Supplementary Figure 1. IQGAP1-scaffolding ERK signaling in the context of head and neck region. Supplementary Figure 2. Gender differences in disease severity and cancer incidence in Iqgap1+/+ and Iqgap1-/- mice treated with 100 μg/ml or 20 μg/ml 4NQO. Supplementary Figure 3. Site differences in disease severity and cancer incidence in Iqgap1+/+ and Iqgap1-/- mice treated with 100 μg/ml or 20 μg/ml 4NQO. Supplementary Figure 4. PI3K signaling in 4NQO-induced tongue cancer is not reduced in the absence of IQGAP1. Supplementary Figure 5. Example demonstration of using inForm Tissue Finder to analyze images for TMA samples. Supplementary Figure 6. Levels of IQGAP1 doesn't correlate with responses to mTORC inhibitor in Patient-Derived Xenografts (PDXs). Supplementary Figure 7. IQGAP3 protein levels increase with the loss of IQGAP1 in females, but not in male mice. Supplementary Table 1. List of Primary antibodies

BACKGROUND:Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that usually occurs in the adult population. Since its first description, only 9 cases have been reported in children. Due to its rarity, there is no standardized treatment. OBSERVATIONS:We present a case of multiply-relapsed FDCS in an adolescent patient that responded favorably to chemotherapy. CONCLUSION:For many, wide local excision of FDCS may be curative. However, more research is required to determine the best course of treatment for patients requiring adjuvant chemotherapy or radiation. In addition, expanding genetic research has the potential to provide targeted therapy in the future.

Bone and soft tissue sarcomas harboring EWSR1::NFATC2 and FUS::NFATC2 fusions (NFATC2-rearranged sarcomas) is a recently defined entity with a morphologic spectrum and clinical behavior that are not fully elucidated. We studied 32 such sarcomas that occurred in 21 male and 11 female patients. The EWSR1::NFATC2 fusion was found in tumors of 25 patients (17 M, 8 F; median age: 40, range: 14-78), 16 of which arose in soft tissue, while 8 originated in bone. Morphologically, they showed relatively consistent morphologic features yet variable degrees of cytologic atypia, mitotic rates and necrosis. Follow-up (19 patients; median: 22 months, range: 1-70) demonstrated local recurrence in 3 patients, while distant metastases occurred in 6 patients. Two patients died of disease (DOD), 4 were alive with disease (AWD) and 13 were without evidence of disease (AWOD). In contrast, the FUS::NFATC2 fusion was exclusively seen in osseous tumors, which occurred in 7 patients (4 M, 3 F; median age: 32, range: 4-62). Further, FUS::NFATC2 tumors showed significant morphologic heterogeneity. Follow-up (6 patients; median: 18 months, range: 13-60) demonstrated local recurrence in 2 patients, and lung metastases in 2 patients. At last follow-up, 3 patients were AWD, while 3 patients were AWOD. Using a two-tiered grading scheme based on cytologic atypia, mitotic rate, and necrosis, patients with low-grade tumors experienced significantly fewer adverse events than those classified as high-grade (p=0.026); however, estimated metastasis-free survival was not statistically significant due to our limited sample size. Overall, our study expands on the morphologic spectrum of NFATC2-rearranged sarcomas and highlights the clinicopathologic, molecular, and genetic differences between the EWSR1- and FUS-rearranged tumors. Although additional long-term follow-up data is required, our study further suggests that a subset of these sarcomas have a protracted clinical course while high-grade morphologic features such as atypia, mitotic activity and necrosis may correlate with worse behavior.

