MYC/BCL2/BCL6 triple hit lymphoma of the pericardium: a case report and review of the literature

Dear Editor,

Malignant lymphomatous involvement of the heart include a variety of different entities with distinct epidemiology, clinicopathological features, phenotype, and prognosis.

The present case report describes the occurrence of a high-grade B-cell lymphoma (HGBL) with MYC, BCL2 and BCL6 rearrangements (triple hit), presenting with pericardial effusion in an immunocompetent patient and highlights the importance of early detection, accurate diagnosis, and prompt therapy.

In October 2018 a 78-year-old man presented to the emergency room (ER) for evaluation of subacute shortness of breath and fatigue that had worsened during the previous days. He had no history of chest pain, B symptoms or nausea.

His medical record included arterial hypertension for which he continued his usual medication (valsartan), dyspepsia (treated with esomeprazole), and a remote smoking history of three pack-years approximately 45 years previously.

His physical examination was significant for dry bibasilar inspiratory crackles and irregular pulse rate with distant heart sounds. There were no palpable peripheral lymph nodes nor organomegaly.

Blood tests were unremarkable except for mild anemia (hemoglobin 123 g/L) and lymphocytopenia (670 per microliter of blood). Electrocardiogram (ECG) exhibited atrial flutter without obvious ischemic alterations. The chest spiral computed tomography (CT) with radiocontrast agent revealed a subsegmental pulmonary embolism of the inferior lobe of the right lung as well as a massive circumferential pericardial effusion. Cardiac tamponade with restricted filling of the cardiac chambers and hypotension was also confirmed by the bedside transthoracic echocardiography (TTE). The patient underwent an urgent pericardiocentesis that yielded 1200 mL of turbid ematic fluid. Microbiological cultures were negative. Cytologic examination of the fluid demonstrated a pathologic monomorphic population of large CD20 and BCL2 positive B-cells with proliferation index (ki67) of approximately 60%. Immunophenotype studies showed lack of CD10, CD30, BCL6, and MUM1 expression. Immunohistochemistry for HHV8 was also negative. Fluorescence in situ hybridization (FISH) analysis was performed in the pericardial fluid detecting MYC, BCL6 and BCL2 gene rearrangement. An iliac crest bone marrow biopsy (BMB) was negative for lymphoid infiltration but bone marrow involvement was established by positron emission tomography (PET) scan that showed multifocal skeletal lesions (Fig. 1a).

Fig. 1.

a Initial staging positron emission tomography (PET) scan showing stage four disease. b Interim PET scan showing resolution of all lesions. c Final PET scan after completion of therapy revealing local recurrence

The final diagnosis in line with the latest revision of the World Health Organization classification of lymphoid neoplasms (2016, WHO) was consistent with a high-grade B-cell lymphoma (HGBL) with rearrangements of MYC, BCL2 and BCL6, activated B cell (ABC) type according to Hans’ classification, stage IV disease (osteomedullary involvement).

The patient refused our standard treatment for this disease (dose adjusted R-EPOCH—rituximab plus etoposide, vincristine, doxorubicin, cyclophosphamide and oral prednisone) and therefore received six cycles of immuno-chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and oral prednisone), with no major complications. For the pulmonary embolism he received low molecular weight heparin (fraxiforte). Serial TTEs during immunochemotherapy did not detect any recurrence of pericardial fluid. While on the interim PET-CT scan (after two cycles) he obtained a complete remission (Fig. 1b), the final PET-CT performed 7 weeks after completion of treatment showed local recurrence to the pericardium (Fig. 1c) and short thereafter symptomatic involvement of the CSF. He was entered in a palliative care program.

Cardiac malignancies include either primary cardiac tumors (extremely rare) or secondary metastatic deposits in the heart, which are over 20 times more common. The most frequent primary cardiac malignant neoplasia are sarcomas and lymphomas. Primary origin of cardiac metastatic infiltration comprise solid tumors (lung, breast, gastro-intestinal tube, thyroid, and melanoma) as well as hematologic neoplasms (lymphoma, leukemia) (Neragi-Miandoab et al. 2007).

