The Role of Muscle Biopsy in the Diagnosis of Inflammatory Myopathy

Muscle biopsies of patients with immune-mediated inflammatory myopathies are characterized by a combination of chronic inflammatory infiltrates and muscle fiber necrosis. In addition, there are typical histochemical, immunohistochemical, and ultrastructural findings of each type of inflammatory myopathy. Accurate classification of inflammatory myopathies is important because inclusion body myositis does not respond to immunosuppressive treatment, polymyositis is frequently part of an overlap syndrome, and dermatomyositis is associated with cancer in adults. Necrotizing myopathy without inflammation may be due to a partially treated inflammatory myopathy, a toxic myopathy, or a paraneoplastic myopathy. Metabolic myopathies and muscular dystrophies may clinically and rarely pathologically mimic inflammatory myopathy. Correct identification of these entities depends on better awareness of clinical similarities between metabolic myopathy and inflammatory myopathy; appropriate utilization of immunohistochemical, ultrastructural, biochemical, and genetic techniques on muscle samples in difficult cases; and maximizing communication between the clinician and the pathologist

Glioneuronal Neoplasms with Malignant Histological Features: A Study of 36 Cases

Objective: Malignant glioneuronal tumors show considerable morphological diversity. Their biological behavior and clinicopathological characteristics are incompletely understood. With the exception of anaplastic ganglioglioma, they are not assigned to a specific entity in the current WHO classification. It is also not clear whether histological features of these neoplasms influence prognosis. Material and Method: We identified 36 glioneuronal tumors with malignant histological features among the departmental archives and neuropathology consultation files of the authors. We reviewed the pathological and radiological features of these tumors to construct a preliminary histological categorization. Results: Based on their pathological features, we divided the study group into three histologically distinct categories: 1) glioneuronal tumors with a malignant glial component (anaplastic gangliogliomas); 2) glioneuronal tumors with a malignant neuronal/neuroblastic component; 3) glioneuronal tumors with both malignant neuronal and glial components. All tumors occurred in a younger age group compared to glioblastomas and appeared radiologically well-defined, cystic and solid with variable contrast enhancement. There was a high rate of local recurrence (29 of 36 patients) and 12 patients died during follow-up period. Median progression-free survival was less than 12 months, and did not differ among categories. Cerebrospinal tumor spread was seen in only one patient. Concurrent WHO grade I ganglioglioma and the presence of a malignant neuronal component did not appear to influence prognosis Conclusion: MGNTs were considered in three simple categories based on their malignant component(s). Tumors in all categories exhibited a high rate of local recurrence and aggressive behavior akin to malignant gliomas as opposed to classical PNET. Nevertheless, MGNT demonstrated clinicopathological features that distinguish them from typical glioblastoma. The exact nosology of MGNTs is unresolved and our study underscores the need for a more comprehensive classification of these neoplasms within the WHO scheme

Central Nervous System Aspergillosis: An Unexpected Complication following Neurosurgery

Post-surgical aspergillosis is an uncommon complication that carries a high mortality rate in affected patients. The diagnosis is challenging given the lack of highly sensitive methods to isolate Aspergillus from surgical sites. Here, we present a case of post-surgical aspergillosis that occurred after the resection of acoustic neuroma in an immunocompetent patient. Imaging revealed leptomeningeal enhancement and a cerebellar extra-axial fluid collection adjacent to the right retrosigmoid craniotomy. The patient was taken to the operating room for debridement, where purulent fluid was obtained from subdural space. The diagnosis was achieved by histopathology and polymerase chain reaction (PCR) in brain tissue. Appropriate investigations failed to detect contamination in the operating room. The patient was successfully treated with 3 months of voriconazole. We highlight the importance of recognizing this uncommon complication and advocate for the use of molecular techniques to improve the diagnostic yield in central nervous system aspergillosis

WP1066 induces cell death in a schwannomatosis patient–derived schwannoma cell line

Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1 , are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2–related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies

Evidence of ambiguous differentiation and mtor pathway dysregulation in subependymal giant cell astrocytoma

Objective: The exact cell of origin of subependymal giant cell astrocytoma is debated but most currently consider the tumor in the astrocytic category. Mutations and subsequent biallelic inactivation of TSC1 encoding hamartin, or TSC2 encoding tuberin appear to be the underlying genetic aberrations. Inactivation leads to loss of proteins that inhibit mammalian target of rapamycin (mTOR) disrupting tightly regulated cell functions. Material and Method: We analyzed the expression of tuberin and hamartin along with an array of neuroepithelial markers in 9 subependymal giant cell astrocytomas. In addition, RPS6 and 4EBP1 regulatory proteins that are downstream in the mTOR pathway were also evaluated. Results: While hamartin and tuberin expression levels were relatively decreased compared to control tissue, this was not of particular practical use to detect the mutated gene since low levels of positivity could be detected throughout the central nervous system. As expected, the levels of RPS6 and 4EBP1 were increased, further confirming the activation of the mTOR pathway. GFAP was positive in 5 cases, while Synaptophysin positivity was found in all tumors. CD34 (a marker often observed in well differentiated glio-neuronal tumors), Olig2 (a nuclear marker present in most gliomas), IDH1 and IDH2 were entirely negative in all tumor cells. Ki67 (MIB-1) showed a low proliferation rate ranging from 2% to 8%. Conclusion: Staining with neuroepithelial markers supports the suggestion of ambiguous differentiation. Subependymal giant cell astrocytomas do not appear to have the typical expression profiles of astrocytic tumors, under which they have been classified

LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases

Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes