X-linked Myopathy with Excessive Autophagy - A Rare Cause of Vacuolar Myopathy in Children.

X-linked myopathy with excessive autophagy (XMEA) is a rare, recently characterized type of autophagic vacuolar myopathy caused by mutations in the VMA21 gene. It is characterized by slowly progressive weakness restricted to proximal limb muscles and generally has a favorable outcome. The characteristic histological and ultrastructural features distinguish this entity from other mimics, notably Danon disease. XMEA is an under recognized disease and should be considered in the differentials of slowly progressive myopathy in children. Awareness of this rare entity is also important for the pathologists in order to distinguish it from other causes of vacuolar myopathy in view of its favourable prognosis. We report the first genetically confirmed case of XMEA from India in an 8-year-old boy which was diagnosed based on the characteristic light microscopic and ultrastructural findings on muscle biopsy and subsequently confirmed by mutation analysis. The differential diagnostic considerations are also discussed.

Correlation of Helicobacter pylori virulence genotype & severity of mucosal inflammation in gastric biopsies from two geographically diverse regions in India.

Background: H. pylori-associated gastritis in patients from the high-altitude area of Ladakh showed severe gastritis, mucosal nodularity, atrophy, and cancer in comparison to those from North India. This study served to analyze if differences in the H. pylori virulence genotypes decide the extent of gastric mucosal inflammation. Methods: Fifty gastric biopsies each from patients with H. pylori-associated gastritis from Ladakh and a tertiary care center in North India were included. The presence of H. pylori strain was confirmed with Warthin starry stain and polymerase chain amplification of the H. pylori-specific 16S rRNA. The cagA, vacA s1, s2, and m1, m2 alleles, and dupA virulence genotypes were studied in all archival samples, followed by their histological correlations. Results: cagA (P 0.009) and vacAs1 m1 (P 0.009) genes were distinctly more in H. pylori strains colonizing the biopsies of North Indian patients. In contrast, the cagA -ve vacAs2 m2 strains were significantly more in H. pylori strain colonizing the biopsies from Ladakhi patients. dupA genotype was almost similarly present in strains from both regions. Among these, only cagA and dupA virulence genes were associated with severe mucosal neutrophilic activity and deep infiltration of H. pylori strains in North Indian patients. Conclusions: Differences in virulence genotypes of H. pylori in gastric biopsies from North Indian and Ladakhi patients were found not significant in deciding the severity of H. pylori-associated gastritis.

Primary Histiocytic Sarcoma of Brain-Illustration of Two Cases with Varied Histomorphological Features.

Histiocytic sarcoma (HS) is an aggressive hematolymphoid malignancy that arises from non Langerhans histiocytes and usually involves the skin, lymph nodes, and intestine. The involvement of the central nervous system (CNS) is a rare occurrence with around 30 cases being reported in English literature. Morphological and immunohistochemical evidence of histiocytic differentiation is essential for diagnosis. Prognosis is very poor and consensus on treatment is not available mainly due to its rarity. We report two cases of HS with varied clinical presentation and pathological findings and elucidate the diagnostic challenges of this rare entity.

Histologic Changes in Core-Needle Liver Biopsies From Patients With Acute-on-Chronic Liver Failure and Independent Histologic Predictors of 28-Day Mortality.

CONTEXT.­: The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully established. OBJECTIVE.­: To evaluate the independent histologic predictors of 28-day mortality in ACLF patients on core-needle liver biopsies. DESIGN.­: Core-needle biopsies from patients with a diagnosis of ACLF (n = 152) as per the European Association for the Study of the Liver criteria were included during 8 years. Liver biopsies from 98 patients with compensated chronic liver disease were included as disease controls for histologic comparison. Features of ongoing changes, such as hepatic necrosis, hepatic apoptosis, cholestasis, hepatocyte degeneration, bile ductular proliferation, Mallory-Denk bodies, steatosis, and extent of liver fibrosis, were analyzed for predicting short-term mortality (28 days). A P value of <.05 was considered significant. RESULTS.­: In our cohort of ACLF patients, the following etiologies for acute decompensation were identified: alcohol, 47 of 152 (30.9%); sepsis, 24 of 152 (15.7%); hepatotropic viruses, 20 of 152 (13.1%); drug-induced liver injury, 11 of 152 (7.2%); autoimmune flare, 9 of 152 (5.9%); mixed etiologies, 5 of 152 (3.2%); and cryptogenic, 36 of 152 (23.6%). On histologic examination, hepatic necrosis (P < .001), dense lobular inflammation (P = .03), cholestasis (P < .001), ductular reaction (P = .001), hepatocyte degeneration (P < .001), and absence of advanced fibrosis stages (P < .001) were identified significantly more othen in ACLF patients than in disease controls on univariate analysis. On multivariate Cox regression analysis, the absence of advanced Ishak histologic activity index fibrosis stages (P = .02) and the presence of dense lobular inflammation (P = .04) were associated with increased 28-day mortality in ACLF patients. After adjusting the clinical causes of acute decompensation, only dense lobular inflammation was found as an independent predictor of short-term mortality (P = .04) in ACLF patients. CONCLUSIONS.­: Dense lobular necroinflammatory activity is a clinically independent histologic predictor of 28-day short-term mortality in patients with ACLF.

