Castleman Disease: An Update on Classification and the Spectrum of Associated Lesions

Among the more common causes of non-neoplastic lymphadenopathy, it is important to recognize and accurately diagnose Castleman disease (CD, also known as angiofollicular lymph node hyperplasia and giant lymph node hyperplasia). Although the classic hyaline-vascular type may be well-recognized, it is the less distinctive human herpes virus-8 (HHV-8)-associated type of CD that has been the subject of recent research and significant advances. In recent years, it has become clear that CD is a morphologic syndrome uniting a group of diseases with related and occasionally overlapping pathogenesis. Recent authors favor classifying CD by histopathogenic type as opposed to the traditional unicentric versus multicentric model1,2 and we will follow that model in this review (Table 1). Clinical diagnosis and treatment of CD are not covered and have been addressed in 2 relatively recent reviews.3,4

T1-5TABLE 1:

Comparison of CD Subtypes

HISTORICAL BACKGROUND

CD was so-termed in reference to a series of 13 cases of localized mediastinal lymph-node hyperplasia described by Dr Benjamin Castleman in 1956.5 A variant rich in plasma cells was described by Flendrig and Schillings in 19696 and further defined in 1972, when Keller et al,7 distinguished the classically described “hyaline-vascular type” from the “plasma cell type,” which was less common and associated with systemic signs and/or symptoms. Although these early papers described localized processes, several authors subsequently noted multicentric lymphadenopathies associated with the constitutional symptoms and histologic features similar to the unicentric types of CD.8–11 A decade later came the discovery of a novel human herpes virus associated with Kaposi sarcoma (Kaposi sarcoma-associated herpes virus or HHV-8).12,13 HHV-8 was subsequently identified in primary effusion (or body-cavity-based) lymphomas14 and in multicentric CD, particularly in human immunodeficiency virus (HIV)-positive individuals.15,16 Since that discovery, there have been remarkable advances in our understanding of the pathogenesis of HHV-8-related CD.

HYALINE-VASCULAR CASTLEMAN DISEASE Clinical Features

The histologically classic hyaline-vascular form usually presents unicentrically, involving a single node or localized group of nodes (76% to 91% of localized CD).7,17,18 It presents in roughly equal numbers of young adult men and women. The median age of presentation is in the fourth decade,5,7,17–19 although the age range is broad and pediatric cases have been reported.20,21 This form of CD presents as a localized mass, most frequently occurring in a thoracic lymph node,5,7,17,18,22 although various extranodal presentations also occur.18,23–25 Most cases of localized hyaline-vascular CD present with a mass lesion and lack the systemic signs and/or symptoms associated with the plasma cell and multicentric forms of CD.7,18 The pathogenesis is unknown, but a relationship to dysplastic follicular dendritic cells has been suggested.1 Vascular endothelial growth factor may contribute to the prominent vascular proliferation seen in this subtype of CD.2

Histopathology

Histologically, hyaline-vascular CD is characterized by distinctive follicles with expanded mantle zones of small lymphocytes forming concentric rings surrounding 1 or more atretic germinal centers. There is prominent vascularity of the germinal centers, often with a single prominent penetrating vessel. Another important feature is vascular proliferation between the follicles, often with perivascular hyalinization.

The “onion-skinning” of mantle zone lymphocytes, together with the prominent central vessel, has been likened to the appearance of a lollipop (Fig. 1).26

F1-5FIGURE 1.:

Hyaline-vascular type Castleman disease. A, The enlarged follicles with multiple atrophic centers contrast with the pale pink vessel-rich interfollicular stroma. B, The increased vessels are associated with hyalinization. C, The Hassall corpuscle-like atrophic follicle center contains a radiating vessel at top simulating a lollipop and the mantle lymphocytes appear to form rings imparting an onion-skin like appearance. D, The CD21 labeling of follicular dendritic cell processes highlights these concentric rings.

Association—Dendritic Cell and Vascular Proliferations

Lymph nodes involved by hyaline-vascular CD are known to have alterations in the follicular dendritic cell networks,26–28 with reports of proliferations of dysplastic follicular dendritic cells (Fig. 2) and follicular dendritic cell tumors (Fig. 3).29,30 Some studies have demonstrated clonal cytogenetic abnormalities in these proliferations.31,32 Pathologists should be aware of these follicular dendritic cell proliferations, as their exact relationship with dendritic cell sarcomas is unknown. The association between hyaline-vascular CD and dendritic cell sarcomas is well documented, with some cases behaving in a malignant fashion.29,30,33–38 Although it is not thought to play a role in the pathogenesis of hyaline-vascular CD, 1 study showed that HHV-8 is not typically found in follicular dendritic cell sarcoma associated with CD.39

F2-5FIGURE 2.:

Dysplastic FDCs in hyaline-vascular Castleman disease (panels A–D). Atypical binucleate or multinucleate FDCs may be seen in the follicles or interfollicular stroma. The nuclei may contain small central nucleoli or have a smudged appearance. The FDCs may occur in isolation, may be more frequent and comprise a FDC proliferation, or form a discrete FDC tumor/sarcoma. Such dysplastic FDCs not uncommonly raise concern for Hodgkin lymphoma. However, the dysplastic FDCs do not label with Hodgkin markers but unfortunately may also not label well with a variety of FDC markers. FDC indicates follicular dendritic cell.

