Castlemans Disease and Autoimmunity

C. Alessandri, F. Viganego and G. Valesini Universitä di Roma "La Sapienza ", Italy

Castleman's disease (CD) is an uncommon lympho-proliferative disorder of unknown aetiology first described by Castleman [1] in 1954. CD histopathologic classification is complex and this disease is also referred to as giant lymph-node hyperplasia, an-giomautous lymphoblastoid hamartoma and follicular lymphoreticuloma [2], Although CD is a distinct clin-icopathology entity, it tends to frequently share some common histological features with other immunological disorders, especially autoimmune diseases [3].

The diagnosis of CD is based on pathological classification of biopsy specimen. Keller et al. [4] described two histopathological pictures of CD: hyaline-vascular (HV) and plasma cells (PC) type. HV hysto-morphology is characterized by small lymphoid follicle with hyalinized germinal centre surrounded by lymphocytes in onion skin appearance, and hyper-vascular interfollicular tissue with a lack of sinuses. On the other hand, PC type is characterized by a large number of mature plasma cells, within interfollicular tissue, normal or prominent germinal centre and absence of capillary proliferation. Nevertheless, this distinction is not absolute because a mixed hys-tomorphology feature has been described largely in the literature. Moreover, polyploid follicular dendridic reticulum cells may be found in HV- and PC-CD. Generally, immunophenotyping of the plasma cells and immunoblasts reveals a polyclonal population. Nevertheless, autonomous clones have been detected in multicentric CD [5].

Several clinical differences between the two pathologic types, unicentric- and multicentric-CD, have been recognized. According to McCarty et al. [2], multicentric-CD can also be divided into two subtypes respectively with or without neuropathy. Neu ropathy, especially progressive sensorimotor polyradiculitis, could also represent an overlap with the so-called POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein and skin lesions) [6, 7], a clinical entity first described in 1980 by Bradwick et al. [8],

The clinical onset of CD is variable from 10 to 70 years. The multicentric subtype of the disease occurs more frequently in older patients [2]. Localized mediastinum large benign lymph node, characterized by HV histological morphology, represents the most frequent clinical presentation of this disease. However, the lymph node mass may occur in other sites, most commonly in the neck. Generally asymptomatic or associated to mechanical symptoms, localized CD has a good prognosis and surgery is curative in the majority of cases. In fact, the development of malignant lymphoma, Kaposi's sarcoma or carcinoma has been rarely described.

However, the PC subtype more frequently develops as a multicentric disease. Constitutional symptoms—such as fever, haemolytic anaemia, weakness, hyper-y-globulinemia, hypoalbuminemia and hepatosplenomegaly—have been described; prognosis is poor and lymphoma or Kaposi's sarcoma frequently complicates the disease.

The aetiology of CD is unclear. Lymphoid hyperplasia in response to chronic infection may be involved. In the past, the Epstein-Barr virus was suspected to be the causative organism [9]; more recently, Kojima et al. [3] detected EBV genomes, using in situ hybridization, in the small lymphocytes of 2 out of 3 patients with systemic lupus erythematosus and CD-like lymphadenopathy. In addition, human Herpesvirus-8 (HHV-8), originally identified in Kaposi's sarcoma, has been involved in a variety of lymphoid disorders, including multicentric CD [10]; HHV-8 is a lymphotropic virus whose infection occurs in 100% of AIDS-related multicentric CD and approximately 40% of AIDS-unrelated multicentric CD [11]-

One of the first evidences of a CD-autoimmunity link came from the finding of immune complexes in the glomerular basement membrane of patients with CD-associated nephrotic syndrome [12], as well as from the description of anemia caused by antiery-thropoietin factor [13], Autoimmunity plays its role in two complementary ways: B and T autoreactive lymphocytes, both arising from lymph nodes. In fact, the whole process of development of a primary immune response begins in secondary lymphoid tissues, such as lymph nodes, spleen and MALT. Physiologically, the secondary lymphoid tissue is the site where naive lymphocytes intercept antigens, become activated, proliferate and cooperate with B cells, giving birth to a complete immune response. Consequently, autoimmune phenomena could be an expression of a disregulation of the immune system, which is permanently activated against several possible unknown antigens. Thus, the polyclonal hyper-y-globulinemia and polyclonal plasma cells infiltrates frequently found respectively in CD patients' sera and pathologic specimens may confirm this "reactive state". Moreover, CD histology and immunohistology are absolutely not specific for CD only: in fact, similar or even identical features may be found in many disorders, including autoimmune diseases. This sort of overlapping has been recently stressed by Kojima, who found lymphadenopathy with histopathological and immunohistochemical features resembling CD in 26% of SLE patients [3]; therefore, sometimes, a differential diagnosis is almost exclusively made on the clinical basis. This sort of lymphatic tissue "overdrive" in patients with CD could evolve, in some of them, into lymphoproliferative diseases [14].

