Interleukin-6 gene expression in Castleman's disease

Defined by histological criteria, Castleman's disease (CD) is a clinically and histologically heterogeneous syndrome. The functional status of immune cells in affected tissues may vary between the different forms of the disease. To address this question, the expression of cytokine genes in eight CD lymph nodes was analyzed by in situ hybridization. Two lymph nodes were taken from patients with a localized form of the disease associated with systemic manifestations, two from patients with a localized form without systemic symptoms, and four from patients with a multicentric form. Five lymph nodes exhibiting a benign follicular hyperplasia were used as controls. The interleukin-6 (IL-6) gene was expressed at a very high level in two cases: the two localized forms of CD associated with systemic manifestations. IL-6 gene overexpression occurred inside follicles of these lymph nodes. The morphology of follicular cells hybridizing with the IL-6 probe or labeled with an anti-IL-6 monoclonal antibody suggested that follicular dendritic cells expressed the IL-6 gene. In contrast, no IL-6 gene expression was detected inside follicles of the six other CD lymph nodes or of the five control lymph nodes. In interfollicular areas, IL-6 gene-expressing cells were detected in all lymph nodes by both in situ hybridization and immunohistochemistry. In CD lymph nodes, positive cells were located outside sinuses, in close contact with blood vessels and plasma cells. This distribution was clearly different from that observed in control lymph nodes, in which IL-6 gene-expressing cells were present inside sinuses. A similar difference between CD and control lymph nodes was observed for the distribution of IL-1 beta and IL-1 alpha gene-expressing cells in interfollicular areas. The morphology of interfollicular IL-6-producing cells was heterogeneous, consistent with that of macrophages, interdigitating cells, lymphocytes, and endothelial cells, and different from that of plasma cells. Taken together these results show that CD is consistently associated with a particular pattern of IL-6 gene expression in interfollicular areas whereas elevated IL-6 gene expression inside follicles only occurs in the localized form of the disease associated with systemic manifestations. The variable pattern of IL-6 gene expression as well as the clinical and histologic heterogeneity of CD indicate that different immune mechanisms may be involved in the different forms of this disease.     

胸部受累的巨淋巴结增生症10例临床分析

目的 提高对少见胸部受累的巨淋巴结增生症的认识,减少误诊,延长患者的生存期.方法 2000年1月至2006年5月对10例胸部受累的巨淋巴结增生症患者的临床表现、影像学、病理学、鉴别诊断、治疗及预后进行研究.结果 10例胸部受累的巨淋巴结增生症患者均为女性,其中5例多中心型患者的年龄为29～49岁,临床表现多样,外周淋巴结多处肿大伴多系统损害,影像学表现为间质性肺炎和纵隔淋巴结肿大,病理分型均为浆细胞型,给予糖皮质激素或化疗后4例部分缓解,1例死于心肺衰竭.5例局灶型患者的年龄为13～49岁,均无症状体征,实验室检查无异常,病灶均位于右侧纵隔,直径6～9 cm,病灶呈均匀显著强化,病理分型均为透明血管型,经手术切除肿块,5例随访均存活.结论 胸部受累的巨淋巴结增生症易误诊,有多发淋巴结肿大或局灶巨大淋巴结者应警惕该病的发生.诊断的关键在于早期多次、多部位淋巴结病理检查,与血管同步显著强化的影像学表现具有诊断价值.     

Expression of vascular endothelial growth factor in sera and lymph nodes of the plasma cell type of Castleman's disease

To evaluate the possible involvement of vascular endothelial growth factor (VEGF) in the pathogenesis of Castleman's disease, we studied VEGF levels in sera and supernatants of cultured lymph nodes from two patients with the plasma cell type of Castleman's disease, and analysed the expression of VEGF immunohistochemically in the lymph nodes. Clinically, one patient was classified as the localized type and the other as the multicentric type. Histologically, mature plasma cells and hyalinized vessels were prominent in the interfollicular region. The VEGF levels of the sera and the supernatants of cultured lymph nodes of both patients were higher than those of normal controls. VEGF was strongly expressed in plasma cells in the interfollicular region of the lymph nodes of both patients, but rarely in normal lymph nodes. Our results suggest that VEGF may be involved in the marked vascular proliferation in the interfollicular region of the lymph nodes of the plasma cell type of Castleman's disease.     

Interleukin-6-producing giant cell carcinoma of the lung with multicentric Castleman's disease-like presentation

We encountered a 59-year-old man with advanced lung cancer with multiple swollen lymph nodes. At autopsy the lung cancer was revealed as giant cell carcinoma. Microscopic examination showed no cancer cells, but there was polyclonal proliferation of plasma cells in the lymph nodes and in the bone marrow. In the kidneys, proliferation of mesangial matrices and mesangial cells was found. This presentation resembled multicentric Castleman's disease (MCD), in which interleukin-6 (IL-6) has a great role. Immunohistochemical staining was positive for IL-6 in cancer cells. This is the first reported case of an IL-6-producing giant cell carcinoma of the lung with MCD-like presentation.     

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

Castleman's disease is a syndrome consisting of giant lymph node hyperplasia with plasma cell infiltration, fever, anemia, hypergammaglobulinemia, and an increase in the plasma level of acute phase proteins. It has been reported that clinical abnormalities disappear after the resection of the affected lymph nodes, suggesting that products of lymph nodes may cause such clinical abnormalities. Interleukin-6 (IL-6) is a cytokine inducing B-cell differentiation to immunoglobulin-producing cells and regulating biosynthesis of acute phase proteins. This report demonstrates that the germinal centers of hyperplastic lymph nodes of patients with Castleman's disease produce large quantities of IL-6 without any significant production of other cytokines. In a patient with a solitary hyperplastic lymph node, clinical improvement and decrease in serum IL-6 were observed following surgical removal of the involved lymph node. There was a correlation between serum IL-6 level, lymph node hyperplasia, hypergammaglobulinemia, increased level of acute phase proteins, and clinical abnormalities. The findings in this report indicate that the generation of IL-6 by B cells in germinal centers of hyperplastic lymph nodes of Castleman's disease may be the key element responsible for the variety of clinical symptoms in this disease.     

Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome

To evaluate a possible implication of cytokines in the pathogenesis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, we studied five consecutive patients with this condition, of which four had sclerotic bone lesions and four had multicentric Castleman's disease. Interleukin-1 beta (IL-1 beta) and IL- 6 serum levels were determined in these patients (13 serum samples) and in patients with multiple myeloma (5) and Waldenstrom's macroglobulinemia (5). In situ hybridization of the relevant mRNAs was performed on lymph node specimens of two patients with POEMS syndrome who had Castleman's disease. Elevated serum levels of IL-1 beta (13/13 samples), and IL-6 (7/13 samples) were found in patients with POEMS syndrome. In the other patients, serum IL-1 beta was undetectable or slightly increased and IL-6 was elevated in a single patient with Waldenstrom's macroglobulinemia. Abundant IL-1 beta mRNA-producing cells were present in interfollicular spaces in the two tested patients, while IL-6 mRNA-producing cells were rare. We conclude that IL-1 beta and IL-6 serum levels may be chronically elevated in patients with POEMS syndrome, and that lymph node may be one site of IL-1 beta overproduction. These results are in keeping with the hypothesis that cytokines mediate systemic manifestations of POEMS syndrome.     

