Burkitt lymphoma masquerading as cardiac tamponade

A 61 year old man presented with diffuse large B cell lymphoma of the skin of the back of the shoulder which was excised and treated with chemotherapy (CHOP regime) in 1998. He was in complete remission till he presented in 2002 with extranodal marginal zone lymphoma of the parotid gland for which he underwent superficial parotidectomy and radiotherapy. He continued in remission till 2006 when he presented with recurrent pericardial effusion and tamponade. At median sternotomy, pericardial effusion was drained, an anterior pericardiectomy was done and a left posterior pericardial window made, and an enlarged hard paraaortic lymph node excised. Histology, immunocytochemistry and chromosome analysis revealed Burkitt lymphoma. Patient underwent chemotherapy with CODOX-M regime and continues in remission. This report is unusual on account of the highly atypical presentation of Burkitt lymphoma as cardiac tamponade, only a few cases having been reported previously, the occurrence of three lymphomas of different pathological and genomic profiles in one patient over a period of eight years and the relatively slow rate of growth of an otherwise fulminant tumour with high tumour doubling time. A review of literature with special emphasis on chromosomal diagnosis, transformation of other lymphomas into Burkitt lymphoma and mediastinal and cardiac involvement with Burkitt lymphoma is presented.


Background
Burkitt lymphoma is a type of B cell Non Hodgkin lymphoma which has endemic (African) and non-endemic (American) sub-divisions. An aggressive tumour involving mostly abdomen, jaw, head, neck and peripheral lymph node sites, it has a tumour doubling time of only 24 hrs. Involvement of mediastinal lymph nodes is extremely rare and there are only isolated instances of presentation with cardiac tamponade. To our knowledge, there are no reports of a delayed transformation of a large diffuse B cell lymphoma or a marginal zone parotid lymphoma into a Burkitt lymphoma after a long period of remission.

Case Presentation
A 61 year old male underwent excision of diffuse large B cell lymphoma of the skin over left shoulder in 1998 which was treated with CHOP chemotherapy including Prednisolone. He stayed in remission till 2002 when he presented with a painless swelling of the preauricular region arising from the parotid gland for which he underwent superficial parotidectomy. The histology revealed extra-nodal marginal zone lymphoma of parotid salivary gland. The immunohistochemistry revealed a composite phenotype: CD20+, CD5-, CD10-, bcl 6-, bcl 1-, bcl 2+, bcl 10-, p53+/-, p21+/-, CD79a+. There was no evidence of the previous diffuse large B cell lymphoma. Radiotherapy was given to left parotid area over 3 weeks in 15 frac-tions to a total dose of 30 Grays. Patient was in remission till May 2006 when he presented with 5 week history of exertional shortness of breath, easy fatigability, lethargy, headache, agitation, poor appetite and erratic blood glucose.
Other significant past history included IDDM, hypertension, hypothyroidism following radioactive iodine therapy for thyrotoxicosis, peripheral neuropathy, chronic asthma, previous anterolateral and inferior myocardial infarctions and excision of basal cell carcinoma from back and right temple in 1998 and 2002 respectively.
Examination, on presentation in May 2006, revealed heart rate of 78 beats per minute, irregular, BP 95/70, 95% saturations on room air, raised JVP, soft bilateral thyromegaly and unremarkable cardiac and respiratory examinations.
Routine blood examination was normal except for ESR which was raised at 84/min and abnormal thyroid function tests. ECG confirmed atrial fibrillation, evidence of old inferior infarct and low voltage complexes. Chest Xray revealed an enlarged globular cardiac silhouette ( Fig  1). Transthoracic echocardiography demonstrated a global 5 cm pericardial effusion with evidence of diastolic right ventricular collapse and impaired right and left ventricular function. Percutaneous drainage of the effusion was performed using an indwelling pigtail catheter introduced subcostally and the fluid sent for cytological and microbiological analysis. Cytology was negative for malignant cells and microbiology showed no bacterial growth. Meanwhile, repeat echocardiography showed rapid reaccumulation of pericardial effusion despite the presence of the indwelling catheter. Contrast CT scan of thorax, abdomen and pelvis confirmed massive pericardial effusion (Fig 2) and an enlarged paraaortic lymph node (Fig 3). Patient was transferred to our tertiary cardiac surgical centre for further management. A coronary angiogram revealed a chronically occluded right coronary artery and minor disease in left coronary system. A left ventriculogram demonstrated inferior and basal akinesia with good function elsewhere.
Patient underwent transoesophageal echocardiogram in theatre which confirmed right heart collapse in diastole associated with large pericardial effusion. A median sternotomy was made in preference to video assisted thoracoscopic procedure, recognising the need for possible resuscitation in view of the fragile haemodynamic state of the patient. Another reason to prefer median sternotomy was the presence of concomitant coronary artery disease and ventricular dysfunction which may have required concomitant surgical revascularisation. Operative findings included a tense pericardial cavity filled with 750 mls of serosanguineous fluid with fibrinous exudates, 3 cm × 2 cm paraaortic lymph node of hard consistency, adherent to the right lateral surface of ascending aorta, below the innominate artery and a diffusely inflamed pericardium. A generous anterior pericardiectomy from great vessels to diaphragm vertically and phrenic nerve to phrenic nerve horizontally was done and a left posterior pericardial window made into the left pleural cavity posterior to the left phrenic nerve. The clearly abnormal, hard and adherent paraaortic lymph node was excised and pericardial fluid evacuated. Pleurae were widely opened and the pleural cavities drained. The thymus, preaortic lymph node and CT scan of chest showing large pericardial effusion pericardium were sent for histopathological analysis, a portion of lymph node for haematological malignancy assay including flow, immunohistochemistry, FISH and morphology, and pericardial fluid for cytology and microbiology.
Microbiology of the pericardial fluid was negative for bacterial and mycobacterial growth. Cytology of pericardial fluid was that of a highly cellular fluid containing erythrocytes, small lymphocytes, mesothelial cells, macrophages and, significantly, a minority population of large lymphoid cells (LCA positive). Histopathology of thymus was normal. Pericardium showed active chronic inflammation with focal florid mesothelial cell reaction, considered to be reactive in nature. Histopathology of the lymph node demonstrated complete effacement of the normal architecture by large population of highly proliferative monomorphic moulded angular neoplastic lymphoid cells with clumped chromatin and small nucleoli and large pale macrophages forming the "stars" in the "starry sky" typical of but not unique to Burkitt Lymphoma ( Fig  4).
Patient's postoperative course was uneventful and he was discharged home 9 days after surgery. He is currently in remission.

