What every physician needs to know:
Castleman’s disease (CD) is a rare, nonclonal lymphoproliferative disorder. It affects a single lymph node region (unicentric) or may affect multiple lymph node areas including hepatosplenomegaly (multicentric).
Although precise incidence of CD in the United States of America (USA) is unknown, only a few hundred cases per year are reported.
Interleukin 6 (IL6) plays an important role in the pathophysiology of the disease, symptomatology, and as a potential therapeutic target.
Typical symptoms of Castleman’s disease are fatigue, night sweats, fever, as well as loss of appetite and weight, and are related with high serum IL6 level. These symptoms are predominant presenting features as well as symptoms that affect patient’s quality of life. Additional symptomatology may be due to the patient’s immune deficiency as well as HIV status; other symptoms are frequently those associated with auto-immune diseases. These include hemolytic anemia, thrombocytopenia, anti-factor VIII antibodies, pure red cell aplasia, and myasthenia gravis.
The unicentric CD presents as mediastinal mass in 60 to 75% of the cases, as cervical mass in 15 to 20%, and in less than 10% with abdominal or other masses. Symptoms are usually related to the area of lymph node enlargement which includes, in a classic case, a large mediastinal mass with pulmonary symptoms or palpable cervical lymphadenopathy. A number of cases have been reported with uncommon sites of unicentric CD including skin, nasopharynx, lungs, as well as intra-abdominal mass. Unicentric Castleman’s disease is less frequently associated with IL6 related constitutional symptoms described above.
Multicentric CD presents with generalized lymphadenopathy and/or hepatosplenomegaly observed in over half of the patients and is associated with systemic symptoms such as fever, night sweats, fatigue, and weight loss. Between 20 and 30% patients have various forms of skin lesions including non-specific rashes, hemangiomata, Kaposi’s sarcoma like lesions, psoriatic type lesions, and pemphigus. A similar proportion of patients present with neurological symptoms including peripheral neuropathy and in rare advanced severe cases, seizure and cerebrovascular accident. High vascular endothelial growth factor (VEGF) levels observed in certain cases of CD can cause extravasation of fluid with development of edema, pleural effusion, and ascites.
A more aggressive form of CD observed predominantly in children or young adults can be associated with pemphigus and bronchiolitis obliterans, leading to progressive rapid respiratory failure and high disease related mortality.
Castleman’s Disease and POEMS syndrome
CD is also one of the features of POEMS syndrome which is associated with endocrinopathy, sclerotic bone lesions, monoclonal gammopathy of undetermined significance, and neuropathy.
There is significant association of CD with HIV and immunosuppression. CD developing in this setting is frequently associated with human herpes virus 8 (HHV8) infection.
Pathologic evaluation of lymph node biopsy is essential for diagnosis. There are two basic types: hyaline vascular type, and plasmacytic variant, with occasional cases having mixed picture. In hyaline vascular type of the CD, lymph node biopsy shows angiofollicular hyperplasia with depleted germinal center cells and with concentric expansion of mantle zones with small lymphocytes (onion skin appearance). The pathology shows hyalinized blood vessels as well as presence of follicular dendritic cells, but lack of plasma cells. The increased blood vessels are considered to be related with production of VEGF, which is produced in presence of and by elevated IL6. Follicular cells seen in hyaline vascular CD express CD20 and CD5 but are not clonal.
The plasmacytic variant of CD shows interfollicular increase in polyclonal plasma cells. The lymphoid architecture is relatively preserved but there are hyperplastic follicles. The mixed type of CD shows features representing both hyaline vascular type and plasmacytic type.
Ninety percent of unicentric CD is hyaline vascular; while 80 to 90% of multicentric CD is either plasmacytic or mixed type.
A very small number of patients, usually multicentric plasmacytic variant, may evolve into lymphoma.
Are you sure your patient has Castleman's disease? What should you expect to find?
The diagnosis of Castleman’s disease should be expected in patients with a localized lymph node enlargement or a generalized lymphadenopathy with typical IL6 related symptoms including fever, night sweats, fatigue, and weight loss.
Additional symptoms as described above may include those due to localized mass or due to production of cytokines (VEGF). Physical examination will mainly demonstrate presence of either localized or generalized lymphadenopathy. Also, patients may present with dermatological or neurological manifestations of the disease, or with signs and symptoms associated with autoimmune disorders and/or anemia, if present.
