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Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

We demonstrate that active esophagitis in pediatric EoE patients is associated with elevated levels of IgG4-positive plasma cells, which was more significant in EoE patients with a documented food allergy. Our study also adds to the growing literature that EoE may involve more than just an exaggerated TH2 immune response.

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Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1, ECRTSMARCA4, and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics‐based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1, potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the ‘rhabdoid tumour’ spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of extreme inflammation occurring in association with genetic defects involving the granule-dependent cytotoxic pathway of CD8+ T cells or NK cells and/or a wide variety of triggers including infections, malignancies, and rheumatologic disorders. Because of its relative rarity and the nonspecific nature of the individual clinical and laboratory abnormalities comprising the characteristic Bpattern^of HLH, the diagnosis can be elusive. Furthermore, some of the laboratory tests included in the diagnostic criteria are time-consuming or not widely available, and since many of these patients are critically ill, HLH must be considered early on so that the diagnosis can be established and potentially life-saving treatment initiated. Since the diagnosis of HLH is truly a clinicopathologic correlation, in this article, we as a team of pediatric clinical and laboratory physicians will use exemplary cases from our own institution with a variety of clinical presentations to illustrate the many Bfaces^of HLH; deconstruct the diagnosis; point out some of the challenges, limitations, pearls and pitfalls; and make it easier to understand the pathophysiology in context. However, while we may see relatively more cases working in a tertiary care children's hospital, HLH is a disease of both children and adults. Illustrative cases Case 1The patient was a previously healthy black 4-month-old girl transferred from an outside hospital. Two weeks prior, she had developed low-grade fever and a rash which was initially attributed to a viral exanthem, but because of worsening fever (to 40°C), she presented to the emergency department (ED), was found to have a platelet count of 70×10 3 /mL, admitted for further evaluation including a full septic work-up, and started on empiric antibiotics. Her white blood cell count, hemoglobin, and platelet count all progressively declined (with a nadir absolute neutrophil count of 0.2×10 3 /mL, hemoglobin dropping to 6.6 g/dL, and 21×10 3 /mL platelets) and she developed mild hepatosplenomegaly which was confirmed by abdominal ultrasonography, prompting bone marrow examination which showed no evidence of leukemia, neuroblastoma, or hemophagocytosis. Although initially her ferritin was 17 ng/dL, at the outside hospital it ultimately reached the 500 s, while fibrinogen decreased to <100 mg/ dL. Steroids were begun as treatment for HLH shortly after transfer to our institution and while an infectious etiology was not uncovered, additional testing revealed a ferritin of 4873 ng/mL, sCD25 level of 34,826 U/mL (age-specific reference range: 334-3026), absent NK cell function, and compound heterozygosity for two previously described mutations in PRF1 that are associated with familial HLH. Her initial cerebrospinal fluid (CSF) showed a minimally elevated protein without pleocytosis which normalized within 2 weeks of therapy and never exhibited neurologic symptoms. Three

Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the SMARCB1 gene. In the last decade, sporadic publications have shown that a different SWI/SNF protein, brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is associated with a similar rhabdoid phenotype and possible germline mutation termed rhabdoid tumor predisposition syndrome type 2. We sought to determine the presence of BRG1 expression in pediatric embryonal tumors. Using a local tissue microarray consisting of 28 tumors diagnosed as having an undifferentiated, polyphenotypic, or rhabdoid morphology, expression of BRG1 by immunohistochemistry was performed. Four cases showed loss of INI1, while 3 of the remaining 24 cases demonstrated loss of BRG1. Two cases were diagnosed as soft tissue sarcomas, and 1 case was diagnosed as a small cell carcinoma of the ovary, hypercalcemic type. Survival ranged from less than 6 months after diagnosis to more than 5 years at the time of last follow-up. In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1.

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