Mina L. Xu

Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability.

OBJECTIVES To evaluate the amount of hemophagocytosis in 64 marrow core biopsy specimens and aspirates from 58 patients with clinical suspicion for secondary hemophagocytic lymphohistiocytosis (HLH) or reported findings of hemophagocytosis. METHODS A review of medical records assigned patients to a low-risk (45 patients) or high-risk (13 patients) HLH group, and association with histologic findings was examined using the Fisher exact test. RESULTS The amount of hemophagocytosis in aspirate or the core biopsy specimen did not correlate with disease probability (P = .17 and P = .63, respectively). Of the clinical/laboratory criteria assessed, the most significant correlations with HLH were highly elevated ferritin (P = .01), cytopenias (P = .02), and fever (P = .009). CONCLUSIONS Our findings indicated that marrow histologic findings alone do not reliably predict the probability of HLH, and an isolated finding of hemophagocytosis, even when present in a high amount, lacks specificity for HLH.

Epithelioid trophoblastic tumor: comparative genomic hybridization and diagnostic DNA genotyping.

Arising from the putative chorionic-type intermediate trophoblast, epithelioid trophoblastic tumor is a recent addition to the spectrum of gestational trophoblastic diseases. Frequently, the tumor involves the uterine cervix and is misdiagnosed as invasive squamous-cell carcinoma. The pathogenesis of the tumor is poorly understood, and its molecular analysis is essentially lacking. This study was designed to explore chromosomal alterations in epithelioid trophoblastic tumor and to use DNA genotyping to demonstrate its trophoblastic origin, therefore separating the tumor from its mimics of the maternal origin. Five cases of epithelioid trophoblastic tumors were included in this study and paired DNA samples from the tumor and normal tissue were extracted from paraffin-embedded archival materials. The status of chromosomal alterations was analyzed by comparative genomic hybridization using conventional metaphase chromosome preparations. The parental genetic contribution was determined by DNA genotyping analysis using AmpFISTR® Identifiler™ Amplification system (Applied Biosystems Inc.). Comparative genomic hybridization analysis was successful in three cases analyzed, all of which showed a balanced chromosomal profile without detectable gain or loss of the genome. DNA genotyping was informative in four epithelioid trophoblastic tumor involving anatomic locations including the cervix (two cases), endomyometrium (one case) and lung (metastatic, one case). All four cases were found to have unique paternal alleles, confirming the trophoblastic nature of the tumors. In summary, chromosomal alterations detectable by conventional comparative genomic hybridization are not features of epithelioid trophoblastic tumors. In difficult cases, the presence of the paternal alleles demonstrated by DNA genotyping is a powerful diagnostic application in separating an epithelioid trophoblastic tumor from its maternal mimics, particularly the far more common squamous-cell carcinoma of the uterine cervix.

Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a unique subtype of DLBCL. The impact of rituximab on survival and patterns of treatment failure in PT-DLBCL patient remain controversial. We analyzed the clinical and biological feature of 280 PT-DLBCL cases, 64% of which were treated with rituximab-containing regimens. Although most (95%) patients achieved complete remission, a continuous risk of relapse was observed. Rituximab significantly reduced the cumulative risk of relapse (P=0.022) and improved both progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027) of PT-DLBCL patients (5-year PFS, 56% vs 36%; 5-year OS, 68% vs 48%). Central nervous system and contralateral testis were the most common sites of relapse, but other extranodal and nodal sites of relapse were also observed. Most cases of PT-DLBCL had a non-germinal center B-cell like (84%) immunophenotype and an activated B-cell like (86%) gene expression profile (GEP) subtype. The distinctive GEP signature of primary testicular lymphoma was relevant to tumor cell proliferation, dysregulated expression of adhesion molecules and immune response, likely accounting for the poor outcome. Accordingly, forkhead box P1 transcription factor (FOXP1) and T-cell leukemia/lymphoma 1 (TCL1) oncogenic activation were confirmed and predicted a significant trend of poor survival. This study provides valuable observations for better understanding of both clinical and biological features in PT-DLBCL patients.

Clinical trials for pathogen reduction in transfusion medicine: a review.

Despite the implementation of highly sensitive methods for the detection of pathogens in donor blood products, the risk of transmission of infectious disease to transfusion recipients remains. Of greatest concern, and accounting for most of the risk, are newly-emerging pathogens for which screening assays do not yet exist or well-known pathogens for which testing regimens are not routinely employed. Furthermore, passive donor screening programs are unlikely to capture all potentially infective donors. A promising strategy to overcome these limitations is the proactive incapacitation of pathogens residing in donor units. Several unique pathogen reduction/inactivation (PR/PI) platforms have been developed and implemented in clinical settings. The aims of this article are to review: (1) the basic methodology underlying PR/PI platforms, (2) the potential toxicities associated with PR/PI treatment of blood products, and (3) the data and outcomes from clinical trials involving currently available PR/PI platforms.

Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia

Dear Editor, Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only about 200 patients described to date meeting the World Health Organization (WHO) criteria and the recently reported CSF3R T618I mutation. Diagnosis of CNL using the World Health Organization 2008 criteria[1] requires a WBC count of ≥25 × 10/L, ≥80 % segmented/band neutrophils, absence of dysgranulopoiesis, exclusion of genetic drivers that are known to occur in others MPNs (such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements), and <10 % immature myeloid cells [2]. Previously, CNL was often confused with chronic myeloid leukemia (CML), atypical CML (aCML), or chronic myelomonocytic leukemia (CMML); however, this changed with the identification of oncogenic mutations in the granulocyte colony-stimulating 3 factor receptor (CSF3R) gene in approximately 83 % of WHO-defined CNL patients [3]. CSF3R mutations in CNL are either nonsense or frameshift mutations truncating the cytoplasmic tail (truncation mutations) or point mutations in the extracellular domain (membrane proximal mutations) [3, 4]. Truncation mutations are sensitive to dasatinib in vitro, while membrane proximal mutations show ligand-independent signaling through the JAKSTAT pathway and cells harboring this mutation are sensitive to Jak1/2 inhibitors in vitro. Additional observations from Mayo Clinic showed that concomitant SETBP1 and ASXL1 mutations in CNL patients with a CSF3R mutation help to further distinguish CNL from aCML and are associated with poorer outcomes [5]. There is as yet limited clinical experience with ruxolitinib in patients with CNL, given the low prevalence of the disease [6, 7]. After the initial case reported by Maxson et al., Dao et al. presented the case of another patient with CNL and a CSF3RT618I mutation who experienced reduction in hepatosplenomegaly and * Maximilian Stahl maximilian.stahl@yale.edu

Composite Peripheral T-cell Lymphoma Not Otherwise Specified, and B-cell Small Lymphocytic Lymphoma Presenting With Hemophagocytic Lymphohistiocytosis:

We report a case of a 68-year-old female patient who developed hemophagocytic lymphohistiocytosis (HLH) secondary to peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS) that developed in the setting of treatment-resistant B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). The patient’s B-cell lymphoma had a good initial response to chemotherapy for 4 years, after which it became less responsive and was thought to have undergone transition to a higher-grade lymphoma. Different regimens of chemoradiotherapy were then tried with modest response until the patient presented 3 years later with signs and symptoms of HLH. The patient died 1 month later, and an autopsy was performed. Significant para-aortic lymphadenopathy and splenomegaly were found. Microscopic, immunohistochemical and molecular evaluations confirmed the presence of composite B-cell and T-cell lymphoma in the para-aortic enlarged lymph nodes. Bone marrow examination showed hemophagocytosis, and the liver demonstrated infiltration by activated macrophages with hepatocellular necrosis. This report highlights the importance of searching for a possible underlying T-cell lymphoma in light of HLH. Different theories have been proposed to explain the rare occurrence of concurrent B- and T-cell lymphomas, but the development of HLH in this patient highlights the importance of immune dysregulation as a proposed mechanism to explain some cases of composite lymphomas. A review of the literature and discussion of the relative merits of these hypotheses are presented in the context of this case.

