Sheeja T. Pullarkat

Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies

The 2008 edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes a new diagnostic entity termed “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” highlighting lymphomas arising in patients treated with immunosuppressive agents for autoimmune disorders. The role of antitumor necrosis factor alpha therapy (anti-TNFα) and lymphoma risk in rheumatoid arthritis (RA) patients remains unclear; therefore, the goal of our study was to determine whether anti-TNFα therapy is associated with iatrogenic lymphomas. A meta-analysis of all randomized controlled clinical trials published (2000–2009) in RA patients receiving anti-TNFα therapy was performed. Fourteen studies fulfilled all search criteria and included 2,306 control patients and 5,179 patients treated with anti-TNFα therapy, namely etanercept, adalumimab, and infliximab. Clinical information including the number of patients, age, gender, lymphoma rates, and follow-up time was recorded. The overall rate and rate differences were analyzed using the DerSimonian and Laird method. Of the control group, four (4/2,306, 0.17%) patients developed hematolymphoid neoplasms. Eleven (11/5,179, 0.21%) patients receiving anti-TNFα therapy developed lymphomas. The adjusted overall rates are 0.36 lymphomas per 1,000 person-years in patients who did not receive anti-TNFα therapy versus 1.65 lymphomas per 1,000 person-years in patients who received anti-TNFα therapy. The corresponding 95% confidence interval for this rate difference is (−0.214, 2.79). The adjusted rate difference is 1.29 lymphomas per 1,000 person-years (95% CI, −0.21, 2.8; p value = 0.093). The corresponding p value is p = 0.0928. There is a suggestion of increased lymphomas in the treated group, with the predominant subset being B-cell lymphomas. Since the outcome of lymphoma is rare, it does not reach statistical significance of p < 0.05.

Mast cell disease associated with acute myeloid leukemia: Detection of a new c-kit mutation Asp816His

Mast cell disease (MCD), a proliferation of mast cells (MC), is occasionally associated with hematologic malignancies. Neoplastic MC have activating c‐kit mutations. c‐kit is a receptor tyrosine kinase required for the development, proliferation, and survival of MC. Interaction of c‐kit with its ligand stem cell factor induces dimerization, receptor phosphorylation, and signal transduction. The most common c‐kit mutation detected in neoplastic MCD is Asp816Val, which results in ligand‐independent autophosphorylation of the receptor leading to MC proliferation. We describe the rare occurrence of MCD associated with acute myeloid leukemia, report a novel c‐kit mutation Asp816 His, and discuss the pathogenesis of MCD associated with hematologic malignancies. Am. J. Hematol. 65:307–309, 2000.

KSHV/HHV8-negative Effusion-based Lymphoma, a Distinct Entity Associated With Fluid Overload States

Human herpesvirus-8 (HHV8)-positive effusion-based lymphomas have been termed primary effusion lymphoma (PEL) in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Kaposi sarcoma herpesvirus (KSHV)/HHV8-negative effusion-based lymphomas (KSHV/HHV8-negative EBLs) resembling PELs have been reported in the literature and in many cases have been (mis)classified as PEL-like lymphomas. Herein, we present a series of cases and a review of KSHV/HHV8-negative EBLs. This lymphoma, although cytomorphologically resembling PEL, is a distinct entity with characteristic clinical and pathologic features. Patients are older, generally human immunodeficiency virus negative and not immunosuppressed, frequently hepatitis C positive compared with the population baseline, and often have an underlying medical condition leading to fluid overload. The lymphoma cells express pan-B-cell antigens in 86.7%, and CD20 is expressed in 71.1% of the cases. The lymphoma is often of germinal center B or mixed germinal center B/activated B-cell signature with the Hans classifier, and Epstein-Barr virus is positive in nearly 30% of cases. Rare T-cell lymphomas were also reported. Clinical outcomes and response to therapy, including isolated aspiration, are relatively favorable compared with cases of PEL. We suggest that HHV8-negative effusion-based lymphoma is a distinct entity associated with fluid overload states.

