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Sclerosing epithelioid fibrosarcoma (SEF) occurring as a primary bone tumor is exceptionally uncommon. Even more rare are cases of SEF that show morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Such hybrid lesions arising within the bone have only rarely been reported in the literature. Due to their variegated histomorphology and non-specific radiologic features, these tumors may pose diagnostic difficulties. Herein we describe three molecularly confirmed primary bone cases of sclerosing epithelioid fibrosarcoma that demonstrated prominent areas showing the features of LGFMS and with areas resembling so-called hyalinizing spindle cell tumor with giant rosettes (HSCTGR). Two patients were female and one was male aged 26, 47, and 16, respectively. The tumors occurred in the femoral head, clavicle, and temporal bone. Imaging studies demonstrated relatively well-circumscribed radiolucent bone lesions with enhancement on MRI. Cortical breakthrough and soft tissue extension were present in one case. Histologically the tumors all demonstrated hyalinized areas with SEF-like morphology as well as spindled and myxoid areas with LGFMS-like morphology. Two cases demonstrated focal areas with rosette-like architecture as seen in HSCTGR. The tumors were all positive for MUC4 by immunohistochemistry and cytogenetics, fluorescence in-situ hybridization, and next-generation sequencing studies identified EWSR1 gene rearrangements confirming the diagnosis in all three cases.Hybrid SEF is exceedingly rare as a primary bone tumor and can be difficult to distinguish from other low-grade spindled and epithelioid lesions of bone. MUC4 positivity and identification of underlying EWSR1 gene rearrangements help support this diagnosis and exclude other tumor types.

AimsTo investigate immunohistochemical expression of the E26 transformation-specific factors (ETS)-related gene (ERG) in a large number of soft tissue neoplasms using a tissue microarray technique.Methods489 cases of soft tissue neoplasms, including benign and malignant entities, were collected from the files of the respective institutions and constructed into tissue microarrays. Tissue microarrays were stained for ERG immunohistochemistry using two antibodies, EP111 and EPR3864.ResultsA total of 25 cases (5.1%) were identified that were positive for ERG using the monoclonal antibody EP111 and 15 cases (3%) using the monoclonal antibody EPR3864, including rhabdomyosarcoma, peripheral nerve sheath tumours, synovial sarcoma, myxofibrosarcoma, epithelioid sarcoma, dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, nodular fasciitis and dedifferentiated liposarcoma. The most consistently stained tumours included synovial sarcoma, rhabdomyosarcoma and benign and malignant peripheral nerve sheath tumours. Various other fibroblastic proliferations, including dermatofibrosarcoma protuberans, myxofibrosarcoma, low-grade fibromyxoid sarcoma and nodular fasciitis, also showed positive staining in a small fraction of cases. One case of dedifferentiated liposarcoma showed nuclear positivity for ERG, and one case of epithelioid sarcoma was also positive.ConclusionsThis study supports the value of ERG as a highly sensitive and specific marker for the diagnosis of vascular neoplasms but also demonstrates rare cases of aberrant staining and underscores the need to assess soft tissue tumours using a panel of stains and interpret the results of immunohistochemistry in the appropriate histological and clinical context.

Insulinoma-associated protein-1 (INSM1) is a recently developed immunohistochemical marker claimed to be highly specific and sensitive for the diagnosis of neuroendocrine malignancies. Recent studies, however, have demonstrated that this marker can also be expressed in non-neuroendocrine neoplasms including squamous cell carcinoma of the thymus. To examine INSM1 expression in lymphoepithelial thymic carcinomas. Thirty-four cases of lymphoepithelial carcinoma of the thymus were examined by immunohistochemistry or in situ hybridization for INSM1, synaptophysin, chromogranin, CD5, CD117, Epstein-Barr virus-encoded small ribonucleic acid (EBER), and Ki-67. Basic clinical information was abstracted from the medical record. The patients were 14 women and 20 men, aged 20 to 85 years. The tumors arose in the anterior mediastinum without any previous history or evidence of malignancy at other sites. Immunohistochemical staining showed moderate to strong positivity of the tumor cells for INSM1 in 65% of cases (22 of 34), focal weak positivity in 20% (7 of 34), and negative staining in 5 cases. Chromogranin staining was focally and weakly positive in 1 case, and synaptophysin showed only focal weak positivity in scattered tumor cells in 12 cases. No significant correlation could be identified between the pattern and intensity of staining for INSM1 and staining for CD5, CD117, and Ki-67. INSM1 positivity in lymphoepithelial carcinoma of the thymus may represent a pitfall for diagnosis, particularly in small biopsy samples. Awareness of this finding may be of importance to avoid misdiagnosis of neuroendocrine malignancy.

