Primary effusion lymphoma in HIV-infected patients with multicentric Castleman's disease

Abstract

Multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) are two B-cell lymphoproliferative diseases associated with Kaposi's sarcoma-associated herpes virus/human herpesvirus-8 (KSHV/HHV-8). Although MCD is considered a prelymphoma state, it is not known whether a pathogenetic link exists between MCD and PEL. This paper reports the clinico-pathological features of four cases of PEL (two pericardial, one pleural, and one peritoneal) developing in the context of HIV-associated MCD. Effusions, lymph nodes, spleen, and additional tissues from three autopsies were examined for morphology/immunophenotype, search for HHV-8 DNA, and assessment of immunoglobulin heavy chain gene (IgH) configuration using polymerase chain reaction (PCR)-based techniques. MCD and PEL samples contained HHV-8 DNA. Clonal IgH rearrangements were detected only in PEL, whereas MCD tissues were polyclonal. Light-chain immunostaining confirmed B-cell clonality in PEL (two lambda, one kappa, one not tested) and polyclonality in MCD. The autopsies revealed different morphological variants of visceral KS and multi-organ atypical infiltrates exhibiting immunoblastic/plasmablastic features reminiscent of PEL morphology, with a restriction of lambda-positive cells. In two cases, using microdissection and IgH PCR analysis, multiple/discrete bands were found in the infiltrates, compatible with polyclonality/oligoclonality. The case showing an oligoclonal IgH ladder contained a rearrangement of identical junctional size to the PEL clone; however, further analysis with PEL-derived clonotypic primers and sequencing of PCR products showed no amplification and nucleotide diversity, respectively, indicating that the two B-cell populations examined were clonally unrelated. These data show that MCD and PEL may co-exist in HIV-infected patients, suggesting a relevant association between these two HHV-8-related disorders. Although a definite clonal relationship between MCD and PEL was not demonstrated, it is hypothesized that in some MCD cases, within expanded polyclonal B-cell populations secondary to HHV-8 infection, clonal expansions may occur that localize into a body cavity, i.e. PEL.

Castleman's Disease: Systematic Analysis of 416 Patients from the Literature

“…Possible causes of such associations are outlined in a number of reviews [6,10,12,29] and reports relating to the specific entities, that is, Kaposi's sarcoma [9,30], PNP [31], POEMS [29], and lymphoma [30,[32][33][34][35].…”

High incidence of Kaposi sarcoma–associated herpesvirus–related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease

“…The association of both diseases, MCD and PEL, has been recently reported and may suggest a higher risk of developing PEL in patients with MCD. 29 Five patients developed a distinct type of lymphoma that shared morphologic and phenotypical characteristics of "classic" PEL. These KSHV/ HHV8 ϩ "extracavitary" tumors differed from "classic" PELs because they were extranodal tumors but not body-cavity based.…”

Combined chemotherapy including high‐dose methotrexate in KSHV/HHV8‐associated primary effusion lymphoma

“…The main causes of death were PEL progression, visceral KS, and severe sepsis. Late deaths related to long-term toxicities of anthracyclines have also been reported [15,17]. The achievement of a long-term CR after CHOP has been reported in only 2 patients [6,14].…”