Discussion
Histologically, Burkitt lymphoma (BL) falls in the category of small noncleaved cell high grade Non-Hodgkin lymphoma [1]. It can be divided into two distinct types which are histologically identical but have important clinical and virological differences. The African endemic form presents as a jaw tumour that spreads to extra-nodal sites, particularly bone marrow and meninges. The American form presents with abdominal disease and ascites and also spreads to bone marrow and meninges [2]. There is an increasing incidence of both types with acquired immunedeficiency states like HIV [3] and, rarely, following immunosuppression after transplantation [4]. Our patient presented with a highly unusual mediastinal lymph node involvement and secondary pericardial effusion and tamponade. He had presented 8 years ago with Diffuse large B cell lymphoma of the skin of the back of the shoulder and 4 years thereafter with Marginal zone lymphoma of the parotid with surprisingly prolonged periods of remission after each presentation.
Sporadic, endemic and HIV associated BL are all characterized by chromosomal rearrangements involving c-myc proto-oncogene that lead to its inappropriate expression. C-myc proto-oncogene plays a central role in fundamental aspects of cell biology and proliferation, differentiation, metabolism, apoptosis and telomere maintenance [5]. BL cells carry a balanced translocation involving the c-myc locus on chromosome 8 and band 32 of chromosome 14 Biopsy of preaortic lymph node showing monomorphic moulded neoplastic lymphoid cells with large pale macro-phage "stars". q. This places c-myc close to the immunoglobulin heavy chain (Cμ), which subjects it to relentless stimulation by the enhancer element of the immunoglobulin gene. Alternately, the translocation causes mutations in the regulatory sequences of the myc gene, the coding sequences of the gene remaining always intact [6]. Rarely, translocation involves chromosomes 2 and 22 instead of chromosome 14 [6]. The specific breakpoint locus differs between various forms of BL, there being a definite relation between the level of myc overexpression in BL and genomic breakpoint location within the myc locus [7], Halembiena et al having identified translocation breakpoints at 190 kb 5' and 50 kb 3' of myc [8]. Based on a study of surface immunoglobulins in 91 biopsy samples, Gunven suggested only one cell clone was involved in BL in the majority of cases [9]. However, novel sporadic BL cell lines (BLUE-1) with a unique t (6; 20) (q15; q11.2) rearrangement in addition to the usual pathognomonic t (8;14)(q24;q32) translocation has been described [10]. Secondary chromosomal abnormalities have been studied to predict outcome in BL, and abnormalities of chromosome 13(13 q) and 22(22 q) had a negative impact on prognosis [11]. Trisomy12 has been described with Burkitt lymphoma [12]. Hummel et al used transcriptional and genomic profiling to generate a molecular signature for BL and identified 58 genes that constituted the molecular BL [13].
Our patient had c-myc rearrangement in the majority of cells which confirmed the diagnosis of Burkitt lymphoma. There was loss of one copy of BCL-2, the significance of which is unknown.
Histologically, BL consists of a sea of strikingly monotonous cells with a characteristically high mitotic index and cell death, accounting for the presence of numerous tissue macrophages with ingested nuclear debris, often surrounded by a clear space, creating a "starry sky" pattern [1]. Our patient showed complete effacement of lymph node architecture by moderate to large lymphoid cells with prominent nucleoli. Immunocytochemically, the tumour cells resemble activated germinal centre B cells and express IgM, pan B cell markers like CD 19, CD 20, CD24, 1a, as well as CD10. The African cases are CD 21 positive and most sporadic cases are CD negative. Mutations of p53 gene lead to accumulation of mutant protein within tumour cells which can be detected on paraffin-embedded tissues [14]. There was p53 deregulation in our patient, with CD 10+, Mib-1 (100%), bcl-2 (neg), FOX-P1 (neg).

