Multicentric Castleman's disease,non-Hodgkin's lymphoma,and Kaposi's sarcoma: a rare simultaneous occurrence

A rare simultaneous occurrence of multicentric Castleman's disease, non-Hodgkin's lymphoma, and Kaposi's sarcoma was diagnosed in a 70-year-old man who presented with fever, polyarthralgia, weight loss, vascular purpura, anemia, generalized lymphadenopathy, and hepatosplenomegaly. He had no risk of HIV infection and serological tests for HIV were negative twice, but a low number of T-cells and a reversed CD4/CD8 ratio were observed. During hospitalization, he developed Kaposi's sarcoma at the right sole. Lymph node biopsies revealed multicentric Castleman's disease together with a large B-cell lymphoma, which showed monotypic IgM-lambda lymphocytes. To our knowledge, this is the first report in which systemic manifestations of all three diseases occurred simultaneously prior to any specific treatment. The altered immune status and human herpesvirus-8 infection might have played a role in the pathogenesis of this occurrence.     

Clonal rearrangement for immunoglobulin and T-cell receptor genes in systemic Castleman's disease. Association with Epstein-Barr virus

Castleman's disease is a morphologically and clinically heterogeneous lymphoproliferative disorder. Both a localized benign variant and an aggressive form with systemic manifestations have been described. To investigate the differences between these variants of Castleman's disease, the authors analyzed lymph node DNA from 4 patients with the localized type and 4 with the systemic type of Castleman's disease for immunoglobulin and T-cell receptor gene rearrangements. The role of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was also studied by viral genomic DNA probes. They detected clonal rearrangements in 3 of the 4 patients with the systemic variant of Castleman's; no patients with localized disease had rearrangements. Copies of EBV genome were also detected in 2 of the 3 patients with clonal rearrangements. These results suggest that systemic Castleman's disease is a disorder distinct from the classical localized variant in that it may evolve into a clonal lymphoproliferation.     

Primary extranodal non-Hodgkin's lymphoma

A total of 52 of 238 patients (22%) with non-Hodgkin's lymphoma presented with disease in a primary extranodal site. The gastrointestinal tract was the commonest site involved (50%) and diffuse large cell was the commonest histological sub-type of the lymphoma (64%). Survivorship analysis of these patients, treated predominantly with chemotherapy, suggests that long-term survival is associated with: low-grade malignancy--median survival greater than 120 months; localized disease or spread of disease confined to the regional lymph nodes--median survival 65.5 months; and the use of aggressive combination chemotherapy for intermediate grade malignancy when the disease is localized or spread is confined to the regional lymph nodes--median survival greater than 110 months.     

No increased human herpesvirus 8 seroprevalence in patients with HIV-associated non-Hodgkin's lymphoma

Human herpesvirus 8 (HHV-8) is closely associated with Kaposi's sarcoma (KS), HIV-associated Castleman's disease, and primary effusion lymphoma. As a high frequency of non-Hodgkin's lymphoma (NHL) has been reported in patients with HIV-associated KS, we hypothesized that HHV-8 infection could be indirectly implicated in the pathogenesis of NHL. We assessed the prevalence of HHV-8 antibodies in 63 patients with NHL compared with 126 HIV-infected matched control patients without NHL. Serum samples from cases and controls were assayed for antibodies to HHV-8 lytic and latent antigens using an indirect immunofluorescence assay. In patients with concordant serologic results, HHV-8 antibodies were detected in 41.5% of the NHL cases and 37% of the controls. This absence of a significant difference in HHV-8 seroprevalence between cases and controls (p =.73) does not support a possible role for HHV-8 infection in the development of NHL in HIV-infected patients.     

Ornithine decarboxylase gene expression in Castleman's disease

Castleman's disease (CD) is a rare atypical lymphoproliferative disorder that is clinically and histologically heterogeneous and is associated with the risk of developing malignant lymphoma. Based on pathological findings CD is divided into two types: a localized form and a multicentric form. The clinical course differs in these two forms. We examined the molecular mechanisms that lie between benign and malignant disease, evaluating a possible implication of oncogenes in the pathogenesis. Since deregulated expression of the gene for ornithine decarboxylase (ODC) has been observed in a variety of human malignancies, we compared ODC expression between the localized and multicentric forms. Using northern blot analysis we found that ODC gene expression clearly differs between the localized and multicentric forms. The findings in this report indicate that the variable pattern of ODC gene expression in the different types of CD could be useful for examining the evolution of this disease.     

Primary large-cell lymphomas of the mediastinum.

