Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results.

AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible. METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.

Evolving educational landscape in pathology: a comprehensive bibliometric and visual analysis including digital teaching and learning resources.

AIMS: Pathology education is a core component of medical training, and its literature is critical for refining educational modalities. We performed a cross-sectional bibliometric analysis to explore publications on pathology education, focusing on new medical education technologies. METHODS: The analysis identified 64 pathology journals and 53 keywords. Relevant articles were collected using a web application, PaperScraper, developed to accelerate literature search. Citation data were collected from multiple sources. Descriptive statistics, with time period analysis, were performed using Microsoft Excel and visualised with Flourish Studio. Two article groups were further investigated with a bibliometric software, VOSViewer, to establish co-authorship and keyword relationships. RESULTS: 8946 citations were retrieved from 905 selected articles. Most articles were published in the last decade (447, 49.4%). The top journals were Archives of Pathology & Laboratory Medicine (184), Human Pathology (122) and the American Journal of Clinical Pathology (117). The highest number of citations was found for Human Pathology (2120), followed by Archives of Pathology & Laboratory Medicine (2098) and American Journal of Clinical Pathology (1142). Authors with different backgrounds had the greatest number of articles and citations. 12 co-authorship, 3 keyword and 8 co-citation clusters were found for the social media/online resources group, 8 co-authorship, 4 keyword and 7 co-citation clusters for the digital pathology/virtual microscopy/mobile technologies group. CONCLUSIONS: The analysis revealed a significant increase in publications over time. The emergence of digital teaching and learning resources played a major role in this growth. Overall, these findings underscore the transformative potential of technology in pathology education.

Improving Transparency in the Residency Application Process: Survey Study.

BACKGROUND: Increasing numbers of residency applications create challenges for applicants and residency programs to assess if they are a good fit during the residency application and match process. Applicants face limited or conflicting information as they assess programs, leading to overapplying. A holistic review of residency applications is considered a gold standard for programs, but the current volumes and associated time constraints leave programs relying on numerical filters, which do not predict success in residency. Applicants could benefit from increased transparency in the residency application process. OBJECTIVE: This study aims to determine the information applicants find most beneficial from residency programs when deciding where to apply, by type of medical school education background. METHODS: Match 2023 applicants voluntarily completed an anonymous survey through the Twitter and Instagram social media platforms. We asked the respondents to select 3 top factors from a multiple-choice list of what information they would like from residency programs to help determine if the characteristics of their application align with program values. We examined differences in helpful factors selected by medical school backgrounds using ANOVA. RESULTS: There were 4649 survey respondents. When responses were analyzed by United States-allopathic (US-MD), doctor of osteopathic medicine (DO), and international medical graduate (IMG) educational backgrounds, respondents chose different factors as most helpful: minimum United States Medical Licensing Examination (USMLE) or Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Step 2 scores (565/3042, 18.57% US-MD; 485/3042, 15.9% DO; and 1992/3042, 65.48% IMG; P<.001), resident hometown region (281/1132, 24.82% US-MD; 189/1132, 16.7% DO; and 662/1132, 58.48% IMG; P=.02), resident medical school region (476/2179, 22% US-MD; 250/2179, 11.5% DO; and 1453/2179, 66.7% IMG; P=.002), and percent of residents or attendings underrepresented in medicine (417/1815, 22.98% US-MD; 158/1815, 8.71% DO; and 1240/1815, 68.32% IMG; P<.001). CONCLUSIONS: When applying to residency programs, this study found that the factors that respondents consider most helpful from programs in deciding where to apply differ by educational background. Across all educational groups, respondents want transparency around standardized exam scores, geography, and the racial or ethnic backgrounds of residents and attendings.

Virtual Pathology Elective, Real Education: The PathElective.com Experience as a Model for Novel Pathology Pedagogy and a Primer for Curricular Evolution.

CONTEXT.­: PathElective.com was created in response to the pandemic's restrictions on interactions with trainees, and since has been incorporated into many training programs worldwide, serving as a unique means of delivering high-quality pathology and laboratory medical education at multiple levels of training. OBJECTIVE.­: To analyze student usage, performance, and satisfaction to provide insight into the effectiveness of virtual education to guide curricular evolution. DESIGN.­: Squarespace (Squarespace, Inc) was used for website development and to collect website analytics. Students were assessed before and after course participation using a dual-form crossover quiz design. Quiz data were anonymous and analyzed with a paired t test to account for varying student background. A novel analysis was performed aimed at examining the attrition rate of students across multiple modules. RESULTS.­: Over the study period (May 1, 2020 to October 31, 2021), PathElective.com received 577 483 page views, 126 180 visits, 59 928 unique visitors, and 10 278 registered users who earned 15 305 certificates. A total of 7338 premodule and postmodule quiz pairs were analyzed. The overall average increase in score was 13.83% (P = .02). All but 5 of the 56 courses experienced a statistically significant increase in score. All courses received median scores of Very Satisfied/Satisfied in all 6 assessment domains. Aggregate attrition data revealed a unique, negative polynomial relationship (R2 = 0.656). CONCLUSIONS.­: PathElective.com is a free, effective means of enhancing anatomic/clinical pathology training in medical education. These analyses offer a unique perspective on the online user experience and could guide the development of future online medical education resources.

