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Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P

Recurrent activating Gαq mutations in the spectrum of blue nevi have been well studied. However, the clinicopathologic characteristics of the recently described CYSLTR2-mutant and PLCB4-mutant blue nevi remain limited, owing to their rarity. Herein, we present 7 CYSLTR2-mutant melanocytic neoplasms, including 1 cellular blue nevus, 4 atypical cellular blue nevi, and 2 blue nevus-like melanomas. They occurred on the scalp, breast, flank, forearm, thigh, leg, and ankle of 3 male patients and 4 female patients, with a median age of 43 (25 to 81) years at diagnosis. Five exhibited an exophytic growth, and 6 were heavily pigmented. A fascicular arrangement of medium to large spindle melanocytes was seen in 6 cases, but epithelioid cytology was present in only 2 cases, one of them being focal. A junctional component was present in 3 cases. Immunoreactivity for HMB45 was diffusely present, except in 1 cellular blue nevus. BAP1 nuclear immunoexpression was lost in 1 melanoma case. A canonical CYSLTR2 L129Q hotspot mutation was present in all cases. Altogether, these histopathologic findings suggest that CYSLTR2-mutant melanocytic blue neoplasms frequently exhibit a heavily pigmented exophytic tumor with a silhouette resembling "pigmented epithelioid melanocytoma" rather than usual cellular blue nevus. Moreover, most of these tumors were not clinically recognized as blue nevi and not located in the classic topography of cellular blue nevus aside from the scalp. However, a fascicular arrangement of medium to large-sized spindled melanocytes, as well as a lack of epithelioid or nevoid melanocytes, could be potential diagnostic clues to morphologically distinguish CYSLTR2-mutant tumors from "pigmented epithelioid melanocytoma."

Clear cell morphology is an uncommon finding in tumors. A subset of clear cell neoplasms also shows melanocytic differentiation, including clear cell sarcoma, PEComa, and some subtypes of renal cell carcinoma. A hallmark of these tumor types is the activation of a member of the MIT/TFE family of transcription factors, which includes MITF, TFE3, TFEB, and TFEC. Microphthalmia transcription factor (MITF is the master regulator of melanin synthesis, while TFEB plays a critical role in lysosome biogenesis. Cytogenetic translocations involving TFE3 and TFEB are now well described in multiple tumor types, but there has been little evidence to suggest similar regulation of MITF. Here we describe a series of 7 clear cell cutaneous neoplasms with melanocytic differentiation that are characterized by ACTIN-MITF gene fusions, either ACTB-MITF or ACTG1-MITF. The chromosomal breakpoints preserve MITF's dimerization and transcriptional activation domains, suggesting that these fusion proteins likely result in hyperactive MITF function, analogously to the previously reported TFE3 and TFEB fusions. Our findings indicate that MITF gene rearrangements may be key drivers of tumor pathogenesis and expand the spectrum of neoplasia associated with the MIT/TFE family.

Melanocytic tumors rarely display extensive dermal myxoid deposits except in the myxoid variant of melanoma. We describe in 4 patients the unusual association of morphologic and genetic features. All cases occurred in males and were located on the limbs or proximal girdle area. Age at diagnosis ranged from 8 to 47 years. Size ranged from 6 to 11 mm. Microscopic analysis showed compound, but mainly dermal melanocytic nevi, all presenting a deep dermal expansion with fascicules of amelanotic spindled cells floating in a myxoid background. Cytologic atypia and mitotic activity were low. The superficial portion was either of spitzoid or nevoid cytology with a limited junctional component. In the initial case, the dermal myxoid component was predominant with rare, barely visible, superficial melanocytic nests. This peculiar morphology was responsible for a delayed diagnostic, which required an extensive panel of antibodies ruling out most, potentially myxoid, soft tissue tumors. We later observed the presence of similar, but more limited, dermal morphologic features in 3 other cases. Immunohistochemistry in the deep myxoid areas was melanA, ALK, SOX10, and MiTF. Molecular studies confirmed the ALK rearrangement by an ALK break-apart fluorescence in situ hybridization technique and by RNA sequencing. The latter identified 4 different 5'-fusion partners. Two gene fusions were undescribed: FBXO28(e2)-ALK(e19) and NPAS2(e2)-ALK(e19), and 2 previously described: TPM3(e7)-ALK(e20) and PPFIBP1(e9)-ALK(e19). No relapse or metastatic evolution was seen during follow-up (3 to 24 mo). We denominated this potentially challenging new variant of compound nevus linked to a kinase fusion: Melanocytic Myxoid Spindle Cell Tumor with ALK Rearrangement.

