The aetiology and management of Castleman disease at 50...

The aetiology and management of Castleman disease at50 years: translating pathophysiology to patient care

Corey Casper

Department of Medicine, Division of Infectious Disease, University of Washington School of Medicine, and The Program in Infectious

Disease, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Summary

Fifty years ago, Dr Benjamin Castleman first described the

unusual lymphoproliferative disorder that now bears his name.

Over the subsequent decades, astute clinical and pathologic

observations coupled with clever molecular biologic research

have increased our understanding of the aetiology of Castle-

man disease (CD). This article proposes three broad CD

variants based on both distinctive histopathology and clinical

behaviour. The pivotal roles of infection with human herpes-

virus 8 and interleukin-6 production in the development of

CD are emphasized. Finally, the natural history of CD and the

myriad of therapeutic options are reviewed in the context of a

unified model of CD pathophysiology, and continued areas of

uncertainty are discussed.

Keywords: lymphoproliferative disease, Castleman disease,

angiofollicular lymph node hyperplasia, human herpesvirus 8.

Fifty years ago, Dr Benjamin Castleman, a pathologist at

Massachusetts General Hospital, first described a rare lympho-

proliferative disorder that now bears his name. Also known as

angiofollicular or giant lymph node hyperplasia, the clinical

manifestations of Castleman disease (CD) are heterogeneous,

ranging from asymptomatic discrete lymphadenopathy to

recurrent episodes of diffuse lymphadenopathy with severe

systemic symptoms. The population prevalence of CD has not

been established; based on the proportion of patients present-

ing to a large cancer centre with lymphadenopathy of

undetermined origin later diagnosed with CD, it was estimated

that the number of cases in the US ranges from 30 000 to

100 000 (Moore et al, 1996a). The infrequency with which CD

is diagnosed has precluded comprehensive clinical studies,

leading to an incomplete understanding of the disease. Current

knowledge is based largely on case series and histopathologic

reviews. Over the last decade, a large body of evidence has

supported the importance of infection with human herpesvirus

8 (HHV-8 or Kaposi sarcoma (KS)-associated herpesvirus) in

the aetiology and management of CD. This article provides an

overview of CD and its variants, proposing a classification

system based on both histopathology and clinical findings.

Furthermore, recent advances in the pathogenesis, natural

history and treatment are summarized, emphasizing the role of

HHV-8 infection.

Classification

Dr Castleman initially described a patient who presented with

many years of fever and weakness, and was eventually found to

have a large mediastinal mass at fluoroscopy. Medical evalu-

ation revealed mediastinal lymphadenopathy, which, upon

surgical excision, was found to have strikingly abnormal

architecture of the affected lymph nodes that have come to

characterize CD (Castleman & Thowne, 1954). One dozen

additional patients who were largely asymptomatic but had

mediastinal masses detected in the course of other medical

procedures were subsequently identified (Castleman et al,

1956). The lymph nodes from these patients showed disarray

in all compartments. Most striking were the lymphoid follicles,

both markedly increased in number and unique in morphol-

ogy. The germinal centres varied in their cellularity, ranging

from a mostly acellular fibrinous hyalinization of capillaries to

proliferations of pale eosinophilic cells with copious cyto-

plasm. The germinal centre was frequently surrounded by a

marginal zone of concentrical lymphocytes. Increased vascu-

larization was noted in the interfollicular space, with vessels

traversing between multiple germinal centres. Finally, sinuses

rarely appeared in affected lymph nodes. All the initial patients

were only mildly symptomatic, if symptomatic at all, and

surgical resection resulted in cure.

In subsequent years, additional cases of patients with diffuse

lymphadenopathy and the histologically characteristic CD

lymph node architecture were identified (Keller et al, 1972;

Gaba et al, 1978; Martin et al, 1985). These series also revealed

a new variant of CD, which differed from the original in two

important ways (Flendrig, 1969). First, the germinal centres in

Correspondence: Corey Casper, University of Washington Virology

Research Clinic, 600 Broadway, Suite 400, Seattle, WA 98122, USA.

E-mail: [email protected]

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ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 3–17 doi:10.1111/j.1365-2141.2004.05311.x

the involved lymph nodes differed little from normal histology

and showed no evidence of hyalinization. However, concentric

sheets of plasma cells surrounded the germinal centres and

were prominent in the interfollicular space, which also lacked

the characteristic hyper-vascularity (Fig 1). In addition,

patients uniformly presented with a host of systemic symptoms

that were uncommon in the previously described variant. This

novel histological variant of CD was termed the ‘plasma cell’

variant (PCV), to contrast it with the ‘hyaline vascular’ variant

(HVV) that was originally described. The recognition of both

patients with localized lymphadenopathy and disseminated

disease led to an additional clinical categorization of CD:

‘unicentric’ (UCD) versus ‘multicentric’ (MCD).

Most recently, a third ‘subvariant’, known as ‘plasmablastic

MCD’, has been described in association with particularly

aggressive cases of MCD. In the first series to describe such a

variant, CD patients with POEMS syndrome (polyneuropathy,

organomegaly, endocrinopathy, monoclonal proteins and skin

changes), also known as Crow-Fukase, were found to have

lymph nodes which resembled those in PCV, but also had large

plasma cells in the mantle zone with copious cytoplasm and

prominent single or multiple nucleoli (Menke et al, 1996,

2000). A second series found the variant to be associated with

HHV-8 infection and progression to plasmablastic lymphoma

(Dupin et al, 2000).

As the aetiology of CD has not been definitively established,

it remains controversial as to whether CD variants represent

different ends of the same spectrum of disease or whether they

are entirely separate disease entities. The recent association of

HHV-8 infection with both HVV and PCV MCD, as discussed

below, and the finding of both HVV and PCV in the same

lymph node (Flendrig, 1969) argue strongly in favour of a

single disease with several variants, as summarized in Table I.

Pathophysiology

Careful clinical and laboratory investigations of patients with

the different CD variants has enabled a greater understanding

of the pathophysiology of CD. From the first reported case

series, the unique histological pattern seen in lymph nodes was

attributed to a ‘chronic non-specific inflammatory process’

(Castleman et al, 1956). The similarity between the abnormal

nodal histology in both variants of CD and the lymph nodes

associated with chronic viral infections spurred a search for a

viral pathogen(Keller et al, 1972). The increased vascularity

that hallmarks CD suggested to some that an angiogenic factor

may play a role in the genesis of the disease (Frizzera, 1988).

Similarly, the proliferation of plasma cells was hypothesized to

be the result of either exogenous (cytokines) or endogenous

(clonal proliferation) stimulation. Investigations over the past

five decades have enabled the development of an incomplete

model of CD pathogenesis that incorporates each of these

aspects.

Viral stimulation

The information gathered from both clinical and pathological

series of patients with CD led early investigators to search for a

viral pathogen in the aetiology of CD. The symptoms common

to many patients with CD, including indolent fever and

lymphadenopathy, as well as the description of mononuclear

cells with multiple nucleoli that resembled Reed–Sternberg

cells in the lymph node mantle zone (Castleman et al, 1956;

Keller et al, 1972), suggested that Epstein–Barr Virus (EBV)

could play a causative role in the development of CD.

Hanson et al (1988) sought EBV DNA by viral genomic

probes in lymph nodes from eight patients with CD, including

four with localized disease and four with systemic symptoms.

Fig 1. Typical histopathology of hyaline vascular and plasma cell

variants of castleman disease (original magnification · 40). (A) Pho-

tomicrograph of hyaline vascular variant Castleman disease showing a

germinal centre with vascular proliferation (solid arrows), eosinophilic

cells with copious cytoplasm (arrowhead), sheets of plasma cells (P)

and vascularization of the interfollicular space (open arrow). (B)

Photomicrograph of plasma cell variant Castleman disease showing a

germinal centre with sheets of plasma cells (P) both in the germinal

centre and interfollicular space (*), and the absence of vascular pro-

liferation.

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4 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 3–17

Only two of the samples had detectable EBV DNA, both in

patients with multicentric disease. These findings were in

contrast to a later series, which detected the EBV non-coding

early RNA (EBER) in the interfollicular region by in situ

hybridization (ISH) in five of 12 (42%) patients with UCD, but

not in a single patient with MCD (Murray et al, 1995). Of

note, none of the EBER-positive lymph nodes had the latent

membrane protein-1 (LMP-1) detected, a staining pattern

more consistent with asymptomatic chronic EBV infection.

Similar results were reported in a study of 20 human

immunodeficiency virus (HIV)-infected persons with MCD,

where zero of five patients with PCV and zero of 15 patients

with a mixed HVV/PCV CD-variant had LMP-1 detected in

lymph nodes with monoclonal antibodies or had EBER by ISH

(Oksenhendler et al, 1996). Finally, the use of the highly-

sensitive polymerase chain reaction (PCR) paired with South-

ern blotting of PCR products only identified EBV DNA in two

of four patients with PCV and zero of two patients with HVV

(Corbellino et al, 1996). It is worth noting that EBV DNA may

be found in lymph nodes in conditions other than CD, so its

presence falls short of proof of causation. Briefly, these small

studies argued against EBV as the aetiological agent for CD.

In 1994, a novel gamma-herpesvirus, HHV-8, was detected

in tissue from a patient with HIV-associated KS (Chang et al,

1994). This virus was found to be the HHV, most closely

related to EBV, and subsequently was determined to be

Table I. Categorization and characteristics of Castleman disease (CD).

