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Previous Volume 330:602-605 March 3, 1994 Number 9 Next

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Castleman's disease (angiofollicular lymphoid hyperplasia) is a heterogeneous group of lymphoproliferative disorders of uncertain cause¹. Two pathologic types, hyaline vascular and plasma-cell disease, have been recognized. The plasma-cell variant of Castleman's disease may be localized or multicentric. Multicentric disease is a systemic lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, and constitutional symptoms. Anemia, hypoalbuminemia, and hypergammaglobulinemia are also common. Interleukin-6, a cytokine with pleiotropic effects on the immune system, hematopoiesis, and acute-phase reactions, is a putative growth factor in multiple myeloma and may also be central to the pathophysiology of Castleman's disease^2,3,4,5,6,7. Administration of a murine anti-interleukin-6 monoclonal antibody (BE-8) was reported to have a transient beneficial effect in one patient with plasma-cell leukemia⁸.

We treated a man who had Castleman's disease and an elevated serum interleukin-6 concentration with a prolonged course of BE-8 monoclonal antibody. The symptoms and signs of disease resolved, and most of the abnormal laboratory values improved dramatically within a few days, but the abnormalities returned on cessation of therapy. Because of a persistent mesenteric mass, the patient was treated with high-dose dexamethasone. Ultimately, the mass was resected, resulting in a sustained remission of all clinical and biochemical manifestations of the disease.

Methods

BE-8 monoclonal antibody⁹ was administered in a dose of 40 mg given intravenously during a one-hour period daily for 2 days, followed by daily doses of 10 mg given intravenously for 82 days. Serum interleukin-6 concentrations were determined with an enzyme-immunoassay kit (Amgen, Thousand Oaks, Calif.). Tissue sections from the patient were used to study cytokine expression in situ. The sections were fixed with B5 (a mercury-based fixative) and embedded in paraffin. To determine the distribution of cells in the tissue sections, staining was performed with monoclonal antibodies that are reactive with B cells (L26, CD20), T cells (Leu-22, CD43), histiocytes (Ki-M1P), plasma cells (cytoplasmic immunoglobulin), or follicular dendritic cells (S-100). The expression of interleukin-6 by lymphoid cells or histiocytes was determined by immunostaining with rabbit antihuman interleukin-6 antibody (Genzyme, Boston), by means of the avidin-biotin-peroxidase method¹⁰. The anti-interleukin-6 antibody was added at a dilution of 1:100, followed by the addition of biotin-labeled goat antirabbit immunoglobulin (dilution, 1:400). After the tissue sections had been washed, they were incubated with avidin-biotin-peroxidase, and the reaction was developed with diaminobenzidine. The sections were then counterstained with hematoxylin, dehydrated, and cleared as in routine processing. In addition, paraffin sections were immunostained for interleukin-1, -4, -7, -8, and -9; granulocyte colony-stimulating factor; and granulocyte-macrophage colony-stimulating factor, as previously described¹¹.

Case Report

A 27-year-old man saw his physician in March 1987 because of a persistent cough, fatigue, and anemia. He had no history of syphilis or autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosus. The physical examination was normal. The patient's hemoglobin concentration was 7.6 g per deciliter (4.7 mmol per liter), the mean corpuscular volume was 57 microm³, the platelet count was 733,000 per cubic millimeter, the serum iron concentration was 25 µg per deciliter (4.5 µmol per liter), the total iron-binding capacity was 330 µg per deciliter (59 µmol per liter), and the ferritin concentration was 283 ng per milliliter. The bone marrow examination was normal. No specific diagnosis was made, and the patient was followed.

In November 1987, a computed tomographic (CT) scan of the abdomen showed a mesenteric mass measuring 10 by 14 by 4 cm. The patient underwent an exploratory laparotomy in December 1987 with a biopsy of the mesenteric mass and liver and a splenectomy. A histologic examination of the biopsy specimens revealed the plasma-cell variant of Castleman's disease in the mass and liver; the spleen was normal. The patient was followed with CT scanning but received no systemic therapy. The remaining mesenteric mass and the hemoglobin concentration were stable until July 1990, when the patient was referred to the University of Arkansas Cancer Research Center.

