RASGRF1-rearranged Cutaneous Melanocytic Neoplasms With Spitzoid Cytomorphology

Abstract

Spitz neoplasms, according to 2018 WHO Blue Book, are morphologically defined by spindled and/or epithelioid melanocytes and genetically by either HRAS mutations or kinase gene fusions. The terminology "spitzoid" refers to lesions with similar morphology but with alternate or undefined genetic anomalies. Herein, we present 3 melanocytic neoplasms with a spitzoid cytomorphology, variable nuclear atypia, and harboring undescribed fusions involving RASGRF1. Two cases presented as unpigmented papules on the heel of a 26-year-old female (case 1) and the forearm of a 13-year-old boy (case 2). They were classified as low-grade melanocytomas (WHO 2018). The third case appeared as a pigmented ulcer on the sole of a 72-year-old female (case 3) that displayed diagnostic features of an invasive melanoma (Breslow thickness 6 mm, Clark level V). A wide skin reexcision identified an epidermotropic metastasis, and sentinel lymph node biopsy displayed multiple subcapsular metastatic deposits. RNA sequencing revealed CD63::RASGRF1, EHBP1::RASGRF1, and ABCC2:: RASGRF1 fusions in cases 1 to 3, respectively. They were confirmed by a RASGRF1 break-apart fluorescence in situ hybridization technique. Translocations of RASGRF1, a gene coding a guanine nucleotide exchange factor but not a kinase, have rarely been reported in tumors. While all these cases showed spitzoid cytomorphology, it is too early to tell if they are true Spitz neoplasms as currently defined.

The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification

“…Three cases of RASGRF1-rearranged spitzoid neoplasms have recently been identified ( 198 ). All three lesions displayed spitzoid morphology including nests of spitzoid epithelial/spindled melanocytes and epidermal hyperplasia; fusion partners included: CD63, EHBP1, and ABCC2 ( 198 ).…”

“…Three cases of RASGRF1-rearranged spitzoid neoplasms have recently been identified ( 198 ). All three lesions displayed spitzoid morphology including nests of spitzoid epithelial/spindled melanocytes and epidermal hyperplasia; fusion partners included: CD63, EHBP1, and ABCC2 ( 198 ). Given that RASGRF1 is a guanine nucleotide exchange factor gene rather than a kinase-encoding gene, although these lesions are spitzoid in morphology, it is still too early to determine whether a RASGRF1 genomic aberration classifies this spitzoid lesion as a Spitz lesion ( 198 ).…”

Wholistic approach: Transcriptomic analysis and beyond using archival material for molecular diagnosis

“…This integrative management of transcriptomic data allowed the first description and refinement of several neoplastic entities in the field of mesenchymal, melanocytic, mesothelial, and rare tumors, using almost exclusively archived FFPE material: alternative rearrangement of PDGFD in dermatofibrosarcoma protuberans , 28 endometrial stromal sarcoma in general, 6 sarcoma with CIC::NUTM1 rearrangement, 29 perivascular myoid neoplasm with SRF fusion , 30 well‐differentiated rhabdomyosarcomas with SRF fusion, 31 heterogeneity of rhabdomyosarcomas, 32 undifferentiated round cell sarcoma with CRTC1::SS18 fusion, 5 superficial pleomorphic tumors with PRDM10 fusion, 33 giant cell tumor with NCOR2 fusion, 34 acral fibrochondromyxoid tumor with THBS1 fusion, 35 unclassified sclerosing malignant melanomas with AKAP9::BRAF gene fusion, 36 cutaneous melanocytoma with CRTC::TRIM11 fusion, 37,38 melanocytic myxoid spindle cell tumor with ALK rearrangement (MMySTAR), 39 melanocytoma with concomitant mutation of IDH1 and NRAS , 40 CYSLTR2 ‐mutant cutaneous melanocytic neoplasms, 41 agminated melanocytic Spitz nevi arising in a giant congenital hyperpigmented macule with three‐way complex rearrangement of TRPM1::PUM1::LCK , 42 agminated Spitz nevi with GOPC::ROS1 mosaicism, 43 primary melanoma of the lung with FNBP1::BRAF fusion, 44 melanocytic tumors with either RASGRF1 45 or RASGRF2 fusion, 46 melanocytic Spitz neoplasms with MAP3K8 fusion, 47 melanocytic spitz tumors in general, 43,48–50 clear cell tumor with melanocytic differentiation and MITF::CREM 51 and ACTIN::MITF fusion, 52 and solid papillary mesothelial tumor 53 …”

Melanocytic Neoplasm With KIT and APC Mutations: A New Subtype of Melanocytoma?

“…[9][10][11][12] Several small series of unusual melanocytic neoplasms with peculiar molecular findings have been reported, expanding the group of the intermediate-grade melanocytic tumor/melanocytoma. [13][14][15] We herewith report a unique case of a morphologically ambiguous melanocytic proliferation characterized by concomitant KIT and APC mutations (Figs. 1-3).…”

“…9–12 Several small series of unusual melanocytic neoplasms with peculiar molecular findings have been reported, expanding the group of the intermediate-grade melanocytic tumor/melanocytoma. 13–15…”