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12/10/2017 Multicentric Castleman's disease - UpToDate
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Multicentric Castleman's disease
Authors: Jon C Aster, MD, Jennifer R Brown, MD, PhD, Nikhil C Munshi, MD
Section Editor: Arnold S Freedman, MD
Deputy Editor: Rebecca F Connor, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Apr 25, 2017.
INTRODUCTION — Castleman's disease (CD, angiofollicular lymph node hyperplasia) is a heterogenous

group of lymphoproliferative disorders associated in a subset of cases with the human immunodeficiency
virus (HIV) and human herpesvirus 8 (HHV-8). CD comprises at least two distinct diseases (unicentric and
multicentric) with very different prognoses. It may also be associated with other malignancies, including
Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, and POEMS syndrome.
CD was first described in 1956 by Benjamin Castleman and colleagues, who identified a series of patients
with solitary hyperplastic mediastinal lymph nodes containing small, hyalinized follicles and a marked
interfollicular vascular proliferation (hyaline vascular variant of CD) [1]. The same investigators later identified
lymph nodes with a similar vascular proliferation associated with large hyperplastic germinal centers and
sheets of interfollicular plasma cells. Hyalinized follicles were present in some, but not all, such cases.
● All of the patients described in these early papers had localized disease, which is now termed unicentric
Castleman's disease (UCD). UCD is associated with systemic symptoms in a subset of cases.
● In contrast, multicentric Castleman's disease (MCD) is a systemic disease with generalized peripheral
lymphadenopathy, hepatosplenomegaly, frequent fevers, and night sweats that is usually associated with
the plasma cell or mixed variant. Unlike UCD, MCD is strongly associated with immunosuppression and
HHV-8 infection.
This topic review will discuss the epidemiology, pathogenesis, clinical features, pathologic features, diagnosis
and treatment of MCD. UCD, diseases associated with HHV-8 infection, and the virology of HHV-8 are
presented separately. (See "Disease associations of human herpesvirus 8 infection" and "Virology,
epidemiology, and transmission of human herpesvirus 8 infection" and "Unicentric Castleman's disease".)
EPIDEMIOLOGY — Patients with multicentric Castleman's disease (MCD) present at a median age between
50 and 65, although those who are HIV-infected tend to be younger [2-12]. Fifty to 65 percent are male.
The incidence of HIV-associated MCD has increased in the years since the introduction of antiretroviral
therapy (ART) for the management of HIV. The incidence of HIV-associated MCD was calculated from a
prospective HIV database with 56,202 patient-years of follow-up and compared with that of Kaposi sarcoma
(KS) during the same time period [13]. The incidence of MCD increased over the time periods designated as
pre-ART (1983-1996), early-ART (1997-2001), and later ART (2002-2007) eras and was 0.6, 2.8, and 8.3
cases/10,000 patient-years, respectively. In contrast, the incidence of KS decreased markedly during the
same three time periods and was 520, 85, and 63 cases/10,000 patient-years, respectively. The explanation
for the apparent increase in MCD with the introduction of ART is uncertain. One possibility is that subtle forms
of immune dysregulation are of greater importance in the etiology of HIV-associated MCD than
immunosuppression per se. On multivariate analysis, risk factors for the development of MCD included the
following [14]:
https://www.uptodate.com/contents/multicentric-castlemans-disease/print?source=search_result&search=CASTELMAN&selectedTitle=2~51 1/32
● Nadir CD4 count >200/microL

● Increased age
● No previous ART exposure
● Non-Caucasian ethnicity
PATHOGENESIS — The pathogenesis of multicentric Castleman's disease (MCD) is poorly understood. Both
unicentric Castleman's disease (UCD) and MCD have been linked to excessive release of interleukin (IL)-6 or
related polypeptides (eg, a homolog of IL-6 that is encoded in the HHV-8 genome). Unlike UCD, MCD is
more commonly associated with human herpesvirus 8 (HHV-8) infection. The role of HHV-8 and IL-6 in MCV
is presented here. The pathogenesis of UCD is discussed in more detail separately. (See "Unicentric
Castleman's disease", section on 'Pathogenesis'.)
Human herpesvirus 8 — A major advance in defining and understanding the pathogenesis of MCD came
with the identification of human herpesvirus 8 (HHV-8) in a significant number of cases [15]. HHV-8 is a
gamma herpesvirus similar to Epstein-Barr virus that has been found in both endemic and HIV-associated
Kaposi sarcoma (KS) [16,17]. (See "Disease associations of human herpesvirus 8 infection" and "AIDS-
related Kaposi sarcoma: Clinical manifestations and diagnosis".)
Two major lymphoproliferative disorders are associated with this virus: primary effusion lymphomas (PEL)
and MCD [18-23]. The latter may progress to a B cell plasmablastic lymphoma [24]. A third rare, but
apparently distinctive, B cell proliferation, referred to as germinotropic lymphoproliferative disorder, has also
been described [25]. HHV-8 positive MCD and plasmablastic lymphoma are not associated with Epstein-Barr
virus (EBV) infection, whereas in PEL and germinotropic lymphoproliferative disorder, co-infection of the
neoplastic B cells by HHV-8 and EBV is common. (See "AIDS-related lymphomas: Primary effusion
lymphoma", section on 'Pathogenesis'.)
A pathogenic relationship between MCD and HHV-8 was sought because of the well-recognized clinical
association of KS and MCD. In one study, HHV-8 DNA was detected in lymph node biopsies in all 14 cases of
HIV-associated MCD tested and in 7 of 17 cases of HIV-negative MCD, compared with 1 of 51 HIV-negative
reactive lymph nodes and 3 of 17 HIV-positive reactive lymph nodes [26,27]. Since then, other studies have
confirmed that HHV-8 involvement is universal in HIV-associated MCD [28] and in approximately 40 to 50
percent of HIV-negative MCD [26,28]. The association between HIV-negative MCD and HHV-8 may vary with
the prevalence of HHV-8 in the population. In Japan, where the seroprevalence of HHV-8 is extremely low,
HHV-8 was found only in HIV-infected patients with MCD [29,30].
Immunohistochemical stains for virally encoded antigens have demonstrated that HHV-8 is present in
approximately 10 to 30 percent of the mantle zone lymphoid cells of HHV-8+ MCD [31-33]. These cells have
immunoblastic morphology, are variably positive for CD20, and express the transcription factor MUM1/IRF4
[24,31-34]. Curiously, the HHV-8 infected cells always express high levels of cytoplasmic IgM lambda
immunoglobulin, which is consistent with in vitro studies showing that HHV-8 preferentially establishes stable
infection in tonsillar B cells expressing IgM lambda immunoglobulin [35]. Somatic hypermutation of the Ig
genes is not observed, which may indicate an origin from a naive B cell or, alternatively, from an IgM-
expressing memory B cell; IgM memory cells have been identified in tonsils [35], the anatomic site where
primary infection with HHV8 is believed to occur. Immunoblasts with these features are absent from UCD and
HHV-8-negative MCD [34]. The interfollicular plasma cells, which are not infected with HHV-8 in MCD,
express IgG or IgA immunoglobulins and are polytypic with respect to light chain expression [34].
HHV-8-infected immunoblasts are highly proliferative [34] and may coalesce to form so-called
"microlymphomas," or give rise to frank plasmablastic lymphoma. Despite their monotypic IgM lambda
expression, the HHV-8-positive proliferation in MCD has polyclonal immunoglobulin gene rearrangements,
even in most cases that have progressed to "microlymphomas" [24]. In addition, HHV-8 genomes within MCD
lesions are also polyclonal [36].
Plasmablastic lymphomas arising out of HHV-8+ MCD are monoclonal [24,34]. It is hypothesized that the
hyperproliferative state induced by HHV-8 permits the accumulation of new mutations in the genomes of the
infected B immunoblasts. Positive selection for clones bearing mutations that enhance growth and survival
then allows an initially reactive process to evolve over time into an overt lymphoma. This model is similar to
that proposed for the continuum of lymphoproliferative disorders that are associated with Epstein-Barr virus in
immunosuppressed patients [24]. (See "Treatment and prevention of post-transplant lymphoproliferative
disorders".)
Role of interleukin-6 — Both UCD and MCD have been linked to excessive release of IL-6 or similar
polypeptides. Early studies linked local production of IL-6 to the systemic manifestations of UCD [37,38] since
lymph node excision resulted in relief of symptoms along with a decrease in IL-6 levels [37]. The precise cells
within the lymph node responsible for production of IL-6 have remained elusive [39]; candidate cells include
blastic B cells of the germinal centers, follicular dendritic cells, or cells present in the interfollicular regions
[37,38]. In mice, transgenic expression of IL-6 by hematopoietic progenitor cells results in a syndrome similar
to MCD, with peripheral lymphadenopathy, extensive plasma cell infiltration of lymphoid tissues,
splenomegaly, anemia, and hypergammaglobulinemia [40].
Particularly during lytic (replicative) infection, but to a lesser degree during latent infection as well, HHV-8-
positive B cells secrete a virally encoded form of IL-6 (vIL-6) that activates the human IL-6 receptor. In
addition to HHV-8-positive Castleman's disease, vIL-6 is also secreted from primary effusion lymphomas, but
only rarely in KS [32,33,41,42]. Between 5 and 25 percent of the HHV-8 infected immunoblasts in the mantle
zone of MCD lymph nodes express vIL-6 [32,33,41,42]. Evidence linking vIL-6 to MCD pathogenesis includes
the following findings:
● High-level expression of vIL-6 in fibroblasts injected into athymic mice has reproduced a syndrome
similar to MCD [43].
● Transgenic expression of vIL-6 in mice produces a disorder with features similar to human MCD,
including splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis [44].
Of interest, this phenotype requires the murine IL-6 gene, suggesting that vIL-6 and endogenous IL-6
interact in some way to produce these abnormalities.
● While vIL-6 induces the proliferation of human myeloma cell lines, it is only approximately 1/1000th as
potent as human IL-6 [41,45]. Of interest, transgenic mice constitutively expressing vIL-6 spontaneously
develop key features of human plasma cell-type MCD, including splenomegaly, lymphadenopathy,
hypergammaglobulinemia, and plasmacytosis [44]. However, this phenotype does not occur if the vIL-6
transgene is crossed into IL-6 knockout mice, indicating that endogenous IL-6 is an important cofactor in
this model.
As suggested by the mouse experiments including those described above and in line with its greater potency,
human IL-6 (hIL-6) may play a larger role in MCD than vIL-6. Several sources of hIL-6 have been proposed in
MCD. HHV-8 gene products, such as LANA-1 and vFLIP, induce the expression of hIL-6 in HHV-8 infected B
cells through activation of the transcription factors NF-kB and AP-1 [46-50]. Alternatively, another model
proposes that vIL-6 secreted by HHV-8+ cells induces vascular endothelial growth factor (VEGF) [43,51], and
that VEGF in turn induces hIL-6 production by endothelial cells [24]. Increased VEGF expression in
interfollicular areas of lymph nodes and elevated serum VEGF levels have been observed in patients with
CD, and are possibly responsible for the increased angiogenesis in lymph nodes involved by CD.
An important pathogenic role for hIL-6 is consistent with effects of neutralizing anti-hIL-6 antibodies.
Treatment with antibodies that specifically inhibit hIL-6 can result in the resolution of the systemic symptoms
and hypergammaglobulinemia of MCD [52,53]. In addition, in two patients with MCD, serum hepcidin levels
fell rapidly following administration of an IL-6 receptor antibody, with subsequent near-normalization of
hemoglobin levels [54]. These initial results suggest that IL-6-induced hepcidin overproduction is involved in
the pathophysiology of the anemia commonly observed in this disease. (See "Anemia of chronic
disease/inflammation", section on 'Hepcidin'.)
Symptomatic patients with HHV-8-positive Castleman's disease have HHV-8 viral loads that are 2 logs
greater than asymptomatic HHV-8-positive patients; the increased viral load correlates with increased serum
levels of IL-6 and IL-10 [55]. On the other hand, this degree of increased serum HHV-8 viral load is not seen
in patients with active KS [55,56].
CLINICAL FEATURES
Signs and symptoms — The clinical presentation in multicentric Castleman's disease (MCD) is variable and
depends on the areas of lymph node involvement, production and levels of cytokines such as IL-6 and VEGF,
and associated conditions such as HIV/HHV8 infection. Most patients present with nonspecific symptoms
suggestive of an inflammatory illness. Less than 10 percent are asymptomatic. Fever is nearly universal and
most patients present with night sweats, weight loss, weakness or fatigue, and lymphadenopathy. A subset of
patients has edema, body cavity effusions, skin findings, and neurologic changes.
Skin findings include rash, hemangiomata, and pemphigus. An uncommon presentation of MCD in young
adults includes perioral pemphigus and idiopathic pulmonary fibrosis and is associated with a poor outcome.
MCD can be part of POEMS, a syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, a
monoclonal immunoglobulin spike, and skin changes such as hypertrichosis or hyperpigmentation.
Neuropathy seen in patients with MCD is variable, and can range from a mild sensory neuropathy to the
severe sensory and motor neuropathy of POEMS [57]. Sclerotic bone lesions are also commonly observed.
MCD may also be associated with autoimmune diseases including autoimmune hemolytic anemia, immune
thrombocytopenia (ITP), and acquired factor VIII deficiency. An associated increased vascular permeability
leading to peripheral edema and, rarely, pleural effusion and ascites can be seen, especially in those with
high VEGF levels and/or hypoalbuminemia. (See "POEMS syndrome".)
Peripheral lymphadenopathy is virtually always present in MCD [2,3,5]. It is frequently generalized and is
associated with hepatosplenomegaly in the majority of patients [58,59]. Only approximately 10 percent of
HIV-negative cases have mediastinal or abdominal lymphadenopathy at presentation, but with disease
progression or in HIV-infected patients at diagnosis, approximately 50 percent have lymph node involvement
of these sites [5].
The pace of disease development in MCD is variable, with some patients reporting a slow onset over a few
years and others becoming acutely ill [5,60]. HIV-infected patients tend to pursue an acute course, with a
median duration of symptoms at the time of diagnosis of MCD of three months (range: 0.5 to 24 months) [9].
A systematic review that included 72 patients with HIV-associated MCD reported the following symptoms at
the time of presentation [61]:
● Fever – 100 percent

