Castleman's Disease

Castleman's disease

Author: Doctor Françoise Sarrot-Reynauld1 Creation Date: November 1999 Update: August 2001

Scientific Editor: Professor Loïc Guillevin

1Département de médecine interne, Centre Hospitalier Universitaire de Grenoble, Hôpital Albert Michallon, BP217, 38043 Grenoble Cedex 9, France. [email protected]

Abstract Keywords Name of the disease and synonyms Names of excluded diseases Diagnostic criteria/Definition Comments on the differential diagnosis Incidence Clinical description Management/Treatments Etiology Biological diagnostic methods Unresolved questions and comments References

Abstract Castleman's disease or angiofollicular lymphoid hyperplasia is a rare disease with two identified forms. The localized form, often pauci-symptomatic, is characterized by an isolated enlarged lymph node that regresses without sequelae after surgical excision. The multicentric form frequently presents general signs, polyadenopathy, organomegaly and sometimes a POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin) syndrome. The prognosis of the latter form is much less favorable and treatment often requires chemotherapy. The etiology of Castleman's disease remains unknown but recent reports have indicated a role of human herpesvirus 8 (HHV-8), especially in certain multicentric forms.

Keywords Castleman's disease, angiofollicular hyperplasia, angiofollicular lymphoid hyperplasia, human herpesvirus 8, POEMS syndrome.

Name of the disease and synonyms lymphoma, even though the latter can be Castleman's disease is also called: associated with it. • angiofollicular lymph-node hyperplasia, • angiofollicular lymphoid hyperplasia, Diagnostic criteria/Definition • giant lymph-node hyperplasia, Castleman's disease constitutes a • lymphoid hamartoma, clinicopathological entity, represented by lymph- • benign lymphoma or follicular node hypertrophy and histologically lymphoreticuloma. characterized by angiofollicular lymph-node hypertrophy. Names of excluded diseases Two forms are known: a localized form, in which Castleman's disease must be distinguished from the disease is restricted to one lymph node, and reactive lymph-node hyperplasia, and malignant a multicentric or systemic form, in which several lymph-node hyperplasia, especially malignant sites are involved.

Sarrot-Reynauld, F; Castleman's disease; Orphanet encyclopedia, August 2001. http://www.orpha.net/data/patho/GB/uk-castleman.pdf 1

Comments on the differential diagnosis time of diagnosis was 43 years with a range of Clinically, Castleman's disease often presents 10-87 years. The time to diagnosis is often long with adenopathies and general signs suggestive (mean: 18 months), attributable to the clinical of a lymphomatous pathology. In contrast, polymorphism and the poor awareness of the histological features of Castleman's disease are disease. not those of a lymphoma. Indeed, Castleman's Localized forms [5, 10] are asymptomatic in 51% disease usually entails a polyclonal lymphocytic of the patients and are often discovered proliferation. Nevertheless, some cases can be fortuitously at the time of a routine physical associated with a monoclonal lymphomatous examination, chest X-ray or abdominal proliferation. ultrasonography. Sometimes, they can present The histological aspect of angiofollicular as thoracic or abdominal pain, when the lesion is lymphoid hyperplasia can also be observed in large and causes local compression. The size of various dysimmune disorders, like rheumatoid the lesion varies widely, with a mean diameter of arthritis or Sjögren's syndrome. It can also occur 6 cm (range: 1-12 cm). It is, by definition, in association with congenital immune localized in one site. The sites preferentially deficiencies, human immunodeficiency virus involved are, in decreasing order of frequency, (HIV) infection, Kaposi's sarcoma, reactions to the abdomen, peripheral lymph-node zones and cancers and hemopathies, vaccinations, skin the mediastinum. However, the most diverse disorders or membranous glomerulonephritis. sites can be affected. General signs, which are A complete clinical, histological and rare but can be observed in 31% of the patients, immunohistochemical analysis is essential to include: asthenia (20%), fever (20%) and weight obtain a definitive and differential diagnosis [8]. loss (11%). The histological diagnosis requires lymph-node excision for peripheral adenopathy Incidence or lymph node biopsy by mediastinoscopy, Castleman's disease is a rare pathology whose thoracotomy or laparotomy for a deep central precise incidence is not known. localization. The localized form, described for the first time by Multicentric forms, on the other hand, are always Castleman et al. [2] in 1956, is the most symptomatic [1, 5, 10]. The symptoms are, for common. More than 400 cases have already the most part, a consequence of the elevated been reported in the international literature. The production of interleukin-6 (IL-6). General signs largest series of 81 patients was published by are quasi-constant, characterized by asthenia Keller et al. [6] in 1972. The multicentric or (65%), weight loss (67%) and fever (69%). systemic form, described for the first time by Peripheral polyadenopathy is very common Gaba et al. [4] in 1978, is less common. Since (84%) with a mean of 4 sites involved and is then, numerous isolated cases have been often associated with hepatomegaly and/or reported. In 1985, Weisenburger et al. [13] splenomegaly (74%). A POEMS (peripheral described their series of 16 patients and, in polyneuropathy, organomegaly, endocrinopathy, 1996, Oksenhendler et al. [7] reported their monoclonal gammopathy (M-protein), and skin study on 20 patients. signs) syndrome [9] is observed in 24% of the To improve our understanding of the patients. Finally, some multicentric forms of evolutionary profile of Castleman's disease, we Castleman's disease are associated with conducted a prospective study under the aegis Kaposi's sarcoma. The histological diagnosis is of the Société Nationale Française de Médecine generally made upon examination of an excised Interne [10]. Between 1995 and 2001, we peripheral lymph node. identified 85 cases of Castleman's disease seen by 41 French internal medicine specialists in 33 Management/Treatments hospital centers. Among the 85 cases, 49 (58%) The best treatment for localized forms of had the multicentric form. This preponderance Castleman's disease is complete surgical does not indicate a higher incidence of this form excision. This treatment allows full recovery but merely reflects a recruitment bias, as without relapse in almost all cases. Further internists more frequently treat the systemic follow-up does not seem necessary. form. As reported in the literature, we never No therapeutic consensus exists at present for observed the transformation of a localized form the multicentric forms of Castleman's disease. into a multicentric one. Indeed, the rarity and heterogeneity of the disease have prevented the undertaking of Clinical description randomized therapeutic trials in this context. In Castleman's disease can occur at any age, even practice, diverse treatments are used, often in during childhood, with a peak frequency during combination, e.g., surgery (35%), corticotherapy adulthood. In our series, the mean age at the (53%) and chemotherapy (63%).

