Sanam Loghavi

Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A , FLT3 and NPM1 mutations

BackgroundDe novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.MethodsWe assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.ResultsPatients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3- ITD among patients with NPM1 mutation.ConclusionsDNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature

Melanomas arising in association with blue nevi or mimicking cellular blue nevi comprise a relatively rare and heterogeneous group of melanomas. It remains controversial which prognostic indicators predictive of outcome in conventional cutaneous melanomas are applicable to this type of melanoma. Here, we describe the clinical and histopathologic features of 24 melanomas arising in association with blue nevi and correlate these with clinical outcome. The mean patient age was 49 years (range: 23–85) with a slight female predominance (15 females:9 males). The most common anatomic locations included the head and neck region (50%), the trunk (21%), and the buttock/sacrococcygeum (17%). Histologically, the tumors were typically situated in the mid to deep dermis with variable involvement of the subcutis, but uniformly lacked a prominent intraepithelial component. The mean tumor thickness (defined as either the standard Breslow thickness or, if not available due to the lack of orientation or lack of epidermis, the largest tumor dimension) was 20.9 mm (range: 0.6–130 mm). The mean mitotic figure count was 6.5/mm2 (range: 1–30/mm2). Perineural invasion was common (38%). Follow-up was available for 21 cases (median 2.1 years). The median overall survival, recurrence-free survival, time to local recurrence, and time to distant recurrence were 5.2, 0.7, 2.6, and 1.6 years, respectively. Logistic regression analyses demonstrated a significant association between tumor thickness and recurrence-free survival (hazard ratio=1.02 per mm; P=0.04) and reduced time to distant metastasis (hazard ratio=1.03 per mm; P=0.02) with a similar trend toward reduced time to local recurrence (hazard ratio=1.02 per mm; P=0.07). No other parameters (age, anatomic location, mitotic figures, lymphovascular or perineural invasion, or type of associated blue nevus) emerged as significant. In addition, we provide a comprehensive review of 109 cases of melanoma blue nevus type described in the English literature and summarize our findings in this context.

Plasma circulating-microRNA profiles are useful for assessing prognosis in patients with cytogenetically normal myelodysplastic syndromes.

Myelodysplastic syndromes are a heterogeneous group of clonal bone marrow hematopoietic stem cell disorders characterized by ineffective hematopoiesis and peripheral cytopenias. Chromosomal abnormalities and gene mutations have been shown to have essential roles in pathogenesis and correlate with prognosis. Molecular markers, however, are not integrated into currently used prognostic systems. The goal of this study is to identify plasma microRNAs useful for classification and risk stratification of myelodysplastic syndromes. We applied a novel, high-throughput digital quantification technology (NanoString) to profile microRNA expression in plasma samples of 72 patients with myelodysplastic syndromes and 12 healthy individuals. We correlated these results with overall survival. In patients with myelodysplastic syndromes associated with a diploid karyotype, we identified and validated a 7-microRNA signature as an independent predictor of survival with a predictive power of 75% accuracy (P=0.008), better than those of the International Prognostic Scoring Systems and the MD Anderson Prognostic Lower Risk Prognostic Model. We also identified differentially expressed plasma microRNAs in patients with myelodysplastic syndromes versus healthy individuals and between patients with myelodysplastic syndromes associated with different cytogenetic features. These results validate the utility of circulating-microRNA levels as noninvasive biomarkers that can inform the management of patients with myelodysplastic syndromes. Our findings also shed light on interactions of gene regulation pathways that are likely involved in the pathogenesis of myelodysplastic syndromes.

TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis

Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS‐F). Expression of TP53 was evaluated in BM core biopsy specimens using dual‐colour CD34/TP53 immunohistochemistry with computer‐assisted image analysis. Mutation analysis was performed using next‐generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 + in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high‐ and very‐high risk IPSS‐R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34‐positive cells was associated with shorter OS and leukaemia‐free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS‐F.

B-acute lymphoblastic leukemia/lymphoblastic lymphoma.

