Phosphorylation of Histone H2A.X Is a Specific Marker To Distinguish Oncocytoma from Chromophobe Renal Cell Carcinoma
M Tretiakova, H Al-Ahmadie. University of Chicago, Chicago
Background: Significant morphologic overlap exists between chromophobe renal cell carcinoma (ChRCC) and oncocytoma (ONC), and the distinction between these 2 entities remains one of the most difficult differential diagnoses in renal cortical tumors, especially when dealing with limited material such as needle biopsy. Genetically, ChRCC is characterized by more extensive chromosomal losses than ONC. Accumulation of DNA repair factors is a known cellular response to DNA damage. One such factor is the phosphorylated form of histone H2A.X (pH2A.X), which is found in cells exposed to radiation, heavy metals, heat stress, growth senescence, and oncogenic transformation. We hypothesized that DNA damage of malignant transformation can be identified by pH2A.X in ChRCC but not in ONC.
Design: Tissue microarray sections containing 32 cases of ChRCC and 12 ONC were stained by immunohistochemistry for pH2A.X and total H2A.X, using radiation-treated tumor sections as positive controls. Each case was represented by three 1-mm tissue cores, for which any reactivity was considered positive. The intensity in positive cases was scored as weak (1), moderate (2) or strong (3). The mean value was recorded for each individual case as the average intensity of all 3 cores.
Results: pH2A.X was negative in all 12 ONC cases while 25 ChRCC cases (78%) were positive (mean value 1.9) (p<0.001, t-test). In ONC, all tumor cells were completely negative and in positive ChRCC, almost all tumor cells exhibited exclusive nuclear labeling. All the 7 negative cases of ChRCC had classical architectural and nuclear features to distinguish them from ONC, even though 3 had oncocytic cytoplasm. H2A.X expression was found in the majority of ONC and ChRCC, but its mean values were significantly lower in ONC (mean=2.11) than in ChRCC (mean=2.55, p=0.015). Evaluation of pH2A.X as a diagnostic test for ChRCC vs. ONC showed 78% sensitivity, 100% specificity, 100% positive predictive value, 63% negative predictive value and 84% accuracy.
Conclusions: The majority of ChRCC express pH2A.X compared to none of ONC, making it a specific marker to distinguish between the 2 entities. Although total H2A.X was stronger in ChRCC compared to ONC, only the phosphorylated H2A.X has discriminating value in this differential diagnosis. The application of pH2A.X as a diagnostic marker in the workup of oncocytic renal cortical tumors may help establish the correct diagnosis on limited material such as needle biopsy specimens, impacting on subsequent management decision.
Category: Genitourinary (including renal tumors)
Monday, March 9, 2009 1:00 PM
Poster Session II # 116, Monday Afternoon