Castleman's Disease: Atypical Manifestation in an 11-Year-Old Gir

Capt Vinod K. Gidvani, USAF, MC, Capt Melissa M. Tyree, USAF, MC, Col Samar K. Bhowmick, USAF, MC, Department of Pediatrics, Keesler Air Force Base, Miss

South Med J. 2001;94(2) 

In This Article


Castleman's disease is an uncommon lymphoproliferative disorder defined as "a localized hyperplasia of lymphoid follicles with and without a germinal center formation and marked capillary proliferation with endothelial hyperplasia."[3] A review of the literature reveals this condition has been called a variety of names, perhaps none more appealing than that chosen by Denenberg et al,[4] who called Castleman's disease "the lymphoma impostor." Our case is rare in that a localized hyaline vascular form initially manifested as and was discovered due to a constellation of systemic symptoms. Recent studies show that such systemic manifestations may be linked to intralesional cytokine dysregulation involving IL-1, tumor necrosis factor a (TNF- ), and IL-6, as is seen with other inflammatory disorders.[5] Therefore, it is more important than ever to revisit this rare diagnosis and keep it in the differential diagnosis of pediatric lymphoproliferative disorders -- so that this "imposter" is not overlooked.

There is no consensus on the underlying etiology of Castleman's disease, but two main theories have been proposed. One theory submits that the disorder represents a reactive lymphoid hyperplasia initiated by chronic antigenic stimulation associated with a viral trigger (which remains undefined), most likely mediated through the respiratory or gastrointestinal tract, the most common sites affected. The other proposes that the masses are due to a developmental growth disturbance of the lymphoid tissue, ie, a vascular lymphoid hamartoma.[6]

Castleman's disease can be found throughout the body at both nodal and extranodal sites. The mediastinum and neck remain the most common sites. Mediastinal masses are mostly found anteriorly and are discovered incidentally on chest radiographs, as was the case in our patient. While Castleman's disease can occur at any age, most cases occur in adolescents or young adults. The youngest patient reported to have this disease was 6 months old.[7] No significant sex predilection has been found, regardless of the histologic type. Clinically, localized disease tends to be seen more commonly in younger patients, while the more severe multicentric variant affects older individuals.[3]

The diagnosis of Castleman's disease is ultimately by histology, thereby requiring either removal or biopsy of the lesion for definitive diagnosis. The hyaline vascular variant is characterized by extensive capillary proliferation and a lymphocyte-predominant infiltrate surrounding small germinal centers. Hyalinized fibrous tissue surrounding the proliferating capillaries is typically present.[3] The plasma cell variant has sheets of mature plasma cells within the interfollicular tissues surrounding larger germinal centers and has significantly less vascularity.[3] The localized form may originate from either of these variants, but the multicentric version is almost exclusively derived from the plasma cell variant. In addition, there are some benign and malignant conditions, including lymphoma and thymoma, that may appear histologically similar to Castleman's disease. Therefore, immunohistologic and immunologic gene rearrangement studies of the specimens can be useful in solidifying the diagnosis. Identifying an immunophenotypically varied population of B lymphocytes with polyclonal surface and cytoplasmic immunoglobulin markers helps to confirm the diagnosis of Castleman's disease and differentiate it from lymphoma.[6]

The clinical manifestations of Castleman's disease are highly dependent on the histopathology of the lesion. The plasma cell variant can be much more severe than the hyaline vascular form and has a strong association with extrathoracic, multicentric, highly aggressive disease.[8] The systemic manifestations associated with the plasma cell variant of Castleman's disease consist of fever, cytopenias, organomegaly, polyclonal hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate, as well as renal and hepatic dysfunction. Isolated case reports also recount such atypical features as peripheral neuropathy, myasthenia gravis, recurrent pleural effusion, amyloidosis, growth retardation, and nephrotic syndrome.[9,10] Contrary to its counterpart, the hyaline vascular variant is rarely associated with systemic disease. However, Summerfield et al[1] described two cases of the hyaline vascular variant with unusual systemic manifestations mimicking lymphosarcoma and hemangioimmunoblastoma, so that the true diagnosis of Castleman's disease was significantly delayed in part because of a low index of suspicion of the possibility of hyaline vascular Castleman's disease in the presence of marked systemic symptoms. Lin et al[11] reported a case of the hyaline vascular type of Castleman's disease that was initially diagnosed as adult-onset Still's disease. The correct diagnosis was not made until a year later, after conclusive biopsy of a mass that had subsequently developed over the right axillary region.

To our knowledge, ours is the youngest patient reported to have a documented hyaline vascular variant of Castleman's disease with marked systemic symptoms. She was ill in appearance and had prolonged intermittent fever, dysphagia, difficulty breathing, fatigue, weight loss, and an elevated serum lactate dehydrogenase level. These symptoms were initially mistakenly attributed to a upper respiratory infection with features of reactive airway disease and sinusitis. In retrospect, the dysphagia and difficulty breathing may be explained by relative compression of structures adjacent to the mediastinal mass.

The exact mechanism of systemic symptoms with either form of Castleman's disease remains to be elucidated. However, a growing body of evidence indicates that Castleman's disease is primarily a lymphoproliferative or inflammatory disorder.[1] Beck et al[12] confirmed that the generation of IL-6 in the germinal centers of hyperplastic lymph nodes and subsequent complex interactions with IL-1 and TNF- may be the key elements responsible for the systemic manifestations of Castleman's disease. Further support of this theory lies in the fact that all systemic manifestations in our patient resolved with surgical excision of the "hyperplastic lymphoid" mediastinal mass.

The treatment of Castleman's disease consists primarily of surgical excision, with complete cure possible if the lesion is removed in its entirety. Selective angiography is helpful preoperatively in identifying the vascular supply of the tumor, and some advocate embolization to prevent bleeding complications with these highly vascular masses.[13] For patients who have incomplete or unresectable lesions, radiotherapy has been used with limited effectiveness. The unfortunate few who have the more aggressive plasma cell variant often require treatment with steroids and systemic chemotherapy. In many cases, all systemic manifestations resolved with administration of steroids, further supporting the hypothesis that Castleman's disease is a part of the spectrum of inflammatory disorders.[1]

Because of its rare occurrence with constitutional symptoms, our case contributes to the growing body of evidence that suggests that the systemic pathogenicity of Castleman's disease is related to associated cytokine dysregulation, and it reinforces the need to keep Castleman's disease in a comprehensive differential diagnosis of pediatric lymphoproliferative disorders.

Views expressed in this report are those of the authors and do not reflect the official opinion of the United States Air Force or Department of Defense.


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