Characteristic Unicentric hyaline vascular variant Unicentric plasma cell variant (PCV) Multicentric PCV

Histopathology Germinal centres involved: usually

‘involuted’ (hyalinized and

lymphocyte depleted)

Interfollicular region: hyperplastic

and fibrotic stroma

Vascularity: increased

Plasma cell infilatration: absent

Germinal centres usually uninvolved,

though mantle zone consists of

concentric sheets of plasma cells

Interfolliuclar region normal with

sheets of plasma cells

Vascular proliferation

Demographics Male ¼ female

Wide age distribution, median

young adults

Male ¼ female

Wide age distribution, mostly

young adults

?Male > female (c. 2:1)

Older age distribution

(fifth–sixth decade)

Prevalence Common (80% of unicentric disease) Less common (20% of unicentric disease)Least common (10% of all CD)

Lymph node

involvement

Single lymph node or chain

Most common in the mediastinum

or cervical lymph nodes

Single lymph node or chain

Most common in the abdomen

Multiple lymph nodes or chains

Aetiology Unknown. May be reactive or

developmental

Related to increased levels of IL-6

60–100% of cases may be attributable

to infection with HHV-8

Associated symptomsRare Common

Fevers

Nightsweats

Malaise

Common

Fevers

Nightsweats

Malaise

Associated signs Marked lymphadenopathy Localized lymphadenopathy

Splenomegaly

Marked lymphadenopathy

Hepatosplenomegaly

Abnormal

laboratories

Elevated lactate dehydrogenase Cytopenias (most commonly anaemia

or thrombocytopenia)

Elevated interleukin-6 levels

Elevated lactate dehydrogenase

Cytopenias (most commonly

anaemia or thrombocytopenia)

Elevated C-reactive protein

Elevated interleukin-6 levels

Evidence of infection with

HHV-8 by serology or PCR

Associated diseases Paraneoplastic pemphigus

Thrombotic thrombocytopenic purpura

Amyloidosis

Renal insufficiency

HIV

POEMS Syndrome

Kaposi sarcoma

Amyloidosis

Renal insufficiency

Treatment Surgical resection

Radiation therapy

Chemotherapy

Antiviral medications

Anti-inflammatories

Monoclonal antibodies to interleukin-6

Long-term sequelae Rare Progression to lymphoma is common

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ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 3–17 5

necessary but not sufficient for the development of KS. KS had

also frequently been reported among patients with MCD.

These findings led researchers to investigate the link between

HHV-8 infection and CD, as summarized in Table II.

Soulier et al (1995a) used PCR and Southern blot analysis to

examine the frequency with which HHV-8 was detected by

PCR in formalin-fixed and fresh-frozen lymph nodes excised

from persons with MCD. Thirty-one patients with all patho-

logical variants, including 17 HIV-negative and 14 HIV-

infected persons, were included in this series. Thirty-four HIV-

uninfected individuals with reactive lymph nodes without

histopathology, characteristic of MCD, were included as

controls. Of the HIV-uninfected participants, seven of 17

(41%) showed evidence of HHV-8 infection, including two of

three (66%) with HVV, three of nine (33%) with PCV and two

of five (40%) with mixed HVV/PCV. All 14 of the HIV-

infected persons had HHV-8 detected in the pathological

lymph nodes, including six patients with PCV, one with HVV

and seven with mixed variant MCD. Only one of 34 (3%) of

persons with reactive lymphadenopathy had HHV-8 detectable

in lymph nodes. A larger series of 82 MCD cases from Japan

also examined excised, paraffin-embedded lymph nodes for the

presence of HHV-8 by monoclonal antibodies, ISH and PCR

(Suda et al, 2001). This series found that only three of 82 (4%)

patients had detectable HHV-8, all of whom were HIV-

infected. Three additional Japanese patients with MCD were

found to have HHV-8 DNA detected in peripheral blood

mononuclear cells (PBMC) by conventional PCR (Kikuta et al,

1997), but none of the 16 HIV-negative Japanese patients with

MCD had HHV-8 DNA detected in lymph nodes or peripheral

blood by conventional PCR in a separate series(Yamasaki et al,

2003). The use of nested PCR in these samples, however,

detected HHV-8 DNA in lymph nodes from 13 of 16 (81%).

Six of seven patients with HHV-8 in the lymph node by nested

PCR had the virus detectable in peripheral blood. The large

discrepancy between these studies is difficult to reconcile, but

may be attributable to differences in methodology. The study

by Soulier et al (1995a), used PCR on fresh-frozen lymph

nodes and the series reported by Kikuta et al (1997) used fresh

PBMCs, while the others relied on preserved specimens. The

use of paraffin-embedded tissues may markedly reduce the

ability to detect genomic DNA in clinical samples (Ben-Ezra

et al, 1991) leading to false-negative results, while the use of

highly sensitive PCR raises the concern for specimen contam-

ination leading to false-positive results.

Three additional lines of evidence support a role for HHV-8

in the pathogenesis of MCD. First, among HIV-infected

individuals, the quantity of HHV-8 DNA in PBMCs or plasma

has been found to correlate with symptoms during flares of

MCD (Grandadam et al, 1997; Bottieau et al, 2000; Oksen-

hendler et al, 2000; Corbellino et al, 2001; Boivin et al, 2002;

Berezne et al, 2004; Casper et al, 2004). Next, there appears to

be a high degree of HHV-8 replication in patients with MCD.

All HHVs establish a life-long infection, with the virus

alternating between active replication (lytic phase) and quies-

cent infection with a minimal gene transcription programme

(latent infection). The majority of cells infected with HHV-8 in

patients with KS contain only latent virus, with a small

population of lytic virus (Grundhoff & Ganem, 2004). The

viral gene expression profile in MCD tissue shows that mostly

lytic genes are active in infected cells (Katano et al, 2000,

2001). Finally, as discussed below, administration of antiviral

medications has been associated with the regression of

symptoms in HIV-infected patients with MCD (Casper et al,

2004).

It is clear that HHV-8 plays a significant role in the

pathogenesis of HIV-associated MCD. Definitively establishing

the causality of HHV-8 in the aetiology of CD will prove

challenging. To date, there is no animal model suitable for

studying infection with HHV-8 and the virus does not actively

replicate in cell culture. Prospective studies documenting

HHV-8 infection, prior to the development of CD, would

support a causative role, but the rarity of CD and its indolent

course would require unfeasibly large and lengthy investiga-

tions. The best opportunity to examine the role of HHV-8 in

CD may come from carefully-designed case–control series,

where cases and controls are thoroughly evaluated for the

presence of HHV-8 infection using standardized and compre-

hensive serological and direct virological assessments from

freshly excised tissue and blood. Whether HHV-8 is the sole

aetiologic agent responsible for all variants of HIV-associated

CD, HIV-unassociated MCD or UCD remains to be deter-

mined and should be the subject of future investigation.

Angiogenesis

Since the identification of angiogenesis-promoting cytokines,

their role in lymphoproliferative disorders has been debated

Table II. Studies examining the proportion of Castleman disease (CD)

cases infected with human herpesvirus 8.

Study

HIV

status CD variant

Proportion

HHV-8 infected

Soulier et al

(1995a)

Negative M-hyaline vascular

variant (HVV)

2/3 (66%)

M-plasma cell

variant (PCV)

3/9 (33%)

M-mixed 2/5 (40%)

TOTAL 7/17 (41%)

Positive M-HVV 1/1 (100%)

M-PCV 6/6 (100%)

M-mixed 7/7 (100%)

Total 14/14 (100%)

Kikuta et al (1997) Negative M-PCV 2/2 (100%)

U-HVV 1/1 (100%)

Suda et al (2001) Negative M-unspecified 0/79 (0%)

Positive 3/3 (100%)

Yamasaki et al

(2003)

Negative M-PCV 13/16 (81%)

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(Folkman, 1995). Perhaps the cytokine which has sparked the

greatest degree of interest is the human vascular endothelial

growth factor (VEGF). VEGF has been found to specifically

promote the growth of endothelial cells and is capable of

controlling blood vessel formation. Its role in the generation of

the characteristic vascular proliferation in CD has been a target

of limited research.

Foss et al (1997) compared the lymph nodes from eight

patients with CD (variant not specified) to those in tonsillar

tissue from patients with and without infectious mononucle-

osis. VEGF was detected by ISH in five of eight (63%) germinal

centres and not in the controls (interfollicular spaces or

tonsillar tissue). Among two patients with CD (one U-PCV

and one MCD), both had elevated levels of serum VEGF which

fell to normal with nodal resection and chemotherapy

respectively (Nishi et al, 1999). The supernatants of the

cultured lymph nodes that had been resected from both

patients had VEGF levels that were 100-times higher than a

control node and nearly all plasma cells from the interfollicular

region of both nodes stained strongly positive for VEGF by

ISH. No mention was made of the HHV-8 infection status of

any participant in these studies.

While the elaboration of VEGF may play a role in the

pathophysiology of CD, it seems unlikely to account for all of

the pathological and clinical manifestations of the disease.

Rather, it may be an important step in the causal pathway and

should be considered in any unifying model of the pathogen-

esis of CD.

Interleukin-6 (IL-6)

In parallel to the search for an angiogenic factor in CD, a role

for cytokines with lymphoproliferative properties was sought.