Pan-Gastrointestinal Tract Mucosal Pathologies in Patients with Celiac Disease with the Demonstration of IgA Anti-Transglutaminase Mucosal Deposits: A Case-Control Study.

BACKGROUND: While celiac disease (CeD) is considered to affect primarily the small intestine, pathological changes in other parts of the gastrointestinal tract (GIT) are also known to occur. IgA anti-tissue transglutaminase-2 antibody (anti-TG2 Ab) deposits at the site of involvement is one of the methods to establish CeD-related tissue pathology. AIMS: To explore the utility of IgA anti-TG2 Ab deposits in pan-gastrointestinal mucosal biopsies as evidence of CeD-related pathologies. METHODS: Forty-two treatment-naive patients with CeD and 45 patients with irritable bowel syndrome were included as cases and controls, respectively. Mucosal biopsies were collected from the esophagus, stomach, duodenum, and rectosigmoid regions at baseline from cases and controls, and additionally after 6-months of gluten-free diet in cases. All biopsies were evaluated for histological changes and subjected to dual-color immunohistochemical staining for identifying IgA anti-TG2 Ab deposits. RESULTS: Significantly higher number of patients with CeD had lymphocytic esophagitis (9.7% vs. 0%, P = 0.05), lymphocytic gastritis (35% vs. 8.8%, P < 0.01) and lymphocytic colitis (17.4% vs. 0%, P < 0.05) than that in controls. IgA anti-TG2 Ab deposits were observed in significantly more numbers in esophagus (30.9% vs. 6%, P < 0.001), stomach (62.2% vs. 9.3%, P < 0.01), duodenum (88.5% vs. 0%, P < 0.001) and rectum (17.4% vs. 0%, P < 0.05) than that in controls. There was a decline, but not statistically significant, in severity of lymphocytosis and intensity of IgA anti-TG2 Ab deposits in follow-up biopsies. CONCLUSION: Significantly higher number of patients with CeD had evidence of lymphocytic infiltration and IgA anti-TG2 deposits along GIT suggesting that CeD affects other parts of GIT.

EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations.

The PFA molecular subgroup of posterior fossa ependymomas (PF-EPNs) shows poor outcome. H3K27me3 (me3) loss by immunohistochemistry (IHC) is a surrogate marker for PFA wherein its loss is attributed to overexpression of Cxorf67/EZH2 inhibitory protein (EZHIP), C17orf96, and ATRX loss. We aimed to subgroup PF-EPNs using me3 IHC and study correlations of the molecular subgroups with other histone related proteins, 1q gain, Tenascin C and outcome. IHC for me3, acetyl-H3K27, H3K27M, ATRX, EZH2, EZHIP, C17orf96, Tenascin-C, and fluorescence in-situ hybridisation for chromosome 1q25 locus were performed on an ambispective PF-EPN cohort (2003-2019). H3K27M-mutant gliomas were included for comparison. Among 69 patients, PFA (me3 loss) constituted 64%. EZHIP overexpression and 1q gain were exclusive to PFA seen in 72% and 19%, respectively. Tenascin C was more frequently positive in PFA (p = 0.02). H3K27M expression and ATRX loss were noted in one case of PFA-EPN each. All H3K27M-mutant gliomas (n = 8) and PFA-EPN (n = 1) were EZHIP negative. C17orf96 and acetyl-H3K27 expression did not correlate with me3 loss. H3K27me3 is a robust surrogate for PF-EPN molecular subgrouping. EZHIP overexpression was exclusive to PFA EPNs and was characteristically absent in midline gliomas and the rare PFA harbouring H3K27M mutations representing mutually exclusive pathways leading to me3 loss.

Metastatic lesions of atrial myxoma. A pathologist can clinch them all.

