What Is Castlemans Disease

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Castleman's disease is a benign disorder first described by Dr. Benjamin Castleman in 1956. Castleman's disease is also referred to as angiofollicular hyperplasia, and is non-clonal disease of the lymphnodes. As the name angiofollicular hyperplasia (1) implies there is a follicular hyperplasia of lymph nodes with abnormally increased interfollicular vascularity. Castleman’s disease can be classified as a) unicentric vs. multicentric, based on clinical and radiological findings, b) hyaline vascular vs. plasmacytic vs. mixed cellularity variety based on histopathology  and c) as HIV negative versus HIV positive based on the HIV status of the patient. All three factors need to be taken into account in the assessment of patients.

Unicentric Castleman’s Disease. Unicentric Castleman’s Disease is usually a slow growing solitary mass typically located in the mediastinium or mesenteries. There are no constitutional symptoms and no elevation of acute phase reactants (Interleukin 6, ESR and CRP).  Symptoms if present are due to a mass effect of bulky lymphadenopathy. In a few cases abnormal clonal, cytogenetic findings have been described arising from a dysplastic follicular dendritic cell network, but these findings are probably secondary and not causative to Unicentric Castleman’s Disease.  In 90-95% cases surgical resection is curative and usually there is no progression to lymphoma or association with other tumors. The prognosis is excellent with a 5 yr survival of close to 100%.

Multicentric Castleman’s Disease.  In multicentric Castleman’s Disease there is usually widespread lymphadenopathy with in some instances hepatosplenomegaly. “B” symptoms including severe fatigue, night sweats, fever, wt-loss, anorexia are typically present. These symptoms are typically driven by overproduction of interleukin 6. Overproduction of interleukin 6 also results in an acute phase reactions with elevated ESR, CRP, fibrinogen, thrombocytosis, and hypergammaglobinemia. Patients typically have peripheral edema poorly responsive to loop-diuretics and suffer from anemia and hypoalbumenia. Approximately 20% of patients have peripheral neuropathy.  The disease is non-clonal with no IgH or TCR gene rearrangements.  Other conditions associated with multicentric Castleman’s Disease include autoimmune hemolytic anemia, multiple myeloma, amyloidoisis, Pemphigus, and overlap syndromes with POEMS.  Multicentric Castleman’s Disease runs a more aggressive course and can progress to non-Hodgkin’s lymphoma. Multicentric Castleman’s Disease often requires systemic therapy.

Histopathologic Classification of Castleman’s Disease. The histopathology of hyaline vascular Castleman’s disease shows that the lymphnode germinal centers are poorly formed with dysplastic/ atrophic CD21+ follicular dendritic cell networks surrounded by an expanded mantle zone consisting of rims of small CD20+ lymphocytes arranged in an onion skin manner.  There is increased interfollicular vascularity with capillary proliferation and endothelial hyperplasia. Plasmacytic variety of Castleman’s Disease is characterized by both more numerous and larger hyperplastic follicles, which have more expanded mantle zones compared to hyaline vascular Castleman’s disease.  Sheets of plasma cells of plasma cells are present in the interfollicular areas. The mixed cellularity form of Castleman’s Disease has features of both hyaline vascular and plasmacytic types Castleman’s Disease.

Relationship between histological type and unicentric versus multicentric disease. Classically it is thought that Unicentric Castleman’s disease is usually of the hyaline vascular variety and multicentric disease of the plasmacytic type or mixed cellularity variety. These relationships are based on the analysis of the small numbers of patients since Castleman’s disease is rare. Review of 37 patients with Castleman’s disease treated at UAMS, which is the largest single institution experience in the world with Castleman’s Disease. We found that patients with Unicentric Castleman’s disease indeed have as pathology the hyaline vascular variety. However, the histopathology of multicentric disease can be evenly divided between hyaline vascular variety on one hand and plasmacytic type and mixed cellularity variety on the other hand. Mixed cellularity clinically behaves more like plasmacytic type rather than hyaline vascular disease.

HIV status and Castleman’s Disease. HIV status is important as HIV+ patients with Multicentric Castleman’s Disease have much frequent plasmacytic disease and the clinical course is less favorable than in HIV negative patients. Further, a good case can be made for HHV8 being the causative agent in HIV+ Castleman’s Disease patient. HIV+ patients have more often Kaposi’s sarcomaand more frequently progress to (plasmablastic non-Hodgkin’s lymphoma).

Pathogenesis of Castleman’s Disease. Human Herpes Virus 8 is a g-Herpes virus, which is homologous to Epstein-Barr virus and Herpes Virus Siamuri, and is tropic for B-lymphocytes. HHV8 has been associated with Kaposi’s sarcoma, Primary Effusion lymphoma and multicentric Castleman’s Disease. HHV8 seropositivity in normal population varies from 5-35%, whereas in HIV+ patients it varies from 12-50%. Also QPCR detection of HHV8 DNA in HIV+ patients antedates development of MCD (5-25%). There is presence of HHV8 DNA in Lymph nodes and peripheral blood mononuclear cells in HIV+ patients with multicentric Castleman’s disease. Viral IL6 and other cellular homologue genes are exposed in LNS from HIV+ patients. Also QPCR for HHV8 DNA can be used for monitoring disease activity/ response in HIV+ patients.

HHV8 DNA positive by nested PCR and vIL6 protein has been detected in LNS of HIV negative patients (paraffin blocks), and vIL6, vBCL-2, vCyclin-D, and viral G-protein coupled receptor in fresh LNS. But no conclusive evidence so far has been found that HHV8 has been involved in HIV- patients.

Castleman's Disease SymptomsIL6 has been implicated in the pathophysiology of CD. It causes B-cell proliferation resulting in hyperplastic follicles and hence the enlarged lymphnodes (LNS). IL6  also increases secretion of vascular endothelial growth factor (VEGF), causing angiogenesis and capillary proliferation with endothelial hyperplasia.  IL6 is also responsible for polarization of T lymphocytes to a Type 2 cytokine profile leading to autoimmune phenomena including AIHA, ANA positivity and elevation of IgE.  IL6 induces an acute phase reaction comprising increases in ESR, CRP, IgGs, serum fibrinogen, and serum Amyloid A Protein (SAA). Increased SAA levels may result in AA Amyloidosis, whilst hyperfibrinogenemia may play a role in venous thrombosis and thrombotic Finally, B-type symptomatology is virtually always associated with increased IL6 levels.

Diagnosis. The diagnosis of CD is based upon a thorough clinical evaluation that includes a detailed patient history, laboratory studies, including IL6 and ESR, CRP, histopathology of affected lymphnode(s) and a variety of imaging techniques (e.g. CT scan, MRI and more recently PET-scanning). Especially PET-scanning can complement CT-scanning by giving information regarding the metabolic status of lymphnodes. Usually the specific uptake values (SUV) of FDG-avid lymphnodes are less than those observed with active lymphoma. However, after therapy with for instance IL6-receptor antibody disappearance of all increased metabolic activity can be observed in responding patients. PET scanning therefore is not only useful in diagnosis, but also in assessment of response to therapy.

Therapy.  Surgical excision is the preferred treatment in most cases of unicentric Castleman’s Disease and adjuvant therapy e.g. steroids and/or rituxan before surgery is very useful to shrink bulky or inoperable disease. In some cases, radiotherapy has proven effective, although this is currently usually avoided.

A number of therapies have been used for multicentric disease:  intravenous immunoglobulin, anti-herpes drugs e.g. acyclovir, (Val) ganciclovir in HIV+ and HHV8+ disease, combination chemotherapy ( e.g. CHOP and in intractable cases even autologous stem cell transplantation. Other therapies include the anti-angiogenesis factor thalidomide and anti-IL6 therapy. Surgery may also be useful in debulking disease.

Anti-IL6 therapies include suramin, anti-IL6- or anti-IL6 receptor antibody. Suramin is polysulfonated urea compound originally used for trypanosomiasis.. Suramin inhibits viral reverse transcriptase and it has a number of biological effects, which include inhibition growth factor and cytokine binding to their respective receptors e.g. IL6, L2, IL6, PDGF, and FGF.  Suramin also modulates cytokine secretion.   Anti-IL6 antibody is particularly effective in controlling IL6 related symptoms, but can also induce disease regression with durable remissions.  More recently, a clinical trial with anti-IL6 receptor antibody has been used started at MIRT with equal if not better responses than observed with IL6 antibody ).

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Castlemans Disease Symptoms

In most cases, Castleman's Disease is characterized by a single, solid growth within lymphatic tissue in the chest, stomach, or neck. Growths may also occur in other lymphatic tissue throughout the body. Usually the growths represent abnormal enlargement of the lymph nodes (lymphoid hamartoma) normally found in these areas. There are three types of Castleman's Disease: hyaline-vascular type; plasma cell type; and a third type that affects more than one area of the body (generalized or multicentric Castleman's) has been also been identified.