A case of multicentric Castleman's disease with pulmonary involvement]

In a man aged 34 who had been experiencing frequent coughing since November 2001, a chest radiograph showed infiltration shadows in both lung fields. Chest CT showed diffuse centrilobular nodules and multiple mediastinal lymphadenopathy. Laboratory examination revealed high values for C-reactive protein and the erythrocyte sedimentation rate, together with polyclonal hyperimmunoglobulinemia and an elevated interleukin-6 level. We suspected multicentric Castleman's disease, and so performed thoracoscopic mediastinal lymph node biopsy and lung biopsy. The former disclosed follicular hyperplasia and plasma cell infiltration in the interfollicular area, suggesting a diagnosis of Castleman's disease, plasma cell type. The lung biopsy showed heavy infiltration of plasma cells. The diagnosis was therefore multicentric Castleman's disease (MCD) with pulmonary involvement. The chest CT findings were tpical characteristics of pulmonary involvement in patients with MCD.     

Castleman's disease (giant lymph node hyperplasia): clinical, biological and developing polymorphism. Apropos of 4 cases

Four cases of plasma cell type Castleman's disease (CD) are described. Two patients had localized forms (one mediastinal and the other mesenteric) and presented systemic manifestations associated with hypergammaglobulinemia and severe anemia. In both cases, the lesions were revealed by computerized tomography scans and cures were obtained by the complete surgical removal of the masses, which led to the rapid disappearance of the systemic manifestations. The other 2 patients had the multicentric form of CD and presented more extensive clinical and biological symptoms. One of these developed severe peripheral neuropathy and endocrine anomalies during the late phase of his disease, which led us to discuss the relationship between multicentric CD and the POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin change) syndrome first described in Japan. Three of our patients presented with hypochromic microcytic anemia too severe to be explained by an inflammatory syndrome alone, and was likely due to several mechanisms. The etiology of CD remains unknown. The histological characteristics of angiofollicular lymph node hyperplasia are among the most important criteria for the diagnosis of localized and multicentric forms of CD, which can easily be made on a lymph node biopsy. However, it must be noted that this lesion can also be observed (but only rarely) in HIV (human immunodeficiency virus) - infected patients. The localized form is always considered to be benign, but, to date, there is no formal argument definitively supporting the malignancy of the multicentric one, in spite of its clinical similarity to a lymphoproliferative syndrome.     

Castleman's disease: A rare lymphoproliferative disorder

Castleman's disease (CD) is an atypical lymphoproliferative disorder. Since it was first described in 1956, it has been referred to as follicular lympho-reticuloma, angiofollicular mediastinal lymph node hyperplasia, and benign giant lymphoma. CD is a heterogeneous disease that can be either localized or systemic (multicentric). The localized form can be divided into two types: the hyaline-vascular (HV) type or the plasma cell (PC) type. The former usually produces few symptoms and histological features include abnormal follicles and increased interfollicular vascularity. The PC type, in which, histopathologically, the presence of sheets of mature plasma cells is the distinguishing feature, is more likely to produce clinical symptoms such as fever, night sweats, and lymphadenopathy. The multicentric form mimics the PC type of localized CD, and patients present with systemic symptoms. In this report, we discuss the spectrum of clinical and pathological findings in localized and multicentric CD.     

Immunodeficiency and IL-6 production by peripheral blood monocytes in multicentric Castleman's disease

Summary. To study the pathogenesis of multicentric Castleman's disease (MCD), IL-6 producing cells and immune function were investigated in four MCD patients. The expression of IL-6 mRNA in one MCD lymph node was analysed by in situ hybridization. IL-6 mRNA expressing cells were scattered in the interfollicular areas and did not resemble plasma cells. Spontaneous IL-6 production was detected in the culture supernatants of peripheral blood mononuclear cells (PBMNC) from four patients. The IL-6 producing cells among the PBMNC were found to be monocytes by both in situ hybridization and immunohistochemistry. We evaluated immune function in four MCD patients. These studies show: (1) a negative PPD skin test in 3/4 patients. (2) decreased IL-2 production in 3/4 patients, (3) decreased T cell colony formation in 3/4 patients, (4) decreased NK activity and NK cell number in 2/4 patients, (5) increased soluble IL-2 receptor in 4/4 patients, and (6) decreased CD4/CD8 ratio in 3/4 patients. These results show that MCD resembles, in several ways, acquired immunodeficiency syndrome (AIDS).     

