Sarcomas Harboring EWSR1::PATZ1 Fusions: A Clinicopathologic Study of 17 Cases.

Soft tissue sarcomas harboring EWSR1::PATZ1 are a recently recognized entity with variable morphology and a heterogeneous immunohistochemical profile. We studied 17 such tumors. The tumors occurred in 12 men and 5 women (median age, 50 years; range, 15-71 years), involved the thoracoabdominal soft tissues (14 cases; 82%), lower extremities (2 cases; 12%), and tongue (1 case; 6%), and ranged from 0.7 to 11.3 cm (median, 4.7 cm). All but 1 patient received complete surgical resection; 7 were also treated with neoadjuvant chemo/radiotherapy. All cases showed typical features of EWSR1::PATZ1 sarcoma, including uniform round to spindled cells, fibromyxoid matrix, fibrous bands, hyalinized vessels, and pseudoalveolar/microcystic spaces. Unusual features, seen in a subset of cases, included degenerative-appearing nuclear atypia, epithelioid cytomorphology, mature fat, abundant rhabdomyoblasts, high mitotic activity, and foci with increased cellularity and nuclear atypia. Positive immunohistochemical results were desmin (16/17, 94%), MyoD1 (13/14, 93%), myogenin (6/14, 43%), GFAP (10/10, 100%), S100 protein (15/17, 88%), SOX10 (7/13, 54%), keratin (10/17, 59%), CD99 (4/11, 36%), H3K27me3 (retained expression 9/9, 100%), p16 (absent expression 1/4, 25%), and p53 (wild type 3/3, 100%). Fusion events included EWSR1 exon 8::PATZ1 exon 1 (14/17, 82%), EWSR1 exon 9::PATZ1 exon 1 (2/17, 12%), and EWSR1 exon 7::PATZ1 exon 1 (1/17, 6%). No evaluated tumor had alterations of CDKN2A/B and/or TP53, or MDM2 amplification. Clinical follow-up (16 patients: median, 13.5 months; range, 1-77 months) showed distant metastases in 3 patients (1/3 at time of presentation) and no local recurrences. At the time of last follow-up, 14 patients were disease free, 1 was alive with disease, 1 was dead of disease (at 13 months), and 1 had an indeterminant pulmonary nodule. We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.

B7-H3 is widely expressed in soft tissue sarcomas.

PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS. PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature. RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1. CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Inflammatory leiomyosarcoma/rhabdomyoblastic tumor: A report of two cases with novel genetic findings.

Inflammatory leiomyosarcoma (ILMS) is a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization. These tumors have significant pathologic and genetic overlap with the recently described "inflammatory rhabdomyoblastic tumor (IRT)," suggesting that ILMS and IRT may belong to one entity. Herein, we describe two cases of ILMS/IRT with attention to new cytogenetic and sequencing findings. The tumors were composed of sheets and fascicles of variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology and a prominent histiocyte-rich inflammatory infiltrate typical of ILMS/IRT. In case 1, chromosomal microarray analysis showed a near-haploid pattern with loss of heterozygosity resulting from loss of one copy of all autosomes except for chromosomes 5, 20, 21, and 22. Case 2 showed areas with high-grade rhabdomyosarcomatous transformation. In this case, the low-grade tumor component revealed a hyper-diploid pattern with loss of heterozygosity for most of autosomes but with a normal diploid copy number state except for chromosomes 5, 20, and 22, which showed a relative gain. The high-grade tumor component showed a similar pattern of copy-neutral loss of heterozygosity with additional abnormalities, including mosaic segmental gains at 1p, 5p, 8q, 9p, 20q, and segmental loss at 8p. Next-generation sequencing identified sequence variants in NF1, TP53, SMARCA4, KRAS, and MSH6. MSH6 variant was confirmed as germline, consistent with the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in one of our study patients and suggestive that ILMS/IRT might be part of the HNPCC cancer spectrum.

Low-grade undifferentiated sarcoma with MEIS1::NCOA2-rearrangement primary to the lung: a case report.