Sarrot-Reynauld, F; Castleman's disease; Orphanet encyclopedia, August 2001. http://www.orpha.net/data/patho/GB/uk-castleman.pdf 2

Cyclophosphamide (750 mg/m2) is given in elevated erythrocyte sedimentation rate (77%), monthly pulses, although Castleman's disease is anemia (61%), thrombopenia (22%) and not recognized as an authorized indication for elevated polyclonal gammaglobulins (73% in our this drug. Vinblastine (6 mg/m2/week) is series). IL-6, synthesized in large quantities in administered intravenously, as authorized, in the the germinal centers of the involved lymph context of associated Kaposi's sarcoma. nodes, is responsible for the plasmacytosis and However, the treatment of choice is monthly hypergammaglobulinemia often seen. polychemotherapy. In this context, the most HIV serology should be systematically effective combinations seem to be regimens like undertaken, with the patient's consent, but CHOP (cyclophosphamide, vincristine, Castleman's disease rarely reveals this infection. doxorubicin, prednisone) or AVBD (etoposide, Rather, it usually occurs in patients already ifosfamide and cisplatin alternating with being followed for HIV infection and afflicted with doxorubicin, vinblastine, bleomycin and Kaposi's sarcoma. HHV-8 serology and search dacarbazine). Overall, the diverse therapies for HHV-8 DNA in peripheral blood by used induce a partial remission in 65% of the polymerase chain reaction (PCR) can be patients and a cure in 21%. But the prognosis of performed. In a cohort of 28 patients with the multicentric forms remains poor, with a 5- Castleman's disease [11], including 71% of year mortality rate of 18% in our study. However, multicentric forms and 5 patients infected with the more systematic use of polychemotherapy HIV, we detected HHV-8 infection in 28.6%. should, in the future, lead to a significant The diagnosis of Castleman's disease is based lowering of the mortality rate. Other therapies, on histological examination of the lesion with like interferon-alpha [15], retinoic acid [16] or immunohistochemical labeling. Castleman's anti-IL-6 antibodies [17] have been tried and disease is defined as angiofollicular lymphoid gave punctually promising results. hyperplasia, which can present in different ways. The hyaline-vascular form, the most common, is Etiology often observed in the localized forms. The The etiology of Castleman's disease is still plasmacytic form, the rarest, is mostly seen in poorly understood. No genetic or toxic factor had multicentric forms. Finally, an intermediary or been identified. The hypothesis of a viral mixed form has also been described. The infection has been raised. Indeed, the authors of lymphocyte proliferation is usually polyclonal. several studies [1, 12] have suggested the role However, monoclonal proliferation and of human herpesvirus 8 (HHV-8), already rearrangement of immunoglobulin and/or T-cell implicated in Kaposi's sarcoma and which could receptor genes have been reported in certain be sexually transmitted. In multicentric forms of patients with multicentric Castleman's disease Castleman's disease, HHV-8 sequences have [3]. been detected in 60% [11] to 100% [12] of the patients infected with HIV and in 20% [11] to Unresolved questions and comments 41% [12] of those who were not. The Because of the rarity of Castleman's disease percentages vary according to whether the and its polymorphic character, few prospective authors searched for the virus in peripheral cohort studies have been conducted. Thus, blood [11] or lymph node tissue [12]. In a small many questions remain unanswered, that is to series of eight patients, two HIV-seronegative say the etiology of the disease and the role of patients with the localized form of Castleman's HHV-8, the relationships between Castleman's disease were also found to be HHV-8 positive disease and lymphomatous pathologies, or the [11]. These findings suggest two possibilities optimal treatment of the multicentric forms. concerning the genesis of Castleman's disease: However, analysis of the data available in the 1) the opportunistic presence of HHV-8, favored literature enables a clear-cut distinction to be by immune perturbations; drawn between the localized forms, often pauci- 2) the direct pathogenic role of HHV-8, in symptomatic and with excellent prognoses after association with a dysregulation of cytokines. lesion excision, and multicentric forms, with Recent studies seem to support the latter systemic involvement and often difficult to treat. hypothesis because it was demonstrated that Indeed, the angiofollicular lymphoid hyperplasia HHV-8 was able to produce an IL-6 homologue, that defines Castleman's disease constitutes a vIL-6 [14]. non-specific histological lesion. It can thus be seen in diverse etiological settings. In light of the Biological diagnostic methods different clinical, virological and evolutionary No specific biological anomalies of Castleman's profiles, localized and multicentric forms of disease have been identified. However, one can Castleman's disease might be two distinct observe, especially in multicentric forms, an

