HIV-associated multicentric Castleman’s disease Justin Stebbing,1* Liron Pantanowitz,2 Farshid Dayyani,3 Ryan J. Sullivan,3 Mark Bower,4,5 and Bruce J. Dezube3
Multicentric Castleman’s disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type-1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposi’s sarcoma-associated herpesvirus proteins, and most HIV-associated MCD features can be attributed to the presence of this c-herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon-a, foscarnet, ganciclovir, and antibodies to interleukin-6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti-CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposi’s sarcoma. MCD represents a model of disease at the interplay between tumor biology, infecC 2008 Wiley-Liss, Inc. tion, and immunology. Am. J. Hematol. 83:498–503, 2008. V Introduction Although there is a trend to eradicate case reports and anecdotes from the medical literature, it is worth recalling an initial description of a particular individual from the Massachusetts General Hospital in 1954 with hyperplastic mediastinal nodes [1]. Two years later, Benjamin Castleman described 13 similar cases of localized, asymptomatic mediastinal masses, and concomitant lymph node hyperplasia resembling thymoma [2]. Thence called Castleman’s disease, is a rare lymphoproliferative disorder whose pathogenesis appears to be related to an aggressive immune response, in many cases against its causative agent Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 [3]. There are two main forms: unicentric Castleman’s disease is typically an asymptomatic localized condition cured by surgical resection; in contrast multicentric Castleman’s disease (MCD) is usually an aggressive condition associated with systemic symptoms, diffuse peripheral lymphadenopathy, an association with KSHV infection, and an apparent predilection for human immunodeficiency virus (HIV)positive individuals in which preexisting immunosuppression provides the environment for KSHV lytic replication and subsequent cellular transformation. No published literature has convincingly identified the prevalence of MCD, and no studies have compared HIV positive and seronegative cases. However, with the emergence of the HIV pandemic [4], there has been a resurgence of interest secondary to an increasing number of reports of HIV-associated MCD [5]. This review seeks to highlight and update the clinical manifestations, pathobiology, and management issues specific to HIV-associated MCD. Clinical Manifestations Patients with multicentric Castleman’s disease (MCD) present with a clinical picture consistent with an inflammatory process although features at presentation appear to show no difference between human immunodeficiency virus (HIV)-seropositive and negative cases. In a retrospective study of 20 HIV-seropositive individuals with MCD, the main symptoms at presentation were fever, peripheral lymphade-
nopathy, hepatosplenomegaly, weight loss, respiratory symptoms, and edema [5]. In addition, every patient had anemia, an increased level of C-reactive protein, polyclonal hypergammaglobulinemia, hypoalbuminemia, and seven were also pancytopenic. Gender data reported in nine case series and therapeutic trials show that 64 of the 92 affected individuals (70%) were male, although this may reflect the general features of the cohorts studied [6–14]. The pathologic lesions of MCD include lymphadenopathy and/or localized extranodal lymphoid tumors with involved lymph nodes grossly measuring 3–7 cm in size [15]. Significant fibrosis, calcification, and even ossification can be seen [16,17], and bone marrow biopsies contain either focal infiltrates of plasma cells [18,19] or plasmablasts within lymphoid follicles and the interstitium [20]. In the lung, a lymphocytic interstitial pneumonia may occur, with thickened alveoli containing plasma cells admixed with fibroblasts [21,22]. Cases may also be complicated by the coexistence or subsequent development of non-Hodgkin lymphoma [23,24], follicular dendritic cell sarcoma [25], Hodgkin lymphoma [26], and another Kaposi’s sarcomaassociated herpesvirus (KSHV)-driven neoplasm primary effusion lymphoma [27].
