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Year : 2021  |  Volume : 64  |  Issue : 2  |  Page : 302-309
Multicentric Castleman's disease in India – Does EBV rather than HHV8 play a role?

1 Department of Pathology, M & J Western Regional Postgraduate Institute of Ophthalmology, affiliated to B. J. Medical College, Ahmedabad, Gujarat, Ex. Praful B. Desai/UICC Fellow, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Pathology and Head of Department of Biochemistry, Tata Memorial Hospital and Homi Bhabha National Institute, Eight Floor Annex Building, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Pathology, Eight Floor Annex Building, Parel, Mumbai, Maharashtra, India
4 Department of Pathology, Convener Adult Hematolymphoid Disease Management Group, Parel, Mumbai, Maharashtra, India
5 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
6 Professor and Secretary Adult Hematolymphoid Disease Management Group, Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

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Date of Submission13-Apr-2020
Date of Decision22-May-2020
Date of Acceptance14-Aug-2020
Date of Web Publication9-Apr-2021


Background and Aim: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder manifesting as multiple lymphadenopathy, multiorgan involvement, and inflammatory symptoms. This study aims at highlighting some unique features of MCD in Indian patients. Materials and Methods: These 17 patients from review of 78 cases of Castleman's disease (CD) diagnosed. Besides routine tissue sections were stained for Human Herpes Virus 8 latency associated nuclear antigen (HHV8-LANA) by immunohistochemistry (IHC) and Epstein Barr virus latent membrane protein (EBV-LMP) or Epstein Barr Virus by in situ hybridization (EBER-ISH). Result: The cases included Plasma cell variant (11 cases), mixed MCD (4 cases) and two concurrent MCD with large B cell lymphoma in HIV positive patients. Median age of disease onset was 47 years and female predominance was seen. Out of 15 MCD uncomplicated by lymphoma, 5 had POEMS (Polyneuropathy, organomegaly, endocrinopathy, myeloma protein, skin changes) and one also had TAFRO (Thrombocytopenia, anasarca, fever, marrow reticulin fibrosis, organomegaly, normal or slightly elevated immunoglobulin) syndrome. Out of 10 MCD without lymphoma, 2 cases showed few EBV positive large cells, both have features of POEMS. All 17 MCD cases were negative for HHV8-LANA IHC. Two HIV patients with MCD had large cell lymphoma, intrasinusoidal pattern, of which one was EBV positive. Though four relapses were seen, none died from disease. One of the two patients complicated by lymphoma died from disease. Conclusion: Indian patients with MCD show female preponderance and are negative for HHV8 but show EBV positive cells. This makes a case for role of EBV in etiopathogenesis of MCD in India.

Keywords: Castleman's disease, Multicentric Castleman's disease, POEMS syndrome

How to cite this article:
Bhanvadia V, Shet T, Rao V, Epari S, Gujral S, Jain H, Bagal B, Sengar M. Multicentric Castleman's disease in India – Does EBV rather than HHV8 play a role?. Indian J Pathol Microbiol 2021;64:302-9

How to cite this URL:
Bhanvadia V, Shet T, Rao V, Epari S, Gujral S, Jain H, Bagal B, Sengar M. Multicentric Castleman's disease in India – Does EBV rather than HHV8 play a role?. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 16];64:302-9. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/302/313279

   Introduction Top

Castleman's disease (CD) may present as unicentric disease (UCD) involving single group of lymph node or multicentric disease (MCD) involving multiple groups of lymph node.[1] UCD is in most cases treated successfully with surgery. First described in 1978, MCD is a systemic disorder with flares of non-specific symptoms like fevers, night sweats, weight loss, malaise, weakness, and fatigue suggestive of a chronic inflammatory syndrome associated with involvement of multiple nodes and organs including the liver and spleen.[2] Laboratory tests of these patients show elevated C-reactive protein (CRP), polyclonal hypergammaglobulinemia, microcytic anemia, lactate dehydrogenase (LDH), and hypoalbuminemia. Around 10% of all CD cases are present as MCD, and these are usually of the plasma cell variant.[2],[3] There is a moderate male predominance with a median age of the fifth-sixth decade.[4] In western countries, MCD in young patients is frequently associated with HHV-8 (Human herpes virus-8) in HIV (Human immunodeficiency virus) positive individuals and carries poor prognosis.[5] There is also a group of HIV-negative and HHV-8 negative patients with unknown etiology and pathophysiology, referred as idiopathic MCD (iMCD).[6] iMCD can occur at any age and is slightly more frequent in men than in women.

Multicentric CD (MCD) is more likely accompanied by acute phase reactions and several autoimmune features. The pleiotropic cytokine IL-6 and other pro-inflammatory cytokines has been found to play a pivotal role in MCD pathogenesis, therefore a new designation for the disease, i.e., IL-6 lymphadenopathy has also been proposed.[7]

To the best of our knowledge, we present the largest series of the MCD with clinical, laboratory features, serology, histopathology, treatment, and prognostic features in Indian patients.

   Material and Methods Top

This was a retrospective study from a tertiary care cancer centre in India covering a period of 10 years from January 2004 to June 2014. Out of total 78 cases of histopathologically confirmed CD, 17 cases of MCD have been reviewed and included in the study. All data were obtained from the electronic medical records and slides reviewed. The follow-up period was from the date of the definitive diagnosis to the final visit. For cases to be included in the study patients were required to have features: -systemic lymphadenopathy, elevated CRP, polyclonal hypergammaglobulinemia in absence of specific infections and a negative work-up for autoimmune disorder like Rheumatoid arthritis and Systemic lupus erythematous. Lymph node biopsy was performed in most cases to rule out a lymphoma.

MCD was divided into three major histological types: hyaline vascular (HV), plasma cell (PC), and mixed.[2],[8] Immunohistochemistry was performed on formalin fixed paraffin sections by automated immunostainers (Ventana Benchmark XT) for following antibodies:- CD3 (1:400, DAKO), CD20 (1:400, L26, DAKO), CD138 (1:250, M15, DAKO), CD23 (1:400, IB2, Biocare), CD5 (1:400, 4C7, Leica), bcl2 (1:300, 124, Cell marque), Kappa (1:1000, L1C, Cell Marque), Lambda (1:700, SHORT 16, Cell Marque), HHV8 (1;25, DAKO), EBVLMP1 (1:800, Cs1-4, DAKO). EBER-ISH was done with Novocastra EBER-ISH kit. Relevant clinical, pathological, serological, laboratory, and radiographic data were recorded in order to evaluate onset of symptoms and treatment response. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA), version 21.0.

   Result Top

Clinical details: There were 11 women and 6 men and had a median age at disease onset was 47 years. The most common symptoms were fatigue, fever, weight loss and lymphadenopathy. The medical history from symptoms to diagnosis was 1.5 to 15 months. Follow-up duration was between 2 to 84 months. Out of 17 cases of MCD, 11 were Plasma cell type (PC-CD), 4 were of mixed type and 2 HIV positive patients presented with lymphoma arising in MCD.

Of the 17 cases, 7 cases had dominant retroperitoneal and abdominal lymph nodes, four had cervical and mediastinal lymphadenopathy. Median size of largest lymph nodes was 4 cm. Common symptoms included fever (12/17), anemia (6/17), splenomegaly (2/17), hepatomegaly (1/17), pleural effusion (2/17), ascites (3/17), and thrombocytopenia (1/17). Out of 15 MCD not complicated by lymphoma, diagnosis of POEMS could be confirmed in 5 and ruled out in 10 cases. Overall, 12 cases show hypergammaglobulinemia. Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were found in 7 patients, 3 patients showed raised LDH and 4 patients had hypothyroidism as part of POEMS syndrome. One patient of POEMS also had additional features of TAFRO (Thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly, normal, or slightly elevated immunoglobulin) syndrome.

All of the clinical details are given in [Table 1]. The bone marrow biopsy in 2 patients showed plasmacytosis while in 1 patient with POEMS and TAFRO showed marrow fibrosis without any myeloid abnormality or maturation defects. FDG-PET/CT was available in 1 case and showed variably avid nodes with range of SUV from 2 to 23.5.
Table 1: Summary of clinical features of MCD patients

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Histopathology findings

The commonest histological pattern in MCD was the plasma cell variant whereby the germinal centers were usually normal or showed hyalinized vasculature with marked interfollicular plasmacytosis in the mantle or paracortical regions [Figure 1]a and [Figure 1]b. Few immunoblasts like large cells were seen in paracortex [Figure 1]c. These did not fulfill criteria for plasmablasts. The mixed type showed chiefly features of hyaline vascular disease but with focal plasmacytosis. On immunohistochemistry the T zone and B cell areas were highlighted by CD3 and CD20, respectively. These plasma cells were highlighted by CD138. In two cases of POEMS syndrome lambda chain restriction could be seen while they were equivocal or polyclonal in others. The few paracortical immunoblast were negative for HHV-8LANA antigen. HHV8 was done in all 15 MCD without lymphoma and was negative. EBV-LMP1 and EBER-ISH were done in 10 cases of MCD uncomplicated by lymphomas and an occasional immunoblast staining showed black signal in 2/10 (20%) cases in the paracortex surrounding the mantles of germinal centers [Figure 1]d. These EBV positive cells were also CD30 positive and this had led to diagnosis of Hodgkin lymphoma in one case. [Table 2] shows association of EBV with POEMS syndrome, as seen none of MCD without POEMS showed EBV, but 2/4 with POEMS showed EBV staining immunoblast.
Figure 1: (a) Multicentric Castleman's disease plasma cell variant with inter follicular plasma cells (H and E : 100) (b) Higher power of the plasma cells (H and E : 200) (c) Paracortical immunoblast (arrow) (H and E :400) (d) Epstein Barr virus in situ hybridization shows black nuclear signals in immunoblast (arrow) (EBERISH: 400)

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Table 2: EBV in various types of MCD

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Two cases of intrasinusoidal B cell lymphoma EBV associated in HIV positive patients were seen. In these while the node showed histology features of Castleman's disease the sinuses showed large cells that were CD20 strong positive [Figure 2]a, [Figure 2]b and [Figure 3] with focal CD30 in both cases. In one case the large cells also partly destroyed lymph node structure. EBER-ISH was positive in one case while negative in the other. HHV8 was negative in both cases.
Figure 2: (a) Intrasinusoidal large B cell lymphoma with node showing features of Castleman's disease (H and E : 40), (b) Higher power of large cells in sinusoids (H and E: 400)

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Figure 3: CD20 expression in the large intrasinusoidal cells (IP: 200), Inset shows EBERISH in these cells (EBERISH:400)

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Treatment details in 15 MCD uncomplicated by lymphomas are as follows: 4 were lost to follow up, 4 patients were treated with steroids, 4 patients were treated with Lenalidomide and dexamethasone (LD) therapy, one with CHOP, two cases were misdiagnosed as treated as marginal zone lymphoma and one as Hodgkin disease respectively. Of the patients who received LD therapy, two had partial response and two had complete response of whom one relapsed subsequently. Of the patients with steroid therapy two were lost to follow up and two are disease free. Of the two patients misdiagnosed and treated as lymphoma, one has no event while the other relapsed, was recognized as MCD and was put on LD therapy. Two HIV positive patients with diffuse large B cell lymphoma were treated with CVEP regimen (Cyclophosphamide, Vinblastine, Etoposide, Prednisone), of whom one patient died and one patient with intrasinusoidal EBV positive tumor and without nodal spillage of tumor is alive after three years follow up. One way of putting this will be to describe the median follow-up and PFS/OS of the entire cohort.

   Discussion Top

The estimated incidence of all forms of CD is 6500-7700 individuals every year in the United States of America or about 2.2 per 100,000.[9] No such information is available from Indian patients and the aim of present study is to highlight the pattern of MCD in India. Multicentric Castleman's disease (MCD) encompasses a spectrum of conditions that give rise to overlapping clinicopathological manifestations. Our current understanding of CD suggests that reactive follicular hyperplasia towards unknown antigenic stimulus.[10] Excess IL-6 in Castleman's disease patients results in increased B-lymphocyte growth, lymph node vascularity and inflammatory response.[11] The fundamental pathogenetic mechanism involves dysregulated cytokine activity, which causes systemic inflammatory symptoms as well as lymphadenopathy.[12] Patients frequently come to medical attention for the evaluation of systemic symptoms. HIV-positive persons are much prone to develop MCD at a younger age and co-infection with HHV-8.[13],[14] Recent data suggest that HHV-8-encoded IL-6 induces marked plasmacytosis, as well as acceleration of hematopoiesis and angiogenesis related to vascular endothelial growth factor (VEGF). VEGF is expressed strongly in plasma cells in the interfollicular area of the lymph node and influences the activity of MCD.[15],[16] Death in MCD is either caused by sepsis, systemic inflammation leading to multi-organ system failure or the development of malignancy (most commonly lymphoma).

