Browsing by Subject "Nerve sheath neoplasms"

Now showing 1 - 3 of 3
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    A Case of Hybrid Cellular Neurothekeoma and Perineurioma With a Folliculin Gene Mutation
    (Wiley, 2025) Prechtel, Taylor J.; Brashear, Emma; Dehner, Carina A.; Alomari, Ahmed K.; Pathology and Laboratory Medicine, School of Medicine
    Hybrid peripheral nerve sheath tumors (PNSTs) are benign tumors that show features of more than one type of PNST. Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma (BCPHTPCN) is a rare, recently described entity that shows various combinations of histomorphologic and immunophenotypic features of the PNSTs perineurioma and cellular neurothekeoma. Our case describes a middle-aged man initially presenting with an acute papulopustular rosacea flare. Rosacea treatment unmasked a prominent erythematous papule on the forehead. A biopsy was taken, and histopathological examination showed a proliferation of epithelioid, ovoid, and spindled cells arranged in a compact nested and intersecting fascicular growth. Immunohistochemical stains were positive for NKI/C3, CD10, PGP9.5, MITF, and GLUT-1. There was weak reactivity with EMA and minimal reactivity with Claudin-1. Tumor cells were negative for SOX10, CD163, CD68, CD34, ALK, and Pan-TRK. The patient was diagnosed with BCPHTPCN. DNA and RNA sequencing showed a folliculin (FLCN) gene mutation, which is most commonly associated with Birt-Hogg-Dubé syndrome. The patient underwent excision and has remained without recurrence or complications several months post-diagnosis. We hope to expand the clinical and histopathologic characteristics of this peculiar neoplasm, as well as provide additional insight that might improve our understanding of BCPHTPCN tumorigenesis.
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    Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma
    (American Association for Cancer Research, 2023) Flint, Alyssa C.; Mitchell, Dana K.; Angus, Steven P.; Smith, Abbi E.; Bessler, Waylan; Jiang, Li; Mang, Henry; Li, Xiaohong; Lu, Qingbo; Rodriguez, Brooke; Sandusky, George E.; Masters, Andi R.; Zhang, Chi; Dang, Pengtao; Koenig, Jenna; Johnson, Gary L.; Shen, Weihua; Liu, Jiangang; Aggarwal, Amit; Donoho, Gregory P.; Willard, Melinda D.; Bhagwat, Shripad V.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
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    Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
    (American Association for Cancer Research, 2024) Mitchell, Dana K.; Burgess, Breanne; White, Emily E.; Smith, Abbi E.; Potchanant, Elizabeth A. Sierra; Mang, Henry; Hickey, Brooke E.; Lu, Qingbo; Qian, Shaomin; Bessler, Waylan; Li, Xiaohong; Jiang, Li; Brewster, Kylee; Temm, Constance; Horvai, Andrew; Albright, Eric A.; Fishel, Melissa L.; Pratilas, Christine A.; Angus, Steven P.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. Experimental design: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. Results: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. Conclusions: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.