In general, the signs and symptoms associated with CD are non-specific and are not sufficient to establish the diagnosis. There is no single pathognomonic presenting feature, and biopsy of the lymph node and histological confirmation remains the only absolute test for diagnosis. In a number of situations, the investigations are performed to exclude other conditions, especially malignant diseases.
Beware of other conditions that can mimic Castleman's disease:
The differential diagnosis of CD is broad and includes disorders that are overlapping with lymphadenopathy, as well as pathological findings.
All the possible causes of localized or generalized lymphadenopathy should be considered as possible differential diagnosis of CD. The first and the foremost conditions to be excluded are the malignant disorders, specifically non-Hodgkin’s or Hodgkin’s lymphoma, as these diseases require a different and specific therapeutic intervention. None of the laboratory studies are able to differentiate malignant conditions from CD, and lymph node biopsy with appropriate histological, immunohistochemical, and molecular analysis is essential for diagnosis. Other conditions in differential diagnosis include autoimmune disorders, such as rheumatoid arthritis and connective tissue diseases. Their diagnosis would also depend on both clinical differentiation, as well as various serological testing.
The pathological evaluation and differential diagnosis includes most importantly identification and differentiation of reactive lymphadenopathy observed in a number of diseases. This again includes autoimmune diseases such as connective tissue disorders and collagen vascular diseases, HIV and other immunodeficiency related lymphadenopathy, as well as infection etiologies.
Which individuals are most at risk for developing Castleman's disease:
No specific predisposing feature or genetic link has been established for CD. Familial cases of CD have also not been reported. CD occurs at a relatively younger age with highest incidence in mid-thirties to forties. Some association with autoimmune disease is considered, essentially based on higher expression of IL6 in these conditions. However, the cause and effect relationship between autoimmune disease and CD is unclear. It is possible that various autoimmune processes may lead to higher IL6 production, with eventual development and/or manifestation of CD. On the other hand, IL6 produced by CD can also induce autoimmune reactions.
Patients with HIV are at an increased risk of developing CD. HIV-related CD is associated with HHV8 infection, which is considered a predisposing condition for CD.
Patients with POEMS syndrome may have associated CD in a small number of cases. It is unclear whether or not CD is part of and/or an effect of POEMS syndrome where higher cytokine levels are observed. However, individuals with POEMS syndrome and lymphadenopathy need to be evaluated for the possibility of CD.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Diagnosis of CD is based on laboratory investigation, as well as pathological evaluation of lymph node biopsy.
The laboratory tests required for diagnosis, but more importantly follow-up of patients with CD, include:
Complete blood counts
– Especially to detect anemia and/or thrombocytosis.
– To detect hypoalbuminemia, or hypergammaglobulinemia.
Serum protein electrophoresis and quantitative immunoglobulins
– To exclude monoclonal protein and to confirm elevated immunoglobulin levels of one or more types (IGG, IGA, and/or IGM [immunoglobulin G, A and /or M]).
Serum cytokine level of interleukin-6 is required and VEGF is optional
– IL6 is elevated in plasmacytic CD, while it is only rarely elevated in hyaline vascular CD.
Markers of acute phase reaction
– CRP (C-reactive protein), fibrinogen, ferritin, and ESR (erythrocyte sedimentation rate). All these markers are elevated in the majority of patients, especially those with elevated IL6. Absence of elevation of these markers does not rule out CD, but its association is frequent and provides one of the measures to evaluate response to therapy. It is important to know that these markers of inflammation can be elevated in a number of other conditions, including autoimmune disorders, inflammation, and infections.
Virology studies, HIV and HHV8 serology, with quantitative polymerase chain reaction (PCR)
– Virology studies, HIV and HHV8 serology, with quantitative PCR if indicated is required to establish association and also direct therapy.
– To evaluate for markers of autoimmune disorders, as well as connective tissues disorders.
Lymph nodes biopsy
– This is the most important of the tests required for diagnosis of CD. Fine needle aspiration of lymph node is not adequate and a lymph node biopsy is essential to confirm the diagnosis, as well as identify the subtype. Hematoxylin and eosin (H and E) staining and histological examination showing any of the features described above for CD are adequate for diagnosis, but also to rule out any other malignant and/or reactive processes that might be present. Analyzing the biopsy for clonality by immunoglobulin heavy chain gene rearrangement is required to rule out any clonal disease process.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of Castleman's disease?
