HHV-8-negative/idiopathic multicentric Castleman disease

INTRODUCTION — 

Castleman disease (CD, angiofollicular lymph node hyperplasia) describes a heterogeneous group of lymphoproliferative disorders that share common histopathologic features.

CD is classified into at least three distinct disorders that have varying clinical features, treatments, and outcomes. Classification is based on the number of regions of enlarged lymph nodes with characteristic histopathologic features and the presence/absence of human herpesvirus 8 (HHV-8, also called Kaposi sarcoma-associated herpesvirus [KSHV]) infection.

●Unicentric CD (UCD) involves one or more enlarged lymph node(s) in a single region of the body that demonstrates histopathologic features consistent with CD. A subset of patients have systemic symptoms.

●Multicentric CD (MCD) involves multiple regions of lymphadenopathy that demonstrate histopathologic features consistent with CD. These patients also have systemic inflammatory symptoms with generalized lymphadenopathy, hepatosplenomegaly, cytopenias, and organ dysfunction due to excessive proinflammatory hypercytokinemia, often including interleukin (IL)-6. MCD is further subclassified according to the presence of HHV-8 into HHV-8-associated MCD and idiopathic MCD (HHV-8-negative MCD).

Emerging evidence suggests that some patients with CD do not meet the criteria for UCD or MCD. The term "oligocentric CD" has been proposed for patients who have enlarged lymph nodes in two to three adjacent lymph node stations but do not meet the laboratory and clinical minor criteria required to diagnose idiopathic MCD. More research is needed, but clinical manifestations and treatment approaches for oligocentric CD appear to be more similar to UCD than MCD.

This topic review will discuss the epidemiology, pathogenesis, clinical features, pathologic features, diagnosis, and treatment of HHV-8-negative/idiopathic MCD. The diagnosis and treatment of UCD, oligocentric CD, and HHV-8-associated MCD are presented separately.

●(See "HHV-8/KSHV-associated multicentric Castleman disease".)

●(See "Unicentric Castleman disease".)

CLASSIFICATION OF CD — 

Classification of CD into the appropriate subtype at diagnosis is essential to assess prognosis and treat patients. Classification is based on the number of regions of enlarged lymph nodes with characteristic histopathologic features, the presence/absence of human herpesvirus 8 (HHV-8, also called Kaposi sarcoma-associated herpesvirus [KSHV]) infection, and the presence/absence of co-occurring POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome or TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) syndrome [1,2].

●Unicentric CD (UCD) involves one or more enlarged lymph node(s) in a single region of the body that demonstrates histopathologic features consistent with CD that lie along a spectrum with hyaline vascular histopathologic subtype on one end, plasmacytic histopathologic subtype on the other, and a "mixed" subtype in the middle. A subset of patients have systemic symptoms. (See "Unicentric Castleman disease".)

●MCD involves multiple regions of lymphadenopathy that demonstrate histopathologic features consistent with CD that lie along a spectrum with hypervascular histopathologic subtype on one end, plasmacytic histopathologic subtype on the other, and a "mixed" subtype in the middle. These patients also have systemic inflammatory symptoms with generalized lymphadenopathy, hepatosplenomegaly, cytopenias, and organ dysfunction due to excessive pro-inflammatory hypercytokinemia, often including interleukin (IL)-6. MCD is further subclassified according to the presence of HHV-8:

•HHV-8-associated MCD – Approximately one-half of MCD cases are caused by HHV-8 infection in human immunodeficiency virus (HIV)-positive or otherwise immunocompromised individuals, and these cases are referred to as HHV-8-associated MCD. (See "HHV-8/KSHV-associated multicentric Castleman disease".)

•HHV-8-negative/iMCD – Approximately one-half of patients with MCD are HHV-8-negative. These cases have nearly identical clinical and histopathologic features as HHV-8-associated MCD, but there is no evidence of the HHV-8 virus, and the etiology is unknown. These cases are referred to as HHV-8-negative MCD, iMCD. HHV-8-negative/iMCD is further categorized based on the presence/absence of co-occurring POEMS syndrome or TAFRO syndrome.

-POEMS-associated MCD – POEMS is a paraneoplastic syndrome that often co-occurs with MCD. Monoclonal plasma cells that have undergone genomic events, such as translocations or deletions, are thought to cause both the POEMS syndrome and the MCD due to excess cytokine production. Nearly all POEMS cases are lambda light chain restricted. These patients should receive POEMS-directed therapy. (See "POEMS syndrome".)

-iMCD-TAFRO syndrome – TAFRO often occurs in patients with iMCD. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathologic features and normal gamma globulin levels. The etiology and pathologic cell types are completely unknown. (See 'iMCD-TAFRO syndrome' below.)

-iMCD-idiopathic plasmacytic lymphadenopathy (iMCD-IPL) – Among patients with iMCD who do not have TAFRO syndrome, some patients have thrombocytosis, hypergammaglobulinemia, and mixed or plasmacytic histopathologic features. These patients have been referred to as iMCD-IPL. The etiology and pathologic cell types are completely unknown.

-iMCD-not otherwise specified (iMCD-NOS) – Patients with iMCD who do not have POEMS syndrome, TAFRO subtype, or iMCD-IPL are considered iMCD-NOS. These patients have laboratory abnormalities that fall between iMCD-TAFRO and iMCD-IPL. The etiology and pathologic cell types are completely unknown.

●Oligocentric CD is a proposed subclassification that falls between UCD and MCD for patients who have enlarged lymph nodes in two to three adjacent lymph node stations but do not meet the laboratory and clinical minor criteria required to diagnose iMCD. Data regarding this subtype are limited, but initial studies suggest that the clinical manifestations and treatment approaches for oligocentric CD appear to be more similar to UCD than MCD.

ETIOLOGY AND PATHOGENESIS

Potential etiologic drivers — While the etiology and pathogenesis of HHV-8-associated MCD are well understood to be directly caused by uncontrolled infection with HHV-8, the etiology of HHV-8-negative/iMCD is poorly understood. The clinical and pathologic abnormalities are heterogeneous and overlap with a wide range of other immunologic disorders, suggesting that multiple processes may give rise to iMCD, each involving immune dysregulation and a common pathway of increased cytokines [3].

Proposed mechanisms include autoimmune, autoinflammatory, neoplastic, and infectious. Research suggests that an acute infectious or viral etiology is unlikely [4]. Growing evidence points to autoimmune mechanisms and potential genomic alterations contributing to pathogenesis [5-13]. In-depth investigation into each of these hypothesized etiologies is underway.

Role of interleukin 6 and other cytokines — iMCD is a cytokine storm disorder characterized by elevated circulating cytokine levels, cytokine-driven organ dysfunction, and acute systemic inflammatory symptoms in the absence of an identifiable causative pathogen [14]. Many cases are driven by interleukin (IL)-6, while others are likely driven by other not yet identified cytokines or soluble factors.