F3-5FIGURE 3.:

Follicular dendritic cell tumor/sarcoma in hyaline-vascular Castleman disease. A, The large cells are interspersed with small lymphocytes. B, The scattered tumor cells show multinucleation and marked nuclear pleomorphism suggesting a wide differential diagnosis. C, The tumor cell processes label strongly for the follicular dendritic cell marker CD21.

In addition to dendritic cell tumors, small case series and anecdotal descriptions also mention various vascular tumors40 and abnormal collections of plasmacytoid dendritic cells (previously referred to as “plasmacytoid T-cells and plasmacytoid monocytes”) (Fig. 4).22,41,42 The significance of these associations is uncertain due to the relative infrequency of their reports in the literature.

F4-5FIGURE 4.:

Clusters of plasmacytoid dendritic cells (plasmacytoid monocytes) in hyaline-vascular Castleman disease. A, The plasmacytoid dendritic cells typically occur in a large cluster that may be associated with apoptotic bodies (not seen in this example). B, The somewhat open chromatin of the nuclei may suggest immature blastic cells, whereas the prominent cytoplasm may suggest plasma cells (these cells were first termed T-zone plasma cells). C, The cells label strongly for the plasmacytoid dendritic cell marker CD123.

PLASMA-CELL CASTLEMAN DISEASE Clinical Features

The plasma cell type of CD is more commonly multicentric than unicentric, and represents 9% to 24% of localized CD.7,17,18 The localized form occurs in a similar patient population as the hyaline-vascular type18; however, the unicentric plasma cell variant is more likely to be associated with the systemic symptoms and abnormal laboratory findings.6,7,18 The most often described clinical findings include fevers, night sweats, malaise, splenomegaly, hypergammaglobulinemias, and cytopenias such as anemia and thrombocytopenia.7,17,18 The localized form of plasma cell CD is probably the least well characterized, with many cases likely representing multicentric plasma cell CD.26 In support of this argument, cases of unicentric plasma cell CD seem to be associated with the increase in serum interleukin (IL)-6, similar to multicentric CD; however, surgical excision is reportedly curative in localized plasma cell CD, as opposed to multicentric CD, which requires systemic therapy.43–48 Both the unicentric and multicentric forms of plasma cell CD have also been associated with POEMS syndrome, a clinical syndrome involving polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.49–52

Histopathology

In contrast to hyaline-vascular type, plasma cell CD has less distinctive histologic features. There is retained lymph node architecture, with variable germinal center hyperplasia with expanded mantle zones and a marked paracortical plasmacytosis. When localized, this type usually affects an aggregate mass of lymph nodes, as opposed to a dominant lymph node in hyaline-vascular unicentric CD.7 There is usually a population of larger plasmablasts (plasmacytoid immunoblasts) that localize to the mantle zone or paracortical regions. As these histologic features are nonspecific, exclusion of other entities that may simulate plasma cell CD is of paramount importance. HHV-8-associated CD must be excluded with clinical information and immunohistochemical staining. Other entities in the differential diagnosis include B-cell lymphomas (such as marginal zone B-cell lymphomas with prominent reactive follicles and plasmacytic differentiation), rare plasmacytomas, and reactive lymphadenopathies associated with infection, autoimmune diseases such as rheumatoid arthritis or reactive lymphoadenopathies associated with other immunodeficiencies.2,26,53 In addition, various HIV-related lymphadenopathies may be difficult to distinguish from multicentric CD.54 The presence of hyaline-vascular type follicles in some cases with a plasma cell component provides a link to the hyaline-vascular type, and some have designated such examples as mixed or transitional types.26 Plasma cells may be monotypic and usually express λ-restricted light chains (either IgG or IgA) (Fig. 5), especially in cases associated with osteosclerotic myeloma or POEMS syndrome.52,55–58

F5-5FIGURE 5.:

Localized plasma cell CD with monotypic plasma cells. A, The follicle centers in this example show some features of hyaline-vascular CD. B, The sheet of plasma cells is a key feature for the diagnosis. These plasma cells label for λ light chains in (C), but not for κ in (D) (exclusive labeling for λ light chains is not uncommon in this entity). CD indicates Castleman disease.

