15:e178–83 Molecular tests for accurate iden.fica.on of melanoma • Fluorescence in situ hybridiza Old assay New assay 6q23 CEP6 6p25, 11q13 8q24 9p21 Unequivocal Sensi • Neogenomics Laboratories (Ft. Myers, FL): $1500 • What about borderline lesions such as this? FISH in histologically ambiguous Spitzoid lesions (AST) Probe set AST w/o “AST” with poor Typical Spitz recurrence outcome (melanoma) OLD sensi OLD specificity 57-91% 4,1 75-100%5,1 NEW sensi NEW specificity 74-87%2,3 1 Demarchis EH et al, Pediatr Dermatol. 2014; 31(5) 561-9 2 Gerami et al, Am J Surg Pathol Feb 2013 3 Tetzlaff et al, Am J Surg Pathol. Dec 2013 4 Massi et al. J Am Acad Dermatol 2011;64:919-35 5 Dika et al Mel Research 2015; 25(4): 295-301 6 Vergier et al. Modern Pathology 2011; 24: 613-623 Specific FISH abnormali.es associated with outcome in borderline lesions (AST) • Homozygous dele.on of 9p21: predicts local recurrence and only feature predic Gerami et al, Am J Surg Pathol, Feb 2013 North et al. Am J Surg Pathol 2014;38:824-31 Raskin et al. Am J Surg Pathol 2011;35:243-52 Compara.ve genomic hybridiza.on • Assesses chromosomal copy number changes across Bas • Most commonly used to dis Superficial spreading>nodular>len.go maligna Compound and dermal nevi Clarke et al. J Cutan Pathol 2015; 42:244-252 Independent valida.on of myPath • 1400 lesions independently reviewed by 3 experts – Triple concordance: 993 lesions (70.9%) – Excluded indeterminate scores: 860 lesions (24% malignant, 76% benign) – Excluded lesions with <10% tumor volume: 763 lesions • Sensi Clarke et al., Cancer, October 2016 Clarke, ASDP October 2016 29 year old pregnant female with changing lesion on back Junc • 39 unequivocal lesions: 62% sensi SUMMARY: myPath score can increase diagnos Minca et al, Modern Pathology, August 2016, 29:832-843. Molecular tests for melanoma diagnosis Summary • FISH and myPath sensi