Sarrot-Reynauld, F; Castleman's disease; Orphanet encyclopedia, August 2001. http://www.orpha.net/data/patho/GB/uk-castleman.pdf 3

entities that merely share a common histological 9- Rose C, Mahieu M, Hachulla E, Facon T, aspect. Hatron PY, Bauters F, Devulder B. Le POEMS syndrome. Rev Med Interne 1997; 18:553-62. References 10- Sarrot-Reynauld F, Cacoub P et le Groupe 1- Cacoub P, Raphaël M, Bolcert F, Wechsler B, Français d'Etude de la Maladie de Castleman. Blétry O, Chomette G, Godeau P. Qui se cache Maladie de Castleman : étude préliminaire d'une derrière la maladie de Castleman multicentrique cohorte nationale de 67 cas. Rev Med Interne ? A propos de 11 observations. Rev Méd Interne 1998; 19 : 413S. 1991; 12:77S. 11- Sarrot-Reynauld F, Morand P, Buisson M et 2- Castleman B, Iverson L, Menendez VP. le groupe français d'étude de la maladie de Localized mediastinal lymph node hyperplasia. Castleman. Maladie de Castleman et infection Cancer 1956; 9:822-30. par le virus HHV-8. Rev Med Interne 1998; 19 : 3- Delmer A, Karmochkine M, Le Tourneau A, 413S. Bouscary D, Rio B, Perez E, Prudent J, Bonnet 12- Soulier J, Grollet L, Oksenhendler E, Cacoub P, Audouin J, Diebold J, Zittoun R. Maladie de P, Cazals-Hattem D, Babinet P, et al. Kaposi's Castleman ou hyperplasie lymphoïde sarcoma-associated herpesvirus-like DNA angiofolliculaire: polymorphisme clinique, sequences in multicentric Castleman's disease. biologique et évolutif. A propos de 4 Blood 1995; 86:1276-80. observations. Ann Méd Interne 1990 ;141:123-8. 13- Weisenburger DD, Nathwani BN, Winberg 4- Gaba AR, Stein RS, Sweet DL, Variakojis D. CD, Rappaport H. Multicentric angiofollicular Multicentric giant lymph node hyperplasia. Am J lymph node hyperplasia: a clinicopathologic Clin Pathol 1978; 6:86-90. study of 16 cases. Hum Pathol 1985; 6: 162-72. 5- Herrada J, Cabanillas F, Rice L, Manning J, 14- Burger R, Neipel F, Fleckenstein B, Savino Pugh W. The clinical behavior of localized and R, Ciliberto G, Kalden JR et al. Human multicentric Castleman disease. Ann Intern Med herpesvirus type 8 interleukin-6 homologue is 1998; 128:657-62. functionally active on human myeloma cells. 6- Keller AR, Hochholzer L, Castleman B. Blood 1998; 92:1858-63. Hyaline-vascular and plasma cell types of giant 15- Pavlidis NA, Briassoulis E, Klouvas G, Bai lymph node hyperplasia of the mediastinum and M. Is interferon-alpha an active agent in other locations. Cancer 1972; 29:670-83. Castleman's disease? Ann Oncol 1992; 3:85-5. 7- Oksenhendler E, Duarte M, Soulier J, Cacoub 16- Rieu P, Droz D, Gessain A, Grunfeld JP, P, Welker Y, Cadranel J, Cazals-Hatem D, Hermine O. Retinoic acid for treatment of Autran B, Clauvel JP, Raphaël M. Multicentric multicentric Castleman's disease. Lancet 1999; Castleman's disease in HIV infection :a clinical 354:1262-3. and pathological study of 20 patients. AIDS 17- Beck JT, Hsu SM, Wijdenes J, Bataille R, 1996; 10:61-7. Klein B, Vesole D et al. Brief report : Alleviation 8- Peterson BA, Frizzera G. Multicentric of systemic manifestations of Castleman's Castleman's disease. Semin Oncol 1993; disease by monoclonal anti-interleukin-6 20:636-47. antibody. N Engl J Med 1994; 330: 602-5.

Sarrot-Reynauld, F; Castleman's disease; Orphanet encyclopedia, August 2001. http://www.orpha.net/data/patho/GB/uk-castleman.pdf 4