● Lymphadenopathy – 96 percent
● Splenomegaly – 86 percent
● Hepatomegaly – 63 percent
● Pulmonary signs or symptoms – 35 percent
● Edema – 29 percent
● Ascites – 6 percent
Kaposi sarcoma was also present in 52 patients (72 percent). Pulmonary symptoms in HIV-infected patients
with MCD often include cough or dyspnea, sometimes associated with non-infectious pulmonary interstitial
lymphocytic and plasma cell infiltrates in the absence of infection, with an overall picture that closely
resembles lymphocytic interstitial pneumonia [7,9,39,62].
With increased screening measures for HIV, many patients are treated with antiretroviral therapy (ART)
before the development of complications such as MCD. It is unknown how the clinical manifestations of MCD
that develops in patients undergoing treatment with ART differ, if at all, from those of patients who are ART-
naive.
Laboratory findings — Typical laboratory abnormalities in MCD include nearly universal anemia,
thrombocytosis, hypoalbuminemia, polyclonal hypergammaglobulinemia, and an elevated erythrocyte
sedimentation rate [63]. All of these features are related to high IL-6 levels. Anemia is usually mild to
moderate, as hemoglobin levels <8 g/dL are uncommon. Platelet counts are normal to slightly elevated in the
majority of patients and are >500,000/mm3 in a small number.
Other findings include elevated serum levels of IL-6, VEGF, lactate dehydrogenase, and C-reactive protein
(CRP). In one report, these laboratory abnormalities were associated with increased levels of a variety of
cytokines, most notably IL-6 and IL-10, but also IL-5, IL-8, IL-12, and interferon-gamma; however, these
investigations are not routinely performed in patients with MCD [63].
While human herpesvirus 8 (HHV-8) infection is common among patients with MCD, serologic assays for
HHV-8 infection are of limited clinical utility, as immunosuppressed patients with HHV-8-related MCD may not
develop HHV-8 antibodies. By contrast, measurement of HHV-8 viral load study or immunohistochemistry for
HHV-8 LANA in lymph node may be helpful in establishing the diagnosis.
Imaging — Imaging findings are nonspecific, but may include the following (image 1):
● Chest radiograph – In patients with MCD, the chest radiograph may show bilateral reticular or ground
glass opacities, mediastinal widening, and/or bilateral pleural effusions [64]. Less commonly, lung
nodules or rounded areas of consolidation are seen.
● Computed tomography (CT) of the chest – On CT of the chest, most patients with MCD have multiple
enlarged mediastinal and hilar lymph nodes (1 to 3 cm diameter) [62,64]. A spectrum of lung
parenchymal findings may be seen, including subpleural nodules, interlobular septal thickening,
peribronchovascular thickening, ground glass opacities, and patchy, rounded areas of consolidation.
Small to moderate bilateral pleural effusions may be present.
● Positron emission tomography (PET) – MCD is PET avid. In one study of seven patients with MCD,
lymph nodes demonstrated enhanced FDG uptake on PET scan with a median SUV of 4.8 (range 2.6 to
9.3) [65].
PATHOLOGY — Multicentric Castleman's disease (MCD) is characterized by nodal expansions that usually
leave the structure of the underlying lymph node at least partially intact. B cells and plasma cells are
polyclonal, and T cells show no evidence of an aberrant immunophenotype. Three major variants are
recognized:
● Hyaline vascular variant (picture 1)
● HHV8-negative plasma cell variant (picture 2)
● HHV8-positive plasma cell variant (picture 3)
The pathologic features of these three variants are the same as those seen in unicentric Castleman's disease
and are described in detail separately. (See "Unicentric Castleman's disease", section on 'Pathology'.)
The plasma cell variants are more common than the hyaline vascular variant, accounting for 75 percent of
MCD [11]. Lymph nodes from HIV-infected patients are nearly always positive for HHV-8, and 40 percent
contain coexistent Kaposi sarcoma (KS) [7]. KS and MCD may also be found together in lymph nodes taken
from HIV-negative patients [8,66-68].
DIAGNOSIS — The diagnosis of multicentric Castleman's disease (MCD) should be suspected in patients
presenting with peripheral lymphadenopathy, fever, splenomegaly and an elevated C-reactive protein.
Computed tomography with fluorodeoxyglucose (FDG) positron emission tomography (FDG-PET) should
demonstrate involvement of multiple sites, usually with a relatively low standardized uptake value (SUV, 2.5
to 5). The diagnosis is confirmed upon pathologic review of a biopsy of involved tissue, typically an excisional
biopsy of a lymph node. The most abnormal node is selected for biopsy. If no single node predominates, the
choice in descending order of preference is supraclavicular, neck, axilla, and groin. Repeat biopsies may be
necessary to confirm the diagnosis if an initial biopsy fails to confirm the diagnosis and the clinical suspicion
remains high. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Localized
lymphadenopathy'.)
The diagnosis of MCD requires the clinical features of active disease described above plus pathologic
confirmation on biopsy. Biopsy demonstrates polyclonal nodal expansions that usually leave the structure of
the underlying lymph node at least partially intact, and histologic features that are consistent with the hyaline
vascular or plasma cell variants. IgH gene rearrangement studies should be performed on the lymph node to
rule out a clonal disorder (eg, occult lymphoma). (See "Unicentric Castleman's disease", section on
'Pathology'.)
Other disorders that can be associated with hyperplastic lymph nodes containing increased numbers of
plasma cells, such as rheumatoid arthritis, other connective tissue diseases, and HIV infection should be
excluded in patients with systemic symptoms. This is discussed in more detail separately. (See "Unicentric
Castleman's disease", section on 'Differential diagnosis'.)
Diagnosis of the 30 to 50 percent of cases that are HHV-8 negative can be particularly challenging and
international consensus-based diagnostic criteria have been proposed (table 1) [69]. These criteria require
clinical involvement of multiple lymph node sites with defined histopathology, two or more clinical/laboratory
changes, and the exclusion of other disorders that may mimic MCD.
PRETREATMENT EVALUATION — Once the diagnosis of multicentric Castleman's disease (MCD) has
been confirmed by pathologic evaluation of an involved lymph node, a pretreatment evaluation provides a
baseline of disease activity and assessment of comorbidities that may impact treatment options (table 2). In
addition to a history and physical examination, it is our practice to perform the following pretreatment studies
in patients with MCD:
● Laboratory studies include a complete blood count with differential; liver and renal function chemistries,
electrolytes, lactate dehydrogenase (LDH), and albumin; serologies for hepatitis B, HHV-8 and HIV, with
quantitative assays if positive; serum protein electrophoresis with immunofixation and quantitative
immunoglobulins; testing for acute phase reactants, including erythrocyte sedimentation rate (ESR), C-
reactive protein (CRP), ferritin, and fibrinogen; and measurement of serum IL-6 (and VEGF in select
cases). Serologic investigations for autoimmune disorders are performed only if suspected clinically.
● Imaging with a combined positron emission tomography (PET) and contrast-enhanced computed
tomography (CT) scan is performed to detect all areas of lymph node involvement and to document the
standardized uptake value (SUV) of involved areas.
TREATMENT
Choice of therapy — Data regarding the treatment of multicentric Castleman's disease (MCD) come from
systematic reviews of the literature, case series, and case reports. Due to the rarity of the condition, there
has been only one randomized trial. There is no standard therapy and clinical practice varies. As such,
patients should be encouraged to enroll on clinical trials, whenever available.
Outside of a clinical trial, the selection of therapy for MCD first depends upon whether the patient is HIV/HHV-
8 positive, and then on the clinical aggressiveness of the disease. Options include the use of IL-6-directed
therapy; the anti-CD20 monoclonal antibody rituximab with or without steroids and/or cytotoxic
chemotherapy; and, in HIV/HHV-8 positive cases, antiviral therapy with ganciclovir and antiretroviral therapy
(ART).
● For most symptomatic, HIV/HHV-8 negative patients without evidence of organ failure, we suggest the
use of immunotherapy alone (tocilizumab, siltuximab, rituximab) rather than immunotherapy plus
chemotherapy or chemotherapy alone. This preference places a high value on the avoidance of toxicities
associated with cytotoxic chemotherapy and a low value on a potential yet unproven improvement in
efficacy with combination therapy. Options for immunotherapy differ by region and are described in more
detail below. (See 'HIV/HHV-8 negative patients' below.)
● For patients with evidence of organ failure or poor performance status thought to be due to the disease,
we suggest combination therapy with rituximab plus chemotherapy rather than immunotherapy or
chemotherapy alone. Experience is greatest with etoposide 100 mg/m2 intravenously for four weeks plus
rituximab. This preference places a high value on the potentially increased efficacy of combination
therapy in a population that is sometimes refractory to single agent rituximab. Experience with anti-IL-6
targeting antibody in combination with chemotherapy is limited. (See 'Chemotherapy' below.)
● For most HIV/HHV-8 positive patients, we suggest a combination of ganciclovir plus rituximab, with
etoposide added for those with more symptomatic or aggressive disease. If patients have a low CD4
count and/or higher HIV load and/or active Kaposi sarcoma (KS), then ART is included with the above
combination regimen. In either setting, rituximab therapy can be administered repeatedly and ganciclovir
can be used as maintenance therapy. (See 'HIV/HHV-8 positive patients' below.)
We generally administer four cycles of therapy prior to reassessing disease status. If responding, but with
evidence of persistent disease activity, then a second round of therapy can be administered two to three
months later. If IL-6-directed therapies are used, they should be given continuously. Treatment with rituximab
alone or rituximab plus various combination chemotherapies can be given at the time of relapse.
While surgical removal of lymph nodes is curative in unicentric disease, it does not have a role in the
treatment of MCD [11]. However, splenectomy can result in transient symptomatic improvement in selected
patients [5,7].
HIV/HHV-8 negative patients — Where available, immunotherapy with monoclonal antibodies directed at IL-
6 (siltuximab) or the IL-6 receptor (tocilizumab) is our preferred therapy for most symptomatic, HIV/HHV-8
negative patients without evidence of organ failure. This approach has resulted in two-year overall and
relapse-free survival rates of 94 to 95 percent and 79 to 85 percent, respectively. A choice among these
agents is primarily based on availability and clinician experience. If both agents are available, siltuximab is
preferred based on its benefit in the only randomized trial. If neither agent is available, we suggest the use of
the anti-CD20 monoclonal antibody, rituximab.
Inhibition of interleukin-6 — Monoclonal antibodies targeted against IL-6 (siltuximab) or the IL-6 receptor
(tocilizumab, also called atlizumab or MRA) have demonstrated clinical efficacy in HIV/HHV-8 negative MCD,
resulting in symptom resolution [52,53,70-74]. Tocilizumab has been approved for use in Japan since 2005,
but not in Europe or the United States. Siltuximab is approved in the United States for the treatment of
patients with MCD who are HIV/HHV-8 negative, and it is under review by regulatory agencies in Europe [75].
Data about combining other modalities with anti-IL-6-directed treatment are limited.
The most common toxicities of immunotherapy include pruritus, increased weight, rash, hyperuricemia, and
upper respiratory tract infection [75]. Symptoms of infusion reaction (eg, back or chest pain, nausea/vomiting,
flushing, erythema, palpitations) are seen in approximately 5 percent. Immunotherapy should not be
administered to patients with severe infection, and physicians should have a high index of suspicion for
infection since these agents may mask common signs and symptoms of acute inflammation (eg, fever, acute
phase reactants). Live vaccines should be avoided.
Anti-IL-6-directed treatment is continued until progression in order to maintain the response. In one study, all
seven patients treated with tocilizumab had resolution of clinical symptoms, followed by improvement in
lymphadenopathy [76]. However, symptoms recurred once therapy was stopped.
The efficacy of siltuximab and tocilizumab in HIV/HIV-8 negative MCD was illustrated in the two studies
described below. The observed efficacy may be restricted to the HIV/HHV8 negative subset of patients, who
probably have a disease that is different from that of HIV-infected patients.
● A multicenter, randomized, double-blind, phase II trial of siltuximab in 79 patients with symptomatic

