A case of multicentric Castleman's disease in an HIV− human herpesvirus 8+ patient who was successfully managed with concurrent bortezomib and ganciclovir is presented.
4897 Castleman's Disease is a clinically heterogeneous entity that can be either localized or multicentric. The Multicentric Castleman's Disease (MCD) is a poorly understood clinical and pathogenic entity without an established therapy. It is considered to be an atypical lymphoproliferative disorder of a plasma cell type related to immune dysfunction. 100% of Human Immunodeficiency Virus (HIV) positive patients with MCD have concurrent infection with Human Herpes Virus 8 (HHV8) while only 50% of HIV negative patients are positive for HHV8. The lifespan of patients with MCD is influenced by the presence of HHV8 infection which has been associated with shorter survival. HHV8 is considered to be an oncovirus which encodes a viral IL-6, a homolog of human IL-6 which is involved in the inflammatory and proliferative response in MCD. Hyperproduction of IL-6 has been proposed as one of the pathogenic mechanisms in MCD. Subsequently, combined therapy with IL-6 antagonists and antiviral therapy seems to be a reasonable therapeutic approach in MCD. We present a case of a 43 year-old male who presented with fever, night sweats, weight loss and enlarging lymph nodes for seven months. Physical examination revealed generalized lymphadenopathy, hepatomegaly and splenomegaly. The laboratory data revealed anemia, thrombocytopenia and renal failure. He was also found to have high serum levels of IL-6. The HIV testing was negative. He rapidly developed multiple organ failure requiring ventilator support and dialysis. A lymph node biopsy was diagnostic for MCD and the immunostaining revealed the presence of HHV8. He was treated with bortezomib and gancyclovir, concurrently, with response after the first cycle of therapy and subsequent normalization of his blood counts and renal function. We performed a literature review on the possible pathogenic loops involved in MCD and the rational of using antiviral therapy and proteasome inhibitors in the treatment of MCD. We found that antiviral therapy was used in HIV positive patients with MCD and produced remissions of varying durations [1,6,7]. Bortezomib was reported to induce remission in MCD associated with Multiple Myeloma [14] or POEMS syndrome [2]. Bortezomib, a proteasome inhibitor, interacts negatively with the autocrine loop of IL-6 production by interfering with the nuclear factor kappa B pathway which is involved in cell survival, tumor growth and angiogenesis [14]. By similarity with multiple myeloma, we expected that the use of bortezomib would break the IL-6 loop and control the lymphoplasmacytic proliferation. Our patient had a dramatic response to the combined therapy with bortezomib and gancyclovir- his constitutional symptoms, adenopathy and splenomegaly resolved, his renal function normalized and his platelet count and hemoglobin returned to baseline. To our knowledge, this case represent the first response to bortezomib and gancyclovir used concurrently in an HIV negative, HHV8 associated MCD. We believe that the concurrent use of gancyclovir and bortezomib can represent a therapeutic option to be further considered in patients with MCD. Disclosures: No relevant conflicts of interest to declare.
e19016 Background: As clinical and histological parameters are unable to precisely predict the behavior of skin melanoma, new criteria are required to improve risk assessment. Caveolin 1 (CAV1), a scaffolding membrane protein, has been implicated in cell proliferation, death and transformation. In melanoma cell lines, CAV1 was found to have an antimetastatic role and loss of stromal CAV1 expression in lymph nodes metastases was associated with poor survival. The objectives of this analysis were to correlate CAV1 expression in primary skin melanoma cells with tumor thickness and disease free survival (DFS). Methods: CAV1 immunostaining was performed on the primary skin melanomas of 40 patients. CAV1 expression was scored semi-quantitatively using a 3-point scale: 0 (no staining), 1 (diffuse weak staining or strong staining in less then 30% of the cells) and 2 (strong staining of 30% or more of the cells). For analysis purposes, CAV1 was dichotomized as present (score 1 or 2) or absent (score 0). Primary melanoma was classified based on 2009 AJCC T-stage. DFS was measured from removal of primary skin melanoma to development of loco-regional or systemic recurrence. Pearson Chi-Square, Kaplan Meier, and Cox-Proportional Hazard Ratio were used for data analyses. Results: T-stage distribution was: Cis 12.5%, T1 32.5%, T2 22.5%, T3 17.5%, T4 15.0%. There was a clear inverse relationship between T stage and Cav 1 expression in tumor cells, with higher CAV1 expression in less invasive melanomas (P= 0.01). Fifteen patients experienced either locoregional or distant recurrence (median time to recurrence 14 months; range <1 month -105 months). Twenty-five patients remained disease free for minimum of 3 years (median 77 months; range 36 – 111 months). Presence of CAV1 in primary melanoma tumor cells was correlated with increased DFS (P = 0.05) but this association was not significant when adjusting for T stage (P=0.59). Conclusions: CAV1 expression in melanoma tumor cells correlates with clinical behavior of skin melanoma as its loss is associated with invasiveness and distant recurrence. Whether the loss of CAV1 in primary melanoma tumor cells is just an epiphenomenon or a causal event is to be decided by further work on a larger population sample.
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