Yang Shi

PURPOSE: CNS involvement in North American adult T-cell leukemia/lymphoma (NA-ATLL) remains poorly understood. This study examined the CNS involvement in patients with ATLL treated at a tertiary hospital in New York City. METHODS: CNS involvement was defined by positive cerebrospinal fluid (CSF) cytology, flow cytometry, positive CNS imaging, or neurological examination findings. RESULTS: Among 94 patients with NA-ATLL, 21 (22.3%) had CNS involvement. CSF was involved in 13 patients at diagnosis and five at relapse. Magnetic resonance imaging detected brain and spinal involvement in 24% and 14% of the patients, respectively. Results of neurological examinations were abnormal in 33% and 14% of the patients at diagnosis and relapse, respectively. The XPO1 E571K mutation was found in two patients with extensive, treatment-refractory CNS disease, with a median overall survival (OS) of 2 months. Other mutations, including KLF2 and PI3KCD , were noted in two patients. The median OS was 8.5 months, and the median relapse-free survival (RFS) was 6.5 months in our series. In most cases (5/21), the lymphomatous phenotype appeared to have a direct mass-like extension, whereas in patients with predominant blood involvement tended to spread to the CSF by traversing the blood-brain barrier. CONCLUSION: In this report, we describe the patterns of CNS involvement in ATLL and their association with mutations. We also describe two rapidly fatal cases with the XPO1 E571K mutation, which may represent a novel therapeutic target for T-cell lymphomas.

A metronomic, low-dose schedule of decitabine and venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an older diverse population. Median overall survival for patients with acute myeloid leukemia and a TP53-mutation was 16.1 and 11.3 months, respectively. This trial was registered at www.clinicaltrials.gov as #NCT05184842.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). Its most common immunophenotype is CD4+/CD7–/CD25+, although unusual immunophenotypes can occur and may lead to misdiagnosis. The immunophenotypes, cytogenetics, molecular features, clinical presentations, treatment, and prognosis of 131 patients with ATLL were retrospectively studied in a large tertiary medical center in the United States. All cases showed loss of CD7 expression. While 82.4% of cases demonstrated CD4+, 17.6% exhibited unusual phenotypes, including CD4+/CD8+ (6.9%), CD4–/CD8– (2.3%), CD5– (3.1%), CD2–, and CD3–. The most common cytogenetics abnormalities included polysomy 3 (34.6%), translocation 1 (23.1%), and abnormalities found on chromosome 11 (30.8%) and chromosome 14 (26.9%). The common gene mutations identified by the next-generation sequencing study were TP53 (16.7%), TBL1XR1 (16.7%), EP300 (14.3%), and NOTCH1 (14.3%). TBL1XR1 mutation is associated with genetic instabilities. There was no significant difference between the clinical presentations of these 2 groups. Adult T-cell leukemia/lymphoma exhibits versatile immunophenotypic, cytogenetic, and molecular features. Simultaneous involvement of blood, lymph nodes, and other organs, along with hypercalcemia in a patient from an endemic area, necessitates HTLV-1 testing to avoid underdiagnosis of this dismal disease that might need aggressive chemotherapy followed by bone marrow transplant.

Myelodysplastic syndrome (MDS) is a clonal malignancy arising in hematopoietic stem cells (HSCs). The mechanisms of MDS initiation in HSCs are still poorly understood. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in acute myeloid leukemia, but in MDS, PI3K/AKT is often down-regulated. To determine whether PI3K down-regulation can perturb HSC function, we generated a triple knockout (TKO) mouse model with Pik3ca , Pik3cb , and Pik3cd deletion in hematopoietic cells. Unexpectedly, PI3K deficiency caused cytopenias, decreased survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. TKO HSCs exhibit impaired autophagy, and pharmacologic autophagy induction improved HSC differentiation. Using intracellular LC3 and P62 flow cytometry and transmission electron microscopy, we also observed abnormal autophagic degradation in patient MDS HSCs. Therefore, we have uncovered an important protective role for PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation and to prevent MDS initiation.

Anaplastic myeloma (AM) is an extremely rare and aggressive histological variant of myeloma. It is characterized by extramedullary presentation in the young and has a poor prognosis. It can be a diagnostic challenge when myeloma is not suspected and even more when the immunophenotype is unexpected. We present a rare presentation of anaplastic myeloma with cardiovascular involvement. Though the patient did not have the typical clinical features of myeloma, except lytic lesion in the femur, the cardiac biopsy showed sheets of anaplastic cells, and some with multinucleation. There were also some areas with a more plasmacytoid appearance. The initial immunohistochemical panel was negative for CD3, CD20, CD138, AE1/3, and kappa. It was positive for lambda. This led to an extended panel which showed positivity for CD79a and MUM1 and negative for LMP-1, HHV-8, CD43, CD117, CD56, and CD30. Even the flow cytometry on the bone marrow showed a small population of atypical cells positive for CD38 and negative for CD138 with lambda restriction. This is an unusual case of anaplastic myeloma with cardiovascular involvement and CD138 negativity. This case highlights the need to add a panel of plasma cell markers when myeloma is suspected, and it is pertinent to read flow cytometry with caution to avoid missing atypical plasma cells which maybe CD38+/CD138−.

