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Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations.

The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC. Acinic cell carcinoma (AciCC) is a rare salivary gland carcinoma that is poorly understood. Here the authors perform genomic, transcriptomic and epigenomic profiling of AciCC and find highly recurrent and specific rearrangements [t(4;9)(q13;q31)], which lead to enhancer hijacking that activates oncogenic transcription factor NR4A3.

Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known “hotspot” pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that “blastoma” is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term “thyroblastoma” might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15–61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient’s death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.

Salivary gland carcinomas (SGC) are rare tumours. The term SGC is not more than an umbrella for a variety of histogenetically, morphologically and biologically distinct entities. Accordingly, SGCs have not been sufficiently investigated to date. Their rarity makes it difficult to reach high patient numbers for individual entities in clinical studies, leading to pooling patients with different histological subtypes to attain sufficient participants. The different histological subtypes of SGC differ significantly in their clinicopathological features, such as their grading, their occurrence and their outcome. SGCs are usually stratified into low-grade, intermediate-grade or high-grade tumours. In most kinds of SGC, specific targetable molecular markers are lacking. The inclusion of immunotherapy (IT), however, might improve the outcome of patients suffering from high-grade SGCs. In order to integrate IT as a therapeutic option for SGC and to facilitate therapeutic decisions based on tumour (immune) biology, predictive and prognostic immunological biomarkers are indispensable. In this prospective study, 500 patients will be enrolled, who are distributed in three arms. The observational cohort includes patients with malignant salivary gland tumours, whereas patients with benign tumours of a salivary gland are grouped in the control group 1. In the control cohort, 2 patients do not have a salivary gland tumour but have a planned functional surgery of the nose or ear or a maxillofacial surgery. The local immune status from the tumour tissue and the microbiome will be sampled before treatment. In addition, the systemic immune status from peripheral blood will be analysed before and after surgery and after the adjuvant and definitive chemoradiotherapy, if applicable. Clinical baseline characteristics and outcome parameters will additionally be collected. Data mining and modelling approaches will finally be applied to identify interactions of local and systemic immune parameters and to define predictive and prognostic immune signatures based on the evaluated immune markers. Approval from the institutional review board of the Friedrich-Alexander-Universität Erlangen-Nürnberg was granted in September 2023 (application number 23-292-B). The results will be disseminated to the scientific audience and the general public via presentations at conferences and publication in peer-reviewed journals. NCT06047236.

Gastrointestinal graft-versus-host disease (GvHD) is a frequent and severe complication after allogeneic stem cell transplantation (aSCTx). Although biopsy and histopathology remain the gold standard for diagnosis of GvHD, this approach can be limited by thrombocytopenia accompanying aSCTx and the diagnostic delay associated with routine histopathology. Here, we report on two patients in which dye-based contact microscopy using a latest generation endocytoscope with 520-fold magnification enabled in vivo diagnosis of GvHD. The first patient was a 23-year-old man with acute lymphoblastic leukemia presenting with non-bloody diarrhea 3 months after aSCTx. After topical staining with crystal violet and methylene blue, endocytoscopy in the rectum showed several apoptotic epithelial cells. Histopathology confirmed GvHD grade III according to the Lerner classification. The second patient was a 59-year-old female with diarrhea 3 months after aSCTx. Apart from pathognomic apoptotic bodies, EC additionally revealed crypt lumina enlargement and mononuclear cell infiltrates in the lamina propria with subsequent crypt distension. The duration of the procedure was less than 5 min in each patient. These findings illustrate that in vivo microscopy using endocytoscopy can enable instantaneous diagnosis of GvHD with the benefit of accelerating therapeutic decisions in patients with suspected severe GvHD.

INTRODUCTION: Localized cystic lymphangiomas (CL) are rare benign tumors deriving from the lymphatic system. CL is diagnosed more frequently in children than in the adult population and, although commonly affecting the cervical and axillary regions, can develop in various parts of the body. Abdominal cystic lymphangioma (ACL) comprises less than 5% of all CL cases.CASE PRESENTATION: A 35-year-old female patient with a history of benign appendectomy in childhood was transferred to our tertiary center for the operative management of a suspected extensive pseudomyxoma peritonei (PMP). In accordance with the multidisciplinary team discussion, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy was planned. Intraoperatively, a typical “jelly belly” with high disease burden throughout the abdominal cavity and the small pelvis was found. A multi-visceral resection with complete cytoreduction (CCR 0) was performed. The postoperative histopathological findings revealed a diffuse, partially cystic lymphangiomatosis involving the peritoneum extensively without evidence of PMP or malignancy.CONCLUSIONS: ACLs are uncommon in the adult population, and diffuse peritoneal involvement is even rarer. Surgical management with complete resection is the preferred treatment option. Other benign cysts, as well as infectious diseases and malignancy, should be considered during the preoperative workup.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct subgroup of head and neck squamous cell carcinoma (HNSCC) characterized by better prognosis and increased radiosensitivity compared to HPV-negative OPSCC. However, current diagnostic and monitoring methods, including tissue biopsies and imaging, are insufficient for precise risk stratification and early detection of recurrence, leading to challenges in treatment de-escalation and surveillance strategies. Circulating tumor HPV DNA (ctHPV-DNA) has emerged as a promising minimally invasive biomarker that offers tumor-specific detection and monitoring capabilities, potentially transforming the management of HPV-related OPSCC through early disease detection, treatment response assessment, recurrence surveillance stratification, and disease monitoring. Despite encouraging results from early clinical studies, current use is limited to trial settings. Large-scale prospective studies are needed to validate its clinical utility and determine whether early ctHPV-DNA testing can improve patient outcome while reducing treatment related morbidity. This review outlines the biological rationale, technological approaches, and current clinical evidence for ctHPV-DNA in HPV-related OPSCC, emphasizing its potential role in treatment monitoring and surveillance.