Although the precise cells responsible for IL-6 production have remained elusive [15], it is clear from human and animal studies that IL-6 is necessary and sufficient to drive iMCD symptomatology, histopathology, and pathogenesis in a portion of patients. IL-6 is a multifunctional cytokine involved in a wide range of activities, including plasmacytosis, hypergammaglobulinemia, thrombocytosis, acute-phase protein production by the liver, and activation of macrophages and T cells [16]. In many patients, clinical symptoms of iMCD wax and wane with IL-6 levels, which can be highly elevated during disease flares [17]. In addition, interruption of IL-6 signaling with anti-IL-6 or anti-IL-6R mAb is effective at ameliorating symptoms and shrinking lymph nodes in a substantial portion of patients [5,18,19].

Some cases appear to be driven by other factors. In fact, some patients have undetectable IL-6 levels during flares [20]. In addition, more than one-half of patients with iMCD in the randomized controlled study of anti-IL-6 mAb did not respond to siltuximab treatment, approximately one-half of whom did not have elevated IL-6 levels [21].

Therefore, it is likely that other cytokines or soluble factors drive iMCD pathogenesis in such cases. It is essential to uncover these mechanisms to use as targets for the treatment of patients with iMCD who do not respond to anti-IL-6 therapy.

Other pathogenic mechanisms — Translational studies have uncovered several additional pathogenic mechanisms in iMCD, including:

●Mechanistic target of rapamycin (mTOR) – mTOR is a regulator of vascular endothelial growth factor (VEGF) expression, T cell activation, and cellular proliferation. Evidence points toward increased mTOR pathway activation in patients with iMCD relative to controls [12]. In one report, three patients with multiply refractory iMCD-TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) that was refractory anti-IL-6 therapy, experienced prolonged remission on the mTOR inhibitor sirolimus [22]. Clinical trials are evaluating sirolimus as a therapy for patients with anti-IL-6-refractory iMCD (NCT0393904).

●Janus kinase (JAK) – JAK tyrosine kinases (JAK1, JAK2) are key regulators of cell proliferation and activation downstream of the receptors for IL-6 and a number of other cytokines. JAK1 and JAK2 lead to activation of mTOR and STAT3, two pathways reported to be involved in iMCD pathogenesis [23].

●IL-1b – IL-1b inhibition has been effective in a few case reports, including two patients with iMCD refractory to anti-IL-6 therapy [24,25]. IL-1b is upstream of IL-6 and VEGF in the inflammatory cascade and leads to IL-6 production through NF-kB activation.

●CXCL13 – CXCL13 is a chemokine that directs migration of B cells in lymph nodes. Evidence suggests that dysregulation of CXCL13 may play a role in iMCD pathogenesis. A proteomic analysis of flare and remission serum samples from six patients with iMCD found marked elevation of CXCL13 during flare across all patients [26]. Further studies are needed to confirm and further characterize the implications of this finding.

Regardless of the cause, excessive activation of inflammatory pathways in immune cells leads to histopathologic changes in the lymph node and systemic symptoms observed in iMCD. It is essential to uncover mechanisms to target for the treatment of patients with iMCD who do not respond to anti-IL-6 therapy.

EPIDEMIOLOGY — 

In the United States, the annual incidence of CD is poorly understood but has been estimated to range from approximately 7000 in a 2014 study to approximately 2000 in a 2022 study that utilized ICD-10 codes from insurance claims data [27,28]. In the 2014 study, approximately 75 percent were estimated to be unicentric CD and the remaining 25 percent were estimated to be split between HHV-8-associated MCD or HHV-8-negative/iMCD. The 2022 study estimated that approximately 50 percent of incident CD cases are iMCD.

In Japan, the incidence appears to be similar to that seen in the United States; however, by contrast with data from other countries and for unclear reasons, MCD appears to be more common than unicentric CD, and HHV-8-associated MCD is rare [29,30]. There is less published information regarding the incidence in other areas, but communication among the international community of CD physicians suggests no clear associations with particular ethnicities. Now that there is a unique ICD-10 code for CD (D47.Z2), more accurate estimations of epidemiology are expected.

Patients with iMCD can present at any age, including during childhood, but patients typically present in adulthood [6,31-42]. Fifty to 65 percent are male.

No trends have been detected in incidence among iMCD cases.

CLINICAL FEATURES — 

Patients with MCD present with lymphadenopathy in multiple lymph node regions [31,32,34,43]. Nearly all patients present with fever and other nonspecific symptoms suggestive of an inflammatory illness, including night sweats, weight loss, weakness, and fatigue [44,45]. Other symptoms include hepatosplenomegaly, cytopenias, organ dysfunction, and skin findings such as rash, hemangiomata, and pemphigus [46,47]. 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 [34,48].

While there are some signs, symptoms, and laboratory findings in common, different subtypes of iMCD can demonstrate quite heterogeneous clinical features and laboratory features, as described in the following sections.

Common signs, symptoms, and laboratory features — A systematic review that included 127 patients with iMCD reported the following systemic symptoms [5]:

●Fever – 26 to 52 percent

●Night sweats – 62 percent

●Unintended weight loss – 16 to 72 percent

●Enlarged liver or spleen – 41 to 78 percent

●Edema (swelling), ascites (fluid accumulation in the abdomen), and/or other symptoms of fluid overload – 23 to 78 percent

Other symptoms included loss of appetite, nausea, and vomiting; severe abdominal pain; weakness and fatigue; peripheral neuropathy (numbness in the hands and feet); decreased urine output and symptoms of systemic toxicity due to kidney failure; bruising, easy bleeding, and risk of infection due to bone marrow failure; and eruption of cherry hemangiomas (benign proliferations of blood vessels) on the skin. Neuropathy seen in patients with iMCD is variable and can range from mild sensory neuropathy to the severe sensory and motor neuropathy of POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes)-associated MCD [49].

In the same study, the following abnormal laboratory values were noted [5]:

●Elevated erythrocyte sedimentation rate (ESR) – 34 to 92 percent

●Elevated C-reactive protein (CRP) – 51 to 82 percent

●Low hemoglobin (anemia) – 62 to 87 percent

●Low platelet count (thrombocytopenia) – 22 to 44 percent

●Elevated creatinine and/or blood urea nitrogen (BUN), proteinuria – 9 to 71 percent

●Low albumin – 45 to 90 percent

●Elevated interleukin (IL)-6 – 45 to 90 percent

●Elevated vascular endothelial growth factor (VEGF) – 13 to 80 percent

●Positive Coombs test – 9 to 71 percent

●Positive antinuclear antibody (ANA test) – 12 to 37 percent

●Hypergammaglobulinemia – 49 to 77 percent

Other notable laboratory features included elevated fibrinogen and the presence of autoimmune antibodies (eg, antierythrocyte autoantibodies and antiplatelet autoantibodies).

POEMS-associated MCD — MCD can co-occur with POEMS, a paraneoplastic syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, a monoclonal immunoglobulin spike, and skin changes such as hypertrichosis, acrocyanosis and plethora, hemangioma/telangiectasia, thickening, or hyperpigmentation [50]. CD is a major criterion in the diagnosis of POEMS syndrome (table 1).