This project was funded in part by a grant from the AIDS Malignancy Consortium of the National Cancer Institute to BJD. 1 Department of Medical Oncology, Imperial College School of Science, Technology and Medicine, The Hammersmith Hospitals NHS Trust, London, United Kingdom; 2Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts; 3Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; 4Department of Oncology, The Chelsea and Westminster Hospital, London, United Kingdom; 5 Department of HIV Medicine, The Chelsea and Westminster Hospital, London, United Kingdom
*Correspondence to: Bruce Dezube, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, MASCO 414, Boston, MA 02215. E-mail:
[email protected] Received for publication 2 December 2007; Accepted 5 December 2007 Am. J. Hematol. 83:498–503, 2008. Published online 7 February 2008 in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/ajh.21137
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Given the association with KSHV, it is not surprising that Kaposi’s sarcoma has been concomitantly noted in 13% of patients with unicentric disease and 75% of individuals with MCD [6]. MCD can also be complicated by neurologic manifestations including polyneuropathy and myesthenia gravis [28–30], either of which may be part of a pentad, in concert with organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, known as the POEMS syndrome [29,31]; CNS involvement by MCD lesions has also been described [32]. The first step toward successfully making the diagnosis of MCD is to consider it in high risk patients, especially if they present with associated conditions (e.g., HIV-infection, Kaposi’s sarcoma, primary effusion lymphoma). Ultimately, the diagnosis needs to be established histologically from procured tissue, usually as an excised lymph node. Once the diagnosis has been established, further workup including laboratory tests and imaging is warranted. Laboratory studies should include where available, testing for KSHV DNA in serum or from peripheral blood mononuclear cells by real time PCR. A study of 31 cases of MCD with abdominal localization showed that the size of the affected lymph nodes determined the appearance on imaging: nodes smaller than 5 cm in diameter showed a homogenous enhancement, and nodes greater than 5 cm were dyshomogenous. In an attempt to distinguish NHL from MCD, Chim et al. studied gallium (67 Ga) uptake in three patients: while lymphomas were shown to readily take up 67 Ga, in all three patients with MCD 67 Ga uptake was absent. It remains to be determined how well negative 67 Ga uptake will distinguish MCD from other nonmalignant lymphadenopathy [33]. Imaging, including use of 18-FDG PET, may be a valuable tool for follow-up and diagnosing relapse after remission with systemic therapy [34]. Pathogenesis The manifestations of MCD are in part due to cytokine dysregulation including increased levels of interleukin-6 (IL6) [35–37], which acts as a B-cell stimulatory factor, mediating B-cell differentiation as well as promoting the growth of B-cell malignancies [38–40]. C/EBP b is a transcriptional regulator of IL-6, and mice that lack this gene overexpress IL-6 and develop a condition similar to MCD [41]; inactivation of IL-6 in these knockout mice prevents the development of this murine Castleman’s like disease [42]. KSHV induces IL-6 production in infected cells [43], and KSHV itself encodes an early lytic pirated homologue of IL-6 [44– 49] (vIL-6). Although there are subtle differences in the receptor activating signaling complex between its human and viral homologues [50–52], KSHV encoded vIL-6 stimulates the known hIL-6-induced signaling pathways via the shared cytokine signaling receptor gp130 coupled to the endogenous JAK/STAT pathway. In mice, these data are supported by evidence that recombinant vIL-6 induces a marked plasmacytosis similar to that found in MCD, as well as accelerating hematopoesis and inducing vascular endothelial growth factor, a proangiogenic cytokine [53]. Additionally, in MCD, high KSHV viral replication and high levels of IL-6, IL-10, and C-reactive protein are associated with a more aggressive disease course, suggesting that these cytokines may be involved in the pathogenesis of this disease [54]. Finally, IL-6 levels have been shown to decrease concomitantly with KSHV levels during therapy [55]. The clonality of MCD and its progression to lymphoma is similarly influenced by KSHV. KSHV has been detected in the large mantle zone plasmablasts of MCD [56]. These plasmablasts express high levels of lambda chain restricted IgM; however, in the interfollicular region mature B cells are KSHV negative, IgM negative, and polytypic. These KSHV