The importance of erythroblast enumeration in myeloid neoplasia

Dear Editor, The proportion of myeloblasts in the bone marrow of patients with myelodysplastic syndromes (MDS) is an independent prognostic factor, and estimation of blast proportion influences disease classification, risk stratification, and clinical management. A blast proportion of ≥20 % defines acute myeloid leukemia (AML), except where certain AMLdefining chromosomal rearrangements such as t(8;21) or t(15;17) are present. Accurate blast enumeration requires counting 500 consecutive nucleated bone marrow cells, but interobserver variability in blast enumeration, even among experienced hematopathologists, has been well documented. One important consideration in blast enumeration is the B50 % rule,^ first proposed in 1985 by the FrenchAmerican-British (FAB) co-operative group and subsequently adopted in the 2001 and 2008 World Health Organization (WHO) classifications of hematopoietic neoplasms. Simply put, this rule states that if erythroid precursors (EP) represent ≥50 % of cells in the marrow and diagnostic criteria for acute pure erythroleukemia (in which ≥80 % of marrow cells are erythroblasts) are not met, then the denominator for blast proportion calculation becomes the nonerythroid nucleated cells (NEC) rather than total nucleated cells (TNC, used when there are <50 % EP) [1]. The 50 % rule has been important in classifying the ∼15 % of MDS cases that have ≥50 % EP in the marrow (MDS with erythroid predominance: MDS-E), as applying this rule upgrades the risk status of many such patients [2]. For example, a patient with dysplasia limited to erythroid cells, 4 % of TNC representing blasts, and 70 % EPs would be assessed as having 13 % blasts (i.e., 4/30 NEC) using the 50 % rule, upstaging the patient from refractory anemia (RA) to refractory anemia with excess blasts-2 (RAEB-2). Using risk-adapted therapy recommendations such as those of the National Comprehensive Cancer Network, treatment would change from low-intensity therapies such as hematopoietic growth factors to treatments more appropriate for higher risk disease, including hypomethylating agents and allogeneic stem cell transplantation (alloSCT). The 50 % rule has been used for more than three decades, despite lack of high-quality evidence supporting its validity. Recently, the 2016 WHO classification of MDS and AML was published in draft format and this classification finally abandons the 50% rule [3]. Two recent publications support such a reclassification [1, 2]. Bennett and colleagues analyzed 1448 patients with MDS in the Düsseldorf MDS registry and found that adjustment of marrow blast proportion by EP percentage, including the 50 % rule, did not alter prediction of leukemic progression rates and overall survival [1]. In another recent publication, Arenillas and colleagues analyzed data from 3692 patients in the Spanish registry, including 465 patients with MDS-E, the largest reported series of MDS-E to date [2]. The Spanish investigators also found no support for the 50 % rule, but recommended using NECs as the denominator for calculation of marrow blast percentage in all cases of MDS, * Amer M. Zeidan amer.zeidan@yale.edu

Venting the Spleen

A 19-year-old woman presented to a community hospital with a 4-day history of abdominal pain, located in the right upper quadrant and epigastrium, with occasional radiation to her back. She described the pain as intermittent and variable in intensity, associated with nausea, and occurring independently of oral intake or body position. A review of systems was notable for profound fatigue and a 13.6-kg (30-lb) weight loss during the preceding months, which she attributed to stress in the wake of her parents’ recent divorce. She reported no fever, sweats, jaundice, dyspnea, vom iting, diarrhea, constipation, urinary abnormalities, joint aches, or rash. An anatomical approach is helpful in formulating the differential diagnosis of abdominal pain. Diseases of the liver and pancreaticobiliary tree are the most common causes of right-upper-quadrant abdominal pain, and in a young person, acute viral hepatitis, autoimmune hepatitis, and hepatic injury due to ingestion of alcohol or another toxic substance should be considered. Cholelithiasis or choledocholithiasis may occur in young adults with predisposing risk factors such as obesity, a family history of gallstones, or an underlying chronic hemolytic disorder. The FitzHugh–Curtis syndrome, or pelvic inflammatory disease with perihepatitis, is man ifested in young women as right-upper-quadrant pain and may mimic hepatobiliary disease. Pancreatitis, gastritis, and peptic ulcer disease are common causes of epigastric and midabdominal pain that may also involve the right upper abdomen. The patient’s recent weight loss, although apparently circumstantial, is of sufficient magnitude to prompt serious consideration of chronic infection, rheumatologic disease, or cancer. The patient had a history of hereditary spherocytosis. Ten years earlier, she had undergone laparoscopic splenectomy and cholecystectomy for chronic hemolytic anemia with symptomatic gallstones, with complete resolution of the hemolytic crises. She had received all requisite vaccinations. Her medications included folic acid and an oral contraceptive. She had smoked one pack of cigarettes per day for 4 years, drank alcohol sparingly, and reported no illicit drug use. She was sexually active with one male partner and reported that she did not have unprotected intercourse. Her most recent menstrual period was 2 weeks earlier. She worked as a waitress, lived in a small town in New England, and had not recently traveled outside the northeastern United States. Her family history was notable for hereditary spherocytosis in her mother and siblings. The patient’s history raises the question of whether hereditary spherocytosis or a complication of splenectomy might explain her abdominal pain. Gallstones, anemia,

A fatal case of primary cutaneous gamma-delta T-cell lymphoma complicated by HLH and cardiac amyloidosis.

Gamma–delta T‐cell lymphomas (GD‐TCL) are rare and rapidly fatal neoplasms that are often associated with Hemophagocytic Lymphohistiocytosis (HLH), a syndrome of fevers, cytopenias, and multiorgan failure that often leads to a rapid death. We report the first case demonstrating an association between GD‐TCL, HLH, and cardiac amyloidosis, presenting a novel mechanism for rapid deterioration in these patients.

Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy

Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.