Castleman Disease: The Great Mimic From the Russell H. Morgan Department of Radiology and Radiological Science (D.B., K.M.H., E.K.F.) and the Department

Castleman Disease: The GreCastleman Disease: The Great Mimicat Mimic

From the Russell H. Morgan Department of Radiology and Radiological Science (D.B., K.M.H., E.K.F.) and the Department of Pathology (R.H.H.), Johns Hopkins

School of Medicine, 601 N Caroline St, JHOC 3140C, Baltimore, MD 21287.

Introduction• Castleman disease was first described by Dr Benjamin Ca

stleman in 1956 (1).

• He reported 13 cases of unicentric hyaline vascular Castleman disease of the chest and described the classic pathologic features of hypervascular lymph nodes with hyalinization of vessels, which form concentric arrangements somewhat reminiscent of Hassall corpuscles in the thymus (1).

• The disease is alternatively known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia. Castleman disease is one of the more common causes of nonneoplastic lymphadenopathy and represents a form of nonclonal lymph node hyperplasia (2,3).

• The classification and clinical features of Castleman disease

• The pathologic and pathophysiologic features

• The radiologic features

• The diseases associated with Castleman disease are discussed.

Classification and Clinical Features

• Castleman disease occurs throughout the body.

• Of all cases of Castleman disease, approximately 70% occur in the chest, 15% in the neck, and 15% in the abdomen and pelvis, involving primarily lymphatic tissues.

• Extralymphatic sites of involvement include the lungs, larynx, parotid glands, pancreas, meninges, and muscles (4–6).

• The morphologic classification distinguishes between unicentric and multicentric Castleman disease on the basis of the extent of local lymph node involvement.

• The histopathogenetic classification distinguishes hyaline vascular Castleman disease, plasma cell Castleman disease, human herpesvirus 8 (HHV-8)–associated Castleman disease(2).

• Unicentric Castleman disease is most commonly the hyaline vascular type of Castleman disease, and multicentric Castleman disease is typically the plasma cell type of Castleman disease (2).

• In addition, a mixed type of Castleman disease is characterized by the occurrence in the same patient of hyaline vascular Castleman disease and plasma cell Castleman disease features (2).

Hyaline Vascular Castleman Disease

• Hyaline vascular Castleman disease represents 90% of the cases of Castleman disease and occurs most often in young adults, with a median age at diagnosis in the 3rd or 4th decade (7). Hyaline vascular Castleman disease is unicentric in 90% of the cases and usually manifests as an asymptomatic mass lesion with a benign course.

• Rarely, multicentric or aggressive forms occur. Possible treatment approaches include (a) curative surgical resection for unicentric disease and (b) steroid treatment and/or systemic chemotherapy if necessary for multicentric and aggressive forms (2,3). Recently, neoadjuvant therapy with rituximab has been suggested (8).

Plasma Cell Castleman Disease

• Plasma cell Castleman disease represents less than 10% of the cases of Castleman disease. The less common unicentric form (between 9% and 24% of the cases of localized Castleman disease) occurs in a similar patient population as that for hyaline vascular Castleman disease, although it has been suggested that many reported cases of the unicentric form may represent incompletely documented multicentric Castleman disease (2). The much more common multicentric form occurs in an older age group, with a median age in the 6th decade.

• Plasma cell Castleman disease is frequently associated with systemic manifestations such as (a) fever, night sweats, and malaise; (b) hematologic and immunologic abnor malities such as anemia, thrombocytopenia, and hyperglobulinemia; and (c) splenomegaly (5).

• Plasma cell Castleman disease is associated with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome.

• Plasma cell Castleman disease has a worse prognosis than hyaline vascular Castleman disease but a better prognosis than HHV-8–associated Castleman disease (9).

• Common therapeutic approaches for plasma cell Castleman disease include systemic chemotherapy, antiproliferative agents, including anti–interleukin 6 (IL-6) receptor therapy, and anti–CD20 antibody therapy (9). Anecdotal cases of curative resection of the unicentric form have been reported (2,3).

HHV-8–associated Castleman Disease

• HHV-8–associated Castleman disease is the plasmablastic variant of Castleman disease and is associated with a poor prognosis. Survival is generally on the order of months (2).

• HHV-8–associated Castleman disease occurs predominantly in immunosuppressed patients and human immunodeficiency virus (HIV)–positive patients and manifests commonly with generalized lymphadenopathy, constitutional symptoms, and hematologic and/or immunologic abnormalities.

• HHV-8–associated Castleman disease generally has a more aggressive course than that of the HHV-8–negative plasma cell Castleman disease (9).