Context.—: Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. Objective.—: To investigate the appropriate approach to diagnose CD138− plasmablastic lymphoma and avoid misdiagnosis. Design.—: We studied 21 cases of CD138− PBL from multiple large institutes in the United States and 21 cases from the literature. Results.—: CD138− PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV− cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Conclusions.—: Our study emphasizes that CD138− PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.

To distinguish a reactive eosinophilia from its malignant counterpart is challenging. Establishing clonality of the eosinophils is crucial and considered the determining factor for establishing a diagnosis. Cases of hypereosinophilia without clear reactive etiologies, no evidence of end-organ damage, normal cytogenetics, and no molecular mutations are termed as Idiopathic Hypereosinophilia (IHE). For cases which lie between the spectrum of chronic eosinophilic leukemia (CEL) and IHE, identification of underlying molecular abnormalities might be helpful in better understanding the disease process and prognosis. Here, we report two cases of hypereosinophilia in which five possible novel molecular mutations were identified by targeted next-generation sequencing (NGS) analysis. They were FBXW7, KM2A, TCF3, ERBB4, and MET. With multiple genetic mutations, these cases could be classified as chronic eosinophilic leukemia. Both these young patients responded well to steroid therapy. While targeted NGS is a useful tool in identifying new molecular mutation associated with hypereosinophilia, our cases raise the question of further investigating this entity and if there is a possibility of an intermediate category lying between the spectrum of CEL and IHE. Defining hypereosinophilia with clonal molecular abnormality as a malignant process may need to be revisited. Even though attempts are being made to identify mutations in IHE, it might be more significant clinically to differentiate them based on response to steroid therapy and prognosis.

Primary effusion lymphoma (PEL) is a rare type of large B-cell lymphoma associated with human herpesvirus 8 (HHV8) infection. Patients with PEL usually present with an effusion, but occasionally with an extracavitary mass. In this study, we reported a cohort of 70 patients with PEL: 67 men and 3 women with a median age of 46 years (range 26–91). Of these, 56 (80%) patients had human immunodeficiency virus (HIV) infection, eight were HIV-negative, and six had unknown HIV status. Nineteen (27%) patients had Kaposi sarcoma. Thirty-five (50%) patients presented with effusion only, 27 (39%) had an extracavitary mass or masses only, and eight (11%) had both effusion and extracavitary disease. The lymphoma cells showed plasmablastic, immunoblastic, or anaplastic morphology. All 70 (100%) cases were positive for HHV8. Compared with effusion-only PEL, patients with extracavitary-only PEL were younger (median age, 42 vs. 52 years, p = 0.001), more likely to be HIV-positive (88.9% vs. 68.6%, p = 0.06) and EBV-positive (76.9% vs. 51.9%, p = 0.06), and less often positive for CD45 (69.2% vs. 96.2%, p = 0.01), EMA (26.7% vs. 100%, p = 0.0005), and CD30 (60% vs. 81.5%, p = 0.09). Of 52 (50%) patients with clinical follow-up, 26 died after a median follow-up time of 40.0 months (range 0–96), and the median overall survival was 42.5 months. The median OS for patients with effusion-only and with extracavitary-only PEL were 30.0 and 37.9 months, respectively (p = 0.34), and patients with extracavitary-only PEL had a lower mortality rate at the time of last follow-up (35% vs. 61.5%, p = 0.07). The median OS for HIV-positive and HIV-negative patients were 42.5 and 6.8 months, respectively (p = 0.57), and they had a similar mortality rate of 50% at last follow-up. In conclusion, patients presenting with effusion-only versus extracavitary-only disease are associated with different clinicopathologic features. PEL is an aggressive lymphoma with a poor prognosis, regardless of extracavitary presentation or HIV status.

We aimed to compare the overall survival (OS) and standardized mortality rate (SMR) of the male breast cancer (MBC) with female breast cancer (FBC) after propensity score matching. Based on the Surveillance, Epidemiology, and End Results (SEER), the early breast cancer patients (T_1–2N_0–2M₀) were extracted from 1998–2007. This study included 1,111 and 2,151 patients with early MBC and FBC, respectively, whose clinicopathological characteristics were well balanced. At a mean follow-up time of 97 months, 10-year OS rate was 58.3% in the MBC group and 68.7% in the FBC (log-rank test, P < 0.001; hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.29 to 1.64). Adjusted HR for OS between MBC and FBC were revealed from propensity score matched-multivariable Cox proportional hazards models (HR = 1.53, 95% CI = 1.35 to 1.73). Similar adjusted SMRs between MBC and FBC ((SMR = 1.98, 95% CI = 1.83,2.14) for FBC and (SMR = 2.07, 95% CI = 1.88–2.28) for MBC) were observed. The nomogram was constructed for FBC, and predicted probabilities were generally good (C-index = 0.71), whose area under curve is higher than TNM stage classification (0.74 vs 0.62). OS was significantly decreased among early MBC patients compared with FBC, but similar SMRs and its trends by age groups were observed between MBC and FBC except for young patients.