OBJECTIVES This session of the 2013 Society of Hematopathology/European Association for Haematopathology Workshop was dedicated to B-acute lymphoblastic leukemia (B-ALL)/lymphoblastic lymphoma (LBL) with recurrent translocations and not otherwise specified. METHODS In this review, we summarize the cases discussed during the workshop, review the pertinent and most recent literature on the respective topics, and provide a few key points that may aid in the workup of patients with B-ALL/LBL. RESULTS Many of the submitted cases showed interesting diagnostic, immunophenotypic, or clinical aspects of B-ALL with BCR/ABL1, MLL-associated, and other recurrent chromosomal abnormalities. Several cases showed rare aberrancies such as coexistent IGH/BCL2 and MYC rearrangements and raised issues in classification. Other cases had unusual clinical presentations, including B-ALL with hypereosinophilia and therapy-related B-ALL. Several cases highlighted the role of flow cytometry immunophenotyping in distinguishing benign B-cell precursors from aberrant lymphoblasts, and other cases raised questions regarding the clinical importance of myeloperoxidase positivity in acute lymphoblastic leukemia. CONCLUSIONS The complexity and spectrum of cases presented in this review highlight the importance of clinicopathologic correlation and the value of ancillary studies in the classification and workup of patients with B-ALL/LBL.

Durable remission with rituximab in a patient with an unusual variant of Castleman's disease with myelofibrosis-TAFRO syndrome

A 28-year-old man was referred to our institution in 2012 with a 3 month history of progressive weakness and fatigue, fever, night sweats, abdominal discomfort, shortness of breath, generalized swelling and an overall poor performance status. His initial investigations showed hemoglobin 89 g/L, white blood cell 2.3 × 109/L, platelets 75 × 109/L, blood urea nitrogen 50 mg/dL, and creatinine 2.5 mg/dL. Physical examination showed diffuse lymphadenopathy and splenomegaly. Computerized tomography scan showed diffuse lymphadenopathy (including mediastinal and retroperitoneal), pleural effusions and massive splenomegaly. Bone marrow (BM) evaluation revealed a hypercellular marrow (90%) showing atypical megakaryocytic hyperplasia with aberrant clustering and frequent nuclear hyperlobulation (Fig. 1A; Hematoxylin and Eosin HE 400×) with an overall MF-2 grade fibrosis. The trabeculated bone was mildly thickened. Cytogenetic analysis of the BM aspirate demonstrated a diploid male karyotype. Molecular studies were negative for a BCR/ABL-1 fusion as well as JAK-2, MPL, and CALR mutations. An inguinal lymph node biopsy demonstrated germinal center regression with vessels extending into the germinal centers, exhibiting the so-called “lollipop” morphology (Fig. 1C,H,E; 200×). The interfollicular regions were expanded by numerous mature-appearing plasma cells and high endothelial venules (Fig. 1D,H,E; 400×). Anti-CD138 immunohistochemistry highlighted numerous plasma cells, which showed polytypic kappa and lambda light chain expression. There was no immunophenotypic aberrancy by flow cytometry analysis. The overall morphologic and immunophenotypic findings supported Castlemans disease (CD) with mixed features of hyaline-vascular and plasma cell variants. At the outside hospital, the patient was treated with packed red blood cell transfusions and oral steroids with improvement in symptoms and cell counts. Our investigations showed elevated LDH and β2 micro-globulin, polymerase chain reaction positive for HHV-6 in the BM and negative for HHV-8, EBV, hepatitis viruses and HIV 1 and 2. Other infectious and autoimmune work up was negative. Serum IL-6 levels were normal (likely due to the steroids he has received at the outside hospital). The patient was treated with 4 weekly doses of single agent rituximab at 375 mg/m2. The patient had remarkable clinical improvement with the first dose of rituximab and after 4 doses achieved remission. After 16 months of follow up, the patient maintains a normal clinical examination, normalized blood counts, and is transfusion-independent. A recent BM biopsy showed minimal reticulin fibrosis and mild dysplasia in megakaryocytes.

Clinicopathologic, Immunophenotypic, Cytogenetic, and Molecular Features of γδ T-Cell Large Granular Lymphocytic Leukemia: An Analysis of 14 Patients Suggests Biologic Differences With γδ T-Cell Large Granular Lymphocytic Leukemia