Computed tomography (CT) scan of neck, chest, abdomen, and pelvis is essential for both diagnosing CD and to stage it between unicentric versus multicentric disease. The CT scan will also help identify presence of hepatosplenomegaly.
Positron emission tomography – computed tomography (PET – CT) is also helpful as lymph nodes from CD are positive with low SUV (Standard Uptake Value). It helps differentiate between lymphoma and other malignancies, where the lymph nodes have much higher SUV.
If you decide the patient has Castleman's disease, what therapies should you initiate immediately?
The therapeutic decision to treat CD depends on primarily whether the patient has unicentric or multicentric disease.
In patients with localized disease, confirmed with imaging modalities, resection with total removal of the mass or lymph nodes is the best therapeutic option. If the mass is unresectable because of its location, and/or size being too large for complete removal, then an approach to decrease the size of the tumor with intervention is adopted prior to reconsidering surgical intervention.
Resection is not treatment of choice for multicentric CD, as complete removal of all masses is not possible and a systemic therapy is needed. The primary objective of treating multicentric CD is to provide relief of the often debilitating symptoms associated with this form of CD, and also it is to achieve a reduction in lymph node size, to get direct clinical benefit. A number of systemic therapies have been evaluated including chemotherapeutic combinations, steroids, some of the novel agents such as thalidomide and lenalidomide, and biologically based therapy targeting IL6.
First line treatment options
The current first line treatment options include the use of any of the three antibodies: anti-IL6, or anti-IL6 receptor, or anti-CD20 monoclonal antibody.
Anti-IL6 monoclonal antibody was evaluated initially in a single patient with plasmacytic variant of CD with significant and rapid improvement in symptomatology and laboratory abnormalities, including improvement in anemia, albumin, and markers of inflammation such as CRP. This patient eventually underwent surgical resection with long-term sustained remission.
Recently a chimeric monoclonal antibody targeting IL6 (siltuximab) is being evaluated in patients with CD to neutralize human IL6. This high affinity antibody has been evaluated in 23 patients in escalating doses. Eighteen of the 23 patients achieved clinical benefit with significant improvement in symptomatology, and half of the patients demonstrated objective radiologic improvements. In this study, patients receiving the highest dose level all achieved clinical benefit, suggesting dose dependent response. In this study, clinical responses preceded the observed radiologic responses. At the highest dose level, eight of the 11 patients had objective response using standard criteria modified from Cheson’s criteria.
A humanized anti-IL6 receptor mAb (monoclonal antibodies) tocilizumab (Actemra) was developed and investigated first in Japan in a Phase II study in 28 patients. Treatment was given twice weekly at 8mg/kg dose for 16 weeks with an adjustment of dose, as necessary, in an extension phase. Most of the patients in the extension phase received the treatment at 8mg/kg every 2 or 4 weeks. Within 16 weeks, rapid normalization of markers of inflammation such as fibrinogen, CRP, and ESR with improvement in albumin as well as hemoglobin and body mass index was observed.
In this study also, significant reduction in lymphadenopathy was observed. Of 28 patients enrolled, 27 (96%) have continued to receive treatment for over 3 years with sustained clinical improvements; 11 of 15 patients on steroids at the time of diagnosis, were also able to go off steroids, or decrease the dose following initiation of tocilizumab therapy. Tocilizumab is approved for therapy of CD in Japan.
Both tocilizumab and siltuximab are well tolerated with limited toxicity such as hyperlipidemia and cholesterol abnormalities requiring close monitoring. In both studies, there is some evidence that a sustained treatment may be required, as some of the patients who discontinued therapy relapsed. Investigation to determine the role of maintenance therapy and/or less frequent administration of this agent is required to establish the ideal schedule for these agents.
Use of either antibodies is most appropriate in multicentric CD, as well as for the occasional patient with unicentric disease that is not operable, because of size and/or location. Efficacy and need to have detectable IL6 level in serum for the IL6 directed antibody to be effective is not currently established. So although it is beneficial to use monoclonal antibody directed at IL6 in those patients where IL6 levels is high, in absence of high IL6, one could also investigate anti-IL6 based therapies.
Serum levels of both IL6 and soluble IL6R markedly increase after therapy with tocilizumab. Presence of free tocilizumab suggests that soluble IL6 Receptor (sIL6R) is saturated with tocilizumab and IL6 signalling is completely inhibited. It is believed that increase in sIL6R may be due to prolonged half life of elimination by the formation of a tocilizumab/sIL6R immune complex. Due to this effect on their kinetics, monitoring levels of IL6 or sIL6R is not helpful in evaluating response to therapy. However, measuring markers of inflammation such as CRP is beneficial and recommended.
