Pathology of Acral Nevi and Melanomas

D Elder, Maui, HI 2020

Subtlety and Uncertainty • More Common in Sun-Susceptible Populations: • Pathway I. Low CSD Melanoma/Superficial Spreading Melanoma (SSM) • Pathway II. High CSD Melanoma/Lentigo Maligna Melanoma (LMM) • Pathway III. Desmoplastic Melanoma

• Incidence about the same world-wide • Pathway IV. Malignant Spitz Tumor (?) • Pathway V. Acral Melanoma • Pathway VI. Mucosal Melanoma • Pathway VII. Melanoma in Congenital Nevus (MCN) • Pathway VIII. Melanoma in Blue Nevus (MBN) • Pathway IX. Uveal Melanoma

• Variable Pathways: Nodular Melanoma Lv, Jiaojie, et al (Shanghai, 2016) Table 1. Classification of Melanocytic Tumors by Epidemiologic, Clinical, Histopathologic & Genomic Attributes

Role of UV: Low UV High UV Low to No (or Variable) CSD

Pathway: I II III IV V VI VII VIII IX

High-CSD Melanoma in Low-CSD Melanoma Desmoplastic Spitz Mucosal Melanoma Melanoma Acral Melanoma Congenital Uveal Melanoma Melanoma Melanoma Melanoma In Blue Nevus Superficial Spreading Melanoma (LMM) Nevus

Congenital Nevus ? IAMP ? IAMP Spitz Nevus ?IAMP Melanosis Blue Nevus ? Benign Nevus (CN)

Atypical Nodular Borderline Low Grade Atypical Spitz Atypical Cellular Blue ? IAMP ? IAMP melanocytic proliferation in Uveal nevus Dysplasia nevus melanosis Nevus Low Bap-1 Deficiency DPN PEM proliferation CN Melanocytoma Melanocytoma Melanocytoma /MELTUMP /MELTUMP /MELTUMP Borderline High Grade IAMPUS/ Lentigo maligna Melanoma in situ STUMP Melanoma in situ ? MIS in CN Atypical CBN ? High Dysplasia SAMPUS

Superficial Mucosal Melanoma in Melanoma in Melanoma in Lentigo Maligna Malignant Spitz Acral lentiginous Melanoma ex Spreading Desmoplastic Melanoma lentiginous Melanoma in CN Uveal melanoma Malignant BPDM (rare) DPN (rare) PEM (rare) Melanoma Tumor melanoma Blue Nevus Melanoma melanoma

BRAF V600E, (BRAF or NRAS) (BRAF, MEK1, or (BRAF NRAS, NF1, HRAS, ALK, KIT, NRAS, KIT, NRAS, NRAS, BRAF GNAQ, GNA11, GNAQ, GNA11, NRAS +BAP1 NRAS) +PRKAR1A) or BRAFnon- ERBB2, MAP2K1, ROS1, RET, BRAF, HRAS, KRAS, or V600E (small or CYSLTR2 CYSLTR2, or +(CTNNB1 or PRKCA V600E, KIT, MAP3K1, BRAF, EGFR, NTRK1, NTRK3, KRAS, BRAF lesions), BRAF PLCB4 APC) NF1 MET, BRAF,MET NTRK3, ALK, NF1

Common mutations TERT, TERT, TERT, NFKBIE, CDKN2A CDKN2A, TERT NF1, CDKN2A BAP1, BAP1 CDKN2A, TP53, CDKN2A, TP53, NRAS, PIK3CA , PTPN11 CCND1, GAB2 SF3B1, EIF1AX, SF3B1 SF3B1, EIF1AX, PTEN PTEN, CCND1, CDK4, RAC1 MDM2

Color Code: Mutations: Red; gain of function; Blue, loss of function; Green, Notes: Progression is not obligate change of function, Black, promoter mutation. Orange, amplifications. and steps can be skipped Purple: Rearrangements. Table 1. Classification of Melanocytic Tumors by Epidemiologic, Clinical, Histopathologic & Genomic Attributes

