Dehner, Carina A

ABSTRACTBackgroundDifferentiating metastatic melanoma from histologic mimics such as malignant gastrointestinal neuroectodermal tumor (GNET), malignant melanotic nerve sheath tumor (MMNST), and epithelioid malignant peripheral nerve sheath tumor (EMPNST) poses significant diagnostic challenges due to overlapping morphology and immunophenotypes. PRAME is a novel immunohistochemical marker increasingly used to distinguish melanoma from its mimics, but remains underexplored in these rare tumor types.MethodsPRAME immunohistochemistry was performed on four GNETs, seven MMNSTs, 10 EMPNSTs, 16 metastatic melanomas (including eight undifferentiated melanomas), and two MITF‐rearranged melanocytic tumors. PRAME expression was scored from 0 to 4+ based on the percentage of tumor nuclei showing moderate to strong staining.ResultsAll GNETs, MMNSTs, and MITF‐rearranged tumors were PRAME‐negative. EMPNSTs showed variable expression: six were negative (0–1), one equivocal (2+), and three positive (3–4+). Fifteen of 16 melanomas were PRAME‐positive. PRAME scores differed significantly among tumor types (p = 1.99 × 10−5). PRAME demonstrated high sensitivity and specificity for distinguishing metastatic melanoma from primary mimickers including GNET and MMNST, but low specificity in EMPNST (71.4%).ConclusionsPRAME reliably distinguishes metastatic melanoma from GNET and MMNST, supporting its use in this differential. However, its reduced specificity in EMPNST limits its standalone diagnostic value in this context, emphasizing the need for a multimodal approach.

ABSTRACTVarious cutaneous adnexal neoplasms have been associated with gene fusions as the main driver of their histogenesis, most of which showed poroid or hidradenomatous differentiation or represented other tumors of sweat glands. Recently, we encountered two cases of primitive basaloid neoplasms of predominantly folliculogenic/pilosebaceous origin, both surprisingly harboring recurrent EWSR1 rearrangements. Both tumors presented in young patients of either sex (1 F; 17 years; 1 M; 37 years) and involved the dermis and subcutaneous tissue of the abdominal wall (case 1) and the buttock (case 2). Histologically, the tumors were composed of primitive, basaloid cells with areas of keratinization (case 1) or foci of sebaceous differentiation (case 2) and stained strongly with keratins, p40 (case 1) or p63 (case 2), while lacking significant CD99 expression in both cases. Case 1 harbored an EWSR1::FLI1 fusion while case 2 harbored an EWSR1::PBX3 fusion. Clinical follow‐up was available for case 2 and showed no evidence of disease at 15 months of follow‐up. Methylation profiling showed case 1 to cluster with cutaneous squamous cell carcinoma, while case 2 was independent but positioned close to salivary gland epithelial‐myoepithelial carcinoma. These findings expand on the histopathologic and molecular genetic features of basaloid tumors with apparent adnexal differentiation and raise awareness to carefully interpret and correlate molecular findings with morphology and immunophenotype to avoid misinterpretation as a mesenchymal neoplasm.

ABSTRACTXanthogranulomatous epithelial tumor (XGET)/Keratin‐positive giant cell tumor (KP‐GCT) represents a spectrum of recently described neoplasms characterized by a proliferation of distinctive mononuclear cells expressing keratin within a background of osteoclast‐like giant cells, mixed inflammatory cells, and a variably prominent xanthogranulomatous component. Recent studies demonstrated a recurrent HMGA2::NCOR2 fusion in many cases. We herein describe a case of XGET/KP‐GCT arising in the right femoral head of a 19‐year‐old male harboring a rare novel HMGA2::COL14A1 fusion.

Abstract Purpose: Early detection of neurofibromatosis type 1 (NF1)–associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. In this study, we describe a cell-free DNA (cfDNA) fragmentomic approach that distinguishes nonmalignant, premalignant, and malignant forms of PNST in the cancer predisposition syndrome, NF1. Experimental Design: cfDNA was isolated from plasma samples of a novel cohort of 101 patients with NF1 and 21 healthy controls and underwent whole-genome sequencing. We investigated diagnosis-specific signatures of copy-number alterations with in silico size selection as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end motifs, and fragment non-negative matrix factorization signatures. Results: The novel cohort of patients with NF1 validated that our previous cfDNA copy-number alteration–based approach identifies malignant PNST (MPNST) but cannot distinguish between benign and premalignant states. Fragmentomic methods were able to differentiate premalignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Conclusions: Novel cfDNA fragmentomic signatures distinguish AN from benign plexiform neurofibromas and MPNST, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant PNST in NF1 and provides a blueprint for decentralizing noninvasive cancer surveillance in hereditary cancer predisposition syndromes.