The mediastinum is a frequent site of involvement for malignant lymphoma. The most common types encountered in this location include Hodgkin's and non-Hodgkin's lymphoma and lymphoblastic lymphoma. With the exception of lymphoblastic lymphoma in children and adolescents, most cases of mediastinal involvement by lymphoma represent part of systemic disease and do not generally pose difficulties for diagnosis. However, a relatively small group of tumors have become increasingly recognized in recent years that are primarily localized in the anterior mediastinum and show features of nonlymphoblastic/non-Hodgkin's large-cell lymphoma. Because such tumors are capable of adopting unusual morphological appearances, they can often pose difficulties for diagnosis and be frequently mistaken for other conditions. This review discusses this group of neoplasms collectively known as diffuse large-cell lymphoma of the mediastinum. The clinicopathologic, immunohistochemical, and molecular genetic aspects of these tumors appear to indicate that a significant proportion of them may correspond to a distinctive type of lymphoproliferative process most likely arising from a native B-cell population of the thymus, thus representing, in essence, a primary extranodal large-B-cell lymphoma of the thymus.     

Multicentric Castleman's disease in HIV infection: a systematic review of the literature

The objective of this study is to systematically review the epidemiology and the clinical and virologic aspects of multicentric Castleman's disease in HIV-positive patients and to evaluate treatment strategies and outcome, especially in relation to HAART administration. The authors have conducted a systematic review of the English literature for all cases of newly diagnosed multicentric Castleman's disease in HIV-positive patients. The 25 studies which met the selection criteria included 84 HIV-positive patients with multicentric Castleman's disease (20 pre-HAART and 64 post-HAART era). Of them, the majority (90%) were men with 33 months median time from detection of HIV-positivity to multicentric Castleman's disease diagnosis in the HAART era. Fever and lymphadenopathy were the most common presenting symptoms and cytopenias, hypoalbuminemia, polyclonal hypergammaglobulinemia and raised C-reactive protein the most frequently revealed laboratory findings. Kaposi's sarcoma was present in 72% of the patients and respiratory system involvement in 34%. Although the majority of cases reported were positive for human herpesvirus-8, none of the reviewed patients was found to suffer from polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Of the 48 patients on HAART, 64% were already on HAART at multicentric Castleman's disease diagnosis, having a better immunologic profile and a lower incidence of Kaposi's sarcoma than the 35% of patients who initiated HAART after multicentric Castleman's disease diagnosis. Nevertheless, the two groups did not have significantly different mortality rates (30 vs. 38%). At multicentric Castleman's disease diagnosis, a wide range of CD4 counts was recorded, suggesting that disease presentation could occur at any CD4 count. With regard to treatment, the study confirmed the high rates of response with rituximab (anti-CD20 monoclonal). Monochemotherapy seems to give short-lived responses, which require maintenance to be sustained. Polychemotherapy with CHOP has given long-term remission in a subset of patients. Other regimens used in the treatment of HIV-related multicentric Castleman's disease were antiviral agents, immunomodulatory agents, and thalidomide. The fatality rate among HIV-related multicentric Castleman's disease cases reviewed was 44%, significantly lower than that of HIV-negative individuals (65%), while median survival of the latter was 29 months longer than that of HIV-infected individuals. The fatality rate among pre-HAART patients was 75 vs. 29% among HAART patients. Infection, multiorgan failure, Kaposi's sarcoma, non-Hodgkin lymphoma and progressive multicentric Castleman's disease were the most often reported causes of death. In conclusion, multicentric Castleman's disease is a lymphoproliferative disorder with an increasing prevalence in HIV-infected individuals. Even though life expectancy in multicentric Castleman's disease seems to have significantly improved in the HAART era, it remains a disease with a poor prognosis and an increased incidence of non-Hodgkin lymphoma in the HIV-context.     

Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma

BACKGROUND: Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. The identification of a common precursor of the two types of lymphoma would show definitively that Reed-Sternberg cells originate from B cells. METHODS: We studied lymphomas from two patients, one with a composite lymphoma (classic Hodgkin's disease and a follicular lymphoma in the same lymph node) and the other with a T-cell-rich B-cell lymphoma that was followed by classic Hodgkin's disease. Single Reed-Sternberg cells and non-Hodgkin's lymphoma cells from frozen sections were micromanipulated. The rearranged immunoglobulin variable-region genes (V genes) of the heavy and light chains were amplified by the polymerase chain reaction from genomic DNA and sequenced. RESULTS: In both patients, the Reed-Sternberg cells were related clonally to the non-Hodgkin's lymphoma B cells. The V genes carried somatic mutations (a hallmark of germinal-center B cells and their descendants). In both patients, some somatic mutations were shared by the Reed-Sternberg and non-Hodgkin's lymphoma cells, whereas other somatic mutations were found exclusively in one or the other cell type. CONCLUSIONS: In two patients with classic Hodgkin's disease and non-Hodgkin's B-cell lymphoma, we identified a common B-cell precursor, probably a germinal-center B-cell, for both lymphomas. This finding suggests that the two types of lymphoma underwent both shared and distinct transforming events and provides proof of the B-cell derivation of Reed-Sternberg cells in classic Hodgkin's disease.     

