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An 81-year-old man was admitted to the Department of Hematology, Shaare Zedek Medical Centre in Jerusalem, Israel, with an extensive unilateral pleural effusion. The patient is a Sephardi Jew who was born in Macedonia and immigrated to Israel 35 years before this admission. He had a history of ischemic heart disease, recurrent cerebrovascular accidents and chronic renal failure. For the past 6 years, he had been followed by a hematologist because of mild systemic lymphadenopathy (mediastinal, axillary, retropritoneal and pelvic) and splenomegaly. His blood counts showed mild leukopenia and thrombocytopenia that were attributed to hypersplenism. Bone marrow biopsies were normal for his age with a normal karyotype. His immunoglobulin levels were very low: IgG = 558 mg% (normal 700–1,600), IgM = 9 [(40–230), IgA = 13 (70–400). His enlarged lymph nodes were approximately 1–2 cm in diameter, stable and not easily amenable to a lymph node biopsy. A presumptive diagnosis of a low grade indolent lymphoma was made; no definitive therapy was offered other than gammaglobulin replacement therapy. About 3 years before the current admission, he was diagnosed with Kaposi's Sarcoma (KS) on his legs and was treated successfully with five doses of low dose liposomal doxorubicin (20 mg/m2). In the month before his admission, he complained of shortness of breath. A chest X-ray revealed a new large right pleural effusion (see Fig. 1).

The patient underwent pleurocentesis where bloody fluid was removed. Bizarre cells with basophilic cytoplasm and a somewhat plasmacytoid appearance were seen on cytocentrifugation (see Fig. 2). Immunophenotypic analysis revealed the cells to be CD45+, CD38+, HLA-DR+, CD138−. All B and T cell markers were negative except for cCD79a (a B cell marker) that was positive (see Fig. 3). On cytological examination, neoplastic cells showed nuclear immunostaining for LANA-1, a gene of Kaposi Sarcoma Herpes Virus/Human Herpes Virus 8 (KSHV/HHV8) (see Fig. 4) and for HUM1 gene which indicates clonality of the disease. LMP immunostaining for Epstein-Bar virus (EBV) and EBV- polymerase chain reaction (PCR) of the fluid (primers and probes were derived from the EBV alkaline DNAse gene) were negative. HIV examination was negative. His CD4 count was 660/μl. A diagnosis of HIV-negative, EBV-negative primary effusion lymphoma (PEL) was made.

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Figure 1. Chest X-ray. Massive right pleural effusion.

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Figure 2. Cytospin of pleural fluid, H&E stain ×40. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Figure 3. Immunophenotype of the pleural effusion. CD45+, cCD79a+, CD38+, HLA DR+,CD3−,CD13−,CD10−,CD34−,CD19−,CD20−,Kappa−,Lambda−,TdT−, CD138−. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Figure 4. Cytological examination. (a)H&E stain ×40. (b)Nuclear immunostaining for LANA-1 (KSHV/HHV8) ×40. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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In 1995, Cesarman [1] described a new type of B cell Non-Hodgkin lymphoma (NHL) in AIDS patients involving body cavities with cells that are positive for KSHV/HHV8. Subsequently, this lymphoma was called primary effusion lymphoma (PEL). In 2001, this new entity was entered into the WHO classification of hematological malignancies [2].

The diagnosis of PEL is based on the classical appearance of the cells in the fluid, a unique immunophenotype and histological evidence of KSHV/HHV8 involvement. The cells may resemble immunoblasts, plasmablasts, or Reed-Sternberg-like bi-nucleated cells. Immunophenotypically, the cells are CD45+ but do not express the classic B cell (CD19, CD20, cCD79a, immunoglobulins) and T cell (CD3, CD4, CD8) markers. Other markers that may be expressed are CD30, CD38, CD71, CD138, and HLA-DR [2].

The typical evidence for KSHV/HHV8 involvement is made by immunohistochemical staining for LANA-1. PCR assays for KSHV/HHV8 are still experimental. The vast majority of HIV-positive PEL have EBV involvement [3]. No evidence of EBV infection was found in the present patient, nor most (30 out of 34) of the reported HIV-negative PEL cases (Table I).

Table I. Summary of the Reported HIV-Negative PEL Patients
ReferenceOriginAgeSexKSMCDCD4IgImmunosuppressionDiseasesEBVTreatmentSurv.PleuraPeric.Perit.Extra
  1. KS, Kaposi's sarcoma; MCD, multicentric Castleman's disease; Ig, Immunoglobulins level; EBV, Epstein Bar virus; Surv., survival; Pleura, pleural involvement; Peric., pericardial involvement; Perit., peritoneal involvement; Extra, extracavitary involvement; M, male; F, female; N, no; Y, yes; NR, not reported; m, months; CHF, congestive heart failure; DC, dilated cardiomyopathy; HCV, hepatitis C virus; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; CVA, cerebrovascular accident; DM, diabetes mellitus; CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; DHAP, dexamethasone + cytosar + cisplatin; ICE, ifosphamide + carboplatin + etoposide; CHIVPP, Chlorambucil + vinblasting + procarbizine and prednisone; INFα, interferon α; Rt, radiotherapy.

