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Immunohistochemical findings. A (Case 1, Immunoperoxidase): diffuse and strong positivity of tumor cells using anti-desmin antibody. B (Case 2, Immunoperoxidase): tumor cells express pancytokeratin AE1/AE3. C (Case 3, Immunoperoxidase): focal expression of EMA by the tumor cells. D. (Case 2, Immunoperoxidase): diffuse ALK protein positivity in tumor cells
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EWSR1/FUS-CREB-rearranged mesenchymal neoplasms are an emerging heterogeneous group of soft tissue tumors that encompasses low-grade lesions (angiomatoid fibrous histiocytoma/AFH) and a group of predominantly intra-abdominal aggressive sarcomas with epithelioid morphology and frequent keratin expression. Both entities occasionally harbor EWSR1::ATF...
Citations
... A new ING3-PHF1 fusion was recently identified in an ovarian ESS [42]. Case reports and small series have identified genomic changes in other entities, e.g., MXD4-NUTM1 fusion transcript in primary ovarian undifferentiated small round cell sarcoma [43], RANBP2-ALK fusion in an epithelioid inflammatory myofibroblastic sarcoma [44] and fusions involving CREB in epithelioid mesenchymal neoplasms [45]. ...
Gynecologic pathology has moved, within only a few years, from being a diagnostic area devoid of molecular testing into a diagnostic discipline in which such analyses are becoming routine. The direct relevance of molecular characterization to the choice of treatment of patients with carcinomas originating in both the uterus and adnexae makes it likely that such testing will only expand along with our understanding of the molecular make-up of these tumors. As a consequence, gynecologic pathologists have become an integral part of patient management, rather than lab personnel providing external services.
In parallel, molecular testing is expanding as a tool for diagnosing rare tumors affecting these organs, including soft tissue tumors, sex cord-stromal tumors and germ cell tumors, as well as other rare entities. Increased knowledge in this area bears directly on the ability to diagnose these tumors in a reproducible manner, as well as recognize and consult on genetic diseases. Hopefully, despite the inherent difficulty in studying rare cancers, it will also translate into new therapeutic options for the malignant ones among these rare cancers.
... In addition, FISH tests can detect gene rearrangements. The three most characteristic AFH translocations are: EWSR-CREB1 t(2;22)(q33;q12), EWSR1-ATF1 t(12;22)(q13;q12), and FUS-ATF1 t(12;16)(q13;p11) [5,15,11,[16][17][18]. The most common translocation is EWSR-CREB1 (90%) [19,20]. ...
Background:
Angiomatoid fibrous histiocytoma (AFH) is a rare, slow-growing soft tissue tumor. It appears mostly on the limbs and trunk in children and young adults. The biology of AFH remains unclear because of the small number of reported cases. Diagnostic testing does not provide definitive results. It has two clinical forms, that differ in terms of gene expression and clinical prognosis. It is important to inform the laboratory which specific gene testing is necessary. Here, we describe a case of rare AFH in the submandibular region using a full genetic panel.
Case summary:
A 13-year-old boy who had been misdiagnosed in the past 6 mo by his dentist visited our clinic because of a lesion in the submandibular area on the right side. The lesion was homogeneous and painless upon palpation. No skin discoloration was observed. Due to the non-specific radiological picture computed tomography (CT), magnetic resonance imaging (MRI), cone-beam CT (CBCT), and ultrasound-guided biopsy were performed. A venous malformation was suspected on the MRI. None of the tests provided a definitive diagnosis. Owing to the non-specific radiological findings, the patient qualified for surgical treatment. The surgical procedure included an excisional biopsy. The diagnostic testing was extended using gene rearrangements. The most distinctive gene translocation in diagnosing AFH is within the EWS RNA-binding protein 1 (EWSR1)-CREB-binding protein. However, in this case, the diagnosis was confirmed by a rearrangement within the EWSR1 gene testing.