HIV/HHV-8 negative MCD demonstrated significant benefit of siltuximab for all end points [77]. When
compared with placebo, siltuximab (11 mg/kg intravenous infusion every three weeks) resulted in the
following:
• Higher overall response rate (34 versus 0 percent) and longer median time to treatment failure (not
reached versus 134 days).
• Improvements in anemia (hemoglobin ≥15 g/L at week 13, 61 versus 0 percent) and markers of
inflammation (CRP, ESR and fibrinogen).
• Durable symptomatic response (57 versus 19 percent).
• Frequencies of treatment-emergent adverse events were similar between siltuximab and placebo.
Infusion reactions were infrequent (8 percent) and low grade, except for one anaphylactic reaction
that led to treatment discontinuation.
• Severe (grade 3/4) adverse events included fatigue (9 percent); night sweats (8 percent); and
hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia,
hypertension, and weight increased (4 percent each).
● A multicenter, prospective, open-label trial evaluated the safety and efficacy of tocilizumab in 28
symptomatic patients with MCD of the plasma cell type [78]. No patient was HIV positive and only two
were seropositive for HHV-8. The patients were initially treated with tocilizumab at a dose of 8 mg/kg IV
every two weeks for 16 weeks, with an extension phase permitting variable dosing after this time. Major
results of this study include:
• After 16 weeks of treatment, nutritional status and fatigue scores were significantly improved, as
were lymphadenopathy and markers of inflammation, such as C-reactive protein and erythrocyte
sedimentation rate.
• Mean hemoglobin levels improved from 9.2 to 12.0 g/dL; no patient required transfusion during this
period.
• Of the 15 patients receiving treatment with corticosteroids at baseline, the average daily dose of
prednisolone (16 mg/day) decreased by approximately one-half over the course of therapy.
• During the extension period, all patients remained on treatment, and the efficacy observed during
the first 16 weeks was sustained or improved over the course of one year, with some subjects
receiving this agent for up to three years.
• Adverse reactions were common but mild, and included symptoms related to the common cold (eg,
cough, rhinorrhea, pharyngitis). Infusion-related symptoms (eg, low grade fever) were also readily
manageable.
These studies establish IL-6 directed therapy as an important treatment option in HIV/HHV-8 negative MCD.
There has been no defined IL-6 level for the activity of these agents in MCD. Further follow-up is needed to
determine whether these high response rates translate into a survival advantage.
Rituximab — An increasing body of evidence suggests that rituximab, alone or in conjunction with
cytostatic agents, is able to stabilize patients and, as initial therapy, can induce durable remissions in a high
percentage of patients [63,79,80]. We use rituximab for the treatment of patients with HIV/HHV-8 negative
MCD without organ dysfunction who do not have access to IL-6-directed therapy or have progressed despite
IL-6-directed therapy. We also use rituximab as part of combination therapy for patients with organ failure and
for those with HIV/HHV-8 positive MCD. This is discussed in more detail below. (See 'Rituximab' below.)
Chemotherapy — Single agent and combination chemotherapy with or without concurrent rituximab have
been evaluated for the treatment of MCD. We typically reserve chemotherapy for patients with evidence of
organ failure or poor performance status thought to be due to the disease. Experience is greatest with
etoposide 100 mg/m2 intravenously for four weeks plus rituximab. There is limited experience with
hematopoietic cell transplantation.
● Single agent chemotherapy – Vinblastine and etoposide have both been used as single agents, with
almost all patients having symptomatic relief and a partial response [81]. However, when single agent
therapy is stopped, symptoms generally recur in two to three weeks, necessitating intermittent
maintenance therapy, often lifelong [7,55,81]. Thus, combination chemotherapy is usually preferred to
monotherapy when chemotherapy is given.
● Addition of glucocorticoids – When chlorambucil was given along with glucocorticoids in a small study,
overall response rates approached 90 percent, with four out of nine patients treated with chlorambucil
plus prednisone reported to have achieved a complete response [2,3,5,8].
● Four-drug combinations – Selected patients may benefit from more aggressive combination
chemotherapy. In two studies, approximately 50 percent of patients achieved durable complete
responses after treatment with four-drug combinations such as CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone)
[2,3]. In a report of nine patients with MCD who were treated with combination chemotherapy, five were
alive with no evidence of disease and four were alive with progressive disease at a mean follow-up of
about four years [2].
● Other agents – Bortezomib is another agent that has been shown to inhibit IL-6 levels and has activity in
plasma cell disorder. In highly anecdotal reports, this agent, alone or in combination with antiviral agents,
has been reported to be effective in some patients with MCD [82-86]. However, its use needs to be
carefully considered in a salvage setting keeping in mind neuropathy as a potential side effect.
Similarly, anecdotal and small size studies have reported efficacy of immunomodulatory agents
(thalidomide, lenalidomide) alone or in combination with rituximab in MCD. These could be considered in
a salvage setting.
● Hematopoietic cell transplantation – Long-term survivals were reported in three patients with MCD
(one with POEMS syndrome and one with non-Hodgkin lymphoma) who were treated successfully with
hematopoietic cell transplantation after failing treatment with chemotherapy [87-89].
Glucocorticoids — Glucocorticoids have been frequently used as a systemic therapy in patients with
MCD. The response rate is 60 to 70 percent with zero to 20 percent being complete responses, which are
usually not durable [3,5,8]. They have not been reported to have efficacy in HIV-associated MCD [7,55].
Duration of response to steroid is usually limited. At present, the main use for glucocorticoids in MCD has
been for symptom control and as part of combination chemotherapy regimens, such as CHOP and CVAD.
Anti-IL-6 antibody treatment needs to be continued for a prolonged period of time, while rituximab course
may be repeated. Need and benefits of maintenance rituximab has not been investigated in MCD.
Ganciclovir treatment is continued as maintenance in HIV/HHV8 positive MCD.
HIV/HHV-8 positive patients — For most HIV/HHV-8 positive patients, we suggest a combination of
ganciclovir plus rituximab, with etoposide added for those with more symptomatic or aggressive disease. If
patients have a low CD4 count and/or higher HIV load and/or active KS, then antiretroviral (ART) therapy is
included with the above combination regimen. In either setting, rituximab therapy can be repeated and
ganciclovir can be administered as maintenance therapy.
Rituximab — We use rituximab for the treatment of patients with HIV/HHV-8 negative MCD without organ
dysfunction who do not have access to IL-6-directed therapy or have progressed despite IL-6-directed
therapy. We also use rituximab as part of combination therapy for patients with organ failure and for those
with HIV/HHV-8 positive MCD. The safety profile is adequate, with the caveat that rituximab use can be
associated with exacerbations of cutaneous KS, reactivation of hepatitis B, and respiratory complications.
Rituximab, alone or in combination with chemotherapy, has significant activity in HIV-associated as well as
HIV-negative MCD [9,58,63,80,90-98], even when used as salvage therapy [99]. These clinical responses
have been associated with significant decreases in plasma levels of IL-5, IL-6, and IL-10 [91,100]. Some HIV-
infected patients have had exacerbation of their KS lesions after rituximab therapy [63,93,101], but others
have undergone remission [92]. Accordingly, care must be taken with rituximab in HIV-positive patients
whose viral load is poorly controlled, who have low CD4 counts or active KS.
The use of rituximab in HIV-infected patients with MCD has only been evaluated in observational studies.
Part of the rationale for these studies was frequent disease recurrence following the cessation of single agent
chemotherapy (see 'Chemotherapy' above).
● A prospective study evaluated 24 HIV-infected patients with MCD [90]. All had stable disease on
treatment with single agent chemotherapy for a median time of 13 months, with at least one disease
recurrence after an attempt to discontinue treatment. Chemotherapy was discontinued 6 to 10 days
before the first of four weekly intravenous (IV) infusions of rituximab (375 mg/m2). The primary endpoint,
sustained remission off treatment at 60 days, was achieved in 22 of the 24 patients (92 percent), with 17
(71 percent) in sustained remission without specific treatment at one year. Mild exacerbation of KS
lesions was noted in 8 of the 12 patients with previous KS.
● In a second study, 21 consecutive patients with symptomatic HIV+ MCD were treated with four weekly IV
infusions of rituximab and followed for a median of 12 months [63]. Of the 20 patients completing the
entire course of treatment, all achieved resolution of symptoms and fever following the fourth infusion,
with partial responses and stable disease in 67 and 29 percent, respectively. Two-year overall survival
was 95 percent, with one- and two-year relapse-free survivals of 92 and 79 percent, respectively. Plasma
HHV-8 was detectable in 80 percent of patients at diagnosis, in 20 percent one month after rituximab
treatment, and in 10 percent three months after treatment. CD4 count and HIV viral load remained
stable. No grade 3 or 4 toxicities were observed, but, as noted in other studies, KS progressed during
rituximab treatment in 4 of 11 (36 percent) patients who had cutaneous disease at the time of diagnosis.
● A third study reported on the treatment of 49 patients with newly diagnosed HIV+ MCD using rituximab
with (14 patients) or without (35 patients) etoposide [9]. Etoposide was added for higher risk patients and
resulted in similar outcomes as rituximab alone in the lower risk patients. Overall survival for the whole
group at two and five years was 94 and 90 percent, respectively, with two- and five-year progression-free
survivals of 85 and 61 percent, respectively. All eight patients with symptomatic, histologically-confirmed
relapsed MCD responded to re-treatment with rituximab-based therapy.
● In another prospective study, 17 patients with symptomatic HIV+ MCD were treated with rituximab (375
mg/m2) plus liposomal doxorubicin (20 mg/m2), administered every three weeks for up to two cycles
beyond symptom resolution [98]. All patients received antiviral therapy and were offered consolidation
with either interferon alfa or the combination of zidovudine plus valganciclovir. Major clinical and
biochemical response rates were 94 and 88 percent, respectively. Estimated event-free and overall
survival rates at three years were 69 and 81 percent, respectively. The most common toxicities were
infusion reaction (70 percent), neutropenia (24 percent), and anemia (12 percent).
Data regarding longer term outcomes come from retrospective analyses of treatment outcomes in HIV
positive patients with MCD:
● In a study in 52 patients with HIV+ MCD, those who had received rituximab-based regimens had
significantly higher complete remission rates (10 of 11, 91 percent) than those receiving chemotherapy
with or without antiviral therapy (9 of 22, 41 percent) and also had significantly longer overall survival
(not reached versus 5.1 years, respectively) [80].
● Data from a single-center prospective cohort of 113 patients with HIV+ MCD followed for a median of 4.2
years, the incidence of development of non-Hodgkin lymphoma was 4.2 and 69.6 per 1000 person-years
for those who did (R+) or did not (R-) receive rituximab-based treatment, respectively (hazard ratio 0.09;
95% CI 0.01-0.70) [101]. Flares of KS occurred in one-third of the R+ patients who had previously stable
KS lesions. Two- and five-year overall survivals were 93 and 90 percent, respectively, for the R+
patients, and 68 and 47 percent, respectively, for the R- patients.
● In a retrospective analysis of 84 patients treated for HIV+ MCD with rituximab-based therapy and
followed for a median of 6.9 years, the five-year overall and relapse-free survival rates were 92 and 82
percent, respectively [102]. The median time to first relapse was 30 months. Most patients were
successfully retreated with rituximab-based therapy at the time of relapse.
Rituximab therapy carries a risk of hepatitis B reactivation among patients positive for HBsAg or anti-HBc.
The risk of hepatitis B reactivation is discussed in more detail separately. (See "Hepatitis B virus reactivation
associated with immunosuppressive therapy".)
Antiviral agents — Clinical manifestations in MCD correlate with the serum viral load of HHV-8, which
suggests that they may be directly related to replicating virus [55]. HHV-8 replication is sensitive in vitro to
ganciclovir, foscarnet, and cidofovir at achievable plasma concentrations [103]. For most HIV/HHV-8 positive
patients, we suggest a combination of ganciclovir plus rituximab, with etoposide added for those with more
symptomatic or aggressive disease.
Although antiviral drugs have not proven effective against KS, which is characterized by latent HHV-8
infection, lytic HHV-8 infection is prevalent in MCD, providing a rationale for such therapies [32,33]. Efficacy
data are limited. In a pilot study, 14 HIV-infected patients with HHV-8-associated MCD were treated with high-
dose zidovudine (600 mg PO every six hours) and valganciclovir (900 mg PO every 12 hours) [104]. Major
clinical and biochemical responses occurred in 12 and 7 patients, respectively. After a median follow-up of 43
months, overall survival at 12 months and beyond was 86 percent. Little clinical activity has been observed
with foscarnet or cidofovir, however.
Data are also limited on the use other antiviral drugs [32,33]:
● Ganciclovir resulted in both clinical and virologic responses in three HIV+/HHV-8+ patients [105].
● Interferon alfa induced a complete response in two of three patients that lasted for three to six months
[7].
● Cidofovir produced little clinical benefit in seven treated cases [92,106,107].
For patients with HIV, the reduction in HIV viral load and improvement in immune function associated with
antiretroviral therapy (ART) is expected to result in better tolerance of chemotherapy, fewer opportunistic
infections, and improvement in overall treatment outcome. With few exceptions, studies in HIV-associated
lymphoma have shown that concomitant ART and antineoplastic chemotherapy have no clinically adverse
effects on the metabolism of drugs in either the antiretroviral or conventional-dose antineoplastic regimens.
There are few data to support one antiretroviral regimen over another. However, use of zidovudine is strongly
discouraged due to the risk of overlapping myelotoxicity. (See "AIDS-related lymphomas: Treatment of
systemic lymphoma", section on 'Incorporating ART'.)
PATIENT FOLLOW-UP — After the initiation of therapy, patients should be evaluated to determine the
disease response to treatment and should be followed longitudinally for progression and complications.
Response evaluation — We generally administer four cycles of therapy prior to reassessing disease status.
The response to treatment should be documented by history, physical examination, and laboratory studies
(complete blood count, lactate dehydrogenase, biochemical profile, interleukin [IL]-6, C-reactive protein,
serum free light chain assay, and quantitative immunoglobulins). Symptomatic improvement is also a major
criterion to judge efficacy of the treatment and was one of the considerations in the randomized study if IL-6-
directed therapy. The post-treatment imaging study of choice is the positron emission tomography/computed
tomography (PET/CT) scan, which provides information on the size and activity of residual masses.
Response to treatment is determined using information gathered from the history, physical, and PET/CT scan
(table 3).
If responding, but with evidence of persistent disease activity, then a second round of therapy can be
repeated two to three months later. If IL-6-directed therapy is used, it should be given continuously.
Treatment with rituximab alone or rituximab plus various combination chemotherapies can be given at the
time of relapse.
Patients who achieve an at least partial response are seen at periodic intervals to monitor for treatment
complications and assess for disease progression. The frequency and extent of these visits depends upon
the comfort of both the patient and physician. Our approach to patient surveillance is to schedule patient
visits every two to three months. At these visits, we perform a history and physical examination and serum
biomarkers, which include IL-6, C-reactive protein, serum free light chain assay, and quantitative
immunoglobulins.
Patients who attain a complete remission are followed annually with PET/CT and serum biomarkers. Annual
imaging can be discontinued after five years if the patient remains disease free.
Complications — Fatal cases of multicentric Castleman's disease (MCD) are associated with fulminant
infection, progressive disease, or related malignancies. Of the 50 patients in one study reported before the
HIV era or in whom HIV status was unknown, 38 percent developed serious infections, with 70 percent of
infections directly contributing to death [3-6,8]. Many patients have been reported to die of progressive
disease with multi-organ system failure [5,6,8]. Whether these patients died of undetected conversion to
lymphoma or uncontrolled HHV-8 infection is not known.
Malignancy — Many deaths are due to the well-described association of Castleman's disease with other
malignancies, particularly Kaposi sarcoma (KS) and hematologic malignancies.
● Kaposi sarcoma – In older reports, KS was noted in approximately 13 percent of patients with MCD; KS
may be diagnosed beforehand, concomitantly, or afterwards [60]. Among HIV-infected patients, fully 70
percent of those with MCD have KS at some time during their course [7,34,108,109]. (See "AIDS-related
Kaposi sarcoma: Staging and treatment" and "AIDS-related Kaposi sarcoma: Clinical manifestations and
diagnosis".)
● Non-Hodgkin lymphoma – Non-Hodgkin lymphoma (NHL) is significantly associated with MCD.