One potential cytokine with such properties is IL-6, a potent

stimulant for the production of B cells. IL-6 had been

associated with lymphoid malignancies, such as multiple

myeloma and lymphoma, and a series of investigations have

led to the recognition of its importance in the pathogenesis of

CD.

In the first study to examine the association between IL-6

production and the pathological and clinical findings of

patients with CD, Yoshizaki et al (1989) described the

elaboration of IL-6 from germinal centres of lymph nodes in

patients with both U-PCV and MCD. Furthermore, in this

series, serum IL-6 levels were elevated in the patient with

U-PCV along with hypergammaglobulinaemia, organomegaly

and elevated acute phase reactants. All symptoms and labor-

atory abnormalities resolved with surgical resection of the

node, which was coincident with declines in serum IL-6 levels.

The findings in this early study were corroborated by studies in

mice, where a murine IL-6 gene expressed in mice via a

retroviral vector caused a syndrome indistinguishable from

MCD in humans (Brandt et al, 1990). Series of patients

observed during symptomatic episodes of MCD have con-

firmed that serum IL-6 levels are elevated to values seen

infrequently with other disease processes and resolve with

treatment (Beck et al, 1994; Nishimoto et al, 2000; Oksenhen-

dler et al, 2000).

A number of different mechanisms for the stimulus of IL-6

production have been proposed. Dysregulation of IL-6

production or the cell-signalling pathway downstream of the

IL-6 receptor have been hypothesized to play a role in a

number of pathologic conditions and may explain the

endogenous production of this human cytokine. Another

possible source of IL-6 production in CD may be from cells

infected with HHV-8. HHV-8 has been shown to produce a

viral analogue of IL-6 (vIL-6) with approximately 50%

similarity to the human IL-6 (hIL-6) gene on an amino acid

level (Moore et al, 1996b). hIL-6 binds the gp130 cellular

receptor and activates the Janus kinase/signal transducers and

activators of transcription (Jak/Stat) cell signalling pathway

through formation of a heterodimer with IL-6 binding protein,

IL-6Ra (Kishimoto et al, 1995). vIL-6 may also bind IL-6Raand complex with gp130 to activate the downstream Jak/Stat

pathway (Aoki et al, 2000). The expression of vIL-6 in mice

resulted in a similar clinical picture to the expression of hIL-6,

with increased haematopoesis in all lineages, plasmacytosis

observed in lymph nodes and organomegaly (Aoki et al, 1999).

vIL-6 has been demonstrated to induce the production of hIL-

6 in cells harvested from the lymph node of a patient with

MCD, providing a link between the higher levels of hIL-6

observed in CD and infection with HHV-8. The expression of

vIL-6 may also link the proliferation of plasma cells and vessels

seen in CD, as VEGF levels in the supernatant of vIL-6

expressing cells have been shown to be several times higher

than the same cells without the expression of vIL-6(Aoki et al,

1999). A role of HHV-8 and vIL-6 in CD has also been

corroborated in several observational studies. vIL-6 is ex-

pressed in the lymph nodes of HIV-negative (Parravinci et al,

1997; Menke et al, 2002) and HIV-positive (Cannon et al,

1999) persons with CD. In the peripheral blood, elevated levels

of vIL-6 in a patient symptomatic with HHV-8-associated

MCD regressed with prednisone and foscarnet therapy (Aoki

et al, 2001).

Together, these studies provide compelling evidence for the

importance of human and viral IL-6 in the pathophysiology of

CD, but again raise further questions regarding their exact

roles in the variants of CD.

Clonality

Castleman disease is often categorized within the family of

lymphoproliferative disorders, among which it is common to

find clonal populations of affected cells and cytogenetic

rearrangements. Limited studies have failed to uniformly

reveal clonal immunoglobin or T-cell receptor gene rearrange-

ments in tissue from CD (Hanson et al, 1988; Hall et al, 1989;

Ohyashiki et al, 1994; Soulier et al, 1995b; Cokelaere et al,

2002) (Table III). A review of four cases of CD did not identify

a single case of immunoglobin gene rearrangement or

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cytogenetic abnormality, leading to the conclusion that these

factors are unlikely to be a major contributor in the

development of CD (Menke & DeWald, 2001).

A unifying model of CD pathogenesis

Important pieces of the chain of events leading to the genesis

of CD remain unclear, but a proposed unified model is as

follows. The initial step in the development of CD appears to

be the production of IL-6 by B cells in the lymph node

mantle zone, stimulated in the majority of cases by HHV-8

infection and in a minority of cases by a heretofore

unidentified exogenous or endogenous factor. Local elabor-

ation of IL-6, and in turn VEGF, produces the characteristic

B-cell proliferation and vascularization of CD. In patients

with multicentric disease, systemic symptoms may result from

the circulation of IL-6 or IL-6-producing B cells, the

generation of excess antibodies or disseminated HHV-8

infection.

Clinical presentation

The clinical manifestations of the CD variants have been well-

described in several large case series (Keller et al, 1972;

Frizzera, 1988; Peterson & Frizzera, 1993; Herrada et al,

1998) and are discussed individually below.

Unicentric hyaline vascular variant (U-HVV)

Both the first variant of CD to be identified and the most

common variant encountered clinically today, U-HVV occurs

in approximately 70% of patients with CD (Fig 2). There is no

predilection for either gender and while patients present with a

range of ages, the median age tends to be in the fourth decade.

By definition, a single node or chain of lymph nodes is

involved in U-HVV. The involved node is typically large, with

a median diameter of 6–7 cm (range of 1–25 cm). Initial case

series found the mediastinum to be the most common location

for lymph node enlargement, but subsequent series have found

Table III. Summary of studies to determine the clonality of Castleman disease (CD).

Study Castleman variant Method(s) for determining clonality Proportion of cases found to be clonal

Hanson et al

(1988)

Unicentric Immunoglobin and T-cell

receptor gene rearrangements

0/4 (0%)

Multicentric 3/4 (75%)

Hall et al (1989) M-plasma cell

variant (PCV)

(1)Lamba/IgA assessment

(2) Immunoglobin and T-cell


(1) 2/5 (40%) with lamba/IgA

restriction

(2) 3/5 (60%) with immunoglobin

gene rearrangements

Ohyashiki et al

(1994)

M-PCV (1)Lamba/IgA assessment



2/2 (100%) with lambda chain

clonal rearrangement, but only

1/2 (50%) with expression of

light chain restriction. 0/2 (0%)

with Ig heavy chain or T-cell

receptor changes

Menke and DeWald

(2001)

1 U-hyaline vascular

variant (HVV)

3 M-PCV

Immunoglobin and T-cell


0/4 (0%) had immunoglobin and

T-cell receptor gene rearrangements

Cokelaere et al

(2002)

U-HVV (1) Cytogenetic testing



Clonal aberration detected on long

arm of chromosome 12 without

immunoglobin and T-cell receptor

gene rearrangements

M-PCV10%

U-PCV18%

U-HVV%27

Fig 2. Distribution of Castleman variants in the population.

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cervical, abdominal and axillary lymphadenopathy to be

equally as common (Castleman et al, 1956; Keller et al, 1972;

Herrada et al, 1998). The presenting symptoms of patients

with U-HVV CD vary according to the site of involvement.

Many patients with mediastinal or abdominal lymphadeno-

pathy either are asymptomatic and alerted to their condition

via radiographic studies or surgical procedures for other

conditions, or come to medical attention because of compres-

sive symptoms. Patients, themselves, often recognize cervical,

inguinal or axillary involvement which is then brought to the

attention of their health care provider. U-HVV lesions most

often present as solitary masses with intense homogeneous

contrast enhancement on computed tomography (CT)

(Ko et al, 2004) and positron emission tomography may not

be useful for distinguishing CD from malignancy (Reddy &

Graham, 2003). In contrast to the plasma cell and multicentric

variants of CD, U-HVV is rarely (<10%) associated with

systemic symptoms. Diagnosis of CD should be established by

excisional lymph node biopsy, with the architecture of the

entire germinal centre and interfollicular zone preserved for

analysis by experienced histopathologists. The normal appear-

ance of cells isolated from the entire lymph node may lead to a

failure to diagnose CD with the use of fine needle aspiration

(Cangiarella et al, 1997).

Unicentric plasma cell variant (U-PCV)

Unicentric plasma cell variant probably accounts for <20% of

all CD variants. It is characterized by the hypertrophy of a

single lymph node chain, although involvement of a solitary

lymph node is unusual (Keller et al, 1972). Abnormal nodes

are most frequently found in the abdomen (Frizzera, 1988).

Like U-HVV, the disease occurs equally in men and women,

and has been reported among younger patients (third decade).

Unlike U-HVV, the majority of U-PCV patients present with

constitutional symptoms. Anaemia and elevated sedimentation

rates are present in most cases, observed in 90% and 80%

respectively. These laboratory anomalies in the setting of

lymphadenopathy may raise the suspicion of U-PCV CD, but

ultimately an excisional lymph node biopsy showing the

characteristic sheets of plasma cells in the interfollicular space

is required for diagnosis.

Multicentric plasma cell variant (M-PCV)

Multicentric plasma cell variant CD is the least commonly

encountered CD variant, but presents with the most protean

manifestations. Affected patients are typically older than

those with unicentric disease (median age fifth–sixth decade).

