Study of High Grade Prostatic Intraepithelial Neoplasia for a Period of Five Years B. Rajashekar Reddy 1, Rameswarapu Suman Babu 2 and P.

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1 Indian Journal of Mednodent and Allied Sciences Vol. 2, No. 2, June-July, 2014, pp DOI : / Original Research Study of High Grade Prostatic Intraepithelial Neoplasia for a Period of Five Years B. Rajashekar Reddy 1, Rameswarapu Suman Babu 2 and P. Sujatha 3 * ABSTRACT A relatively new development in the arena of prostatic histopathological study is the premalignant proliferative high grade prostatic intraepithelial neoplasia (HGPIN) in the glandular epithelium, possibly relating to carcinoma. Aim of the study is HGPIN and its association with Prostatic hyperplasia and Prostatic carcinoma. The present study was undertaken in the Upgraded Department of Pathology, King George Hospital, Andhra Medical College for a period of five years from January 2002 to December A total of 340 cases evaluated, 277 (81.47%) were benign, 11 (3.23%) were premalignant and 52 (15.29%) malignant lesions. Premalignant lesions were preceded by a decade as compare to malignant lesions, with a mean age of 8 years difference. Among premalignant lesions only high grade prostatic intraepithelial lesion is seen in association with prostatic carcinoma (40%). KEYWORDS: Prostate cancer (PC), Premalignant lesions, High grade prostatic intraepithelial neoplasia (HGPIN), Prostrate intraepithelial neoplasia INTRODUCTION The term prostate was originally derived from the Greek word prohistani, meaning to stand in front of, and has been attributed to Herophilus of Alexandria who used the term in 335 B.C (Kirby et al., 2001). Early detection and management of prostate cancer (PC) is an important public health problem in all industrialized countries, where the relative rate of the elderly population is rapidly increasing. Diseases of the prostate are common causes of morbidity in adult males and show wide geographical and ethnic variations in incidence and mortality worldwide. There are several benign proliferations and normal histo-anatomical structures of prostate, which mimic malignancy, and their awareness is essential to avoid diagnostic pitfalls. Currently, two premalignant lesions have been recognized: prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperolasia (AAH), there is a need to determine their significance, as there are many important unanswered questions. The present study aims at high lightening on all these issues. Prostatic Intraepithelial Neoplasia PIN consists of architecturally benign prostatic acini or ducts lined by cytologically atypical cells. High-grade PIN encompasses both PIN-2 and PIN-3, and lowgrade PIN is equivalent to PIN-1. The distinction between low and high-grade PIN is the finding of prominent nucleoli in high-grade PIN[2]. Low grade PIN should not be documented as a finding in pathology reports for several reasons. First, there is a lack of reproducibility in its diagnosis even by uropathologists. In a study of interobserver reproducibility of PIN, no specimens were uniformly interpreted by a panel of experts as representing low grade PIN. Mc Neal s quotation summarizes his consideration of lowgrade PIN: That there is no sharp line of demarcation between grade-i dysplasia and mild degrees of deviation 1 Department of Pathology, 2 Department of Anatomy, MediCiti Institute of Medical Sciences, Ghanpur, Ranga Reddy District , Telangana, India; 3 Department of Biochemistry, Katuri Medical College, Guntur, Andhra Pradesh, India *Corresponding author id: drsujathapasula@gmail.com 149

2 B. Rajashekar Reddy, Rameswarapu Suman Babu and P. Sujatha from normal histology. More importantly, the finding of low-grade PIN on biopsy does not confer an increased likelihood of finding prostate cancer in a given individual on subsequent biopsy and the risk of cancer with low-grade PIN on biopsy is the same as with totally benign tissue on biopsy[4]. De Silva MV et al.[9] observed that PIN-2 and PIN-3 were strongly associated with coexistent carcinoma but PIN-1 was not. Keeping in view of above observations present study mainly focused on high grade PIN. Aim of Study of high grade prostatic intraepithelial neoplasia (HGPIN) and its association with Prostatic hyperplasia and Prostatic carcinoma. MATERIAL AND METHODS The present study was undertaken in the Upgraded Department of Pathology, King George Hospital, Andhra Medical College for a period of five years from January 2002 to December Specimens were obtained from the patients with prostatic lesions who underwent transurethral resection of prostate (TUPR) or radical prostatectomy attending to the department of surgery and urology. The study comprises a retrospective analysis of 187 cases received from January 2002 to May 2004 and prospective analysis of 153 cases received from June 2004 to December The material obtained is embedded as per the guidelines suggested in Ackerman s surgical pathology (9 th edition, 2004). All the prostatic specimens fixed in 10% formalin were received. They were weighed and subjected to a careful detailed gross examination, then fixed in 10% buffered formalin for 24 hours, after fixation bits were given from represent areas and processed routinely. Sections were prepared after routine processing and embedding, and then stained with Haematoxylin and Eosin. RESULTS In present study out of 340 cases, 277 cases had BPH, 8 cases had BPH with HGPIN, 3 cases had BPH with AAH, while 50 cases had prostate cancer, and 2 cases had secondary carcinomas in prostate extending from bladder (Tables 1 and 2; Figures 1 and 2). The maximum incidence of prostatic lesions was in the sixth and seventh decades. Maximum incidence of benign and premalignant lesions was sixth decade and malignant lesions were in the seventh decade. Table 2: HGPIN association with nature of specimen Lesion TURP Prostat- Total ectomy Benign with HGPIN Malignant with HGPIN Total Changes of HGPIN were observed most commonly in prostatectomy specimens when compare to TURP chips. Table 1: Age wise distribution of lesions Age (years) BPH Premalignant Malignant Total BPH HGPIN BPH-AAH** Malignant Malignant with HGPIN (0.9%) (9.7%) * (38.2%) (36.4%) * 2 48 (14.1%) (0.58%) Total (100%) *Secondary carcinomas-prostate; one case in each category; n = 2; **typical adenomatous hyperolasia (AAH) 150 Vol. 2, No. 2, June-July 2014

