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Prevalence of High-Grade Prostatic Intraepithelial Neoplasia in Prostate Gland of Korean Men: Comparisons Between Radical Prostatectomy and Cystoprostatectomy
Adult Urology Prevalence of High-Grade Prostatic Intraepithelial Neoplasia in Prostate Gland of Korean Men: Comparisons Between Radical Prostatectomy and Cystoprostatectomy Kyung Seok Han, In Gab Jeong, Jea Young Joung, Seung Ok Yang, Jinsoo Chung, Ho Kyung Seo, Weon Seo Park, and Kang Hyun Lee OBJECTIVES METHODS
RESULTS
CONCLUSIONS
To evaluate the prevalence of high-grade prostatic intraepithelial neoplasia (HGPIN) and its association with prostate cancer in Korean men. A total of 160 patients who underwent radical prostatectomy for clinical prostate cancer were included as study subjects and 29 patients who underwent radical cystoprostatectomy for muscle-invasive bladder cancer were included as controls. Each intact prostate gland was serially sectioned at 3-mm intervals perpendicular to the posterior surface. The presence and prevalence of prostate cancer and HGPIN were assessed and their association evaluated. High-grade prostatic intraepithelial neoplasia was present in 81 (70.4%) of 115 patients who underwent radical prostatectomy and in 8 (27.6%) of 29 patients who underwent cystoprostatectomy. This difference was statistically significant (P ⬍0.001). Among the patients who underwent cystoprostatectomy, HGPIN was present in 5 (33.3%) of 15 patients with prostate cancer and in 3 (21.4%) of 14 patients with no evidence of prostate cancer. The presence of HGPIN had no correlation with prostate-specific antigen level, disease stage, tumor volume, grade, lymphovascular invasion, or surgical margin status. The prevalence of HGPIN in Korean men with clinical prostate cancer was as great as that of Western men. Previous studies, and our results, had demonstrated a lower prevalence of HGPIN in Asian men who underwent cystoprostatectomy. The different prevalence of HGPIN found in incidental prostate cancer, between Asian and Western men, suggests that factors could be preventing the progression of prostate cancer or different characteristics of the prostate cancer in Asian populations. UROLOGY 70: 1100 –1103, 2007. © 2007 Elsevier Inc.
T
he prevalence of prostate cancer reportedly varies among different ethnic groups and populations.1,2 An increase in the prevalence of prostate cancer has been observed in Asian countries during recent decades.3 In Korea, the prevalence of prostate cancer is also increasing, but this increase has not been as great as that in Western countries.4 High-grade prostatic intraepithelial neoplasia (HGPIN) is accepted as a premalignant lesion that has the potential to progress to prostate adenocarcinoma.5 The prevalence of both HGPIN and prostate cancer inFrom the Urologic Oncology Clinic, Division of Specific Organs Cancer, National Cancer Center, Division of Specific Organs Cancer, Research Institute, National Cancer Center, Goyang, South Korea Reprint requests: Kang Hyun Lee, M.D., Ph.D., Urologic Oncology Clinic, National Cancer Center, 809 Madu-dong, Ilsan-dong-gu, Goyang-si, Gyeonggi-do 411769, Republic of South Korea. E-mail: [email protected] Submitted: February 22, 2007; accepted (with revisions): July 3, 2007
1100
© 2007 Elsevier Inc. All Rights Reserved
crease with patient age, and HGPIN precedes the onset of prostate cancer by less than one decade.6 –9 However, as with prostate cancer, the prevalence of HGPIN is reportedly different among ethnic groups and populations. Several studies have reported ethnic differences in the prevalence of HGPIN consistent with those of prostate cancer.9 –14 Ethnic differences for HGPIN showing similar patterns with the prevalence of prostate cancer have supported HGPIN as a premalignant lesion of prostate cancer. However, most studies of racial differences have compared African Americans and whites; few studies have investigated Asians. Therefore, we investigated the prevalence of HGPIN in the prostate glands of Korean patients who had undergone radical prostatectomy for prostate cancer and those who had undergone radical cystoprostatectomy for 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.07.015
bladder cancer and compared these results with the reported Western prevalence data.
Table 1. Clinical and pathologic characteristics of patients with prostate cancer in both groups Characteristic
MATERIAL AND METHODS A total of 190 prostate glands were obtained from November 2001 to January 2007. The study subjects included 160 patients who had undergone radical prostatectomy for clinical prostate cancer; 30 patients who had undergone radical cystoprostatectomy for muscle-invasive bladder cancer were included as controls. Patients who had had androgen deprivation therapy before surgery were excluded. Insignificant prostate cancers included those with the following characteristics: size less than 0.5 cm3, disease confined to the prostate gland, seminal vesicles and lymph nodes negative for tumor, and an absence of Gleason pattern 4 or 5.14,15 All specimens included intact whole prostate gland specimens that had been totally embedded. Each prostate gland was serially sectioned at 3-mm intervals perpendicular to the posterior surface. Hematoxylin-eosin slides were reviewed by the pathologist for assessment of the tumor grade and stage. To assist with the diagnosis of malignancy, immunohistochemical staining with monoclonal antibodies to high-molecular-weight cytokeratin (34betaE12, Dako, Glostrup, Denmark) and p63 (4A4, Dako) was used to confirm the status of basal layers on atypical lesions. The PIN lesions were divided into low and high grade. The presence of prostate cancer and HGPIN was assessed. In addition, tumor stage, Gleason grade, tumor volume, tumor location, extraprostatic extension, perineural invasion, lymphovascular invasion, and surgical margin status were evaluated. Tumor stage was assessed according to the TNM system (American Joint Committee on Cancer, 2002) and tumor grade according to the Gleason grading system. Age was compared with the paired t test among each group. The prevalence was compared using the chi-square test. Correlations between several pathologic characteristics and the presence of HGPIN were assessed by logistic regression analysis. All tests were performed at the 5% significance level using the Statistical Package for Social Sciences, version 11.5, for Windows (SPSS, Chicago, