Primary Cardiac Lymphoma: Report of Two Cases

Occurring in Immunocompetent Subjects

GABRIEL ANGHELa, VALERIO ZOLIa, NICOLA PETTIa, DANIELE REMOTTIb, MARIANO FECCIAc,PAOLO PINOc and IGNAZIO MAJOLINOa,*

aHematology and Bone Marrow Transplantation Unit, Ospedale ‘‘S. Camillo – Forlanini’’, Rome, Italy; bPathology Service Unit, Ospedale ‘‘S.Camillo – Forlanini’’, Rome, Italy; cCardiology Service Unit, Ospedale ‘‘S. Camillo – Forlanini’’, Rome, Italy

(Received 12 August 2003)

Primary cardiac lymphomas (PCLs), involving solely heart and/or pericardium at presentation, arerare events. They are frequently recognized at autopsy and generally carry a poor prognosis due eitherto a delay in the diagnosis or to infiltration of heart structures. We report here on two patients withlarge B-cell PCL. One is a 52-year-old man who presented with multiple cardiac tumors infiltratingmainly the right atrium and the inter-atrial septum. Diagnosis was established by ultrasound-assistedtransesophageal biopsy of the intra-atrial multilobated tumor mass. He was treated with Rituximab-implemented high-dose sequential (R-HDS) chemotherapy followed by autologous peripheral bloodstem cell transplantation, attaining complete response. He had no evidence of disease 24 months fromonset. The second patient was a 70-year-old woman who presented with pericardial tamponade andlow-output cardiac failure. Despite prompt pericadiocentesis and chemotherapy with cyclopho-sphamide and vincristine, she died 2 weeks later. Postmortem examination revealed large B-celllymphoma proliferation confined to the heart. Whether primitive heart localizations represent anindependent prognostic factor, and what specific measures should be adopted in patients with this rarepresentation is the subject of the present report and review of the literature.

Keywords: Primary cardiac lymphomas; Heart tumors; Echocardiography

INTRODUCTION

Primary cardiac lymphomas (PCLs) are rare malignancies

with isolated, often bulky involvement of the heart and/or

pericardium [1]. PCLs represent about 1 – 5.6% of all

primary cardiac tumors. Cardiac localizations of systemic

non-Hodgkin’s lymphomas (NHLs) are much more

frequent, representing 20 – 28% of secondary cardiac

neoplasias [2 – 4].

In recent years, the increasing number of PCLs reported

in the literature seems to be due, at least in part, to the

increasing incidence of severe immunodeficiency, either

due to HIV infection or to organ transplantation [5 – 13].

In fact, primary lymphomas of the heart are extremely

rare in immunocompetent patients, so that their clinical

and biological behavior is largely unknown.

The majority of patients with PCLs present with

congestive heart failure, hemopericardium with or

without cardiac tamponade, superior vena cava

syndrome, cardiac arrhythmias and nonspecific

electrocardiographic abnormalities. Only a few of

them are asymptomatic [1,4,14,15]. PCLs are envis-

aged as prognostically poor, as most patients go

untreated and diagnosis is frequently made at post-

mortem.

The present report is focused on 2 patients with large

B-cell PCL seen at the Hematology Unit, S. Camillo

Hospital, Rome. One is a 52-year-old man who

presented with multiple cardiac tumors involving right

atrium and inter-atrial septum and only slight pericardial

effusion. He had a complete response with high-dose

sequential chemotherapy supplemented with Rituximab

and also including autologous peripheral blood stem cell

transplantation. The other was a 70-year-old woman

with a pericardial tamponade who died 2 weeks after

diagnosis.

*Corresponding author. Address: Hematology and BMT Unit, Azienda Ospedaliera S.Camillo-Forlamni, Circonvallazione Gianicolense 87, 00152,Roma, Italia. Tel.: +39-6-5870 4418. Fax: +39-6-58704644. E-mail: imajolino@libero.it

Leukemia & Lymphoma, April 2004 Vol. 45 (4), pp. 781–788

ISSN 1042-8194 print/ISSN 1029-2403 online # 2004 Taylor & Francis LtdDOI: 10.1080/10428190310001617259