3 Study of High Grade Prostatic Intraepithelial Neoplasia for a Period of Five Years DISCUSSION Benign prostatic hyperplasia and prostrate carcinoma were the two principal conditions that involve the prostrate and account for majority of all prostrate diseases. In this study, out of 340 prostatic specimens, 3 (1%) cases of AAH, 28 (9.72%) cases of HGPIN were observed. In total, they constituted 31 (10.76%) cases. Study by Mijan Ortiz et al. reported 20.6% incidence of premalignant lesions (PIN and AAH) [Figure 3] in benign prostatic hyperplasia. In the present study 3 (1%) cases of AAH was reported, prostatic specimens studied showed proliferation of small glands lined by a single row of epithelial cells with little intervening stroma. The lining epithelial cells showed neither nuclear atypia nor nucleoli. Study by Qian J, Bostwick DG et al.[11] in totally embedded radical prostatectomies with prostate cancer [Figure 4], AAH was identified in 23% of the cases, and was more frequent in transitional zone than in the non transitional zone. AAH showed a weak but significant association. In the present study, only three cases of AAH were observed. All the cases were observed in TURP specimens. None of the cases was associated with carcinoma. AAH should not be mistaken for adenocarcinoma. The above mentioned studies were done in totally embedded prostatic specimens where wide tissue sampling was possible and likelihood of detecting AAH was much higher. The present study included mainly TURP chips, where only limited material was available and this could be the probable reason for fewer incidences of AAH cases. In the present study, out of 340 prostatic biopsy specimens observed, 28 (9.72%) cases showed HGPIN, 8 (2.77%) cases were associated with BPH, 20 (40%) cases were associated with carcinoma. HGPIN was most commonly observed in the age group of years (mean age 58 years). In the study conducted by Lee et al. the mean age for PIN was 65 years (Lee et al., 1989) and in the study by Mc Neal and Bostwick (1986), the frequency of PIN was highest in the age group of years. The present study correlated well with the above studies. Mc Neal and Bostwick (1986) in their study, reported HGPIN in 33% of prostates with carcinoma and in 4% of the cases without carcinoma (Mc Neal and Bostwick 1986). In the study by Troncoso et al. HGPIN was found in 72.1% of prostates with carcinoma and in 17.9% of prostates without carcinoma (Troncoso et al., 1989). Study by Desai et al. observed that none of the BPH were found to harbor HGPIN, where as 85.24% of the samples from malignant prostate did so. S.No. Studies Prostates Prostates with without carcinoma carcinoma (%) (%) 1. Mc Neal and Bostwick Troncoso et al Desai et al Present study Incidence of HGPIN on needle biopsies S.No. Study by author Incidence (%) 1. Novis Renshaw Orozco Horninger Alsikafi Hu 8.0 All the studies indicate that HGPIN was the most commonly observed premalignant lesion, thereby suggesting it to be likely precursor of prostatic carcinoma. The incidence of HGPIN in transurethral resection of prostate is relatively uncommon with the studies reporting a rate of 2.3% and 2.8% respectively. Study by Pacelli A, Bostwick DG., reported 4.2% of HGPIN in TUPR chips. Including 2.8% of those with BPH and 10.2% of those with cancer and BPH[12]. Indian Journal of Mednodent and Allied Sciences 151

4 B. Rajashekar Reddy, Rameswarapu Suman Babu and P. Sujatha Figure 1: TURP specimen displaying grey white bits of prostatic tissue Figure 3: Atypical adenomatous hyperplasia with localized proliferation of the glands 2(a) Gleasons pattern-3 varying size and shape of the gland Figure 4: High grade prostatic intraepithelial lesionsepithelial crowding and stratification In the present study, the incidence of HGPIN in transurethral resection of prostate was 4.29% coinciding with the above studies. This includes cases with benign prostatic hyperplasia and prostatic carcinoma. Incidence of HGPIN was lower in TURP chips (4.29%) compare to prostatectomy specimens (17.47%) and still lower in benign lesions (2.77%) compare to malignant lesions (40%). 2(b) Gleasons pattern-3c cribriform glands Figure 2: Prostatic cancer Gleasons pattern The clinical importance of HGPIN is based on its strong association with prostate carcinoma. Because HGPIN has high predictive value as a marker for adenocarcinoma. The presence of HGPIN should be reported by the pathologist, in addition entire specimen 152 Vol. 2, No. 2, June-July 2014