• Common therapy approaches include systemic chemotherapy and antiviral and antiproliferative regimens, including anti–IL-6 receptor therapy (eg, tocilizumab and siltuximab) and anti-CD20 antibody therapy (eg, rituximab) (2,9–12).

• Administration of the anti-CD20 monoclonal antibody rituximab has been found to induce a high percentage of complete and sustained remission in HHV-8–associated Castleman disease in HIV-positive patients (9), although concerns have arisen about a possible reactivation of Kaposi sarcoma with rituximab therapy (9).

Pathologic and Pathophysiologic Features

• Lymphoid-hamartomatous hyperplasia, autoimmune phenomena, immunodeficiency, and chronic low-grade inflammation have been suggested as potential etiologic factors for the development of Castleman disease. In hyaline vascular Castleman disease, follicular dendritic cell abnormalities and vascular endothelial growth factor have been implied as causative factors (2).

• Pathologically, hyaline vascular Castleman disease is characterized by (a) hyaline vascular lymph follicles with expanded mantle zones that contain small lymphocytes forming concentric rings (“onionskin” appearance) (Fig 1b) and (b) an interfollicular capillary proliferation with perivascular hyalinization (Fig 1a) (2,5). Often, a single penetrating vessel is seen in the center of the follicle. Plasmacytoid dendritic cell collections may be found associated with these lesions (2).

Typical histologic features of hyaline vascular Castleman disease in a 27-year-old woman.

Bonekamp D et al. Radiographics 2011;31:1793-1807

©2011 by Radiological Society of North America

Typical histologic features of hyaline vascular Castleman disease in a 27-year-old woman.



Radiologic Features• The classic CT appearance of hyaline vascular Castlema

n disease is that of a solitary enlarged lymph node or localized nodal masses that demonstrate homogeneous intense enhancement after contrast material administration.

• Three patterns of involvement have been described, including a solitary noninvasive mass (most common: 50% of cases), a dominant infiltrative mass with associated lymphadenopathy (40% of cases), and matted lymphadenopathy without a dominant mass (10% of cases) (6).

• Hyaline vascular Castleman disease can manifest as a mesenteric or retroperitoneal mass with mild contrast enhancement, with an imaging appearance mimicking retroperitoneal adenopathy and carcinoid tumor (Fig 2).

Surgically diagnosed hyaline vascular Castleman disease mimicking a mesenteric or retroperitoneal mass in a 29-year-old woman, a finding that was incidentally depicted at

CT imaging of the abdomen for known right xanthogranulomatous pyelonephritis.















• Hyaline vascular Castleman disease has a considerable predilection for involvement of the thorax, where it typically manifests as an avidly enhancing mediastinal nodal mass.

• Mediastinal Castleman disease can mimic thymoma, lymphoma, sarcoma, hemangiopericytoma, neural crest–derived neoplasms such as paraganglioma, neurofibroma, or schwannoma, and chest wall tumors (Fig 3).

• Hilar Castleman disease may be confused with bronchial adenoma (5).

• Pleural Castleman disease is unusual and can manifest as a well-defined mass or with an associated pleural effusion (15).

• Pericardial Castleman disease can mimic a pericardial cyst (16).

• Intercostal Castleman disease can show rib erosion and simulate other chest wall masses (17).

• Prominent feeding vessels in the close vicinity of a nodal mass are a clue to the diagnosis and are predominantly seen in hyaline vascular Castleman disease (Fig 4).

• Approximately 10% of the lesions have internal calcifications, which are characteristically coarse or demonstrate a distinctive branching pattern (3). More commonly, however, nonspecific calcifications are observed (Fig 5).

• Central hypoattenuation in nodal masses is unusual but may be seen in few cases (3).

Hyaline vascular Castleman disease mimicking a mass in the posterior mediastinum, lung, pleura, and chest wall in a 39-year-old man who presented with paraneoplastic

pemphigus, which led to severe hemorrhagic erosions of the lips, gingiva, and buccal and co...



Hyaline vascular Castleman disease mimicking a mesenteric neoplasm in a 44-year-old woman who presented with abdominal pain.












Surgically diagnosed hyaline vascular Castleman disease mimicking a pancreatic neck tumor in a 27-year-old woman who had a 2-year history of a peripancreatic mass that

was initially depicted at CT imaging for acute abdominal pain.















• At magnetic resonance (MR) imaging, the lesions of hyaline vascular Castleman disease classically exhibit heterogeneous T1 and T2 hyperintensity compared with skeletal muscle (3,6). Prominent flow voids may be seen, which identify the feeding vessels. MR imaging is well suited to depict the extent of disease and the relationship to adjacent structures, although evaluation of calcifications is limited.