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PATIENTS AND METHODS

Case 1

A 52-year-old man with hypertension and ischemic heart

disease, presented on June 2001 with dyspnea, cyanosis,

night sweats, diffuse itching and intense fatigue. His heart

rate was 96/min, respiration rate 26/min, and arterial

pressure 140/110 mm Hg. A bilateral ankle significant

edema was present. An initial chest X-ray was normal,

and an electrocardiogram only showed non-specific low-

voltage changes. His hemoglobin was 16 g/dl, hematocrit

50.2%, white blood cell (WBC) count 7.86 109/l with

normal differential, platelet count 1936 109/l. His serum

lactate dehydrogenase (LDH) was 780 U/L (nv: 230 –

460 U/L) and bilirubin 2.3 mg/dl (nv: 0.2 – 1 mg/dl),

mainly unconjugated (1.6 mg/dl). Despite these minor

alterations, CT scan and echocardiography (transthor-

acic, TTE and transesophageal, TEE) showed an

incomplete thrombotic occlusion of inferior vena cava

with multiple cardiac tumors involving the right atrium,

and in part the interatrial septum (Fig. 1). There was a

slight pericardial effusion, and a partial obstruction of the

inferior vena cava and sovrahepatic veins. A slight

abdominal effusion was also present. An echocardiogra-

phy-assisted transesophageal biopsy of the multilobated

tumor mass located in the right atrium showed a

histologic picture of diffuse large B-cell lymphoma

(ECA+, CD2O+). Trephine bone marrow biopsy

and aspiration were negative. The patient was treated

with R-HDS (Rituximab-implemented high-dose sequen-

tial chemotherapy). After an initial debulking with 3

monthly courses of APO (doxorubicin 75 mg/m2, iv, day

1; prednisone 40 mg/m2 orally, day 1 to 21; vincristine

1.4 mg/m2, iv, day 1) the patient received high-dose

cyclophosphamide (HD-CY) 7 g/m2, iv, followed by G-

CSF 5 mcg/kg/day, and high-dose etoposide (HD-VP16)

2 g/m2 plus G-CSF 5 mcg/kg/day. The apheretic

collection of mononuclear cells was attempted at two

time points, the first following HD-CY with the collection

of 0.26 l06/kg CD34+ cells, and the second following

HD-VP16 with the collection of 9.26 106/kg CD34+

cells.

Four doses of Rituximab1 375 mg/m2 each were also

given during this treatment phase. The first and the

second dose were administrated 48 h after HD-CY, and

24 h before the first leukapheresis, respectively. The third

and fourth Rituximab administrations were given 24 h

after the last dose of VP16 and 24 h before the second

planned leukapheresis, respectively. Before the autograft

the patient was considered to be in good partial

remission, with 80% tumor mass reduction. He then

underwent an autologous transplantation with the

previously cryopreserved autologous peripheral stem

cells. BEAM [16] was the preparative regimen. Following

the autograft, he recovered 0.56 l09/l PMN on day +12,

and 506 l09/l platelets on day +10. Two months later,

CT scan and both transthoracic and transesophageal

echocardiography showed complete disappearance of the

lymphoma (Fig. 2). The patient received no further

treatment, and is currently free of disease and in good

clinical condition 16 months from completion of therapy,

24 months from diagnosis.

Case 2

A 70-year-old woman with a history of diabetes,

hypertension, chronic renal failure and hemolytic anemia,

was admitted to our hospital with a picture of heart

failure. During the last few weeks she had developed

worsening dyspnea, fatigue, ankle edema and cyanosis.

On examination she was severely dyspnoic, and appeared

mentally disorientated and cyanotic. Her pulse rate was

94/min, and her blood pressure was 110/60 mmHg. There

were signs of pericardial tamponade and systemic venous

FIGURE 1 Case #1. Transthoracic (a) and transesophageal (b) echocardiography at onset showing a large, multilobated tumoral mass (discontineousline) involving the right atrium, RA (arrow) and the interatrial septum.

782 G. ANGHEL et al.

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hypertension, with jugular vein distension, and painful

hepatomegaly. Laboratory studies showed hemoglobin

11.4 g/dl, WBC count 5.26 109/l, platelet count

1446 109/l. Blood urea nitrogen was 74 mg/dl

(nv=10 – 50), creatinine 1.6 mg/dl, LDH 1415 U/l

(nv=230 – 460 U/L), total bilirubin=0.89 mg/dl (nv

0.2 – 1). The direct antiglobuline was positive. All other

blood tests, including liver function tests and CPK were

within normal range. However, a chest X-ray showed

marked cardiomegaly and CT scan and a two-dimension

transthoracic echocardiogram showed the presence of 2

multilobated tumors of the right atrium, with abundant

pericardial effusion and signs of cardiac tamponade.

