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.

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.

Molecular profiling and target actionability for precision medicine in neuroendocrine neoplasms: real-world data.

BACKGROUND: Key molecular alterations (MA) of neuroendocrine neoplasm (NEN) of various grade/primaries have been described but the applicability of molecular profiling (MP) for precision medicine in NEN remains to be demonstrated. METHODS: We conducted a retrospective study of all patients with metastatic NEN who had MP on tumour tissue at Gustave Roussy. The primary objective was to assess the clinical applicability of MP by evaluating the growth modulator index (GMI) as the primary end-point. RESULTS: MPs were obtained in 114 out of 156 eligible patients, including 12% NET-G1, 42% NET-G2, 13% NET-G3 and 35% neuroendocrine carcinoma (NEC). Primary sites were lung/thymus (40%), pancreas (19%), gastro-intestinal (16%), head&neck (10%), unknown (10%) and others (10%) with synchronous metastases in 61% of the patients. Most frequent MA were: MEN1 (25%), PTEN (13%), TP53 (11%) and TSC2 (9%), in neuroendocrine tumour (NET), and TP53 (50%) and RB1 (18%) in NEC. ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) classification of these MA were: I(5%), III(20%), IV(23%), X(27%); a putative actionable MA was identified in 48% patients. Median TMB was 5.7 Mut/Mb, with 3 TMB > 10 and 1 MSI NET. No MA was found in 26% patients. Molecularly matched treatment was administered to 19 patients (4 NEC, 15 NET): immunotherapy (n = 3), tipifarnib (n = 1), NOTCHi (n = 1), EGFRi (n = 2), HER2i (n = 1) and everolimus (n = 11). Overall, 67% of patients had a clinical benefit defined as a GMI over 1.3 with a 78% disease control rate. CONCLUSION: We report 48% of NEN with a putative actionable MA of which 35% received molecularly matched treatment, with a clinical benefit in 67% of the cases.

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.

Second-line treatment and prognostic factors in neuroendocrine carcinoma: the RBNEC study.

Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an 'adenocarcinoma-like' or a 'neuroendocrine-like' 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum-etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum-etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.

Male adnexal tumor of probable Wolffian origin: a new entity in males similar to female adnexal tumor of probable Wolffian origin.

Female adnexal tumor of probable Wolffian origin is a rare tumor listed in the 2016 WHO classification of the female reproductive tract. It does not have a WHO-recognized counterpart in the male urogenital tract. However, some cases of male adnexal tumors have been described in the literature. We present the case of a 41-year-old male who presented with a 2-cm nodule in the testicle. LDH, HCG, and AFP blood levels were normal. Gross examination showed an intratesticular, whitish, microcystic, firm, and encapsulated nodule of 2 cm. Microscopically, the tumor was well circumscribed, solid, and microcystic. In the solid areas, cells were fusiform or polygonal with an eosinophilic pale cytoplasm and a regular oval nucleus. Cysts were surrounded by a fibromuscular stroma and lined by a single layer of cylindrical epithelium, with apical cilia. On immunohistochemistry, tumor cells expressed AE1/AE3 and vimentin and were negative for calretinin, epithelial membrane antigen (EMA), and inhibin. All the differential diagnoses at this localization being ruled out, the tumor was compared to a female adnexal tumor of probable Wolffian origin. Both tumors had approximately the same morphological and immunohistochemical profile. Naming our tumor MATPWO is therefore justified, but it remains of a probable origin because further studies need to be performed in order to certify this hypothesis.

Multifocal in situ mantle cell neoplasia of the ileocecal region: a case report with simultaneous nodal and extranodal involvement.

In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.

Prognostic factors of metastatic neuroendocrine carcinoma under first-line treatment with platinum etoposide with a focus on NEC score and Rb expression: Results from the multicentre RBNEC study of the Groupe d'Etude des Tumeurs Endocrines (GTE) and the ENDOCAN-RENATEN network.