Localized Castleman's disease and nephrotic syndrome not responsive to resection plus colchicine therapy

We describe one patient with localized Castleman's disease (CD) of the mixed hyaline vascular and plasma cell type located at the mesentery of the small bowel, associated with systemic amyloidosis and nephrotic syndrome. A true nephrotic syndrome has rarely been reported in patients with CD. In the literature, it has been suggested that clinical and laboratory manifestations generally improved after surgical resection of the tumor. However, in our case, clinical and laboratory findings did not regress after operation followed by colchicine therapy.     

AL amyloidosis manifesting as systemic lymphadenopathy

We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. Two of the patients were considered to be classifiable as primary systemic AL amyloidosis based on the presence of M-protein in serum and abnormal plasma cells or lymphoplasmacytoid cells in the bone marrow probably producing the precursor immunoglobulin, although no visceral organs were affected. The size of the involved lymph nodes in these two patients increased gradually, and one was treated with rituximab and VAD (vincristine, doxorubicin and dexamethasone) followed by high-dose melphalan with autologous peripheral blood stem cell transplantation (auto-PBSCT). The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.     

Frequent detection of Kaposi's sarcoma herpesvirus in germinal centre macrophages from AIDS-related multicentric Castleman's disease

Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma is able to infect several cell types. By investigating hyperplastic lymph nodes from AIDS patients with multicentric Castleman's disease, we demonstrate, for the first time, by dual colour immunohistochemistry, that KSHV is frequently detectable in germinal centre macrophages. These macrophages, which display a latency programme and frequently contain apoptotic bodies, may represent a non-negligible reservoir for the virus in lymphoid organs.     

Interleukin-6-producing dermoid cyst associated with multicentric Castleman’s disease

Dysregulated overproduction of interleukin-6 (IL-6) from activated B cells in affected lymph nodes has been implicated in the pathogenesis of multicentric Castleman’s disease (MCD), a rare lymphoproliferative disorder accompanied by systemic manifestations. We here report the case of a 32-year-old female presenting with MCD associated with a dermoid cyst in the pelvic cavity. The co-occurrence of MCD and dermoid cyst has not been reported before. Immunohistochemical analysis of the tissue sections showed IL-6 production in CD68-positive macrophage cells, which had infiltrated the dermoid cyst. Removal of the cyst resulted in partial improvement in systemic symptoms accompanied by a decrease in serum IL-6, while complete improvement was obtained by treatment with an anti-IL-6 receptor antibody following resection of the dermoid cyst. To the best of our knowledge, this is the first study to provide evidence of IL-6 production by CD68⁺ cells in a dermoid cyst involved in MCD.     

A benign course of multicentric Castleman's disease with involvement of the spleen and bone marrow

The multicentric variant of Castleman's disease (MCCD) is associated with a rapidly progressive and fatal course. The case described herein manifested unique clinical and histological features. Initial presentation as isolated splenomegaly was subsequently followed by widespread organ involvement, including lymph nodes and bone marrow. In spite of this, the patient had a very benign course of her disease. The case serves to expand even further the already wide clinical spectrum of Castleman's disease.     

Localized Castleman's disease: description of a case and review of the literature

Castleman's disease is a rare entity which is caracterized by its histological features: hyperplasia of lymph nodes and capillary proliferation. Two histological patterns has been described: hyaline vascular type and plasma cell type. From a clinical viewpoint has been identified two different clinical course: a localized type (ECL) usually of benign clinical course and a multicentric type (ECM) of worst prognosis. We present a case of Castleman"s disease localized in the neck region in which the excision was both diagnostic and therapeutic. The variety histological was hyaline-vascular type.     

Is there a place for interferon-alpha in the treatment strategy of multicentric Castleman's disease?