Phenotypic clues that predict underlying cytogenetic/genetic abnormalities in myeloid malignancies: A contemporary review.

Precise subclassification of myeloid malignancies per the World Health Organization (WHO) classification system and the International Consensus Classification of Myeloid Neoplasms and Acute Leukaemias (ICC) requires investigation and documentation of the presence of cytogenetic and/or molecular genetic changes. These ancillary studies not only help in diagnosis, but also the prognosis of disease; however, they take time to be completed. In contrast, morphological evaluation of material from the blood and bone marrow specimens of cases where myeloid malignancies are suspected is usually completed quickly. Cytomorphological assessment may predict genetic changes and can be helpful in triaging acuity. This is especially true in haematological emergencies such as acute promyelocytic leukaemia (APL), where prompt APL-specific therapy can be life changing. Similarly, some morphological clues may help identify core binding factor leukaemias where a diagnosis of acute myeloid leukaemia (AML) could be rendered without reaching the 20% blast cutoff with immediate treatment-decision implications, or even a subset of cases of AML with FLT3 ITD/NPM1 mutation(s) which show characteristic features. Even though FISH/cytogenetics and/or PCR are still required for establishing the final diagnosis, evaluation for the presence of specific cytomorphological features that help predict genetic changes can be a useful tool to help guide early therapy.

Polyamine catabolism is concentrated in tumor-associated histiocytes in diffuse large B-cell lymphoma and classic Hodgkin lymphoma.

Polyamines are cationic molecules necessary for cell survival, growth, and replication [1-5]. Polyamines come in a variety of structural forms and are principally regulated by two enzymes, spermine/spermidine acetyltransferase-1 (SAT1) and ornithine decarboxylase-1 (ODC1). SAT1 targets the polyamines spermidine and spermine for degradation via acetylation, while ODC1 is involved in converting the polyamine precursor molecule to more complex polyamines [6-8]. Polyamines and their regulatory enzymes have been implicated in tumor metastasis [9,10] and in crosstalk between oncogenes [11-13] in numerous types of cancer, but their role has never been evaluated in B-cell malignancies. In this study, we examine the expression of SAT1 in diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). We found that SAT1 is expressed in all examined cases of DLBCL (n = 15) and HL (n = 5), though the levels of expression across cases vary. We also note that SAT1 expression appears to be concentrated in tumor-associated histiocytes, rather than tumor cells in both DLBCL and HL. We propose that these findings indicate that the polyamine catabolic enzyme, SAT1, plays an unappreciated role in the pathogenesis of B-cell neoplasms.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future.

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

Critical role of pathology and laboratory medicine in the conversation surrounding access to healthcare.

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.

Toward a More Just System of Care in Molecular Pathology.

Policy Points 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. It is critical to understand the economic and sociocultural influences that drive patients to undergo or forgo molecular testing, especially in marginalized patient populations. 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. METHODS: We provide case scenarios-loosely based on real-life patients-so that nonexperts can see the impacts of complex policy decisions and unintentional biases in technology without needing to understand all the intricacies. We use data to explain these findings from an extensive literature search examining both peer-reviewed and gray literature. FINDINGS: Access to diagnostic molecular genetic testing is not equitable or sufficient, owing to at least five major factors: (1) cost to the patient, (2) location, (3) lack of provider buy-in, (4) data-set bias, and (5) lack of public trust. CONCLUSIONS: Molecular genetic pathology can be made more equitable with the concerted efforts of multiple stakeholders. Confronting the five major factors identified here may help us usher in a new era of precision medicine without its discriminatory counterpart.

Indolent T-Cell Lymphoproliferative Disease: A Rare Case of a Benign Lymphoma of the Gastrointestinal Tract With Extra-Gastrointestinal Involvement.

Indolent T-cell lymphoproliferative disease of the gastrointestinal (GI) tract is an exceedingly rare benign proliferation of clonal and mature-appearing lymphoid cells originating from the GI tract. We discuss the case of a 52-year-old woman with indolent T-cell lymphoproliferative disease of the GI tract manifesting as chronic diarrhea and profound weight loss. Interestingly, the patient also had extra-GI involvement of her disease process, which has not been previously reported. Our patient was managed with steroids with improvement in symptoms and weight gain. We provide a review of the literature to highlight the importance of early recognition and intervention of this disease entity.