While plasma cell variant is commonly seen in MCD, nodes frequently show histologic features of both subtypes and are characterized by a histologic triad: (1) diffuse marked plasmacytosis; (2) prominent germinal centers often showing hyaline vascular changes, and (3) preserved nodal architecture.[12] and similar findings were seen in our study albeit in four cases only.

In our study MCD comprised 21.7% of patients with CD, and this may be higher due to the referral centre bias. Since MCD is a rare clinical entity, very few large study of MCD has been published in literature till date. Kawabata et al., reported 21 Japanese MCD patients with median age of 46 years.[17] Shin et al., studied 27 MCD cases in Korea with median age of 47 years.[8] In our study, median age of MCD was 47 years. There are many reports of association of the MCD type with HIV infection with a global incidence of 4.3/10,000 patient-years.[5],[18] In our study only 2/17 MCD were HIV positive. A study from our institute on 13 patients with HIV associated lymphadenopathy, 2 case showed features of MCD and were positive for EBV (Epstein Barr virus) by EBER-ISH (Epstein Barr encoded RNA-In situ hybridization) and negative for HHV-8 LANA antigen.[19] In India, seroprevalance of HHV-8 is lower in both healthy individual and HIV infected population.[20] Thus our finding of absence of HHV-8 in MCD reflects the same and this may also have contributed to less aggressive behavior or mortality in our study. Due to lack of definitive etiologic agent most cases in this series are actually iMCD or idiopathic MCD.[6] An International study using VirCapSeq data on iMCD cases showed that in HHV8 negative iMCD cases, EBV was detected in 5 of 11 iMCD cases but quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection in lymph node tissue is due to occult, local reactivation in iMCD.[21] Very few studies address seroprevalance of EBV in India but it does occur fairly commonly. Venkitaraman et al. in their study of 181 children and young adults from South India documented that primary EBV infection occurs early in life with highest prevalence (55%) in the third year of life and incidence remained between 30% and 40% thereafter.[22] In this small series we found that EBV positive immunoblast were seen only in MCD with POEMS syndrome. One group of authors from Taipei studied 20 CD and all of them were EBV-positive by PCR amplification of both EBER and EBNA-2. On EBER-ISH, 12 cases had positive cells and signals localized to GC and rest to interfollicular space.[23] Murray et al. in their 15 cases of Castleman's disease demonstrated 6/15 cases with EBV-positive cells confined to the inter-follicular areas.[24] Our findings are similar to Murray et al. and while they do not confirm disease association, its association with POEMS syndrome at least hints at role in disease development. We agree that whether EBV infections is pathogenic, contributory to clinical severity, coincidental, or secondary to iMCD immune dysregulation remains unanswered.[6]

The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria (polyneuropathy, monoclonal plasma cell proliferation), one of the three other major criteria (Castleman disease, sclerotic bone lesions and VEGF raised), and one of the six minor criteria (Organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and thrombocytosis/polycythemia) are present.[25] In this study of MCD, 5/15 (33.3%) had evidence of POEMS syndrome. However in only two patients with clonal plasma cells and neuropathy a true POEMS syndrome is likely and others would be actually would be labeled as Castleman's disease variant of POEMS as these are from a cohort with histologic diagnosis of CD and then investigated for POEMS syndrome. Those patients without both of the above major mandatory criteria but with pathologically diagnosed Castleman's disease could be classified as Castleman's disease variant of POEMS syndrome if they have other POEMS syndrome features.[26] As the M-protein level is not very high in patients with POEMS syndrome to confirm clonal plasma cells many cases of POEMS may go unrecognized. Hara et al., advocate biopsy of sclerotic lesions to document clonal plasma cells.[27] While such lesions do show plasma cells, it has been hypothesized that VEGF, a marker of POEMS syndrome, is expressed by osteoblasts and causes new bone formation.[28] It was shown that multicentric CD patients without sclerotic bone lesions and with POEMS syndrome (non-osteosclerotic variant) had a significant risk for death while those with osteosclerotic lesions behaved better. The 5-year overall survival for 10 patients with osteosclerotic variant of POEMS syndrome was 90%, but was only 27% for the 9 patients with POEMS syndrome without osteosclerotic lesions.[29] This and the fact that we have reported Castleman variant of POEMS may be cause for better behavior in our series.

Takai K et al. in 2010 first described TAFRO syndrome, but MCD with TAFRO symptoms have been observed and reported for decades.[30] Although vast majority of cases have been reported from Japan. In our series one patient have TAFRO syndrome associated with POEMS. TAFRO syndrome is characterized by a more aggressive clinical course, corticosteroid refractoriness.[31] The patient with TAFRO in our study had only one month follow up.