Sperm quality in Hodgkin's disease versus non-Hodgkin's lymphoma

The study was conducted to determine the deleterious effect of lymphoma disease on spermatogenesis and to evaluate the possibility that the disease is mediated primarily by inherent mechanisms in Hodgkin's disease and non-Hodgkin's lymphoma patients. A total of 89 patients with lymphoma disease (Hodgkin's and non-Hodgkin's) were referred for sperm preservation prior to adjuvant treatments. A comparison was made of pre- and post-thaw sperm quality between lymphoma patients and healthy volunteers who applied for sperm donation. This was followed by further assessment of the differences between patients with Hodgkin's disease and non-Hodgkin's lymphoma in terms of sperm variables, clinical parameters and blood hormone concentrations. It was found that patients with lymphoma disease had significantly impaired pre-freeze and post-thaw sperm quality compared with that of healthy volunteers. Patients with non-Hodgkin's lymphoma had spermatozoa of higher quality than patients with Hodgkin's disease. No differences were found in the clinical or hormonal parameters between these two groups. As expected, reduced testicular size and abnormal testicular consistency were correlated with decreased sperm quality. The mere presence of cancer disease has a direct negative effect on spermatogenesis, which is probably not related to incidental side-effects. A variable degree of impairment should be expected with different categories of cancer.      

Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease.

Castleman's disease is a rare B cell lymphoproliferative disorder related to excess interleukin-6 (IL-6)-like activity. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8), which encodes a functional cytokine (vIL-6), has been found in some patients with Castleman's disease. Lymph nodes from 14 HIV-seronegative Castleman's disease patients were compared to hyperplastic lymph nodes from 25 HIV-seronegative patients as well as Kaposi's sarcoma lesions from 48 patients for KSHV infection and vIL-6, human IL-6, and Epstein-Barr virus EBER expression. While all Kaposi's sarcoma tissues examined were polymerase chain reaction-positive and all control lymph nodes were polymerase chain reaction-negative for KSHV, none had detectable vIL-6 expression. Six of 14 (43%) Castleman's tissues were positive for KSHV by polymerase chain reaction and all 6 had evidence of vIL-6 expression by immunohistochemistry. vIL-6-positive Castleman's disease patients generally had the multicentric plasma cell variant form of the disease and had a rapidly fatal clinical course frequently associated with autoimmune hemolytic anemia and gammopathy. In contrast, 7 (88%) of the 8 vIL-6-negative Castleman's disease patients had localized disease and have remained disease-free after therapy. KSHV vIL-6 expression appears to be limited to hematopoietic cells and is not present in Kaposi's sarcoma spindle cells. These data suggest that Castleman's disease is a syndrome of multiple etiologies involving aberrant IL-6 activity from either endogenous or viral sources.     

Morphological and immunohistochemical investigation of non-Hodgkin's lymphoma combined with Hodgkin's disease

Twenty cases with a morphological picture highly suspicious for a combination of non-Hodgkin's lymphoma and Hodgkin's disease were investigated. The infiltrates of Hodgkin's disease differed from those of non-Hodgkin's lymphoma in their cellular component of Hodgkin and Sternberg-Reed cells and the irregularity in the fibre pattern. Based upon histological and immunohistochemical criteria the 20 cases were divided into three groups. Group 1 (n = 10) contained seven chronic lymphocytic leukaemias of B type, one lymphoplasmacytoid immunocytoma, and two centroblastic/centrocytic lymphomas. The non-Hodgkin's lymphoma components showed a monotypic immunoglobulin distribution pattern and/or leukaemic blood picture. Adjacent to the non-Hodgkin's lymphoma was typical Hodgkin's disease in which Hodgkin and Sternberg-Reed cells were positive for both immunoglobulin light chains and IgG and reacted with anti-CD15. Group 2 (n = 5) consisted exclusively of centroblastic/centrocytic lymphoma in combination with Hodgkin's disease in which the few Hodgkin and Sternberg-Reed cells were negative with anti-CD15 monoclonal antibody. Group 3 (n = 5) consisted of four chronic lymphocytic leukaemias of B type and one lymphoplasmacytoid immunocytoma. In these cases no combination with Hodgkin's disease could be diagnosed apart from the presence of partially CD15 positive Hodgkin and Sternberg-Reed cells. The following conclusions were drawn: anti-CD15 (LeuM1 and 3C4/C3D-1) can neither confirm nor exclude Hodgkin's disease since, while they do not detect Hodgkin and Sternberg-Reed cells in all cases of Hodgkin's disease, they do recognize Hodgkin and Sternberg-Reed cells in some B-cell lymphomas; anti-CD30 (Ber-H2) reacted with Hodgkin and Sternberg-Reed cells in all cases of Hodgkin's disease and also detected these cells in cases of non-Hodgkin's lymphoma.     

