A case of VEXAS syndrome presenting with unusual bone marrow granulomas: a diagnostic dilemma.

BACKGROUND: VEXAS is a recently described inflammatory disease caused by mutations in the UBA1 gene. Symptoms are diverse and include fevers, cartilaginous inflammation, lung inflammation, vasculitis, neutrophilic dermatoses, and macrocytic anemia. Cytoplasmic inclusions in myeloid and erythroid progenitors in the bone marrow are a hallmark feature. Here we report the first case of VEXAS with non-caseating granulomas in the bone marrow. CASE PRESENTATION: A 62-year-old Asian male presented with fevers, erythema nodosum, inflammatory arthritis, and periorbital inflammation. Labs were significant for persistently elevated inflammatory markers and macrocytic anemia. Over the years his symptoms and inflammatory markers only improved with glucocorticoids and recurred when prednisone dose was lowered below 15-20 mg daily. He underwent bone marrow biopsy showing non-caseating granulomas and PET scan showing hilar/mediastinal lymphadenopathy. He was initially diagnosed with IgG4-related disease (treated with rituximab) and later sarcoidosis (treated with infliximab). After failing these agents, the possibility of VEXAS was considered and later confirmed by molecular testing. CONCLUSIONS: To the best of our knowledge, this is the first observation of non-caseating granulomas in VEXAS, a cautionary reminder of its non-specificity since misinterpretation can lead to diagnostic delay. VEXAS should be in the differential in patients with symptoms of chronic inflammation responding positively to steroids (but not to B-cell depletion or TNF inhibition), which is in line with previous literature.

Positron Emission Tomography-Computed Tomography Imaging of Selective Lobar Delivery of Stem Cells in Ex Vivo Lung Model of Mechanical Ventilation.

Introduction: The delivery of cell therapies may be an important frontier to treat different respiratory diseases in the near future. However, the cell size, delivery conditions, cell viability, and effect in the pulmonary function are critical factors. We performed a proof-of-concept experiment using ex vivo lungs and novel subglottic airway device that allows for selective lobar isolation and administration of drugs and biologics in liquid solution deep into the lung tissues, while simultaneously ventilating the rest of the lung lobes. Methods: We used radiolabeled cells and positron emission tomography-computed tomography (PET-CT) imaging to demonstrate the feasibility of high-yield cell delivery to a specifically targeted lobe. This study proposes an alternative delivery method of live cells labeled with radioactive isotope into the lung parenchyma and tracks the cell delivery using PET-CT imaging. The technique combines selective lobar isolation and lobar infusion to carry large particles distal to the trachea, subtending bronchial segments and reaching alveoli in targeted regions. Results: The solution with cells and carrier achieved a complete and homogeneous lobar distribution. An increase in tissue density was shown on the computed tomography (CT) scan, and the PET-CT imaging demonstrated retention of the activity at central, peripheral lung parenchyma, and pleural surface. The increase in CT density and metabolic activity of the isotope was restricted to the desired lobe only without leak to other lobes. Conclusion: The selective lobe delivery is targeted and imaging-guided by bronchoscopy and CT to a specific diseased lobe during mechanical ventilation. The feasibility of high-yield cell delivery demonstrated in this study will lead to the development of potential novel therapies that contribute to lung health.

Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.

PURPOSE: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML). METHODS: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases. RESULTS: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1, FLT3, KRAS, and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML (NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070). CONCLUSION: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.

Human herpesvirus 8-negative effusion-based large B-cell lymphoma: a distinct entity with unique clinicopathologic characteristics.