A predilection for male sex had initially been reported in the

literature (Frizzera et al, 1985; Weisenburger et al, 1985), but

the total cases in these series number less than three dozen

and subsequent studies have not found that the prevalence of

the disease varies by gender (Herrada et al, 1998; Bowne et al,

1999; Chronowski et al, 2001). Patients frequently come to

medical attention for the evaluation of systemic symptoms.

Fever is reported by most patients, while approximately half

will experience weight loss and night sweats (Peterson &

Frizzera, 1993; Chronowski et al, 2001). Organomegaly is

inconsistent, with splenomegaly reported in 33–79% of

patients; hepatomegaly, almost exclusively in the presence

of splenomegaly, may occur in up to 63% of M-PCV

patients. Thirteen per cent of patients in three case series

were found to have KS concurrent with CD, as reviewed in

Peterson and Frizzera (1993). A number of abnormal

laboratory results are seen, including uniformly elevated

sedimentation rates, frequent anaemia (up to 90%), thromb-

ocytopenia or transaminitis (nearly two-third of the patients)

(Peterson & Frizzera, 1993). There are no characteristic

features of M-PCV on CT and uptake of gallium on

scintigraphy is inconsistent (Stansby et al, 1991; Okamoto

et al, 2003).

One of the most devastating diseases associated with M-PCV

is the POEMS syndrome, seen in up to 15% of MCD cases

(Peterson & Frizzera, 1993). POEMS syndrome is thought to

result from a plasma-cell dyscrasia and the subsequent

production of monoclonal proteins. Lymph node biopsies

are not routinely performed as part of the management of

POEMS syndrome, but the few large case series have

documented MCD in 11–24% of POEMS cases (Nakanishi

et al, 1984; Soubrier et al, 1994; Dispenzieri et al, 2003).

Patients dually-diagnosed with MCD and POEMS may be

more likely to be infected with HHV-8. In a small series of

patients with MCD and POEMS, six of seven (85%) had HHV-

8 detected in lymph nodes by PCR, and all had serum

antibodies to HHV-8 (Belec et al, 1999a). The prevalence of

HHV-8 in POEMS patients with MCD is nearly five times that

of POEMS patients without MCD (75% vs. 13% in a study of

22 patients) (Belec et al, 1999b). Therefore, it is reasonable to

test patients presenting with MCD who have evidence of

neuropathy for infection with HHV-8.

Clinical course and prognosis

Few studies exist because of the natural history of untreated

CD. The diversity of patients and therapies in the various CD

series makes drawing conclusions about natural history and

prognosis challenging.

Unicentric CD is almost universally cured after the resection

of involved lymph node(s) and has not been associated with

increased mortality. Rare patients with U-PCV may require

additional therapy after resection for persistent systemic

symptoms, but the course of these patients has not been

well-characterized.

After the initial presentation of patients with MCD, 33–50%

experience symptoms that recur repeatedly over the course of

several weeks to over 4 years (Frizzera et al, 1985; Weisen-

burger et al, 1985). In the four largest series of MCD, median

survival ranged from 14 to 30 months, although some patients

lived only several weeks following diagnosis, while others were

Review


reported to be alive at 20 years (Frizzera et al, 1985; Weisen-

burger et al, 1985; Oksenhendler et al, 1996; Herrada et al,

1998). Death in MCD is either caused by sepsis, systemic

inflammation leading to multi-organ system failure, or the

development of malignancy (most commonly lymphoma).

Careful attention to infectious and neoplastic complications, as

well as treatment of associated conditions such as HIV may

lead to meaningful increases in the life expectancy of patients

with MCD.

Special populations

Paediatrics. The clinical manifestations of CD in children that

have been reported in the literature differ little from those

observed among adults (Salisbury, 1990; Parez et al, 1999).

Presentation at <12 years of age is unusual and it has been

suggested that the course of MCD among children is less

morbid. The proportion of childhood CD cases which may be

attributable to infection with HHV-8 has not been

determined.

HIV. Lymphadenopathy is frequently encountered among

patients infected with HIV and often requires excisional

biopsy for aetiological diagnosis. The proportion of HIV-

infected patients with lymphadenopathy attributable to CD has

not been studied, but a number of published series suggest that

the condition is not rare. It also remains to be determined

whether the frequent observation of CD in patients with HIV is

attributable to the higher prevalence of HHV-8 co-infection

among HIV-infected patients or whether HIV-infection itself

predisposes to the development of CD.

HIV-associated CD is almost always either M-PCV or

multicentric mixed variant (Oksenhendler et al, 1996). Fever

and splenomegaly are universal and commonly remit sponta-

neously after several weeks. Anaemia is present in approxi-

mately half of the HIV-infected patients with MCD, but all will

have elevated C-reactive protein (CRP) and HHV-8 detected

in PBMCs during symptomatic flares (Grandadam et al, 1997;

Oksenhendler et al, 2000; Aaron et al, 2002). Symptomatic

flares of MCD may occur at any CD4 count, with reports in the

literature from 0Æ001 to >1Æ0 · 109 T cells/l (Grandadam et al,

1997; Oksenhendler et al, 2000; Aaron et al, 2002; Casper et al,

2004; Loi et al, 2004). There seems to be no clear effect of

antiretroviral therapy on the course of MCD, although data are

limited. Three patients treated with highly-active antiretroviral

therapy were noted to have a ‘rapidly progressive’ course of

MCD shortly after initiating treatment (Zietz et al, 1999).

Improvements in T-cell count and suppression of HIV

replication did not affect the course of MCD in five of seven

patients in one series (Aaron et al, 2002) and two of three in

another (Casper et al, 2004).

Patients with MCD and HIV-infection are at an increased

risk of developing non-Hodgkin’s lymphoma (NHL). Sixty

HIV-infected patients with MCD were followed for a median

of 20 months and a total of 14 of 60 (23%) developed NHL

(Oksenhendler et al, 2002). Of them, three developed primary

effusion lymphoma, five developed extranodal NHL and an

additional six were diagnosed with an aggressive plasmablastic

lymphoma. It was estimated from this series that the 2-year

probability of developing NHL after MCD diagnosis was 24%

and neither HIV plasma RNA level nor CD4 count was

predictive. A similar study of 11 patients followed for

48 months in Australia found that four (37%) developed

NHL (Loi et al, 2004).

Treatment

Early interventions in the treatment of CD were iterations of

standard therapy for lymphoproliferative diseases, including

surgical excision, cytoreductive chemotherapy and radiation

therapy. With a greater understanding of CD pathogenesis,

therapies directed at specific targets have been developed and

show great promise.

Surgical excision

Case series have repeatedly illustrated that surgery is almost

always curative for unicentric disease of either the hyaline

vascular or PCV (Castleman et al, 1956; Keller et al, 1972;

Herrada et al, 1998; Bowne et al, 1999). Because of the

disseminated nature of the lymphadenopathy with multicen-

tric disease, complete surgical debulking is rarely possible. The

few patients with MCD in whom surgery has been reported

have not had meaningful or lasting improvements in their

disease symptoms (Herrada et al, 1998; Bowne et al, 1999). As

splenomegaly is a constant feature of MCD, diagnostic or

therapeutic splenectomy is often performed but has not been

shown to be of clinical benefit.

Cytoreductive therapy

Chemotherapy for MCD has been modelled on regimens

designed for the treatment of NHL. Accordingly, the most

common regimen reported in the literature is the use of

cyclophosphamide, vincristine, doxorubicin and either pred-

nisone (CHOP) or dexamethasone (CVAD), both with mixed

success. Two series documented the induction of remission

with chemotherapy lasting from 1 to 10 years in four of six

(67%) treated with CVAD and two of four (50%) patients

treated with CHOP (Herrada et al, 1998; Chronowski et al,

2001). Other series have documented minimal success with

cyclophosphamide, vincristine and prednisone, and

cyclophosphamide, vincristine, procarbazine and prednisone

(Frizzera et al, 1985; Weisenburger et al, 1985). A host of other

regimens have been described in case reports, but in the

absence of larger case series or controlled trials, efficacy is

difficult to assess. The HHV-8 infection status was not

reported for any patient in these case series and whether

HHV-8 infection influences the response to chemotherapy is

not known.

Review


Radiation therapy

A recent review of 18 cases of CD that were treated with

radiotherapy found that 13 patients (72%) had a complete or

partial response to radiotherapy (Chronowski et al, 2001).

Only three of the 13 responders (23%) had multicentric

disease; the benefit in these patients may have been attributable

to adjuvant chemotherapy or corticosteroids that was concur-

rently administered.

Immune modulators

Steroids. The use of corticosteriods to control the intense

inflammation associated with multicentric disease is common,

but has not been subjected to clinical trials. Six of 15 (40%)

patients in one series were treated with glucocorticosteroids, of

whom two had ‘control of disease’ during long-term

administration and four saw no lasting response (Frizzera

et al, 1985), while a ‘partial response’ was documented in three

of five (60%) MCD patients treated exclusively with

prednisone (Weisenburger et al, 1985). The few patients

receiving prednisone alone in other case series saw transient

improvements while on the drug (Herrada et al, 1998; Bowne

et al, 1999). Prolonged therapy with low-dose prednisone

(10 mg/d) was successful in two patients with M-HVV

(Summerfield et al, 1983), but failed in a patient with

aggressive M-PCV (Bertero et al, 2000). Long-term

corticosteroids may be associated with a high risk of

bacterial infection in MCD patients, as a large number were

noted to die of sepsis during therapy (Frizzera et al, 1985;

Bowne et al, 1999).