• Systemic manifestations of hyaline vascular Castleman disease are rare, compared with the other forms, and include pleural and pericardial effusions, hepatomegaly, and diffuse lymphadenopathy. Such an aggressive course can mimic that of an aggressive lymphoma (Fig 6).

• As discussed in the following section, associated diseases are less commonly observed in hyaline vascular Castleman disease than in the other forms but do occur with hyaline vascular Castleman disease.

• The combination of adenopathy and osseous lytic or sclerotic lesions may be a clue to the diagnosis of hyaline vascular Castleman disease with associated POEMS syndrome (Fig 7),

• A history of mucosal hemorrhagic erosions may be suggestive of hyaline vascular Castleman disease with associated paraneoplastic pemphigus (Fig 3).

• Hyaline vascular Castleman disease can occur in unusual locations, such as the presacral region, mimicking a nerve sheath tumor (Fig 8), inflammatory pseudotumor, desmoid tumor, or lymphoma.

Systemic multicentric hyaline vascular Castleman disease mimicking lymphoma in a 25-year-old woman who presented with a history of recurrent lymphadenopathy after a

previous complete remission.















Hyaline vascular Castleman disease associated with plasma cell dyscrasia and polyneuropathy in a 34-year-old man who presented with progressive lower extremity

weakness and received a diagnosis of chronic inflammatory demyelinating polyneuropathy and parapr...











Surgically diagnosed hyaline vascular Castleman disease mimicking a presacral nerve sheath tumor in a 61-year-old woman who presented with abdominal discomfort and

had an incidentally detected presacral mass.



Surgically diagnosed hyaline vascular Castleman disease mimicking a presacral nerve sheath tumor in a 61-year-old woman who presented with abdominal discomfort and

had an incidentally detected presacral mass.



• Plasma cell Castleman disease typically demonstrates less avid enhancement after contrast material administration compared with hyaline vascular Castleman disease. Calcification is uncommon. Intralesional fibrosis and necrosis may lead to a heterogeneous appearance, especially in lesions larger than 5 cm.

• Plasma cell Castleman disease occurs more frequently as multicentric Castleman disease, with diffuse lymphadenopathy that involves multiple anatomic regions, including bilateral hilar and mediastinal lymphadenopathy and diffuse thoracic, abdominal, pelvic, or cervical lymphadenopathy.

• There is a tendency for increased abdominal and pelvic involvement compared with hyaline vascular Castleman disease.

• Unicentric plasma cell Castleman disease is not uncommon and manifests as a focal mass. Near the pancreas, it may mimic pancreatic lymphoma, adenocarcinoma, or neuroendocrine tumor (Fig 9). Plasma cell Castleman disease may cause localized cervical (Fig 10) or axillary (Fig 11) lymphadenopathy. In both unicentric Castleman disease and multicentric Castleman disease, the presence of hepatomegaly, splenomegaly, ascites, pleural effusions, or pericardial effusions may indicate systemic involvement.

Surgically diagnosed plasma cell Castleman disease mimicking a pancreatic tumor in a 51-year-old woman with a pancreatic mass that was incidentally depicted at US

performed for right upper quadrant discomfort.























Surgically diagnosed plasma cell Castleman disease causing isolated left-sided lymphadenopathy of the neck in a 27-year-old otherwise asymptomatic woman with

long-standing fluctuating left cervical masses that were unresponsive to antibiotic and medical the...



Surgically diagnosed plasma cell Castleman disease causing isolated left-sided lymphadenopathy of the neck in a 27-year-old otherwise asymptomatic woman with

long-standing fluctuating left cervical masses that were unresponsive to antibiotic and medical the...



Plasma cell Castleman disease mimicking right axillary metastatic lymphadenopathy in a 66-year-old man with large cell carcinoma of the left lung who presented for PET/CT

staging.



• The CT appearance of HHV-8–associated Castleman disease is often indistinguishable from that of plasma cell Castleman disease, although more severe systemic manifestations are generally observed.

• Similarly to plasma cell Castleman disease, the nodal masses in HHV-8–associated Castleman disease usually demonstrate an absence of substantial hyperenhancement (2,3).

• The CT appearance of HHV-8–associated Castleman disease characteristically shows systemic disease with diffuse lymphadenopathy, hepatomegaly, splenomegaly, pericardial and pleural effusions, and ascites.

• HHV-8–associated Castleman disease occurs more commonly in immunosuppressed patients and may be difficult to distinguish from opportunistic infection or lymphoma in this group.

• HHV-8–associated Castleman disease should be considered in patients with diffuse lymphadenopathy and imaging findings or a history of Kaposi sarcoma, plasmablastic lymphoma (diffuse large B-cell lymphoma), and hemophagocytic syndrome (Fig 12).