Role of UV: Low UV High UV Low to No (or Variable) CSD

Pathway: I II III IV V VI VII VIII IX

Congenital Nevus ? IAMP ? IAMP Spitz Nevus ?IAMP Melanosis Blue Nevus ? Benign Nevus (CN)

Bastian BC, de la Fouchardiere, A, Elder, DE, Gerami P, Lazar AJ, Massi D, Nagore E, Scolyer RA, Yun SJ. Genomic Landscape of Melanoma. In Elder DE, Massi D, Scolyer RA, Willemze R: WHO Classification of Skin Tumours, Lyon, 2018 No CSD Melanomas (Pathways IV-IX)

Atypical melanocytic proliferation Melanoma in situ Acral lentiginous melanoma KIT, NRAS, BRAF, HRAS, KRAS (GOF), NTRK3, ALK (Fusions), NF1 CDKN2A (LOF), TERT CCND1, GAB2 (amplifications)

• Moon KR, Choi YD, Kim JM, Jin S, Shin MH, Shim HJ, et al. Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features. J Invest Dermatol. 2018;138(4):933-45.

• Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80. Significance of Nevi.

• Nevi are important mainly in relation to melanoma – Precursors – but risk for individual lesions is low – Risk markers – important mainly in high risk situations – Simulants – important in everyday clinical decision-making

• Acral nevi are most important as simulants – Probably not precursors, not clearly risk markers Acral junctional nevus

In DifficultHistopathological Cases, ClinicopathologicDifferential Diagnosis is not easy! Correlation is Essential!

Acral lentiginous melanoma Puccio FB et al. Arch Pathol Lab Med 2011;135:847-52. Histopathology of Acral Nevus S J Yun, MD, PhD, S. Korea

Saida T et al. Am J Dermatopathol 2011;33:468-73. Ishihara Y et al. Am J Dermatopathol 2006;28:21-27.

Acral Nevus; Parallel Furrow Pattern Acral Melanoma; Parallel Ridge Pattern Dermoscopy for Acral Nevus vs Melanoma

Acral Nevus; Parallel Furrow Pattern Acral Melanoma; Parallel Ridge Pattern Histopathology of Acral Nevus

• Junctional or compound nevi, only slight to moderate atypia • Large, vertically oriented junctional nests, not usually bridging • Transepidermal elimination • Lentiginous junctional melanocytic proliferation • Limited degree of pagetoid scatter often present (85%) – Melanocytic acral nevus with intraepidermal ascent of cells (MANIAC, LeBoit) • Discrete melanin columns in cornified layer Crease Vertical S J Yun, MD, PhD, S. Korea Tissue section: Dermatoglyphics Vertical

Furrow pigment column Crease Line : S J Yun, MD, PhD, S. Korea Long axis of nevus parallel to Dermatoglyph

Tissue section: Dermatoglyphics Parallel

Difficult evaluation of Furrow or Ridge pattern S J Yun, MD, PhD, S. Korea Acral Nevus vs Acral Melanoma

• Overlapping histopathologic features of acral nevus, special site nevus, dysplastic nevus, and melanoma • Size : Important criteria for distinction • Excisional biopsy – punch Bx often nondiagnostic • When the case is difficult, clinicopathologic correlation is essential! • Intraepidermal Atypical Melanocytic Proliferation of Uncertain Significance (IAMPUS), MELTUMP Descriptive terms, D/D should be expressed. S J Yun, MD, PhD, S. Korea Next Case Your Diagnosis?

Nevus?

Melanoma? Acral Junctional nevus 34F, Lt sole, 3x2mm, 3ms, Lee OO

Pagetoid scatter NEXT CASE - 67 year old female

• 7 Feb 2014: 2 cm x 2 cm brown black, irregularly bordered left heel lesion in a surrounded by an approximately 1-1/2 cm light brown macular fringe.

• Clinical impression: Melanoma.

• Procedure: Punch biopsy. Bruce Ragsdale MD

Your Diagnosis?