5 Study of High Grade Prostatic Intraepithelial Neoplasia for a Period of Five Years Table 3: Clinical follow-up results of pin (Bostwick and Amin 1996) Author Number of cases No. (%) with cancer on Follow-up follow-up studies Brawer et al (57%)* Immediate rebiopsy Weinstein et al (53%) Immediate rebiopsy Davidson et al (33%) Up to 4 years Markham (41%) Up to 1.5 years * Includes cases with low-grade and high grade PIN; other studies only included HGPIN should be submitted for histopathologic examination to exclude carcinoma and close surveillance and followup biopsy are indicated. HGPIN with adjacent atypical glands seems to confer a higher risk for subsequent diagnosis of carcinoma compare to HGPIN alone. Due to the magnitude of the risk, all men with this finding should undergo rebiopsy (Table 3). Follow-up examination at 6-month intervals for 2 years is suggested; thereafter follow-up examinations should be scheduled at 12-month intervals for life. Most authors agree that the identification of premalignant lesions in the prostate should not influence or dictate the therapeutic decisions. PIN also offers promise as an intermediate end-point in studies of the chemoprevention (Bostwick and Amin, 1996). There are significant variations in the reported prevalence of HGPIN in prostatic biopsies. This is likely to result from several reasons (World Health Organization, 2002) like population studied (ethnicity, extent of screening/early detection activities) or observer variability as there is an inherent degree of subjectivity in applying diagnostic criteria and in setting the threshold for establishing diagnosis or the technical quality of the material evaluated (fixation, section thickness and staining quality) and also the extent of sampling. In India the incidence of PIN is much lower when compared to the western studies (World Health Organization, 2002). In the above studies, the incidence of PIN was studied in step sectioned whole prostatectomy specimens, where wide tissue sampling is possible. Therefore, the likelihood of detecting associated PIN changes were much higher. In the present study, HGPIN changes were studied mostly on TURP chips, prostatectomy specimens where the chances of detecting HGPIN is limited by the amount of biopsy material available and the amount of material embedded[11]. These differences may be responsible for the overall lower incidence of HGPIN. CONCLUSION In present study most common incidence of benign and pre-malignant lesions was in the 6th decade (40.3 and 61.2% respectively), with a mean age of 58 years. Prostatic carcinoma was in 7 th decade (50%), with a mean age of 66 years. Premalignant lesions were preceded by a decade as compare to malignant lesions, with a mean age of 8 years difference. Among premalignant lesions, only high grade prostatic intraepithelial lesion [Figure 5] is seen in association with prostatic carcinoma (40%). REFERENCES [1] Bostwick DG, Amin MB, Damjanov I, Linder J, Prostate and seminal vesicles.editors. Anderson s pathology. 10 th ed. St. Louis: Mosby (1996) [2] Bostwick DG, Brawer MK. Prostatic intraepithelial neoplasia and early invasive cancer. Cancer (1987). 59: [3] Epstein JI, Grignon DJ, Humphrey PA, McNeal JE, Sesterhenn IA, Troncoso P et al. Inter observer reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol (1995). 19: Indian Journal of Mednodent and Allied Sciences 153

6 B. Rajashekar Reddy, Rameswarapu Suman Babu and P. Sujatha [4] Kirby RS, Timothy J Christmas, Brawer MK. Prostate cancer. 2 nd ed. Mosby International Ltd. (2001). [5] Lee F, Torp Pederson ST, Carroll JT, Siders DB, Christensen-Day C, Mitchell AE. Use of transrectal ultrasound and prostate specific antigen in the diagnosis of prostatic intraepithelial neoplasia. Urology (1989). 24: 4-8. [6] Mc Neal JE, Bostwick DG. Intraductal dysplasia; a premalignant lesion of the prostate. Hum Pathol (1986). 17: [7] Troncoso P, Babaian RJ, Rojy et al. Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinomas in cystoprostatectomy specimens. Urology (1989). 34: [8] Eble JN, Sauter G, Epstein JI, Sesterhenn IA. editors. World Health Organization Classification of Tumours. Pathology and Genetics Tumours of the urinary system and male genital organs (2002) [9] De Silva MV, Fernando MS, Abeygunasekera AM, Serozsha Goonewardene SA. Prevalence of prostatic intraepithelial neoplasia (PIN) in surgical resections. Indian J Cancer (1998). 35: [10] Arrabal-Polo MA, Jimenez-Pacheco A, Mijan-Ortiz JL, Arrabal-Martin M, Valle-Diaz de la Guardia F, et al. Relationship between biopsy Gleason score and radical prostatectomy specimen Gleason score in patients undergoing sextant vs 12 core biopsies. Arch Esp Urol (2010). 63: [11] Qian J, Wollan P, Bostwick DG. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol (1997). 28: [12] Pacelli A, Bostwick DG. Clinical significance of highgrade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology (1997). 50(3): Vol. 2, No. 2, June-July 2014