In most cases of the hyaline-vascular type of Castleman's Disease, individuals exhibit no symptoms of this type of the disorder (asymptomatic) or may develop a non-cancerous (benign) growth in the lymph tissue; most frequently in the chest. Symptoms with this type are usually secondary to the size and location of the growth. For example, a growth may form in a vein, resulting in a bulge and possible obstruction in the involved blood vessel.

In the plasma cell type of Castleman's Disease, individuals may exhibit a variety of symptoms including fever, fatigue, excessive sweating, weight loss, skin rash, early destruction of red blood cells, leading to unusually low levels of circulating red blood cells (hemolytic anemia), and/or abnormally elevated amounts of certain immune factors in the blood (hypergammaglobulinemia).

Multicentric or generalized Castleman's Disease affects many areas of the body. Individuals with this type of Castleman's Disease often exhibit symptoms similar to those associated with the plasma cell type. In addition, some individuals may have an enlarged liver and spleen (hepatosplenomegaly). Some cases of multicentric Castleman's Disease have been associated with POEMS Syndrome. (For more information on this disorder, choose "POEMS" as your search term in the Rare Disease Database.) Researchers have speculated that individuals with this type of Castleman's Disease may have a greater risk of developing malignant complications such as Kaposi's Sarcoma or malignant lymphoma.

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Castlemans Disease Variants

Hyaline Vascular Variant

The hyaline vascular sub-type accounts for 90% of cases of Castleman's disease and patients are generally asymptomatic (58% to 97% of patients are asymptomatic). Most patients come to clinical attention when a solitary middle or posterior mediastinal mass (adenopathy) is detected incidentally on chest radiographs. In order of frequency, the intrathoracic sites involved include the anterior mediastinum, particularly right paratracheal, hilar nodes, and the posterior mediastinum. About 70% of affected patients are less than 30 years old, and males are affected more than females (females greater than males [4:1] in the AFIP series), while other authors state that there is no sex preference. Symptomatic patients may complain of dry cough, dyspnea, or recurrent infection due to airway compression. Lesions may demonstrate slow growth. Histologically, there is extensive capillary proliferation within the affected lymph nodes, and a lymphocyte predominant infiltrate surrounding small germinal centers. The treatment is surgical with a low recurrence rate if the resection is subtotal. Rare cases have been complicated by the development of vascular neoplasms that resemble Kaposi's sarcoma, or Hodgkin's lymphoma .

Plasma Cell Variant

In this form there is typically more generalized (thoracic, mesenteric, and retroperitoneal) lymph node involvement (although localized nodal involvement can be seen) and the disorder tends to be multicentric (although focal disease can be found in 10% of cases). Histologically there are sheets of mature plasma cells within interfollicular tissues that surround normal to large germinal centers and the intense capillary proliferation seen in the hyaline vascular sub-type is absent. Dysregulation of interleukin-6 has been implicated in the pathogenesis of plasma cell Castlemans disease. Affected patients typically have systemic symptoms such as fever, weight loss, moderate anemia, elevated ESR, polyclonal hypergammaglobulinemia, and hypoalbuminemia. Non-Hodgkins lymphoma and Kaposi's sarcoma occur with increased frequency in patients with the multicentric variant. Patients with multicentric disease tend to be older individuals in their 5th or 6th decade. Treatment combines steroids and chemotherapeutic agents- although no single regimen has been effective in achieving a durable remission. Prognosis is poor with an overall mortality of 50% and a median survival of 26 months. Patients with multicentric disease and an associated neuropathy have an extremely poor prognosis despite treatment with steroids and chemotherapy. The clinical and histopathologic abnormalities associated with multicentric plasma cell variant Castleman's disease are similar to those found in osteosclerotic myeloma and the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein abnormality, and skin abnormalities).

Causes

The exact cause of Castleman's Disease is not known. Some researchers speculate that increased production of interleukin-6 (IL-6) may be involved in the development of Castleman's Disease. IL-6 is a substance produced by structures within the lymph nodes.