OBJECTIVES T-cell large granular lymphocytic (T-LGL) leukemia is a rare disorder in which the neoplastic cells usually express the αβ T-cell receptor (TCR). To determine the significance of γδ TCR expression in this leukemia, we compared the clinicopathologic, immunophenotypic, and genetic features of patients with T-LGL leukemia expressing γδ TCR or αβ TCR. METHODS We used the World Health Organization classification criteria to confirm the diagnosis. All patients were diagnosed and treated at our institution. RESULTS We identified 14 patients with γδ T-LGL leukemia, 11 men and three women; six (43%) patients had a history of rheumatoid arthritis, 10 (71%) had neutropenia, four (29%) had thrombocytopenia, and three (21%) had anemia. Eight (67%) of 12 patients had a CD4-/CD8- phenotype, and four (33%) had a CD4-/CD8+ phenotype. The median overall survival was 62 months. Patients with γδ T-LGL leukemia were more likely to have rheumatoid arthritis (P = .04), lower absolute neutrophil count (P = .04), lower platelet count (P = .004), and a higher frequency of the CD4-/CD8- phenotype (P < .0001). However, there was no significant difference in overall survival between the two groups (P = .64). CONCLUSIONS Although patients with γδ and αβ T-LGL leukemia show some different clinical or phenotypic features, overall survival is similar, suggesting that γδ TCR expression does not carry prognostic significance.

Immunophenotypic and diagnostic characterization of angioimmunoblastic T-cell lymphoma by advanced flow cytometric technology

Abstract Angioimmunoblastic T-cell lymphoma (AITL) often shows systemic symptoms related to immune dysregulation and cytokine production. Biopsy usually harbors few malignant cells in an abundant reactive background, which can be diagnostically challenging in cases with small biopsies. This study was performed to assess the value of flow cytometry (FC) and to determine the immunophenotypic alterations in 155 samples from 38 patients with AITL. FC detected an aberrant T-cell population in 97 of 155 samples that represented 0.5–90% of lymphocytes. Blood was involved in 11 of 16 patients. The most frequent immunophenotypic aberrancies included loss of CD3; altered T-cell receptor expression and aberrant CD10 expression. Altered CD3 expression was more frequently seen in peripheral blood (PB) and bone marrow (BM), whereas aberrant CD10 expression was more common in lymph node (LN). AITL cells often exhibit abnormal CD4+ immunophenotype with diminished or absent CD3 and variable CD10 expression. Multiparameter FC is an effective tool for supporting the diagnosis of AITL in any fluid and various tissue specimens types.

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

Although generally considered a clinically indolent neoplasm, CLL/SLL may undergo transformation to a clinically aggressive lymphoma. The most common form of transformation, to DLBCL, is also known as Richter syndrome. Transformation determines the course of the disease and is associated with unfavorable patient outcome. Precise detection of transformation and identification of predictive biomarkers and specific molecular pathways implicated in the pathobiology of transformation in CLL/SLL will enable personalized therapeutic approach and provide potential avenues for improving the clinical outcome of patients. In this review, we present an overview of the pathologic features, risk factors, and pathogenic mechanisms of CLL/SLL transformation. Am. J. Hematol. 91:1036–1043, 2016.

Shared clonality in distinctive lesions of lymphomatoid papulosis and mycosis fungoides occurring in the same patients suggests a common origin

Lymphomatoid papulosis (LyP) lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Approximately 10% to 15% of patients with LyP develop other lymphomas, most commonly mycosis fungoides (MF), suggesting a biological relationship between these distinctive diseases. Here, we describe the clinical and histopathologic features of 11 patients who had both LyP and MF, including a total of 30 biopsy specimens (14 LyP and 16 MF). Clinically, LyP lesions were characterized by clustered papules undergoing spontaneous regression and were classified as type A (n = 11), type C (n = 2), or type D (n = 1). All cases of MF were characterized clinically by patch/plaque disease, were stage I or II at the time of diagnosis, and consisted of a CD4-predominant epidermotropic T-cell infiltrate. We used polymerase chain reaction-based methods to assess the TCR-β chain (TCRB) and TCR-γ chain (TCRG) in both LyP and MF lesions of all patients. Monoclonal TCR gene rearrangements were detected in 13 LyP lesions from 10 of 11 patients and in 14 MF lesions from 10 of 11 patients. All 10 patients in whom their skin lesions carried monoclonal TCR gene rearrangements exhibited overlapping clones in both their LyP and MF lesions; additional non-overlapping clones were identified in 3 LyP lesions from 2 patients and 1 MF lesion from another patient. The demonstration of shared monoclonal T-cell receptor gene rearrangements in LyP and MF lesions in almost all patients suggests a common origin between these distinctive clinicopathological diseases.