Lara Chalabreysse

BACKGROUND: Sudden death is a possible consequence of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Prevalence of ARVC/D in unexpected sudden cardiac death (USCD), however, remains imprecise, as do circumstances of death and ARVC/D-associated gross and microscopic findings, especially His bundle anomalies. METHODS AND RESULTS: We reviewed 14 000 forensic autopsies required by judicial authorities from January 1980 to January 1999 in a 2 000 000-resident area. Age, gender, and circumstances of death were recorded. Hearts were examined macroscopically and microscopically. In this series, the ARVC/D group accounted for 200 consecutive cases (10.4%) of USCD, including 108 males and 92 females (average age 32.5 and 34.5 years, respectively). Nearly one third of deaths occurred during the fourth decade of life. Circumstances of death were various, but 75.6% occurred during everyday life events (at home, 63.1%; in the street, 6.6%; or at work, 6.1%); only 7 cases (3.5%) occurred during sports activity. Nineteen cases (9.5%) happened during the perioperative period. Adipose infiltration of the right ventricle was either isolated (20%) or associated with fibrosis (74.5%) and lymphocytes (5.5%). A total of 14.5% of cases had cardiac hypertrophy, assessed by an increase in heart weight and/or left ventricular wall thickness. In most cases, the His bundle and its branches were abnormal either because of infiltration of adipose tissue (8.1%), fibrosis (54.3%), or both (5.6%). CONCLUSIONS: In ARVC/D, both sexes are equally affected, and there is a peak of risk during the fourth decade. Death most frequently occurs during sedentary activity. His abnormalities and left ventricular hypertrophy may be associated with ARVC/D.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies. Patients ranged from 28 to 90 years of age (median: 48 y), with a marked male predominance (male:female=9:1) and they were usually smokers. Tumors were generally large compressive masses located in the mediastinum (n=13), pleura (n=5), lung (n=2) or in 2 or more of these topographies (n=10). Treatment strategies were varied, including 1 case treated with EZH2 inhibitors. Median overall survival was 6 months. Histologically, tumors were poorly differentiated frequently showing rhabdoid features. A subset of cases showed a focal myxoid stroma (7%, n=2/30) and rare cases displayed a previously unreported pattern simulating desmoplastic small round cell tumors (7%, n=2/30). Making a diagnosis was challenging when dealing with biopsy material from massively necrotic tumors and in this setting the expression of SOX2, CD34, and SALL4 proved useful. All tested cases displayed concomitant loss of SMARCA4 and SMARCA2 and most tumors expressed epithelial markers (Pan-keratin or EMA) (n=29/30), SOX2 (n=26/27), and CD34 (n=17/27). SMARCB1 expression was retained in all cases (23/23). SALL4 and Claudin-4 were expressed in a subset of cases (n=7/21 and 2/19, respectively). TTF-1 and P63 were focally expressed in 1 case each. P40 and NUT were not expressed (0/23 and 0/20, respectively) The SMARCA4-DTS immunohistochemical signature was both sensitive and specific, with only a subset of small cell carcinoma of the ovary hypercalcemic type showing overlapping phenotypes. Our study confirms and expands the specific features of SMARCA4-DTS, emphasizing the fact that they can be straightforwardly identified by pathologists.

A series of 90 thymic epithelial tumors were reviewed and classified by histopathologic characteristics into the three major categories (A, B, and C) recognized by the WHO schema. Each tumor type was correlated with patient characteristics and clinical data (age, sex, presence of myasthenia gravis, tumor size and invasiveness, and completeness of resection), and with outcome (survival, recurrence, and metastasis). All tumors were categorized by the WHO schema. Myasthenia gravis was present in 32 patients, mostly young and with type B thymic epithelial tumors. Tumors were invasive in 56% of cases, but resection was total in 67% of patients and only partial in the rest. Five factors were shown by univariate analysis to be associated with a favorable prognosis: presence of myasthenia gravis (p = 0.0389), younger age (p = 0.0022), completeness of resection (p = 0.0001), noninvasiveness (p = 0.0138), and tumor type A or B, as opposed to type C (p = 0.0001). Prognosis for types A and B was not significantly different, suggesting that the subtypes of types A and B thymic epithelial tumors should be regarded as a morphologic continuum rather than as distinct histologic variants.