Affected Population

Castleman's Disease is a rare disorder of the lymphatic system that affects males and females in equal numbers. All types of Castleman's Disease may affect individuals of any age; however, the plasma cell type has greater prevalence among young males and females. Children are rarely affected by this disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of Castleman's Disease. Comparisons may be useful for a differential diagnosis:

Hodgkin's Disease is a form of cancer of the lymphatic system. Tumors occur in the lymph nodes and/or the areas around the nodes. Symptoms associated with this disorder may include fever, night sweats, weight loss, and/or enlarged or swollen lymph nodes. The tumors occur most often in the chest, stomach, or spleen. Hodgkin's Disease is usually progressive and may spread to involve lymph nodes located in other areas of the body. The exact cause of Hodgkin's Disease is not known. (For more information on this disorder, choose "Hodgkin" as your search term in the Rare Disease Database.)

The following disorders may be associated with Castleman's Disease as secondary characteristics. They are not necessary for a differential diagnosis:

Malignant Lymphoma is a general term for a group of lymphatic tumors. Malignant lymphomas generally occur in the chest and/or stomach. Symptoms common to all forms of malignant lymphomas include fevers, excessive sweating at night, weight loss, and/or an abnormally enlarged liver and/or spleen (hepatosplenomegaly).

Kaposi's Sarcoma is a malignant skin tumor that may spread to other parts of the body. Affected individuals may have skin lesions (e.g., papules, plaques, etc.) that may grow and come together (coalesce). In some cases, the lesions may reduce in size and number (regress). In addition, on rare occasions these lesions may be painful.

Standard Therapies

The diagnosis of Castleman's Disease may be based upon a thorough clinical evaluation that includes a detailed patient history and a variety of specialized imaging techniques (e.g., computer-assisted tomography [CT scan], magnetic resonance imaging [MRI], and ultrasonography). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ's tissue structure. MRI uses a magnetic field and radio waves to create cross-sectional images of the organ. In ultrasonography, reflected sound waves create an image of the organs in question. These tests can identify abnormal growths associated with Castleman's Disease. Identifying the presence of elevated levels of interleukin-6 may also assist a diagnosis of Castleman's Disease.

The treatment of Castleman's Disease is directed toward the specific symptoms that are apparent in each individual. Specific therapies for the treatment of this disorder are symptomatic and supportive. Surgical removal (excision) of the growth is the preferred treatment in most cases of localized Castleman's Disease. In some cases, ionizing radiation (radiotherapy) has proven effective. Corticosteriods have been used to treat specific symptoms that may be associated with the plasma cell and multicentric types of this disorder.

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References:

Castlemans Disease:

(1) Weisenburger DD, Nathwani BN, Winberg CD, Rappaport H.Multicentric angiofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases. Hum Pathol 1985; 16:162-172

(2) Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant node hyperplasia of the mediastinium and other locations. Cancer 1972:29:670-683(3) J Thoracic Imag 1997; Multicentric Castleman's disease and POEMS syndrome: CT findings.12: 75-77 (No abstract available)(4) AJR 1996; Castleman's disease of the lung: radiographic, high-resolution CT, and pathologic findings.167: 1055-56 (No abstract available)

(5) Lachant NA, Sun NC, Leong LA, Oseas RS, Prince HE. Multicentric Angiofollicular lymph node hyperplasia (Castleman’s disease) followed by Kaposi’s sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol 1985; 83:27:3312) Pavlidis NA, Skopouli FN, Bai MC, Bourantas CL. A successfully treated case of multicentric Angiofollicular hyperplasia with oral chemotherapy (Castleman’s disease). Med Pediatr Oncol 1990; 18:333-335

6) Renne, R., Lagunoff, M., Zhong, W. & Ganem, D (1996) The size and conformation of Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) DNAin infected cells and virons. Journal of Virology, 70, 8151-8154

(7) Staskus, K.A., Sun, R., Miller, G., Racz, P., Jaslowski, A., Metroka, C., Bret-Smith, H, & Haase, A.T.(1999) Cellular tropism and viral interleukin6 expression distinguish human herpesvirus8 involvement in Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Journal of Virology, 73, 4181-4187

8) Staskus, K.A., Zhong, W., Gebhard, K., Herndier, B., Wang, H., Renne, R., Beneke, J., Pudney, J., Anderson, D.J., Ganem, D. & Haase, A.T. (1997) Kaposi’s sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. Journal of Virology, 71, 715-719.

(9) Parravicini C., Corbellino, M., Paulli, M., Magrini, U., Lazzarino, M.,  Moore, P. & chang. (1997) Expression of a virus-derived cytokine, KSHV viL-6, in HIV- seronegative Castleman’s disease. American Journal of Pathology, 151, 1517-1522

Castlemans Disease Symptoms/Variants:
Frits vanRhee, MD - Castleman's Disease. ;  Classification of Castleman's Disease.