Interferon-a. Interferon-a has both immunoregulatory and

antiviral properties, making it a plausibly effective therapy for

patients with MCD. Two patients with HIV-associated MCD

have been reported to have lasting remissions after

administration of interferon-a chronic therapy, one HHV-8

infected patient with a dose of 5 million units thrice weekly

(Kumari et al, 2000) and the other with 5 million units weekly

whose HHV-8 infection status was not stated (Nord & Karter,

2003). One HIV-negative patient with MCD (HHV-8 status

unknown) was observed to relapse 4 years after receiving

1 year of 3–5 million units of interferon-a thrice weekly

(Andres & Maloisel, 2000). All patients in these reports

tolerated the drug well. The relative importance of the antiviral

and immunomodulatory properties of interferon has not been

characterized and therefore it remains to be seen whether it is

an effective therapy for MCD in patients who are not infected

with HHV-8.

All-trans retinoic acid. All-trans retinoic acid (ATRA) has

been shown to have antiproliferative effects (Kane et al, 1996)

and may also decrease IL-6-dependent cell signalling (Zancai

et al, 2004). It was hypothesized that both these properties

could be beneficial in the treatment of MCD, and a case

report describing its successful administration in a HIV and

HHV-8 uninfected woman has been described (Rieu et al,

1999).

Thalidomide. Similar to interferon-a and ATRA, thalidomide

also has immunomodulatory properties (Franks et al, 2004).

Thalidomide, however, may act specifically to decrease the

production of IL-6, but also possess anti-angiogenic

properties. Two patients have been reported to receive

thalidomide. One HIV- and HHV-8 infected man had

improvements in platelet count but persistent constitutional

symptoms with thalidomide and etoposide (Jung et al, 2004),

and one HIV-negative woman (HHV-8 infection status not

stated) had a complete response lasting over 1 year with

300 mg of thalidomide daily (Lee & Merchant, 2003).

Monoclonal antibodies

Anti-IL-6 monoclonal antibody. A 27-year-old man with M-

PCV CD was the first patient to receive anti-IL-6 antibodies for

the treatment of CD (Beck et al, 1994). Administration of a

murine monoclonal antibody (BE-8) led to a rapid

improvement in symptoms and CRP, haematocrit, platelet

count and albumin, while levels of serum IL-6 rose to over

10,000 pg/ml. After 84 d of continuous administration, the

drug was discontinued; symptoms and laboratory

abnormalities quickly returned. It was hypothesized that the

generation of mice anti-IL antibodies failed to completely

neutralize hIL-6 in serum, resulting in an increase in the serum

IL-6 level via homeostatic mechanisms. Therefore, a new

product (atlizumab, Roche Pharmaceuticals, Basel,

Switzerland) with two substantial changes was developed: the

target of this new drug was the IL-6 receptor and it was

engineered to be a hybrid between mouse and human

antibodies to avoid the development of auto-antibodies with

repeated administration (Sato et al, 1993). Treatment of seven

HIV and HHV-8 negative patients with once- or twice-weekly

intravenous infusions resulted in resolution of symptoms and

normalization of laboratory values over 2 months, but

discontinuation of the infusions led to relapse within

2 weeks (Nishimoto et al, 2000). Re-exposure did not result

in the generation of antibodies to the drug. The long-term

effects of IL-6 receptor blockade are not known, but none was

reported in this series.

Rituximab. Plasma cells in the mantle zone of some patients

with HHV-8 positive and HHV-8 negative M-PCV CD have

been shown to express the cell surface marker CD20 (Hall et al,

1989; Dupin et al, 2000; Gholam et al, 2003). The drug

rituximab is a monoclonal antibody to CD20 that targets cells

expressing this surface marker for death by either complement

or cytotoxic cells. Successful therapy with rituximab has been

reported in a small number of patients with and without HIV

and HHV-8 infection. Eight patients with HIV and HHV-8-

associated MCD received infusions of rituximab (Corbellino

Review


et al, 2001; Marcelin et al, 2003; Kofteridis et al, 2004;

Newsom-Davis et al, 2004). In the largest series, three of five

(60%) achieved a complete response, which was durable for as

long as 14 months and the other two died of multi-organ

system failure (Marcelin et al, 2003). It is notable that the two

patients who did not respond, both presented with ‘severe

haematologic autoimmune phenomenon’, and that two of the

four patients with KS saw a worsening of their KS while

receiving rituximab. Three HIV-negative MCD patients,

including two without evidence of HHV-8 infection, also

have been reported in the literature to respond to rituximab.

All three patients, however, received either previous or

concurrent therapy, including steroids (Ide et al, 2003),

chemotherapy (Gholam et al, 2003) and cidofovir (Marietta

et al, 2003).

Antiviral therapy

Several antiviral medications have shown the ability to

effectively inhibit the replication of HHV-8 in vitro, including

ganciclovir, foscarnet and cidofovir (Kedes & Ganem, 1997;

Medveczky et al, 1997; Neyts & De Clercq, 1997). A handful of

HHV-8-associated MCD patients have been treated with

antiviral medications, with mixed success. Of four patients

treated with foscarnet, two had no improvement (Bottieau

et al, 2000; Senanayake et al, 2003) and two had persistent

remission for 12–24 months (Revuelta & Nord, 1998; Nord &

Karter, 2003). Seven patients treated with a combination of

cidofovir and chemotherapy exhibited no response in either

symptomatology or HHV-8 viraemia (Corbellino et al, 2001;

Senanayake et al, 2003; Berezne et al, 2004). The use of

ganciclovir or the oral derivative valganciclovir, however,

reduced HHV-8 viraemia in three patients and led to

remissions lasting 12–18 months (Casper et al, 2004). A

number of factors may explain the heterogeneity in the

response to antiviral therapy for HHV-8-associated MCD.

First, as the current in vitro models may not adequately

characterize the in vivo efficacy of these drugs, clinical studies

to determine which of the antiviral medications has the

greatest effect on HHV-8 are needed. Next, if the symptoms of

HHV-8-associated MCD are attributable, at least in part to the

production of vIL-6, then the current medications that inhibit

DNA synthesis may fail to uniformly abort the production of

this early-lytic gene product (Zoeteweij et al, 1999). Finally,

the optimal time to administer antivirals is not currently

understood. If the relationship between MCD and HHV-8 is

akin to that of post-transplant lymphoproliferative disorder

and EBV, then the use of antivirals prior to cell transformation

may be a successful strategy.

Conclusions

Drawing definitive conclusions regarding the optimal treat-

ment of CD from the current medical literature is limited by

the small number and heterogeneous characteristics of patients

receiving any one therapy, the use of multiple therapies

together, the relapsing and remitting nature of CD and

continuing uncertainties regarding the pathophysiology of the

disease. It seems clear that patients with unicentric disease are

almost always cured by surgery alone and that radiotherapy

may be a viable option for patients who are poor surgical

candidates. A myriad of treatment options exist for patients

with MCD and one approach to treatment may be to consider

other factors associated with MCD. Ganciclovir, interferon-aor rituximab may be the best treatment options in patients

with HHV-8 infection, while CHOP or CVAD may be most

appropriate for patients with severe systemic manifestations of

MCD. Randomized trials are desperately needed to determine

those treatment regimens that are most effective.

Approach to the patient with suspected CD

A diagnosis of CD most often is not entertained until its

characteristic features are noted on an excisional lymph node

biopsy. Prior to biopsy, however, clinical suspicion for CD

should be elevated in patients who have diseases often

associated with CD, including KS and POEMS syndrome. A

suggested algorithm for the evaluation and management of

patients suspected to have CD is shown in Fig 3. Patients

with lymph node histology consistent with CD should first

have other causes of similar-appearing reactive lymphaden-

opathy ruled out. These include rheumatoid arthritis, lupus,

Sjorgen syndrome, HIV infection, lymphoma and drug

sensitivity. To differentiate between localized and systemic

disease, obtaining a complete blood count (CBC), CRP, and

liver function tests (LFTs) are helpful along with a radiologic

assessment of cervical, thoracic, abdominal and pelvic

lymphadenopathy. Testing for serum interleukin-6 and

plasma or PBMC HHV-8 levels are not uniformly available

at all laboratories, but should be strongly encouraged in

patients with systemic symptoms to help select the most

appropriate therapy. Appropriate follow up should be

tailored to CD variant and symptoms. Patients with unicen-

tric disease without systemic involvement should have an

additional radiological assessment 6–12 months after therapy

to verify cure, with additional testing or therapy only pursued

with new symptoms. Patients with MCD need to be followed

more closely, with repeat CBC, LFT, CRP and radiology at

regular intervals or when symptoms suggest recurrence. A

suggested algorithm is depicted in Fig 3.