Atrial myxomas are the most common primary benign cardiac tumors. The embolization of tumor particles is not infrequent, and in nearly half of them, the cerebral arteries are affected, usually leading to embolic ischemic stroke. Formation of intracranial aneurysms, development of parenchymal brain metastasis, and intracerebral hemorrhage due to ruptured aneurysms are rarer. Diagnosis of such lesions in a previously undiagnosed case of myxoma may be challenging for a pathologist. Herein, we present two patients of cardiac myxoma with varied neurological manifestations and their pathological findings.

Composite tumor of the larynx: A Case Report.

Composite tumor of larynx, a recently included entity in the current WHO classification, is often a difficult pathological diagnosis, especially in small biopsies. We report a case of laryngeal composite tumor, initially misdiagnosed as squamous cell carcinoma, which later turned out to be composite in nature, with associated neuroendocrine (small cell carcinoma) component. This report emphasizes the need for obtaining deeper biopsies and their thorough pathological examination to improve the diagnostic accuracy. Keywords: combined small cell carcinoma; composite tumor; larynx; small cell carcinoma; squamous cell carcinoma.

Uterine tumor resembling ovarian sex cord tumor: A series of six cases displaying varied histopathological patterns and clinical profiles.

INTRODUCTION: Uterine tumors resembling ovarian sex cord tumor (UTROSCT) are a unique group of neoplasms with diverse morphology and immunophenotypic characteristics, coexpressing sex cord, epithelial, and smooth-muscle markers. To date, less than 100 cases have been reported and there is paucity of data concerning their clinical behavior. MATERIALS AND METHODS: All cases of uterine body tumors diagnosed over a period of two and a half years (2016-2018) were retrieved. Histopathological features were reviewed and extended panel of immunohistochemistry was performed to identify cases of UTROSCTs. RESULTS: Six cases of UTROSCTs were identified with a median age of 46.5 years. Four of them presented with menorrhagia, while two with postmenopausal bleeding including one with a history of carcinoma breast. Three of these cases were initially misdiagnosed as endometrial stromal sarcoma and adenocarcinomas. They all underwent hysterectomy with bilateral salpingo-oophorectomy. CONCLUSION: It is considered a tumor with low malignant potential; however, one out of six cases (16.7%) in our study showed metastasis, within 1 year of diagnosis. It is important to recognize this entity as it mimics a wide range of both benign and malignant tumors. Molecular pathogenesis and exact management protocols remain elusive due to rarity,hence, multi-institutional studies are warranted.

Recurrent Sinonasal CD34-Negative Malignant Solitary Fibrous Tumor Diagnosed on STAT6 Immunohistochemistry and NAB2-STAT6 Fusion.

A spectrum of mesenchymal neoplasms occur in the sinonasal region. One of these is solitary fibrous tumor (SFT), a translocation-associated neoplasm characterized by NAB2-STAT6 gene fusion. Sinonasal SFTs characteristically display CD34 immunopositivity, which aids in diagnosis. However, a small proportion of SFTs may be negative for CD34, making diagnosis difficult. The availability of STAT6 immunohistochemistry (IHC) has helped to overcome this. Malignant SFTs, characterized by increased cellularity and mitoses > 4 per ten high power fields, are extremely unusual in the sinonasal region, with only ten such cases reported to date. We report a case of a CD34-negative malignant SFT that was diagnosed using STAT6 IHC and confirmed by demonstrating NAB2 ex 4-STAT6 ex 2 fusion, and recurred 8 months after complete excision, to highlight the aggressive nature of this tumor.

Sequential EGFR mutation and ALK rearrangement in adenocarcinoma lung, with rare metastasis to bilateral breast, ovary and endometrium.

With the advent of targeted therapies there was a paradigm shift in the treatment of metastatic adenocarcinoma of lung. Immuno-histopathology and molecular subtyping in metastatic adenocarcinoma lung have enabled personalized treatment for each patient. Oncogenic driver mutations in non-small cell lung cancer are commonly EGFR (Epidermal Growth Factor Receptor) gene mutation and ALK (Anaplastic Lymphoma Kinase) gene rearrangement, which are mutually exclusive. Almost 60-64% patients have oncogenic mutation, which are mutually exclusive. Here, we present a case with EGFR mutation and ALK gene rearrangement which was expressed sequentially and with metastasis to rarest sites bilateral breast, ovaries and endometrium. Even though presented with upfront metastatic disease, patient was treated with multiple lines of targeted agents, by which patient survived for 5 years with good quality of life.