Isolated leukemia cutis as extramedullary relapse of acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. In rare instances, AML can recur with prominent extramedullary manifestations (i.e., leukemia cutis or myeloid sarcoma), either simultaneously or preceding marrow involvement, or as a sole site of primary disease relapse.

The utility of a gross dissection anatomical model for simulation-based learning in pathology.

INTRODUCTION: The examination of morphological alterations in tissues is fundamental in Pathology. Traditional training in gross dissection has several limitations, including the risk of transmissible diseases, formaldehyde exposure and limited specimen availability. We describe a teaching method using anatomical simulators. METHODS: Liquid silicone-based artisan neoplastic anatomical models were used in conjunction with clinical scenarios. Eighty-five medical students participated in a gross dissection experience and were asked to complete a feedback questionnaire. Additionally, a workshop was organized for students to compare three different teaching methods. The first one used still images (Group1-G1), the second a video explanation (Group2-G2), and the third directly observed a pathologist while grossing (Group3-G3). RESULTS: The knowledge acquisition questionnaire showed an average value of 4.4 out of 5 (1-5) (range 3.4-4.7, σ0.89). The categories 'knowledge of resection margins' and 'macroscopic diagnosis' received the highest values (4.8, σ0.11 and 4.7, σ0.32, respectively), followed by 'understanding of handling and gross examination of the surgical specimen' (4.5, σ0.49), 'prognosis' (4.3, σ0.67) and 'understanding of a tumor resection' (3.9, σ0.96) (p<0.05). Regarding teaching methods, G3 spent less time than G2 and G1 with mean times of 15'39″ (σ2'12″), 16'50″ (σ3'45″), and 17'52″ (σ2'12″), respectively (p<0.05). Gross dissection marks (0-5) showed statistically significant differences (p<0.05). G2 obtained better results (3.7;σ0.54) than G3 (3.4;σ0.94) or G1 (3.1;σ0.8). CONCLUSIONS: This preliminary study demonstrates that it is possible to implement a gross dissection simulation module at medical school and thus enable the acquisition of skills in a secure environment.

The utility of a gross dissection anatomical model for simulation-based learning in pathology

Introduction: The examination of morphological alterations in tissues is fundamental in Pathology. Traditional training in gross dissection has several limitations, including the risk of transmissible diseases, formaldehyde exposure and limited specimen availability. We describe a teaching method using anatomical simulators. Methods: Liquid silicone-based artisan neoplastic anatomical models were used in conjunction with clinical scenarios. Eighty-five medical students participated in a gross dissection experience and were asked to complete a feedback questionnaire. Additionally, a workshop was organized for students to compare three different teaching methods. The first one used still images (Group1-G1), the second a video explanation (Group2-G2), and the third directly observed a pathologist while grossing (Group3-G3). Results: The knowledge acquisition questionnaire showed an average value of 4.4 out of 5 (1–5) (range 3.4–4.7, σ0.89). The categories ‘knowledge of resection margins’ and ‘macroscopic diagnosis’ received the highest values (4.8, σ0.11 and 4.7, σ0.32, respectively), followed by ‘understanding of handling and gross examination of the surgical specimen’ (4.5, σ0.49), ‘prognosis’ (4.3, σ0.67) and ‘understanding of a tumor resection’ (3.9, σ0.96) (p<0.05). Regarding teaching methods, G3 spent less time than G2 and G1 with mean times of 15′39″ (σ2′12″), 16′50″ (σ3′45″), and 17′52″ (σ2′12″), respectively (p<0.05). Gross dissection marks (0–5) showed statistically significant differences (p<0.05). G2 obtained better results (3.7;σ0.54) than G3 (3.4;σ0.94) or G1 (3.1;σ0.8). Conclusions: This preliminary study demonstrates that it is possible to implement a gross dissection simulation module at medical school and thus enable the acquisition of skills in a secure environment.(AU)