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positive, IgM lambda restricted plasmablasts are often isolated cells, but they may coalesce into microscopic aggregates known as microlymphomas and in some cases develop into frank plasmablastic lymphomas. The clonality of plasmablasts in 13 cases of MCD including eight with microlymphomas and two with plasmablastic lymphomas were evaluated by immunoglobulin (Ig) gene rearrangement studies. These studies demonstrated that the KSHV positive plasmablasts were polyclonal in MCD-involved lymphoid tissue and in six of eight microlymphomas, but monoclonal in two individuals with microlymphoma and plasmablastic lymphoma [14]. Moreover, the absence of somatic Ig gene rearrangements suggests that the KSHV positive plasmablasts are derived from naı¨ve B cells. KSHVencoded vIL-6 was only detected in 10–15% of KSHV positive plasmablasts; however, the hIL-6 receptor was expressed by all KSHV positive plasmablasts. It can be hypothesized that activation of the IL-6 signaling pathway by KSHV vIL-6 may transform naı¨ve B cells into plasmablasts and lead to the lymphoproliferative diseases associated with this virus including MCD. Pathologic Characteristics There are two main pathologic types of MCD, hyalinevascular, and plasma-cell types according to the histologic features of the affected lymph nodes. The latter type is more likely to be encountered in an excisional biopsy from an HIV-positive patient. The hyaline-vascular type is rarely seen in HIV-infected individuals, unless it coexists with the plasma cell type (i.e., mixed variant). In the hyaline-vascular variant, lymph node architecture is altered by an increased number of abnormal lymphoid follicles. Often germinal centers appear to be transfixed by radially penetrating capillaries surrounded by a broad mantle of concentrically arranged lymphocytes, so called ‘‘onion skin’’ layering giving the follicle a target appearance (Fig. 1A and 1B). The interfollicular region also contains numerous proliferating blood vessels, and such hypervascularity explains the occasional significant bleeding during surgery [57]. Stromal cell proliferations, such as angiomyoid proliferative lesions [58] and fibrous pseudotumors [59], may occasionally supervene. These stroma-rich variants likely arise from proliferating interfollicular actin-positive fibroblastic reticulum cells (myoid cells) and dendritic cells [60]. Lymphoid follicles in the plasma cell variant tend to be more hyperplastic, with larger and more active germinal centers that are surrounded by a narrower mantle of mature lymphocytes (Fig. 1C). These follicles usually have poorly defined borders, although hyalinized follicles may occasionally be present. The overall size of the lymphoid follicles, however, is similar to that seen in the hyaline-vascular type [61]. Although the interfollicular areas and medulla are similarly vascular, referred to as being ‘‘Kaposilike’’ by some authors [62], they are predominantly expanded by large sheets of plasma cells. The plasmablastic variant, the most common type observed during HIV infection, is characterized by increased numbers of medium-sized to large plasmablasts which morphologically resemble immunoblasts. They are characterized by a moderate amount of amphophilic cytoplasm and a large vesicular nucleus with 1–2 prominent nucleoli. Plasmablasts can comprise up to 50% of the follicular mantle zone in some follicles, and may also colonize the germinal centers [14]. They may even coalesce to form ‘‘microlymphomas’’ and develop into frank lymphoma. Immunohistochemical staining with a monoclonal antibody directed against the latency-associated nuclear antigen of KSHV often shows nuclear staining of B cells (Fig. 1D), located in 10–30% of lymphocytes in the mantle
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Figure 1. A: Small target-shaped lymphoid follicle with an involuted germinal center and mantle comprised of concentric layers of small lymphocytes (H&E stain). B: A germinal center is seen transfixed by a penetrating blood vessel (so-called lollipop structure) (H&E stain). C: A hyperplastic lymphoid follicle seen in a case of plasma cell variant Castleman disease (H&E stain). D: Several lymphocytes, including plasmablasts, within the mantle zone of this lymphoid follicle are KSHV1 in a case of HIV-associated plasmablastic variant Castleman’s disease (LNA-1 immunohistochemical stain). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
zone [56,63], in germinal center macrophages [64], as well as in endothelial cells and subcapsular spindle cell proliferations [63]. The highest copy number of KSHV appears to be present within subcapsular spindle cells [63]. In the plasmablastic variant, KSHV positive cells are mainly plasmablasts [14,65]. EBV can occasionally also be detected in some cases by means of immunohistochemistry (LMP-1), in situ hybridization studies (EBER) and molecular techniques [66,67]. Treatment There has never been a randomized study in any form of MCD, and the best evidence in HIV-positive patients has been derived from two recent clinical cohorts using rituximab [68,69]. Surgery Surgery has a limited role in MCD although in unicentric Castleman’s disease complete removal of the mediastinal lesions is curative. Splenectomy, in addition to establishing the histological diagnosis, may have a therapeutic benefit as a debulking procedure. Some of the hematological