HHV-8–associated multicentric Castleman disease with associated Kaposi sarcoma mimicking an opportunistic infection in a 37-year-old man with HIV infection, who was

febrile despite therapy with multiple antibiotics.











• At combined imaging with positron emission tomography (PET) and CT (PET/CT), Castleman disease can be a cause of false-positive findings by mimicking metastatic adenopathy.

• A notable difference between the glycolytic activity of the involved nodes and the primary tumor should be suggestive of the possibility of nonmetastatic nodal disease, including Castleman disease (Fig 11).

• Clues from the clinical history and associated imaging findings should be carefully considered, such as a history of mucosal disease, organomegaly, bone lesions, plasmablastic B-cell lymphoma, and Kaposi sarcoma.

• Imaging findings are often nonspecific, and histologic diagnosis is required in nearly all cases for confirmation. Nondiagnostic findings from repeated needle biopsies should increase the suspicion for Castleman disease, and an excisional biopsy is often needed to establish the final diagnosis.

Diseases Associated with Castleman Disease

• In as many as 25% of the cases, the multicentric forms of Castleman disease have been associated with the development of non-Hodgkin lymphoma, predominantly the immunoblastic or plasmablastic B-cell lymphoma subtypes. Other associated lymphomas are Hodgkin disease and plasmacytoma (20).

• Hyaline vascular Castleman disease is associated with follicular dendritic cell neoplasms, including dendritic cell sarcomas and vascular and stromal neoplasms.

• Paraneoplastic pemphigus is a debilitating chronic blistering mucocutaneous disease. The cutaneous findings may resemble those of lichen planus （平癣） , pemphigus, erythema multiforme( 多形性红斑 ), or graft versus host （移植排斥） disease (7).

• Paraneoplastic pemphigus is associated with occult neoplasms and Castleman disease and should be suspected in patients with treatment-resistant erosive mucosal lesions. The development of paraneoplastic pemphigus heralds a poor prognosis, with a mortality rate near 90% (7), which, however, is better when paraneoplastic pemphigus is found associated with benign forms of Castleman disease or thymoma.

• Between 11% and 30% of patients with POEMS syndrome have multicentric Castleman disease, most commonly the HHV-8–positive variant. As many as 50% of cases of POEMS syndrome coincide with sclerotic myeloma, but only 1%–8% of multiple myeloma patients have the sclerotic form (22).

• POEMS syndrome has a predilection for the male sex, with a peak in the 5th to 6th decades. Many findings of systemic Castleman disease and hematologic disorders overlap with POEMS syndrome, including ascites, hepatosplenomegaly, lymphadenopathy, and polyneuropathy.

• HHV-8–associated Castleman disease is associated with various types of lymphomas, specifically with the HHV-8–positive plasmablastic lymphoma, a particular form of large B-cell lymphoma.

• Both HHV-8–associated Castleman disease and Kaposi sarcoma are vascular lesions that are associated with the same viral agent, HHV-8 (2), and both occur frequently together in HIV-infected patients. Small foci of Kaposi sarcoma can be found in lymph nodes involved with multicentric Castleman disease (2).

Conclusions• Castleman disease includes a wide spectrum of pathologic findings,

manifestations, and associations.

• Castleman disease most commonly manifests as unicentric disease with a hyperenhancing lymph nodal mass and should be considered in the differential diagnosis of lymphoma, metastatic adenopathy, and infectious and/or inflammatory causes of adenopathy.

• Because of the diverse manifestations of Castleman disease and its ability to affect any body region, Castleman disease is a great mimic of both benign and malignant findings in the neck, chest, abdomen, and pelvis.

• Castleman disease includes a spectrum of pathologic variants, including the classic hyaline vascular Castleman disease and the less common plasma cell Castleman disease, multicentric Castleman disease, and HHV-8–associated Castleman disease.

• Castleman disease can be associated with HIV/AIDS, lymphoma, POEMS syndrome, paraneoplastic pemphigus, and plasma cell dyscrasias.

• HHV-8–associated Castleman disease occurs predominantly in patients with immunosuppression and/or HIV infection and commonly takes an aggressive and fatal course, with a poor prognosis.

• Aggressive forms with systemic manifestations may occur with plasma cell Castleman disease and are rare with unicentric hyaline vascular Castleman disease.

• Unicentric hyaline vascular Castleman disease is often curable with surgery; treatment of multicentric Castleman disease may require steroid therapy, chemotherapy, antiviral medication, or the use of antiproliferative regimens.

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Castleman Disease: The Great Mimic From the Russell H. Morgan Department of Radiology and Radiological Science (D.B., K.M.H., E.K.F.) and the Department