At that time, the patient reported fatigue and had a low-grade fever (temperature, 37.8 °C). The physical examination was normal. A chest roentgenogram revealed no abnormalities, and repeated blood cultures were negative. Abnormal laboratory values included a hemoglobin concentration of 9 g per deciliter (5.6 mmol per liter), a white-cell count of 14,600 per cubic millimeter, a platelet count of 1,360,000 per cubic millimeter, a total serum protein concentration of 8.6 g per deciliter, an albumin concentration of 2.1 g per deciliter with polyclonal hypergammaglobulinemia (3.5 g per deciliter) on serum protein electrophoresis, an alkaline phosphatase concentration of 440 U per liter (7.3 microkat per liter), an interleukin-6 concentration of 45 pg per milliliter, and a C-reactive protein concentration of 16.7 mg per deciliter. Monoclonal plasma cells were not detected by flow-cytometric studies of bone marrow specimens; immunoelectrophoresis of serum and urine samples did not disclose monoclonal gammopathy. On review, the biopsy specimens of the mesenteric mass from December 1987 were interpreted as showing mixed plasma-cell and hyaline vascular variants of Castleman's disease, and the liver-biopsy specimens were interpreted as normal.

With the approval of the institutional review board and the consent of the patient, he was treated with BE-8 monoclonal antibody for 84 days. His fever and constitutional symptoms improved within 24 hours; however, one to two weeks were required for the hemoglobin concentration to increase and for the platelet count to decrease (Figure 1). The serum interleukin-6 concentration increased markedly during therapy and returned to the base-line value after the treatment had been discontinued; the mesenteric mass did not change. Fever, constitutional symptoms, anemia, thrombocytosis, and other biochemical abnormalities recurred within a few days after the therapy had been discontinued. The patient was then treated with three cycles of dexamethasone at 35-day intervals. During each cycle, an oral dose of 40 mg of dexamethasone was given daily for four days on three occasions, each separated by four days. This treatment had little effect on symptoms, laboratory values, or the mesenteric mass. Approximately two and a half months later, the mass was resected. No clinical or biochemical signs of disease remained after the operation (Figure 1). The mesenteric mass proved to be a mass of lymph nodes and showed mixed hyaline vascular and plasma-cell Castleman's disease on histologic examination (Figure 2).

View larger version (63K): [in this window] [in a new window]   Figure 1. Changes in the Hemoglobin Concentration, Platelet Count, and Serum Biochemical Values in a Patient with Castleman's Disease, during Treatment with Anti-Interleukin-6 Monoclonal Antibody (BE-8) (Dark Shading) and Dexamethasone (Light Shading) and after Resection of the Mesenteric Lymph Nodes (Arrows).

 

View larger version (130K): [in this window] [in a new window]   Figure 2. Photomicrographs of Sections of Mesenteric Lymph Nodes from the Patient. Panel A and Panel B show sections stained with hematoxylin and eosin, and the other panels show immunohistologic sections counterstained with hematoxylin (Panel D, Panel E, and Panel F) or methyl green (Panel C and Panel G). The brownish areas in Panels C, D, E, F, and G represent antigens detected by appropriate antibodies with the avidin-biotin-peroxidase method. The sections contained hyperplastic follicles (G) with a mantle layer of varying thickness (M) surrounded by numerous plasma cells (P). The follicles were composed primarily of a mixture of cleaved and noncleaved small and large cells expressing cytoplasmic interleukin-6 (Panel C) and CD20 (a B-cell antigen) (Panel D). Scattered CD43-positive T lymphocytes (Panel E), rare Ki-M1P-positive macrophages (arrow, Panel F), and S-100-positive follicular dendritic cells (arrows, Panel G) were also present. (Panel A, Panel C, and Panel E, x160; Panels B, D, F, and G, x250.).