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sequelae such as thrombocytopenia and anemia may in part be due to splenomegaly. Following splenectomy, there is often resolution of the constitutive symptoms, but this is typically short lived, and 1–3 months later symptoms tend to relapse, and an additional form of therapy is required [5]. Chemotherapy For immunocompetent patients, chemotherapy regimens for MCD are based on lymphoma schedules such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). In the pre-HAART era, these schedules were associated with marked toxicity in HIV-positive individuals, and consequently, other schedules were developed. In the largest published study from Paris of 20 HIV-seropositive patients, the partial response rate was 100% (nine out of nine patients) with single agent vinblastine; however, only four patients remained stable with maintenance therapy (4–6 mg/2 weeks). Five patients relapsed and required combination chemotherapy, which was ABV (doxorubicin, bleomycin, and vincristine) or partial splenectomy. Four patients received up-front ABV, and three had a partial
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response. In three patients, intermittent treatment with cyclophosphamide achieved a partial response [5]. Two HIVpositive patients were treated with oral etoposide for MCD and had remissions of 1.5 and 6 months, respectively, although the former patient had previous chemotherapy and ganciclovir [70]. Although there are few published data on which to base treatment strategies, in many centers combination chemotherapy is used initially to induce remission in aggressive forms of MCD. This may be followed by single agent chemotherapy, such as vinblastine or etoposide, as maintenance. HAART The introduction of highly active antiretroviral therapy (HAART) has been associated with a reduction in the incidence of many HIV-associated malignancies including Kaposi’s sarcoma [71]. Furthermore, HAART leads to a decrease in KSHV viral replication and is associated with the resolution of individual KS lesions and prolonged time to progression [72,73]. The effect of HAART has been described in seven patients with HIV-associated MCD [74]. Six of these patients were treated with chemotherapy and responded to it, and immune reconstitution was observed in five patients. However, patients in this study continued to require long-term chemotherapy to prevent further episodes of MCD. The mean survival was 48 months, which was longer than described in the pre-HAART era when most individuals succumbed to opportunistic infections related to their HIV infection. Interestingly, in an early case series of three HIV-associated MCD patients treated with HAART, the development of aggressive MCD was thought to be part of the immune reconstitution disease spectrum associated with the starting of HAART [75]. Unfortunately, all three patients died, indicating the life threatening nature of this disease, particularly in the setting of immune reconstitution. Immunotherapy Interferon-a has been administered either alone or in combination with HAART or chemotherapy for patients with HIV-associated MCD, both to induce remission and as maintenance therapy [5,76,77]. Mechanistically, this is thought to have both an antiproliferative effect by directly binding to cell surface receptors, and an antiviral effect by inhibiting viral replication and increasing natural killer cell activity via upregulation of the major histocompatibility class I expression of KSHV infected cells [78]. In combination with vinblastine and splenectomy, long-term remission was seen in two-thirds of patients [5]. In a case report, a patient was initially treated with antiviral therapy and splenectomy, followed by chemotherapy to induce remission. When chemotherapy failed to achieve sustained remission, interferon-a therapy was started leading to remission for over a year [76]. Another report of treatment of MCD with HAART and low dose interferon-a alone demonstrated a sustained remission of 24 months [79]. In HIV-seronegative individuals with MCD, the use of anti-IL-6R monoclonal antibodies (altizumab) [9] and separately the use of thalidomide [80,81] in small series has met with some success, but their efficacy and toxicity in HIV-associated MCD has not been defined. Anti-KSHV therapy The effect of specific anti-herpesvirus therapy to reduce the KSHV viral replication and alleviate disease has been examined in KSHV-associated diseases in the HIV setting. Kaposi’s sarcoma incidence was reduced when prophylactic ganciclovir or foscarnet was used to prevent CMV retinitis [82,83], and antiviral treatment which has led to a clinical improvement has been shown to reduce KSHV viral
