Unknown 21

Clinical History: A 26-year-old man presented to the emergency department with several stab wounds to the right anterior thorax. A chest radiograph was obtained in the trauma room. Abnormal findings on chest radiography prompted evaluation with a CT of the thorax and thoracic angiography.

Figure 1. Frontal Chest Radiograph

Frontal radiograph shows a right paratracheal mass. The paper clip marks the location of stab wound entry sites.

Figure 2. Thoracic CT

Axial thoracic CT through the upper chest was obtained because of suspicion of mediastinal hematoma and vascular injury based on chest radiographic findings. CT shows an enhancing right paratracheal mass with small areas of increased attenuation suggesting calcification. The CT scan was interpreted as consistent with a mass, perhaps neoplastic, but the trauma service requested aortography to definitively exclude vascular injury. (A chest tube is present on the left.)

Figure 3. Thoracic Aortography

Left anterior oblique thoracic aortography shows a right paratracheal mass with large feeding vessels. Findings are consistent with a highly vascular mass, not subclavian artery pseudoaneurysm. The patient was taken to the operating room for removal of the mass.

What is the differential diagnosis?

Answer

Figure 4. Section of Resected Mass

A circumscribed, soft mass, 6 x 5 x 3 cm, with a smooth, yellow-tan surface and homogeneous tan cut surface was resected. Focal white fibrous strands were present centrally.

What type of tissue is present?

Answer

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Localized Castleman's Disease (CD)

Introduction: CD, also known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia, is a condition of unknown etiology, which was first described in the mid '50s as a localized lymph node hyperplasia in the mediastinum [1]. In 1972, Keller and colleagues described two histopathological variants of the disease--the hyaline-vascular type and the plasma-cell type. The hyaline-vascular variant (CD-HV) is more commonly encountered and usually presents as isolated lymph node enlargement involving the pulmonary hilum or the mediastinum. Usually asymptomatic, it is detected incidentally on screening chest radiography or imaging obtained for unrelated reasons, as in the present case [1].

The plasma cell variant of Castleman's disease (CD-PC) is often accompanied by systemic symptoms, such as fever, anemia, and hyperglobulinemia. The occurrence of histologically-mixed forms (CD-mixed) is believed to link the two entities [1].

The solitary forms of Castleman's disease are usually cured by surgical resection. When the plasma cell variety is present and associated with systemic manifestations, symptoms usually resolve after resection [1,2]. A multicentric form of CD, not discussed here, also occurs [2].

Clinical features: The CD-HV variant comprises 91% of cases [1]. In a study of 102 patients with CD-HV, the age range was 7-75 years (median 30), and 66% were female [3]. Patients with this variant are usually asymptomatic although there may be compression or invasion of adjacent structures (bronchus with dyspnea, recurrent infections, cough [1]; or vena cava with superior vena cava syndrome [4]), pain, palpable mass, or pleural effusion [1]. Lesions are located in cervical (42%), mediastinal (31%), abdominal (18%), or other (4%) nodes: five percent of lesions are extranodal [3].

Patients with the PC variant range from 3-45 years old, and males predominated 9/3 in one series [1]. Locations are similar to those for the HV variant [1]. Symptoms in patients with the CD-PC variant may resemble those of the HV type, but additionally there may be systemic symptoms and signs. These include sweats, fever, hyperglobulinemia, anemia, and increased sedimentation rate [1].

Radiographic findings: The primary radiographic manifestation of the solitary variety of Castleman's disease is a smooth or lobulated mass in the hilum or mediastinum: middle or posterior mediastinal involvement is most common, whereas anterior mediastinal involvement is rare (4 of 24 (17%) in one series) [5]. Involved lymph nodes may show intense enhancement, but the degree of enhancement is often more pronounced in the HV variant than in the PC variant. Small foci of calcification may be encountered within involved lymph nodes.

Magnetic resonance imaging of lymph nodes affected by Castleman's disease typically shows slightly increased signal on T1-weighted imaging compared to skeletal muscle, with hyperintense signal on T2-weighted imaging. Intense enhancement with gadolinium-based contrast material is typical. Foci of markedly decreased signal intensity on either T1- or T2-weighted imaging may reflect focal calcifications or curvilinear flow voids of vessels [5].

Pathologic changes--HV type: Although HV lesions are usually solitary, adjacent lymph nodes with a similar morphology are sometimes found (1). The hyperplastic nodes vary up to 25 cm in diameter [5]. Histologically, typical follicles of CD-HV variant have small germinal centers (GC) with concentric layers of lymphocytes in the prominent mantle zone (MZ), but occasional hyperplastic GC may be found. The MZ and GC are penetrated by increased numbers of vessels, which often have hyalinized, fibrotic walls. This hyalinization may compress the cells of the GC, which are mainly comprised of follicular dendritic cells: B lymphocytes are sparse [6]. The interfollicular region has increased numbers of high endothelial venules, which often have thickened, hyalinized walls. A mixed population of T lymphocytes and a few plasma cells are present around the vessels. Both the lymphocytes and the plasma cells are polyclonal [2]. Typically, the normal nodal lymphatic sinuses are obliterated [3]. Interfollicular perivascular fibrosis, as well as more extensive areas of fibrosis, visible on gross inspection, may be present [1].

PC type: The infrequent, localized PC variant is usually composed of several discrete nodes that create masses up to 13 cm in diameter [1]. The main histologic feature of the PC variant is the prominence of sheets of polyclonal plasma cells in the IF zones. Germinal centers are either of normal size or enlarged and cellular. B cells are the most frequent cell type in the GC [6]. IF vascularization is not so prominent as in the HV type, and lymphoid sinuses can usually be found [1].