Other therapeutic approaches
Rituximab (anti-CD20 mAb) has been used in a small number of patients, single case studies, and small patient number studies. It is predominately used as a single agent, or in some cases with steroids or chemotherapy. Use of rituximab in these studies has suggested significant efficacy with reduction in tumor size in the majority of cases.
As hyaline vascular CD has predominance of CD20 expressing cells, rituximab appears to be effective; however, in plasmacytic variant of CD, the efficacy of rituximab appears to be limited, due to predominant mature plasma cell population which are CD20 negative. Rituximab should be considered in patients with unicentric CD who are being prepared for surgical intervention.
Use of steroids has been widely reported again in a small number of patients and specifically to manage acute exacerbation of symptomatology and/or lymph node size. High-dose steroids tend to counteract both markers of inflammation, which is the main driving pathology in CD and its symptomatology. Its immunosuppressive effects provide benefit in regards to lymph node size. A number of cases achieving significant remission, and in some cases complete remission, have been reported with steroids. However, in the majority of cases responses have been short lived and eventually a tolerance develops. With the associated risks of side effects with steroids, its use is now limited specifically with the availability of antibody-based therapies.
Use of chemotherapy in CD
A number of chemotherapeutic options have also been evaluated. These include the use of Cytoxan with regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone), VAD (vincristine, Adriamycin, dexamethasone) or nucleoside analogues. Again, chemotherapy has not been extremely effective in this setting for long term control of the disease and patients with multicentric CD invariably relapse following utilization of these regimens. With the availability of antibody-based therapy, chemotherapy regimens have had a more restricted use, usually in the setting of relapse after the initial interventions.
Radiation therapy as a possible means of controlling unicentric CD has been evaluated, specifically in cases where a reduction in tumor size is required for resection of the main mass.
HIV-positive patients with multicentric CD require slightly different therapeutic intervention. They are predominantly HHV8 positive and are driven by expression of genes including IL6 genes of viral origin. The therapy for these patients have been evaluated using antiviral agents specifically acyclovir/ganciclovir. Valganciclovir has been utilized as a maintenance therapy to suppress HHV8 replication in patients with CD. The trial of antiviral agents in HHV8/HIV positive patients is recommended as one of the possible initial interventions.
Optimal therapy for HIV in patients with CD utilizing highly active antiretroviral therapy (HAART) may also provide benefit with or without rituximab.
Anecdotal case studies have reported effectiveness of novel agents utilized in patients with myeloma such as thalidomide, lenalidomide, and bortezomib, in CD. Similarly, a single case experience with use of high-dose therapy and autologous transplantation has also been reported with beneficial effect. With the availability of effective antibody-based therapies, use of such modalities is reserved for very extreme cases. Use of bortezomib and lenalidomide needs to be evaluated in larger patient populations to determine its efficacy and role in treatment of CD.
More definitive therapies?
Although there are no absolute curative therapies for CD, in patients with elevated IL6, the first agent of choice will be anti-IL6 or anti-IL6R antibody.
In patients with normal IL6 level and with hyaline vascular disease, rituximab is the first agent of choice.
In localized disease, most definitive therapy will be surgical removal of the mass.
What other therapies are helpful for reducing complications?
No specific supportive, preventive, or ancillary therapies are recommended for CD at the present time.
What should you tell the patient and the family about prognosis?
CD is a non malignant disorder with overall good prognosis. Patients with unicentric CD are cured following complete surgical resection with recurrence in very occasional patients.
The main goal of the therapy is to improve symptoms and quality of life. The current antibody-based therapies achieve this goal in majority of patients.
Patients would require at least yearly follow-up with laboratory investigation and imaging for the first 3 to 5 years.
"What if" scenarios.
If patients receive the described therapy for CD (surgery and/or antibody-based therapies) and have residual symptomatic disease, then other, less commonly utilized approaches could be applied. This includes use of steroids, chemotherapy, thalidomide and lenalidomide as well as Velcade. Rare use of high-dose therapy with autologous transplant has also been reported.
The efficacy of therapy is judged first by symptom relief, second, by a change in enlarged lymph nodes, and finally by a normalization of laboratory abnormality. If patient does not have measurable disease then laboratory abnormalities can be used as primary evalution method for response assessment.