 
An immunohistochemical analysis of the lymph nodes removed during the second operation showed abundant interleukin-6 staining in cells in germinal centers, in large transformed lymphoid cells, and in immunoblastoid cells in both the mantle layer and interfollicular areas (Figure 2C). The specificity of the interleukin-6 staining reaction was confirmed by studies of control sections in which the primary antibody had been omitted or anti-interleukin-6 antibody had been preabsorbed with recombinant interleukin-6. The interleukin-6-positive cells were B cells, as shown by their staining pattern with monoclonal antibody L26 (CD20) (Figure 2D). Very few T cells, histiocytes, or follicular dendritic cells were present in the germinal centers. Probably because of interleukin-6 secretion by germinal-center cells, there was also extracellular staining of interleukin-6. The mantle-layer lymphocytes showed only weak staining for interleukin-6. T lymphocytes and plasma cells did not stain for interleukin-6. Germinal-center cells did not stain for the other cytokines studied. The degree of background staining for other cytokines did not differ from that in nonspecific reactive lymphoid tissue.

Discussion

After the original report in 1956 by Castleman et al. describing a group of patients with benign localized enlargement of hyperplastic lymph nodes,¹² Keller et al. divided Castleman's disease into two types: a hyaline vascular variant consisting of small hyaline vascular follicles and interfollicular-capillary proliferation and a plasma-cell variant consisting of large follicles with intervening sheets of plasma cells¹³. Yoshizaki et al. noted elevated serum interleukin-6 concentrations in patients with Castleman's disease, which declined to normal values after the lymph-node masses had been resected. Interleukin-6 was detected in germinal-center B cells and in the supernatant of cultured lymph nodes¹⁴.

As reported in a patient with myeloma,⁸ the monoclonal antibody BE-8, which neutralizes interleukin-6, temporarily controlled the symptoms and corrected many of the biochemical abnormalities in our patient with mixed hyaline vascular and plasma-cell Castleman's disease. C-reactive protein is an indicator of interleukin-6 activity in vivo³. Although the initial doses of BE-8 lowered the serum C-reactive protein concentration from 16.7 to 0.9 mg per deciliter, the concentration increased to about 4 mg per deciliter during maintenance therapy. Most of the other abnormal laboratory values also improved during BE-8 therapy and worsened after it was discontinued. The extremely high serum interleukin-6 concentration during therapy (10,000 pg per milliliter) probably represented circulating complexes of BE-8 and interleukin-6. High doses of dexamethasone, given with the expectation that they would reduce the production of interleukin-6,² ameliorated the patient's symptoms and biochemical abnormalities, although less effectively than BE-8.

The resection of the lymph-node mass corrected all abnormalities, as reported in other patients¹⁴. The presence of interleukin-6 in polyclonal B cells in germinal centers and in immunoblasts of interfollicular zones suggests that the high serum interleukin-6 concentration resulted from its production in hyperplastic lymph nodes.

That the symptoms and biochemical abnormalities were controlled by anti-interleukin-6 monoclonal antibody and subsequent resection of the enlarged mesenteric lymph nodes suggests that interleukin-6 has a key role in the pathophysiology of Castleman's disease. The presence of interleukin-6 in various B cells except plasma cells is consistent with recent studies of multiple myeloma, a disease in which interleukin-6 is expressed and produced by preplasma cells but not by mature plasma cells¹⁵.

Supported in part by a grant (CA-55819) from the National Cancer Institute.

We are indebted to Mrs. Sandy Mattox for technical assistance and Mrs. Madeline Scallan for assistance in the preparation of the manuscript.

Source Information

From the Departments of Medicine and Pathology, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences (J.T.B., D.V., K.H., S.J., B.B.), and the Department of Pathology, John L. McClellan Memorial Veterans Hospital (S.-M.H.) -- both in Little Rock; the Department of Hematology, Centre Hospitalier Universitaire, Nantes, France (R.B., B.K.); and the Innotherapie Laboratoires, Besancon, France (J.W.).

Address reprint requests to Dr. Barlogie at the University of Arkansas for Medical Sciences, Slot 508, 4301 W. Markham, Little Rock, AR 72205.

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