Immunodetection of NUT Protein: Implementation, Indications, and Results in a Tertiary Reference Center.

The immunodetection of NUT protein is a reliable tool to identify NUT carcinoma, a rare and still underdiagnosed tumor entity. The technique was implemented in 2017 in our department, a tertiary reference center with a large recruitment in all tumor types, including head and neck and thoracic tumors. We evaluated its use over a 6-year period (2017-2022) to (a) describe the indications for the technique, (b) determine the number of NUT carcinomas detected and confirmed by Fluorescence in situ hybridization, and (c) describe briefly the characteristics of these tumors. Over the study period, 382 NUT immunodetections were performed; the annual number of requests varied from 45 to 83. All 21 pathologists of the department made at least one request (range: 1 to 94; annual mean: 18.2). 54.7% of immunodetections were performed for internal cases, 37% for cases submitted for consultation, and 8.3% for cases submitted for confirmation of a suspected diagnosis. The main indications were poorly differentiated tumors of the head and neck region (39%) and the thorax (19.6%), and difficult-to-classify soft tissue tumors (11.8%). Twelve cases of NUT carcinoma were detected by immunohistochemistry and confirmed by Fluorescence in situ hybridization. Seven were from the head and neck region (4.7% of the tumors tested), 4 from lung or mediastinum (5.3%), 1 from an unknown primary at the time of diagnosis. In conclusion, the implementation of NUT immunodetection in the daily workflow of a pathology department improves the detection of NUT carcinoma. This becomes essential with the emergence of potential targeted therapies.

Epithelial-Myoepithelial Carcinoma of the Maxilla Arising From Minor Salivary Glands of Hard Palate: A Rare Case Report.

Epithelial-myoepithelial carcinoma is a rare malignant neoplasm of salivary glands. It is specifically found in the major salivary glands. The cases that emerge from minor salivary glands are rarely described. Histologically, it commonly exhibits a characteristic biphasic pattern consisting of epithelial and myoepithelial components. The histopathological resemblance to other benign and malignant neoplasms that also display myoepithelial characteristics makes the differential diagnosis challenging. Each differential diagnosis requires a very different management approach. Considering the difficulties of anatomopathological diagnosis and the rarity of epithelial-myoepithelial carcinomas emerging from minor salivary glands, we report a rare epithelial-myoepithelial carcinoma case of minor salivary glands in a 58-year-old woman. She was referred for a palatal swelling, evolving for more than 35 years, and reported recent pain and nasal obstruction. The mucosal swelling was located in the left maxilla within the hard palate, of a 45-mm-long axis crossing the medial line and extending to the premaxilla, without cervical lymph node involvement. A computed tomography scan revealed a palatal lesion involving the left and the right maxilla. Furthermore, the superior alveolar process, both left and right maxillary sinuses, the nasal cavities, and the nasal septum were included in the lesion. The final diagnosis was difficult to confirm despite multiple biopsies and was determined only from the excised specimen. The diagnosis of this tumor was challenging due to the clinical and histological similarities with other salivary tumors. The aim of this case report is to shed light on the distinctive features of these tumors and explore optimal screening and related management strategies.

DICER1-mutated rhabdomyosarcoma of the ovary with teratoid features.

DICER1-mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1-mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous-like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer-like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous-like tubes were negative for SALL4 and Inhibin. Whole RNA- and targeted DNA-sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1-mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous-like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1-mutated sarcomas and devise specific therapeutic strategies.

Longitudinal characterization of primary osteosarcoma and derived subcutaneous and orthotopic relapsed patient-derived xenograft models.

Osteosarcoma is a rare bone cancer in adolescents and young adults with a dismal prognosis because of metastatic disease and chemoresistance. Despite multiple clinical trials, no improvement in outcome has occurred in decades. There is an urgent need to better understand resistant and metastatic disease and to generate in vivo models from relapsed tumors. We developed eight new patient-derived xenograft (PDX) subcutaneous and orthotopic/paratibial models derived from patients with recurrent osteosarcoma and compared the genetic and transcriptomic landscapes of the disease progression at diagnosis and relapse with the matching PDX. Whole exome sequencing showed that driver and copy-number alterations are conserved from diagnosis to relapse, with the emergence of somatic alterations of genes mostly involved in DNA repair, cell cycle checkpoints, and chromosome organization. All PDX patients conserve most of the genetic alterations identified at relapse. At the transcriptomic level, tumor cells maintain their ossification, chondrocytic, and trans-differentiation programs during progression and implantation in PDX models, as identified at the radiological and histological levels. A more complex phenotype, like the interaction with immune cells and osteoclasts or cancer testis antigen expression, seemed conserved and was hardly identifiable by histology. Despite NSG mouse immunodeficiency, four of the PDX models partially reconstructed the vascular and immune-microenvironment observed in patients, among which the macrophagic TREM2/TYROBP axis expression, recently linked to immunosuppression. Our multimodal analysis of osteosarcoma progression and PDX models is a valuable resource to understand resistance and metastatic spread mechanisms, as well as for the exploration of novel therapeutic strategies for advanced osteosarcoma.

NF1-Associated Inflammatory Polyp of the Colon: First Report of a Sporadic Case.

"Juvenile-like (hyperplastic/inflammatory) mucosal polyp" is a term proposed for rare benign mesenchymal lesions of the gastro-intestinal tract so far reported only in patients with type 1 neurofibromatosis (NF1). We report here a first sporadic case of NF1-associated mucosal inflammatory polyp of the colon. The diagnosis was made in a 53-year old female patient with a large polypoid tumor of the cecum. The lesion was predominantly mucosal, made of fibroblast-like cells associated with inflammatory infiltrates rich in eosinophils and containing entrapped, distorted epithelial glands, responsible for the juvenile-like appearance. Whole exome sequencing showed a pathogenic variant of NF1. The patient had no evidence of NF1; no NF1 mutation was detected in normal tissues. Our observation may support the existence of juvenile-like inflammatory polyps associated with NF1 alterations, either germline or somatic. This justifies to test NF1 in difficult-to-classify gastrointestinal mesenchymal tumors.

International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.

EWSR1-PATZ1 fusion sarcoma - A new case report and review of the literature / Sarcome avec transcrit de fusion EWSR1-PATZ1 - Une nouvelle observation avec revue de la littérature.

Sarcoma with EWSR1-PATZ1 gene fusion is an exceedingly rare and newly described Ewing-like sarcoma harboring EWSR1 rearrangements involving fusion partners other than ETS family genes. The clinical, histopathologic and immunophenotypic features of cases reported in literature are fairly diverse and not specific. We report a new case report posing real challenges for histological and molecular diagnosis.