We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms, RUNX1, ASXL1, TET2, CEBPA, IDH1, IDH2, DNMT3A, FLT3, NPM1, TP53, NRAS, EZH2, CBL, U2AF1, SF3B1, SRSF2, JAK2, CSF3R, and SETBP1, across 93 cases of acute myeloid leukemia (AML) using capture target enrichment and next-generation sequencing. Of these cases, 79% showed at least one nonsynonymous mutation, and cases of AML with recurrent genetic abnormalities showed a lower frequency of mutations versus AML with myelodysplasia-related changes (P<0.001). Mutational analysis further demonstrated that TP53 mutations are associated with complex karyotype AML, whereas ASXL1 and U2AF1 mutations are associated with AML with myelodysplasia-related changes. Furthermore, U2AF1 mutations were specifically associated with trilineage morphologic dysplasia. Univariate analysis demonstrated that U2AF1 and TP53 mutations are associated with absence of clinical remission, poor overall survival (OS), and poor disease-free survival (DFS; P<0.0001), whereas TET2 and ASXL1 mutations are associated with poor OS (P<0.03). In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance in OS and DFS, respectively. Our results demonstrate unique relationships between mutations in AML, clinicopathologic prognosis, subtype categorization, and morphologic dysplasia.

Hemophagocytic lymphohistiocytosis is a rare multi-system inflammatory disorder with diagnostic criteria based on the HLH-2004 trial. Hemophagocytosis is the only histomorphologic criterion, but in isolation is neither specific nor sensitive for the diagnosis of hemophagocytic lymphohistiocytosis. While objective thresholds for clinical and laboratory criteria have been established, specific criteria for histomorphologic evidence of hemophagocytosis in hemophagocytic lymphohistiocytosis have not been rigorously evaluated or established. We sought to determine if numerical and objective criteria for morphologic hemophagocytosis could be identified, and if such criteria would aid in the diagnosis of hemophagocytic lymphohistiocytosis. We analyzed the morphologic features of hemophagocytosis in 78 patients presenting with clinical features suspicious for hemophagocytic lymphohistiocytosis: 40 patients with hemophagocytic lymphohistiocytosis and 38 patients without hemophagocytic lymphohistiocytosis. We demonstrate that non-nucleated erythrophagocytosis alone is a non-specific finding, while hemophagocytosis of granulocytes (1 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.86, 0.99), nucleated erythrocytes (4 per 1000 cells, area under the curve: 0.92, 95% confidence interval: 0.87, 0.98), and at least one hemophagocyte containing multiple nucleated cells (area under the curve: 0.91, 95% confidence interval: 0.85, 0.95) are strongly associated with hemophagocytic lymphohistiocytosis. Joint modeling of hemophagocytes containing engulfed granulocytes, nucleated erythrocytes, and lymphocytes effectively distinguished between hemophagocytic lymphohistiocytosis and non-hemophagocytic lymphohistiocytosis (cross-validated area under curve: 0.90, 95% confidence interval: 0.83, 0.97).

T-lymphoblastic lymphoma is an aggressive neoplasm requiring prompt clinical treatment. Conversely, indolent T-lymphoblastic proliferation mimics T-lymphoblastic lymphoma but consists of a proliferation of non-neoplastic TdT+ T cells, requiring no treatment. Recently, we identified several cases of indolent T-lymphoblastic proliferations in extrathymic lymphoid tissues: 1 in a patient suffering from Castleman disease (CD) associated with a follicular dendritic cell sarcoma/tumor, 1 in a patient with a history of angioimmunoblastic T-cell lymphoma (AITL), and 1 in association with acinic cell carcinoma. Interestingly, in the case of the patient with a history of AITL, these TdT+ T cells were seen in multiple anatomic sites over the span of 5 years. Here we review these 3 cases and extend our findings by demonstrating that TdT+ T-lymphoblastic populations are increased in lymph nodes of patients with CD (P=0.011), CD in association with follicular dendritic cell tumors, and AITL (P<0.01) compared with other T-cell or B-cell lymphomas or reactive lymph nodes. Finally, analysis of 352 nonhematolymphoid tumors including carcinomas, melanomas, and sarcomas demonstrates that TdT+ T cells are not increased in these tumors. Our studies not only present several detailed cases of indolent T-lymphoblastic proliferations, but also correlate these populations with specific hematologic diseases.

In recent years, a new pathologic entity has emerged: indolent T-lymphoblastic proliferation (iT-LBP). iT-LBPs share immunophenotypic similarities with T-lymphoblastic lymphoma; however, T-lymphoblastic proliferations are clinically indolent, and unlike the malignant counterpart, these expansions of nonclonal terminal deoxynucleotidyl transferase (TdT)+ T cells do not require treatment. Here we review the clinical and pathologic features, which are required for an accurate diagnosis of an iT-LBP. We demonstrate specific criteria can be used to accurately diagnose iT-LBP, notably: (1) confluent groups of TdT+ T cells in a biopsy specimen, (2) relative preservation of surrounding normal lymphoid architecture, (3) TdT+ T cells without morphologic atypia, (4) absence of thymic epithelium, (5) nonclonal TdT+ T cells, (6) immunophenotype of developmentally normal immature thymic T cells, and (7) clinical evidence of indolence (follow-up >6 mo without progression).

Key Points: A single rare DNMT3A mutation and recurrent amplification of ETS1, PTPN6, and TGFBR2 are identified in iMCD and UCD. Genetic alterations in oncogenes, tumor suppressors, and chromatin-remodeling genes are seen in FDCS.

Kids armed with anti-coronavirus B cells: It remains unclear whether B cell repertoires against coronaviruses and other pathogens differ between adults and children and how important these distinctions are. Yang et al. analyzed blood samples from young children and adults, as well as tissues from deceased organ donors, characterizing the B cell receptor (BCR) repertoires specific to six common pathogens and two viruses that they had not seen before: Ebola virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Children had higher frequencies of B cells with convergent BCR heavy chains against previously encountered pathogens and higher frequencies of class-switched convergent B cell clones against SARS-CoV-2 and related coronaviruses. These findings suggest that encounters with coronaviruses in early life may produce cross-reactive memory B cell populations that contribute to divergent COVID-19 susceptibilities. Science , this issue p. 738