Atypical burkitt's lymphoma transforming from follicular lymphoma
© Hwang et al; licensee BioMed Central Ltd. 2011
Received: 28 March 2011
Accepted: 8 July 2011
Published: 8 July 2011
Amongst follicular lymphoma that transforms into a high-grade lymphoma, majority are diffuse large B cell lymphoma. Here we reported a rare atypical Burkitt's lymphoma transformation from an asymptomatic follicular lymphoma. Lymph node biopsy showed a composite lymphoma with infiltration of the inter-follicular areas by high grade small non-cleaved lymphoma cells amongst neoplastic follicles. Moreover, FISH and molecular genetic study confirmed concomitant MYC translocations and t(14;18) in the high-grade component, thereby suggesting the transformation of atypical Burkitt's lymphoma from an undiagnosed antecedent follicular lymphoma. The disease followed an aggressive clinical course, terminating in refractory disease 13 months after diagnosis. This is followed by a comprehensive review of the literature on lymphoma transformations from underlying follicular lymphoma after acquisition of MYC translocation, using Burkitt's lymphoma, follicular lymphoma, transformation and MYC translocations as keywords.
Follicular lymphoma (FL) is a low grade lymphoproliferative disease which frequently presents with generalized lymphadenopathy and frequent bone marrow involvement. The lymphoma arises from germinal centre lymphocytes with three histological grades based on the number of centroblasts in the neoplastic follicles. The pathogenesis of disease is due to the overexpression of the anti-apoptotic Bcl-2 associated with t(14;18), which juxtaposes BCL-2 gene on chromosome 18 to the enhancer of the immunoglobulin heavy chain gene (IgH) locus on chromosome 14. Moreover, as in their normal counterparts, the FL cells have on-going somatic hypermutations , which are implicated as a possible mechanism of high grade transformation .
Up to 30% of patients with FL had high grade transformation of their disease . In a study of 38 patients with histological progression from antecedent follicular lymphoma, the most common histology was diffuse large cell (68%), followed by diffuse mixed (21%), and small non-cleaved cell histology only constituted 5% of transformations from FL . On the other hand, in patients presenting with atypical Burkitt's lymphoma, about 25% were transformations from an antecedent FL .
MYC, located at chromosome 8q24, is a transcription factor involved in various translocations [t(8;14), t(8;22), t(2;8)], leading to its dysregulation and hence carcinogenesis. Acquisition of MYC translocation was reported in some high grade transformation of FL. Here we presented a patient with atypical Burkitt's lymphoma showing evidence of transformation from an undiagnosed antecedent FL. This is followed by a review of the literature on lymphoma transformations from underlying FL after acquisition of MYC translocation.
Report of a case
He received intravenous cyclophosphamide and vincristine together with oral prednisolone. After initial cytoreduction, he was induced with Stanford V regimen . He achieved only a partial response after a total of 5 cycles of Stanford regimen. Subsequent reassessment CT scan showed that while the other small intra-abdominal deposits reduced in size remarkably, there was only moderate shrinkage of the major central abdominal mass, which still measured seven cm in diameter (Figure 1B). The chemotherapy was therefore switched to ifosfamide, etoposide and high dose cytarabine (IVAC) . The disease remained refractory despite two cycles of IVAC with development of new hepatic lesions, progressive enlargement of central abdominal mass and serum LDH rising to more than 5000 U/L. This was further complicated by gastrointestinal bleeding but the bleeding source could not be localized despite upper endoscopy and colonoscopy. He was further salvaged with fludaradine, mitoxantrone and dexamethasone but he succumbed finally to refractory lymphoma.
Our patient had intermediate-high risk atypical Burkitt's lymphoma transforming from underlying FL. This is based on the composite histology which showed the histological and molecular features of FL (follicles with aberrant expression of BCL2 protein and presence of IgH-BCL2 translocation by PCR), and features of atypical Burkitt's lymphoma in the interfollicular regions (starry sky appearance, high mitotic rate, 95% MIB1 positivity, CD10 expression and FISH evidence of MYC translocations in the small noncleaved lymphoma cells). Despite the absence of a history of low grade lymphoma in our patient, the evidence supporting transformation from an underlying FL includes the followings. First, in the submandibular lymph node, neoplastic follicles with aberrant expression of BCL2 were present amongst the high-grade lymphoma infiltration. Moreover, in the abdominal lymph node biopsy, which contained atypical Burkitt's lymphoma cells only, t(14;18) translocation was present, suggesting that the atypical Burkitt's lymphoma has transformed from an underlying FL which might have been clinically occult prior to this presentation. We believed the underlying FL cells acquired secondary MYC translocations during their somatic hypermutations. It is highly likely that additional cytogenetic abnormalities being acquired during this transformation process contributing to the histological progression and aggressive clinical course. We treated this patient with the Stanford V regimen as first line therapy, which yielded an unsatisfactory clinical response. Therefore we switched to IVAC, which comprised of a combination of different chemotherapeutic agents not seen by the patient in previous chemotherapies. Unfortunately, the disease was primarily refractory to chemotherapy.
Herein we reviewed the English literature of high-grade lymphoma transformation from underlying FL upon acquisition of MYC translocation as evidenced by metaphase cytogenetic, FISH or Southern hybridization. Patients with either de novo high-grade lymphoma or lymphoblastic leukemia, in which tumor cells possessed concomitant t(14;18) and c-MYC translocations [8, 9], were not discussed as there was no evidence of underlying FL by history or histology.
In a review of the patients with histological transformations from underlying FL acquiring MYC translocations, two forms of presentation were identified. Majority developed aggressive Burkitt's transformation after a variable period from the diagnosis of underlying FL, ranging from 6 to 13 months [10–16]. Only three patients, in addition to the present case, were reported in the literature presenting with concomitant Burkitt's and FL. (Table 1) These three patients had composite histology showing features of both Burkitt's and FL in the same specimen, as in our case [17–19].
The acquisition of MYC translocation is reported in DLCL, lymphoblastic lymphoma and pre-B acute lymphoblastic leukemia transformation from FL, but only rarely in atypical Burkitt's lymphoma or Burkitt's leukemia transformation [4, 5].
Patients with composite histology of atypical Burkitt's and follicular lymphoma
Site and stage at initial presentation
Submand LN + abd LN, ascites
LN + BM
LN + BM
Temporal sequence of transformation
Composite follicular + Burkitt's
Composite Follicular + Burkitt's
Cytogenetics at transformation
t(14;18) by PCR +
MYC translocation by FISH
t(14;18) + t(8;14)
t(14;18) in follicular area
t(14;18) + t(8;14) in transformed area
t(14;18) + t(8;14)
Chemo → CR
Chemo → CR
Primary refractory died 13 months after Dx
Primary refractory and died 4 months after diagnosis
Relapsed 3 months later with partial response to salvage chemo
CNS relapse 6 months later and died
In summary, atypical Burkitt's transformation in our patient was illustrated by the composite histology, and FISH evidence of MYC translocation in addition to the presence of t(14;18). Moreover, additional MYC translocations in underlying FL may lead to high-grade lymphoma transformations with a wide range of histological subtypes in addition to atypical Burkitt's lymphoma/leukemia.
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