Context.— Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. Objective.— To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. Data Sources.— Peer-reviewed literature. Conclusions.— HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.

The COVID-19 pandemic put most in-person pathology electives on-hold as departments adapted to changes in education and patient care. To address the subsequent void in pathology education, we created a free, virtual, modular, and high-quality pathology elective website. Website traffic from June 1, 2020, to October 1, 2020, was monitored using the built-in analyses on Squarespace. Twitter engagement was analyzed using Twitter analytics and the Symplur Social Graph Score. A voluntary satisfaction survey was sent to all PathElective users and results were analyzed. During this time, the site saw 25 467 unique visitors, over 34 988 visits, 181 302 page views, and 4449 subscriptions from 99 countries. Countries with the highest traffic are the United States (14 682), India (5210), and the Philippines (2195). PathElective’s Twitter social graph score increased from 63.59 to 89.3 with the addition of 1637 followers. Data from surveyed users (n = 177) show most to be pathology residents (41%). Most subscribers (89%) are committed to a career in pathology. The majority heard of the website via Twitter (55%). Almost half of those surveyed engaged with the PathTwitter community on Twitter and of those who participated, 99% found that interaction useful. In all survey questions surrounding satisfaction and usefulness, a large majority of the users were either satisfied or very satisfied. PathElective is a novel pathology elective that offers a unique opportunity to educate medical students and residents from around the globe and demonstrates high effectiveness and satisfaction among users.

Pathology and laboratory medicine are a key component of a patient’s healthcare. From academic care centres, community hospitals, to clinics across the country, pathology data are a crucial component of patient care. But for much of the modern era, pathology and laboratory medicine have been absent from health policy conversations. Though select members in the field have advocated for an enhanced presence of these specialists in policy conversations, little work has been done to thoroughly evaluate the moral and ethical obligations of the pathologist and the role they play in healthcare justice and access to care. In order to make any substantive improvements in access to care, pathology and laboratory medicine must have a seat at the table. Specifically, pathologists and laboratorians can assist in bringing about change through improving clinician test choice, continuing laboratory improvement programmes, promoting just advanced diagnostic distribution, triage testing and be good stewards of healthcare dollars, and recruiting a more robust laboratory workforce. In order to get to that point, much work has to be done in pathology education and the laboratory personnel training pipeline but there also needs to be adjustments at the system level to better involve this invaluable group of specialists in these policy conversations.

Nodular histiocytic/mesothelial hyperplasia (NHMH) is a rare histologic entity, characterized by localized benign reactive proliferation of histiocytes and mesothelial cells. The presence of this rare entity poses a challenge in differential diagnosis, both in radiological findings and pathological interpretations under certain circumstances, and consequently has been misdiagnosed as malignancy. Here, we report a case of mesenteric NHMH in a patient with colonic mucinous adenocarcinoma. Histology shows numerous large calretinin (+) mesothelial cells mixed with CD68 (+) histiocytes by immunohistochemistry. In contrast to almost all previously reported cases with typical features of histiocytic predominance, the current case of NHMH mainly consists of mesothelial cells with intermixed histiocytes. The findings expand the histologic spectrum of NHMH and contribute to awareness of this entity in the differential diagnosis.

No abstract

Orphan nuclear receptor 4A2 (NR4A2/Nurr1) is a constitutively active transcription factor with potential roles in the onset and progression of inflammatory arthropathies. NR4A2 is overexpressed in synovium and cartilage from individuals with rheumatoid arthritis (RA), psoriatic arthritis, and osteoarthritis. This study documents the expression and tissue localization of NR4A2 and upstream regulator nuclear factor kappa B (NF-κB) in the human tumor necrosis factor-alpha (hTNF-α) transgenic mouse model of RA. Since TNF-α is a potent inducer of NR4A2 in vitro, we hypothesized that NR4A2 would also be upregulated and active during disease progression in this model. Expression levels of NR4A2, related receptors NR4A1 (Nur77) and 3 (NOR1), and NF-κB1 transcripts were quantified by RT-qPCR in hTNF-α and wild-type joints at three stages of disease. The protein distribution of NR4A2 and NF-κB subunit RelA (p65) was analyzed by quantitative immunohistochemistry. Global gene expression of 88 RA-related genes was also screened and compared between groups. Consistent with previous reports on the hTNF-α model, transgenic mice exhibited significant weight loss and severely swollen paws by 19 weeks of age compared to age-matched wild-type controls. NR4A1-3 and NF-κB1 were constitutively expressed at disease onset and in healthy joints. NF-κB1 transcript levels increased 2-fold in hTNF-α paws with established disease (12 weeks), followed by a 2-fold increase in NR4A2 at the late disease stage (19 weeks). NR4A2 and RelA proteins were overexpressed in inflamed synovium prior to symptoms of arthritis, suggesting that gene expression changes documented in whole paws were largely driven by elevated expression in diseased synovium. Broader screening of RA-related genes by RT-qPCR identified several differentially expressed genes in hTNF-α joints including those encoding inflammatory cytokines and chemokines, matrix-degrading enzymes and inhibitors, cell surface receptors, intracellular signaling proteins and transcription factors. Consensus binding sites for NR4A receptors and NF-κB1 were enriched in the promoters of differentially expressed genes suggesting central roles for these transcription factors in this model. This study is the first comprehensive analysis of NR4A2 in an animal model of RA and validates the hTNF-α model for testing of small molecules and genetic strategies targeting this transcription factor.

Human intestinal spirochetosis (HIS) refers to the colonization of spirochetal bacteria in the human intestinal tract. HIS caused by Brachyspira spp. has been recognized for decades, but their pathological and clinical significance is largely unclear. The coincidence of dysplasia in adenoma or adenocarcinoma and HIS is very rare, and whether spirochetes can colonize on dysplastic epithelium remains controversial. Here, we report a case that showed abrupt abolition of mucosal surface fringe formation on a tubular adenoma (TA) and increased cytoplasmic MUC1 expression in the dysplastic epithelial cells compared with adjacent nondysplastic colonocytes. The findings support the hypothesis that the epithelial colonization of spirochetes is significantly reduced by dysplasia likely due to loss of microvilli, and an increase of epithelial MUC1 expression might contribute to reduced spirochetal colonization in colonic mucosa.

r American health care policy must be critically assessed to establish the role it plays in sustaining and alleviating the health disparities that currently exist in molecular genetic testing.r It is critical to understand the economic and sociocultural influences that drive patients to undergo or forgo molecular testing, especially in marginalized patient populations.r A multipronged solution with actions necessary from multiple stakeholders is required to reduce the cost of health care, rebalance regional disparities, encourage physician engagement, reduce data bias, and earn patients' trust. Context:The health status of a population is greatly influenced by both biological processes and external factors. For years, minority and low socioeconomic patient populations have faced worse outcomes and poorer health in the United States. Experts have worked extensively to understand the issues and find solutions to alleviate this disproportionate burden of disease. As a result, there have been some improvements and successes, but wide gaps still exist. Diagnostic molecular genetic testing and so-called personalized medicine are just now being integrated into the current American health care system. The way in which these tests are integrated can either exacerbate or reduce health disparities.