Primary cardiac CD5-positive diffuse large B-cell lymphoma:A case report and review of literature

Background (cid:0) Primary cardiac CD5 positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a rare subtype of DLBCL with many diagnostic challenges. The case is reported, along with a review of several characteristics of the disease. Case presentation (cid:0) We described a 64-year-old female who presented with a 12-month history of cough, and a mass in the right atrium observed on imaging studies that extended into the right ventricle. Conclusions (cid:0) CD5+ DLBCL was conrmed nally by pathological examination of the cardiac biopsy. The patient responded well to the modied R-CHOP regime. The poor prognosis factors include CD5 positive, non-GCB immunophenotype, myc, bcl-2 and bcl-6 gene rearrangements etc. Early diagnosis and aggressive treatment play a key role on improving the prognosis of primary cardiac CD5+ DLBCL.


Introduction
Diffuse large B cell lymphoma(DLBCL)is the most common type of Non-Hodgkin's lymphoma (NHL), and representing 30%~40% of all NHLs with a high aggressiveness and poor prognosis, and occurring mostly in immune compromised patients. Primary cardiac CD5 positive diffuse large B-cell lymphoma (CD5 + DLBCL) is extremely rare subtype of DLBCL that involves only the heart and/or pericardium,accounting for < 2% of all primary cardiac tumors [1,2] . Gene expression studies support the idea that CD5 + DLBCL is distinct from other DLBCL. The prognosis is poorer due to stronger invasive ability. However, the diagnostic criteria and molecular features are still unclear. Herein, we report a patient who suffered primary cardiac CD5 + DLBCL and summary its clinical characteristics by reviewing literature.

Patient Information
Clinical history A 64-year-old female presented with 12-month history of cough. No facial pu ness, exertional chest tightness, and dyspnoea, absent lower limb oedema and no lymphadenopathy. Magnetic resonance imaging MRI revealed a mass in the right atrium, in ltrating into the right wall of the right ventricle. The bicuspid valve was squeezed. MRI enhanced Scan demonstrated asymmetrical intensi cation in mass, while showed a low density in the foci compared with the cardiac cavity ( Figure 1A-C). Transesophageal echocardiography with color Doppler imaging (TECDI) demonstrated the bicuspid valve was squeezed and cardiac insu ciency with abundant blood ow signal in the lesions ( Figure 1D-E). Electrocardiogram (ECG) showed ST Segment and T -wave alternated. In that case, Malignant tumor from right atrial wall was considered. The patient had a history of renal amyloidosis for 5 years and multiple myeloma IgG type for 4 years. No space occupying lesions were found in the lung, liver, spleen and kidney. It showed that Lactate dehydrogenase (LDH), creatine phosphokinase, hydroxybutyrate dehydrogenase and troponin were signi cantly increased to test the level of serum myocardial enzymogram before biopsy operation.
After diagnosis, the patient underwent comprehensive physical examination prior to rituximab, 600mg mono-therapy. Considering the deterioration of renal amyloidosis during treatment, she received PC chemotherapy regimen bortezomib 2mg, day 1; cyclophosphamide 0.3mg, day 1. Then, she received following four cycles of R-CHOP chemotherapy regimen: rituximab, 600mg, day 0; cyclophosphamide, 0.5g, days 1-2; doxorubicin hydrochloride liposome, 40mg, day 1-2; vincristine, 4mg, day 1; prednisone, 15mg, days 1-5. The patient was in remission after 7 months treatment courses. PET/CT showed no obvious morphological changes in the right atrium, and FDG metabolism was normal in the right atrium and the whole body (including brain tissue). However, pancytopenia and suppression of cellular immunity were observed. The patient is receiving further treatment for increasing white cells currently. The further following up is performing.