Megakaryocytic blast crisis as a presenting manifestation of chronic myeloid leukemia

Acute megakaryocytic leukemia is a rare form of acute myelogenous leukemia and may occur either de novo or by transformation of a preexisting myelodysplastic or myeloproliferative process including blast crisis of chronic myeloid leukemia (CML). Megakaryocytic blast crisis as the presenting manifestation of CML is extremely rare. We describe such a patient with no prior hematologic disease who presented with acute megakaryoblastic leukemia and extramedullary involvement, in whom the leukemic cells carried the BCR-ABL1 translocation as part of a complex karyotype. Using targeted sequential fluorescence in situ hybridization (T-FISH) technique, we detected two copies of BCR-ABL1 fusion gene in the leukemic blasts while the neutrophils carried a single copy of BCR-ABL1 fusion gene, thereby proving the origin of the megakaryoblastic leukemia from a previously undiagnosed CML clone. Blast crisis as a presenting manifestation of CML is rare and detecting clonal evolution of acute leukemia by specialized cytogenetic techniques may have important diagnostic and therapeutic implications.

Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009.

Burkitt lymphoma (BL) occurs at all ages, but the patterns of Epstein–Barr virus (EBV) positivity in relation to human immunodeficiency virus (HIV), immunoprofiles and age have not been fully explored. BL tissues from residual tissue repositories, and two academic centers in the United States were examined by expert hematopathologists for morphology, immunohistochemistry, MYC rearrangement, EBV‐encoded RNA (EBER), and diagnosed according to the 2008 WHO lymphoma classification. Analysis was done using frequency tables, Chi‐squared statistics, and Students t‐test. Of 117 cases examined, 91 were confirmed as BL. The age distribution was 26%, 15%, 19%, and 29% for 0–19, 20–34, 35–59, 60+ years, and missing in 11%. MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0–19 to 55% in age group 20–34, and fell to 25% in age group 60+ years, p = 0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p = 0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p = 0.03). EBER positivity was demonstrated in about one‐third of tumors and it was strongly associated with race and HIV status, and marginally with age‐group.

Adult leukemic synovitis is associated with leukemia of monocytic differentiation.

Background:Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse. Methods:A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy. Results:A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis. Conclusions:Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.

High lifetime incidence of adult acute lymphoblastic leukemia among hispanics in California.

Background: The higher incidence of acute lymphoblastic leukemia (ALL) among Hispanic children relative to that in other racial/ethnic groups is well-known. We evaluated the incidence patterns of ALL in adults. Methods: We analyzed the incidence patterns of ALL (International Classification of Diseases for Oncology 3 codes 9835-9837) among all patients diagnosed from 1988 to 2004 in California using data from the California Cancer Registry to determine whether adult Hispanics also had higher incidence rates of ALL compared with non–Hispanic Whites (Whites). Age-adjusted incidence rates (AAIR), incidence rate ratios (IRR), and 5-year survival rates were obtained using SEER*Stat. AAIRs of other leukemia subtypes and IRRs relative to non–Hispanic Whites were also examined as references for ALL. Results: AAIRs of ALL in Hispanic males and females ages 20 to 54 years were higher compared with those in White males and females (IRR, 1.99; 95% confidence interval, 1.74-2.28 and IRR, 1.91; 95% confidence interval, 1.60-2.25, respectively). A higher AAIR of ALL was also observed among older (55+ years) Hispanic females (IRR, 1.84; 95% confidence interval, 1.52-2.21), but not in males (IRR, 1.07; 95% confidence interval, 0.84-1.34). Among Hispanics, low socioeconomic status was associated with a higher AAIR compared with high/middle socioeconomic status (IRR, 1.33; 95% confidence interval, 1.04-1.70). The respective 5-year survival rates among ALL patients were 38% and 30% for Whites and Hispanics ages 20 to 54 years, and 8% and 12% for patients 55 years of age or older. Compared with other racial/ethnic groups, Hispanics did not have an increased IRR of the other major leukemia subtypes. Conclusion: Hispanics experience a higher incidence of ALL throughout life, but not other subtypes. (Cancer Epidemiol Biomarkers Prev 2009;18(2):611–5)

Acute myeloid leukemia with t(7;21)(p22;q22) and 5q deletion: a case report and literature review

The gene RUNX1 at chromosome 21q22 encodes the alpha subunit of Core binding factor (CBF), a heterodimeric transcription factor involved in the development of normal hematopoiesis. Translocations of RUNX1 are seen in several types of leukemia with at least 21 identified partner genes. The cryptic t(7;21)(p22;q22) rearrangement involving the USP42 gene appears to be a specific and recurrent cytogenetic abnormality. Eight of the 9 cases identified in the literature with this translocation were associated with acute myeloid leukemia (AML), with the remaining case showing refractory anemia with excess blasts, type 2. Herein, we present a patient with two preceding years of leukopenia and one year of anemia prior to the diagnosis of AML, NOS with monocytic differentiation (myelomonocytic leukemia) whose conventional cytogenetics showed an abnormal clone with 5q deletion. Interphase FISH using LSI RUNX1/RUNXT1 showed three signals for RUNX1. FISH studies on previously G-banded metaphases showed the extra RUNX1 signal on the short arm of chromosome 7. Further characterization using the subtelomeric 7p probe showed a cryptic 7;21 translocation. Our case and eight previously reported leukemic cases with the t(7;21)(p22;q22) appear to share similar features including monocytic differentiation, immunophenotypic aberrancies (often with CD56 and/or CD7), and a generally poor response to standard induction chemotherapy. About 80% of these cases had loss of 5q material as an additional abnormality at initial diagnosis or relapse. These findings suggest that t(7;21) may represent a distinct recurrent cytogenetic abnormality associated with AML. The association between the t(7;21) and 5q aberrancies appears to be non-random, however the pathogenetic connection remains unclear. Additional studies to evaluate for RUNX1 partner genes may be considered for AML patients with RUNX1 rearrangement and 5q abnormalities; however knowledge of the prognostic implications of this rearrangement is still limited.

Strong expression of chemokine receptor CCR9 in diffuse large B-cell lymphoma and follicular lymphoma strongly correlates with gastrointestinal involvement

The gastrointestinal (GI) tract is the most common site of extranodal B-cell lymphomas. However, it is unclear how neoplastic lymphoid cells preferentially home there. We hypothesize that expression of the GI-homing chemokine receptor CCR9 may account for the dissemination of B-cell lymphomas to the GI tract. To test our hypothesis, we compared the expression of CCR9 using immunohistochemistry on GI versus nodal diffuse large B-cell lymphoma and follicular lymphoma. We found that 27 (66%) of 41, 12 (29%) of 41, and 2 (5%) of 41 of GI lymphoma cases demonstrated 3+, 2+, and 1+ CCR9 staining, respectively. In contrast, 2 (5%) of 39, 5 (13%) of 39, 8 (20.5%) of 39, and 24 (61.5%) of 39 nodal-restricted lymphoma cases demonstrated 3+, 2+, 1+, and 0+ CCR9 staining (P < .0001). This was observed for both diffuse large B-cell lymphoma (P < .001) and follicular lymphoma (P < .001). We also compared the expression of CCR9 on nodal B-cell lymphomas with involvement of the GI tract with those restricted to the lymph node. We found that 10 (62%) of 16, 3 (19%) of 16, and 3 (19%) of 16 nodal lymphomas with GI involvement showed 3+, 2+, and 1+ CCR9 staining, respectively. In contrast, 2 (5%) of 39, 5 (13%) of 39, 8 (20.5%) of 39, and 24 (61.5%) of 39 nodal lymphomas without GI involvement demonstrated 3+, 2+, 1+, and 0+ CCR9 staining, respectively (P < .001). Our finding that CCR9 expression is elevated in the nodal lymphomas of patients with GI involvement suggests the potential clinical utility of chemokine receptor status, as assessed by immunohistochemistry, to potentially predict GI dissemination and progression to higher stage in patients who initially present with limited nodal-restricted disease.