Thymomas are rare tumors characterized by a broad range of morphologic appearances that can sometimes give rise to difficulties for classification. We have studied a series of 120 thymoma patients in whom the tumors were characterized by sheets of atypical epithelial cells with squamoid and/or spindle cell features. They occurred in 63 men and 57 women and presented as a discrete mass in the anterior mediastinum measuring 2–23 cm (mean: 8.2 cm). Patients' ages ranged from 14 to 86 years (mean: 57.8) and most had symptoms referable to a mass lesion. 20 patients had myasthenia gravis or other autoimmune disorder. 76 cases were characterized by a predominant population of round to polygonal tumor cells while 32 cases were characterized by atypical oval or spindle cells. 12 cases showed mixed features and 16 cases showed the development of thymic carcinoma arising from thymoma. All cases were positive for p40/p63 and cytokeratin AE1/AE3. 23 cases were positive for CD5 (25%), and 13 for CD117 (14%). MIB1 showed a significant increase in proliferative activity (mean = 11.6%). Next generation sequencing in 47 cases did not disclose any variants amenable to current targeted therapies. Clinical follow up ranging from 2 to 29 years showed a progressive increase in aggressive behavior and fatality rate with advancing stage. Overall survival was 87% at 5 years, 67% at 10 years, and 23% at 20 years. Completeness of resection and staging were the most significant parameters for survival. The more aggressive tumors followed a protracted clinical course with multiple recurrences and metastases over a long period of time (mean = 19.8 years from time of initial relapse to death). Atypical thymomas are a distinct category of thymic epithelial neoplasm characterized by a slowly progressive clinical course with increased potential for metastases, transformation to a higher-grade malignancy, and fatal outcome in some cases.

Non-small cell lung carcinoma with predominantly clear cell features is a rare histologic presentation of lung carcinoma. We have examined 31 cases of lung carcinomas showing extensive clear cell features. The patients were 10 women and 21 men aged 47–92 years (mean: 70 years). The tumors showed a predilection for the right upper and lower lobes and measured from 0.8 to 9.5 cm (mean: 4.2 cm). By immunohistochemistry, 9 cases were typed as adenocarcinoma, 19 cases as squamous cell carcinoma, and 3 showed a “null” phenotype with complete loss of markers for adenocarcinoma or squamous cell carcinoma. Most cases that typed as adenocarcinoma showed a solid growth pattern. A subset of the solid adenocarcinoma cases showed a distinctive “pseudosquamous” morphology. Next-generation sequencing was performed in 20 cases and showed a variety of molecular alterations. The most common abnormalities were found in the TP53 gene (9 cases), FGFR gene family (8 cases), KRAS (5 cases), AKT1 (5 cases), and BRAF (3 cases). Clinical follow-up was available in 21 patients; 16/21 patients died of their tumors from 6 months to 12 years after initial diagnosis (mean: 4.2 years, median: 1.5 years). Four patients were alive and well from 4 to 27 years (mean: 11.5 years, median: 7.5 years); all were pathologic stage 1 or 2. NSCLC with clear cell features can display aggressive behavior and needs to be distinguished from various other tumors of the lung that can show clear cell morphology. The identification of targetable molecular alterations in some of these tumors may be of value for therapeutic management.

Precision and personalized therapeutics have witnessed significant advancements in technology, revolutionizing the capabilities of laboratories to generate vast amounts of genetic data. Coupled with computational resources for analysis and interpretation, and integrated with various other types of data, including genomic data, electronic medical health (EMH) data, and clinical knowledge, these advancements support optimized health decisions. Among these technologies, next-generation sequencing (NGS) stands out as a transformative tool in the field of cancer treatment, playing a crucial role in precision oncology. NGS-based workflows are employed across a range of applications, including gene panels, exome sequencing, and whole-genome sequencing, supporting comprehensive analysis of the entire cancer genome, including mutations, copy number variations, gene expression profiles, and epigenetic modifications. By utilizing the power of NGS, these workflows contribute to enhancing our understanding of disease mechanisms, diagnosis confirmation, identifying therapeutic targets, and guiding personalized treatment decisions. This manuscript explores the diverse applications of NGS in cancer treatment, highlighting its significance in guiding diagnosis and treatment decisions, identifying therapeutic targets, monitoring disease progression, and improving patient outcomes.