Pericardiocentesis was urgently performed, yielding

1200 ml of effusion fluid. Cytospin preparations were

microscopically examined and showed a large number of

medium and large-sized lymphoid cells of B-cell origin,

characterized by irregular shape and large convoluted

nuclei, most with evident nucleoli. Trephine bone marrow

biopsy was normal. The diagnosis was of primary large-

B-cell lymphoma of the heart. Respiratory distress

improved in the following days, and steroid therapy was

started with i.v. methylprednisolone at the dose of

1.5 mg/kg/day for 15 days. Her condition however

remained critical, and despite chemotherapy with vincris-

tine 1 mg iv, cyclophosphamide 600 mg iv and methyl-

prednisolone 1 mg/kg/day, she died with progressive

cardiac failure 2 weeks from diagnosis. Post-mortem

examination confirmed the diagnosis.

REVIEW OF THE LITERATURE

We performed a medline-based extensive literature review

of primary malignant lymphoma of the heart. We only

considered cases of lymphoma confined to the heart and/

or pericardium, with no bone marrow involvement or

blasts in the peripheral blood, as well as those with a

single and asymptomatic extracardiac disease involve-

ment or minimal loco-regional spread due to massive

cardiac involvement according to the previously

suggested criteria for PCLs [1,17].

We found 68 cases whose characteristics responded to

these criteria [2,4,14,15,17 – 75]. Patients who did not

benefit from modern diagnostic criteria, e.g. ultrasound

imaging evaluation, and/or total body CT scan or

magnetic resonance imaging (MRI), like those reported

before 1980 [14,15,19 – 23] as well as case reports where

essential data were lacking or not available, were not

included in this analysis [17,18,24,28,36 – 38].

Overall we analysed 56 patients reported in the

literature which fulfilled the above mentioned criteria

[2,4,25 – 27,29 – 35,39 – 76]. The male-to-females ratio was

1.6. Median age was 67 years (range 29 – 90). The

reported site involvement at presentation is summarized

in Table I. In the majority of cases (72%) the tumor arose

in the right chambers of the heart, most frequently

involving the right atrium alone (42%), or in concomi-

tance with the right ventricle (28%). Isolate pericardial

effusion was found in 16% of cases, while 7 patients

(14%) presented with a tumoral mass and concomitant

pericardial effusion. The majority (78%) also had

myocardial involvement.

Symptoms at onset are non-specific. Dyspnea was

present in 46.1%, edema in 25.6%, weakness or fatigue

in 20.5%, chest pain or angina in 12.8%, arrhythmia

and palpitations in 17.9%, weight loss, fever or night

sweats in 8%. Superior vena cava syndrome and

congestive heart failure were present at onset in 5%

and 28%, respectively, while cardiac rupture at onset is

an exceptional event [52]. Approximately 3% of patients

were asymptomatic at the initial clinical assessment in

the reports analyzed here.

Imaging technology combined with invasive proce-

dures, as myocardial biopsy during cardiac catheteriza-

tion [26,76], transvenous endomyocardial biopsy or

transthoracic needle biopsy [2,4,49,58,59,69,73] or peri-

cardiocentesis with cytology examination [29,41,54,57 –

FIGURE 2 Case #1. Transthoracic (a) and transesophageal (b) echocardiography showing complete disappearance of the previously describedlymphoma mass involving the right atrium (RA)—arrow.

783PRIMARY CARDIAC LYMPHOMA IN IMMUNOCOMPETENT SUBJECTS

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59,65, our case #2] were the main diagnostic procedures,

especially when patients were not eligible for mediastinal

thoracothomy, due to their critical condition.

Cytology of the pericardial effusion proved diagnostic

in 60% of cases. In some cases, however, highly invasive

procedures were needed, as mediastinal thoracothomy

and subsequent biopsy [4,42,46,48,50,51,57,63 – 65,70,72].

Two-dimensional transthoracic echocardiography

[2,29 – 32,42,46,50,51,58,64,65,69,74, our cases] and

recently transesophageal procedure [4,70,76, our case

#1] with or without subsequent gallium-67 isotope study

[42,58] or CT scan [31,32,44,46,49,51,57 – 59,63 –

65,70,71, our cases], demonstrated their utility in

revealing and accurately characterize the intracardiac

mass, as well in excluding other tumor localizations.

