Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.

BACKGROUND: Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS: Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. RESULTS: Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS: This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.

The genetics of interdigitating dendritic cell sarcoma share some changes with Langerhans cell histiocytosis in select cases.

Histiocytic disorders have been noted to have evidence of transdifferentiation; examples of cases with combinations of different lineages have been shown. In our index case, we identified interdigitating dendritic cell (IDC) differentiation in a case of Langerhans cell histiocytosis (LCH). Little is currently known about the genetics of IDC sarcoma (IDCS) because they are exceedingly rare. Using array comparative genomic hybridization (aCGH), we evaluated 4 cases of IDCS and compared them with our index case, as well as genetic abnormalities previously found in LCH. Four cases of paraffin-embedded samples of IDCS and 1 case of LCH with IDC differentiation were evaluated using aCGH. Array CGH results showed no abnormalities in a case of LCH with interdigitating cell differentiation. In 3 of 4 cases of IDCS, genetic abnormalities were identified; 1 case had no identifiable abnormalities. Interdigitating dendritic cell sarcoma case 1 had gains of 3q and 13q; IDCS case 2 had trisomy 12; IDCS case 3 had deletions of 7p, 12p, 16p, 18q, 19q, and 22q; and IDCS case 4 had no detectable abnormalities. Our index case, LCH with IDC differentiation, showed no abnormalities by aCGH. A number of LCH cases do not have detectable genetic abnormalities. In contrast, 3 of 4 cases of IDCS evaluated had identifiable abnormalities by aCGH. Furthermore, 2 of these shared abnormalities, albeit of large genetic regions, with published abnormalities seen in LCH. No recurrent abnormalities were identified in the IDCS cases. However, the possibility of a relationship between IDCS and LCH cannot be entirely excluded by these results.

Atypical presentation of isolated peripheral T-cell lymphoma in the hand: case report.

Peripheral T-cell lymphoma is a rare malignancy that characteristically demonstrates generalized lymphadenopathy and extranodal involvement. We describe an atypical case of peripheral T-cell lymphoma manifesting as isolated hand swelling without evidence of nodal disease or systemic symptoms. This report emphasizes the highly variable clinical presentation of T-cell lymphomas and the importance of expeditious incisional biopsy in the setting of an undiagnosed hand mass.

How do I allocate blood products at the end of life? An ethical analysis with suggested guidelines.

Blood products are scarce resources requiring prudent and reasoned allocation. The utilization of red blood cells and platelets in terminally ill patients can be complicated and requires guidelines tempered by individualized considerations. Representative cases are discussed in which blood products are requested or utilized by patients at the end of life. Relevant literature is reviewed and ethical issues pertaining to each case are discussed. A practical approach to blood product utilization at the end of life is suggested.

Syphilis in Hematopathology Practice: A Diagnostic Challenge.

CONTEXT.­: Syphilis, a reemerging disease caused by spirochete Treponema pallidum, is becoming more frequent in surgical pathology and hematopathology practices. Hematopathologists typically receive lymph node biopsies from patients with syphilis who have localized or diffuse lymphadenopathy. Occasionally, syphilis infection in the aerodigestive tract can show a prominent lymphoplasmacytic infiltrate and mimic lymphoma. Besides the varying and occasional atypical morphology, the fact that clinical suspicion tends to be low or absent when histologic evaluation is requested adds to the importance of making this diagnosis. OBJECTIVE.­: To summarize histologic features of syphilitic lymphadenitis and syphilis lesions in the aerodigestive tract, and to review differential diagnosis and potential diagnostic pitfalls. DATA SOURCES.­: Literature review via PubMed search. CONCLUSIONS.­: Characteristic histologic findings in syphilitic lymphadenitis include thickened capsule with plasma cell-rich inflammatory infiltrate, reactive follicular and paracortical hyperplasia with prominent lymphoplasmacytic infiltrate, and vasculitis. Lymph nodes, however, can show a number of other nonspecific histologic features, which frequently makes the diagnosis quite challenging. In the aerodigestive tract, syphilis is characterized by plasma cell-rich infiltrates. Immunohistochemistry for T pallidum is the preferred method for detecting spirochetes; however, this immunohistochemical stain shows cross-reactivity with other treponemal and commensal spirochetes. Differential diagnosis of syphilis in lymph nodes and the aerodigestive tract is broad and includes reactive, infectious, and neoplastic entities. Pathologists should be aware of the histologic features of syphilis and keep this challenging entity in the differential diagnosis.

Strategies for Combatting Health Disparities in Prioritization Schema for Medically-Necessary Time-Sensitive Orthopaedic Surgeries.