Pathogenesis—the Role of Interleukin-6

The association between the systemic features of plasma cell CD and a factor secreted by affected lymph nodes was recognized in 1989.48 Subsequently known as IL-6, this B-stimulatory cytokine was intimately linked with the systemic manifestations of CD.43,45,47,59 IL-6 was shown to induce a CD-like condition in mice44 and induce B-cell proliferation in other B-cell malignancies.60 In addition, therapy with anti-IL-6 antibodies resulted in complete (although in some cases temporary) resolution of the systemic manifestations of CD in patients.46,61 Interestingly, the genome of HHV-8 encodes a viral analog to human IL-6.62,63 Viral IL-6 is known to have both hematopoietic and angiogenic effects,64–66 although the exact role of viral IL-6 in the pathogenesis of HHV-8-related diseases has yet to be elucidated.4

MULTICENTRIC CASTLEMAN DISEASE, NOT OTHERWISE SPECIFIED

Although older literature considered all cases of multicentric CD together, it is now known that a significant subset of cases are associated with HHV-8 infection. The form of multicentric CD associated with HHV-8 infection occurs frequently in the HIV-positive patient population and is discussed separately below. As these cases were not distinguished in many of the older case series, it is difficult to interpret historical literature concerning multicentric CD. Regardless, there are cases of multicentric CD unrelated to HHV-8 infection, usually of the plasma cell or intermediate types, which fall into the waste-basket of “multicentric CD, not otherwise specified.”2 It is especially important to note that this is a diagnosis of exclusion. In general, multicentric CD presents with generalized or multicentric lymphadenopathy with histologic features of CD (usually the plasma cell type) and often with relatively preserved lymph node architecture. The patient population is generally older than that of localized CD, with the median age being in the sixth decade. The systemic features are similar to those occurring in the unicentric plasma cell type of CD described previously.8,11,17,18,53,67

HUMAN HERPES VIRUS-8-ASSOCIATED (PLASMABLASTIC) MULTICENTRIC CASTLEMAN DISEASE Clinical Features

Although the unique natural history of multicentric CD is still being elucidated, it is known that this entity occurs most frequently in immunosuppressed individuals, especially the HIV-positive patient population. This CD variant is referred to variably as the HHV-8-positive, HHV-8-associated, or plasmablastic variant of CD.2,68–71 It is unknown exactly what percentage of multicentric CD is caused by HHV-8, but most studies looking for viral particles in cases of multicentric CD have shown high rates of HHV-8 infection, especially in HIV-positive patients.15,72–82 In fact, to the best of our knowledge, only a single case of multicentric CD associated with HIV-infection tested negative for HHV-8.83 It is now thought that HHV-8-associated multicentric CD represents a distinct entity with a risk of progression to a particular form of large B-cell lymphoma (HHV-8-positive plasmablastic lymphoma). The prognosis of HHV-8-associated multicentric CD in general is poor, with the survival being generally on the order of months.26,84

Histopathology and “Microlymphomas”

Initial studies showed that in a subset of cases previously called multicentric plasma cell CD, the plasmablastic cells (plasmacytoid immunoblasts) express an HHV-8-related antigen (specifically, latency-associated nuclear antigen-1) by immunohistochemistry.63,68,85 Subsequently, these particular HHV-8-positive plasmablasts were found to uniformly express cytoplasmic IgM and λ-restricted light chains.68,71 Histologically similar to plasma cell CD, HHV-8-positive CD may have distinct features, in addition to expressing HHV-8 related antigens by immunohistochemistry. In most cases of HHV-8-positive CD, these “plasmablasts” are scattered throughout the interfollicular regions among the plasma cell infiltrate; however, expansions of these plasmablasts may form microscopic collections (microlymphomas) (Fig. 6) and form frank HHV-8-associated plasmablastic lymphomas in others. Initially the IgM λ-restricted plasmablasts are monotypic, but polyclonal, and may progress to monoclonal proliferations later in the disease course. 68,86

F6-5FIGURE 6.:

Plasmablastic proliferation in HHV-8-associated multicentric Castleman disease in the setting of human immunodeficiency virus. A, The plasmablastic cells have largely replaced a follicle. B, The large lymphoid cells resemble plasma cells, hence the term plasmablastic. The cells label exclusively for λ light chains in (C) and also show nuclear labeling for the latency-associated nuclear antigen of HHV-8 in (D). HHV-8 indicates human herpes virus 8.

Association—Large B-cell Lymphoma Arising in Human Herpes Virus-8-associated Multicentric Castleman Disease (Human Herpes Virus-8-positive Plasmablastic Lymphoma)

The current World Health Organization classification of hematopoietic tumors now distinguishes large B-cell lymphomas arising in the setting of HHV-8-positive CD as a separate entity, called “large B-cell lymphoma arising in HHV-8-associated multicentric CD” or HHV-8-positive plasmablastic lymphoma.58 The entity was distinguished from classic plasmablastic lymphomas arising in other settings because the neoplastic cells show a genetically distinct neoplastic population, having arisen from naive, IgM-producing plasma cells without immunoglobulin hypermutation. In addition to HHV-8-positive plasmablastic lymphoma, multicentric CD seems to be associated with an increased risk of other types of lymphoma, which is further discussed below.