The diagnosis of POEMS syndrome in a patient with MCD requires both polyneuropathy and monoclonal plasma cell proliferative disorder (positive M protein, almost always lambda) along with at least one of the following (see "POEMS syndrome"):

●Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)

●Extravascular volume overload (edema, pleural effusion, or ascites)

●Endocrinopathy (adrenal, pituitary, gonadal, parathyroid, thyroid and pancreatic)

●Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails)

●Papilledema

●Thrombocytosis or polycythemia

Patients also experience sclerotic bone lesions, extravascular fluid accumulation (edema, pleural effusion, ascites), papilledema, clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, and diarrhea.

In POEMS-associated MCD, typical laboratory abnormalities include a monoclonal (M) protein on serum protein electrophoresis, increased VEGF, thrombocytosis, polycythemia, low vitamin B12 levels, and abnormal endocrine laboratory tests (increased prolactin, hypothyroidism).

iMCD-TAFRO syndrome — iMCD cases with TAFRO (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly) often have an acute, critical clinical course [51-53]. The median time from symptom onset to lymph node biopsy is six weeks, which is shorter than other forms of iMCD [51].

Diagnosing iMCD-TAFRO requires pathology-confirmed iMCD as well as four of the following major criteria along with at least one minor criterion [54].

Major criteria include:

●Anasarca (pleural effusion, ascites, and generalized edema)

●Thrombocytopenia (≤100,000/microL)

●Systemic inflammation (fever of unknown etiology above 37.5°C and/or serum CRP concentration ≥2 mg/dL)

●Organomegaly (hepatomegaly, splenomegaly, or lymphadenopathy)

Minor criteria include (need at least one):

●Reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow

●Renal insufficiency

Patients with iMCD-TAFRO often have smaller lymph nodes than the other subtypes of iMCD [51,54-56]. Occasionally these enlarged lymph nodes are painful [51,55]. Patients with iMCD-TAFRO often exhibit:

●Fever without obvious infection (61 to 84 percent)

●Severe anasarca with massive pleural effusions and/or ascites (96 to 100 percent)

●Organomegaly (89 to 100 percent)

●Abdominal pain at disease onset (32 percent)

Typical laboratory abnormalities include severe thrombocytopenia; normal to mildly elevated gamma globulin levels; elevated alkaline phosphatase levels typically without corresponding elevations in transaminase levels; anemia; hypoalbuminemia; and elevated levels of CRP, sIL2R, and creatinine, which can represent progressive acute kidney failure that requires transient hemodialysis. Serum lactate dehydrogenase (LDH) levels are not often elevated in iMCD-TAFRO [51,55].

Autoantibodies, such as ANA, red blood cell antibodies (Coombs), and antiplatelet antibodies are often present. iMCD-TAFRO may co-occur with autoimmune disorders, including autoimmune hemolytic anemia, immune thrombocytopenia (ITP), and acquired factor VIII deficiency. Autoimmunity-related symptoms, including arthritis, renal dysfunction, and proteinuria, are more often observed in iMCD than HHV-8-associated MCD or unicentric Castleman disease (UCD).

iMCD-IPL — The term iMCD-idiopathic plasmacytic lymphadenopathy (iMCD-IPL) is used for patients without TAFRO syndrome who have thrombocytosis, hypergammaglobulinemia, and mixed or plasmacytic histopathologic features [57]. The etiology and pathologic cell types are unknown [51].

Though hepatosplenomegaly and fluid accumulation can occur in iMCD-IPL, they are less intense than in iMCD-TAFRO. Lymphocytic interstitial pneumonitis and violaceous papules with lymphoplasmacytic infiltrate may be present in iMCD-IPL. An uncommon presentation of iMCD in young adults includes perioral pemphigus and idiopathic pulmonary fibrosis and is associated with a poor outcome.

Typical laboratory abnormalities in iMCD-IPL include:

●Thrombocytosis (required)

●Polyclonal hypergammaglobulinemia with negative immunofixation and no monoclonal spike (required)

●Anemia

●Hypoalbuminemia

●Elevated total protein, LDH, IL-6, VEGF, CRP, ferritin, and fibrinogen

iMCD not otherwise specified — Patients with HHV8-negative MCD who do not have POEMS syndrome, the TAFRO subtype, or iMCD-IPL are considered to have iMCD, not otherwise specified (iMCD-NOS) [57]. These patients often have constitutional symptoms, cytopenias, and organ dysfunction but do not fit into either iMCD-TAFRO or iMCD-IPL [51]. iMCD-IPL and iMCD-NOS both tend to have more of a chronic inflammatory presentation than iMCD-TAFRO, which is acute and life-threatening.

Though hepatosplenomegaly and fluid accumulation can occur in iMCD-NOS, they are less intense than in iMCD-TAFRO. Lymphocytic interstitial pneumonitis and violaceous papules with lymphoplasmacytic infiltrate may be present in iMCD-NOS. An uncommon presentation of iMCD in young adults includes perioral pemphigus and idiopathic pulmonary fibrosis and is associated with a poor outcome.

Typical laboratory abnormalities in iMCD-NOS include:

●Anemia

●Mild thrombocytopenia or thrombocytosis

●Mild polyclonal hypergammaglobulinemia with negative immunofixation and no monoclonal spike (not co-occurring with thrombocytosis as that would be iMCD-IPL)

●Hypoalbuminemia

●Elevated total protein, LDH, IL-6, VEGF, CRP, ferritin, and fibrinogen

We are also aware of patients with only two regions of enlarged lymph node stations in neighboring areas and mild symptoms. These cases typically can demonstrate features like UCD and iMCD and may warrant a new disease subtype of "oligocentric" or "regional" CD. The lymphadenopathy in these cases is generally confined to either above or below the diaphragm. Often such cases are managed similarly to UCD but they are often not surgically resectable [58]. Further data are needed to better characterize this overlap syndrome and determine the best treatment approach. (See "Unicentric Castleman disease".)

Imaging — Imaging findings are nonspecific but may include the following:

●Chest radiograph – The chest radiograph may show bilateral reticular or ground glass opacities, mediastinal widening, and/or bilateral pleural effusions [59]. Less commonly, lung nodules or rounded areas of consolidation are seen.

●Computed tomography (CT) of the chest – On CT of the chest, most patients have multiple enlarged mediastinal and hilar lymph nodes (1 to 3 cm diameter) [59,60]. 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) – iMCD is ¹⁸F-fluorodeoxyglucose (FDG)-PET avid, usually with a relatively low standardized uptake value (SUV; 2.5 to 8). High SUVs (eg, >8) are uncommon and should raise the suspicion of alternative diagnoses (eg, lymphoma). SUV may also differ by subtype. As an example, uptake of FDG in the enlarged lymph nodes is only slightly elevated in iMCD-TAFRO [61].

PATHOLOGY — 

HHV-8-negative/iMCD is characterized by enlarged lymph nodes with histopathologic features consistent with CD that exist across a spectrum. These nodal expansions usually leave the structure of the underlying lymph node intact. B cells and plasma cells are polyclonal, and T cells show no evidence of an aberrant immunophenotype.

The mantle zone lymphocytes in all histopathologic subtypes are polyclonal immunoglobulin (Ig)M- or IgD-expressing cells [48,62]. The plasma cells in the interfollicular areas are generally also polyclonal. Localized clonal expansions are sometimes seen [63-65] but do not appear to affect prognosis [63,66,67].