FISH showing IgH region not rearranged
Differentiation between Diffuse large B cell lymphoma (DLBCL) and BL is of crucial importance since prognosis and treatment differ. Nakamura et al differentiated between BL and DLBCL with c-mycR and identified the following criteria for BL: growth fraction of nearly 100%, monotonous proliferation of medium sized cells and CD10+, bcl 2-and low frequency of mutation of VH genes [15]. Cogliatti et al set the following criteria for differentiation: a mature B cell phenotype of CD 10+, bcl 6+, bcl 2-, a proliferation rate greater than 95% and c-myc rearrangements in the absence of t(14;18)(q32;q21) [16]. Dave et al, using gene expression profiling suggested the following criteria: high level of expression of c-myc target genes, expression of a subgroup of germinal centre B cell genes, low level of expression of major MHC-class 1 genes and nuclear factor Kappa B target genes [17]. WHO criteria for BL include classical/atypical histology, CD20+, bcl 6+, CD 10+, BCL2-, CD 5-, Ki 67 score =/>95% and IG -myc+ [13]. Our patient met all the above criteria in support of BL.
Transformation of histologically and genetically different lymphomas into BL has been anecdotally reported. Mukhopadyay et al reported the extremely rare transformation of a follicular lymphoma into a Burkitt-like lymphoma in a single lymph node illustrating the unusual oncogenic stimulus that resulted from inhibition of apoptosis of bcl-2 combined with deregulation of cell growth by c-myc [18]. Raghoebier reported the histological conversion of follicular lymphoma into BL with extensive alterations within both the functional IG heavy chain allele and around the t (14; 18) breakpoint, indicating clonal evolution rather than the appearance of an independent lymphoma [19]. Tomita reported atypical BL arising from follicular lymphoma, inguinal lymph node biopsy having shown composite lymphoma and chromosomal analysis of marrow having revealed t (8; 14) and t (14; 18) in identical cells. The patient died after 4 months despite chemotherapy [20]. HeIntel et al reported BL in a patient with previous splenic marginal zone lymphoma with IgH sequence showing no identity between the two clones [21]. Our patient, to the best of our knowledge, is the first patient in world literature to have had 3 histologically different lymphomas over a period of 8 years, starting with Diffuse large B cell lymphoma of the skin over the back of shoulder in 1998, followed by Marginal zone lymphoma of the left parotid in 2002 followed by Burkitt lymphoma in 2006.
There have been isolated reports of Burkitt lymphoma of heart, pericardium or mediastinum. Singh et al reported AIDS-related BL of the heart presenting with acute right heart failure with fatal secondary pulmonary hypertension [22]. Fatimi et al reported intracardiac BL mimicking acute pulmonary embolism [23]. Bergler-Klein et al reported the case of young woman with generalised BL presenting with myocardial infiltration mimicking HOCM which resolved with high intensity chemotherapy with modified B-ALL protocol [24]. Hoffmeier described complete remission of intracardiac BL in an 85 year old man treated with 6 courses of CHOP regime [25]. Ikematsu et al reported a 26 year old woman with abdominal BL requiring laparotomy, presenting with cardiac tamponade due to pericardial infiltration treated successfully with drainage, doxycycline, 7 courses of chemotherapy and CNS prophylaxis [26]. Chalabreysee [27] and Graham [28] reported BL presenting with pericardial effusion. In a large series of 92 patients of BL reported by Kemeny, 5 patients developed pericardial effusion [29]. Helfland reported cardiac tamponade caused by BL infiltrating pericardium and heart in a homosexual man [30]. Our patient presented with a large bloody pericardial effusion with tamponade and had para-aortic lymph node involvement. Pericardium was grossly inflamed but there was no infiltration with lymphoma.
To conclude, Burkitt lymphoma may present exceptionally with recurrent pericardial effusion or tamponade. Treatment should be aggressive and optimistic and a significant number of patients respond favourably to treatment.