Copy number signatures and CCNE1 amplification reveal the involvement of replication stress in high-grade endometrial tumors oncogenesis.

PURPOSE: Managing high-grade endometrial cancer in Martinique poses significant challenges. The diversity of copy number alterations in high-grade endometrial tumors, often associated with a TP53 mutation, is a key factor complicating treatment. Due to the high incidence of high-grade tumors with poor prognosis, our study aimed to characterize the molecular signature of these tumors within a cohort of 25 high-grade endometrial cases. METHODS: We conducted a comprehensive pangenomic analysis to categorize the copy number alterations involved in these tumors. Whole-Exome Sequencing (WES) and Homologous Recombination (HR) analysis were performed. The alterations obtained from the WES were classified into various signatures using the Copy Number Signatures tool available in COSMIC. RESULTS: We identified several signatures that correlated with tumor stage and disctinct prognoses. These signatures all seem to be linked to replication stress, with CCNE1 amplification identified as the primary driver of oncogenesis in over 70% of tumors analyzed. CONCLUSION: The identification of CCNE1 amplification, which is currently being explored as a therapeutic target in clinical trials, suggests new treatment strategies for high-grade endometrial cancer. This finding holds particular significance for Martinique, where access to care is challenging.

"Hemispheric pilocytic astrocytoma" revisited: A comprehensive clinicopathological and molecular series emphasizing their overlap with other glioneuronal tumors.

Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.

CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions.

Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.

Thoracic Endometriosis Syndrome (TES) in Martinique, a French West Indies Island.

INTRODUCTION: Endometriosis is a female disease that affects 5-10% of women of childbearing age, with predominantly pelvic manifestations. It is currently declared as a public health priority in France. Thoracic endometriosis syndrome (TES) is the most common extra-pelvic manifestation. OBJECTIVE: The objective of this study was to describe the epidemiological and clinical characteristics, and outcomes of patients with TES in Martinique. PATIENTS AND METHODS: We performed a descriptive, retrospective study including all patients managed at the University Hospital of Martinique for TES between 1 January 2004 and 31 December 2020. RESULTS: During the study period, we identified 479 cases of pneumothorax, of which 212 were women (44%). Sixty-three patients (30% of all female pneumothorax) were catamenial pneumothorax (CP) including 49 pneumothoraxes alone (78% of catamenial pneumothorax) and 14 hemopneumothorax (22% of catamenial pneumothorax). There were 71 cases of TES, including 49 pneumothoraxes (69%), 14 hemopneumothoraxes (20%) and 8 hemothorax (11%). The annual incidence of TES was 1.1 cases/100,000 inhabitants. The prevalence of TES was 1.2/1000 women aged from 15 to 45 years and the annual incidence of TES for this group was 6.9/100,000. The annual incidence of CP was 1 case/100,000 inhabitants. The average age at diagnosis was 36 ± 6 years. Eight patients (11%) had no prior diagnosis of pelvic endometriosis (PE). The mean age at pelvic endometriosis diagnosis was 29 ± 6 years. The mean time from symptom onset to diagnosis was 24 ± 50 weeks, and 53 ± 123 days from diagnosis to surgery. Thirty-two patients (47%) had prior abdominopelvic surgery. Seventeen patients (24%) presented other extra-pelvic localizations. When it came to management, 69/71 patients (97%) underwent surgery. Diaphragmatic nodules or perforations were found in 68/69 patients (98.5%). Histological confirmation was obtained in 55/65 patients who underwent resection (84.6%). Forty-four patients (62%) experienced recurrence. The mean time from the initial treatment to recurrence was 20 ± 33 months. The recurrence rate was 16/19 (84.2%) in patients who received medical therapy only, 11/17 (64.7%) in patients treated by surgery alone, and 17/31 (51.8%) in patients treated with surgery and medical therapy (p = 0.03). CONCLUSIONS: We observed a very high incidence of TES in Martinique. The factors associated with this high incidence in this specific geographical area remain to be elucidated. The frequency of recurrence was lower in patients who received both hormone therapy and surgery.

