Ann Thorac Surg 2003;75:1648-1650
© 2003 The Society of Thoracic Surgeons
Case report
Castleman’s disease associated with myasthenia gravis
Jonathan R.S Day, MRCSa,*,
Duncan Bew, MBBSa,
Mark Ali, FRCSa,
Roberto Dina, FRC(Path)b,
Peter L.C Smith, FRCSa
a Departments of Cardiothoracic Surgery, London, United Kingdom
b Pathology, Hammersmith Hospital, London, United Kingdom
Accepted for publication November 1, 2002.
Keywords 13
* Address reprint requests to Dr Day, Department of Cardiothoracic Surgery, Hammersmith Hospital, Du Cane Rd, London W12 0HS, UK (Email: j.day{at}ic.ac.uk).
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Abstract
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Castleman’s disease presents as a peculiar type of lymph node hyperplasia. Traditionally, the disease has been classified on clinical grounds (solitary or multicentric) and by histologic appearance (hyaline vascular pattern, plasma cell predominance, or mixed lesions). It is now increasingly clear that there are different etiologies for each of these different subtypes. Reported associations include POEMS syndrome (polyneuropathy, organomegally, endocrinopathy, monoclonal gammopathy, and skin changes), paraneoplastic pemphigus, Hodgkin’s disease, and follicular dendritic cell sarcoma. We present a case of Castleman’s disease associated with myasthenia gravis, the third reported case in the literature. We discuss Castleman’s disease and review the literature.
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Introduction
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Castleman’s disease is a distinct lymphoproliferative disorder of uncertain origin, with more than 70% of lesions being located in the chest. It is commonly associated with POEMS syndrome, paraneoplastic pemphigus, Hodgkin’s disease, and follicular dendritic cell sarcome, but very rarely with myasthenia gravis.
A previously healthy, 39-year-old woman was transferred to our hospital for thymectomy. She initially presented with mild speech impairment, a decreased swallowing reflex, and a right-sided ptosis, and had recently been diagnosed with acetylcholine receptor–positive myasthenia gravis. A computed tomogram (CT) and magnetic resonance imaging scan (MRI) had been performed and revealed a mass in the left anterior mediastinum, thought to be a thymoma. Before transfer, she underwent 60% plasmaphoresis, 5 days of immunoglobulin therapy, and was started on pyridostigmine 60 mg qid.
At operation, through a median sternotomy, the thymus was removed intact and separate from a mass in the left side of the chest. The mass was a pinkish nodule (Fig 1) adherent to adjacent structures, particularly the pulmonary artery, aortic arch, and the lung. Running through it was the vagus nerve, and over it was the left phrenic nerve. The left phrenic nerve was identified and preserved, and the mass was carefully dissected from the pulmonary artery and the aorta. The left vagus nerve was electively sacrificed as it ran through the tumor. After successfully removing the mass and gaining adequate hemostasis, the chest was closed. Postoperative recovery was uneventful, although as anticipated she developed a hoarse voice.
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Fig 1. The mass, measuring 5.5 x 4.5 x 2.5, has been bisected to show the lobular pattern with paler areas surrounded by a congested rim of tissue.
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Tissue samples were sent for histologic analysis. The thymus was extensively replaced by fat, surrounding islands of thymic tissue. A thin peripheral strip of epithelial cells represented the cortex, whereas the medulla contained Hassall’s corpuscles and a few germinal centers. Due to the low ratio of thymic-to-fat tissue, the findings were considered consistent with thymic atrophy and mild thymitis. Lymph nodes removed together with the thymus and from the left mediastinum showed variable features of sinus histiocytosis and sinusoidal dilation, with no evidence of vascular proliferation. Some of these features were interpreted as evidence of lymphostasis. The removed mass consisted of lymphoid tissue with follicles containing multiple capillaries surrounded by hyaline sheaths (CD 21+). Postcapillary venules were prominent at the periphery of the follicles, which were surrounded by concentric cuffs of lymphocytes arranged in an onion skin pattern (Fig 2). Only a small number of plasma cells and eosinophils were present in the paracortex. The changes were consistent with the diagnosis of mediastinal solitary Castleman’s disease, of the hyaline vascular type. Immunohistochemical detection of endothelial markers (CD 31, CD 34) highlighted the vascular nature of the lesion. No evidence of involvement by Castleman’s disease was noted beyond the boundaries of the tumor.
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Fig 2. At high magnification (hematoxylin & eosin, x400), the hyaline vascular pattern is recognizable. The pale follicles, containing a central irregular area with a peripheral cuff of lymphocytes, are readily apparent.
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Comment
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Castleman’s disease, also referred to as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a distinct lymphoproliferative disorder of uncertain origin that was first described by Castleman in 1956 [1]. More than 70% of lesions are located in the chest, along the tracheobronchial tree, in the mediastinum or lung hilus. Other sites commonly involved include the neck, pelvis, retroperitoneum, and axilla [2]. There is no significant gender predominance or identifiable risk factors in the development of the disease [2]. Patients are usually asymptomatic or have nonspecific complaints, often due to tracheobronchial compression, such as cough, dyspnoea, chest pain, respiratory infection, and back pain [2].
