A 50-year-old female with no medical history presented with B-symptoms for 2 weeks including generalized weakness, fevers, fatigue, and night sweats. Physical exam revealed diffuse cervical and axillary lymphadenopathy with splenomegaly. Initial laboratories showed Coombs-negative hemolytic anemia with agglutination of red blood cells and moderate thrombocytopenia. Some tear drop cells were also seen pointing toward the presence of bone marrow infiltration. Computed tomography (CT) of the body showed a mediastinal mass with widespread lymphadenopathy and splenomegaly.
Bone marrow biopsy was reported as suspicious for high-grade lymphoma. Right axillary lymph node excisional biopsy showed BCL-2 positive ( Image 1, Panel A), CD10 positive (Image 1, Panel B), follicular low-grade lymphoma (Image 1, Panel C) with low MIB1 (Image 1, Panel D). Due to the contradictory nature of the results, a mediastinal mass needle biopsy and a repeat bone marrow biopsy were performed subsequently showing diffuse large B-cell lymphoma (DLBCL) with blastoid features (Image 1, Panel E), high MIB1 (Image 1, Panel F), and cytogenetic evidence of c-MYC t(8;14) and t(14;18) IGH/BCL-2 gene rearrangement. Baseline CT showing a mediastinal mass (Image 1, Panel G) which rapidly responded to R-hyper CVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) achieving radiographic complete response after three cycles (Image 1, Panel H). At this point, the patient had a 2-week delay in therapy due to an admission secondary to neutropenic fever. All cultures remained negative and fever remitted after a course of antibiotic therapy was delivered as per standard management. Before commencing Cycle 4 of R-hyper CVAD, the patient presented with non-specific symptoms and imaging studies showed a moderate sized left pleural effusion that was pathologically confirmed as DLBCL. RICE chemotherapy (rituximab, ifosfamide, carboplatin, etoposide) was commenced although her pleural effusion progressed after two cycles requiring thoracocentesis, chest tube placement, and video-assisted thoracoscopic surgery. DHAP chemotherapy (dexamethasone, cytarabine, cisplatin) was initiated although the patient developed pulmonary embolism and worsening respiratory distress after one cycle of such regimen. Flexible bronchoscopy showed left lung obstruction due to malignant extrinsic compression secondary to recurrence of her mediastinal mass (Image 1, Panel I) encasing the major thoracic organs. Palliative radiation therapy to her left lung was given albeit the patient expired shortly afterwards, 9 months after her initial diagnosis of “double-hit” lymphoma.
High-grade non-Hodgkin lymphomas have been associated with multiple cytogenetic abnormalities including MYC with t(14;18), BCL-6 or BCL-2 rearrangements. “Double-hit” lymphomas (DHL) are categorized in the provisional entity “B-cell lymphoma, unclassifiable, with features intermediate between large B-cell lymphoma and Burkitt lymphoma” of the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . DHL has the double disadvantage of MYC (proliferation) and BCL-2 (anti-apoptosis) [2, 3], hence they are highly aggressive with poor prognosis and lack of response to therapy [4, 5]. Recently, it has been proposed that this unclassifiable entity could be named “double-hit” or “triple-hit” lymphoma depending on the number of aberrations present including MYC rearrangements in the setting of a complex karyotype with the addition of rearrangements in BCL-2 and, less commonly, BCL-6 . The incidence of histologic transformation from follicular lymphoma to DLBCL varies widely (16–60%) depending on the duration of follow-up and the definition criteria, based on tissue diagnosis or solely in clinical presentation . It is possible that our patient initially developed a nodal follicular lymphoma and, subsequently, an extranodal DLBCL when further molecular aberrations occurred. Nevertheless, the fact that her nodal follicular lymphoma was low grade, without signs of progression to Grade 3 or diffuse pattern or morphology, might point toward the development of both lymphomas in a synchronous manner. To further categorize these “unclassifiable” lymphomas, gene expression profiling has defined molecular subgroups as DLBCL derived from lymph node germinal centers and DLBCL derived from activated B-cells, the latter group has inferior overall survival; hence several diagnostic algorithms are being tailored for unclassifiable cases in which DHL may be suspected [8–12]. Standard chemotherapy for DLBCL remains R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), however, DHL with t(14;18) and MYC rearrangements respond poorly to such regimen . Hyper-CVAD chemotherapy is generally reserved for use in the treatment of aggressive forms of hematological malignancies as DHL. DHL should be suspected in all DLBCL when the proliferative index is high or when there is evidence of MYC or BCL-2 rearrangement . A timely diagnosis with early aggressive intervention including hematopoietic stem cell transplantation at first remission should be considered.