Acute pulmonary histoplasmosis of immunocompetent subjects from Martinique, Guadeloupe and French Guiana: a case series.

INTRODUCTION: Histoplasmosis is a fungal disease caused by Histoplasma capsulatum. Histoplasma capsulatum var capsulatum is found in Martinique. Cluster cases following working in deserted house, have been described in Martinique. Cases of acute pulmonary histoplasmosis have been described in immunosuppressed individuals, or in case of substantial exposure to reservoirs of Histoplasma capsulatum; however, cases of acute histoplasmosis are rare in immunocompetent individuals. CASES SERIES: We report a series of 4 cases of sporadic acute pulmonary histoplasmosis in immunocompetent subjects. Investigation revealed definite exposure in one patient and 3 cases with potential exposure. The diagnosis was microbiological and histological in 3 patients and histological in one patient. All subjects had positive serology to histoplasmosis. Pulmonary involvement was in the form of nodules and micronodules in 3 cases and ground glass lesions in one case. Patients were treated with itraconazole for 3 months and all had a favourable outcome. CONCLUSION: We report a series of 4 cases of acute pulmonary histoplasmosis in immunocompetent individuals, occurring in a context where exposure was uncertain. This raises the problem of occult exposure in the Caribbean. Interventions to raise awareness and encourage caution are warranted targeting the population of the French West Indies and French Guiana.

Overall survival of triple negative breast cancer in French Caribbean women.

To describe survival according to prognostic factors of women with breast cancer in French overseas territory (Martinique) during 2008-2017. We performed a Cox model for prognostic factors for OS in breast cancer patients. The cut-off date for the analysis was 13/10/2018. The main factors were demographic data, stage, hormone receptors (HR) status and HER2 status. Curves were compared with the log rank test to select candidate variables for the multivariate analysis. We included 1,708 patients; median age at diagnosis was 57 years. Triple negative breast cancer (TNBC) accounted for 20.9% (n = 332). Among the patients, 72.3% (n = 1015) had localised or local spread cancer. One-year OS was 95.2% and was 80.1% at 5 years. In TNBC, 1-year-survival was 90.4%, which fell to 70.1% at 5 years. Patients with metastatic disease at diagnosis had 1-year-survival of 74.5%, and 20.1% at 5 years. Multivariate analysis by Cox regression identified 4 factors significantly associated with an increased risk of death: metastatic disease at diagnosis (hazard ratio (HR) = 15, p<0.0001), TNBC (HR 2.84, p<0.0001), HR+/HER2- status (HR 2.05, p<0.0084) and age >75 years (HR 3.8, p<0.0001). This is the first study performed on breast cancer survival in Martinique. Our findings show that breast cancer has overall good prognosis in patients and also how prognosis factors are distributed in the population.

MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories.

Targetable kinase fusions are extremely rare (<1%) in colorectal cancers (CRCs), making their diagnosis challenging and often underinvestigated. They have been shown particularly frequently among MSI-High, BRAF/KRAS/NRAS wild-type CRCs with MLH1 loss (MLH1loss MSI-High wild-type). We searched for NTRK1, NTRK2, NTRK3, ALK, ROS1, BRAF, RET, and NRG1 kinase fusions in CRCs using methods easy-to-implement in pathology laboratories: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and fully automated real-time PCR targeted analyses. RNA-sequencing analyses were used for confirmation. Among 84 selected MLH1 deficient (IHC) CRCs cases, MLH1loss MSI-High wild-type CRCs consisted first in 19 cases after Idylla™ analyses and finally in 18 cases (21%) after RNA-sequencing (detection of one additional KRASG12D mutation). FISH (and when relevant, IHC) analyses concluded in 5 NTRK1, 3 NTRK3, 1 ALK, 2 BRAF, and 2 RET FISH positive tumors. ALK and NTRK1 rearranged tumors were IHC positive, but pan-TRK IHC was negative in the 3 NTRK3 FISH positive tumors. RNA-sequencing analyses confirmed 12 of 13 fusions with only one false positive RET FISH result. Finally, 12/18 (67%) of MLH1loss MSI-High wild-type CRCs contained targetable kinase fusions. Our study demonstrates the feasibility, but also the cost-effectiveness, of a multistep but rapid diagnostic strategy based on nonsequencing methods to identify rare and targetable kinase fusions in patients with advanced CRCs, as well as the high prevalence of these kinase fusions in MLH1loss MSI-High wild-type CRCs. Nevertheless, confirmatory RNA-sequencing analyses are necessary in case of low FISH positive nuclei percentage to rule out FISH false-positive results.