In summary, five decades of steady research into the

aetiology and management of the unusual and fascinating

lymphoproliferative disorder named after Dr Benjamin Cas-

tleman has resulted in many answers, but generates a myriad

of questions. Meticulous review of the histopathology in

affected lymph nodes in conjunction with astute clinical

observations has enabled the categorization of CD into

variants with meaningful treatment and prognostic implica-

tions. Basic science work has elucidated many of the

important components of CD pathophysiology, including

Review


the role of IL-6 production, HIV and HHV-8 infection and

angiogenesis. Innovative treatment strategies have been

developed that appear to meaningfully affect the natural

history of CD. In the coming years, however, fundamental

questions remain to be answered. Why is CD seen only in a

small proportion of patients infected with HHV-8? Are all

variants of CD caused by HHV-8 infection? What is the

stimulus for the production of IL-6 and angiogenesis in the

absence of HHV-8 infection? Why do some patients present

with localized disease and other systemic? How are

Fig 3. Suggested approach to the patient

with Castleman disease. LN, lymph node;

LAN, lymphadenopathy; LFT, liver function

test; ANA, anti-nuclear antibodies; Bx,

biopsy; Dx, diagnosis; RF, rheumatoid

factor; EIA, enzyme immunoassay; WB,

Western blot; RPR, rapid plasma reagin.

Review


recurrences of CD initiated, and can they be clinically

predicted? Which therapeutic regimens are best, are there

subsets of patients who benefit more from one over another,

and do any prevent the development of lymphoma or death

in the most serious cases? The next half-century promises to

bring great advances in understanding the aetiology of CD, in

turn translating to novel therapeutic approaches for patients

afflicted with this disease.

Acknowledgements

I am indebted to Dr Anna Wald for her thoughtful comments

and review of the manuscript, as well as her infectious

enthusiasm for advancing our understanding and treatment of

Castleman Disease.

Grant support: National Institute of Health, K23 1AI054162.

References

Aaron, L., Lidove, O., Yousry, C., Roudiere, L., Dupont, B. & Viard,

J.P. (2002) Human herpesvirus 8-positive Castleman disease in

human immunodeficiency virus-infected patients: the impact of

highly active antiretroviral therapy. Clinical Infectious Diseases, 35,

880–882.

Andres, E. & Maloisel, F. (2000) Interferon-alpha as first-line therapy

for treatment of multicentric Castleman’s disease. Annals of Oncol-

ogy, 11, 1613–1614.

Aoki, Y., Jaffe, E.S., Chang, Y., Jones, K., Teruya-Feldstein, J., Moore,

P.S. & Tosato, G. (1999) Angiogenesis and hematopoiesis induced

by Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6.

Blood, 93, 4034–4043.

Aoki, Y., Jones, K.D. & Tosato, G. (2000) Kaposi’s sarcoma-associated

herpesvirus-encoded interleukin-6. Journal of Hematotherapy and

Stem Cell Research, 9, 137–145.

Aoki, Y., Tosato, G., Fonville, T.W. & Pittaluga, S. (2001) Serum viral

interleukin-6 in AIDS-related multicentric Castleman disease. Blood,

97, 2526–2527.

Beck, J.T., Hsu, S.M., Wijdenes, J., Bataille, R., Klein, B., Vesole, D.,

Hayden, K., Jagannath, S. & Barlogie, B. (1994) Brief report: alle-

viation of systemic manifestations of Castleman’s disease by

monoclonal anti-interleukin-6 antibody. The New England Journal of

Medicine, 330, 602–605.

Belec, L., Mohamed, A.S., Authier, F.J., Hallouin, M.C., Soe, A.M.,

Cotigny, S., Gaulard, P. & Gherardi, R.K. (1999a) Human herpes-

virus 8 infection in patients with POEMS syndrome-associated

multicentric Castleman’s disease. Blood, 93, 3643–3653.

Belec, L., Authier, F.J., Mohamed, A.S., Soubrier, M. & Gherardi, R.K.

(1999b) Antibodies to human herpesvirus 8 in POEMS (poly-

neuropathy, organomegaly, endocrinopathy, M protein, skin chan-

ges) syndrome with multicentric Castleman’s disease. Clinical

Infectious Diseases, 28, 678–679.

Ben-Ezra, J., Johnson, D.A., Rossi, J., Cook, N. & Wu, A. (1991) Effect

of fixation on the amplification of nucleic acids from paraffin-em-

bedded material by the polymerase chain reaction. Journal of His-

tochemistry and Cytochemistry, 39, 351–354.

Berezne, A., Agbalika, F. & Oksenhendler, E. (2004) Failure of cido-

fovir in HIV-associated multicentric Castleman disease. Blood, 103,

4368–4369; author reply 4369.

Bertero, M.T., De Maestri, M. & Caligaris-Cappio, F. (2000) Cyclo-

phosphamide/cyclosporin-A treatment of multicentric Castleman’s

disease with Kaposi’s sarcoma. Haematologica, 85, 216–217.

Boivin, G., Cote, S., Cloutier, N., Abed, Y., Maguigad, M. & Routy, J.P.

(2002) Quantification of human herpesvirus 8 by real-time PCR in

blood fractions of AIDS patients with Kaposi’s sarcoma and

multicentric Castleman’s disease. Journal of Medical Virology, 68,

399–403.

Bottieau, E., Colebunders, R., Schroyens, W., Van Droogenbroeck, J.,

De Droogh, E., Depraetere, K., De Raeve, H. & Van Marck, E. (2000)

Multicentric Castleman’s disease in 2 patients with HIV infection,

unresponsive to antiviral therapy. Acta Clinica Belgica, 55, 97–101.

Bowne, W.B., Lewis, J.J., Filippa, D.A., Niesvizky, R., Brooks, A.D.,

Burt, M.E. & Brennan, M.F. (1999) The management of unicentric

and multicentric Castleman’s disease: a report of 16 cases and a

review of the literature. Cancer, 85, 706–717.

Brandt, S.J., Bodine, D.M., Dunbar, C.E. & Nienhuis, A.W. (1990)

Dysregulated interleukin 6 expression produces a syndrome re-

sembling Castleman’s disease in mice. Journal of Clinical Investiga-

tion, 86, 592–599.

Cangiarella, J., Gallo, L. & Winkler, B. (1997) Potential pitfalls in the

diagnosis of Castleman’s disease of the mediastinum on fine needle

aspiration biopsy. Acta Cytologica, 41, 951–952.

Cannon, J.S., Nicholas, J., Orenstein, J.M., Mann, R.B., Murray, P.G.,

Browning, P.J., DiGiuseppe, J.A., Cesarman, E., Hayward, G.S. &

Ambinder, R.F. (1999) Heterogeneity of viral IL-6 expression in

HHV-8-associated diseases. Journal of Infectious Diseases, 180, 824–

828.

Casper, C., Nichols, W.G., Huang, M.L., Corey, L. & Wald, A. (2004)

Remission of HHV-8 and HIV-associated multicentric Castleman

disease with ganciclovir treatment. Blood, 103, 1632–1634.

Castleman, B. & Thowne, V.W. (eds) (1954) Case records of the Mas-

sachusetts General Hospital Weekly Clinicopathological Exercises:

Case 40011. The New England Journal of Medicine, 250, 26–30.

Castleman, B., Iverson, L. & Menendez, V.P. (1956) Localized med-

iastinal lymphnode hyperplasia resembling thymoma. Cancer, 9,

822–830.

Chang, Y., Cesarman, E., Pessin, M.S., Lee, F., Culpepper, J., Knowles,

D.M. & Moore, P.S. (1994) Identification of herpesvirus-like DNA

sequences in AIDS-associated Kaposi’s sarcoma. Science, 266, 1865–

1869.

Chronowski, G.M., Ha, C.S., Wilder, R.B., Cabanillas, F., Manning, J.

& Cox, J.D. (2001) Treatment of unicentric and multicentric Cas-

tleman disease and the role of radiotherapy. Cancer, 92, 670–676.

Cokelaere, K., Debiec-Rychter, M., De Wolf-Peeters, C., Hagemeijer, A.

& Sciot, R. (2002) Hyaline vascular Castleman’s disease with

HMGIC rearrangement in follicular dendritic cells: molecular evi-

dence of mesenchymal tumorigenesis. American Journal of Surgical

Pathology, 26, 662–669.

Corbellino, M., Poirel, L., Aubin, J.T., Paulli, M., Magrini, U., Bestetti,

G., Galli, M. & Parravicini, C. (1996) The role of human herpesvirus

8 and Epstein–Barr virus in the pathogenesis of giant lymph node

hyperplasia (Castleman’s disease). Clinical Infectious Diseases, 22,

1120–1121.

Corbellino, M., Bestetti, G., Scalamogna, C., Calattini, S., Galazzi, M.,

Meroni, L., Manganaro, D., Fasan, M., Moroni, M., Galli, M. &

Parravicini, C. (2001) Long-term remission of Kaposi sarcoma-

associated herpesvirus-related multicentric Castleman disease with

anti-CD20 monoclonal antibody therapy. Blood, 98, 3473–3475.

Review


Dispenzieri, A., Kyle, R.A., Lacy, M.Q., Rajkumar, S.V., Therneau,

T.M., Larson, D.R., Greipp, P.R., Witzig, T.E., Basu, R., Suarez, G.A.,

Fonseca, R., Lust, J.A. & Gertz, M.A. (2003) POEMS syndrome:

definitions and long-term outcome. Blood, 101, 2496–2506.

Dupin,N.,Diss, T.L., Kellam,P., Tulliez,M.,Du,M.Q., Sicard,D.,Weiss,

R.A., Isaacson, P.G. & Boshoff, C. (2000) HHV-8 is associated with a

plasmablastic variant of Castleman disease that is linked to HHV-8-

positive plasmablastic lymphoma. Blood, 95, 1406–1412.

Flendrig, J.A. (1969) Benign giant lymphoma: the clinical signs and

symptoms and the morphological aspects. Folia Medica, 12, 119–120.