Primary cardiac lymphoma (PCL) is a subgroup of non-Hodgkin lymphomas defined as extranodal lymphoma involving only the heart or pericardial space, or both, with no evidence of a tumor present in any other organ/cavity. Primary cardiac involvement is very uncommon as normal cardiac tissue does not contain lymphocytes. The pathogenesis of this disease is still not well understood, while several hypothesis have been speculated: it seems to share the same background as extranodal NHL at non-cardiac sites, which is often associated with chronic infection (e.g., H. pylori, EBV, HHV8), inflammation (e.g., rheumatoid arthritis; thyroid lymphomas associated with Hashimoto thyroiditis), or immunosuppression (e.g., HIV) (Sanna et al. 1998).

The largest review of case-series of PCL was performed by Petrich et al. (2011) and included 197 cases. The most common histological type is diffuse large B-cell lymphoma (DLBCL), presenting more frequently in the elderly age (median age of 63 years). Prognosis of PCL seems to be poor (median overall survival of 3 months) due to both local factors (complications caused by the primary lesion such as circulatory failure, tamponade, arrhythmia) and systemic factors (thrombotic complications) (Economopoulos et al. 1996) although recent literature suggests that after introduction of immunotherapy with CD20-targeting regimen and improved supportive care, reports of complete remission and long-term survivors are increasing (Gordon et al. 2016).

In rare cases, malignant lymphomas emerge as a body cavity–based effusion including the pericardium, without an identifiable tumor mass and absence of disseminated disease. These are known as primary effusion lymphoma (PEL), which is a different entity form PCL. PEL is a human herpes virus-8 (HHV8)-positive B-cell lymphoma occurring in HIV-positive adults, who generally are coinfected with Epstein-Barr virus (EBV). PEL often lacks B-cell markers (CD19, CD20, CD79a), but expresses plasma cell–related markers (CD30, CD38, CD138) and it has an aggressive clinical course with a median overall survival of 6 months (Simonelli et al. 2003).

Recently, HHV8-negative effusion-based lymphoma (HHV8-negative PEL) has been reported that presents different epidemiology, phenotype, and disease course. Patients are frequently older, without an HIV/EBV context and with a good prognosis independently of treatment that vary from simple drainage to systemic chemotherapy and stem cell transplantation. In contrast to HHV8-positive PEL, HHV8-negative EBL has a complete mature B-cell phenotype, is frequently non-GCB and is generally EBV-negative, similar to conventional diffuse large B-cell lymphoma (DLBCL). A recent work by Mendeville et al. (2019) explored the genomic alterations of 11 cases of HHV8-negative EBL and noted frequent translocations at the MYC, BCL2, and BCL6 loci that in DLBCL confer aggressive features. Surprisingly, in HHV8-negative EBL despite these adverse prognostic features, like MYC translocations, the disease course is remarkably indolent.

While primary cardiac lymphoma accounts for only 1–2% of all cardiac tumors, secondary cardiac involvement in the setting of disseminated lymphoma is more common, occurring in up to 20% of patients with non-Hodgkin lymphoma (NHL). In contrast, cardiac involvement is very rare in Hodgkin’s Lymphoma (HL) (Adler and Cestero 2012).

As described by Gordon et al. (2016) amongst NHL with cardiac involvement DLBCL is the most common histologic subtype (58%), followed by T-cell lymphoma (16%), Burkitt’s lymphoma (9%) and CLL/SLL (6%). The median age at diagnosis is around 55 years. Symptoms and signs can be cardiac (heart failure, angina, conduction abnormalities) or constitutional (fever, chills, weight loss). Interestingly, authors found that patients with B-cell PCL showed better survival trends than their counterparts with secondary cardiac infiltration (median survivals 6 vs. 3 months). This is consistent with previous evidence that primary involvement of extra-nodal organs (non-cardiac) confer better prognosis compared to cases when extra-lymphatic disease is detected during staging of known lymphoma where, in general, extranodal involvement is considered a negative prognostic factor (Ferry 2008).