Approximately 15 to 20 percent of MCD patients present with or develop NHL, most commonly some
variant of diffuse large B cell lymphoma [3,5,6,8,110]. The incidence of NHL reported in retrospective
series does not appear to vary with HIV status, but is limited by small numbers. The reported death rate
is 85 percent for patients who develop NHL together with MCD, despite use of standard therapies
[8,110].
The pathogenesis of NHL in this setting is not entirely clear, but at least some cases appear to be related
to uncontrolled HHV-8 infection. A prospective cohort study of 60 HIV-infected patients with MCD found
that 14 developed NHL at up to 76 months after MCD diagnosis, for an actuarial two-year incidence of
24 percent, 15-fold greater than that expected for HIV-infected patients in general [109]. All of the NHLs
were positive for HHV-8, with approximately half being primary effusion lymphomas and half being
plasmablastic lymphomas.
Of interest, the plasmablastic lymphomas have morphology similar to the HHV8+ immunoblasts (or
"plasmablasts") found in the mantle zone of MCD lymph nodes. Four of these plasmablastic lymphomas
presented with a fulminant leukemic phase and were fatal within one week. The median survival from
diagnosis of NHL in the HIV/HHV-8 positive patients was one month [109]. (See "Unicentric Castleman's
disease", section on 'Pathogenesis'.)
However, not all NHL that is associated with CD is HHV-8 related, since cases have been reported in
unicentric Castleman's disease and in HHV-8-negative MCD [42,110,111].
● Hodgkin lymphoma – Although less common than non-Hodgkin lymphoma, there are multiple reports in
the literature of Hodgkin lymphoma arising in association with unicentric Castleman's disease (UCD) and
MCD [66,110,112-118].
POEMS syndrome — MCD could be a component of another well-described constellation of symptoms,

the POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin
changes; also called osteosclerotic myeloma due to frequent associated bone changes). POEMS syndrome
is described in more detail separately. (See "POEMS syndrome".)
Approximately 75 to 100 percent of patients with POEMS syndrome have a monoclonal gammopathy; 87 to
98 percent have sclerotic bone lesions; and up to 20 percent of patients having plasma cell infiltration of the
bone marrow. Conversely, approximately 50 percent of patients with POEMS syndrome have an associated
MCD of the plasma cell type [119,120].
Of patients with POEMS and MCD, approximately 80 percent have evidence of HHV-8 infection [119-122].
Patients with POEMS syndrome almost invariably have lambda light-chain bearing paraproteins, which is of
interest given the lambda light-chain restriction of the "plasmablasts" in HHV8-associated MCD. In contrast,
only 10 to 15 percent of patients who have POEMS without MCD show evidence of HHV-8 infection
[119,120].
In one study in which four of five patients with the POEMS syndrome also had MCD, increased levels of IL-1
beta were noted in 13 of 13 serum samples, while IL-6 was increased in seven [123]. These similarities
between POEMS syndrome and MCD suggest a common underlying mechanism in at least some cases,
perhaps infection with HHV-8 with resulting increased cytokine production [124,125].
PROGNOSIS — The natural history of multicentric Castleman's disease (MCD) is variable. Several different
patterns of disease progression have been described [5,8]:
● An indolent form of MCD sometimes persists for months to a few years without worsening.
● An episodic relapsing form may be aggressive for a short period and then remit spontaneously or in
response to treatment, only to recur at a later time.
● A rapidly progressive form that can lead to death within weeks may be more common in HIV-infected
patients [34,108]. Initiation of anti-retroviral therapy in patients who are positive for both HIV and HHV-8
may increase the likelihood of developing acute, fulminant MCD [108], but this remains to be confirmed.
The prognosis of untreated MCD is poor. The median survival of patients with MCD in the pre-HIV era was 26
to 30 months [5,8]. In the two largest series of HIV-associated MCD (n = 28), the outcome was even poorer,
with an overall mortality of 70 to 85 percent and a median survival of 8 to 14 months [7,34]. A retrospective
study analyzed factors that predicted for the onset of active disease in 52 HIV infected patients with MCD
[126]. The strongest association on multivariate analysis was with rising plasma levels of HHV-8 DNA (HR
2.9; 95% CI 1.3-6.7).
HIV-infected patients with MCD are almost universally infected with HHV-8. At present, it is unclear whether
the poor outcomes in this group are primarily due to HIV alone, to HHV-8 alone, or to an interaction between
the two. The available literature suggests that HHV-8 infection may be the more important factor:
● Of six MCD patients identified in the literature as HIV-negative and HHV-8-negative, four are alive and
reportedly well, with two deaths due to lymphoma [34,42,110,127].
● Of 10 patients identified as HIV-negative and HHV-8-positive, seven have died, including several within a
few months of diagnosis. Three of 10 developed lymphoma and 4 of 10 had Kaposi sarcoma [34,42,110].
SUMMARY AND RECOMMENDATIONS
● Castleman's disease (CD, angiofollicular lymph node hyperplasia) is a heterogenous group of rare
lymphoproliferative disorders associated in a subset of cases with the human immunodeficiency virus
(HIV) and human herpesvirus 8 (HHV-8). CD comprises at least two distinct diseases (unicentric and
multicentric) with very different prognoses. Both conditions can be associated with development of
malignancies, such as non-Hodgkin lymphoma. (See 'Complications' above.)
● Multicentric Castleman's disease (MCD) generally presents in the fifth to sixth decade of life with
peripheral lymphadenopathy and systemic symptoms including fever, night sweats, weight loss, and
fatigue. Imaging with combined positron emission tomography (PET) and computed tomography (CT)
demonstrates involvement of multiple sites, usually with a relatively low standardized uptake value
(SUV). Results from laboratory studies include nearly universal anemia, thrombocytopenia,
hypoalbuminemia, polyclonal hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate.
(See 'Clinical features' above.)
● The diagnosis is confirmed upon pathologic review of a biopsy of involved tissue, typically an excisional
biopsy of a lymph node. Biopsy demonstrates polyclonal nodal expansions that usually leave the
structure of the underlying lymph node at least partially intact. Histologic features are consistent with the
hyaline vascular or plasma cell variants. (See "Unicentric Castleman's disease", section on 'Pathology'.)
● Outside of a clinical trial, the selection of therapy for MCD first depends upon whether the patient is
HIV/HHV-8 positive, and then on the clinical aggressiveness of the disease (see 'Choice of therapy'
above):
• For most symptomatic, HIV/HHV-8 negative patients without evidence of organ failure, we suggest
the use of immunotherapy alone rather than immunotherapy plus chemotherapy or chemotherapy
alone (Grade 2B). Where available, we prefer monoclonal antibodies directed at IL-6 (siltuximab) or
the IL-6 receptor (tocilizumab). If neither agent is available, rituximab is an acceptable alternative.
(See 'Inhibition of interleukin-6' above.)
• For those patients with evidence of organ failure or poor performance status thought to be due to
the disease, we suggest combination therapy with rituximab plus chemotherapy rather than either
immunotherapy or chemotherapy alone (Grade 2C). Experience is greatest with etoposide 100
mg/m2 intravenously for four weeks plus rituximab. (See 'Chemotherapy' above.)
• For most HIV/HHV-8 positive patients, we suggest a combination of ganciclovir plus rituximab, with
etoposide added for those with more symptomatic or aggressive disease (Grade 2C). If patients
have a low CD4 count and/or higher HIV load and/or active Kaposi sarcoma, then antiretroviral
therapy is included with the above combination regimen. (See 'HIV/HHV-8 positive patients' above.)
● Patients should be evaluated to determine the disease response to treatment, and should be followed
longitudinally for disease progression and complications. We generally administer four cycles of therapy
prior to reassessing disease status. If responding, but with evidence of persistent disease activity, then a
second round of therapy can be repeated two to three months later. If IL-6-directed therapy is used, it
should be given continuously. Treatment with rituximab alone or rituximab plus various combination
chemotherapies can be given at the time of relapse. (See 'Patient follow-up' above.)
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Acta Oncol 2003; 42:784.
Topic 4707 Version 37.0
GRAPHICS
Multicentric Castleman's disease
(A) The posteroanterior (PA) chest x-ray is from a 45-year-old male who presented after falling off a
ladder. A mass is noted in the region of the right costophrenic angle (arrow). A diagnosis of multicentric
Castleman's disease was made after computed tomography (CT) scan and pathological examination.
(B) A vascular mass in the right posterior sulcus (arrow).
(C) A coronally reconstructed view of the right sided mass.
Courtesy of Priscilla J Slanetz, MD, MPH, FACR.
Graphic 87767 Version 2.0
Pathologic features of hyaline-vascular variant Castleman's

disease
(A) Two follicles are present in this field. The follicle to the left of the field contains more
than one germinal center ("twinning"). Hematoxylin and eosin stain.
(B) Hyaline deposits are present within the germinal center. Hematoxylin and eosin stain.
(C) Hyaline vascular ("lollipop") lesion in which a follicle is radially penetrated by a sclerotic
blood vessel. Hematoxylin and eosin stain.
(D) The follicle is surrounded by a broad mantle zone composed of concentric rings of small
lymphocytes (so-called "onion skin"). Hematoxylin and eosin stain.
Reproduced with permission from: Castleman lymphadenopathy. In: Ioachim's Lymph Node
Pathology, 4th ed, Ioachim HL, Medeiros LJ (Eds), Lippincott Williams & Wilkins, Philadelphia
2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.
Pathologic features of HHV8 negative plasma cell variant

Castleman's disease
(A) Reactive lymphoid follicles and interfollicular plasmacytosis are present.