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replication in patients with Kaposi’s sarcoma [84], primary effusion lymphoma, and hemophagocytic syndrome [85]. In a series of three patients treated with ganciclovir, there was a reduction in the frequency of acute symptoms of MCD for two patients treated with oral and intravenous ganciclovir [7]. For the third patient, who was in the intensive care unit, there was resolution of pulmonary and renal failure with intravenous ganciclovir. All the patients had a reduction in KSHV viral replication with ganciclovir therapy, accompanying the resolution of their symptoms. However, the use of foscarnet and cidofovir antiviral therapy was ineffective in a HIV-negative MCD patient with proven KSHV viremia, and treatment with corticosteriods in combination with chlorambucil chemotherapy was required to achieve a clinical response [86]. While there are few data on valganciclovir [87], a short course (e.g., 3 months) of this antiviral is often used following rituximab therapy by clinicians treating HIV-associated MCD; KHSV replication may be monitored during the valganciclovir treatment period. Rituximab The use of the anti-CD20 monoclonal antibody rituximab routinely prescribed as therapy for B cell lymphomas and autoimmune diseases, to target KSHV infected plasmablasts in MCD is a novel and potentially beneficial approach to the treatment of this disease. Before 2007, it has been the subject of case reports and very small clinical series, totaling 12 patients. These patients were often pretreated with chemotherapy and follow-up was brief [13,55,88–91,92], however, most patients (10 of 12) experienced a complete response. More recently, the efficacy and safety of four weekly infusions of 375 mg/m2 of rituximab in 21 consecutive patients with previously untreated plasmablastic HIV-associated has been investigated [69]. Apart from one individual who died from multiorgan failure within 2 weeks of receiving rituximab, all achieved clinical remission of symptoms, hematological and serum chemistry normalization, and 70% achieved a radiological response. The overall survival and disease free survival at 2 years were 95% and 79%, respectively, with no grade 3 or 4 toxicities. In three patients who relapsed, retreatment with rituximab was successful [93]. These data corroborate the benefit seen in the aforementioned case reports and demonstrate that rituximab therapy results in an impressive clinical, biochemical, and radiological sustained response in HIV-related MCD (see Fig. 2). The main adverse event seen in these patients is reactivation of Kaposi’s sarcoma, which is intriguing and may be due to a rapid B cell depletion that is observed during rituximab therapy, or an immune reconstitution inflammatory syndrome to hitherto latent antigens [94]. Rituximab therapy was associated with a decline in KSHV levels initially and at the successful treatment of relapse. In a prospective study of 24 individuals with chemotherapy-dependent HIV-associated MCD, the ANRS 117 CastlemaB Trial [68], use of the same schedule of rituximab was associated with sustained remission off treatment at day 60 (the primary end point) in 22 patients (92%). Conclusions While the optimal treatment for HIV-associated MCD is debatable, we personally favor initiating treatment with upfront rituximab. Corticosteroids and/or chemotherapy may be given depending on the situation (disease burden, clinical presentation). HAART is necessary to treat the underlying HIV infection. For those patients who are antiretroviral naı¨ve at the time of MCD diagnosis, initiation of HAART may be delayed until a course of rituximab has been given. A short course of valganciclovir (e.g., 3 months) may be useful to control KSHV replication until the patient’s immune system has been partially reconstituted
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Figure 2. A: CT scan pre- (top) and post- (bottom) 4 infusions of weekly rituximab demonstrating resolution of splenomegaly and lymphadenopathy (white arrow). B: FDG-PET scan performed at relapse. The patient had been treated 14 months previously with a splenectomy and rituximab and represented with fevers, anemia and lymphadenopathy. The PET scan shows increased activity in axillary, supraclavicular, paratracheal, coeliac axis, iliac and inguinal lymph nodes and absence of the spleen. The patient responded to retreatment with rituximab.
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