Folkman, J. (1995) Angiogenesis in cancer, vascular, rheumatoid and

other disease. Nature Medicine, 1, 27–31.

Foss, H.D., Araujo, I., Demel, G., Klotzbach, H., Hummel, M. & Stein,

H. (1997) Expression of vascular endothelial growth factor in lym-

phomas and Castleman’s disease. Journal of Pathology, 183, 44–50.

Franks, M.E., Macpherson, G.R. & Figg, W.D. (2004) Thalidomide.

The Lancet, 363, 1802–1811.

Frizzera, G. (1988) Castleman’s disease and related disorders. Seminars

in Diagnostic Pathology, 5, 346–364.

Frizzera, G., Peterson, B.A., Bayrd, E.D. & Goldman, A. (1985) A

systemic lymphoproliferative disorder with morphologic features of

Castleman’s disease: clinical findings and clinicopathologic correla-

tions in 15 patients. Journal of Clinical Oncology, 3, 1202–1216.

Gaba, A.R., Stein, R.S., Sweet, D.L. & Variakojis, D. (1978) Multi-

centric giant lymph node hyperplasia. American Journal of Clinical

Pathology, 69, 86–90.

Gholam, D., Vantelon, J.M., Al-Jijakli, A. & Bourhis, J.H. (2003) A case

of multicentric Castleman’s disease associated with advanced sys-

temic amyloidosis treated with chemotherapy and anti-CD20

monoclonal antibody. Annals of Hematology, 82, 766–768.

Grandadam, M., Dupin, N., Calvez, V., Gorin, I., Blum, L., Kernbaum,

S., Sicard, D., Buisson, Y., Agut, H., Escande, J.P. & Huraux, J.M.

(1997) Exacerbations of clinical symptoms in human

immunodeficiency virus type 1-infected patients with multicentric

Castleman’s disease are associated with a high increase in Kaposi’s

sarcoma herpesvirus DNA load in peripheral blood mononuclear

cells. Journal of Infectious Diseases, 175, 1198–1201.

Grundhoff, A. & Ganem, D. (2004) Inefficient establishment of KSHV

latency suggests an additional role for continued lytic replication in

Kaposi sarcoma pathogenesis. Journal of Clinical Investigation, 113,

124–136.

Hall, P.A., Donaghy, M., Cotter, F.E., Stansfeld, A.G. & Levison, D.A.

(1989) An immunohistological and genotypic study of the plasma

cell form of Castleman’s disease. Histopathology, 14, 333–346; dis-

cussion 429–332.

Hanson, C.A., Frizzera, G., Patton, D.F., Peterson, B.A., McClain, K.L.,

Gajl-Peczalska, K.J. & Kersey, J.H. (1988) Clonal rearrangement for

immunoglobulin and T-cell receptor genes in systemic Castleman’s

disease. Association with Epstein–Barr virus. American Journal of

Pathology, 131, 84–91.

Herrada, J., Cabanillas, F., Rice, L., Manning, J. & Pugh, W. (1998) The

clinical behavior of localized and multicentric Castleman disease.

Annals of Internal Medicine, 128, 657–662.

Ide, M., Ogawa, E., Kasagi, K., Kawachi, Y. & Ogino, T. (2003) Suc-

cessful treatment of multicentric Castleman’s disease with bilateral

orbital tumour using rituximab. British Journal of Haematology, 121,

818–819.

Jung, C.P., Emmerich, B., Goebel, F.D. & Bogner, J.R. (2004) Suc-

cessful treatment of a patient with HIV-associated multicentric

Castleman disease (MCD) with thalidomide. American Journal of

Hematology, 75, 176–177.

Kane, K.F., Langman, M.J. & Williams, G.R. (1996) Antiproliferative

responses to two human colon cancer cell lines to vitamin D3 are

differently modified by 9-cis-retinoic acid. Cancer Research, 56, 623–

632.

Katano, H., Sato, Y., Kurata, T., Mori, S. & Sata, T. (2000) Expression

and localization of human herpesvirus 8-encoded proteins in pri-

mary effusion lymphoma, Kaposi’s sarcoma, and multicentric Cas-

tleman’s disease. Virology, 269, 335–344.

Katano, H., Sato, Y., Itoh, H. & Sata, T. (2001) Expression of human

herpesvirus 8 (HHV-8)-encoded immediate early protein, open

reading frame 50, in HHV-8-associated diseases. Journal of Human

Virology, 4, 96–102.

Kedes, D.H. & Ganem, D. (1997) Sensitivity of Kaposi’s sarcoma-

associated herpesvirus replication to antiviral drugs. Implications for

potential therapy. Journal of Clinical Investigation, 99, 2082–2086.

Keller, A.R., Hochholzer, L. & Castleman, B. (1972) Hyaline-vascular

and plasma-cell types of giant lymph node hyperplasia of the

mediastinum and other locations. Cancer, 29, 670–683.

Kikuta, H., Itakura, O., Ariga, T. & Kobayashi, K. (1997) Detection of

human herpesvirus 8 DNA sequences in peripheral blood mono-

nuclear cells of children. Journal of Medical Virology, 53, 81–84.

Kishimoto, T., Akira, S., Narazaki, M. & Taga, T. (1995) Interleukin-6

family of cytokines and gp130. Blood, 86, 1243–1254.

Ko, S.F., Hsieh, M.J., Ng, S.H., Lin, J.W., Wan, Y.L., Lee, T.Y., Chen,

W.J. & Chen, M.C. (2004) Imaging spectrum of Castleman’s disease.

AJR. American Journal of Roentgenology, 182, 769–775.

Kofteridis, D.P., Tzagarakis, N., Mixaki, I., Maganas, E., Xilouri, E.,

Stathopoulos, E.N., Eliopoulos, G.D. & Gikas, A. (2004) Multi-

centric Castleman’s disease: prolonged remission with anti CD-20

monoclonal antibody in an HIV-infected patient. AIDS, 18, 585–

586.

Kumari, P., Schechter, G.P., Saini, N. & Benator, D.A. (2000) Suc-

cessful treatment of human immunodeficiency virus-related Cas-

tleman’s disease with interferon-alpha. Clinical Infectious Diseases,

31, 602–604.

Lee, F.C. & Merchant, S.H. (2003) Alleviation of systemic manifesta-

tions of multicentric Castleman’s disease by thalidomide. American

Journal of Hematology, 73, 48–53.

Loi, S., Goldstein, D., Clezy, K., Milliken, S., Hoy, J. & Chipman, M.

(2004) Castleman’s disease and HIV infection in Australia. HIV

Medicine, 5, 157–162.

Marcelin, A.-G., Aaron, L., Mateus, C., Gyan, E., Gorin, I., Viard, J.-P.,

Calvez, V. & Dupin, N. (2003) Rituximab therapy for HIV-asso-

ciated Castleman disease. Blood, 102, 2786–2788.

Marietta, M., Pozzi, S., Luppi, M., Bertesi, M., Cappi, C., Morselli, M.

& Torelli, G. (2003) Acquired haemophilia in HIV negative, HHV-8

positive multicentric Castleman’s disease: a case report. European

Journal of Haematology, 70, 181–182.

Martin, J.M., Bell, B. & Ruether, B.A. (1985) Giant lymph node

hyperplasia (Castleman’s disease) of hyaline vascular type. Clinical

heterogeneity with immunohistologic uniformity. American Journal

of Clinical Pathology, 84, 439–446.

Medveczky, M.M., Horvath, E., Lund, T. & Medveczky, P.G. (1997) In

vitro antiviral drug sensitivity of the Kaposi’s sarcoma-associated

herpesvirus. AIDS, 11, 1327–1332.

Menke, D.M. & DeWald, G.W. (2001) Lack of cytogenetic abnorm-

alities in Castleman’s disease. Southern Medical Journal, 94, 472–474.

Review


Menke, D.M., Tiemann, M., Camoriano, J.K., Chang, S.F., Madan, A.,

Chow, M., Habermann, T.M. & Parwaresch, R. (1996) Diagnosis of

Castleman’s disease by identification of an immunophenotypically

aberrant population of mantle zone B lymphocytes in paraffin-

embedded lymph node biopsies. American Journal of Clinical

Pathology, 105, 268–276.

Menke, D.M., Isaacson, P.G. & Boshoff, C. (2000) Ly-1b cells and

Castleman disease. Blood, 96, 1614–1616.

Menke, D.M., Chadbum, A., Cesarman, E., Green, E., Berenson, J.,

Said, J., Tiemann, M., Parwaresch, R. & Thome, S.D. (2002) Analysis

of the human herpesvirus 8 (HHV-8) genome and HHV-8 vIL-6

expression in archival cases of castleman disease at low risk for HIV

infection. American Journal of Clinical Pathology, 117, 268–275.

Moore, D.F., Preti, A. & Tran, S.M. (1996a) Prognostic implications

following an indeterminate diagnostic work-up of lymphoma. Blood,

88 (Suppl. 1), 229a (abstract).

Moore, P.S., Boshoff, C., Weiss, R.A. & Chang, Y. (1996b) Molecular

mimicry of human cytokine and cytokine response pathway genes by

KSHV. Science, 274, 1739–1744.

Murray, P.G., Deacon, E., Young, L.S., Barletta, J.M., Mann, R.B.,

Ambinder, R.F., Rowlands, D.C., Jones, E.L., Ramsay, A.D. &

Crocker, J. (1995) Localization of Epstein–Barr virus in Castleman’s

disease by in situ hybridization and immunohistochemistry.