Three histopathologic subtypes are recognized for iMCD [44,45], though the clinical utility of distinguishing these histologic subtypes is unknown [68]. These subtypes are thought to lie along a spectrum, with hypervascular histopathology on one end, plasmacytic histopathology on the other end, and a mixed subtype in between:

●The hypervascular histopathologic subtype of iMCD (previously referred to as hyaline vascular, which is now reserved only to describe unicentric CD [UCD]) – This subtype is characterized by the following lymph node features:

•Small, regressed, or atrophic germinal centers – There are increased numbers of follicles that vary in size from hyperplastic to regressed. Most germinal centers are regressed and depleted of lymphocytes.

•"Onion-skin appearance" of the mantle zone around the germinal centers – The follicles are surrounded by prominent/widened mantle zones containing small lymphocytes arranged in a concentric fashion.

•Prominent follicular dendritic cells (FDCs) – The regressed germinal centers are depleted of lymphocytes and mainly consist of a prominent population of FDCs.

•"Lollipop appearance" – Blood vessels radially penetrate atrophic germinal centers.

•Increased vascularity, most notably of high endothelial venules in interfollicular zones – The interfollicular lymphoid tissue contains numerous small blood vessels known as high endothelial venules that are lined by plump, activated endothelial cells.

•Patent sinuses with no architectural disruption.

The hypervascular histopathologic subtype of iMCD and hyaline vascular histopathologic subtype of UCD have overlapping features (eg, "onion-skin" and "lollipop" appearances), but the hypervascular subtype does not typically demonstrate twinning, FDC dysplasia, hyalinized sclerotic vessels, obliterated sinuses/architectural disruption, or aggregates of plasmacytoid dendritic cells. Therefore, hypervascular was proposed to replace hyaline vascular when describing iMCD, and hyaline vascular is reserved only when there is a solitary, UCD lymph node. (See "Unicentric Castleman disease", section on 'Pathology'.)

●The plasmacytic histopathologic subtype of iMCD – This subtype is identical to the plasmacytic histopathologic subtype of UCD and characterized by the following lymph node features:

•Interfollicular plasmacytosis – The interfollicular region is hypervascular and contains sheets of plasma cells.

•Hyperplastic germinal centers – The germinal centers are primarily hyperplastic (unlike the regressed germinal centers in hypervascular histopathologic subtype). They can also have typical reactive features, including polarization into light and dark zones, frequent mitotic figures, and numerous macrophages containing apoptotic debris (tingible body macrophages).

•Follicle size variability – Abnormally enlarged or hyperplastic germinal centers are often present along with some regressed or "hypervascular"/"hyaline vascular"-like follicles in the same lymph node.

•Increased vascularity, most notably of high endothelial venules in interfollicular zones – The interfollicular lymphoid tissue contains numerous small blood vessels known as high endothelial venules that are lined by plump, activated endothelial cells.

•Patent sinuses with no architectural disruption.

●Mixed variant histopathologic subtype of iMCD – This subtype is characterized by a mix of hypervascular (predominantly regressed germinal centers) and plasmacytic (hyperplastic germinal centers and interfollicular plasmacytosis) features in the same lymph node.

The clinical utility of these histopathologic subtypes is not clear. Patients with iMCD-idiopathic plasmacytic lymphadenopathy (IPL) often have mixed or plasmacytic histopathologic features [51], and hypervascular pathology is often seen among patients with iMCD-TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) [69]. However, histopathologic subtypes should not be used to guide iMCD subtype classification or treatment. Transitions between histopathologic subtypes on subsequent biopsies in the same patient have been reported in iMCD as well as the simultaneous presence of different histopathologic subtypes at separate sites within the same patient.

Findings on bone marrow biopsy may inform the diagnosis of iMCD; however, more research is needed as the findings are relatively nonspecific and can be seen in various other infectious, malignant, and autoimmune diseases. In one study of 24 patients with iMCD, common bone marrow findings included hypercellularity (58 percent), megakaryocytic atypia (54 percent), reticulin fibrosis (60 percent), and plasmacytosis (50 percent) [70]. By contrast to the bone marrow in patients with iMCD (which included iMCD, not otherwise specified [NOS] and iMCD-IPL), the bone marrow of patients with iMCD-TAFRO had more megakaryocytic hyperplasia (70 versus 0 percent). These findings were consistent with the bone marrow findings in other published cases of iMCD-NOS and iMCD-TAFRO.

DIAGNOSIS

Evaluation — The diagnosis of HHV-8-negative/iMCD should be suspected in patients presenting with peripheral lymphadenopathy, constitutional symptoms, and an elevated C-reactive protein. Whole-body CT with fluorodeoxyglucose (FDG) positron emission tomography (PET) should demonstrate multiple regions of enlarged lymph nodes, usually with a relatively low standardized uptake value (SUV; 2.5 to 8).

The diagnosis of iMCD requires a pathologic review of an excisional biopsy of a lymph node. The most enlarged or FDG-avid node should be selected for biopsy. If no single node predominates, the choice should be made based on accessibility (peripheral is more accessible than visceral). The pathologic review of the lymph node should evaluate for pathologic features described above. (See 'Pathology' above.)

Once CD-like histopathology is identified, immunohistochemical staining of the patient's lymph node for latency-associated nuclear antigen-1 (LANA-1) should be performed to determine whether the patient has HHV-8-associated MCD or iMCD. Repeat biopsies may be necessary to confirm the diagnosis if an initial biopsy fails to confirm the diagnosis and the clinical suspicion remains high.

The evaluation must exclude other disorders that can demonstrate iMCD-like histopathologic lymph node features, such as Hodgkin lymphoma, rheumatoid arthritis, other connective tissue diseases, and HIV infection (table 2). This includes IgH gene rearrangement studies to evaluate for a clonal B cell disorder. This is discussed in more detail separately. (See "Unicentric Castleman disease", section on 'Differential diagnosis'.)

A lymph node biopsy displaying characteristic histopathologic features is required to diagnose CD. However, it may be difficult to identify resectable lymph nodes for biopsy in patients with a suspected diagnosis. In very rare cases, empiric treatment may be considered in critically ill patients with multicentric lymphadenopathy and minor criteria for iMCD when all other disease mimickers have been excluded.

Diagnostic criteria — Diagnostic criteria for iMCD have been established by an international working group of pediatric and adult pathology and clinical experts and are shown in the table (table 2) [44]. The proposed consensus criteria require characteristic histopathologic findings on lymph node biopsy, enlargement of multiple lymph node regions, the presence of multiple clinical and laboratory abnormalities, and the exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. (See 'Pathology' above.)

PRETREATMENT EVALUATION

Evaluation — Once the diagnosis of HHV-8-negative/iMCD has been established based on clinical features and pathologic evaluation of a lymph node, a pretreatment evaluation provides a baseline of disease activity and assessment of comorbidities that may impact treatment decisions. 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:

●Complete blood count with differential; liver and renal function chemistries, electrolytes, lactate dehydrogenase (LDH), and albumin.