The disease has been classified on clinical grounds (solitary or multicentric) and histologic appearance. Three histologic types have been described: hyaline vascular, plasma cell, and a mixed type [3]. It is now increasingly clear that there are different aetiologies for each of these different subtypes. Reported associations with Castleman’s disease include POEMS syndrome (polyneuropathy, organomegally, endocrinopathy, monoclonal gammopathy, and skin changes) [4], paraneoplastic pemphigus [5], Hodgkin’s disease [6], and follicular dendritic cell sarcoma [7]. The multicentric plasma cell variant is strongly associated with infection by human herpes virus 8 (HHV 8), and patients have an increased risk for the development of other HHV 8–associated neoplasms, including Kaposi’s sarcoma and extranodal B-cell lymphoma [8]. The solitary plasma cell variant of Castleman’s disease is often seen in patients with a history of lymphoma [6]. Overproduction of the cytokine interleukin 6 (IL-6), either native or virally encoded, has been hypothesized to drive plasma cell proliferation in these subtypes [9]. The pathogenesis of the hyaline vascular variant of Castleman’s disease is currently unknown; however, vascular and dendritic cell proliferations are common in this disorder [10]. Localized clonal proliferations of stromal elements, particularly follicular dendritic cells, occur in hyaline vascular Castleman’s disease and possibly explain the increased incidence of follicular dendritic cell sarcomas in this subtype [10].
Simple excision of solitary nodules is usually curative, especially in the hyaline vascular type [9]. The plasma cell type is frequently associated with systemic manifestations, such as amyloidosis, and is often refractory to systemic therapy with corticosteroids and chemotherapy, particularly in the multicentric form [9]. Overproduction of IL-6 from affected lymph nodes is thought to be responsible [9]. Therefore, interference with IL-6 signaling may constitute a new therapeutic strategy for this disease. In one study immediately after administration of rhPM-1 (an anti-IL-6 receptor antibody), fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathological examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment [9].
Two previous cases of Castleman’s disease associated with myasthenia gravis have been reported in the literature. The first, by Emson [11] in 1973, described a 14-year-old girl with solitary retroperitoneal Castleman’s disease of the hyaline vascular type. The second, by Pasaoglu at el [12] in 1994, reported a 15-year-old girl with multicentric extrathoracic Castleman’s disease with features of both the hyaline vascular and plasma cell types. The finding of thymus showing mild follicular hyperplasia is relatively common in myasthenia gravis, being the only thymic abnormality in approximately 65% of cases. Such a finding is often present in other autoimmune diseases [13], however not with Castleman’s disease, and is therefore most likely associated with myasthenia gravis. It is possible that the association between Castleman’s disease and myasthenia gravis is more than coincidental, and an underlying autoimmune mechanism may be involved.
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References
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- Castleman B, Iverson L, Menendez VP. Localized mediastinal lymphonode hyperplasia resembling thymoma Cancer 1956;9:822-830.[Medline]
- Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other localizations Cancer 1972;29:670-676.[Medline]
- Frizzera G. Castleman’s disease and related disorders Semin Diagn Pathol 1988;5:346-364.[Medline]
- Adelman HM, Cacciatore ML, Pascual JF, Mike JM, Alberts WM, Wallach PM. Case report. Castleman disease in association with POEMS. Am J Med Sci 1994;307:112-114.[Medline]
- Caneppele S, Picart N, Bayle-Lebey P, Paul J-L, Irsutti M, Oksman F, Joly P, Bazex J. Paraneoplastic pemphigus associated with Castleman’s tumour Clin Exp Dermatol 2000;25:219-221.[Medline]
- Abdel-Reheim FA, Koss W, Rappaport ES, Arber DA. Coexistence of Hodgkin’s disease and giant lymph node hyperplasia of the plasma-cell type (Castleman’s disease) Arch Pathol Lab Med 1996;120:91-96.[Medline]
- Chan ACL, Chan KW, Chan JKC, Au WY, Ho WK, Ng WM. Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman’s disease of the nasopharynx. tracing its evolution by sequential biopsies. Histopathology 2001;38:510-518.[Medline]
- Cesarman E. The role of Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) in lymphoproliferative diseases Rec Res Cancer Res 2002;159:27-37.[Medline]
- Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy Blood 2000;95:56-61.[Abstract/Free Full Text]
- Pauwels P, Dal Cin P, Vlasveld LT, Aleva RM, van Erp WF, Jone D. A chromosomal abnormality in hyaline vascular Castleman’s disease. evidence for clonal proliferation of dysplastic stromal cells. Am J Surg Pathol 2000;24:882-888.[Medline]
- Emson HE. Extrathoracic angiofollicular lymphoid hyperplasia with coincidental myasthenia gravis Cancer 1973;21:241-245.
- Pasaoglu I, Dogan R, Topcu M, Gungen Y. Multicentric angiofollicular lymph-node hyperplasia associated with myasthenia gravis Thorac Cardiovasc Surg 1994;42:253-256.[Medline]
- Okabe H. Thymic lymph follicles. a histopathological study of 1,356 autopsy cases. Acta Pathol Jpn 1966;16:109-130.[Medline]
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Abstract
Introduction