(B) In this field, the reactive germinal center is radially penetrated by a prominent
blood vessel.
(C) Sheets of cytologically mature plasma cells are present within the interfollicular
region. Hematoxylin and eosin stain.
Reproduced with permission from: Castleman lymphadenopathy. In: Ioachim's Lymph

Node Pathology, 4th ed, Ioachim HL, Medeiros LJ (Eds), Lippincott Williams & Wilkins,
Philadelphia 2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.
Pathologic features of HHV8 positive plasma cell variant

Castleman's disease
(A) In this field, the interfollicular regions are expanded by numerous plasma cells, and
sinuses are patent. Small lymphoid follicles are also present. Hematoxylin and eosin stain.
(B) In this field, the boundary between the follicle mantle zone and the interfollicular region
is indistinct. Hematoxylin and eosin stain.
(C) In the follicle mantle zones, large, atypical plasmablasts are present. Hematoxylin and
eosin stain.
(D) Human herpes virus-8+ cells are preferentially identified in the mantle zones. Some of
these cells are large, consistent with plasmablasts. Immunohistochemistry with antibody
specific for HHV-8 latent nuclear antigen-1 with hematoxylin counterstain.
Reproduced with permission from: Castleman lymphadenopathy. In: Ioachim's Lymph Node
Pathology, 4th ed, Ioachim HL, Medeiros LJ (Eds), Lippincott Williams & Wilkins, Philadelphia
2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.
Consensus diagnostic criteria for idiopathic multicentric Castleman disease

(iMCD)
I. Major criteria (need both)
1. Histopathologic lymph node features consistent with the iMCD spectrum. Features along the iMCD spectrum
include (need grade 2-3 for either regressive GCs or plasmacytosis at minimum):
Regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric
rings of lymphocytes in an "onion skinning" appearance
FDC prominence
Vascularity, often with prominent endothelium in the interfollicluar space and vessels penetrating into the
GCs with a "lollipop" appearance
Sheetlike, polytypic plasmacytosis in the interfollicular space
Hyperplastic GCs
2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations
II. Minor criteria (need at least 2 of 11 criteria with at least 1 laboratory criterion)
Laboratory:*
1. Elevated CRP (>10 mg/L) or ESR (>15 mm/hour) ¶
2. Anemia (hemoglobin <12.5 g/dL for males, hemoglobin <11.5 g/dL for females)
3. Thrombocytopenia (platelet count <150 k/microL) or thrombocytosis (platelet count >400 k/microL)
4. Hypoalbuminemia (albumin <3.5 g/dL)
5. Renal dysfunction (eGFR <60 mL/min/1.73 m 2) or proteinuria (total protein 150 mg/24 hours or 10
mg/100 mL)
6. Polyclonal hypergammaglobulinemia (total gamma-globulin or immunoglobulin G >1700 mg/dL)
Clinical:
1. Constitutional symptoms: Night sweats, fever (>38°C), weight loss, or fatigue (≥2 CTCAE lymphoma score
for B-symptoms)
2. Large spleen and/or liver
3. Fluid accumulation: Edema, anasarca, ascites, or pleural effusion
4. Eruptive cherry hemangiomatosis or violaceous papules
5. Lymphocytic interstitial pneumonitis
III. Exclusion criteria (must rule out each of these diseases that can mimic iMCD)
Infection-related disorders:
1. HHV-8 (infection can be documented by blood PCR, diagnosis of HHV-8–associated MCD requires positive
LANA-1 staining by IHC, which excludes iMCD)
2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV

(detectable EBV viral load not necessarily exclusionary)
3. Inflammation and adenopathy caused by other uncontrolled infections (eg, acute or uncontrolled CMV,
toxoplasmosis, HIV, active tuberculosis)
Autoimmune/autoinflammatory diseases (requires full clinical criteria, detection of autoimmune

antibodies alone is not exclusionary):
1. Systemic lupus erythematosus
2. Rheumatoid arthritis
3. Adult-onset Still disease
4. Juvenile idiopathic arthritis
5. Autoimmune lymphoproliferative syndrome
Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same

time as iMCD to be exclusionary):
1. Lymphoma (Hodgkin and non-Hodgkin)
2. Multiple myeloma
3. Primary lymph node plasmacytoma
4. FDC sarcoma
5. POEMS syndrome Δ
Select additional features supportive of, but not required for diagnosis:
Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M
Reticulin fibrosis of bone marrow (particularly in patients with TAFRO syndrome)
Diagnosis of disorders that have been associated with iMCD: Paraneoplastic pemphigus, bronchiolitis
obliterans organizing pneumonia, autoimmune cytopenias, polyneuropathy (without diagnosing POEMS Δ),
glomerular nephropathy, inflammatory myofibroblastic tumor
GC: germinal center; FDC: follicular dendritic cell; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; eGFR:
estimated glomerular filtration rate; CTCAE: common terminology for adverse events; PCR: polymerase chain reaction;
LANA-1: latency-associated nuclear antigen; IHC: immunohistochemistry; EBV: Epstein-Barr virus; CMV:
cytomegalovirus; IL: interleukin; VEGF: vascular endothelial growth factor; Ig: immunoglobulin; LDH: lactate
dehydrogenase; B2M: β-2-microglobulin.
* We have provided laboratory cutoff thresholds as guidance, but we recognize that some laboratories have slightly
different ranges. We suggest that you use the upper and lower ranges from your particular laboratory to determine if a
patient meets a particular laboratory Minor criterion.
¶ Evaluation of CRP is mandatory and tracking CRP levels is highly recommended, but ESR will be accepted if CRP is not
available.
Δ POEMS is considered to be a disease "associated" with Castleman's disease. Because the monoclonal plasma cells are
believed to drive the cytokine storm, we do not consider it iMCD, but rather "POEMS-associated MCD."
Reproduced with permission of the American Society of Hematology, from: Fajgenbaum DC, Uldrick TS, Bagg A, et al.
International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease.
Blood 2017; 129:1646; permission conveyed through Copyright Clearance Center, Inc. Copyright © 2017.
Pretreatment evaluation in patients with Castleman's disease
Investigation Common findings
Complete blood count Anemia, thrombocytosis
Serum chemistry Hypoalbuminemia, elevated lactate dehydrogenase
Acute phase reactants Elevated ESR, CRP, ferritin, and fibrinogen
SPEP, quantitative immunoglobulin, immunofixation Elevation in one or more immunoglobulin class (IgG,
IgA, IgM), no M spike, IFE negative
Serum cytokine levels: IL-6 and VEGF (in select cases) Elevated IL-6 (not all cases in UCD), elevated VEGF in
small number of cases
Serological investigations for autoimmune disorders: Variable

only if clinically suspected
Viral serology for HHV-8, HIV; if positive, quantitative Positive in limited number of cases. Rarely in hyaline
assay. Staining of lymph node biopsy for HHV-8. vascular variant, more common in plasmacytic variant.
Imaging: PET/CT Initially to detect any other area of lymph node

involvement (distinguish UCD from MCD) and to assess
disease activity by SUV (2.5 to 5)
IgH gene rearrangement study on lymph node specimen Rule out clonal disorder, mainly occult lymphoma
ESR: erythrocyte sedimentation rate; CRP: c-reactive protein; SPEP: serum protein electrophoresis; IFE: immunofixation;
IL-6: interleukin-6; VEGF: vascular endothelial growth factor; UCD: unicentric Castleman's disease; HHV-8: human herpes
virus 8; PET/CT: positron emission tomography/computed tomography; MCD: multicentric Castleman's disease; SUV:
standardized uptake value.
Lugano criteria for response assessment in lymphoma
Response and
PET/CT-based response CT-based response
site
Complete Complete metabolic response Complete radiologic response (all of the

following)
Lymph nodes and Score 1, 2, or 3* with or without a residual Target nodes/nodal masses must regress to
extralymphatic mass on 5PS ¶ ≤1.5 cm in LDi
sites It is recognized that in Waldeyer's ring or No extralymphatic sites of disease
extranodal sites with high physiologic uptake
or with activation within spleen or marrow
(eg, with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater
than normal mediastinum and/or liver. In
this circumstance, complete metabolic
response may be inferred if uptake at sites
of initial involvement is no greater than
surrounding normal tissue even if the tissue
has high physiologic uptake.
Nonmeasured Not applicable Absent

lesions
Organ Not applicable Regress to normal

enlargement
New lesions None None
Bone marrow No evidence of FDG-avid disease in marrow Normal by morphology; if indeterminate,