●Viral testing for hepatitis B, HHV-8 (polymerase chain reaction [PCR] of serum during acute symptoms), and HIV, with quantitative assays if positive.

●Serum protein electrophoresis with immunofixation, free light chains, and quantitative immunoglobulins.

●Testing for acute phase reactants, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and fibrinogen is important in all cases. In some cases, measurement of serum interleukin (IL)-6, soluble IL-2 receptor, and vascular endothelial growth factor (VEGF) along with a panel of other proinflammatory cytokines may help guide management and assess response to therapies, when available. Of note, serum/plasma IL-6 measurements should not be performed or used to guide therapy for at least 18 to 24 months after the last dose of siltuximab or tocilizumab. We are aware of cases where a spuriously elevated IL-6 level due to recent siltuximab use was interpreted incorrectly as indicating a relapse [71].

●Serologic investigations for autoimmune disorders, such as antinuclear antibody (ANA test), rheumatoid factor, SS-A, SS-B, and anti-dsDNA are performed if suspected clinically.

Imaging with a combined whole-body ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with contrast-enhanced CT is performed to detect all areas of lymph node involvement and to document the standardized uptake value (SUV) of involved areas. CT of the neck, chest, abdomen, and pelvis may be used as an alternative if FDG PET/CT is not readily available. (See 'Imaging' above.)

Assess disease severity — A more aggressive treatment approach is used for patients with iMCD who are described as "severe" and present with poor performance status thought to be due to the iMCD or who develop life-threatening complications such as respiratory failure, kidney failure, liver failure, and/or pancytopenia. We and others consider patients with any two of the following five features to have severe disease requiring close monitoring and more aggressive therapy [72]:

●Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (table 3)

●Estimated glomerular filtration rate <30 or creatinine >3

●Anasarca, ascites, pleural effusion, and/or pericardial effusion

●Hemoglobin ≤8 g/dL

●Pulmonary involvement or interstitial pneumonitis with dyspnea

TREATMENT OF MCD WITH POEMS SYNDROME — 

Our management of patients with MCD with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (table 1)) syndrome is focused on treating the POEMS syndrome. The MCD is considered to be a secondary finding in these cases and traditional iMCD-directed treatments are typically ineffective in these cases. (See "POEMS syndrome".)

TREATMENT OF iMCD WITHOUT POEMS SYNDROME — 

There are limited data regarding the treatment of iMCD without POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome. Clinical practice varies between centers, and the approach described below reflects our practice and is generally consistent with guidelines from an international group of adult and pediatric iMCD experts from the Castleman Disease Collaborative Network (CDCN) [72] and the National Comprehensive Cancer Network (NCCN) [73]. Treatment consistent with these guidelines is associated with improved outcomes [74]. We believe there is insufficient evidence to use the histopathologic subtype to guide treatment decisions in iMCD [68]. We encourage patients to enroll themselves directly on the ACCELERATE Natural History Study, which collects data on clinical features, treatments, and treatment efficacy. There is a paucity of interventional clinical trials.

Interleukin (IL)-6 inhibitor-based therapy (siltuximab or tocilizumab) with or without glucocorticoids is the preferred initial therapy for patients with iMCD. In patients with severe disease who are not responding to IL-6 inhibitor-based therapy and experiencing progressive organ dysfunction, we add combination chemotherapy. In patients with mild to moderate disease who are not responding to IL-6 inhibitor-based therapy, we suggest rituximab plus glucocorticoids with or without an immunomodulator/immunosuppressant rather than cytotoxic chemotherapy. While surgical removal of lymph nodes is curative in unicentric CD, it does not have a role in the treatment of iMCD [40]. Likewise, while radiation therapy may be used for the treatment of iMCD with POEMS syndrome, there is no role for radiation therapy in iMCD without POEMS syndrome.

IL-6 inhibitor-based therapy

Use in severe disease — Treatment of iMCD without POEMS syndrome and with life-threatening organ failure or poor performance status thought to be due to the iMCD is complicated, and coordination with an expert in iMCD is advised. For such patients, we suggest (algorithm 1):

●Initial treatment with siltuximab plus high-dose glucocorticoids (eg, methylprednisolone 500 mg daily).

•Siltuximab is preferred based on its benefit in the only randomized trial and its approval in the United States and Europe for this purpose. If siltuximab is not available, tocilizumab is an acceptable alternative. (See 'Efficacy' below.)

•We offer high-dose glucocorticoids with the goal of decreasing the time to symptom control. This is consistent with guidelines from the CDCN [72]. By contrast, NCCN guidelines suggest single-agent siltuximab [73]. Approximately 50 percent of patients will respond to siltuximab with or without glucocorticoids, although studies have not directly assessed the value of adding glucocorticoids to siltuximab. Single-agent glucocorticoids should not be used for iMCD as they offer only mild symptomatic improvement with very low response rates [5,51,74,75].

•Aggressive monitoring and treatment should be continued even in the setting of multiorgan failure and ventilator support because critically ill patients with iMCD can have dramatic responses and durable remissions following IL-6 blockade and/or cytotoxic chemotherapy.

•Accelerated dosing of siltuximab at weekly intervals is used while the patient is experiencing severe disease [72].

●Response is assessed daily using clinical features and laboratory studies (C-reactive protein [CRP], complete blood count [CBC], particularly hemoglobin and platelet counts, albumin, biochemical profile, particularly creatinine, and liver function tests).

●This initial treatment is continued as long as the clinical status is stable or improving. If clinical and laboratory values normalize, glucocorticoids are tapered, and single-agent siltuximab is administered every three weeks to maintain remission. Siltuximab is given until disease progression or continued indefinitely (as indicated on the label) if worsening/disease progression does not occur. Although trials have not studied the duration of therapy, symptoms can recur once therapy is discontinued [3,76].

Some physicians and patients are interested in spacing out doses or discontinuing siltuximab after improvement. In our experience, some patients can successfully spread out siltuximab dosing with close laboratory monitoring. By contrast, we do not advise discontinuing therapy as it can lead to relapse. When considering adjustments to siltuximab frequency, it is important that the physician and patient consider the risk of relapse based on the disease severity at presentation and iMCD subtype.

●If the patient's organ (liver, kidney, pulmonary) function worsens at any time, we add multiagent systemic chemotherapy. In our experience, aggressive multiagent chemotherapy is effective even in the setting of multiorgan failure, ventilator support, and signs consistent with imminent death, resulting in stabilization, followed by improved status and long-term remission.

The optimal systemic chemotherapy approach has not been determined, but cyclophosphamide-based regimens with or without etoposide, rituximab, and/or doxorubicin have been shown to be effective. (See 'Options for refractory disease' below.)

If clinical and laboratory values normalize, we select a maintenance regimen based on whether the iMCD is likely to be sensitive to siltuximab. If the patient received three or more doses of siltuximab before the chemotherapy was started, the iMCD is siltuximab refractory, and other immunomodulators should be used in maintenance. If fewer than three doses of siltuximab were given before the chemotherapy was started, then it is reasonable to offer maintenance siltuximab. (See 'Options for refractory disease' below.)

