C. Cameron Yin

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2 /t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n=24) or atypical Burkitt lymphoma with BCL2 expression (n=9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n=23) or more aggressive chemotherapy regimens (n=34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, ≥2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index >2 were associated with worse overall survival (P<0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n=6) or MYC rearrangement with extra BCL2 signals (n=2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.

Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors†

BCR‐ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib‐resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)‐positive acute lympho‐ blastic leukemia (ALL) are less well studied.

Extranodal NK/T-cell lymphoma, nasal type: A report of 73 cases at MD anderson cancer center

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is uncommon in the United States. We report 73 patients with ENKTL, including 49 men and 24 women (median age, 46 y). Sixty-three patients had nasal/upper aerodigestive tract disease; 10 had extranasal disease involving skin, small intestine, epiglottis, testis, adrenal glands, kidney, and breast. Complete staging data were available for 68 patients: 44 stage I/II and 24 stage IV. Fifteen of 69 (22%) had lymphadenopathy and 10/63 had bone marrow involvement. Histologically, 67/73 (92%) showed necrosis, and 48/70 (69%) had an angiocentric/angiodestructive growth pattern. The neoplastic cells showed a wide spectrum: medium sized (n=34), mixed small and large (n=21), large (n=13), and small (n=5). In situ hybridization for Epstein-Barr virus–encoded small RNA was positive in every case. Immunohistochemical studies showed expression of cytotoxic markers (100%), T-bet (96%), CD2 (96%), CD3 (93%), CD56 (90%), and ETS-1 (64%). Ki-67 was ≥60% in 46% cases. Therapy was known for 64 patients; 14 received only chemotherapy, 8 radiation alone, and 42 received combined radiation and chemotherapy. Median survival was 4.2 years, and 5-year overall survival was 46% (median follow-up, 3.8 y). Extranasal disease, high International Prognostic Index score, and high proliferation rate correlated with poorer prognosis. We conclude that ENKTL cases in the United States are similar to those reported in Asia and other countries. Absence of the angiocentric/angiodestructive pattern and presence of lymphadenopathy, features underemphasized in the literature, occurred in appreciable subsets of patients. The International Prognostic Index score, anatomic site of disease, and proliferation rate had prognostic value in this patient cohort.

t(8;21)(q22;q22) in Blast Phase of Chronic Myelogenous Leukemia

The blast phase of chronic myelogenous leukemia (CML) frequently is associated with cytogenetic evidence of clonal evolution, defined as chromosomal aberrations in addition to the t(9;22)(q34;q11.2). We identified the t(8;21)(q22;q22) and other cytogenetic abnormalities by conventional cytogenetics and fluorescence in situ hybridization in 2 patients with t(9;22)-positive CML at the time of blast phase. The t(8;21), which typically is associated with a distinct subtype of de novo acute myeloid leukemia (AML) carrying the aml1/eto fusion gene, was accompanied by increased bone marrow myeloblasts (33%) in case 1 and extramedullary myeloid sarcoma in case 2, suggesting its possible role in disease progression. In case 1, the leukemic cells in aspirate smears had salmon-colored cytoplasmic granules, and immunophenotypic studies showed that the blasts expressed CD19. These findings suggest that the pathologic features of blast phase CML with the t(8;21) resemble those of de novo AML with the t(8;21).

MYC/BCL2 double hit high grade B-cell lymphoma

Double-hit lymphoma (DHL) has been defined by others as a B-cell lymphoma with MYC/8q24 rearrangement in combination with a translocation involving another gene, such as BCL2, BCL3, or BCL6. The most common form of DHL has translocations involving MYC and BCL2, also known as MYC/BCL2 DHL. In recent years, a number of case series of MYC/BCL2 DHL have been published. Most cases of MYC/BCL2 DHL morphologically resemble diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. These tumors are of B-cell lineage, have a germinal center B-cell immunophenotype with a high proliferation rate, and a complex karyotype. Patients with these tumors have an aggressive clinical course and poor prognosis despite high-intensity chemotherapy. More recently, studies have suggested expanding the spectrum of MYC/BCL2 DHL to include cases that have concurrent MYC and BCL2 cytogenetic abnormalities, but not necessarily translocations. In addition, overexpression of MYC and BCL2 has been shown in an appreciable subset of DLBCL tumors. These tumors show overlap with MYC/BCL2 DHL, but are not equivalent. In this review, we discuss the clinicopathologic, immunophenotypic, cytogenetic, and prognostic features of MYC/BCL2 DHL.

EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient

Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.

t(3;21)(q26;q22) in myeloid leukemia: An aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy

The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1.

Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53.

Isolated isochromosome (17q) is a rare cytogenetic abnormality in Philadelphia chromosome‐negative myeloid neoplasms, usually myelodysplastic and/or myeloproliferative neoplasms (MDS/MPN). De novo acute myeloid leukemia (AML) with isochromosome 17q has rarely been reported. The frequency of genetic mutations is unknown.

Sequence analysis proves clonal identity in five patients with typical and blastoid mantle cell lymphoma

Mantle cell lymphoma (MCL) is typically composed of small irregular lymphoid cells. Blastoid variants, composed of lymphoblast-like (classic type) or large (pleomorphic type) cells, arise de novo or in patients with typical MCL. Although it has been assumed that blastoid variant represents histologic transformation of typical MCL, the clonal relationship between the two tumors has rarely been assessed at the molecular level. We identified five patients with typical MCL who subsequently developed the blastoid variant. There were two men and three women with a median age of 65 years (range, 34–70) at diagnosis of typical MCL involving lymph nodes. The median interval between typical and blastoid MCL was 36 months (range, 11–103). Subsequent blastoid variant MCL involved soft tissue (two), lymph node (one), ileum (one), or rectum (one). All typical and blastoid neoplasms were positive for CD20, cyclin D1, and monotypic surface immunoglobulin light chain, and all typical cases were positive for CD5. Two blastoid neoplasms lost CD5 expression, one of which aberrantly expressed CD10. Immunostaining for Ki-67 showed a median proliferative fraction of 20% in typical and 70% in blastoid neoplasms. Sequence analysis of the VDJ regions of the rearranged IgH allele proved clonal identity in each set of paired samples in all five patients. These results support the concept that blastoid MCL arising in patients with typical MCL represents histologic transformation of the original neoplastic clone.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Associated With IgM Paraprotein

We studied the clinicopathologic, immunophenotypic, and cytogenetic features of 26 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with serum IgM paraprotein. The study group (16 men; 10 women; median age, 64 years; range, 40-82 years) represents approximately 2.5% of CLL/SLL cases at our institution. The paraprotein level ranged from 1 to 14 g/L (median, 4 g/L). Neoplasms in bone marrow were composed of small round lymphocytes arranged in nodular (n = 6), diffuse (n = 5), interstitial (n = 5), or mixed (n = 10) patterns. All cases were positive for monotypic surface immunoglobulin light chain, IgM/IgD, CD5, CD19, CD20, and CD23. CD11c (14/20 [70%]), CD79b (11/19 [58%]), FMC-7 (11/26 [42%]), CD22 (8/20 [40%]), and ZAP-70 (6/19 [32%]) were expressed in subsets of cases. Of 17 bone marrow specimens assessed by conventional cytogenetics, 6 were abnormal and 11 were diploid. The overall survival of this group (median follow-up, 24 months) was not significantly different from that for an age-, sex-and stage-matched group of 52 CLL/SLL patients without IgM paraprotein (P = .60). We conclude that CLL/SLL cases with serum IgM paraprotein are similar to other CLL/SLL cases in their clinicopathologic and immunophenotypic features.