Journal of Hematopathology

Hereditary spherocytosis (HS) is a common, hereditary hemolytic anemia (HHA) that is attributed to the disturbance of five erythrocyte membrane proteins. HS is also common in Guangxi, China. Target region capture high-throughput sequencing technology was used to analyze genetic mutations found in HS patients. Pedigree analysis was also performed, in some cases, to provide an optimized approach for the etiological diagnosis of complex, hereditary hemolytic anemia. Blood samples from the probands and their families were assessed by laboratory tests, target region capture high-throughput sequencing technology, and Sanger sequencing. We detected 79 HS patients from 37 unrelated families. The mutations observed in these patients were found mainly in four HS-related genes. These included SLC4A1, which was mutated in 31.65% of patients (25/79), SPTA1 (30.78% (24/79)), EPB42 (6.33% (5/79)), and SPTB (5.06% (4/79)). Composite genotype was observed in 26.58% (21/79) of patients and included mutations in two or more HS-related genes or mutations in HS-related genes combined with thalassemia or G6PD deficiency. No significant differences in clinical symptoms were found among patients of various genotypes except total bilirubin. Mean reticulocyte volume (MRV) and mean sphered cell volume (MSCV) of the composite genotype were significantly different from other groups. A total of 28 mutation types were found in HS-related genes. Using high-throughput sequencing technology, we also found some cases that had been misdiagnosed. MRV and MSCV are more significant in compound mutations as sensitive determinants of HS. High-throughput sequencing technology can be used to provide a more effective etiological diagnostic method for HS, with high efficiency and specificity.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from clonal proliferation of plasmacytoid dendritic cells. The disease has two patterns of presentation: cutaneous and leukemic. Herein we describe the case of a 9-year-old boy who presented with an unusual morphologic variant of leukemic BPDCN, showing bone marrow infiltration by medium to large cells with eccentric nuclei, regular round to oval shape, finely dispersed chromatin, one or more distinct nucleoli, and abundant basophilic cytoplasm, forming a pattern that resembled plasmablasts. Multiparameter flow cytometric immunophenotyping confirmed the diagnosis of BPDCN by identifying the expression of CD4++, CD56++, HLA-DR+++, and CD123+++ in abnormal cells, without significant expression of myeloid or lymphoid lineage-specific markers. Awareness of this plasmablastic variant of BPCDN can be helpful for directing the flow cytometry panel and the subsequent investigation of patients presenting with bone marrow infiltration by cells with plasmablastic features.

TAFRO syndrome is a recently proposed subtype of multicentric Castleman’s disease. Some patients have a refractory and aggressively fatal course. Here we report a case of TAFRO syndrome with a rapid fatal course despite corticosteroid and tocilizumab therapy. A 68-year-old Japanese male suffered from abdominal pain, watery diarrhea, fever, and general fatigue. On the 12th hospital day, severe thrombocytopenia, anasarca, and renal failure developed. The histopathological findings of lymph node biopsy were indicative of MCD. Although corticosteroid and tocilizumab were administered, the patient died of multiple organ failure on the 30th hospital day. Autopsy findings revealed that inflammation due to TAFRO syndrome was suppressed but multiple infarctions progressed and became the direct cause of death. Our case suggested that TAFRO syndrome should not be excluded even if clinical findings are insufficient for the diagnostic criteria at the onset and that in patients with TAFRO syndrome who are at a high risk of thrombosis, multiple infarctions may become a direct cause of death.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic disease characterized by abnormal or impaired function of cytotoxic T cells and natural killer cells leading to an exaggerated but ineffective immune response. We report a 3-year-old boy who is the only common son of a nonconsanguineous couple from Honduras without any history of hemophagocytic lymphohistiocytosis or other hematologic disorders in any of his half-siblings. He first presented to the emergency department with left leg pain. He underwent a left inguinal hernia repair 4 days prior to his initial presentation. He had several subsequent visits to the ER with abdominal pain, emesis, and headaches and was admitted when his symptoms did not resolve. On admission, he was found to have splenomegaly; elevated C-reactive protein, indirect bilirubin, C3 fraction; and pancytopenia. Bone marrow aspirate revealed paucicellular trilineage hematopoiesis with rare atypical histiocytic cells and no evidence of malignancy. An unequivocal diagnosis of HLH could not be made at that time, but was strongly considered. The patient’s neurologic status progressively deteriorated leading to brain death. Postmortem genetic analysis showed the patient to be a compound heterozygote with a 681 C > T (R232C) mutation and a novel Perforin1 missense mutation 659 G > A (G220D).

In this paper, we describe a case of nodular lymphocyte predominant Hodgkin lymphoma with the subsequent development of a peripheral T cell lymphoma. This case is unusual in that the sheets of atypical and small to intermediate-sized T cells in the diffuse component were CD8 positive and expressed cytotoxic proteins. The diagnosis of peripheral T cell lymphoma was supported by the demonstration of a clonal T cell receptor beta chain gene rearrangement by Southern blot analysis. Peripheral T cell lymphoma with a cytotoxic phenotype is a rare entity with an aggressive clinical behavior. As such, this report emphasizes the need to consider a diagnosis of coexisting peripheral T cell lymphoma in cases of nodular lymphocyte predominant Hodgkin lymphoma with atypical features, such as few or poorly defined B cell macronodules and diffuse T cell areas. The examination of both T cell receptor gamma and beta chain gene rearrangements should be performed to confirm such cases.

Reactive myelofibrosis (MF) may be associated with infectious, inflammatory, or neoplastic conditions. Extensive myelofibrosis and indolent course are frequent in acute megakaryoblastic leukemia, but these findings are rarely reported in acute promyelocytic leukemia (APL). Patients with neoplastic disorders associated with MF are reported to have an inferior outcome. However, the effect of this association is not apparent in APL patients. This report presents a case of APL in a pediatric patient in association with significant reticulin fibrosis and osteosclerosis. The case highlights that fibrosis in the marrow can make it more challenging to diagnose acute leukemia. The PML-RARA transcripts can be present with subtle clinical or hematological findings, emphasizing the importance of molecular studies in unexplained cytopenias. Furthermore, in the case of APL, as opposed to other myeloid neoplasms, fibrosis does not appear to be associated with a worse prognosis and can resolve after treatment.

In some patients with chronic myeloproliferative neoplasms, myelofibrosis (MF) develops as natural evolution of the disease. The aim of this study was to analyze predictive factors that may cause MF in polycythemia vera (PV) and essential thrombocythemia (ET) patients. This retrospective study was conducted on PV and ET patients who attended our hospital between 2008 and 2019. The development of MF during follow-up was recorded, and comparisons were made of the patients who developed MF and those who did not develop MF. Evaluation was made of 126 ET and 105 PV patients. During follow-up period, MF had developed 5.7% of PV and 7.1% of ET patients. It was determined that JAK-2 mutant allele burden, lymphocyte count, vitaminB12 levels, and grade of bone marrow fibrosis at diagnosis had statistically significant impact on the development of MF in all patients. In the logistic-regression analysis, it was found that initial hemoglobin, hematocrit, neutrophil-to-lymphocyte ratio, and monocyte count for PV patients; vitaminB12, the presence of splenomegaly; and BM fibrosis at diagnosis for ET patients have statistically significant effect on MF development. The results of the current study demonstrated that some parameters especially vitamin B12 levels can be used as predictive markers for the development of MF.