Use of Leu M1 and antiepithelial membrane antigen monoclonal antibodies for diagnosing Hodgkin's disease

Biopsies of 82 patients diagnosed as having Hodgkin's disease were reviewed. Seventeen were reclassified histologically as non-Hodgkin's lymphoma or reactive lymphoid hyperplasia. A substantial number of cases of Hodgkin's disease were negative when stained with Leu M1. Staining for Leu M1 was not found in the cases of non-Hodgkin's lymphoma or reactive lymphoid hyperplasia. With the exception of the lymphocyte predominant nodular subtype of Hodgkin's disease, epithelial membrane antigen staining was seen in a few cases of Hodgkin's disease and non-Hodgkin's lymphomas. This was not a useful discriminating feature.     

Cytologic demonstration of "dysplastic" follicular dendritic cells in a case of hyaline-vascular Castleman's disease

Large atypical follicular dendritic cells, considered dysplastic by some authors, were first described in association with Castleman's disease in 1991, but until now there has been no cytologic account regarding these cells. We report the cytologic and histologic findings of a case of hyaline-vascular Castleman's disease associated with "dysplastic "follicular dendritic cells which presented as a mediastinal mass in a young man. The presence of giant cells within the preoperative fine-needle aspirate specimen caused initial diagnostic uncertainty and their true nature was only confirmed retrospectively following application of an immunostain for CD21 to direct smears. Awareness of "dysplastic" follicular dendritic cells within aspirates of Castleman's disease will result in less cytological confusion in the future and may help to avoid the possibility of misdiagnosing Hodgkin's lymphoma which has certain cytologic similarities.     

Primary cutaneous CD5+ marginal zone B-cell lymphoma resembling the plasma cell variant of Castleman's disease. Case report

Marginal zone B-cell lymphoma (MZBL) is occasionally associated with prominent plasma cell differentiation. However, MZBL rarely exhibits histological features that resemble plasmacytoma arising from a localized plasma cell variant of Castleman's disease (PCCD). We here report a histologically similar case that was associated with primary cutaneous tumor. The patient was a 57-year-old woman with a 5-year history of cutaneous nodules. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the cutaneous tumor, whereas various numbers of CD5+ centrocyte-like (CCL) cells, which were arranged in a marginal zone distribution pattern, occupied the peripheral region of the tumor. The majority of the lymphoid follicles had atrophic or regressive germinal centers resembling hyaline-vascular Castleman's disease. CCL cells were observed to have colonized a few of the lymphoid follicles. Immunohistochemistry revealed that these cells had a monotypic intracytoplasmic kappa chain. Without treatment, the patient was quiescent, but 2 years later, there was a transformation to the large cell type. These observations suggest that MZBL needs to be distinguished from PCCD, and that untreated cutaneous MZBL may undergo a high-grade blastic transformation similar to other indolent lymphoproliferative disorders.     

Mediastinal lymphoma

Malignant lymphoma may involve the mediastinum as a component of disseminated disease or as a primary lesion. The most common types of primary mediastinal lymphomas (ML) are Hodgkin's disease (HD, usually of the nodular sclerosis type), large cell lymphoma (often associated with sclerosis), and lymphoblastic lymphoma (frequently seen in conjunction with acute lymphoblastic leukemia). The characteristic clinical, morphologic, and immunophenotypic features of these three neoplasms are reviewed. ML must be distinguished from Castleman's disease, an enigmatic lymphoid proliferation that frequently involves the mediastinum.     

Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease.

