B-cell Lymphomas With Concurrent IGH-BCL2 and MYC Rearrangements Are Aggressive Neoplasms With Clinical and Pathologic Features Distinct From Burkitt Lymphoma and Diffuse Large B-cell Lymphoma

Abstract

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as “double-hit” lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathological features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathological spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we performed case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32-91). Six patients had a history of grade 1-2 follicular lymphoma (FL); review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 months) was inferior to both BL (p=0.002) and IPI-matched DLBCL (p=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (p<0.0001), Mum1/IRF4 (p=0.006), Ki-67 <95% (p<0.0001), and absence of EBV-EBER (p=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen in most BL controls (p=0.001), and exhibited a higher number of chromosomal aberrations (p=0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multi-agent chemotherapy, and clinical and pathological features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches.

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…Snuderl et al [54] confirm by studying 20 cases that these aggressive neoplasms are distinct from DLBL and BL.…”

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

“…In the 20 cases of MYC/BCL2 double-hit lymphoma reported by Snuderl et al, 15 one patient had MYC rearrangement with extra copies of BCL2 and had a poor prognosis. Jiang et al 38 studied 60 cases of DLBCL and identified 18 cases with BCL2 gene amplification.…”

“…[4][5][6][7][8][9][10][11][12][13][14] Numerous case series of MYC/BCL2 double-hit lymphoma are reported in the literature. [15][16][17][18][19][20][21][22][23][24] MYC/ BCL2 DHLs represent B10% of all lymphomas that otherwise resemble diffuse large B-cell lymphoma (DLBCL). 10 Although different studies have focused on different aspects or details of double-hit lymphoma, all studies suggest that patients with these lymphomas commonly have an aggressive clinical course characterized by advanced stage disease, extranodal involvement, and high serum lactate dehydrogenase levels.…”

“…15,20,22,23 To our knowledge, however, little is known about atypical DHL and there is no large study in the literature that has focused on atypical MYC/BCL2 double-hit lymphoma. In this study, we assess the clinicopathologic, immunophenotypic, and cytogenetic features of a large group of patients with atypical double-hit lymphoma, and compare this patient group to a group of patients who had typical double-hit lymphoma as well as a group of patients who had DLBCL not associated with either MYC or t(14;18)(q32;q21)/ IGH@BCL2.…”

Scoring of MYC protein expression in diffuse large B-cell lymphomas: concordance rate among hematopathologists

“…3,4 In particular, the so-called 'double-hit' lymphomas that are characterized by MYC rearrangement and a concurrent rearrangement of other B-cell lymphomaassociated genes such as BCL2 or BCL6 are associated with poor response to therapy, aggressive clinical course and dismal prognosis. [5][6][7] These lymphomas are classified as 'B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma' in the current 2008 WHO classification of hematopoietic neoplasms. 8 Evaluation for MYC alterations in diffuse large B-cell lymphoma is typically performed by fluorescence in situ hybridization (FISH).…”