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.
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
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
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
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
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
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
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.
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
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.
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.
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.
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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