We report 5 cases of primary intradermal nodular unpigmented tumors with a melanocytic immunophenotype associated with a novel CRTC1-TRIM11 fusion. Clinically, the cutaneous nodules were slowly growing in 3 women and 2 men (25 to 82 y old, median, 28 y) with no specific topography. Lesion size ranged from 4 to 12 mm (median, 5 mm). The tumors were strictly located in the dermis with a nodular pattern. The cells were arranged in confluent nests and fascicules. Central fibronecrotic areas were present in 2 cases. Cells were medium to large, sometimes multinucleated, and presented a spindled and epithelioid cytology with prominent nucleoli. Cytonuclear atypia was constant, and mitotic activity in hotspot areas ranged from 1 to 5/mm². Immunohistochemistry found a constant positivity with S100, MiTF, and Sox10, and a heterogenous staining by MelanA or HMB45. NTRK1 was strongly positive in 3 cases. In all cases, RNA sequencing found an invariable CRTC1(e1)-TRIM11(e2) fusion, confirmed by fluorescent in situ hybridization techniques with a TRIM11 break-apart probe. In 4/4 cases, nuclear TRIM11 expression was positive by immunohistochemistry. Fluorescent in situ hybridization techniques showed no rearrangement of NTRK1 or EWSR1, and array-comparative genomic hybridization displayed no alteration (1 case) or only a whole chromosome 7 gain (2 cases) when performed. No relapse or metastatic event was observed during follow-up [3 to 72 months (median, 14 mo)]. Cutaneous clear cell sarcoma was the main differential diagnosis. Overlapping morphologic features previously described in primary dermal melanomas and paraganglioma-like melanocytic tumors were present. The CRTC1-TRIM11 fusion appears to be specific of an unpigmented nodular tumor combining a melanocytic phenotype and low-grade tumor behavior.

Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

The authors describe a case of a 5 cm mixed desmoplastic melanoma occurring on the cheek of an 88-year-old white woman. The epidermis showed the features of lentigo maligna. Within the dermis, there was a mixed desmoplastic melanoma with 2 components. The first component consisted of infiltrative malignant spindled cells with prominent stromal fibrosis and had the typical appearance of desmoplastic melanoma. The second component was within the deep half of the tumor and consisted of a densely cellular nodule composed of spindled melanocytes admixed with many osteoclast-like giant cells. There was a peripheral neurotropism and tumor invaded bone. The Breslow thickness was 14 mm. On followup, a sacral metastasis was discovered, which had a similar morphology to the deep cellular nodule. Immunohistochemistry of spindled cells both inside and outside the nodule showed S100 positivity with the absence of other melanocytic markers (HMB-45, Melan-A). Smooth muscle actin and p63 were focally positive. The osteoclast-like giant cells expressed CD68 and MiTF. Array comparative genomic hybridization of the typical desmoplastic melanoma region had a flat profile, whereas the cellular osteoclast-like giant cell–rich region displayed important cytogenetic anomalies, some of which have been previously described in melanomas. The main array comparative genomic hybridization findings were confirmed by fluorescence in situ hybridization using specific probes. The differences in morphology and molecular cytogenetics between the 2 areas suggest that these might represent the progression or emergence of a more aggressive clone within the tumor. Subsequent metastatic spread to the bone may be a result of accumulated cytogenetic abnormalities.

Primary low-grade B-cell lymphomas of the skin are separated into marginal zone and follicle center lymphomas according to the recent World Health Organization-European Organization for Research and Treatment of Cancer classification, with distinct histologic and immunohistochemical profiles. Some cases remain difficult to distinguish. The degree of relationship with their extracutaneous counterparts is currently being investigated on clinical, histologic and molecular grounds. Cytogenetic analysis using fluorescence in situ hybridization was performed on 12 frozen samples of infiltrated skin that had been classified as marginal zone lymphoma (MZL). Chromosomal changes known to be recurrently observed in systemic MZL of the mucosa-associated lymphoid tissue type, and in follicular center lymphoma were analyzed. These included trisomy for chromosomes 3, 7, 12, and 18 as well as t(14;18) IGH/BCL2, t(14;18) IGH/MLT1, and t(11;18) API2/MLT1 translocations. Complementary molecular search of IGH/BCL2 rearrangement using a polymerase chain reaction technique and of API2/MLT1 mRNA expression by reverse transcriptase-polymerase chain reaction were performed. Two cases showed evidence of trisomy 3 at levels varying from 14% to 20% of the analyzed cells. No other chromosomal abnormalities were found with those techniques in the remaining cases. These results demonstrate that known recurrent chromosomal abnormalities rarely occur in primary cutaneous MZLs and suggest the possibility of a variety of initial oncogenic events leading to a common downstream pathway. These data also underline that fluorescence in situ analysis on routine skin punch biopsies represents a reliable tool for the detection of chromosomal changes, but requires consistent dermal infiltration.