Gastrointestinal manifestations of Kaposi sarcoma are rare but may cause morbidity. Lower gastrointestinal involvement is particularly rare, and lesions may resemble conventional bowel polyps. To study 15 patients who presented with lower gastrointestinal tract Kaposi sarcoma with polypoid architecture. The surgical pathology files of the departments of pathology at multiple institutions were searched for cases of Kaposi sarcoma forming polyps in the lower gastrointestinal tract (jejunum, colon, rectum); 15 cases with such features were identified. Clinicopathologic information was extracted from the medical record and documented by reviewing individual hematoxylin-eosin-stained slides. The patients were 13 men and 2 women aged 26-80 years (median = 44 years). Gastrointestinal tract involvement was multifocal in 11 cases and unifocal in 4. The tumors involved the rectum, rectosigmoid junction, cecum, ascending colon, transverse colon, and descending colon and presented as polypoid lesions measuring 0.2-2.1 cm. Six patients had upper gastrointestinal tract involvement in addition to lower gastrointestinal lesions. Histologically, the tumors were characterized in 6 cases by a dense spindle cell proliferation in the lamina propria; however, the remaining cases showed only a subtle fascicular spindle cell proliferation in the lamina propria that did not form an expansile mass. Biopsies of gastrointestinal polyps showing absence of the common features of hyperplastic or adenomatous polyps, particularly in immunocompromised patients, should be carefully examined for the presence of a stromal spindle cell proliferation. Use of immunohistochemical stains, particularly human herpesvirus-8, can help in establishing the correct diagnosis.

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.

Nodular fasciitis is a rare but benign fibroblastic proliferation that typically presents as a solitary lesion with rapid growth and variable mitotic activity. The lesions usually occur on the extremities and occasionally in the head/neck region. Involvement of the buccal mucosa is extremely rare with only few reports in the literature; in this case report, we describe a 41 year old female who presented with a 6-month history of a stable intraoral lump at the junction of the upper and lower lip. Fine needle aspiration revealed an atypical spindle cell population with plump cells. The surgical excision demonstrated a well circumscribed tan-white firm nodule. Histologic examination revealed a spindle cell proliferation that grew in short, intersecting fascicles with focal storiform architecture. The lesion had a pushing border that was not overtly infiltrative and the stroma contained focal myxoid changes giving a “tissue culture” appearance to the cells. Immunohistochemical testing showed the tumor cells were vimentin (+), SMA (+), weakly Calponin (+), and desmin (-), cytokeratin (-), AE1/AE3 (-), S100 (-), ALK (-), STAT6 (-), and beta-catenin (-). Fluorescence in-situ hybridization (FISH) revealed a USP6 gene rearrangement with an atypical probe pattern. Next generation sequencing identified a novel SPTAN1::USP6 fusion gene confirming the diagnosis of buccal nodular fasciitis. Identification of the characteristic histologic features and USP6 gene rearrangements helped support the diagnosis. A review of the literature identified 25 cases of nodular fasciitis involving the buccal mucosa. The occurrence of this tumor in an unusual location may pose difficulties for diagnosis.

Conventional well-differentiated, dedifferentiated, and myxoid liposarcomas have long been known to harbor numerous typical genetic alterations that allow for diagnosis of these tumors. These include MDM2 and CDK4 amplification in well-differentiated and dedifferentiated liposarcomas as well as FUS-DDIT3 rearrangements in myxoid liposarcoma. More recently, in-frame TRIO-TERT fusion genes have been described in a subset of non-translocation-related sarcomas including myxofibrosarcoma, dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, pleomorphic rhabdomyosarcoma, and leiomyosarcoma. These genetic rearrangements lead to TERT mRNA expression levels hundreds of times higher than normal, causing increased telomerase activation in these tumors. Herein, we describe an unusual case of a liposarcoma with spindle cell features and a TRIO-TERT fusion transcript identified through next-generation sequencing.