International cooperation in public health in Martinique: geostrategic utility for cancer surveillance in the Caribbean.

BACKGROUND: Cooperation in public health and in oncology in particular, is currently a major issue for the island of Martinique, given its geopolitical position in the Caribbean region. The region of Martinique shares certain public health problems with other countries of the Caribbean, notably in terms of diagnostic and therapeutic management of patients with cancer. We present here a roadmap of cooperation priorities and activities in cancer surveillance and oncology in Martinique. MAIN BODY: The fight against cancer is a key public health priority that features high on the regional health policy for Martinique. In the face of these specific epidemiological conditions, Martinique needs to engage in medical cooperation in the field of oncology within the Caribbean, to improve skills and knowledge in this field, and to promote the creation of bilateral relations that will help to improve cancer management in an international healthcare environment. CONCLUSIONS: These collaborative exchanges will continue throughout 2020 and will lead to the implementation of mutual research projects across a larger population basin, integrating e-health approaches and epidemiological e-cohorts.

Gastrointestinal stromal tumors (GIST) presenting in the liver: Diagnostic, prognostic and therapeutic issues.

CONTEXT: Extra-gastrointestinal stromal tumors (E-GIST) presenting in the liver are exceedingly rare and raise difficult diagnostic and therapeutic challenges. METHODS: We report on two cases of liver E-GIST with different clinical presentations. We describe their clinical and imaging features, their histopathological and molecular characteristics, their treatment and their course. RESULTS: The first case was that of a 56-year-old male presenting with a 10-cm liver mass; the initial diagnosis, made in 1986 from a biopsy sample, was leiomyosarcoma; liver transplantation was performed in 1987; no extra-hepatic tumor was found; the course was uneventful until 1999, when tumor recurrence was diagnosed along the initial biopsy route; after reevaluation of available material, the definitive pathological diagnosis was GIST; imatinib treatment resulted in major response; the patient died of end-stage kidney disease 22 years after the initial diagnosis and 9 years after tumor recurrence. The second case is that of a 59-year-old female presenting with a 23-cm abdominal mass connected to the liver; on biopsy, the tumor was diagnosed as epithelioid GIST with exon 11 KIT mutation; imatinib treatment resulted in stable disease. CONCLUSIONS: The diagnosis of E-GIST must be for any sarcoma presenting in the liver and confirmed by immunohistochemical and molecular techniques. Treatment might require aggressive strategies, which can be successful despite apparently adverse histoprognostic factors.

Incidence of Lung Adenocarcinoma Biomarker in a Caribbean and African Caribbean Population.

INTRODUCTION: Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Biomarker testing is critical to personalized therapy in lung adenocarcinoma and has been extensively investigated in whites and Asians. However, little information addresses the underlying genetic changes among Caribbean and African Caribbean patients. In this study, we identified targetable biomarkers in Caribbean patients with lung adenocarcinoma. METHODS: DNA extracted from lung adenocarcinoma specimens collected from 157 patients in whom primary lung adenocarcinoma was diagnosed from 2013 to 2015 in the University Hospital of Martinique was tested for mutation of the epidermal growth factor receptor gene (EGFR), Kirsten rat sarcoma viral oncogene homolog gene (KRAS), B-Raf proto-oncogene, serine/threonine kinase gene (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS), and MMNG HOS Transforming gene (MET). Clinical characteristics of our patients have been retrospectively gathered and correlated with mutational status. RESULTS: Mutations in EGFR were identified in 57 cases (36%). Women accounted for 68% of patients with mutations versus 38% of those without mutations (p < 0.001). Eighteen percent of patients with mutations were smokers versus 62% of patients without mutations (p < 0.001). Sex, smoking habit, and age were significantly associated with differences in mutational status in univariate analysis, and the difference remained statistically significant in multivariate analysis (p = 0.0411, p = 0.001, and p = 0.0483, respectively). After the analysis was restricted to patients born in the French West Indies, the mutation rates reached 41%. CONCLUSION: Patients in Martinique, and specifically those of African descent, show very high levels of EGFR mutation as opposed to what can be found in mainland France or in African Americans. These findings may be ascribed to low tobacco consumption as well as to genetic factors. Systematic screening in patients of African Caribbean origin should be prescribed.

