HHV-8 Related Castleman Disease in the Absence of HIV Infection

Castleman Disease (CD) is a rare atypical lymphoproliferative disorder of unknown aetiology that covers an extremely wide clinical spectrum. It ranges from a localized disease with benign outcome after surgical removal to a life threatening multicentric disease (MCD). In the context of HIV infection, CD is almost always multicentric and linked to HHV-8. Clinical, pathological and laboratory features of HIV+ MCD are well described. In contrast, there is no published series of HHV-8 related CD in HIV negative patients.

From January 1995 through June 2012, we identified in a single centre 55 HIV seronegative patients with pathologically proven CD (25 localized and 30 multicentric). Among them 18 were related to HHV-8. We report on their clinical, pathological and laboratory features.

All cases were multicentric. Patients were aged 42–83 years old (median 65,9) and were referred with a relapsing remitting syndrome of fever (94%), general status alteration (100%), peripheral lymphadenopathy (100%), splenomegaly (72%), hepatomegaly (50%) and oedema (28%). Kaposi Sarcoma was observed in 9 cases. Anaemia was a constant finding. White blood cells abnormalities were noted on blood smear during the flares in 13/16 patients. Serum markers of inflammation were present in all cases: a high level of C reactive protein (median 111mg/L; range 36–423), hypergammaglobulinemia (median 31g/L; range 7,3–55), hypoalbuminemia (median 32g/L; range 16–52). PCR for HHV-8 DNA was positive on blood samples in all cases (median 5,5 Log₁₀ copies of KSHV DNA/10⁶PBMCs; range 2,3–6,6), whereas only 12/16 patients tested had a positive HHV-8 serology at diagnosis. All cases showed the classic histological features of the mixed cell type or of the plasma cell type, and LANA-1 immunostaining identified HHV-8 infected plasmablasts in 16/16 tested cases. Reactive hemophagocytic syndrome (44%), Autoimmune Haemolytic Anaemia (33%) and lymphoma (22%) (2 Primary Effusion Lymphoma, 1 lymphoplasmacytic lymphoma and 1 unproved) were the commonest associated complications. Ten patients (55%) have received corticosteroids (CS). CS had little or no effect on lymphoid organs enlargement, inflammatory markers or hemophagocytic syndrome. Occurrence or worsening of KS appeared in one patient each soon after corticosteroids introduction. Remission was obtained with low dose and usually single agent chemotherapy with etoposide in 13/16 cases. Nevertheless, etoposide had only suspensive effect in most cases. Thirteen patients were treated with rituximab, all of them achieved prolonged remission off therapy. After a median follow up of 18 months (range 1–99) after rituximab treatment, only 2 patients experienced relapses. These relapses were successfully retreated with the association of rituximab and etoposide. Fatal outcome occurred in 3 patients not treated with rituximab. Altogether, these features were similar to those described in HIV+ HHV-8 related MCD. On the contrary, comparison between these 18 cases and 12 HIV- HHV-8 unrelated MCD cases showed marked discrepancies. Arthritis, cutaneous manifestations, renal disease, lupus symptoms or POEMS symptoms were more frequently observed in patients with HHV-8 negative MCD.

HHV-8 associated MCD should be considered as a single clinicopathological entity whatever the HIV status is. This is a step forward towards a better delineation of CD clinical spectrum, and subsequently of HHV-8 related lymphoproliferative disorders. It also offers the opportunity to improve clinical management of such patients, as it appears that the treatments used in HIV+ HHV-8 related MCD are efficient in HIV- HHV-8 related MCD.

No relevant conflicts of interest to declare.