Use in mild to moderate disease — For patients with iMCD without POEMS syndrome and without evidence of life-threatening organ failure or poor performance status thought to be due to the iMCD, we suggest (algorithm 1):

●Initial treatment with single-agent siltuximab with or without glucocorticoids. While glucocorticoids can decrease the time to symptom control, they also increase toxicity. Single-agent glucocorticoids should not be used for iMCD as they offer only mild symptomatic improvement with very low response rates [5,51,74,75].

Siltuximab is preferred based on its benefit in the only randomized trial and its approval in the United States and Europe for this purpose. If siltuximab is not available, tocilizumab is an acceptable alternative. (See 'Efficacy' below.)

While elevated pretreatment IL-6 levels are associated with a trend toward an increased likelihood of response to siltuximab, IL-6 levels should not be used to guide treatment decisions. In the phase 2 trial of siltuximab, there were iMCD patients with low/normal IL-6 levels who responded to siltuximab while others with high IL-6 levels did not [21].

●Initially, we perform a clinical assessment and laboratory studies (CRP, CBC, creatinine, albumin) every two weeks until laboratory values normalize.

●While a formal response assessment is performed after four cycles, disease progression involving organ failure and/or meeting the above criteria for "severe" disease at any time should lead to an escalation of treatment. (See 'Assess disease severity' above and 'Response evaluation' below.)

•If clinical and laboratory values normalize after four cycles, siltuximab is typically continued indefinitely since symptoms can recur once therapy is discontinued [3,76].

•If clinical and laboratory values remain abnormal after four cycles without a trend toward improvement and there is still no evidence of progressive organ dysfunction, we discontinue siltuximab and offer rituximab plus glucocorticoids with or without an immunomodulator/immunosuppressant (eg, sirolimus, cyclosporine, anakinra, thalidomide, bortezomib, intravenous immunoglobulin [IVIg]) until a response is achieved. Our preference for this approach over cytotoxic chemotherapy places a high value on the avoidance of toxicities associated with cytotoxic chemotherapy in a patient without evidence of progressive organ dysfunction. (See 'Options for refractory disease' below.)

•Patients who achieve a sufficient response following therapy that incorporates an immunomodulator/immunosuppressant proceed to maintenance with that immunomodulator/immunosuppressant. Whether that agent should be continued indefinitely, dosing extended, or discontinued at some point is not known.

•Patients are followed with serial computed tomography (CT) scans every three months until maximum response has occurred after which the frequency of imaging can be reduced to six and later 12 months.

●If the patient's clinical status does not improve with first-line siltuximab or second-line rituximab plus glucocorticoids with or without an immunomodulator/immunosuppressant, but the patient does not progress to "severe" disease, then we offer serial administration of other immunomodulators/immunosuppressants (eg, sirolimus, cyclosporine, anakinra, thalidomide, bortezomib, IVIg). (See 'Options for refractory disease' below.)

●If the patient experiences progression to "severe" disease (life-threatening organ failure) at any time, we treat the patient as a "severe" disease patient with serial trials of various combinations of systemic chemotherapy with or without an immunomodulator/immunosuppressant. Once a sufficient clinical response is achieved with chemotherapy, an immunomodulator/immunosuppressant should be selected or continued for maintenance therapy. (See 'Options for refractory disease' below.)

Toxicities and assay interference — The most common toxicities of anti-IL-6 treatment include pruritus, weight gain, rash, hyperuricemia, and upper respiratory tract infection [77]. Infusion reactions (eg, back or chest pain, nausea/vomiting, flushing, erythema, palpitations) are seen in approximately 5 percent of patients. Anti-IL-6 treatment should not be administered to patients with severe infection, and clinicians 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.

Of note, serum/plasma IL-6 measurements should not be performed or used to guide therapy for at least 18 to 24 months after the last dose of siltuximab or tocilizumab. These assays detect complexed IL-6 plus siltuximab or increased levels of IL-6 due to an increased half-life in tocilizumab-treated patients and are therefore uninterpretable [71]. Values often rise above the upper limits of quantification almost immediately after these drugs are administered, changes which likely represent a false-positive result.

Efficacy — Where available, a treatment that incorporates the anti-IL-6 monoclonal antibody siltuximab is preferred for most patients with iMCD (algorithm 1). The anti-IL6 receptor monoclonal antibody tocilizumab is an acceptable alternative if siltuximab is not available.

The efficacy of these agents in iMCD was illustrated in two small trials described below. Both trials demonstrated high response rates and improvement in symptoms and laboratory abnormalities. Two-year overall survival and relapse-free survival rates are approximately 94 to 95 percent and 79 to 85 percent, respectively. Further follow-up is needed to determine whether these high response rates translate into a survival advantage.

A multicenter, randomized, double-blind, phase II trial of siltuximab in 79 HIV-negative patients with symptomatic iMCD demonstrated significant benefit of siltuximab for all endpoints in a large portion of patients [78-80]. 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 superior progression-free survival (91 versus 37 percent at two years; median not reached versus 14.5 months). Overall survival data are immature with few deaths in either arm (3 of 53 patients assigned to siltuximab and 4 of 26 patients assigned to placebo).

●Improvements in anemia (hemoglobin ≥15 g/L at week 13, 61 versus 0 percent) and markers of inflammation (CRP, erythrocyte sedimentation rate [ESR], and fibrinogen).

●Durable symptomatic response (57 versus 19 percent).

●Clinical response typically occurred in the following sequence: improvements in platelet counts and symptoms within the first month, followed by correction of CRP, albumin, and hemoglobin over the next few months. Improvements in fibrinogen, IgG levels, and lymph node size occurred later.

●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).

●On subgroup analysis, siltuximab appeared to be similarly effective in newly diagnosed and previously treated iMCD [81].

A multicenter, open-label, single-arm trial evaluated the safety and efficacy of tocilizumab in 26 symptomatic patients with HIV-negative iMCD of the plasmacytic histopathologic subtype [82]. The patients were initially treated with tocilizumab at a dose of 8 mg/kg intravenously 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 CRP and ESR.

●Mean hemoglobin levels improved from 9.2 to 12 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.

Options for refractory disease — IL-6 inhibitor-based therapy with or without glucocorticoids is the preferred initial therapy for patients with iMCD. However, at least one-half of patients with iMCD will not achieve a sufficient clinical response with IL-6-directed therapy and are treated with alternative treatments to target the highly activated immune cells.

Immunomodulators/immunosuppressants target immune cell populations and have demonstrated responses in case reports and small case series. Cytotoxic chemotherapy nonspecifically targets rapidly dividing cells for destruction, which includes many immune cell populations but is more toxic.

These agents have not been evaluated for the treatment of iMCD in a clinical trial, and data on efficacy are limited to case reports and case series, many of which were included in a 2016 systematic review [5]. We offer immunomodulators/immunosuppressants to patients who do not achieve an adequate response to initial therapy with siltuximab and do not demonstrate evidence of organ failure (algorithm 1). We typically reserve cytotoxic chemotherapy for patients with evidence of organ failure or poor performance status thought to be related to the iMCD.