BACKGROUND: MEIS1::NCOA2 is a rare fusion gene that has been recently described in a subset of spindle cell rhabdomyosarcomas and multiple low-grade undifferentiated spindle cell sarcomas predominantly arising in the genitourinary and gynecologic tracts with no specific line of differentiation. We present the first documented case of this neoplasm arising as a lung primary tumor. CASE PRESENTATION: A 74-year-old woman with a 40-year smoking history presented with a 2.1 × 1.7 cm lung nodule discovered on computed tomography (CT) scan. A biopsy and subsequent lobe resection were performed, as well as an extensive metastatic work up, which revealed no additional masses. No specific line of differentiation was found by immunohistochemical staining, and an RNA-based fusion panel revealed a MEIS1::NCOA2 fusion, at which point a diagnosis of Low-Grade Undifferentiated Sarcoma with MEIS1::NCOA2-Rearrangement was rendered. CONCLUSIONS: This report represents the first diagnosis of this tumor primary to the lung, and provides additional insight into the origin and localization of these rare tumors.

Transoral Excision of a Hypopharyngeal Liposarcoma.

Liposarcomas are the most common soft tissue sarcoma in adults, whereas liposarcomas of the head and neck, particularly the hypopharynx, are incredibly rare - with approximately 50 cases reported in the literature. We present a case of an otherwise healthy and asymptomatic 42-year-old male who presented dramatically after vomiting up a large soft tissue mass. The lesion was surgically removed via transoral approach with blue laser, and diagnosis of well-differentiated liposarcoma was made via MDM2 gene amplification by FISH. Oral extrusion is a rare feature of this disease. This is the first documented case of an orally extruded liposarcoma to present in an otherwise asymptomatic and healthy patient, demonstrating how this entity may be indolent until initial presentation. Laryngoscope, 134:4688-4690, 2024.

Management of a Rare Mitral Valve Sarcoma Requiring Valve Replacement and Chemotherapy.

A woman with dyspnea is diagnosed with a rare mitral valve primary sarcoma. Patient underwent mechanical mitral valve replacement requiring therapeutic anticoagulation with adjuvant systemic anthracycline-based chemotherapy. The challenges of preventing thromboembolism in a new mechanical prosthesis with risk of bleeding due to cancer and/or its therapies are described.

What's new in bone and soft tissue pathology 2023: guidelines for molecular testing.

Our understanding of bone and soft tissue tumors has thoroughly evolved as a consequence of modern molecular techniques. DNA and RNA sequencing methods play an important diagnostic and therapeutic role in sarcoma pathology. Herein, we discuss current guidelines and best practices for molecular testing in bone and soft tissue tumors.

Solitary Fibrous Tumors of the Head and Neck: A Single-Institution Study of 52 Patients.

Objective: To evaluate the clinicopathologic characteristics of head and neck solitary fibrous tumors and features that may predict tumor recurrence. Study Design: Retrospective review. Setting: University of California-Los Angeles Medical Center. Methods: A single-center retrospective study was conducted on pathologically confirmed cases of head and neck solitary fibrous tumors between 1996 and 2021. Patient demographics, clinical course, and histopathologic features were evaluated. Recurrence-free survival was estimated via Kaplan-Meier analysis. Results: A total of 52 patients were reviewed. The average patient age was 54.7 years (range, 15-89). The most common subsite was the orbit (53.8%, n = 28), but other involved areas included the nasopharynx, paranasal sinuses, and scalp. The median tumor size was 2.95 cm (range, 1.3-11.2). Strong STAT6 (100%) and CD34 (97.9%) expression was observed on immunohistochemistry. Almost all patients were initially managed with wide local excision; 82% of patients (n = 14) had positive margins on pathologic review; and 15% (n = 4) had recurrence at a median 28.5 months (range, 10-113). White patient race was the only significant predictor of tumor recurrence. Patient age (≥55 years), tumor size (≥4), high mitotic rate, and disease subsite were not associated with recurrence. Conclusion: Head and neck solitary fibrous tumors demonstrate a significantly larger local recurrence rate as compared with their rate of metastasis. They can recur many years following initial therapy, warranting long-term surveillance and follow-up to assess for tumor recurrence.

Immunologic Gene Signature Analysis Correlates Myeloid Cells and M2 Macrophages with Time to Trabectedin Failure in Sarcoma Patients.

Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = -0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions.

Oropharyngeal carcinoma: A single institution study of 338 primaries with special reference to high-risk human papillomavirus-mediated carcinoma with aggressive behavior.