Discussion And Conclusions
DLBCL is the most common subtype of non-Hodgkin's lymphoma. Many studies showed that the heterogeneity were apparent in clinical features, morphological characteristics, immunophenotype, genetics, therapeutic response and prognosis. As a transmembrane receptor that mainly regulates T cell functions and development, CD5 is also expressed by a small subset of normal B cells. It contributes to the progression of tumor by inhibiting the T cell response and protecting B cells from B cell receptor (BCR) signaling-mediated apoptosis [3] . Generally, CD5 is expressed in the B cell lymphoma such as chronic lymphocytic leukemia (CLL) and Mantle cell lymphoma (MCL) [4] . In addition, a number of CD5 positive hairy cell leukemia cases have been reported [5] . Recent years, Increasing CD5 + DLBCL cases, especially primary occurred in cardiac, have been reported with the imaging examination and technological progress.
As a matter of fact, there were no speci c clinical symptoms, which further led to misdiagnosis or missed diagnosis. The most common symptoms are dyspnea, chest pain, and constitutional complaints such as Page 4/8 fever, night sweats, loss of appetite, and weight loss. It usually involves the right heart, in particular the right atrium. Only less than 10% of cases show isolated left heart involvement. Yang Xiao et al [6] reported a 64 years old female patient with primary CD5 + DLBCL in the right atrium. The patient's main clinical manifestations were facial edema, tiring chest tightness and dyspnea, with jugular vein lling, and no edema of lower limbs. All 3 of cases reported by Gwyneth Soon, MBBS et al [2] had right heart involvement. Only 1 case involved all 4 chambers of the heart. In our case, the mass occupied the right atrium, in ltrating into the right wall of the right ventricle.
Primary cardiac lymphomas were uncommon and accounted for only 1-2% of all primary cardiac tumors. Over 90% primary cardiac lymphomas are of B-cell type,eg. Burkitt lymphoma (BL) and plasmablastic lymphoma, while the most of those are DLBCL [7,8] . Generally, molecular classi cation was according to the WHO classi cation for tumors of hematopoietic and lymphoid tissue (2017), which emphasizes that DLBCL is classi ed according to different gene expression pro ling (GEP), i.e. germinal center B-cell (GCB) type activated B-cell (ABC) type and unclassi ed DLBCL. Most of CD5 + DLBCL were ABC type [9] . Immunophenotypic subtyping of primary cardiac CD5 + DLBCL into cell-of-origin GCB and non-GCB subgroups is less commonly reported in the literature compared with DLBCL originating from other sites. In our study, the diagnosis of the case is belonged to non-GCB immunophenotype using the Hans IHC algorithm method.
Patients with DLBCL demonstrating high myc and bcl-2 protein expression by IHC, regardless of status of myc or bcl-2 gene rearrangements, have been shown to have a poorer prognosis. High-grade B-cell lymphomas with both myc and bcl-2 gene rearrangements or double-hit lymphomas are known to have an extremely poor prognosis [10,11] . The median survival time was less than 2 years [12] . Primary cardiac CD5 + DLBCL with myc gene rearrangement and primary cardiac double-hit B-cell CD5 + lymphoma with myc and bcl-2 gene rearrangements are rarely previously reported in the literature. A case of cardiac CD5 + DLBCL co-expressing c-myc and bcl-2 was reported by Yang Xiao et al [6] . In our case,bcl-6 gene rearrangement was detected positive but no detectable myc and bcl-2 gene rearrangements. Primary studies have shown that compared with CD5-DLBCL, the prognosis of patients with CD5 + DLBCL is characterized by poor prognosis and a high frequency of central nervous system relapse, and there is no signi cant correlation between CD5 expression and myc, bcl-2 and / or bcl-6 gene rearrangement [4,13] . Further studies would be helpful to evaluate the prognostic signi cance of MYC, BCL-2 and BCL-6 protein co-expression as well as those gene rearrangements with speci c reference to primary cardiac CD5 + DLBCL.
There is still no standard and uni ed scheme for the treatment of CD5 + DLBCL by the now. Early diagnosis and aggressive treatment play a key role on improving the prognosis of primary cardiac CD5 + DLBCL. R-CHOP is still recommended in the current standard rst-line therapy. In our case, R-CHOP chemotherapy is adopted and symptoms of the patient have been signi cantly relieved. However, CD5 + DLBCL occurs frequently in elderly patients who cannot tolerate high-dose chemotherapy and combination therapy. That will be a problem we must face in the future. A phase II study conducted by Kana Miyazaki et al [14] showed that dose-adjusted (DA)-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) might be a rst-line therapy option for stage II-IV CD5 + DLBCL.
In conclusion, primary cardiac CD5 + DLBCL is an uncommon and aggressive subtype lymphoma with higher risk of central nervous system (CNS) relapse. The factors of poor prognosis include CD5 positive, non-GCB immunophenotype, myc, bcl-2 and bcl-6 gene rearrangements or double/three-hit, Ki-67 positive rate no less than 90% or a higher LDH value (more than 3 times compared with normal value). Earlier detection and diagnosis contribute to promote patient's prognosis. Advanced radiological techniques and con rmatory histologic and / or cytologic diagnosis via periodic uid drainage or variable endocardial biopsy techniques are the main diagnostic procedures.

Consent for publication
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.