In the absence of tumor-specific clinical, biochemical, and radiologic features, final diagnosis of CD depends on histopathological examination. Unfortunately, the morphologic features of CD are not entirely specific with wide range of differential diagnosis. Nodal marginal zone lymphoma rich in plasma cells will mimic plasma cell variant of CD. However, light chain restriction in plasma cells is the clue towards a diagnosis of lymphoma.[32] In one case in this series this misdiagnosis was encountered. Classical Hodgkin's lymphoma (CHL) misdiagnosis was made in our case due to CD30 positive immunoblasts and sometimes interfollicular Hodgkins does show follciles with castleman like features.[33] Useful clues would be absence of typical RS cells or even Hodgkin cells with typical nucleolar features and also clinically nodes in Hodgkin's lymphoma are larger with rubbery feel. On review of the literature, identified 34 cases of coexistent CHL and CD reported previously, about two-thirds of all cases are interfollicular variant of CHL and 89% of CD were Plasma cell variant, 93% were HHV8-negative.[34]

Patients with MCD and HIV-infection are at an increased risk of developing Non-Hodgkin Lymphoma (NHL) chiefly plasmablastic lymphomas or primary effusion lymphomas (PEL)/diffuse large B cell lymphomas (DLBCL). Loi S et al., found that 2 patients out of 11 HIV Positive MCD, developed NHL.[35] In our study, 2 HIV positive patients having MCD developed a unusual intrasinusoidal variant of DLBCL. The mature B-cell phenotype of most cases of HHV-8-unrelated PEL-like lymphoma is opposite of the CD20 negative phenotype of HHV-8-associated PEL. This lymphoma is labelled as HHV8 unrelated EBV associated PEL (primary effusion lymphoma) like intra sinusoidal lymphoma. HHV-8-unrelated PEL-like lymphomas are heterogeneous group of lymphoma that resemble PEL but differ immunophenotypically and genotypically from HHV-8-positive PEL and constitute a rare but distinct pathological entity.[36] Wu W et al., studied 55 cases of HHV-8 unrelated PEL like lymphoma, 4 cases were HIV positive, median age was 42.8 years & male preponderance. All 4 cases were EBV positive, suggest role of EBV in lymphomagenesis.[36] In our study both our patients were females in keeping with female preponderance seen in our series with MCD and one was positive for EBV. The very first study to record seroprevalance of HHV8 in India recorded a seroprevalance of 2.4%.[20] But their sample size was very small (42 patients; 36 males and 12 females).[20] Another study carried out on 87 HIV-infected subjects from South India also reported a prevalence of <5% and there was no difference in seroprevalence between HIV infected and non-infected individuals.[37] However another study showed a 26.1% seroprevalence of HHV-8 in 165 patients from North India.[38] But based on personal experience of rarity of PEL in HIV patients we tend to favor the lower seroprevalance rates reported.

In MCD, mainstay of treatment is chemotherapy. MCD patients commonly require systemic therapy (CHOP regimen), Rituximab, Interferon alpha etc.[17] Recently Tocilizumab, anti-IL-6 receptor antibody has been used to dramatically alleviate symptoms & biochemical abnormality of MCD.[39] Siltuximab, a monoclonal antibody binds to IL-6 shows promising result as a new treatment option in MCD.[40] Corticosteroids is often given to manage acute exacerbations of MCD. Many of the patients in our study had POEMS syndrome but survived and this may be because they were osteosclerotic and Castleman's variants of POEMS syndrome. Given its anti-angiogenic activity, lenalidomide has a role in the treatment of POEMS syndrome. In a recent study of 15 patients treated at 39 months of follow-up, all patients were alive with a 3-year progression-free survival of 59%.[41] On similar lines LD therapy seemed to be effective in our patients with POEMS though few experienced relapses.

Though our study has drawbacks like lack of serum VEGF estimation or documentation of clonality of plasma cells or its retrospective nature, we have managed to capture the essence of MCD in India. MCD is a female dominant process with better behaving variants of POEMS syndrome and may be EBV associated rather than HHV8 associated. Identifying such patterns will help in early diagnosis and therapy in our patients.


Mrs Sonali Tambe for EBERISH and HHV8 staining.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Tanuja Shet
Department of Pathology, Eight Floor Annex Building Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_310_20

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