In a retrospective review, we identified 332 patients with 338 pathologically diagnosed primary oropharyngeal carcinomas (OPC) between January 2013 and March 2020 with known p16/HPV status from a tumor registry at Northwestern Memorial Hospital. The tumors predominantly involved the palatine tonsil (51 %) and the base of the tongue/lingual tonsil (38 %). The most common type of cancer was non-keratinizing squamous cell carcinoma (60 %), and the majority of primaries were p16 positive/HPV-mediated (86 %). A cohort of p16 positive/HPV mediated OPC (27/283, 9.5 %) presented with aggressive clinical behavior, including multiple distant metastases at unusual sites. Tumor size >2 cm and the presence of tumor anaplasia/multinucleation were significantly associated with an increased rate of distant metastases in p16 positive/HPV mediated cases, both in unadjusted and adjusted analyses (all P < 0.05). Of the 332 individuals in the overall cohort, 38 individuals died due to their disease within the observed follow-up time. Among the 283 patients with p16 positive/HPV mediated tumors, survival was estimated at 97 % (95 % CI 95 %, 100 %) at 1 year, 95 % (95 % CI 92 %, 98 %) at 2 years, and 80 % (95 % CI 72 %, 89 %) at 5 years. The presence of tumor anaplasia/multinucleation and distant metastasis were both significantly associated with poorer disease-specific survival in p16 positive/HPV mediated cases (both P < 0.05), with the survival effect of tumor anaplasia/multinucleation likely mediated in part through its association with distant metastasis. For p16 positive/HPV-mediated OPC, age, smoking status, tumor status, and lymph node status were not significantly associated with disease-specific survival in our study.

Spinocerebellar Ataxia Type 3: A Case Report and Literature Review.

Spinocerebellar ataxia type 3 (SCA3), also known by the eponym Machado-Joseph disease, is an autosomal dominant CAG trinucleotide (polyglutamine) repeat disease that presents in young- to middle-aged adults. SCA3 was first described in Azorean individuals and has interesting epidemiological patterns. It is characterized clinically by progressive ataxia and neuropathologically by progressive degenerative changes in the spinal cord and cerebellum, along with degeneration of the cortex and basal ganglia. Here, we describe the clinical and neuropathologic features in a case of SCA3 with unique findings, including involvement of the inferior olivary nucleus and cerebellar Purkinje cell layer, which are classically spared in the disease. We also discuss research into the disease mechanisms of SCA3 and the potential for therapeutic intervention.

Sinonasal glomangiopericytoma: A clinicopathologic study.

Sinonasal glomangiopericytoma (SNGP) is a neoplasm arising in the nasal cavity and paranasal sinuses that shows perivascular myoid differentiation. The diagnosis of SNGP may be diagnostically challenging due to a large number of potential mimics. In the present study, we sought to characterize the histological and molecular features of six cases of SNGP found in prior surgical pathology records over a 15-year period. The average age at diagnosis was 48.5 years (range: 31-78 years), and the male-to-female ratio was 1:1. Imaging studies in all six cases demonstrated avidly enhancing, lobulated soft tissue masses in the nasal cavity, extending into the sinuses and nasopharynx. Histologically, the tumors were unencapsulated and composed of a proliferation of closely packed, bland, and uniform spindle cells growing deep to an intact surface respiratory epithelium. The cells were separated by a distinctive vascular network ranging from capillaries to large vascular spaces. All cases demonstrated strong positivity for smooth muscle actin, cyclin D1, CD99, and ß-catenin (100%). Targeted sequencing revealed recurrent CTNNB1 missense mutations in all cases tested. Additionally, TLE1 was positive in all cases which has not been previously reported. No tested cases harbored SS18 translocations. We found that while no single marker resolves immunohistochemical overlap between SNGP and its histologic mimics, an extended immunohistochemical panel that includes ß-catenin, cyclin D1, STAT6, smooth muscle actin, pan-cytokeratin cocktails, S100, and SOX10 helps to support the diagnosis of SNGP in diagnostically challenging cases without the need for molecular studies.

Ewing sarcoma with myxoid stroma: Case report of an unusual histological variant.

