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Should Gleason Score 6 Still Be Called Cancer?
Introduction
While the lifetime risk of a prostate cancer diagnosis for a man living the United States is estimated to be 1 in 7, the incidence to mortality ratio is nearly 8:1. Thus, most men diagnosed with prostate cancer will not die of the disease. The era of prostate-specific antigen (PSA) screening has resulted in the diagnosis of lower grade and volume cancers. While PSA screening has reduced the incidence of advanced disease and mortality, the trade-offs have included over-diagnosis and overtreatment. These issues have led to an effort to identify and surveil men with “clinically insignificant” disease. Some have argued that Gleason 6 prostate cancer is not in and of itself a lethal cancer and have advocated for reclassification of this pattern as a nonmalignant precursor lesion. This chapter outlines differences in the molecular and clinical characteristics of Gleason 6 prostate cancer compared with higher grade disease as well as the issues of diagnostic uncertainty that have prevented acceptance of a shift in nomenclature.
Molecular characteristic of Gleason pattern 3 versus 4
In a framework provided by Hanahan and Weinberg, neoplastic cells acquire six biological capabilities during the multistep progression to a neoplastic state: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. In an elegant review, Ahmed et al. present a convincing argument that pure Gleason pattern 3 prostate cancers lack the molecular characteristics of each of these hallmarks ( Figure 5.1 ).
Self-Sufficiency in Growth Signals
The EGFR pathway has been proposed to play a prominent role in prostate cancer progression to castration-resistant disease. Ross et al. demonstrated differential in expression EGF and EGFR in cancer cells isolated by laser capture microdissection from low-grade (Gleason 3 + 3 = 6) or high-grade (Gleason 4 + 4 = 8) tumors of men with localized disease. Both EGF and EGFR regulate cell growth, differentiation, motility, and adhesion by signaling through several signal transduction mechanisms. Also, amplification of HER2 / neu , a member of the EGFR family, is associated with high tumor volume of greater than 2.0 cm 3 . There is greater degree of HER2 / neu amplification in Gleason pattern 4 lesions when compared to Gleason pattern 3 lesions.
Insensitivity to Antigrowth Signals
The D-type cyclins (cyclins D1, D2, and D3) are involved in the regulation of transition from G 1 to S during the cell cycle. Inactivation of cyclin D2 by promoter hypermethylation has been reported in breast and prostate cancer, supporting the tumor suppressor role in these tumor types. Tumors with a Gleason sum ≥7 have been shown to have significantly greater methylation frequency than tumors with a Gleason sum ≤6. Guo et al. showed progressive loss of cell cycle inhibitor p27 Kip1 with increasing Gleason grade by immunohistochemistry of 101 radical prostatectomy specimens.
Resisting Cell Death
DAD1, a downstream target of the NFκB survival pathway, exhibits an antiapoptotic function and has been associated with perineural invasion in in vitro studies. True et al. evaluated the expression of DAD1 protein by immunohistochemistry and RT-PCR in prostatectomy cores and demonstrated higher expression in Gleason pattern 4 and 5 cancers than low-grade cancers of pattern 3. BCL2 , another antiapoptotic gene, has likewise been demonstrated to be upregulated in Gleason pattern 4 and 5 lesions compared with those that were only pattern 3.
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