Clonality in Human Herpes Virus-8-positive Multicentric Castleman Disease

Early investigators sought to understand the nature of multicentric CD, and interestingly mention λ-restricted proteinopathies or plasma cell populations throughout the history of CD.55,57,71,87–89 Despite identification of these monotypic λ-restricted populations in HHV-8-positive CD, rigorous studies have shown that these cases are not necessarily monoclonal, with many lacking clonal immunoglobulin gene rearrangements by molecular techniques.31,55–57,68,69,88,90–94 More recent authors have speculated that IgM λ-monotypic B-cells may represent a distinct population of IgM-positive naive B-cells that are infected by HHV-8, which expand to form neoplastic proliferations later in the disease course. This hypothesis has been tentatively and theoretically compared with the better-understood process of lymphoproliferation associated with Epstein-Barr virus (EBV)-infections.69

Association—“Kaposi Sarcoma-associated Herpes Virus-associated Germinotropic Lymphoproliferative Disorder”

Several authors have noted coinfection with HHV-8 and EBV in CD, although no clear significance of this association was ever demonstrated.21,95–97 In 2002, Du et al86 described a form of localized lymphadenopathy with morphologic features similar to those seen in HHV-8-associated multicentric CD, but with coinfection of the plasmablastic population by both HHV-8 and EBV. The plasmablastic population in these cases showed polyclonal or oligoclonal patterns of immunoglobulin gene rearrangement, with 1 case demonstrating switched IgA heavy chains. The patients in this small series had favorable response to chemotherapy or radiotherapy. As very few cases have been described, it is difficult to draw conclusions regarding this newly defined entity.

Association—Hodgkin and Other Forms of non-Hodgkin Lymphoma

In addition to the recently described progression of HHV-8-associated multicentric CD to large B-cell lymphoma (HHV-8-positive plasmablastic lymphoma), there is also an increased risk of other lymphoma types among both HIV-positive and HIV-negative subgroups.11,54,98–101 In fact, a recent cohort study demonstrated that there was a 15-fold increased risk of lymphoma among HIV-positive patients with multicentric CD over case-matched HIV-positive patients without CD.70 Hodgkin disease has also been rarely associated with CD, although the exact relationship between these entities is unclear.95,102–108 Despite the association with Hodgkin disease, one should be careful not to interpret dysplastic follicular dendritic cells as Reed-Sternberg cells.

Association—Kaposi Sarcoma

Several case reports and small case series noted the coincidence of multicentric CD and vascular lesions including Kaposi sarcoma, even before the discovery of HHV-8.29,40,54,101,109–113 Now it is known that both diseases are associated with the same viral agent (HHV-8), and frequently occur together in the HIV-acquired immunodeficiency syndrome population.70 Although demonstrating distinct patterns of HHV-8 immunohistochemical staining with latency-associated nuclear antigen-1, multicentric CD and Kaposi sarcoma may be more that coincidentally linked.114,115 Viral IL-6 is known to have angiogenic activity,64,66 and vascular endothelial growth factor is thought to be a part of the pathophysiology of CD.116,117 A recent study showed that small foci of Kaposi sarcoma-like lesions were more frequently found in lymph nodes involved by multicentric CD than case-matched controls,115 and careful examination may reveal coexistence of the 2 entities (Fig. 7). Although the clinical significance of these microscopic HHV-8-positive vascular lesions is unknown, pathologists should be mindful of this association and its potential prognostic or therapeutic implications.

F7-5FIGURE 7.:

Multicentric Castleman disease and Kaposi sarcoma in the same lymph node in a patient with human immunodeficiency virus. A, Note the hyaline-vascular type follicle at lower left and the subcapsular focus of Kaposi sarcoma at upper right. B, Multiple vessels radiate into the atrophic follicle center, whereas the interfollicular stroma shows increased vessels and numerous plasma cells (λ monotypia not illustrated). C, The Kaposi sarcoma shows the typical slit-like vascular spaces and extravasated red cells. D, The spindled cells label for the latency-associated nuclear antigen of human herpes virus 8.

CONCLUSIONS

The spectrum of CD is broad, and seems to represent several related clinicopathologic entities. The emergence of HHV-8-related CD and the characterization of the plasmablastic variant have contributed to our understanding of this complex disorder, and generally to the pathogenesis of viral-related lymphoproliferative disorders. Despite our imperfect understanding of the complex pathogenesis of this disorder, pathologists must be aware of the various forms of CD and their relationship to follicular dendritic cell tumors, malignant lymphomas, and Kaposi sarcoma.

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