INTRODUCTION AND AIM: Neuroendocrine carcinomas (NECs) are aggressive malignant diseases. Platinum-etoposide (PE) combination is the standard first-line treatment, whatever the primary location. The NEC score and also retinoblastoma protein (Rb) status have been suggested to be predictive/prognostic factors in NEC. The primary objective of our multicentric retrospective study was to evaluate the prognostic relevance of the NEC score and Rb status, assessed by immunohistochemistry in PE-treated patients with metastatic NEC. METHODS: Seven centres participated. The inclusion criteria were NEC, whatever the primary site, metastatic stage, first-line treatment with PE and tissue samples available. Rb status was determined centrally. RESULTS: We report multicentric data from 185 metastatic patients (37% women, median age 63). There were 108 small-cell NECs (SCNECs, 58.4%), 50 large-cell NECs (LCNECs, 27%) and 27 not otherwise specified NECs (nosNECs, 14.6%). The primary sites were the thorax (37%), gastroenteropancreatic sites (38%), unknown (15%) and other (9%). The mean Ki-67 index was 76% (range 20-100). Rb status was interpretable in 122 cases. Rb expression was lost in 74% of the cases: 84% of SCNEC vs. 60% and 63% of LCNEC and nosNEC, respectively (p = 0.016). Objective response was seen in 70% of SCNEC, 45% of LCNEC and 48% of nosNEC (p < 0.001) and in 62% of Rb-negative tumours vs. 46% of Rb-positive tumours (p = 0.3). There was no difference in median progression-free survival or overall survival (OS) as per Rb status. Age, NEC score and response to chemotherapy were the main factors associated with OS in our cohort. CONCLUSION: In our series, Rb status had no prognostic impact in PE-treated metastatic patients with NEC, whereas age, NEC score and response to chemotherapy were the main factors associated with OS.

Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection.

Few data are available concerning human papillomavirus (HPV) in early esophageal squamous cell carcinoma (ESCC) in Western population. Our study intended to determine the prevalence of HPV infection and the histological characteristics in such early tumors. A monocentric and retrospective study was conducted including 86 patients with early ESCC treated by endoscopic resection or esophagectomy, from 2012 to 2018. Histopathological prognostic criteria were evaluated. Immunohistochemistry for p16 and p53 and an HPV mRNA in situ hybridization were performed. The tumors were composed of 25 (29%) in situ carcinomas, 21 (24%) intramucosal carcinomas, and 40 (47%) submucosal carcinomas, of which 34 had a deep infiltration (> 200 µm). Emboli, present in 12 cases, were associated with deep infiltration. P16-positive ESCC accounted for 21% of the patients. It was not correlated with active HPV infection as no cases were found to be positive in RISH analysis for RNA detection of this virus. However, there was a correlation between p16 expression and alcohol or tobacco consumption. The only histopathological criterion correlated with p16 positivity was marked inflammatory infiltrate. Local or distant neoplastic recurrence occurred in 25% of patients. Overall survival was 95.8% and local or metastatic recurrence-free survival was 75%. There was a correlation between positive resection margins and tumor recurrence. In contrast to oropharynx carcinoma, our study showed that ESCC were not associated with an active HPV infection, highlighting the negligible role of this virus in early ESCC carcinogenesis in the Western world.

Colon Cancer Metastasis Within a NIFTP: A Case Report and Review of the Literature.

The thyroid is an unusual site for metastasis, and metastases in a preexisting primary thyroid tumor are exceedingly rare. We report the first case of a patient with colon cancer who was diagnosed with a thyroid metastasis in a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). A 55-year-old male patient presented with a 19 mm thyroid nodule in the inferior left lobe. It was EU-TIRADS 5 on echography and suspicious of papillary thyroid carcinoma (Bethesda V) on cytology. Macroscopically, the nodule was fleshy and completely encapsulated. At frozen section examination, it demonstrated follicular architecture with mild atypia. Inside the nodule was a focus of tumor with glandular architecture, marked cellular atypia, and necrosis. These findings suggested a secondary malignancy. The patient's medical history was significant for metastatic colon cancer. The definitive histology showed features of metastatic colorectal adenocarcinoma within a NIFTP. Immunohistochemical studies were confirmatory with expression of CDX2 and CK20 localized to the metastatic focus. PAX8, TG, and TTF were negative in the metastasis but expressed in the surrounding NIFTP lesion. The possibility of a metastasis to the thyroid may be considered in patients presenting with a solitary thyroid nodule with a previous history of cancer. Metastatic colorectal adenocarcinoma occurring in a NIFTP has never been reported before now, although metastases to the thyroid are documented in the literature. In cases of a secondary malignancy to the thyroid, treatment is controversial.