Conclusion:
AFH in the submandibular location is rare, and surgical treatment with genetic evaluation defines AFH type that affects subsequent procedures.
The high mortality rate and postoperative recurrence of hepatocellular carcinoma (HCC) contribute to the burden on society and healthcare. The prognostic value and underlying mechanisms of cellular senescence and tumor microenvironment (TME) in HCC remain unclear. Bulk transcriptomic data were obtained from 368 HCC samples in The Cancer Genome Atlas‐liver hepatocellular carcinoma cohort and 64 samples from the GSE116174 dataset. Single‐cell RNA sequencing (scRNA‐seq) data of HCC were obtained from the GSE149614 dataset, including 18 tumor samples from 10 patients. Prognosis‐related cellular senescence genes and immune cells were identified through univariate analysis. Least absolute shrinkage and selection operator regression analysis was performed to construct the CellAge score and TME score, both of which were identified as independent prognostic factors for HCC based on multivariate Cox analysis. The combined CellAge and TME scores showed improved prognostic stratification for HCC patients, as confirmed by multivariate Cox analysis ( p < .001). The gene set enrichment analysis (GSEA) revealed enrichment of the extracellular matrix receptor interaction signaling pathway in the group with high CellAge scores and low TME scores, which exhibited a worse prognosis. Single‐cell sequencing results revealed higher expression activity of the cAMP response element modulator (CREM) extended transcription factor in HCC cells and most immune cells, indicating its involvement in TME remodeling. Finally, the tumor immune dysfunction and exclusion (TIDE) analysis demonstrated that the combined scores could predict the outcomes of immune therapy in patients with HCC. In conclusion, cellular senescence contributes to TME remodeling in HCC, and the developed CellAge and TME scores serve as independent prognostic factors and predictors of immune therapy in HCC.
Simple Summary
In the present review, we illustrate the interests of molecular pathology for establishing an integrated histomolecular diagnosis of ovarian sex cord–stromal tumors as well as its use for prognosis and treatment. We discuss the key morphological, immunohistochemical and molecular features of each entity, as well as their respective differential diagnoses. This review is organized from the predominant cell morphology to the molecular pathology, based on a practical point of view for the pathologist. Five groups are defined: (i) Group 1: predominance of fibromatous/thecomatous cells and/or stromal cells of unusual morphology; (ii) Group 2: predominance of steroid or luteinized cells; (iii) Group 3: predominance of follicular cells; (iv) Group 4: predominance of Sertoli cells; and (v) Group 5: predominance of sarcomatoid/unclassified/poorly differentiated cells. Diagnostic algorithms are proposed to differentiate each entity within the sex cord–stromal tumor category, and the contribution of molecular pathology for diagnostic purposes is discussed.
Abstract
Ovarian sex cord–stromal tumors (SCSTs) account for 8% of all primary ovarian neo-plasms. Accurate diagnosis is crucial since each subtype has a specific prognostic and treatment. Apart from fibrosarcomas, stromal tumors are benign while sex cord tumors may recur, sometimes with a significant time to relapse. Although the diagnosis based on morphology is straightforward, in some cases the distinction between stromal tumors and sex cord tumors may be tricky. Indeed, the immunophenotype is usually nonspecific between stromal tumors and sex cord tumors. Therefore, molecular pathology plays an important role in the diagnosis of such entities, with pathognomonic or recurrent alterations, such as FOXL2 variants in adult granulosa cell tumors. In addition, these neoplasms may be associated with genetic syndromes, such as Peutz–Jeghers syndrome for sex cord tumors with annular tubules, and DICER1 syndrome for Sertoli–Leydig cell tumors (SLCTs), for which the pathologist may be in the front line of syndromic suspicion. Molecular pathology of SCST is also relevant for patient prognosis and management. For instance, the DICER1 variant is associated with moderately to poorly differentiated SLCTS and a poorer prognosis. The present review summarizes the histomolecular criteria useful for the diagnosis of SCST, using recent molecular data from the literature.