Introducción: En Anatomía Patológica el examen macroscópico y la disección resultan fundamentales para alcanzar un diagnóstico correcto. Los métodos tradicionales de enseñanza de esta habilidad presentan limitaciones, como el riesgo de enfermedad transmisible, la exposición al formol y la disponibilidad de especímenes. Describimos aquí un método de enseñanza en disección utilizando simuladores anatómicos. Material y métodos: Se usaron modelos anatómicos neoplásicos artesanales que utilizan silicona líquida. Ochenta y cinco estudiantes de medicina participaron en una experiencia de examen macroscópico y disección y cumplimentaron un cuestionario sobre su percepción de aprendizaje adquirido. Además, se organizó un taller para comparar 3 metodologías distintas: imágenes estáticas (Grupo 1), vídeo (Grupo 2) y observación directa de un patólogo tallando (Grupo 3). Resultados: El cuestionario de conocimientos adquiridos mostró una valoración media de 4,4 sobre 5 (1-5) (rango 3,4-4,7, σ=0,89). Las categorías de «conocimiento sobre márgenes quirúrgicos» y «diagnóstico macroscópico» obtuvieron las mejores valoraciones (4,8, σ=0,11 y 4,7, σ=0,32, respectivamente), seguidas del «manejo de una pieza quirúrgica y su disección» (4,5, σ=0,49), el «pronóstico» (4,3, σ=0,67) y la «comprensión de una cirugía tumoral» (3,9, σ=0,96) (p<0,05). En relación con el método de enseñanza, el Grupo 3 realizó la disección en menos tiempo que el Grupo 2 y el Grupo 1, con unos tiempos medios de 15′39″ (σ=2′12″), 16′50″ (σ=3′45″), y 17′52″ (σ=2′12″), respectivamente (p<0,05). Por otra parte, se encontraron resultados estadísticamente significativos en función de la metodología utilizada (0-5) (p<0,05). El Grupo 2 obtuvo mejores resultados (3,7; σ=0,54) comparado con el Grupo 3 (3,4; σ=0,94) y el Grupo 1 (3,1; σ=0,8). Conclusiones: Este estudio preliminar demuestra que es posible implementar un módulo de simulación en disección en el Grado en Medicina, permitiendo esta metodología adquirir la habilidad en un entorno seguro.(AU)

Heterotopic Mesenteric Ossification With Trilineage Hematopoiesis.

Heterotopic ossification (HO) histologically refers to extraskeletal bone formation in non-ossifying tissues, most commonly noted in the extremities, buttocks, abdominal wall, and hip joints. HO developing in the mesentery (heterotopic mesenteric ossification, HMO) is very rare, with fewer than 100 cases reported in the literature. It usually occurs in adult male patients with a history of repeated abdominal trauma. So far, only two cases of HMO have been reported with the development of hematopoietic bone marrow. Here, we report the third case of HMO with true trilineage hematopoiesis in a 66-year-old female with suspicious mesenteric-retained foreign material from prior surgical procedures, including hysterectomy for endometrial adenocarcinoma and multiple repairs for incisional hernia.

Nodular Histiocytic/Mesothelial Hyperplasia Mimicking Mesenteric Metastasis.

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.

Challenges and Opportunities in Using Twitter as a Pedagogical Tool in Pathology and Laboratory Medicine Education.

OBJECTIVES: Even though the benefits of using Twitter for teaching and information exchange within the pathology community are primarily undisputed, a fair number of users refrain from sharing educational content on this social media platform. The survey aims to identify challenges in using Twitter as a pedagogical tool and discuss ways of converting those challenges into opportunities. METHODS: We performed a cross-sectional survey-based study involving 174 participants from the pathology community on Twitter. RESULTS: The results demonstrated that procurement of content was the major challenge faced by 36.2% of the participants, with most participants being concerned or very concerned regarding institutional policies and Health Insurance Portability and Accountability Act issues. Content procurement concerns were followed by social media inertia, stated by 23% of the participants as an obstacle to posting educational content on Twitter. CONCLUSIONS: The report helps elicit some common obstacles faced by the pathology and laboratory medicine community and allows us to recommend solutions to overcome these obstacles.

Measuring the Efficacy of Pathology Career Recruitment Strategies in US Medical Students.

CONTEXT.­: Multiple articles and surveys in the literature suggest that medical students find a career in pathology undesirable and believe it is disproportionately focused primarily on the autopsy. OBJECTIVE.­: To measure the effect of applied interventions on medical student attitudes about the field of pathology. DESIGN.­: This prospective study involving medical students from first through fourth year was conducted as a pilot study in 2 medical schools in the United States. A 2-part anonymous survey regarding interest in pathology as a career and familiarity with the specialty using a 10-point scale was given to first- and second-year medical students before and after they listened to a 10-minute pathology career presentation. The same survey was given to third- and fourth-year medical students before and after a 4-week pathology elective. RESULTS.­: A total of 121 and 83 students responded to the survey before and after the intervention, respectively. Of the 121 students who responded to the survey before the intervention, 106 (87.6%) had not spent significant time in a pathology laboratory before the intervention. The majority of responses in interest in career, job responsibilities, and features of pathologists before and after the intervention demonstrated a statistically significant difference (P < .001). We compared survey scores of presentation versus 4-week rotation groups before and after the intervention. Students who experienced the presentation did not differ from students who experienced the rotation in the majority of questions related to interest in career, job responsibilities, and features of pathologists. CONCLUSIONS.­: Our study suggests that pathology exposure strategies can have a beneficial effect on student perceptions of the field and consideration of a career in pathology. Overall, the presentation intervention seemed to have the greatest effect on the first- and second-year students.

Hemophagocytic Lymphohistiocytosis.

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.