[4]USA85MNN288NR CHFNNone6 mY   
 USA78MNNNRNR NRYNR6 m  Y 
[5]Russia85FYNNRNR NRNPalliative4 mY   
 NR46FNNNRNR Breast implantsNNRNR  Y 
[6]Italy69FNNNRNR CirrhosisNChemotherapy1 m  Y 
[7]NR94MYNNRNR Colon CancerNParacentesis72 mYYY 
[8]Japan101MNN   CHFYEtoposide8 mY   
[9]Haiti67MYNNRNRCyclosporine+ PrednisoneHeart transplant d/t CHFYCHOP, Pleurodesis7 mY   
[10]NR85MNYNRNR NYCHOP2 mY   
[11]Italy89MNNNRNormal Colon carcinomaNNRNRY   
 Italy75MNN1052Normal MyocardiopathyNNone>12 mY   
[3]Spain83MNNNRNR IHD,CHFNNone<1 mY   
[12]Moroco58MNN210NR CirrhosisNCHOPX23 m  Y 
[13]NR56MNNNRNRCyclosporine+ AzathioprineHeart transplant d/t DC, HCV Paracenthesis1 m  Y 
[14]Morocon Jew68MNNNRNR IHDNCHOPX49 mY YLN
[15]NR80MNNNRNR IHD,COPD,CRFNRCHOPX4>8 mY   
[16]Ashkenazi Jew74FYYNRNR  NCHOPX44 m  YLN
[17]NR72MNNNRNR Previous LymphomaNRituximab>13 mY YLN
[18]Eastern Europe78MNNNRNR CVANCHOPX818 mY   
[19]France78MNN255NR CHFNPrednisone+ Cyclophospamide1.5 m  Y 
 France86FYYNRNR Breast carcinomaNlow dose CHOP2 m  Y 
[20]Ashkenazi Jew74MNNNRNR IHDNNRNRY   
[21]Italy96MNNNRNR CHFNRintracavitary Cidofovir10 mY   
 Italy70MYNNRNR NRNRintracavitary CidofovirNR  Y 
 Italy77MNNNRNR CHFNRintracavitary Cidofovir>15 mY   
[22]Italy78MNNNRNR  NRCHOP,DHAP,INFα, intracavitary Cidofovir+ Rt>15mY   
[23]Korean62MNNNRNR NNCHOPX6, ICEX3, Autologous transplant> 24m Y  
[24]Italy36FYN231NRIdiopathic CD4+ lymphopeniaNNNR7 mY Y 
[25]Italy78MNNNRNR IHD, CVANBortezomib+ Liposomal Doxo+ Rituximab>24 mY   
[26]African57MYNNRNRRapamycin+ PrednisoneRenal transplantNCHOPX4+Bleomycin8 mY   
 African63MNNNRNRRapamycin+ PrednisoneRenal transplantNIV Cidofovir<1 m?Y? 
[27]NR73FNNNRNR DMNRPleurodesis38 mY   
 NR43MNNNRNRChemo-ChlVPP, INFαHodgkin, HCVNRPleurodesis, CHOP24 mY  LN
Presented studySephardi jew81MYN660hypoLiposomal DoxoIHD,recurrent CVA,NPleurodesis8 mY   

The patient was treated successfully by pleurodesis, and has remained stable without reaccumulation of fluid for 8 months following which he died from unexpected sepsis.

COMMENTARY

  1. Top of page
  2. COMMENTARY
  3. References

KSHV/HHV8 is a lymphotropic virus of the gamma herpes virus family, similar to EBV. Infection by KSHV/HHV8 has a wide geographical distribution with a low incidence in North America and northern Europe, a high incidence in sub-Saharan Africa and an intermediate incidence in the Mediterranean [28].

In high incidence areas, some infections are acquired vertically by contact with infected parents. However, many infections are acquired by horizontal and often intra-familial spread during childhood. In these high incidence settings, saliva is the most probable vector of transmission. In low incidence areas, the transmission is mainly sexual [28].

KSHV/HHV8 is the causative agent not only for PEL but also for KS and multicentric Castleman's disease (MCD). There are patients who suffer from more than one KSHV/HHV8 induced disease. In this report, the patient suffered from KS years before the appearance of PEL. In the 34 cases of HIV negative PEL reported in the literature which includes this case, nine suffered in addition from KS, three from MCD, and two suffered from all three diseases (Table I).

The true incidence of PEL in HIV negative patients is unknown, but is presumed to be rare as from 1996 until the present, there are only 34 reported cases (Table I). Some of these patients had well established immunodeficiencies such as idiopathic CD4+ T lymphocytopenia [24] or secondary to immunosuppressive therapy following solid organ transplantation [13]. Others are elderly people in the 8th to 9th decade who live, mainly, in areas of high incidence of KSHV/HHV8 [29]. Whether these elderly patients have any occult immune deficiency is unknown. In a review article, Carbone [30] suggested that “HIV-negative patients with PEL are likely to have an underlying immunodeficient state such as advanced age or associated conditions such as cirrhosis, cancer, or after solid organ transplantation.” In this case, the patient had a different type of immunodeficiency. He was hypogammaglobulinemic for several years before the development of PEL. In all previous reports of HIV negative PEL, immunoglobulin levels were not reported with the exception of a single Italian case [11] who had normal immunoglobulin levels.