In our case report, we describe a rare disseminated NHL presenting with pericardial involvement and effusion in an immunocompetent individual. It cannot be considered PCL nor HHV8-negative PEL as we had proof of bone marrow involvement at the time of diagnosis (second synchronous extra-nodal site of disease). Interestingly, our case shares common immunohistochemical, genomic epidemiological features with the HHV8-negative PEL. Our patient was older, the tumor was assessed as non-GCB and presented rearrangements at MYC/BCL2/BCL6 genes. It showed however a more aggressive clinical course, which distinguishes it from HHV8-negative PEL. To our knowledge, this is the first HGBL reported in literature involving two extra-nodal sites (heart, bone marrow) and harboring these genomic characteristics (triple hit).

In fact, the largest series to date of triple-hit NHL cases conducted by Huang et al. (2018) included 40 patients, with a median age of 61 years. Almost 85% of patients had extranodal sites of disease at diagnosis that included: bone marrow, central nervous system, gastrointestinal tube, kidneys, breasts, liver, skin, soft tissue, and testes. No cardiac involvement was described. Treatments included R-CHOP (30%) as well as more aggressive regimens such as R‐DA‐EPOCH (55%), R-HyperCVAD (8%) and R-ICE (7%). 44% of patients achieved complete remissions at end of treatment while 20% were primary refractory (progression while on first line treatment). The median overall survival (OS) was 18 months and the one-year OS rate was 61%.

Since the 2016 revision of the WHO classification of lymphoid neoplasms we get to understand more about molecular heterogeneity of aggressive lymphomas (double and triple hit lymphomas) but at the same time it has raised many challenges trying to define the optimal therapeutic strategy to their management. Many centers have adopted more intensified regimes for this population driven by their success in Burkitt lymphoma, where the molecular hallmark is MYC translocation. From a multi‐institutional series in North America (Petrich et al. 2014) higher complete remissions rates could be achieved with R-DA-EPOCH compared with R‐CHOP. PFS was also greater for those receiving anyone of the three intensified regimens (R‐DA‐EPOCH, R‐HyperCVD, and R‐CODOX‐M/R‐IVAC) over R‐CHOP (median PFS 21.6 vs 7.8 months). There was however no difference in OS between the treatments. In a meta‐analysis of 394 patients with double hit lymphoma, first line therapy with R‐DA‐EPOCH significantly diminished the risk of progression but again had no survival benefit (Howlett et al. 2015). Concerning consolidation approaches, accumulative evidence shows that the addition of autologous stem cell transplant in first complete remission does not improve OS and therefore is not justified, unless patients have undergone less intensive front line induction (R-CHOP) where it confers a survival advantage (Landsburg et al. 2017).

Even though there is no standard of care for the management of patients with double and triple hit lymphomas centers worldwide have adopted mainly the R-DA‐EPOCH for this sub-group given these findings and the relatively modest toxicity compared with the other intensified approaches.

Concerning pericardial infiltration, according to the European Society of Cardiology 2015 Guidelines pericardiocentesis is the first line treatment for cardiac tamponade due to neoplastic disease (Class I, B) (Adler et al. 2015). Our patient, after pericardial drainage, received conventional systemic therapy. As it often happens in double/triple hit lymphomas, after an initial complete remission at the interim-PET he developed secondary refractory disease at the pericardium site. This is not astonishing, as large malignant pericardial effusions show, independently of the treatment choice, higher recurrence rates (40–70%) (Vaitkus et al. 1994). It can be speculated that inadequate chemotherapy penetration into the pericardial space because of poor vascularization could partly explain the limited treatment efficacy.

After relapse of disease the patient opted for radiation therapy which represents an effective palliative treatment in controlling symptoms in patients with radiosensitive tumours such as lymphomas. However, radiotherapy of the heart can increase risk of myocarditis and chronic pericarditis.

Triple hit lymphomas can present at uncommon sites. This case underlines the importance of performing an accurate diagnosis and an adequate staging when confronted with malignant pericardial effusions due to lymphoma because of the potential aggressive clinical behavior of some histologies. The majority of pericardial lymphomas described in the literature had a poor prognosis, and this is even more true in the presence of a very aggressive histology, as triple hit lymphoma.

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The authors received no specific funding for this work.

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The authors declare no conflict of interest.

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