Magnetic resonance imaging (MRI) [2,4,41,49,59,67,69,

72,76] showed the highest sensitivity (88%). There has

been a substantial improvement of diagnosis with the

advent of modern diagnostic techniques. In fact, in the

earliest reports, at a time when these technologies were

not available, diagnosis was frequently made post-

mortem, and often no specific treatment could be

instituted [29,30,32,35,44,45].

From a pathological point of view, the analysis of the

published reports shows a predominance (78%) of

medium and/or large B-cell high grade lymphomas (G

subtype, according to Working Formulation) [2,4,29 –

34,39 – 44,46,53,57,58,64,65,69,74,76] most of them

having a diffuse pattern, while uncleaved small cells

lymphomas [24,45] or immunoblastic cells lymphomas are

exceptionally rare [38].

Information on treatment is available for 52 patients

(Table II). This was chemotherapy (CHT) alone in 27

(52%), CHT plus radiotherapy in 4, CHT combined with

surgery in 2, RT solely (n=3 cases), CHT combined with

RT and surgery (n=1 case). Four patients underwent

surgery, 1 patient was submitted to orthotopic heart

transplantation [48], followed after severe acute rejection

and tumor relapse by concomitant immunosuppression

(cyclosporine) and chemotherapy. One patient (our case

TABLE I Literature review. Disease localizations in immunocompetent patients with PCLs including the 2 cases reported herein (data were

available for 50 patients out of the 56 analyzed)

Involved site Patients Percent of cases References

Right A 21 42 [4,26,28,31,32,40,43,46,50 – 53^,57,61,64,65,69,76], our 2 cases

Right+ left A 1 2 [49]

Right V 1 2 [54]

Left V 2 4 [29,74]

Right V+ left V 3 6 [2,48^^,67]

Right A+right V 14 28 [25,30,44,45,47,54,56,58 – 60,62,63,70,72]

Pericardial effusion* 15* 30 [32,34,35,40,42,43,53,54,59,71,73,74,75], our 2 cases

Abbreviations: A, atrium; V, ventricle; [53]^: the cited author reported 2 cases of PC1s with right atrial involvement; [48]^^ in this patient there was an extensive replace-

ment of myocardium with lymphoma; *in seven patients, pericardial effusion was concomitant to other localizations of the tumoral mass: right atrium (n=5), left ventri-

cle (n=1), and right atrium+right ventricle (n=1).

TABLE II Literature review. Treatment in the immunocompetent patients with PCLs (data were available for 52 patients out of the 56

analyzed)

Treatment

No of

patients AND AWD DD

Median

follow-up (range) References

CHT 27 6 12 9 7 m (0.07 – 144 m) [2,4**,29**,33,34,40,41,53,57**,59,60,

62 – 65,69,71 – 73**,75,76], our case #2**

RT 3 1 – 2 11 m (0.25 – 15 m) [39,42,58**]

CHT+RT 4 3 – 1 26.5 m (11 – 36 m) [42,46,66,67]

Surgery 4 – – 4 1.5 m (0.03 – 7 m) [30**,31,35,50**]

Surgery+CHT 2 – – 2 1 m, 13 m (1 – 13) [55,56]

Surgery+RT+CHT 1 1 – – 3 m [51]

CHT+autologous

PBSCT

1 1 – – 24 m Our case #1

Orthotopic heart

transplantation^

1 – – 1 16 m [48]^

No therapy^^ 9 – – 9** 7 days (3 – 30 days) [25,26,29,32,44,45,54,55]

Abbreviations: CHT, chemotherapy; RT, radiotherapy; PBSCT, peripheral blood stem cell transplantation; AND, alive with no evidence of disease; AWD, alive with

disease; DD, dead for disease progression; m, months; **cases of sudden death (4 30 days from onset); ^patient submitted to heart transplantation, followed by severe

acute rejection and tumor relapse, than treated with concomitant immunosuppression and chemotherapy; ^^patients not submitted to specific treatment, undergoing only

palliative/symptomatic therapy (pericardiocentesis, diuretics, antibiotics etc).

784 G. ANGHEL et al.

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#1) underwent CHT plus autologous stem cell transplan-

tation. Nine patients did not receive any specific therapy.

