Castleman's disease is an uncommon clinicopathologic entity that results in unregulated growth of lymphoid tissue. It may present as benign involvement of one lymph node group or as multicentric disease with serious systemic symptoms. Pleural effusions are an uncommon manifestation of Castleman's disease. We present a patient with Castleman's disease who initially presented with a chylous pleural effusion. (CHEST 1999; 115:285-288)
Key words: Castleman's disease; chylothorax; giant lymph node hyperplasia; pleural effusion; sickle cell anemia
Castleman's disease, also known as angiofollicular or giant lymph node hyperplasia, is a rare disorder that results in the unregulated growth of lymphoid tissue. Initially, Castleman's disease was reported as an indolent disorder which was usually confined to a single lymph node group. However, recent case reports have described a multicentric form of Castleman's that often manifests a more malignant clinical course. Patients with Castleman's disease may present with a variety of signs and symptoms, but pleural effusions are an uncommon manifestation of this disease.
We present a case of the transitional or mixed variant of Castleman's disease in a young male with a history of sickle cell anemia, who initially presented with large bilateral chylous pleural effusions. To our knowledge, this is the first case report of Castleman's disease in association with a chylous pleural effusion.
A 24-year-old man with a history of sickle cell anemia presented to our emergency department with a 10-day history of dyspnea, both with exertion and at rest. He also reported subjective fevers, occasional night sweats, and a mild cough productive of yellow sputum. During the week prior to admission, his shortness of breath progressively worsened until he could no longer sleep in a recumbent position. During the final 2 days prior to admission, he developed his typical sickle cell crisis pain in his chest, back, and legs.
This patient had been hospitalized on many previous occasions for sickle cell crises, lie had a remote history of bilateral subclavian vein thrombosis secondary to multiple central line insertions, He did not drink alcohol, smoke, or use illicit drugs. His only medication at the time of admission was folic acid.
On admission, his temperature was 37.7 [degrees] C, pulse was 72 beats/min, BP was 148/76 mm Hg, and respiratory rate was 34 breaths/min. He was an ill-appearing, thin young man. There was no palpable lymphadenopathy. The jugular veins were distended to 5 cm at 30 degrees of elevation. His heart rate and rhythm were regular. He had a 2/6 systolic murmur along the left sternal border. Chest examination revealed decreased expansion, decreased breath sounds, and dullness to percussion on the right side. The left side was clear to auscultation and without dullness. The abdominal, neurologic, and skin examinations were unremarkable. The admission chest radiograph is shown in Figure 1.
[Figure 1 ILLUSTRATION OMITTED]
Laboratory examination revealed a hemoglobin of 9.9 g/dL, hematocrit of 28.6%, WBC count of 14.6 x [10.sup.9]/L, and platelet count of 433 x [10.sup.9]/L. His blood chemistries were within normal limits, with a lactate dehydrogenase level of 198 U/L and a total protein level of 6.3 g/dL. The erythrocyte sedimentation rate was 147 mm/h and the reticulocyte count was 7%. An arterial blood gas on 32% supplemental oxygen revealed a pH of 7.45, a [PCO.sub.2] of 32 mm Hg, and a [PO.sub.2] of 69 mm Hg. The patient underwent a diagnostic thoracentesis, which revealed turbid fluid, 5,944 nucleated cells (1% segmented neutrophils, 96% lymphocytes, and 3% histiocytes), protein 4.3 g/dL, glucose 85 mg/dL, amylase 66 U/L, lactate dehydrogenase 182 U/L, and triglycerides 1,050 mg/dL. Cytologic examination of the pleural fluid revealed no malignant cells. Serum assay revealed an IgG level of 2,730 mg/dL (normal range, 694 to 1,618 mg/dL) and an IgA level of 453 mg/dL (normal range, 63 to 378 mg/dL). The IgM level was normal at 89 mg/dL, and no paraprotein was found. Blood, sputum, and urine cultures revealed no microbial growth. The patient was seronegative for HIV-1 and HIV-2. CT scan of the thorax revealed bilateral pleural effusions, compressive atelectasis of the lower lobes bilaterally, and mediastinal adenopathy.
The patient was initially treated with bilateral chest tube thoracostomies and central hyperalimentation. When a significant decrease in the chylous drainage failed to occur after 14 days of conservative therapy, a surgical approach was deemed necessary. The patient underwent a right thoracotomy with ligation of the thoracic duct above the diaphragm, which was successful in diminishing the amount of chylous drainage. Because of adhesions, the mediastinum could not be reached to biopsy the mediastinal lymph nodes. In an attempt to determine the etiology of the mediastinal adenopathy, a CT-guided needle biopsy was subsequently performed; however, the tissue was nondiagnostic. The patient underwent a Chamberlain procedure to gain access to the mediastinum. The surgeon reported areas of lobulated fat dispersed within a large mass of nodal tissue lying along the thymic region. A biopsy specimen from this nodal tissue revealed rare, small, involuted germinal centers that lacked follicular center cells (Fig 2, 3). The mantle zone of the germinal center was inconspicuous and some of the involuted follicles had a radially oriented, thin-walled blood vessel that originated in the perifollicular tissue and penetrated the germinal center. The remainder of the lymph node revealed sheets of mature plasma cells and increased vascularity of the interfollicular region (Fig 4). The immunohistochemical stain demonstrated positive staining of the interfollicular plasma cells for both kappa and lambda light chains. These morphologic features are consistent with the diagnosis of the transitional or mixed type of Castleman's disease.
