• Pro • Con March et al. Practical applications of new technologies for melanoma. JAAD June 2015

• Pros

• Cons • • •

Diagnostic criteria for Familial Atypical Multiple Mole Melanoma syndrome

1. Malignant melanoma in one or more first- or second-degree relatives

2. High total body nevi count (often >50) including some of which are clinically atypical (asymmetric, raised, color variegation present, of variable sizes)

3. Nevi with certain histologic features on microscopy*

* architectural disorder with asymmetry, subepidermal fibroplasia, and lentiginous melanocytic hyperplasia with spindle or epithelioid melanocytes gathering in nests of variable size and fusing with adjacent rete ridges to form bridges; variable dermal lymphocyte infiltration and the “shouldering" phenomenon wherein intraepidermal melanocytes extend alone or in groups beyond the main dermal component may also be present

All three criteria are needed to make a diagnosis

Clinical validity and prognostic value of DecisionDx-Melanoma have been demonstrated in 690 Stage I-III patients

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Time (Years) Time (Years) Time (Years) Class 1A Class 1B Class 2A Class 2B n=312 n=80 n=84 n=214

GEP 5-year RFS Events 5-year DMFS Events 5-year MSS Events Class (95% CI) (%) (95% CI) (%) (95% CI) (%) 1A 90% (87-93%) 37 (12%) 94% (91-97%) 24 (8%) 99% (97-100%) 4 (1%) 1B 81% (73-90%) 18 (23%) 85% (77-93%) 15 (19%) 95% (90-100%) 5 (6%) 2A 68% (58-79%) 32 (38%) 75% (66-85%) 25 (30%) 91% (85-98%) 7 (8%) 2B 37% (31-44%) 130 (61%) 50% (43-58%) 100 (47%) 75% (69-83%) 42 (20%)

Leachman et al. Soc Melanoma Res Meeting 2017

SLNB positivity risk for patients with T1-T2 tumors and inform SLNB guidance

30% NCCN Recommendations Probability of a Positive Sentinel Lymph for SLNB (v2.2018) DecisionDx- Node for T1-T2 Patients 20% Melanoma <55 years 55-64 years ≥65 years Discuss and Offer result 10% Class 1A 7.6% 4.9% 1.6%

Class 1B/2A 19.6% 7.7% 6.9% Discuss and Consider Class 2B 24.0% 30.8% 11.9%

5% SLN Positivity Positivity SLN Rate Do not Recommend SLN+ probability in T1-T2 patients: • Is below the 5% threshold established by 0% guidelines in those ≥55 years old with a Class <55 55-64 ≥65 1A result Age (years) • Is above the 10% threshold established by Class 1A Class 1B/2A Class 2B guidelines in all age groups with a Class 2B result Thresholds based on NCCN Guidelines (v2.2018) n=1,421

•Weinstock et al23 • Characteristics of melanocytes at the DE junction • Grades dysplasia • Substantial to low agreement Reflectance Confocal Microscopy and Dysplastic Nevi HISTOLOGICAL CONTROVERSY

• Weinstock et al23 • Characteristics of melanocytes at the DE junction • Grades dysplasia • Substantial to low agreement

Source: Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the Source: Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the Source: Shea CR, Vollmer RT, Prieto VG. Correlating architectural disorder and Source: Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch cytologic atypia in Clark (dysplastic) melanocytic nevi. Hum Pathol. 1999; 30(5):500-5. histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch Dermatol. 1997; 133(8): 953-8. Dermatol. 1997; 133(8): 953-8. Dermatol. 1997; 133(8): 953-8.

Mild atypia Moderate atypia Severe atypia Melanoma in situ

23. Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch Dermatol. 1997; 133(8): 953-8. 51 Nevo-Melanocytic Industrial Complex

• Term describing what may be perceived as an increasing tendency to over-biopsy and over-treat dysplastic nevi • Reflectance Confocal Microscopy may be an alternative What is Reflectance Confocal Microscopy?

Detector Pinhole Reflectance Confocal Microscopy (RCM) create Focusing Lens images by illuminating the skin with a low power Laser(s) laser diode and reflecting the light back though the system, utilizing customized optics to display Scanning Optics the final image computer screen. Wave Plate Objective Lens Window

Tissue Sample

DE J Procedure

Start to Finish: 5 to 10 Minutes Classification

Normal Features Atypical Features • Ringed pattern • Atypical Cells at DEJ • Meshwork pattern • Irregular junctional nests • Clod patterns • Non-edged papilla • Edged papilla RCM produce Horizontal Sections

Stratum Corneum

Granular layer

Spinous layer

Basal layer

Papillary dermis

Superficial reticular dermis Histology & Confocal: Dermo-epidermal Junction

• Dark areas w/ microcirculation • capillary loops and collagen bundles • Ring of basal keratinocytes

ATYPICAL DENDRITIC CELLS

Dysplastic Nevi

• On RCM, dysplastic nevi often have a primarily ring-meshwork pattern with 1-2 atypical features • Benign nevi usually have no atypical features • Melanoma often has greater than 2 atypical features on RCM

Fig 1 Melanocytic nevus. An irregular pigment Fig 2 Melanocytic nevus. A ringed and edged pattern Fig 3 Melanocytic nevus with a bright DEJ network with central dots and globules. with numerous dermal and junctional nests. with several dermal and junctional nests.

MELA Sciences Inc, Irvington, New York)

Fink et al. Diagnostic performance of the MelaFind device in a real‐life clinical setting. Journal of the German Society of Dermatology. March 2017