Chemotherapy meanly consisted in CHOP or other

anthracyclin containing regimens (n=22 patients),

alkylating agents and/or Vinca alkaloids (n=5 patients),

or other compounds as procarbazine, ifosfamide, metho-

trexate, etoposide, bleomycin, (n=4). Radiotherapy was

administrated alone or in combination with CHT or

surgery (radiation dose 20 – 40 Gy). All patients who did

not undergo any specific therapy (n=9) died within 30

days from diagnosis (range 3 – 30), but it is difficult to say

whether they were not treated due to the severity of

disease or death ensued due to lack of treatment. Among

the 27 patients who were given CHT alone, after a median

follow-up of 7 months (range 0.07 – 144) only 5 were alive

and free of disease. In the other treatment groups,

analysis of outcome is difficult due to the small number

of patients. However, only a few patients were alive and

in complete remission at the time of reporting, a fact that

seems to indicate the superiority of the chemotherapeutic

approach also in this rare variety of malignant

lymphoma.

DISCUSSION

We described here 2 cases of PCLs, the first being a 52-

year-old man who presented with multiple cardiac tumors

infiltrating the right atrium and the interatrial septum,

while the second patient was a 70-year-old woman who

presented with pericardial tamponade and low-output

cardiac failure. Diagnosis of a cardiac tumor was made

both with the help of echocardiogram, as well with CT

scan which confirmed the presence of a tumoral mass. In

patient #1, diagnosis of PCL was established by

transvenous echoguidated biopsy, while in the second

case, pericardiocentesis solely revealed lymphoma cells,

so that diagnosis of malignant lymphoma was possible

even without tissue histology. In the first case, treatment

consisted in Rituximab-implemented high-dose sequential

(R-HDS) chemotherapy followed by autologous periph-

eral blood stem cell transplantation (ABSCT), attaining a

long lasting complete response (24 months from onset). In

the second case, despite prompt pericadiocentesis and

chemotherapy with cyclophosphamide and vincristine,

the patient died 2 weeks from diagnosis. Postmortem

examination revealed B-cell lymphoma proliferation

confined to the heart.

The primitive occurrence of a cardiac tumor within the

heart structures (i.e. heart or pericardium) represents a

rare event. In autopsy series the figure is 0.0017% to

0.25% of total primary cardiac tumors [32,69]. Among

them, PCLs are extremely rare pathologic entities,

representing about 5.6% out off all malignant cardiac

tumors [4]. Although the definition of PCLs includes only

those lymphomas localized to heart and/or pericardium

[1], cases with massive cardiac involvement but minimal

lymphoma dissemination to other sites are worth being

included [17,54], as they probably originate from a

primitive heart localization. Beside those with isolated

heart involvement, we have analyzed as PCLs also tumors

with single asymptomatic extracardiac localization or

minimal locoregional dissemination.

In 1949, Whorten reviewed the 87 malignant neoplasies

out of the 329 cases of primary cardiac tumors previously

collected by Mahaim [14]. Among them, only 3 met the

criteria for a primary cardiac lymphoma. In the next two

decades, only a few authors [1,3,19 – 23] described a limited

number of so-defined reticulum-cell sarcoma of the heart.

The first review of interest is that published by Ceresoli

et al. in 1997 [53]. They analyzed 48 cases with PCLs,

including 8 with minimal extracardiac disease. Diagnostic

procedures mainly used were chest X-rays, TTE, TEE,

MRI and CT scan, combined with invasive procedures as

pericardiocentesis and thoracotomy. Cytology of peri-

cardial effusion was diagnostic in 67% of cases, while

thoracotomy and biopsy yielded a positive result in all.

Among the noninvasive techniques, TEE and MRI

showed a sensitivity 4 90%.

Chim et al. [57] described 2 cases of PCLs and

performed a 21 cases literature review, showing that only

9 patients were diagnosed ante-mortem as follows: 5 by

cytological examination of the pericardial effusion, 2 by

surgical biopsy and 2 by pericardial and myocardial

biopsies during pericardiocentesis respectively. This

stressed the possible role of the cytological examination

in case when open biopsy cannot be proposed because of

the critical clinical conditions. However, one should take

into consideration the scarse sensitivity of this procedure

(approximately 60% according to our analysis).

Percutaneous intracardiac biopsy with combined

fluoroscopic and TEE imaging was the main diagnostic

procedure in the case published by Jurkovich et al. [69]. In

this report, the author stressed the fact that although no

complications have been reported during transvenous

intracardiac tumor biopsy, potential complications as

perforation and cardiac tamponade, arrhytmias, vasova-

gal reactions and pneumothorax may be taken into

account. It also should be considered that TEE is very

useful for characterization of the tumoral intracardiac

masses and combined with fluoroscopy provides an

accurately and safely ultrasound-guided transvenous

biopsy diagnosis.