Rare cases of human herpesvirus 8 (HHV8)-negative effusion-based large B-cell lymphoma (EB-LBCL) occur in body cavities without antecedent or concurrent solid mass formation. In contrast to HHV8 + primary effusion lymphoma (PEL), EB-LBCL has no known association with HIV or HHV8 infection. However, the small sample sizes of case reports and series worldwide, especially from non-Japanese regions, have precluded diagnostic uniformity. Therefore, we conducted a retrospective, multi-institutional study of 55 cases of EB-LBCL and performed a comprehensive review of an additional 147 cases from the literature to identify distinct clinicopathologic characteristics. In our study, EB-LBCL primarily affected elderly (median age 80 years), immunocompetent patients and manifested as lymphomatous effusion without a solid component. The lymphomatous effusions mostly occurred in the pleural cavity (40/55, 73%), followed by the pericardial cavity (17/55, 31%). EB-LBCL expressed CD20 (53/54, 98%) and PAX5 (23/23, 100%). Most cases (30/36, 83%) were of non-germinal center B-cell subtype per the Hans algorithm. HHV8 infection was absent (0/55, 0%), while Epstein-Barr virus was detected in 6% (3/47). Clinically, some patients were managed with drainage alone (15/34, 44%), while others received rituximab alone (4/34, 12%) or chemotherapy (15/34, 44%). Eventually, 56% (22/39) died with a median overall survival (OS) of 14.9 months. Our findings were similar to those from the literature; however, compared to the non-Japanese cases, the Japanese cases had a significantly higher incidence of pericardial involvement, a higher rate of chemotherapy administration, and longer median OS. Particularly, we have found that Japanese residence, presence of pericardial effusion, and absence of MYC rearrangement are all favorable prognostic factors. Our data suggest that EB-LBCL portends a worse prognosis than previously reported, although select patients may be managed conservatively. Overall, EB-LBCL has distinct clinicopathologic characteristics, necessitating the establishment of separate diagnostic criteria and consensus nomenclature.

A Flow Cytometric Study of Reagent Cells to Resolve ABO Typing Discrepancy.

OBJECTIVES: RBC alloantibodies can lead to ABO grouping discrepancies unrelated to A or B antigens or antibodies posing challenges in the blood bank testing. Routine blood bank testing and flow cytometry were used to immunophenotype reagent cells and elucidate the cause of ABO discrepancies in two patients. METHODS: ABO discrepancy was identified in two patients after transfusion with several units of RBCs. For both patients, the pretransfusion type and screen demonstrated blood group A. Eight and 16 days later, both patients showed an apparent antibody to reagent group A cells, which prompted additional study with patients' samples and flow cytometric testing of commercial reagent cells. RESULTS: In both patients' specimens, posttransfusion evaluation demonstrated an emerging antibody to the Kell antigen (K). The RBCs of both patients typed negative for K, and both were transfused with K-positive RBCs. Flow cytometric analysis of reagent RBCs demonstrated that five of seven lot numbers were positive for K. CONCLUSIONS: Emerging anti-K antibody led to agglutination of the K-positive reagent A1 cells, highlighting the importance of considering RBC alloantibodies and the composition of reagent cells when interpreting cases with an apparent ABO grouping discrepancy.

EBV-Positive Primary Large B-Cell Lymphoma: The Role of Immunohistochemistry and XPO1 in the Diagnosis of Mediastinal Lymphomas.

Primary mediastinal (thymic) large B-cell lymphoma (PMBL) is described as almost always negative for Epstein-Barr virus (EBV). In the context of a mediastinal lymphoma, the distinction between PMBL, classical Hodgkin lymphoma, diffuse large B-cell lymphoma, and mediastinal gray-zone lymphoma can be very difficult; hence, EBV positivity often argues against PMBL. We present a 19-year-old man with mediastinal mass morphologically consistent with PMBL. The tumor expressed classic immunophenotype, including positivity for CD20, CD19, MAL, OCT2, BOB1, BCL6, CD79a, and subset positivity for CD30. However, the tumor was EBV-positive by in situ hybridization. Next-generation sequencing detected somatic mutations in XPO1 (E571K), SMARCB1 (L356fs), and MYCC (T73A). Although the immunophenotype and XPO1 mutation are characteristic of PMBL, EBV expression is uncommon. Since EBV positivity can occur in rare PMBLs, it should not be the deciding factor in the diagnosis. This is the first EBV-positive PMBL in which mutational profiling has been reported. Aside from providing diagnostic support, the finding of the XPO1 E571K mutation may suggest a targeted therapeutic option.