Indeed, to confirm its close association with autoimmune disorders there is also much evidence of CD either following or preceding the onset of autoimmune clinical manifestations. In 1981, Lenner and Lundgren [15] described a case where the onset of autoimmunity (in this case, temporal arteritis) was preceded by recurrent HV-CD localized in a peripheral lymph node; on the other hand, many cases of CD have been described, even after a long time, subsequent to manifestations or diagnosis of autoimmune diseases: among them, for example, cases of patients diagnosed as Sjogren's syndrome (SS) who later developed CD are present in the literature [16, 17],

This heterogeneity in CD onset time in relation to the appearance of autoimmunity signs makes working out a pathogenetical connection between these two disorders even more difficult.

Nevertheless, the association between SS and CD does not surprise at all, since both diseases are characterized by lymphocytic infiltration of nodal and extran-odal tissues; moreover, SS has been clearly associated with lymphoproliferative disorders [18].

Indeed, many authors reported (mainly multicentric) manifestations of CD with clinical features of autoimmunity, such as Sicca syndrome, cardiomyopathy, palmar and plantar rash [19], hepatosplenomegaly, polyserositis, polyneuropathy [20], temporal arteritis [15], severe orogenital ulcers, bilateral uveitis, necrotic purulent nodules consistent with diagnosis of Behcet's disease [21], relapsing polychondritis [22]. In all these cases, such clinical manifestations seem to reflect organ damage due to lymphocytic infiltration or cytokines overproduction normally observed in multicentric CD. Some authors pointed out that the production of interleukin-(IL)-6 by B cells located in the hyperplastic lymph nodes may be responsible for acute phase manifestations of autoimmunity [23]. Indeed, it is a fact that a high serum IL-6 level has been detected in sera from patients with CD [24]. Besides, inappropriate IL-6 production has been noted in several autoimmune diseases such as RA, SLE and SS [19, 25]. Moreover, anti-IL-6 monoclonal antibody has been reported to produce improvement of constitutional symptoms and laboratory abnormalities in one patient with PC-CD [26], The bare fact that in many cases of localized CD resection of the lymph node mass brought to the resolution of the disease and to a definitive declining of IL-6 to normal values [24] could be another clue suggesting that the mass itself may play a sustaining role into the inflammatory process, by means of cytokines perturbation—i.e., IL-6 overproduction [27]—triggering the autoimmune phenomenon. This process could be hypothetically "primed" by some common or uncommon infective agent, such as a virus (i.e., HHV-8), in genetically predisposed individuals.

Several haematological autoimmune features, such as autoimmune thrombocytopenia and/or neutropenia [17, 28, 29], haemolytic anemia [30, 31] have also

Table 1. Clinical and serological features of 3 patients with CD

Patient name/sex/age

Histopathological type

Clinical findings

Laboratory findings

Hyaline-vascular

Plasmacellular

Plasmacellular

Fever

Weakness

Lymphadenopathy

Hepatosplenomegaly

Polyserositis

Polyarthralgias

Thrombophlebitis

Palmar rash

Interstitial lung disease

Fever

Weakness

Weight loss

Lymphadenopathy

Hepatosplenomegaly

Polyarthralgias

Polyneuropathy sensorimotor

Polyserositis

Palmar rash

Fever

Weakness

Lymphadenopathy

Hepatosplenomegaly

Pleuritis

Interstitial lung disease

Hyper-y-globulinaemia ANA (coarse speckled pattern) anticardiolipin antibodies

Hyper-y-globulinaemia RF

ANA (nucleolar pattern) anticardiolipin antibodies

Hyper- y-globulinaemia ANA (nucleolar pattern)

been presented coincidentally with CD. Interesting is also the described association of CD with paraneoplastic pemphigus (PNP) [32, 33] and myasthenia gravis

[34], This could account for the extremely wide range of possible organ-targeted pathogenic autoantibodies that CD may be able to raise.

In the end, descriptions of a few cases of CD occurring together with disorders somehow connected to manifestations of autoimmunity—like Crohn's disease [29] or renal amyloidosis with red cell aplasia

[35]—have recently made their appearance in the literature.

During the last 10 years, among approximately 6000 patients who referred to our department for autoimmune-rheumatic diseases, we happened to observe three cases of CD, whose clinical and serological features are shown in Table 1. Among the clinical manifestations which could be associated to autoimmunity, we observed polyarthralgias, polyserositis, thrombophlebitis and interstitial lung disease, whereas, hyper-y-globulinemia, antinuclear antibodies (ANA), rheumatoid factor and anticardiolipin antibodies (anti-CL) were the most common serological abnormalities.

It is noteworthy that 2 out of 3 patients presented ANA positivity with nucleolar pattern, while the last patient, who was positive for anti-CL, had experienced thrombophlebitis.

In the end, these clinical and immunological aspects that CD shares with autoimmune diseases could be useful to understand the pathogenesis of this rare lymphoproliferative disorder.

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