Multicentric Castleman’s disease in human immunodeficiency virus infection: two case reports

Castleman’s disease (CD) was described in 1954 in a case report of a 40-year-old man presenting a mediastinal mass characterized histologically as lymph node hyperplasia and follicles with small hyalinized foci [1, 2]. In the United States of America (USA), the incidence of CD is estimated to be approximately 21 to 25 cases/million people per year, with 23% of these cases potentially representing the multicentric form of CD [3, 4]. CD is classified into unicentric and multicentric forms. The unicentric or localized form, the most common type, occurs around 35 years of age [5], involving only one chain of lymph nodes. Thoracic, mediastinal, or abdominal lymph nodes are mostly affected. In the multicentric or disseminated form, the most affected age group comprises individuals between 50 and 60 years of age [6], in which there is involvement of a larger number of lymph nodes with more important systemic involvement. CD can result in malignant neoplasms such as Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. There are three histological variants: hyaline vascular, plasma cells, and mixed [7, 8]. The literature data about multicentric CD (MCD) are limited for patients in their fourth and fifth decades of life. We present two rare cases of MCD in a 41-year-old feoderm men and a 35-year-old feoderm men, which were initially thought to be due to tuberculosis.

The majority of patients diagnosed with Castleman's Disease (CD) are typically between 30 and 40 years (middle-aged individuals). The etiopathogenesis is poorly understood although there can be association with HHV-8 and HIV infection [1]. One of the explanations is a reactive hyperplasic lymphoid initiated by chronic antigenic stimulation in association with a viral infection mainly in the respiratory and gastrointestinal tract. Another hypothesis suggested that the cause might be a lack of immune regulation with increased expression of the interleukin (IL)-6 gene, a cytokine with pleiotropic effects on the immunological system and hematopoiesis, which is related to the etiology of multiple myeloma [2].

Regarding the histological classification, there are three variants: hyaline vascular, plasma cell, and mixed variant. Hyaline vascular are multiple tight aggregates of follicular dendritic cells with concentric form. Plasma cell variants show hyaline vascular changes with polytypic plasma cells. The histological plasma form, found in both cases in this study, occurs around 10% in the unicentric form and in 80–90% in the multicentric form [1]. Regarding the age group, it can affect individuals of any age; the localized form of the disease has a higher incidence in adolescents and young adults, whereas the multicentric form affects older individuals and patients with immunodeficiency, especially in AIDS, more, as observed in both cases of this report. Individuals living with HIV/AIDS appear to be at increased risk of developing multicenter CD, which usually arises concomitantly with KS as occurred in the first case reported in this study [3].

When present in the multicentric form, it is usually symptomatic, due to the release of cytokines: tumor necrosis factor (TNF)-alpha, IL-1, and IL-6. In both cases, asthenia, weight loss, and fever were recorded as the main clinical manifestations of CD [3, 4]. Polyadenopathy is common and presents on average with four involved sites and is frequently associated with hepatosplenomegaly [3, 4]. Laboratory test results usually indicate thrombocytopenia, hypergammaglobulinemia, hypoalbuminemia, and anemia. Diagnosis can only be defined by histological examination of the ganglion or tissue affected by the lymphoproliferative process. Some thymomas and lymphomas have a similar appearance to CD in anatomopathological examination, and an immunohistochemical study is sometimes necessary to confirm the diagnosis.

From a clinical and imaging perspective, CD is indistinguishable from other lymphoproliferative diseases. It also presents radiological and surgical features similar to: other diseases including neoplasms, reactive lymph node hyperplasia, and HIV infection; autoimmune diseases, such as rheumatoid arthritis and Sjögren’s syndrome; inflammatory diseases, such as sarcoidosis and tuberculosis; or neoplasms such as neurofibroma; and Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. Syndromic symptoms misdiagnosed as tuberculosis have CD as an important differential diagnosis, which is often described in the literature [3].

Localized CD is treated by surgical excision that allows complete recovery without relapse in almost all cases [3]. However, there is no therapeutic consensus for MCD and several treatments such as surgery, corticosteroid therapy, and chemotherapy are proposed, often in combination [3]. Anti-IL-6 antibody has also been successfully tested for the relief of systemic manifestations in patients who are HIV/HHV-8 negative [3, 6, 7].

Ganciclovir, interferon-α, or rituximab may be the best option for patients with MCD with HHV-8 infection [8], while CHOP or cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) may be better suited for patients with severe systemic manifestations [9]. Considering the limited experience in the treatment of CD, the administration of anti-CD20 monoclonal antibody (rituximab) was chosen in the first case presented, due to the impossibility of surgical resection of the mass, as this option is pointed out in the literature as effective in the treatment of immune manifestations, such as hemolytic anemia associated with CD [8]. Hemolytic anemia may possibly be a consequence of the production of cytokines that inhibit hematopoiesis. In the second case, it was decided to use the combination of CHOP, since some authors suggested starting treatment with corticosteroids and chemotherapy [9‐11].

Unlike the localized form, the plasma type has a less favorable prognosis and its clinical evolution is frequently aggressive and fatal due to the development of infections and neoplasias, such as KS and lymphomas [3, 9, 12]. Our two patients had a satisfactory evolution and to date there has been no relapse of the disease.

The reports of these cases reinforce the need to include CD in the differential diagnosis of lymphoproliferative diseases in individuals living with HIV/AIDS, requiring a high degree of clinical suspicion in order to arrive at the correct diagnosis and management. MCD may have a poor prognosis and depend on its stage at the moment of diagnosis, reinforcing the importance of histological diagnosis in patients presenting with lymphadenopathy.