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A 24-year-old woman was involved in a motor vehicle accident. Upon radiological work-up, a large incidental mass was identified in the anterior mediastinum. Excisional biopsy of a single enlarged lymph node was performed.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, and Case 3 is angiofollicular hyperplasia (Castleman disease).
Criteria for Diagnosis and Comments:
Histologic sections of the lymph node show numerous hyperplastic and variously sized, but mostly small, lymphoid follicles. This characteristic appearance has been termed giant lymph node hyperplasia. Some follicles have more than one germinal center. Some germinal centers show features of regressive transformation with a small atrophic appearance, few centroblasts and penetrating small vessels with hyaline changes. Their appearance may be likened to that of Hassall’s corpuscles, but they consist mostly of follicular dendritic cells rather than epithelial cells. They are surrounded by concentrically arranged lymphocytes which give the illusion of an expanded mantle zone and create a classic “onion skin” appearance. There is abundant interfollicular tissue containing primarily lymphocytes with some plasma cells, eosinophils, and immunoblasts. These areas also have rich vasculature with some fibrosis, as well as numerous macrophages. These morphological features are typical of hyaline vascular variant of angiofollicular hyperplasia (Castleman disease).
Castleman disease is found predominantly in the lymph nodes, but may also affect the thymus. Clinically, the disease can be unicentric or multicentric. In terms of histology, unicentric disease includes the hyaline vascular and plasma cell variants, while multicentric disease is mostly of the plasma cell type. The hyaline vascular type, as seen in this case, is the most common form accounting for approximately 80% of cases. It typically presents as a mediastinal mass without other symptomatology. Compression by the mass may also be a presenting symptom. Most typically, only a single lymph node is involved. The disease can affect any age; male and female incidence rates are equal. Surgical removal of the mass is usually curative. The plasma cell type more frequently involves extranodal sites outside of the chest. It usually involves many lymph nodes and patients can have systemic symptoms like anemia, hypergammaglobulinemia, and fever. The multicentric type typically affects older patients, males slightly more often than females. Multiple lymph nodes at multiple sites are involved. Patients typically present with systemic symptoms and hepatosplenomegaly. This type is often seen in patients with HIV and is strongly associated with human herpesvirus 8 (HHV-8). Additionally, there is an increased incidence of malignant neoplasms like carcinomas or lymphomas, in up to a third of patients. Lab studies may reveal cytopenias, proteinuria, an increased sedimentation rate, and hypoalbuminemia. Clinically, this type may be stable or progressive. Symptomatic patients with multicentric disease often require systemic therapy like steroids. Chemotherapeutic agents, rituximab (monoclonal antibody to CD20) and interleukin-6 antagonists have also been used.
In addition to the clinical differences, the plasma cell variant has histological features which delineate it from the hyaline vascular type. The follicles are expanded/hyperplastic instead of the predominantly small and regressive follicles seen in the hyaline vascular type. Their appearance is more akin to that of reactive follicular hyperplasia, although a few hypo-cellular follicles such as those seen in the hyaline-vascular type may also be seen. The interfollicular areas are expanded with sheets of plasma cells, as opposed to the mix of lymphocytes and plasma cells typically seen in the hyaline vascular type. Unlike the hyaline vascular variant that can be diagnosed based on histological features, plasma cell variant can be histologically indistinguishable from reactive hyperplasia seen in systemic conditions like rheumatoid arthritis and viral lymphadenitis. In all types of Castleman disease, kappa and lambda stains will show a polyclonal plasma cell population. Only rarely will flow cytometry of Castleman disease show clonality. CD5 positive lymphoid cells are found at the periphery of the abnormal follicles suggesting that Castleman disease may have its histogenesis as a proliferation of CD5 positive lymphocytes stimulated by specific lymphokines. In addition, abnormalities of follicular dendritic cells, and defective nodal microenvironmental factors involving interactions between T-lymphocytes, antigen processing, dendritic cells and angiogenesis have been recently described.
Histologically, follicular lymphoma, as compared with Castleman disease, most commonly forms a nodular pattern which may appear diffuse in areas. The blood vessels, which are prominent and hyalinized in Castleman disease, are instead displaced to the periphery of these nodules. There are numerous cytologically abnormal cells present, many with cleaved nuclei representing centrocytes. While Castleman disease is almost always comprised of a polyclonal plasma cell population, follicular lymphoma is defined by the presence of monoclonal B cells. Immunohistochemistry with positivity for CD20, CD10 and bcl2 is characteristic.
Lymphocyte-predominant thymoma lacks the typical features seen in Castleman disease like regressive follicles, hyalinized blood vessels and prominent mantle zones. Hassall’s corpuscles may be present within lymphocyte-predominant thymoma. The plasma cells and eosinophils commonly seen in Castleman disease are scarce to absent. Thymomas typically show an organoid pattern of growth with thick fibrous septa. Cytokeratin can demonstrate the epithelial component in thymomas.
As compared with Castleman disease, plasmacytoma is comprised of a pure population of clonal plasma cells. While there have been reports of monoclonal plasma cells representing a component of the interfollicular area of Castleman disease, the entity is most normally identified as a polyclonal plasma cell population, both by kappa and lambda staining as well as flow cytometry. Finally, in plasmacytoma there will be neither hyalinized germinal centers present nor the characteristic “onion skin” appearance usually seen in Castleman disease.
When compared to Castleman disease, reactive follicular hyperplasia also has much fewer plasma cells within its population. The interfollicular infiltrate differs from that of Castleman as noted by its composition of lymphocytes and the presence of more characteristic immunoblasts.
The patient with regressing follicular hyperplasia will present with a clinical history of waning lymph node enlargement. This entity most often involves peripheral lymph nodes and does not present incidentally with a mediastinal mass. Finally, the classic “onion skin” pattern characteristic of the hyalinized germinal centers of Castleman disease will also not be present.