[Figure 2-4 ILLUSTRATION OMITTED]
The patient was started on high-dose corticosteroid therapy, with an initial dose of 1,000 mg of solumedrol followed by three 125-mg doses of solumedrol. The patient then received 100 mg/d of prednisone. After 2 months of therapy, no response was noted clinically or radiographically on subsequent CT scans of the chest. A total of 2,000 rads of radiation therapy was then delivered to the mediastinum over a 10-day period, followed by chemotherapy with cytoxan 800 mg/[m.sup.2] and vincristine 2 mg. In spite of this aggressive therapy, the patient continued to require increasing amounts of oxygen. A repeat CT scan of the chest demonstrated no change in the size of the mediastinal adenopathy. The patient expired on hospital day 125 after a prolonged and difficult hospital course.
Castleman's disease is an unusual disorder of immune regulation that results in abnormal proliferation of B lymphocytes and plasma cells in lymphoid organs. Histologically, it is usually differentiated into three types: a hyaline vascular variant, a plasma cell variant, and a transitional (mixed cell) type. Pathologically, the hyaline vascular type features abnormal follicles with a striking interfollicular vascularity, expanded mantle zones composed of small lymphocytes, and one or more small blood vessels. These vessels may have thickened walls that form hyalinized germinal centers. In contrast, the plasma cell variant displays lymph nodes with an intact mantle zone surrounded by sheets of mature plasma cells and no vascular proliferation. The transitional or mixed cell variant is the least common type of Castleman's disease and, as in our case, it is characterized by histologic features predominantly of the hyaline-vascular type with foci of numerous plasma cells and some large normal-appearing germinal centers.
Clinically, patients with Castleman's disease may present with an asymptomatic abnormality on chest radiograph, localized symptoms caused by compression of the tracheobronchial tree, or systemic symptoms such as fever or weight loss. The latter, known as multicentric disease, is most often associated with the plasma cell variant. Typically, the multicentric variant occurs in individuals in their fourth or fifth decade as an aggressive malignant-like syndrome with associated features of elevated sedimentation rate, hepatosplenomegaly, hypergammaglobulinemia, granulocytosis, and plasmacytosis of the bone marrow. The multicentric variety has been reported to have mortality rates as high as 50%.
The presence of pleural effusions is an uncommon occurrence in patients with Castleman's disease. Presently, only seven cases of Castleman's disease presenting as a pleural effusion have been reported in the literature. Several of these were described as large effusions, but none were chylous in nature. Chylous pleural effusions result from disruption of the thoracic duct with subsequent leakage of lymphatic fluid or chyle into the chest cavity. It occurs most commonly with malignancy (usually lymphoma) and trauma, but several other causes have been described, including sarcoidosis, tuberculosis, yellow nail syndrome, Turner's syndrome, Noonan's syndrome, and lymphangiomyomatosis. There have been several reported cases of chylous pleural effusions associated with subclavian vein thrombosis. All of the reported cases have occurred in newborn infants. Although our patient had a remote history of a subclavian vein thrombosis, the CT scan shortly after his admission revealed patent subclavian veins bilaterally.
The diagnosis of a chylous pleural effusion is usually suspected when cloudy or milky fluid is obtained on thoracentesis. However, 50% of chylous effusions may not have the classic milky appearance and the diagnosis should be suspected if a cloudy, serosanguineous or bloody effusion does not clear with centrifugation. A pleural effusion is diagnosed as a chylous effusion if the pleural fluid triglyceride level is greater than 110 mg/dL. The location of the pleural effusion is related to the level of obstruction of the thoracic duet. Normally, the thoracic duet crosses to the left side of the thoracic cavity between the fourth and sixth vertebrae. Therefore, the critical obstruction in this patient with a right pleural effusion was below the level of the fourth thoracic vertebra.
Once the diagnosis of a chylothorax is established, a course of therapy should be chosen to avoid the known sequelae of malnutrition, metabolic abnormalities, and an immunocompromised state. By administering total parenteral nutrition with a low-fat, high-calorie, and high-protein formula, chyle formation will be decreased while an adequate nutritional status is maintained. The chylothorax should also aspirated either by repeated thoracentesis or by tube thoracostomy. When appropriate, therapy should also be directed at the specific etiology of the chylothorax, such as radiation or chemotherapy therapy for lymphoma involving mediastinal structures. If there is a loss of chyle of more than 500 mL/d in an adult or more than 100 mL/d in a child for more than 14 days, conservative therapy should be abandoned and surgical intervention with either thoracic duct ligation or pleuroperitoneal shunt insertion should be considered.
To our knowledge, this is the first case report of any variant of Castleman's disease presenting as a chylous pleural effusion, and we suggest that Castleman's disease be added to the differential diagnosis of a chylous effusion.
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(*)From the Division of Pulmonary and Critical Care Medicine, Department of Medicine (Drs. Ten Hoor and Moss), Department of General Thoracic Surgery (Dr. Miller), and Department of Pathology (Dr. Hewan-Lowe), Crawford Long Hospital and the Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA.
Manuscript received December 18, 1997; revision accepted April 1, 1998.
Correspondence to: Marc Moss, MD, Crawford Long Hospital of Emory University, Suite 5310, 550 Peachtree St, NE, Atlanta, GA 30365
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