Hematologic Pathology, 9, 17–26.

Nakanishi, T., Sobue, I., Toyokura, Y., Nishitani, H., Kuroiwa, Y.,

Satoyoshi, E., Tsubaki, T., Igata, A. & Ozaki, Y. (1984) The Crow-

Fukase syndrome: a study of 102 cases in Japan. Neurology, 34, 712–

720.

Newsom-Davis, T., Bower, M., Wildfire, A., Thirlwell, C., Nelson, M.,

Gazzard, B. & Stebbing, J. (2004) Resolution of AIDS-related Cas-

tleman’s disease with anti-CD20 monoclonal antibodies is associated

with declining IL-6 and TNF-alpha levels. Leukemia and Lymphoma,

45, 1939–1941.

Neyts, J. & De Clercq, E. (1997) Antiviral drug susceptibility of human

herpesvirus 8. Antimicrobial Agents and Chemotherapy, 41, 2754–

2756.

Nishi, J., Arimura, K., Utsunomiya, A., Yonezawa, S., Kawakami, K.,

Maeno, N., Ijichi, O., Ikarimoto, N., Nakata, M., Kitajima, I.,

Fukushige, T., Takamatsu, H., Miyata, K. & Maruyama, I. (1999)

Expression of vascular endothelial growth factor in sera and lymph

nodes of the plasma cell type of Castleman’s disease. British Journal

of Haematology, 104, 482–485.

Nishimoto, N., Sasai, M., Shima, Y., Nakagawa, M., Matsumoto, T.,

Shirai, T., Kishimoto, T. & Yoshizaki, K. (2000) Improvement in

Castleman’s disease by humanized anti-interleukin-6 receptor anti-

body therapy. Blood, 95, 56–61.

Nord, J.A. & Karter, D. (2003) Low dose interferon-alpha therapy for

HIV-associated multicentric Castleman’s disease. International

Journal of STD and AIDS, 14, 61–62.

Ohyashiki, J.H., Ohyashiki, K., Kawakubo, K., Serizawa, H., Abe, K.,

Mikata, A. & Toyama, K. (1994) Molecular genetic, cytogenetic, and

immunophenotypic analyses in Castleman’s disease of the plasma

cell type. American Journal of Clinical Pathology, 101, 290–295.

Okamoto, I., Iyonaga, K., Fujii, K., Mori, T., Yoshioka, M., Kohrogi,

H., Matsumoto, M. & Suga, M. (2003) Absence of gallium uptake in

unicentric and multicentric Castleman’s disease. Internal Medicine,

42, 735–739.

Oksenhendler, E., Duarte, M., Soulier, J., Cacoub, P., Welker, Y.,

Cadranel, J., Cazals-Hatem, D., Autran, B., Clauvel, J.P. & Raphael,

M. (1996) Multicentric Castleman’s disease in HIV infection: a

clinical and pathological study of 20 patients. AIDS, 10, 61–67.

Oksenhendler, E., Carcelain, G., Aoki, Y., Boulanger, E., Maillard, A.,

Clauvel, J.P. & Agbalika, F. (2000) High levels of human herpesvirus

8 viral load, human interleukin-6, interleukin-10, and C reactive

protein correlate with exacerbation of multicentric castleman disease

in HIV-infected patients. Blood, 96, 2069–2073.

Oksenhendler, E., Boulanger, E., Galicier, L., Du, M.Q., Dupin, N.,

Diss, T.C., Hamoudi, R., Daniel, M.T., Agbalika, F., Boshoff, C.,

Clauvel, J.P., Isaacson, P.G. & Meignin, V. (2002) High incidence of

Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lym-

phoma in patients with HIV infection and multicentric Castleman

disease. Blood, 99, 2331–2336.

Parez, N., Bader-Meunier, B., Roy, C.C. & Dommergues, J.P. (1999)

Paediatric Castleman disease: report of seven cases and review of the

literature. European Journal of Pediatrics, 158, 631–637.

Parravinci, C., Corbellino, M., Paulli, M., Magrini, U., Lazzarino, M.,

Moore, P.S. & Chang, Y. (1997) Expression of a virus-derived

cytokine, KSHV vIL-6, in HIV-seronegative Castleman’s disease.

American Journal of Pathology, 151, 1517–1522.

Peterson, B.A. & Frizzera, G. (1993) Multicentric Castleman’s disease.

Seminars in Oncology, 20, 636–647.

Reddy, M.P. & Graham, M.M. (2003) FDG positron emission tomo-

graphic imaging of thoracic Castleman’s disease. Clinical Nuclear

Medicine, 28, 325–326.

Revuelta, M.P. & Nord, J.A. (1998) Successful treatment of multi-

centric Castleman’s disease in a patient with human immunodefi-

ciency virus infection. Clinical Infectious Diseases, 26, 527.

Rieu, P., Droz, D., Gessain, A., Grunfeld, J-P. & Hermine, O. (1999)

Retinoic acid for treatment of multicentric Castleman’s disease. The

Lancet, 354, 1262–1263.

Salisbury, J.R. (1990) Castleman’s disease in childhood and adoles-

cence: report of a case and review of literature. Pediatric Pathology,

10, 609–615.

Sato, K., Tsuchiya, M., Saldanha, J., Koishihara, Y., Ohsugi, Y., Ki-

shimoto, T. & Bendig, M.M. (1993) Reshaping a human antibody to

inhibit the interleukin 6-dependent tumor cell growth. Cancer

Research, 53, 851–856.

Senanayake, S., Kelly, J., Lloyd, A., Waliuzzaman, Z., Goldstein, D. &

Rawlinson, W. (2003) Multicentric Castleman’s disease treated with

antivirals and immunosuppressants. Journal of Medical Virology, 71,

399–403.

Soubrier, M.J., Dubost, J.J. & Sauvezie, B.J. (1994) POEMS syndrome:

a study of 25 cases and a review of the literature. French Study

Group on POEMS Syndrome. American Journal of Medicine, 97,

543–553.

Soulier, J., Grollet, L., Oksenhendler, E., Cacoub, P., Cazals-Hatem, D.,

Babinet, P., d’Agay, M.F., Clauvel, J.P., Raphael, M., Degos, L.

(1995a) Kaposi’s sarcoma-associated herpesvirus-like DNA

sequences in multicentric Castleman’s disease. Blood, 86, 1276–1280.

Soulier, J., Grollet, L., Oksenhendler, E., Miclea, J.M., Cacoub, P.,

Baruchel, A., Brice, P., Clauvel, J.P., d’Agay, M.F., Raphael, M.

(1995b) Molecular analysis of clonality in Castleman’s disease.

Blood, 86, 1131–1138.

Stansby, G., Hilson, A. & Hamilton, G. (1991) Gallium scintigraphy in

the diagnosis and management of multifocal Castleman’s disease.

British Journal of Radiology, 64, 165–167.

Suda, T., Katano, H., Delsol, G., Kakiuchi, C., Nakamura, T., Shiota,

M., Sata, T., Higashihara, M. & Mori, S. (2001) HHV-8 infection

Review


status of AIDS-unrelated and AIDS-associated multicentric Castle-

man’s disease. Pathology International, 51, 671–679.

Summerfield, G.P., Taylor, W., Bellingham, A.J. & Goldsmith, H.J.

(1983) Hyaline-vascular variant of angiofollicular lymph node hy-

perplasia with systemic manifestations and response to corticoster-

oids. Journal of Clinical Pathology, 36, 1005–1011.

Weisenburger, D.D., Nathwani, B.N., Winberg, C.D. & Rappaport, H.

(1985) Multicentric angiofollicular lymph node hyperplasia: a

clinicopathologic study of 16 cases. Human Pathology, 16, 162–172.

Yamasaki, S., Iino, T., Nakamura, M., Henzan, H., Ohshima, K.,

Kikuchi, M., Otsuka, T. & Harada, M. (2003) Detection of human

herpesvirus-8 in peripheral blood mononuclear cells from adult

Japanese patients with multicentric Castleman’s disease. British

Journal of Haematology, 120, 471–477.

Yoshizaki, K., Matsuda, T., Nishimoto, N., Kuritani, T., Taeho, L.,

Aozasa, K., Nakahata, T., Kawai, H., Tagoh, H. & Komori, T. (1989)

Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s

disease. Blood, 74, 1360–1367.

Zancai, P., Cariati, R., Quaia, M., Guidoboni, M., Rizzo, S., Boiocchi,

M. & Dolcetti, R. (2004) Retinoic acid inhibits IL-6-dependent

but not constitutive STAT3 activation in Epstein–Barr virus-

immortalized B lymphocytes. International Journal of Oncology, 25,

345–355.

Zietz, C., Bogner, J.R., Goebel, F.D. & Lohrs, U. (1999) An unusual

cluster of cases of Castleman’s disease during highly active antiret-

roviral therapy for AIDS. The New England Journal of Medicine, 340,

1923–1924.

Zoeteweij, J.P., Eyes, S.T., Orenstein, J.M., Kawamura, T., Wu, L.,

Chandran, B., Forghani, B. & Blauvelt, A. (1999) Identification and

rapid quantification of early- and late-lytic human herpesvirus 8

infection in single cells by flow cytometric analysis: characterization

of antiherpesvirus agents. Journal of Virology, 73, 5894–5902.

Review


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