High grade PIN is strongly associated with prostate cancer, according to virtually all available evidence to date. The incidence and extent of PIN appear to increase with patient age.(8, 16, 19, 54, 55) An autopsy study of step-sectioned whole mount prostates from older men showed that the prevalence of PIN in prostates with cancer increased with age, predating the onset of carcinoma by more than five years Fig.7 Frequency of PIN with increasing age.(19) A similar study of young men revealed that PIN is first seen in men in their twenties and thirties (9% and 22% frequency , respectively), and precedes the onset of carcinoma by more than ten years.(54) Most foci of PIN in young men are low grade, with increasing frequency of high grade PIN with advancing age. The prevalence of PIN is similar in blacks and whites.(54) The volume of high grade PIN also increases with patient age (8).
The frequency of PIN in prostates with cancer is greater than in prostates without cancer in men over 50 years of age (82% versus 43%, respectively); similarly, the severity of PIN is greater in prostates with cancer Fig.8 Freedom from cancer from time of first biopsy (3). The mean volume of PIN in prostates with cancer is 1.2- 1.32 cc, and the volume increases with increasing pathologic stage, Gleason grade, positive surgical margins, and perineural invasion.(8, 56) These findings underscore the close spatial and biologic relationship of PIN and cancer, and may result from an increase in PIN with increasing cancer volume.
PIN and cancer are usually multicentric.(8, 13 53, 57, 59, 60) PIN is multicentric in 72% of radical prostatectomies with cancer, including 63% of those involving the non-transition zone and 7% of those involving the transition zone; 2% of cases have concomitant single foci in all zones.(8) The peripheral zone of the prostate, the area in which the majority of prostatic carcinomas occur (70%), is also the most common location for PIN.(8, 13, 16 53, 57, 58) Cancer and PIN are frequently multicentric in the peripheral zone, indicating a "field" effect similar to the multicentricity of urothelial carcinoma of the bladder (59).
PIN is associated with progressive abnormalities of phenotype and genotype which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis Fig.9 Genetic changes associated with progression of prostate cancer. There is progressive loss of some markers of secretory differentiation, including prostate-specific antigen, (60) Fig. 10A, B Progressive loss of markers of secretory differentiation prostatic acid phosphatase, secretory proteins (61-63), cytoskeletal proteins (63), glycoproteins such as blood group antigens (64), neuroendocrine cells (65), p-cadherin (66), fibroblast growth factor-2 (67), inhibin (68), prostate-specific transglutaminase (69), androgen receptor expression (70, 71), insulin-like growth factor binding protein-3(72), and telomerase.(73) A member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium.(74) Other markers show progressive increase, including including human glandular kallikrein 2 (hK2),(75) c-erbB-2 (Her-2/neu) and c-erbB-3 oncoproteins (67, 76,77), c-met proto-oncogene (78),bcl-2 oncoprotein (77, 79, 80), mutator (RER(+)) phenotype (81), epidermal growth factor and epidermal growth factor receptor (67, 82), type IV collagenase (83), Lewis Y antigen, TGF-alpha, apoptotic bodies (77, 81, 84, 85), mitotic figures (85), PCNA expression (86), Ki-67 expression (87), MIB-1 expression (71, 87), tenascin-C (88), aneuploidy and genetic abnormalities Fig.11.1, 11.2 Whole mount section of Prostate (71, 89-98), microvessel density, (99) Ep-Cam transmembrane glycoprotein (100), Insulin-like growth factor binding protein IGFBP-rP1 (101), and p53 mutations (102), although one group found no p53 expression immunohistochemically in PIN. (77) Prostate-specific membrane antigen, an abundant transmembrane glycoprotein, shows increased expression in PIN and cancer when compared with benign epithelium (103, 104), and this expression was unaffected by short-term androgen deprivation therapy.(104) Estrogen receptor alpha is present in up to 28% of cases of PIN and 43% of cancers, but estrogen receptor beta is absent (105); prolactin receptor expression is increased in PIN (106).
A model of prostatic carcinogenesis has been proposed based on the morphologic continuum of PIN and the multi-step theory of carcinogenesis (4).