Rb Is Hyperphosphorylated in Most Merkel Cell Carcinomas
EM Cham, TA Victor, R Orr, M Morgan, KW Lannert, SM Share, TC Pereira, WB Laskin, CD Sturgis. North Shore University Health System, Evanston, IL; Allegheny General Hospital, Pittsburgh, PA; Northwestern University Feinberg School of Medicine, Chicago, IL; CellNetix, Seattle, WA
Background: Merkel cell carcinoma (MCC) is an aggressive skin tumor with epithelial and neuroendocrine differentiation. MCC oncogenesis is not well understood, but may involve polyomavirus (PyV) mediated dysregulation of the retinoblastoma (Rb) pathway. Rb controls cell cycle progression. During cell transition from G1 to S phase, Rb is converted from a hypo- to hyperphosphorylated state. Previously, we showed that p16, an upstream regulator of Rb, is overexpressed in nearly all MCCs. The aim of our study is to characterize the expression pattern of Rb in MCCs.
Design: 45 specimens from 34 patients obtained from 3 institutions' archives (NSUHS 1992-2007, NWMH 2000-2006, AGH 1994-2005), included 28 primary, 11 metastatic, 5 recurrent, and 1 MCC without available info. There were 27 (60%) males, 17 (38%) females, and 1 patient without available info. Mean age was 60 years (44-94 years). A tissue microarray with 3 to 5 cores (0.6 mm) of each MCC was made. Anti-human phospho-Rb (pRb, conc. polyclonal antibody, 1:500, Cell Signaling Technology) IHC was done with antigen retrieval (decloaking chamber, Biocare Medical). Results for pRb staining were interpreted by EMC and scored on a semiquantitative 4-tiered scale.
Results: Nuclear and/or cytoplasmic reactivity for pRb was seen in 83% (37 of 45) of the MCCs. 76% (22 of 29) of primary, 91% (10 of 11) of metastatic, and 80% (4 of 5) of recurrent MCCs showed nuclear and/or cytoplasmic staining in varying intensities. Of the 37 MCCs positive for pRb, 22, 11, and 4 had nuclear only, nuclear + cytoplasmic, and cytoplasmic only staining, respectively. Of the 33 MCCs with nuclear staining, 12 and 21 showed strong and weak intensity, respectively. Of the 15 MCCs with cytoplasmic staining, all showed weak intensity.
Conclusions: Our data show most MCCs express pRb in the nucleus and/or cytoplasm. This Rb hyperphosphorylation explains the high proliferation rate seen in many MCCs and why p16 is overexpressed in most MCCs. The pRb expression patterns varied in cellular location, reactivity, and intensity, suggesting multiple mechanisms may be responsible for the Rb dysregulation. PyV transforms cells through deregulation of tumor suppressors such as Rb. Our results are consistent with studies showing that human PyV may play a role in MCC oncogenesis.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 73, Monday Morning