The importance of the cellular immunity in defense against KSHV/HHV8 diseases is supported by the relatively high incidence of KSHV/HHV8 diseases in patients with AIDS who have low CD4+T cell counts and the regression of KS following the reduction of immunosuppressive treatment after solid organ transplantation [31]. In contrast, only a single report associated humoral deficiencies with these diseases. Mazzucchelli [32] described a complex immune deficiency state of idiopathic CD4+ T lymphocytopenia and hypogammaglobulinemia in a patient with KS but not with PEL. The patient reported herein is the first report of a possible connection between an impairment of the humoral immunity (hypogamaglobulinemia) and PEL. He lived in an area with an intermediate incidence of KSHV/HHV8 for about 30 years before suffering from any KSHV/HHV8 induced disease. The hypogammaglobulinemia may have had a role in allowing the KSHV/HHV8 to develop into two distinct diseases, Kaposi sarcoma and PEL.

In PEL, as in KS, the viral genomes persist as extrachromosomal episomal DNA circles. This means that the majority of the viruses are in the latent state [29]. PEL cells also express the same latent genes as KS cells (as LANA, v-cyclin, v-FLIP) [33]. These genes and others encode for numerous proteins that have a role in the tumorigenesis of PEL. LANA, for example alters the function of the tumor suppressor proteins p53 and the retinoblastoma protein; vGPCR leads to the expression of vascular endothelial growth factor-A (VEGF-A) which activates the mTOR pathway; and vFLIP causes constitutive activation of NF-kB [31]. KSHV/HHV8 also encodes for viral IL-6 [34], a human IL-6 homologue, which activates the JAK/STAT pathway [31].

Accumulation of fluid in one or more of the body cavities (pleural, pericardial, or peritoneal) is characteristic of PEL and is the cause of the majority of the symptoms, however, systemic symptoms such as fatigue and B symptoms may occur.

Of the 34 HIV-negative PEL patients that were described in the literature, 23 (67%) had pleural involvement, 13 (38%) peritoneal involvement, and only three patients (9%) had pericardial involvement. Involvement of more than one cavity was described in four patients (11%). It is possible that the reported distribution does not reflect the true frequency of the type of serous lining involvement, but rather that pleural effusions are more likely to be symptomatic.

In 1997, only 2 years after the first description of PEL, De Pond [35] described an HIV patient with KSHV/HHV8 positive non-cavitary lymphoma that preceded PEL. It opened the way for several reports of what was called “solid PEL,” PEL like lymphoma without any effusion. Only four out of the 34 patients with HIV-negative PEL (11%) had lymph node involvement in addition to the cavity involvement.

Due to the rarity of this entity there is no consensus on the therapy for patients with either HIV-positive or negative PEL.

There are no controlled studies, neither in HIV-positive or negative patients that address the question of treatment. Historically therapy was based on chemotherapy (CHOP or others) and recurrent paracentesis. Newer strategies include biological agents (bortezomib, rituximab), immunosuppressive drugs (rapamycin), anti-viral therapy (systemic or intracavitary), and pleurodesis.

Bortezomib was described as a very effective therapy against PEL cell lines [36] and in one case report [25] it was effective when used in conjunction with pegylated liposomal doxorubicin and rituximab. The OS in this case exceeded 24 months. Rituximab is not an option in the majority of PEL patients as CD20 is usually negative. There is a single report using rituximab alone as therapy for a patient whose disease was CD20+ [17] and the description mentioned above of rituximab in combination with other drugs [25]. Rapamycin has been described as effective against PEL cells in vitro and in a PEL-SCID xenograft model [37]. Despite these findings, rapamycin did not prevent or control the disease in two renal transplant patients who received this drug as part of their immunosuppressive therapy [26]. Intracavitary cidofovir was injected successfully to four Italian patients with relatively tolerable side effects and OS greater than 15 months in one of them [21, 22]. Pleurodesis appears to be a reasonable treatment option for pleural PEL [27].

In the present patient, intracavitary cidofovir was considered, however his prior chronic renal failure precluded its use due to the danger of systemic absorption and resultant nephrotoxicity. Ultimately, he was treated successfully by pleurodesis.

The prognosis of PEL patients is generally remains dismal. The median survival for AIDS patients is approximately 6 months [38]. In a pooled retrospective survival analysis (Kaplan Meier estimate) of the 34 HIV-negative PEL patients in the literature, the probability of 7 month survival is 53% with a confidence interval of 34–69%.

In conclusion, this patient highlights the clinical features of PEL and its molecular genesis and suggest that immunoglobulin levels may play a role in the complex permissive milieu that leads to PEL. Definitive prospective studies are needed to establish an optimal therapeutic strategy for this rare lymphoproliferative disorder.

References

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