We studied the clinical and pathological features of six cases of non-Hodgkin's lymphoma (diffuse undifferentiated in four cases and diffuse histiocytic in two cases) occuring in patients treated for Hodgkin's disease. All six patients had received both radiation and chemotherapy. Abdominal or gastrointestinal involvement was present in five of the six cases. None of the patients had evidence of Hodgkin's disease when the diagnosis of non-Hodgkin's lymphoma was made. Five of the six patients were among a study group of 579 patients with Hodgkin's disease, prospectively followed since diagnosis. At 10 years the actuarial risk of development of non-Hodgkin's lymphoma in this study group is 4.4 per cent (1.2 to 15.0) (per cent probability with 95 per cent confidence limits) and is similar to that of developing acute leukemia: 2.0 per cent (0.3 to 12.9). Non-Hodgkin's lymphoma is a second tumor that may occur late in the course of patients treated for Hodgkin's disease--particularly in patients who have received both radiation therapy and chemotherapy. Like acute leukemia, non-Hodgkin's lymphoma may be another cancer that represents a substantial late risk of combined-modality therapy.     

Non-Hodgkin's lymphoma of the central nervous system after treatment of Hodgkin's disease

A case of a 34-year-old man with stage IIIB nodular sclerosis Hodgkin's disease complicated by the development of a central nervous system non-Hodgkin's lymphoma is described. The second tumor became symptomatic eight months after the initial diagnosis of Hodgkin's disease, but a tissue diagnosis was not made until autopsy two months later. The Hodgkin's disease was, at that time, in remission, and the autopsy revealed no persistent or recurrent Hodgkin's disease. Despite radiotherapy, the brain lymphoma had progressed to involve the spinal leptomeninges extensively, but there was no lymphoma outside the central nervous system (CNS) at autopsy. The significance of this unique case is discussed in light of the known risk for non-Hodgkin's lymphoma as a second malignancy after Hodgkin's disease and in view of recent information concerning CNS lymphoma.     

Monoclonal antibodies reactive in routinely processed tissue sections of malignant lymphoma, with emphasis on T-cell lymphomas

The immunoreactivity of eight monoclonal antibodies was evaluated on 45 routinely processed lymphomas (22 T-cell lymphomas, 11 B-cell lymphomas, and 12 cases of Hodgkin's disease). Two antibodies reactive with leukocyte common (T200) antigens (PD7/26 and 2B11) stained most of the B- and T-cell lymphomas but did not stain the Reed-Sternberg cells and variants in Hodgkin's disease. Two antibodies known to stain B cells (LN-1 and LN-2) reacted with some of the B-cell lymphomas, but LN-2 also reacted with the neoplastic cells in six of 22 T-cell lymphomas and with the Reed-Sternberg variants in eight of 12 cases of Hodgkin's disease. The granulocyte antibody anti-Leu M1 reacted with most cases of Hodgkin's disease but also reacted with two of 11 B-cell non-Hodgkin's lymphomas. An antibody to epithelial membrane antigen (anti-EMA) stained some cases of T-cell lymphoma, B-cell lymphoma, and Hodgkin's disease. Leu 7 was expressed in one T-cell lymphoma and in one case of Hodgkin's disease. A novel antibody reactive with T cells (L60) stained all cases of T-cell lymphoma but also stained some cases of B-cell lymphoma and one case of Hodgkin's disease. We conclude that none of these antibodies, when used alone on routinely fixed paraffin-embedded material, is completely sensitive and specific for T-cell lymphoma, B-cell lymphoma, or Hodgkin's disease. However, a panel of antibodies is useful in distinguishing Hodgkin's disease from non-Hodgkin's lymphoma and in suggesting the B- or T-cell phenotype of non-Hodgkin's lymphomas.     

A case of primary osseous malignant immunoblastic B-cell lymphoma with intracytoplasmic mu lambda immunoglobulin inclusions

Primary malignant lymphoma of bone, so-called Parker-Jackson reticulosarcoma, is a rare form of extranodal lymphoma with a relatively good prognosis. It often corresponds to B-cell lymphoma of high-grade malignancy. We report a case of mu lambda immunoblastic lymphoma showing two distinctive features: an abundant reactive T-lymphocytic population and unusual intra-cytoplasmic inclusions. These inclusions were PAS positive and consisted of monotypic mu lambda immunoglobulin localized in peculiar aggregates of rough endoplasmic reticulum. Their morphological appearances resembled the well-documented inclusions described in some varieties of non-Hodgkin's lymphoma.     

Mesenteric Castleman's disease

We report here a rare case of mesenteric Castleman's disease presenting as a mesenteric mass. A 13-year-old female child was admitted to our hospital complaining of intermittent vague abdominal pain. She had hypochromic anemia, thrombocytosis and an elevated erythrocyte sedimentation rate (ESR). Ultrasonography and computed tomography indicated an intra- abdominal mass might represent a lymphoma or gastrointestinal stromal tumor or leiomyoma, but the definitive preoperative diagnosis couldn't be confirmed. The surgical resection of the mass revealed the mesenteric hyaline vascular-type Castleman's disease.