A mixed HV and PC variant with sheets of plasma cells in the IF areas and small germinal centers has been thought to link the two variants [1].

Associations: The HV variant may rarely be associated with focal distinctive stromal hyperplasias or even neoplasias arising in the involved node [7]. One type of focal hyperplasia is composed of a network of compressed vessels and cells resembling pericytes and smooth muscle (angiomyoid type). It tends to occur in the abdomen of women (ages 22-51), and is apparently cured by resection. A distinct neoplastic lesion (follicular dendritic cell type) occurs in involved nodes of older patients (ages 31-76) of either sex and at various sites. It is composed of a mixture of lymphocytes and spindled cells, the latter having an immunologic profile similar to follicular dendritic cells. The dendritic cells show varying degrees of atypia, and the course is often characterized by recurrence or metastasis [7]. Other types of focal proliferations arising in HV nodes are reviewed by Lin, et al. [7].

The solitary PC variant has been associated with amyloidosis AA in a few cases [8]. IL-6, which stimulates the production of acute-phase reactants, including serum amyloid A (SAA), may be involved in its pathogenesis. In one such case a 6.2 cm by 4 cm abdominal tumor was removed from a 21-year-old woman with systemic (AA) amyloidosis. Preoperatively, serum concentrations of IL-6 and SAA were elevated, and both declined following excision of the mass [8]. Other clinical associations of HV and PC variants, including hematologic, pulmonary, renal, neurologic, and oncologic diseases, are reviewed by Shahidi, et al [2].

Pathogenesis: Reaction to infection, immunodeficiency, and autoimmunity are possible causes of CD [2]. Although the pathogenesis of the HV variant is unknown, the pathogenesis of the PC variant may be related, in part, to IL-6, which promotes B-cell proliferation and maturation to plasma cells, and stimulates the production of multiple acute-phase reactants [6]. IL-6 has been demonstrated immunohistochemically in GC B cells of PC-type, but not of HV-type, nodes [6].

Further, IL-6 has been shown to be elevated in the serum before, and to decline to normal values after, the mass is resected. In one patient with CD-PC/HV mixed type, treatment with an antibody to IL-6 resulted in remission of symptoms and signs of disease. Relapse occurred when the treatment was stopped, but excision of the mass led to prolonged remission [9].

Treatment: Resection is almost always curative in cases of discrete nodal disease without a malignant component [1,5]. Because of the high degree of vascularity of the HV lesion, it has sometimes been embolized before excision [5]. Successful thoracoscopic removal has been reported [10]. Incompletely resected or nonresectable infiltrative disease has been treated with radiation [2]. The patient should be followed to detect recurrence or associated conditions [2].

Summary of Thoracic Imaging Studies:

Summary of Pathologic Findings: HV Variant

PC Variant [1,2]

Mixed Variant

Diagnosis: Castleman's disease, localized, hyaline-vascular type

References: To return to reference section after viewing abstract, click here before clicking on "abstract".

l. Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972; 29:670-683. No abstract

2. Shahidi H, Myers J, Kvale PA. Castleman's disease. Mayo Clin Proc 1995; 70:969-977. Abstract

3. Danon A, Krishnan J, Frizzera G. Morpho-immunophenotypic diversity of Castleman's disease, hyaline-vascular type: with emphasis on a stroma-rich variant and a new pathogenetic hypothesis. Virchows Arch A Pathol Anat Histopathol 1993; 423:369-382. Abstract

4. Dhingra H, Sondhi D, Fleischman J, Ayinla R, Chawla K, Rosner F. Castleman's disease and superior vena cava thrombi: a rare presentation and a review of the literature. Mt Sinai J Med 2001; 68:410-416. Abstract

5. McAdams HP, Rosado-de-Christenson M, Fishback NF, Templeton PA. Castleman disease of the thorax: radiologic features with clinical and histopathologic correlation. Radiology 1998; 209:221-228. Abstract

6. Hsu S, Waldron J, Xie S, Barlogie B. Expression of interleukin-6 in Castleman's disease. Hum Pathol 1993; 24:833-839. Abstract

7. Lin O, Frizzera G. Angiomyoid and follicular dendritic cell proliferative lesions in Castleman's disease of hyaline-vascular type: a study of 10 cases. Am J Surg Pathol 1997; 21:1295-1306. Abstract

8. Ikeda S, Chisuwa H, Kawasaki S, Ozawa J, Hoshii Y, Yokota T, Aoi T. Systemic reactive amyloidosis associated with Castleman's disease: serial changes of the concentrations of acute phase serum amyloid A and interleukin 6 in serum. J Clin Pathol 1997; 50:965-967. Abstract

9.Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B. Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 1994; 330:602-605.

10. Seirafi PA, Ferguson E, Edwards FH. Thoracoscopic resection of Castleman disease: case report and review. Chest 2003; 123:280-282. Abstract

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Radiographic differential diagnosis: The differential diagnosis of a right paratracheal mass is quite large. Incidentally detected thyroid goiters are common causes of right paratracheal masses. Lymphadenopathy is also a common cause of a right paratracheal mass, and may result from metastatic disease, lymphoma, sarcoidosis, and certain infections, most notably tuberculosis and coccidioidomycosis. Lymphadenopathy may occur with extremely rare infections, such as anthrax, tularemia, and plague. A rare cause of lymphadenopathy affecting the right paratracheal region is Castleman's disease. Aneurysms involving the right subclavian artery, internal mammary artery, and right brachiocephalic artery may also produce right paratracheal masses on chest radiography. Neoplasms involving the medial right upper lobe or pleura and the vagus nerve (schwannoma) may also cause right paratracheal masses.

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