INTRODUCTION: Castleman's disease is an unusual condition of unknown cause, consisting of massive proliferation of lymphoid tissue. Two forms (localized and multicentric) have been described. Interleukin-6 (IL-6) is at the core of the disease, being responsible for most of the clinical and biological signs that may be observed. Despite the benignancy of this pre-lymphoma condition, its course is usually aggressive and of poor prognosis in regard to the multicentric form. No consensus regarding treatment has been defined. Available data on the multicentric form of the disease are to scarce to allow any conclusion about the treatment timing and type of chemotherapy best suited to this condition. We report the case of a patient in whom interferon alpha (IFN-alpha) was used as first line treatment. EXEGESIS: The case of a 52-year-old man with multicentric Castleman's disease combined with high IL-6, in whom, however, testing for human herpes virus-8 proved to be negative, is described. Interferon alpha (4.5 MU/m2 three times per week during 18 months) administered as first line treatment induced dramatic improvement in the patient's general condition and normalization of the tumoral syndrome. Moreover, biological parameters and IL-6 returned to normal. Two years after interferon disruption, complete remission is still present. CONCLUSION: On the basis of the present data and those of two previous observations, anti-IL-6 and anti-infective properties of IFN-alpha are discussed. Treatment of multicentric Castleman's disease is based on corticosteroids and drugs derived from those pertaining to treatment of malignant lymphomas. Our results indicate that IFN-alpha is truly directed against Castleman's disease and has less toxicity than drugs usually prescribed. This argues for early use of IFN-alpha in Castleman's disease, in association or not with corticosteroids.     

Multicentric angiofollicular lymph node hyperplasia with peripheral neuropathy, pseudotumor cerebri, IgA dysproteinemia, and thrombocytosis in women. A distinct syndrome

Four women with multicentric angiofollicular lymph node hyperplasia had a distinct clinical syndrome characterized by peripheral neuropathy, pseudotumor cerebri, IgA dysproteinemia, and thrombocytosis. The nodes displayed typical morphologic changes of the plasma cell variant of multicentric angiofollicular lymph node hyperplasia. The pathologic changes are morphologically distinct from angioimmunoblastic lymphadenopathy with dysproteinemia although clinical similarities do exist. In these four cases, the lymphadenopathy was usually bulky and multicentric. There was frequent splenic involvement. The neuropathies were severe and disabling. Clinical courses have been variable with some responses to therapy with steroids and alkylating agents. No neoplastic transformations have occurred. Multicentric angiofollicular lymph node hyperplasia may represent a reactive lesion in which the antigenic stimulus is unknown but results in follicular hyperplasia, angiogenesis, and the systemic manifestations of hyperimmune stimulation. We believe this clinical syndrome may represent a distinct variant of multicentric angiofollicular lymph node hyperplasia, and it requires close observation for neoplastic transformation and other complications of its multisystem nature.     

Autoimmune findings resembling connective tissue disease in a patient with castleman's disease

Summary Multicentric angiofollicular lymphnode hyperplasia (multicentric Castleman's disease) may be associated with acute phase reaction and several autoimmune features. Since lymphadenopathy is a common feature in connective tissue disease, a clear distinction between the different disease entities may be difficult. We describe a 26-year-old male patient with predominant cervical lymphadenopathy, hepatosplenomegaly and polyserositis, diagnosed as collagen disease. He showed several autoimmune features including autoimmune haemolytic anaemia, cryoglobulinaemia, positive antinuclear and anti smooth muscle antibodies, serum immune complexes and a sensorimotor polyneuropathy. Under immunosuppressive therapy with prednisolone and azathioprine, only partial remission was achieved. Repeated lymph node biopsy together with the clinical features led to the diagnosis of multicentric Castleman's disease in this patient nine years later. Interleukin-6 seems to play an important role in the pathogenesis of clinical and serum biochemical features in patients with Castleman's disease.