Melanoma in situ? Invasive melanoma? Our Diagnosis

Malignant melanoma, acral-lentiginous type, in situ, transected at the specimen peripheral margins Note: There may be a few cells in the dermis. The biopsy may not be representative

CASE 2 – Follow up

• No signs of in-transit disease were recorded. • 1 mo. after punch biopsy, a wide excision of the lesion with reconstruction by rotational flap. • Final thickness = 1.1 mm, margins free. • Sentinel groin lymph node = negative.

• PUNCH BIOPSY WAS NOT REPRESENTATIVE No UV Acral Melanoma Acral Melanoma

• Palms, soles, subungual • Great toe region most common • Incidence similar in all races, thus most common form of melanoma in African, Asian and Indian populations • May be deceptively thick even in absence of a raised nodule The spectrum of acral lentiginous melanoma Amelanotic melanoma pink plantar lesion in a 92 Y/o M., growing 1.5 years.

Sentinel node – MART 1 Subungual melanoma

• Incidence, distribution and genomic attributes generally similar to ALM • Differentiation from subungual nevus can be difficult – Lentigo, junctional nevus, compound nevus • Ridge and furrow patterns do not apply • Confluence, atypia (high grade, uniform), scatter, mitoses • Most lesions in children are benign • WHEN THE CASE IS DIFFICULT, CLINICOPATHOLOGIC CORRELATION IS ESSENTIAL!

Hutchinson’s Sign – Extension of Pigment onto the Nail Fold

DermNet New Zealand https://creativecommons.org/licenses/by-nc-nd/3.0/nz/legalcode Acral Melanomas

Radial Growth Phase (RGP)

Vertical Growth Phase (VGP)

Hutchinson’s sign

Lv, Jiaojie, et al (Shanghai, 2016) Acral-lentiginous Melanoma

• Lentiginous nontumorigenic compartment (RGP) • Continuous basal proliferation of uniformly atypical melanocytes • May be very subtle at the periphery • Often a spindle cell tumori- genic compartment (VGP) – often desmoplastic and/or neurotropic (local recurrence risk) • May be deceptively thick even in absence of a raised nodule S J Yun, MD, PhD, S. Korea Histopathology of Early Acral Melanoma

• Histopathologic features of early acral melanoma are minimal. – only scattered hyperchromatic cells – scattered spindle cells with prominent dendrites

• Excisional biopsy including the deepest area is recommended. Punch Biopsy S J Yun, MD, PhD, S. Korea 61M, Lt heel, 3yrs, Lee OO Scattered small ovoid cells HMB45 61M, Lt heel, 3yrs, Lee OO Prominent dendrites 61M, Lt heel, 3yrs, Lee OO Melanoma, Acral Lentiginous Type HMB45

Your Diagnosis?

Nevus? Melanoma?

Recurrent melanoma at site of prior biopsy

Field Cells (Bastian)

• Cells at periphery of acral melanomas that have initiating mutations and copy number increase, no morphological abnormalities • Could account for greater tendency of these melanomas to recur locally – Also perhaps reluctance to perform “wide” excisions • Follow-up protocols should pay particular attention to risk of local recurrence

Bastian BC, Kashani-Sabet M, Hamm H, Godfrey T, Moore DH 2nd, Bröcker EB, LeBoit PE, Pinkel D. Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res. 2000; 60:1968-73 • Analyzed chromosomal aberrations of 15 AMs and 15 SSMs using comparative genomic hybridization (CGH). • AMs significantly more amplifications than the SSMs (mean 2 vs. < 1, p < 0.0001). • Most frequently amplified regions in AMs were at 11q13 (47%, cyclin D). • Amplifications of 11q13 were found in AM in situ showing that changes arise early in the progression of AM. • Isolated epidermal melanocytes with amplifications were found up to 3 mm beyond the histologically recognizable extent of the melanomas in 5/15 invasive AMs. 11q amplification (red probe) in acral melanoma. Bastian et al, 2000 Margin Evaluation in Acral Melanoma

• “Field cells” at periphery of acral melanomas have initiating mutations and copy number increase, no morphological abnormalities • SUBTLETY and UNCERTAINTY • May account for greater tendency of these melanomas to recur locally • Follow-up protocols should pay particular attention to risk of local recurrence 50