We describe the case of a Ewing sarcoma with prominent myxoid stroma of the temporal bone in a 26-year-old female. Histologically, the tumor exhibited a fascicular growth pattern of round to spindled cells with a minimal amount of pale eosinophilic to clear cytoplasm and oval or spindled nuclei with finely dispersed chromatin and small nucleoli. Myxoid changes were prominent (>50%), with reticular or pseudoacinar growth of the loosely cohesive cells. The tumor showed strong expression of CD99, FLI1, and CD56 and was positive for the EWSR1-FLI1 fusion transcript. The diagnosis of Ewing sarcoma with myxoid stroma (myxoid variant) is particularly problematic owing to the large number of potential mimics. The tumor extends the morphologic spectrum of Ewing sarcoma beyond the previously described histological variants, and broadens the differential diagnosis. For any round/spindle cell sarcoma, prominent myxoid stroma and CD99 immunoreactivity should prompt consideration for molecular studies that include analysis of both EWSR1 and FLI1.

Ectopic hamartomatous thymoma in an immunocompromised male.

Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm classically occurring in the lower neck of adult males. Here we present a case of EHT occurring in a 43-year-old immunocompromised male and a brief review of existing literature. The patient presented with a palpable mass overlying the left clavicle which, on imaging, showed a solitary nodule possibly eroding the cortical bone. A biopsy predominantly showed spindle cells that were immunopositive for keratin AE1/AE3 as well as weakly positive for CD99, SMA, and CD34. A diagnosis of synovial sarcoma was favored; at which point surgical resection was performed. The resected mass was well-demarcated with a tan-yellow cut surface. Microscopically, the lesion was composed of a mixture of spindle cells, glands, and mature adipose tissue. The spindle cells were plump with bland nuclei, and the epithelial component showed morphology similar to glands of salivary or breast tissue with a bilayered appearance (luminal and basal). No pleomorphism, mitotic figures, or necrosis was present. Immunohistochemical stains were performed and showed the spindle cells to express a myoepithelial phenotype (cytokeratin AE1/AE3, p63, calponin positive). The glands showed SMA and p63 positivity in the basal cells (similar to salivary gland and breast). Overall, given the clinical context, histomorphologic, and immunohistochemical profile, a diagnosis of EHT was made. At 12 months of follow-up there was no evidence of recurrence.

Coordinate mapping of hyolaryngeal mechanics in swallowing.

Characterizing hyolaryngeal movement is important to dysphagia research. Prior methods require multiple measurements to obtain one kinematic measurement whereas coordinate mapping of hyolaryngeal mechanics using Modified Barium Swallow (MBS) uses one set of coordinates to calculate multiple variables of interest. For demonstration purposes, ten kinematic measurements were generated from one set of coordinates to determine differences in swallowing two different bolus types. Calculations of hyoid excursion against the vertebrae and mandible are correlated to determine the importance of axes of reference. To demonstrate coordinate mapping methodology, 40 MBS studies were randomly selected from a dataset of healthy normal subjects with no known swallowing impairment. A 5 ml thin-liquid bolus and a 5 ml pudding swallows were measured from each subject. Nine coordinates, mapping the cranial base, mandible, vertebrae and elements of the hyolaryngeal complex, were recorded at the frames of minimum and maximum hyolaryngeal excursion. Coordinates were mathematically converted into ten variables of hyolaryngeal mechanics. Inter-rater reliability was evaluated by Intraclass correlation coefficients (ICC). Two-tailed t-tests were used to evaluate differences in kinematics by bolus viscosity. Hyoid excursion measurements against different axes of reference were correlated. Inter-rater reliability among six raters for the 18 coordinates ranged from ICC = 0.90 - 0.97. A slate of ten kinematic measurements was compared by subject between the six raters. One outlier was rejected, and the mean of the remaining reliability scores was ICC = 0.91, 0.84 - 0.96, 95% CI. Two-tailed t-tests with Bonferroni corrections comparing ten kinematic variables (5 ml thin-liquid vs. 5 ml pudding swallows) showed statistically significant differences in hyoid excursion, superior laryngeal movement, and pharyngeal shortening (p < 0.005). Pearson correlations of hyoid excursion measurements from two different axes of reference were: r = 0.62, r2 = 0.38, (thin-liquid); r = 0.52, r2 = 0.27, (pudding). Obtaining landmark coordinates is a reliable method to generate multiple kinematic variables from video fluoroscopic images useful in dysphagia research.