IHC negative
Partial Partial metabolic response Partial remission (all of the following)
Lymph nodes and Score 4 or 5 ¶ with reduced uptake compared ≥50 percent decrease in SPD of up to six
extralymphatic with baseline and residual mass(es) of any target measurable nodes and extranodal
sites size sites
At interim, these findings suggest When a lesion is too small to measure on CT,
responding disease assign 5 mm x 5 mm as the default value
At end of treatment, these findings indicate When no longer visible, 0 x 0 mm
residual disease For a node >5 mm x 5 mm, but smaller than
normal, use actual measurement for
calculation
Nonmeasured Not applicable Absent/normal, regressed, but no increase

lesions
Organ Not applicable Spleen must have regressed by >50

enlargement percent in length beyond normal
Bone marrow Residual uptake higher than uptake in Not applicable

normal marrow but reduced compared with
baseline (diffuse uptake compatible with
reactive changes from chemotherapy
allowed). If there are persistent focal
changes in the marrow in the context of a
nodal response, consideration should be
given to further evaluation with MRI or
biopsy or an interval scan.
No response or No metabolic response Stable disease

stable disease
Target Score 4 or 5 with no significant change in <50 percent decrease from baseline in SPD
nodes/nodal FDG uptake from baseline at interim or end of up to six dominant, measurable nodes
masses, of treatment and extranodal sites; no criteria for
extranodal lesions progressive disease are met
Nonmeasured Not applicable No increase consistent with progression

lesions
Organ Not applicable No increase consistent with progression

enlargement
Bone marrow No change from baseline Not applicable
Progressive disease Progressive metabolic disease Progressive disease requires at least one of
the following
Individual target Score 4 or 5 with an increase in intensity of PPD progression

nodes/nodal uptake from baseline and/or
masses
Extranodal lesions New FDG-avid foci consistent with lymphoma An individual node/lesion must be abnormal
at interim or end-of-treatment assessment with: LDi >1.5 cm and
Increase by ≥50 percent from PPD nadir and
An increase in LDi or SDi from nadir
0.5 cm for lesions ≤2 cm
1.0 cm for lesions >2 cm
In the setting of splenomegaly, the splenic
length must increase by >50 percent of the
extent of its prior increase beyond baseline
(eg, a 15 cm spleen must increase to >16
cm). If no prior splenomegaly, must increase
by at least 2 cm from baseline.
New or recurrent splenomegaly
Nonmeasured None New or clear progression of preexisting

lesions nonmeasured lesions
New lesions New FDG-avid foci consistent with lymphoma Regrowth of previously resolved lesions
rather than another etiology (eg, infection, A new node >1.5 cm in any axis
inflammation). If uncertain regarding
A new extranodal site >1.0 cm in any axis; if
etiology of new lesions, biopsy or interval
<1.0 cm in any axis, its presence must be
scan may be considered
unequivocal and must be attributable to
lymphoma
Assessable disease of any size unequivocally
attributable to lymphoma
Bone marrow New or recurrent FDG-avid foci New or recurrent involvement
5PS: 5-point scale; CT: computed tomography; FDG: fluorodeoxyglucose; IHC: immunohistochemistry; LDi: longest
transverse diameter of a lesion; MRI: magnetic resonance imaging; PET: positron emission tomography; PPD: cross
product of the LDi and perpendicular diameter; SDi: shortest axis perpendicular to the LDi; SPD: sum of the product of
the perpendicular diameters for multiple lesions.
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim
scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as
inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes,
nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be
from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal
lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted
on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease
should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well
as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other
lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver,
bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no
higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid
growth factors).
¶ PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related
to lymphoma.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of
Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2014; 32(27):3059-67. Reprinted with
permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Contributor Disclosures
Jon C Aster, MD Consultant/Advisory Boards: Regeneron [Hematologic malignancies (Notch inhibitors)];
Lilly [Hematologic malignancies (Notch inhibitors)]; Cellestia [Hematologic malignancies (Notch inhibitors)];
Anastasis [Hematologic malignancies (Notch inhibitors)]. Equity Ownership/Stock Options: Cellestia;
Anastasis. Jennifer R Brown, MD, PhD Consultant/Advisory Boards: Pharmacyclics, Infinity, Janssen,
Celgene, Roche/Genentech, Gilead [CLL (ibrutinib, IPI-145, lenalidomide, obinutuzumab, idelalisib)]; Abbvie
(venetoclax); Astra-Zeneca (acalabrutinib). Nikhil C Munshi, MD Consultant/Advisory Boards: Janssen
[Castleman's disease (siltuximab)]. Arnold S Freedman, MD Consultant/Advisory Boards: Kahr
Therapeutics [SAB]. Other Financial Interest: Novartis [DMB (Ofatumumab)]; Bayer [DMB (Bayer
17833)]. Rebecca F Connor, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
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12/10/2017 Multicentric Castleman's disease - UpToDate

Official reprint from UpToDate®

Multicentric Castleman's disease

INTRODUCTION — Castleman's disease (CD, angiofollicular lymph node hyperplasia) is a heterogenous

● Nadir CD4 count >200/microL

● Fever – 100 percent

● Hyaline vascular variant (picture 1)

● HHV8-negative plasma cell variant (picture 2)

● HHV8-positive plasma cell variant (picture 3)

● A multicenter, randomized, double-blind, phase II trial of siltuximab in 79 patients with symptomatic

• Durable symptomatic response (57 versus 19 percent).

● Non-Hodgkin lymphoma – Non-Hodgkin lymphoma (NHL) is significantly associated with MCD.

POEMS syndrome — MCD could be a component of another well-described constellation of symptoms,

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

1. CASTLEMAN B, IVERSON L, MENENDEZ VP. Localized mediastinal lymphnode hyperplasia

Topic 4707 Version 37.0

Multicentric Castleman's disease

Courtesy of Priscilla J Slanetz, MD, MPH, FACR.

Graphic 87767 Version 2.0

Pathologic features of hyaline-vascular variant Castleman's

Graphic 90402 Version 4.0

Pathologic features of HHV8 negative plasma cell variant

(A) Reactive lymphoid follicles and interfollicular plasmacytosis are present.

Reproduced with permission from: Castleman lymphadenopathy. In: Ioachim's Lymph

Graphic 90404 Version 4.0

Pathologic features of HHV8 positive plasma cell variant

Graphic 90403 Version 4.0

Consensus diagnostic criteria for idiopathic multicentric Castleman disease

I. Major criteria (need both)

Sheetlike, polytypic plasmacytosis in the interfollicular space

2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations

1. Elevated CRP (>10 mg/L) or ESR (>15 mm/hour) ¶

4. Hypoalbuminemia (albumin <3.5 g/dL)

6. Polyclonal hypergammaglobulinemia (total gamma-globulin or immunoglobulin G >1700 mg/dL)

2. Large spleen and/or liver

3. Fluid accumulation: Edema, anasarca, ascites, or pleural effusion

4. Eruptive cherry hemangiomatosis or violaceous papules

5. Lymphocytic interstitial pneumonitis

2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV

Autoimmune/autoinflammatory diseases (requires full clinical criteria, detection of autoimmune

1. Systemic lupus erythematosus

3. Adult-onset Still disease

4. Juvenile idiopathic arthritis

5. Autoimmune lymphoproliferative syndrome

Malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same

1. Lymphoma (Hodgkin and non-Hodgkin)

3. Primary lymph node plasmacytoma

Elevated IL-6, sIL-2R, VEGF, IgA, IgE, LDH, and/or B2M

Reticulin fibrosis of bone marrow (particularly in patients with TAFRO syndrome)

Graphic 112477 Version 1.0

Pretreatment evaluation in patients with Castleman's disease

Investigation Common findings

Complete blood count Anemia, thrombocytosis

Serum chemistry Hypoalbuminemia, elevated lactate dehydrogenase

Acute phase reactants Elevated ESR, CRP, ferritin, and fibrinogen

Serological investigations for autoimmune disorders: Variable

Imaging: PET/CT Initially to detect any other area of lymph node

Graphic 93417 Version 1.0

Lugano criteria for response assessment in lymphoma

Complete Complete metabolic response Complete radiologic response (all of the

Nonmeasured Not applicable Absent

Organ Not applicable Regress to normal

New lesions None None