●Immunomodulators/immunosuppressants – Case reports and small case series have described durable responses to other agents, including the combination of sirolimus and IVIg [3]; single-agent bortezomib [83-86]; ruxolitinib [87]; anakinra [24,25]; cyclosporine [88-90]; immunomodulatory agents (thalidomide, lenalidomide) [91,92]; and adalimumab [93]. We use these agents for patients with relapsed and refractory disease. Based on our experiences, our preference is to use sirolimus, ruxolitinib, or thalidomide.

Patients who achieve a sufficient response following therapy that incorporates an immunomodulator/immunosuppressant proceed to maintenance with that agent.

●Rituximab – While there is strong evidence for the use of rituximab in HHV-8-associated MCD [94-96], there is sparse evidence for its effectiveness in iMCD. Single-agent rituximab is an alternative for patients with mild symptoms who do not achieve a sufficient clinical response to anti-IL-6 therapy. Case series have reported variable response rates. In one series, five of eight patients receiving rituximab without cytotoxic chemotherapy attained a complete response with a median time to response of two months [5]. Other series have reported complete response rates of 22 to 27 percent in patients with iMCD treated with rituximab with or without glucocorticoids [74,97], and up to 64 percent in patients with the TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) subtype [97]. Rituximab can be combined with cytotoxic chemotherapy for patients with severe, refractory disease. (See "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Rituximab-based therapy'.)

●Single-agent chemotherapy – Cyclophosphamide, vinblastine, and etoposide have all been used as single agents to induce remissions [5]. However, symptoms generally recur after treatment discontinuation. Once a sufficient clinical response is achieved with chemotherapy, an immunomodulator/immunosuppressant should be selected or continued for maintenance therapy.

●Multidrug combinations – Selected patients may benefit from more aggressive combination chemotherapy, including agents like cyclophosphamide, etoposide, doxorubicin, rituximab, and bortezomib as part of regimens such as [1,5,22,51,98-100]:

•CER (cyclophosphamide, etoposide, and rituximab)

•VDT-ACE-R (bortezomib, dexamethasone, thalidomide, doxorubicin, cyclophosphamide, etoposide, and rituximab)

•R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab)

•R-CVP (cyclophosphamide, vincristine, prednisone, and rituximab)

•TCP (thalidomide, cyclophosphamide, and prednisone)

•BCD (bortezomib, cyclophosphamide, and dexamethasone)

Limited data guide therapy selection. Experience is greatest with rituximab, cyclophosphamide, and/or etoposide as an initial regimen. CER is our preferred initial regimen. If CER doesn’t appear to be working or if there are increased plasma cells on lymph node and/or bone marrow histology ("plasmacytic" histopathology), we use VDT-ACE-R. For CER, we follow a dosing regimen that uses a four-day continuous infusion of cyclophosphamide (400 mg/m²/day) and etoposide (40 mg/m²/day) and rituximab (375 mg/m²) on day one and every week for four weeks. For VDT-ACE-R, we follow a dosing regimen of bortezomib administered subcutaneously at 1 mg/m² (days 1, 4, 8, and 11), dexamethasone (40 mg orally daily for 4 days), thalidomide given orally at 100 mg daily, and a four-day continuous infusion of doxorubicin (10 mg/m²/day), cyclophosphamide (400 mg/m²/day), and etoposide (40 mg/m²/day).

Paradoxically, the most acutely ill iMCD patients may be the cases that benefit from multiagent chemotherapy the most. We continue aggressive multiagent chemotherapy treatment even in the setting of multiorgan failure and ventilator support because critically ill iMCD patients can have dramatic responses and durable remissions following IL-6 blockade and/or cytotoxic chemotherapy. In two studies, approximately 50 percent of patients with HHV-8-unknown MCD achieved durable complete responses after treatment with four-drug combinations such as CHOP or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) [31,32]. A single-center, single-arm phase 2 study of TCP in iMCD reported durable tumor and symptomatic response in 48 percent of patients treated [98]. Similarly, in another single-center, single-arm phase 2 study of first-line BCD in iMCD, most patients experienced an at least partial lymph node response and symptom control, and the median time to next treatment was 36 months [100]. Case reports of CHOP in iMCD and HHV-8-unknown MCD have had mixed results with some patients achieving durable response [101,102].

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 — Patients with organ dysfunction or poor performance status are assessed daily using clinical features and laboratory studies (C-reactive protein [CRP], hemoglobin and platelet counts, albumin, creatinine, and liver function tests) to adjust treatment as needed. (See 'Use in severe disease' above.)

By contrast, for iMCD without organ dysfunction or poor performance status, we generally administer four doses of therapy (eg, siltuximab every three weeks for four doses) prior to reassessing disease status and a formal response to treatment. Concern for disease progression with organ failure at any time (to "severe") should lead to earlier evaluation and an escalation of treatment if confirmed. (See 'Use in mild to moderate disease' above.)

Response evaluation includes a clinical assessment of physical findings and symptoms (fatigue, anorexia, fever, weight), laboratory studies (complete blood count [CBC], creatinine, albumin, and CRP), and imaging (CT of the neck, chest, abdomen, and pelvis or whole-body positron emission tomography [PET]/CT, if available) [72]. A clinical assessment and laboratory studies are performed every two weeks until laboratory values normalize. Imaging is performed six weeks after the initiation of therapy and then every three months until maximum response.

Uniform response criteria have been proposed by an international working group of pediatric and adult iMCD experts [72]:

●Complete response (CR) – Symptoms resolved to baseline, laboratory studies (CRP, hemoglobin, albumin, glomerular filtration rate) within normal range, and lymph nodes meet Lugano criteria for CR (table 4).

●Partial response (PR) – An overall PR requires nothing less than a PR across all three categories but not meeting the criteria for CR. Improvement in all symptom categories but not to baseline, at least 50 percent improvement in all laboratory studies, and lymph nodes meet Lugano criteria for PR.

●Progressive disease (PD) – An overall PD occurs when any category has a PD. Worsening in any symptoms on at least two assessments and/or >25 percent increase in lymph node size and/or >25 percent worsening in any laboratory study.

●Stable disease – Does not meet the criteria for CR, PR, or PD.

Regardless of the subtype or treatment approach, patients who achieve an at least PR are seen at periodic intervals to monitor for treatment complications and assess for disease progression. The frequency and extent of these visits depend on the comfort of both the patient and clinician. Our approach to patient surveillance is to schedule visits every two to three months. At these visits, we perform a history and physical examination and serum biomarkers, which include CBC, blood chemistries, vascular endothelial growth factor (VEGF), sIL2R, CRP (erythrocyte sedimentation rate [ESR], if CRP is not available), fibrinogen, liver function tests with albumin, serum free light chain assay, and quantitative immunoglobulins.

Patients who attain a CR and remain in remission for a full year are followed every 6 to 12 months with CT or PET/CT and serum biomarkers. Annual imaging can be discontinued after five years if the patient remains disease-free. Patients should continue to diligently monitor their disease symptoms.