The cases of PCLs with available data mentioned in the

literature since 1980 were the object of the present review.

In accordance to the published data, PCLs occur more

frequently in male patients and typically in the elderly,

with lesions mainly localized in the heart’s right chambers

(classically in the right atrium) or pericardium, while in a

few cases other sites are involved (left atrium or ventricle,

interatrial or interventricular septum etc.). Clinical

presentation is variable, and in many cases aspecific as

arrythmias, lower edema, congestive heart failure,

pericardial effusion or superior vena cava syndrome. In

most cases, lymphoma cells originate from the B-

lymphocyte lineage, being frequently diffuse, medium or

785PRIMARY CARDIAC LYMPHOMA IN IMMUNOCOMPETENT SUBJECTS

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large cells high grade lymphomas [77]. Echocardioagraphy

(both transesophageal, as well as transthoracic echocar-

diography), CT scan and MRI are the mainly used

imaging techniques to detect cardiac tumors, but

histologic and immunochemical examination of the

involved tissue, as well as cytologic examination with

cytogenetic studies of pericardial effusion are always

required to confirm diagnosis. Early diagnostic workup,

based upon TEE, MRI or CT scan seems to have a major

contribution in revealing the heart involvement and

confirm the nature of the tumor. In order to exclude the

involvement of the bone marrow a trephine bone marrow

biopsy and aspiration is indicated. In rare cases

thoracotomy may be useful but this approach is highly

invasive and therefore with elevated risk, as death before

appropriate therapy have been occasionally reported

[29,32,44,45,55]. Polymerase chain reaction performed in

the pericardial fluid effusion samples [44,76], may be

useful in confirming the presence of a monoclonal

population lymphoid lineage. Therefore, the availability

of non invasive diagnostic procedures, including imaging

techniques as ultrasound, CT scan, orMRI, made possible

a precoceous diagnosis of PCLs [53,78]. On the other

hand, it should be mentioned that in our literature review,

the number of ante-mortem diagnosis strikingly increased

(31 out of 39), which may suggest that in the last years,

modern diagnostic procedures might have changed

outcome and prognosis of PCLs. Systemic chemotherapy

solely or in combination with irradiation of the tumoral

lesions, as well as surgery, consisting in resection of the

intracardiac tumor or pericardium, are the main ther-

apeutic approaches. Chemotherapy, alone or in associa-

tion with RT, showed at the moment the most relevant

results, as out of 30 patients undergoing CHT solely or

combined with RT, 20 (67%) were alive (8 with no

evidence of disease and 12 in partial remission), some after

more than 3 years since onset [41,71]. The analysis of the

mainly reported complications of the therapeutic

approaches for PCLs reported in the literature stresses

the iatrogenic nature of some of them as: cardiac toxicity

due to chemotherapy, post-radiotherapy pericarditis,

increased incidence of coronaris damage after radio-

therapy. Although a gold standard therapy for cardiac

lymphoma was still not established, and the reported

therapeutic attempts are quite unhomogenous, from the

analyse of the data reported in the literature, surgery did

not seem to have improved the prognosis.

A peculiar role of the sequential high-dose chemother-

apy followed by autologous stem cell transplantation in

the long survival, as might be taken into consideration in

the future especially in those clinically aggressive, large

cell lymphomas. Literature data show that if the disease is

promptly diagnosed at an early stage (with limited

extension), chemotherapy combined or not with radio-

therapy may improve the usually rapidly infaust prog-

nosis [26,30,53].

However, despite modern, early highly sensitive

diagnostic approaches such as transvenously or transoe-

sophageal intracardiac biopsy, cytologic analysis of

pericardial effusion when present including immunophe-

notyping, combined with non specific diagnostic proce-

dures such as electrocardiography, transthoracic 2D-

echocardiogram, computed tomography or magnetic

resonance imaging, [53,69,79,80] which mainly contrib-

uted to make this variety of lymphoma a treatable and

curable disease when promptly diagnosed, the prognosis

of PCLs still remains poor due both to diagnostic delay as

well as of the aggressiveness of this pathological entity.

Acknowledgements

This work was supported in part by a grant from AIRC,

Associazione Italiana per Ia Ricerca Contro il Cancro. Dr

Gabriel Anghel is a fellow of AIRC.

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