Squamous cell carcinoma (SCC) development in mammals is thought to require months or years from the time that initial changes occur. We show that SCCs induced by the mouse papillomavirus MmuPV1, which are generally diagnosed 4-6 months post infection, can be found as soon as 2 weeks post infection. SCCs developed within 2 weeks in immune-competent, adult FVB (FVB/NTac) mice at sites prone to human papillomavirus (HPV)-induced tumors and cancers in human patients: the base of the tongue, the anus, and the skin. The anterior tongue, less susceptible than the base of the tongue to HPV-induced cancer in humans, was resistant to rapid-onset cancer. The presence of invasive cancer in histological tissue sections was verified by multiple pathologists. These diagnoses were corroborated by the results of a classic test of malignancy: skin tumors obtained two weeks post infection grew ectopically as subcutaneous grafts in immune-deficient hosts. Preventative treatment with a novel BRD4 inhibitor dramatically reduced the frequency of ear skin SCCs present 2 weeks post infection and significantly reduced overall disease severity. Like many human papillomaviruses, MmuPV1 lacks an E5 gene. Expression of HPV16 E5 driven by the Keratin 14 promoter in FVB mice (FVB/NTac-Tg(KRT14-HPV16E5*)33Plam/Plam) significantly increased the frequency of rapid-onset invasive cancers caused by MmuPV1 at the base of the tongue and in the anus. In an E5-transgenic mouse with a persistent MmuPV1-induced ear skin lesion, we detected a lymph node metastasis at 38 weeks - further demonstrating a cancer phenotype. Cancers and less severe dysplasia induced by infection at the base of the tongue or the anus spontaneously regressed within 4 to 8 weeks of infection; however, ear lesions persisted. When CD4+ and CD8+ T cells were depleted, lesions at the base of the tongue and anus also persisted, indicating that spontaneous regression involves a T cell-mediated immune response. These results indicate that papillomavirus infection alone is sufficient to induce rapid onset of invasive cancer, and that persistence of disease depends on the tissue-specific immune microenvironment. Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert. Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7237.

Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only 5 cases of extraaxial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied 6 cases of EAPDC, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in 4 women and 2 men, ranging from 37 to 68 years of age (median, 57.5 years) and involved or originated in the left knee joint (3 cases), right knee joint (2 cases), and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial PDC, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1 deficient. Molecular genetic analysis identified SMARCB1 loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of EAPDC showed clustering with axial PDC. Clinical follow-up (6 patients; median, 11.5 months; range, 1-26 months) showed 4 patients to have received transfemoral amputation and 1 extraarticular resection. None received neoadjuvant radiotherapy; 1 received neoadjuvant chemotherapy and 1 adjuvant chemotherapy/ immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), 1 died of disease (20 months), and 3 were disease free (1-26 months). We conclude that EAPDC are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Benign peripheral nerve sheath tumors (PNSTs) represent a heterogeneous group of neoplasms with varying histologic and molecular characteristics. Although traditional classifications categorize these tumors based on predominant cell types, recent advances in molecular pathology have revealed the presence of hybrid tumors featuring elements from at least 2 nerve sheath tumors (hybrid peripheral nerve sheath tumor [hPNST]). We herein studied 20 cases of hPNST involving 15 female and 5 male patients (median age, 29.5 years; range, 3 weeks-71 years). Tumors occurred on the upper extremity (6), scalp (3), trunk (3), face (3), lower extremity (2), right lateral neck (1), nasal sinus (1), and retroperitoneum (1). Follow-up information was available in 9 of 20 cases (45%; median, 10 months; range, 2 weeks-144 months) and documented local recurrence in 2 of 9 patients (22%) at 10 and 144 months after incomplete excision. Next-generation sequencing demonstrated vestigial-like family member 3 (VGLL3) fusions in 14 cases, fused with CHD7 (10 tumors), CHD9 (3 tumors), and MAMLD1 (1 tumor), an alternative TEAD1::NCOA2 (1 tumor) fusion and several novel fusions including TOX::TEAD1 (2 tumors), RREB1::LPP (1 tumor), SRF::MYOCD (1 tumor), and KANK1::CDK5RAP2 (1 tumor). Most tumors with VGLL3 fusions showed morphologically and immunophenotypically classic features of hybrid schwannoma-perineurioma, whereas rare cases showed unusual microscopic features, such as prominent myxoid stroma, pseudolipoblasts, prominent Schwannian nodules, or solely schwannomatous morphology. The RREB1::LPP-driven tumor showed features of hybrid schwannoma-neurofibroma. Lastly, 1 tumor with a novel SRF::MYOCD fusion displayed morphologic features reminiscent of desmoplastic melanoma although exhibiting a combined neural and smooth muscle phenotype. Our data expand on the morphologic and molecular spectrum of fusion-driven hPNSTs, including 5 previously undescribed fusions, and further expand on noncentral nervous system schwannomas with VGLL3 fusions.