Pseudo-Peritoneal Carcinomatosis Presentation of a Crystal-Storing Histiocytosis With an Unmutated Monoclonal κ Light Chain.

Crystal-storing histiocytosis (CSH) is a rare complication of monoclonal gammopathies caused by accumulation of crystalline material inside macrophages, and it may result in a variety of clinical manifestations depending on the involved organs. Although immunoglobulin κ light chains (LCs) seem to be the most frequent pathogenic component, very few molecular data are currently available.A 69-year-old man presented with a very poor performance status. Remarkable features were mesenteric lymph node enlargement and proteinuria, including a monoclonal κ LC. Light and electron microscopy studies revealed the presence of crystals within macrophages in the lymph nodes, bone marrow, and kidney, leading to the diagnosis of CSH. The pathogenic κ LC variable domain sequence was identical to the germline Vk3-2001/Jk201 gene segments, without any somatic mutation, suggesting an extra-follicular B cell proliferation.The patient was successfully treated with 4 cycles of bortezomib and dexamethasone. After a 12-month follow-up, he remains in hematological and renal remission.CSH may present as pseudo-peritoneal carcinomatosis and relate to a monoclonal κ LC encoded by an unmutated gene. Bortezomib-based therapy proved efficacious in this case.

The spectrum of chronic CD8+ T-cell expansions: clinical features in 14 patients.

Chronic CD8(+) T-cell expansions can result in parotid gland swelling and other organ infiltration in HIV-infected patients, or in persistent cytopenias. We report 14 patients with a CD8+ T-cell expansion to better characterize the clinical spectrum of this ill-defined entity. Patients (9 women/5 men) were 65 year-old (range, 25-74). Six patients had ≥ 1 symptomatic organ infiltration, and 9 had ≥ 1 cytopenia with a CD8(+) (>50% of total lymphocyte count) and/or a CD8(+)/CD57(+) (>30% of total lymphocyte count) T-cell expansion for at least 3 months. One patient had both manifestations. A STAT3 mutation, consistent with the diagnosis of large granular lymphocyte leukemia, was found in 2 patients with cytopenia. Organ infiltration involved lymph nodes, the liver, the colon, the kidneys, the skin and the central nervous system. Three patients had a HIV infection for 8 years (range, 0.5-20 years). Two non-HIV patients with hypogammaglobulinemia had been treated with a B-cell depleting monoclonal antibody (rituximab) for a lymphoma. One patient had a myelodysplastic syndrome with colon infiltration and agranulocytosis. The outcome was favorable with efficient antiretroviral therapy and steroids in HIV-infected patients and intravenous immunoglobulins in 2/3 non-HIV patients. Six patients had an agranulocytosis of favorable outcome with granulocyte-colony stimulating factor only (3 cases), cyclophosphamide, methotrexate and cyclosporine A, or no treatment (1 case each). Three patients had a pure red cell aplasia, of favorable outcome in 2 cases with methotrexate and cyclosporine A; one patient was unresponsive. Chronic CD8(+) T-cell expansions with organ infiltration in immunocompromised patients may involve other organs than parotid glands; they are non clonal and of favorable outcome after correction of the immune deficiency and/or steroids. In patients with bone marrow infiltration and unexplained cytopenia, CD8(+) T-cell expansions can be clonal or not; their identification suggests that cytopenias are immune-mediated. Our results extend the clinical spectrum of chronic CD8(+) T-cell expansions.