IL6 plays a central role in pathophysiology of CD through IL6 receptor. The original suspicion of involvement of IL6 was provided by IL6 transgenic mice which developed Castleman’s-like syndrome with plasmacytosis, splenomegaly, and enlarged lymph nodes. IL6 is considered to be produced by the enlarged lymph node in CD, as confirmed by quick decline in IL6 level following surgical removal. Additionally, therapeutic intervention directed at IL6 provides symptomatic, as well as clinical, benefit.
The pathophysiologic basis of the frequent association of HHV8 in the form of CD associated with HIV infection is the production of a viral homologue of IL6. IL6 is thought to mediate some of the signaling effects associated with human IL6 in CD. Viral IL6 may also induce secretion of VEGF, induce pro-inflammatory reactions, as well as induce proliferation of plasma cells and autoimmune manifestations of the disease.
What other clinical manifestations may help me to diagnose Castleman's disease?
Besides the typical signs and symptoms of CD, dermatological or neurological symptoms or signs, as described above, may be present in one third of the patients.
What other additional laboratory studies may be ordered?
Besides the above described laboratory studies, no additional tests need to be performed.
What’s the evidence?
Castleman, B, Towne, VW. “Case records of the Massachusetts General Hospital; weekly clinicopathological exercise; founded by Richard C. Cabot”. N England J of Med. vol. 251. 1954. pp. 396-400. [This is the original first case report of CD. Describes the disease and its clinical manifestations.]
Soulier, J, Grollet, L, Oksenhendler, E. “Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease”. Blood. vol. 86. 1995. pp. 1276-1280. [This study establishes the association of CD with HHV8.]
Casper, C, Nichols, WG, Huang, ML, Corey, L, Walk, A. “Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment”. Blood. vol. 103. 2004. pp. 1632-1634. [The first report demonstrating efficacy of ganciclovir in CD.]
Gerard, L, Berezne, A, Galicier, L. “Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease; ANRS 117 Castleman B Trial”. J Clin Oncol. vol. 25. 2008. pp. 3350-3356. [This report establishes the efficacy of rituximab in CD.]
Beck, JT, Hsu, SM, Wijdenes, J. “Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody”. N Engl J Med. vol. 330. 1994. pp. 602-605. [First report of successful use of anti-IL6 antibody in CD. This is a single case report that establishes the role of IL-6 in CD as well as proof of principle if IL-6 directed therapy.]
Nishimoto, N, Honda, O, Sumikawa, H, Johkoh, T, Aozasa, K, Kanakura, Y. “A long-term (5 year) sustained efficacy of Tocilizumab for multicentric Castleman's disease and the effect on pulmonary complications”. Blood. [A large experience using anti-IL6R antibody in CD. It establishes the efficacy and long term outlook of using tocilizumab in CD.]
Frizzera, G, Peterson, BA, Bayrd, ED, Goldman, A. “A systemic lymphoproliferative disorder with morphologic features of Castleman's disease; clinical findings and clinicopathologic correlations in 15 patients”. J Clin Oncol. vol. 3. 1985. pp. 1202-1216. [This study reports clinical presentations and features of CD.]
Oksenhendler, E, Carcelain, G, Aoki, Y. “High levels of human herpes-virus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV-infected patients”. Blood. vol. 96. 2000. pp. 2069-2073. [This study establishes the role of HHV-8 and HIV in CD, along with study of other markers of inflammation such as C-reactive protein (CRP)
Brandt, SJ, Bodine, DM, Dunbar, CE, Nienhuis, AW. “Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice”. J Clin Invest. vol. 86. 1990. pp. 592-599. [This animal model data suggested possible link between IL6 and CD.]
Van, Rhee, Stone, K, Szmania, S, Barlogie, B, Sigh, Z. “Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy”. Clin Adv Hematol Oncol. vol. 8. 2010. pp. 486-98. [This paper reviews all the aspects of CD including diagnosis and therapy.]
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- Castleman's disease
- What every physician needs to know:
- Are you sure your patient has Castleman's disease? What should you expect to find?
- Beware of other conditions that can mimic Castleman's disease:
- Which individuals are most at risk for developing Castleman's disease:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of Castleman's disease?
- If you decide the patient has Castleman's disease, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- "What if" scenarios.
- What other clinical manifestations may help me to diagnose Castleman's disease?
- What other additional laboratory studies may be ordered?