Summary: Standard of care treatment for metastatic cutaneous adnexal carcinomas is not well established. In this case report, we highlight the successful use of anti–programmed cell death protein 1 (anti-PD-1) therapy in treating a patient with low tumor mutation burden, microsatellite stable, high programmed death-ligand 1 (PD-L1) gene expression, metastatic primary cutaneous adnexal carcinoma with significant radiographic, and circulating tumor DNA response with durable benefit. Immune checkpoint inhibitors hold promise as a future treatment option in rare instances of metastatic disease from primary skin adnexal carcinoma. Further studies are needed to identify better immune checkpoint inhibitor predictive biomarkers for rare, advanced-stage non-melanoma skin cancers.

Epidermodysplasia verruciformis (EV) is a rare genetic skin disorder that is characterized by the development of papillomavirus-induced skin lesions that can progress to squamous cell carcinoma (SCC). Certain high-risk, cutaneous β-genus human papillomaviruses (β-HPVs), in particular HPV5 and HPV8, are associated with inducing EV in individuals who have a homozygous mutation in one of three genes tied to this disease: EVER1, EVER2, or CIB1. EVER1 and EVER2 are also known as TMC6 and TMC8, respectively. Little is known about the biochemical activities of EVER gene products or their roles in facilitating EV in conjunction with β-HPV infection. To investigate the potential effect of EVER genes on papillomavirus infection, we pursued in vivo infection studies by infecting Ever2-null mice with mouse papillomavirus (MmuPV1). MmuPV1 shares characteristics with β-HPVs including similar genome organization, shared molecular activities of their early, E6 and E7, oncoproteins, the lack of a viral E5 gene, and the capacity to cause skin lesions that can progress to SCC. MmuPV1 infections were conducted both in the presence and absence of UVB irradiation, which is known to increase the risk of MmuPV1-induced pathogenesis. Infection with MmuPV1 induced skin lesions in both wild-type and Ever2-null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between Ever2-null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in Ever2-null mice compared with wild-type mice. These studies demonstrate that Ever2-null mice infected with MmuPV1 do not exhibit the same phenotype as human EV patients infected with β-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent β-genus human papillomavirus (β-HPV) skin infections, which can progress to skin cancer. To investigate how EVER2 confers protection from papillomaviruses, we infected the skin of homozygous Ever2-null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected Ever2-null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these Ever2-null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in Ever2-null mice, indicating that mouse EVER2 does not confer protection from papillomaviruses. These findings suggest that there are functional differences between MmuPV1 and β-HPVs and/or between mouse and human EVER2.

Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression. Summary Graphic:

Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a peculiar variant of fibrosarcoma in 1995. Subsequent studies showed that conventional SEF was associated with both immunohistochemical expression of MUC4 and EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibrous tumors characterized by YAP1::KMT2A and KMT2A::YAP1 gene rearrangements and SEF-like morphology has been described. These YAP1::KMT2A-rearranged sarcomas were further shown to lack both immunohistochemical expression of MUC4 and canonical EWSR1/FUS gene rearrangements. To better understand whether the YAP1::KMT2A-rearranged sarcomas represent a subset of MUC4-negative SEF or a distinct entity, we studied 22 cases of YAP1::KMT2A-rearranged sarcomas, the largest series to date, and performed a literature review of all previously reported next-generation sequencing (NGS)-confirmed cases. These sarcomas often arose in young adults with a median age of 38 years and a male to female (M:F) ratio of 1.4:1. They predominantly involved somatic soft tissue; however, we report the first case of a tumor that primarily developed inside bone. Immunohistochemical studies showed that the tumors often demonstrated expression of YAP1 and EMA, while all tested cases were negative for MUC4. NGS confirmed the presence of YAP1::KMT2A gene fusions in all cases, some of which initially had false negative results with targeted FISH and solid tumor panel testing. Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrence occurred in three patients (21%) and metastasis developed in seven patients (50%). DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.

Xanthogranulomatous 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.