A decrease in non-emergent procedure volume was observed during the COVID-19 pandemic to conserve protective equipment, increase hospital capacity, and limit nosocomial infection. Decreasing COVID-19 infection rates, paired with increasing hospital financial pressure and concerns for patient welfare, have prompted the development of guidelines for re-introduction of medically-necessary time-sensitive (MeNTS) procedures. Such protocols have received criticism for potentially perpetuating inequities disfavoring vulnerable populations. Limited access to testing supplies and protective equipment, coupled with higher incidence of medical comorbidities attributable to social determinants of health, disadvantages vulnerable populations in seemingly objective prioritization schema. Here, we detail both an analysis of current guidelines as well as strategies aimed at mitigating these disparities (including prioritizing essential infrastructure workers, implementing questionnaires, improving scheduling communication, tracking patients via ZIP codes and insurance status, facilitating post-operative rehabilitation, acknowledging physician bias, and favoring lottery selection over first-come, first-served). These guidelines and strategies can apply to future pandemics and even routine prioritization schema.

High-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations: clinicopathologic, cytogenetic, and molecular characterization of 4 cases.

High-grade B-cell lymphoma with 11q aberrations (LBL-11q) resembles Burkitt lymphoma (BL), is negative for MYC rearrangement, and harbors chromosome 11q aberrations. Rare cases of high-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations (HGBCL-MYC-11q) have been described. In this study, we report the clinicopathologic, cytogenetic, and molecular findings in 4 such cases. Diagnoses were made on tissue or bone marrow biopsies. Karyotype, fluorescence in situ hybridization, genomic microarray analyses, and next-generation sequencing were performed. All patients were male (median age, 39 years). Three cases were diagnosed as BL, while one was diagnosed as diffuse large B-cell lymphoma. Karyotypes (available in 2 patients) were complex. In 1 patient, copy number analysis showed gains at 1q21.1-q44 and 13q31.3 and loss of 13q34, abnormalities typically seen in BL. All of our cases showed 2 or more mutations that are recurrent in BL, including ID3, TP53, DDX3X, CCND3, FBXO1, and MYC. Two cases showed a GNA13 mutation, commonly seen in LBL-11q. Cases of HGBCL-MYC-11q display overlapping morphologic and immunophenotypic, as well as cytogenetic and molecular features between BL and LBL-11q, with a mutational landscape enriched for mutations recurrent in BL. Concurrent MYC rearrangement with 11q abnormalities is important to recognize, especially as it has implications for their classification.

Classic Hodgkin Lymphoma - Old Disease, New Directions: An Update on Pathology, Molecular Features and Biological Prognostic Markers.

The aim of this paper is to review morphologic, immunophenotypic, and molecular features of classic Hodgkin lymphoma, as well as different prognostic markers in this neoplasm. Classic Hodgkin lymphoma (CHL) accounts for 15-25% of all lymphomas in the Western world. The hallmark of this disease is the neoplastic Hodgkin/Reed-Sternberg (HRS) cell, which is favored to be derived from germinal center B-cells but has lost many of the B-cell markers. HRS cells are scattered within a dense inflammatory infiltrate, and through a network of cytokines and chemokines they shape their microenvironment, evade immune response, survive, and grow. In the last two decades multiple prognostic markers related to HRS cells, the microenvironment or both, have been evaluated in patients with CHL. They include clinical, immunohistochemical, cytogenetic, and molecular markers that can predict survival and identify high-risk patients who will likely relapse after therapy. More recently, circulating tumor DNA analysis by next-generation sequencing has opened new avenues for diagnosis and disease monitoring after therapy. The increased understanding of molecular mechanisms underlying CHL pathogenesis has led to successful implementation of novel therapies, such as anti-PD-1 antibodies, which are becoming a mainstay of treatment in relapsed/refractory patients. CONCLUSION: Currently, pathologic prognostic markers are not routinely assessed at initial diagnosis of CHL. However, as more therapies become available, it will be important to identify patients with high-risk disease who may benefit from more intense or targeted therapy upfront.

The Patient-Pathologist Consultation Program: A Mixed-Methods Study of Interest and Motivations in Cancer Patients.

CONTEXT.­: There is a wide disconnect between patients and the pathologists who make their diagnoses. Recent literature highlights successful programs in which patients meet with pathologists to review their pathology reports and see their tissue under a microscope. We do not know how many patients are interested in such a service, nor do we understand what drives interested patients to want to meet with their pathologist and what specific value it may provide. OBJECTIVE.­: To quantify patient interest in a patient-pathologist consultation program and qualitatively assess motivations for patient interest or disinterest. DESIGN.­: Subjects were recruited from an academic cancer center and a local community cancer support group to respond to a survey about their interest in a patient-pathologist consultation program. Both online forms and paper surveys were available. The online survey was promoted via social media. RESULTS.­: There was a high level of patient interest, with 75% of respondents indicating they were definitely interested in a patient-pathologist consultation program. Key themes of interest were enhanced understanding of the diagnosis and disease, an opportunity to demystify the diagnostic process, and the perception that additional knowledge would empower the patient. CONCLUSIONS.­: In a select group of cancer patients, there is a very high level of interest in a patient-pathologist consultation program. Pathologists, clinicians, and hospital leadership should work together to pilot these programs in diverse settings. Additional quantitative work to scale interventions for the interested population and qualitative work to design effective, patient-centered consultation programs and to assess value are needed.