Of importance, after siltuximab or tocilizumab is administered, laboratory tests for IL-6 levels become uninterpretable; the assays detect complexed interleukin (IL)-6 plus siltuximab and tocilizumab increase the half-life of inactive/circulating IL-6. Therefore, IL-6 levels should not be used to guide or contribute to treatment decisions for at least 18 to 24 months after the last dose of siltuximab or tocilizumab is given.

Complications — Fatal cases of iMCD are associated with fulminant infection, multiorgan failure due to PD [34,35,37], or related malignancies.

Malignancy — Patients with iMCD appear to have an increased risk of malignancies.

●Solid tumors – A systematic literature review found that 24 (19 percent) of 128 patients with iMCD were diagnosed with a separate malignant disease before (n = 4), concurrent with (n = 12), or after (n = 8) their diagnosis, which is higher than the expected age-adjusted prevalence of 6 percent [5]. Of these 24 patients, 11 had a hematologic malignancy and 13 had a solid tumor. The solid tumors included three cases of adenocarcinoma (two unknown primary sites, one gastric), two cases of inflammatory myofibroblastic tumors, and one case each of basal cell carcinoma, dendritic cell sarcoma, metastatic gastric cancer, medullary thyroid cancer, neurinoma, spindle cell sarcoma, squamous cell carcinoma of the lung, and tonsil cancer.

●Hematologic malignancies – The hematologic malignancies identified in the systematic literature review included six cases of non-Hodgkin lymphoma (two diffuse large B cells, one angioimmunoblastic T cell, one mantle cell, one orbital-mucosal associated lymphoid tissue, one not specified), three cases of Hodgkin lymphoma, one case of acute myeloid leukemia, and one case of multiple myeloma [5,103-105].

PROGNOSIS — 

The natural history of HHV-8-negative/iMCD is variable. Several different patterns of disease progression have been described [34,37,106]:

●An indolent form 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. This form is most common in iMCD cases with TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) clinical features [107,108].

A prognostic score (iMCD-IPI) has been proposed that stratifies patients into one of three risk groups with worse outcomes associated with increasing numbers of five clinical variables (age >40 years, plasmacytic variant subgroup, hepatomegaly and/or splenomegaly, severe anemia [<8 g/dL], and pleural effusion) [109].

The prognosis of untreated MCD is poor. Few studies have investigated the overall survival of iMCD cases alone. Four large series reported overall survival for HIV-negative, likely-HHV-8-negative MCD cases. Five-year overall survival ranges from 55 to 77 percent [47,110-112].

Progress in long-term outcomes of iMCD is anticipated with the advent of antibodies targeting the interleukin (IL)-6 signaling cascade. The ACCELERATE Natural History Registry is collecting data on effective treatments and their relation to long-term survival. Patients can e-consent and register themselves directly at www.cdcn.org/patients-loved-ones/join-the-registry.

ADDITIONAL RESOURCES — 

The Castleman Disease Collaborative Network (CDCN) connects an international community of physicians, researchers, patients, and loved ones to advance research and treatments for all subtypes of CD.

Patients can visit the CDCN website to learn about and enroll themselves onto an international natural history registry of CD. The CDCN also provides opportunities for patients to consent online to donate blood samples or excess lymph node tissue for research (CDCN.org/samples). The CDCN also provides patient information and opportunities to engage others interested in CD through virtual communities and in-person meetings.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Castleman disease".)

SUMMARY AND RECOMMENDATIONS

●MCD classification – Multicentric Castleman disease (MCD) describes a heterogeneous group of lymphoproliferative disorders associated with systemic inflammatory symptoms.

MCD is subclassified into human herpesvirus 8 (HHV-8)-associated MCD and HHV-8-negative/idiopathic MCD (iMCD) by staining lymph node tissue for latency-associated nuclear antigen-1 (LANA-1). HHV-8-associated MCD is caused by uncontrolled infection with HHV-8. The etiology of iMCD is unknown. (See 'Etiology and pathogenesis' above.)

●Clinical features – iMCD can present at any age with peripheral lymphadenopathy and systemic symptoms, including fever, night sweats, weight loss, and fatigue, accompanied by nearly universal anemia, thrombocytosis or thrombocytopenia, hypoalbuminemia, polyclonal hypergammaglobulinemia, and an elevated C-reactive protein or erythrocyte sedimentation rate. (See 'Epidemiology' above and 'Clinical features' above.)

Imaging with combined fluorodeoxyglucose (FDG) positron emission tomography (PET) and CT demonstrates the involvement of multiple sites, usually with a low standardized uptake value relative to aggressive lymphomas.

●Diagnosis – The diagnosis of iMCD requires characteristic histopathologic findings on lymph node biopsy, multiple regions of enlarged lymph nodes, the presence of certain clinical and laboratory abnormalities, and the exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD (table 2). (See 'Diagnostic criteria' above.)

●Management – Our initial management of iMCD depends on whether the patient meets the criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome and disease severity (algorithm 1). (See 'Assess disease severity' above.)

•Patients with POEMS syndrome and concurrent MCD are managed similarly to those with POEMS syndrome alone. (See "POEMS syndrome", section on 'Management'.)

•For patients with mild to moderate iMCD without POEMS syndrome, we suggest the use of siltuximab with or without glucocorticoids rather than other therapies (Grade 2C). Glucocorticoids may decrease the time to symptom control, but they also increase toxicity. (See 'Use in mild to moderate disease' above.)

If effective, siltuximab is typically continued indefinitely since symptoms can recur once therapy is discontinued.

If there is insufficient response to initial therapy and no evidence of progressive organ dysfunction (liver, kidney, pulmonary) or other signs of severe disease, we suggest switching to rituximab plus glucocorticoids with or without an immunomodulator/immunosuppressant rather than adding cytotoxic chemotherapy (Grade 2C).

•For all patients with severe iMCD without POEMS syndrome, we suggest combining accelerated weekly dosing of siltuximab with high-dose glucocorticoids (Grade 2C). If clinical and laboratory values normalize, patients are transitioned to maintenance siltuximab every three weeks. (See 'Use in severe disease' above.)

•For patients with iMCD without POEMS syndrome who experience progressive organ dysfunction that meets the criteria for severe disease (liver, kidney, pulmonary) while on treatment with siltuximab (with or without glucocorticoids), we suggest the addition of multiagent systemic chemotherapy (Grade 2C). (See 'Options for refractory disease' above.)

A significant proportion of patients with iMCD do not improve with interleukin (IL)-6 blockade. Patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for disease progression and complications. In cases with severe, life-threatening organ dysfunction, we assess disease response daily. The response is best assessed by tracking laboratory values, including albumin, creatinine, hemoglobin, platelet count, and C-reactive protein. For more stable cases, we assess disease response every two to four weeks. (See 'Response evaluation' above.)

●Follow-up – Patients are followed clinically and with biochemical and imaging exams. Importantly, IL-6 assays cannot be used to guide therapy for at least 18 to 24 months after the administration of siltuximab or tocilizumab because these assays detect complexed IL-6 plus drugs and are therefore uninterpretable. (See 'Response evaluation' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Nikhil C Munshi, MD, Jon C Aster, MD, and Jennifer R Brown, MD, PhD, who contributed to earlier versions of this topic review.