Atretic cephalocele and encephalocele: A single-institution clinicopathological study.

BACKGROUND: Encephaloceles are neural tube defects characterized by herniation of meninges, neural tissue and cerebrospinal fluid, while atretic cephaloceles denote a rudimentary connection to the intracranial space with absence of herniated neural tissue and represent an infrequent dermatopathologic diagnosis. Limited reports of these entities confound the challenge in their histopathologic distinction. Accurate classification is important given associated anomalies and neurologic manifestations that impact prognosis. METHODS: We describe the clinicopathological and immunohistochemical [glial fibrillary acidic protein (GFAP), S100, epithelial membrane antigen (EMA), and somatostatin receptor subtype 2A (SSTR2A)] features in a retrospective series encountered at a single institution between 1994 and 2020. RESULTS: We identified 13 cases classified as atretic cephalocele (n = 11) and encephalocele (n = 2). Hamartomatous changes and multinucleated cells were unique to atretic cephaloceles while myxoid areas were unique to encephaloceles. At least focal staining for SSTRA was seen in all atretic cephaloceles with the majority (87.5%) staining for EMA; negative staining for GFAP and S100 confirmed absence of neural tissue. Encephaloceles were GFAP and S100 positive, and negative for SSTR2 and EMA. Atretic cephaloceles had a favorable prognosis compared to encephaloceles, with severe morbidity present in both encephalocele cases. CONCLUSION: Our study raises awareness of atretic cephalocele and encephalocele among dermatopathologists and reveals a mutually exclusive immunophenotype that facilitates their distinction for prognostication and management.

World Health Organization 2021 Classification of Central Nervous System Tumors and Implications for Therapy for Adult-Type Gliomas: A Review.

Importance: Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians' ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care. Observations: In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas. Conclusions and Relevance: The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.

Quantitative and histologically validated measures of the entorhinal subfields in ex vivo MRI.

Neuroimaging studies have routinely used hippocampal volume as a measure of Alzheimer's disease severity, but hippocampal changes occur too late in the disease process for potential therapies to be effective. The entorhinal cortex is one of the first cortical areas affected by Alzheimer's disease; its neurons are especially vulnerable to neurofibrillary tangles. Entorhinal atrophy also relates to the conversion from non-clinical to clinical Alzheimer's disease. In neuroimaging, the human entorhinal cortex has so far mostly been considered in its entirety or divided into a medial and a lateral region. Cytoarchitectonic differences provide the opportunity for subfield parcellation. We investigated the entorhinal cortex on a subfield-specific level-at a critical time point of Alzheimer's disease progression. While MRI allows multidimensional quantitative measurements, only histology provides enough accuracy to determine subfield boundaries-the pre-requisite for quantitative measurements within the entorhinal cortex. This study used histological data to validate ultra-high-resolution 7 Tesla ex vivo MRI and create entorhinal subfield parcellations in a total of 10 pre-clinical Alzheimer's disease and normal control cases. Using ex vivo MRI, eight entorhinal subfields (olfactory, rostral, medial intermediate, intermediate, lateral rostral, lateral caudal, caudal, and caudal limiting) were characterized for cortical thickness, volume, and pial surface area. Our data indicated no influence of sex, or Braak and Braak staging on volume, cortical thickness, or pial surface area. The volume and pial surface area for mean whole entorhinal cortex were 1131 ± 55.72 mm3 and 429 ± 22.6 mm2 (mean ± SEM), respectively. The subfield volume percentages relative to the entire entorhinal cortex were olfactory: 18.73 ± 1.82%, rostral: 14.06 ± 0.63%, lateral rostral: 14.81 ± 1.22%, medial intermediate: 6.72 ± 0.72%, intermediate: 23.36 ± 1.85%, lateral caudal: 5.42 ± 0.33%, caudal: 10.99 ± 1.02%, and caudal limiting: 5.91 ± 0.40% (all mean ± SEM). Olfactory and intermediate subfield revealed the most extensive intra-individual variability (cross-subject variance) in volume and pial surface area. This study provides validated measures. It maps individuality and demonstrates human variability in the entorhinal cortex, providing a baseline for approaches in individualized medicine. Taken together, this study serves as a ground-truth validation study for future in vivo comparisons and treatments.

Entorhinal Subfield Vulnerability to Neurofibrillary Tangles in Aging and the Preclinical Stage of Alzheimer's Disease.

BACKGROUND: Neurofibrillary tangle (NFT) accumulation in the entorhinal cortex (EC) precedes the transformation from cognitive controls to mild cognitive impairment and Alzheimer's disease (AD). While tauopathy has been described in the EC before, the order and degree to which the individual subfields within the EC are engulfed by NFTs in aging and the preclinical AD stage is unknown. OBJECTIVE: We aimed to investigate substructures within the EC to map the populations of cortical neurons most vulnerable to tau pathology in aging and the preclinical AD stage. METHODS: We characterized phosphorylated tau (CP13) in 10 cases at eight well-defined anterior-posterior levels and assessed NFT density within the eight entorhinal subfields (described by Insausti and colleagues) at the preclinical stages of AD. We validated with immunohistochemistry and labeled the NFT density ratings on ex vivo MRIs. We measured subfield cortical thickness and reconstructed the labels as three-dimensional isosurfaces, resulting in anatomically comprehensive, histopathologically validated tau "heat maps." RESULTS: We found the lateral EC subfields ELc, ECL, and ECs (lateral portion) to have the highest tau density in semi-quantitative scores and quantitative measurements. We observed significant stepwise higher tau from anterior to posterior levels (p < 0.001). We report an age-dependent anatomically-specific vulnerability, with all cases showing posterior tau pathology, yet older individuals displaying an additional anterior tau burden. Finally, cortical thickness of each subfield negatively correlated with respective tau scores (p < 0.05). CONCLUSION: Our findings indicate that posterior-lateral subfields within the EC are the most vulnerable to early NFTs and atrophy in aging and preclinical AD.

Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report.

Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., POLG) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the POLG gene. Thus, the sequencing of the POLG gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in POLG lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.

Recurrent Intramuscular Hemangioma (Infiltrating Angiolipoma) of the Lower Lip: A Case Report and Review of the Literature.

OBJECTIVE: To report a case of a recurrent intramuscular hemangioma (IMH) of the lower lip of a 68-year-old female and review the published literature to provide an overview of the presentation, diagnostic strategy, pathological classification, and management of these lesions within the oral cavity. METHODS: A case report was conducted by reviewing the documentation at a single institution. A systematic literature review on OVID MEDLINE and PubMed was performed using the MESH terms "intramuscular hemangioma" and "oral cavity," "tongue," "cheek," "buccal," "gingiva," and "lip." RESULTS: A 62-year-old female presented to our institution with a 2 × 2 × 1 cm IMH of the lower lip involving the surrounding orbicularis oris muscle. She underwent a submucosal resection and did well postoperatively. Six and a half years later, she represented to our institution with a new lower lip lesion in the area of her previous resection. Preoperative magnetic resonance imaging showed a new 10 × 11 mm lesion with a well circumscribed central component surrounded by ill-defined tissue. Preoperative angiography showed that the lesion was supplied by vessels branching off the left facial artery, which were embolized. She underwent wide-local excision (WLE) with bilateral advancement flaps and at her 2-month postoperative visit has not had recurrence. CONCLUSION: Only 39 cases of IMH in the oral cavity have been reported, with only 3 others occurring in the lower lip. Here we add the first case of an IMH of the oral cavity that recurred after primary WLE. The patient was successfully retreated with WLE. At a 3-month follow-up visit, she noted some incompetence with oral secretions and occasional tingling along the incision site but no evidence of recurrence.

Empirical ordering of stains in cytology-are we saving or losing?

INTRODUCTION: Bronchoalveolar lavage (BAL) and body cavity fluids (pleural and peritoneal) have a useful role in the detection of infectious diseases, especially when combined with ancillary stains (Grocott methenamine silver, acid-fast bacilli, Fite, and cytomegalovirus). However, empirical ordering of stains and duplicate testing by concurrent microbiology cultures leads to unnecessary wastage of resources. The aim of our study was to optimize the use of resources. MATERIALS AND METHODS: We performed a retrospective review of all BALs and body cavity fluids from 2016 to 2018 to determine the baseline stain order rate, which was then used in conjunction with clinical information to create a reasonable target for 2019. The methods implemented included communication with the clinical team to modify current ordering practice, monitoring stain orders prospectively through 2019, and updating the cytology requisition form to limit upfront ordering of ancillary stains. RESULTS: From 2016 to 2018, of the 1270 specimens reviewed, 323 (55%) were BALs and 108 (16%) were body cavity fluids that had had ≥2 stains preordered. This was reduced by the end of 2019 to 10% of BALs and 3.4% of body cavity fluids, leading to $25,935.24 in costs savings (including 275 hours of technician time and 39.3 hours of pathologist time). CONCLUSIONS: We found that ancillary microorganism stains have limited utility in cytology specimens and should only be ordered when indicated after a review of the initial smears. In today's era of cost savings, upfront ordering of ancillary stains can lead to significant wastage of resources that can be prevented by improving workflow.

Giant cell myositis associated with concurrent myasthenia gravis: a case-based review of the literature.

The term "giant cell myositis" has been used to refer to muscle diseases characterized histologically by multinucleated giant cells. Myasthenia gravis is an autoimmune neuromuscular junction disorder. The rare concurrence of giant cell myositis with myasthenia gravis has been reported; however, the clinical and histological features have varied widely. Here, we present such a case and a review of the literature. An 82-year-old woman admitted for subacute, progressive, proximal muscle weakness developed acute-onset dysphagia, dysphonia, and respiratory distress 5 days after admission. Laboratory findings were positive for acetylcholine receptor binding antibodies and striational muscle antibodies against titin. Muscle biopsy demonstrated widespread muscle fiber necrosis with multinucleated giant cells, consistent with giant cell myositis. She died despite treatment with pulse methylprednisolone and plasma exchange. A literature review of the PubMed and Scopus databases from 1944 to 2020 identified 15 additional cases of these co-existing diagnoses. We found that giant cell myositis with myasthenia gravis primarily affects female patients, is typically diagnosed in the 6-7th decades, and is characterized by the presence of thymoma. Muscle histology predominantly shows giant cell infiltrate without granulomas. The onset of myasthenia gravis symptoms may precede, follow, or coincide with symptoms of myositis. Treatment with thymectomy, anticholinesterase inhibitors, or immunosuppressive therapy may lead to favorable clinical outcomes.

Primary meningeal melanoma masquerading as neurofibromatosis type 2: illustrative case.

BACKGROUND: Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS: The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS: This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.