Follicular Lymphoma With a Burkitt Translocation-Predictor of an Aggressive Clinical Course: A Case Report and Review of the Literature

Archives of Pathology & Laboratory Medicine,  Feb 2004  by Voorhees, Peter M,  Carder, Kathryn A,  Smith, Scott V,  Ayscue, Lanier H,  Et al

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* Follicular lymphoma is an indolent lymphoma characterized by the (14;18) translocation, which leads to aberrant expression of Bcl-2. Translocations involving 8q24 are most commonly associated with Burkitt lymphoma and result in c-Myc overexpression. We report a case of follicular lymphoma of predominant small cleaved-cell type (grade 1) associated with both a t(14;18)(q32;q21) and a t(8; 22)(q24;q11). The 8q24 translocation predicted an aggressive clinical course, as the lymphoma transformed into acute lymphoblastic leukemia within a year of initial diagnosis. Routine cytogenetic analysis is recommended at initial diagnosis of follicular lymphoma to better identify abnormalities that may predict prognosis and influence therapy.

Approximately 70% to 90% of follicular lymphomas (FLs) are associated with t(14;18), resulting in aberrant expression of Bcl-2, a 26-kd protein that inhibits apoptotic pathways, resulting in a survival benefit to the cell.1,2 While deregulated expression of Bcl-2 plays a crucial role in follicular lymphomagenesis, it is not sufficient for malignant transformation. Transgenic mice harboring the bcl-2 gene adjacent to the immunoglobulin heavy (IgH) chain enhancer develop a lymphoproliferative syndrome characterized by polyclonal lymphoid hyperplasia.3 Investigators think that prolonged B-cell survival allows for the acquisition of new chromosomal translocations and/or genetic mutations that lead to the clinical expression of malignant lymphoma.

8q24 Translocations (t[8;14][q24;q32], t[8;22][q24;q11], and t[2;8][p12;q24]) lead to deregulation of c-Myc expression and are most commonly seen in Burkitt lymphoma.1 c-Myc is a nuclear protein that regulates transcription of genes essential for cell proliferation. Interestingly, many of the lymphomas that the Bcl-2 transgenic mice acquired over time harbored c-myc translocations, suggesting that sequential bcl-2 and c-myc deregulation may be one important mechanism of lymphomagenesis.2

The acquisition of 8q24 translocations has been reported in the transformation of FL to diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, and various subtypes of acute lymphoblastic leukemia (ALL).4-10 In those cases in which cytogenetic analysis of the original FL was performed, the 8q24 translocation was not seen. Whether the 8q24 translocation predated the transformation in the other cases is not known, owing to lack of cytogenetic data at the time of the original diagnosis. Regardless, the clinical outcome in these patients was uniformly poor.

We describe a patient with stage IVA, grade 1 FL, who 1 year after initial diagnosis developed early pre-B common ALL (CALL). The original FL and subsequent CALL each contained t(14;18)(q32;q21) and t(8;22)(q24;q11). To our knowledge, this is only the second case of transformed FL reported in the English literature in which both translocations were identified in the original FL. We suggest that the presence of 8q24 translocations predicts an aggressive clinical course in patients with FL that may mandate more aggressive treatment.

REPORT OF A CASE

The patient was a 53-year-old who presented in July 2000 with generalized lymphadenopathy. Excisional biopsy of a right axillary lymph node (LN) revealed a grade 1 FL. A bone marrow (BM) biopsy showed 50% replacement by malignant lymphoma. The patient's initial lactate dehydrogenase level was normal (569 U/L) and B symptoms were absent. The patient was treated at an outside institution with 6 cycles of CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone), followed by 8 weekly treatments with rituximab. Repeatstaging computed axial tomographic scans demonstrated a partial response.

In July 2001, repeat computed tomographic scans of the neck, chest, abdomen, and pelvis were unchanged. The patient's white blood cell count was 12600/µL with large atypical cells on review of the peripheral blood smear. The patient's lactate dehydrogenase level was 24236 U/L. A BM biopsy revealed early preB CALL. A lumbar puncture did not demonstrate evidence of central nervous system involvement. The patient was treated per the hyper-CVAD protocol (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) with intrathecal prophylaxis and achieved a complete remission. Owing to the lack of an HLA-matched sibling donor, patient age, and the morbidity of prior therapy, an allogeneic bone marrow transplant was not pursued.

In April 2002, the patient developed global confusion and a headache. A lumbar puncture at an outside hospital demonstrated central nervous system recurrence of ALL. The patient was treated with intrathecal chemotherapy and cranial radiation, but relapsed systemically shortly thereafter and died in July 2002.

MATERIALS AND METHODS

Morphologic Testing and Immunohistochemistry

The right axillary LN sections were fixed in nonbuffered formalin and B5 fixative and stained with hematoxylin-eosin. The nonbuffered formalin-fixed tissue sections were additionally stained with the following immunohistochemical stains: CD3, CD20, CD43, Bcl-2, and [kappa] and [lambda] light chains (Dako Corporation, Carpinteria, Calif).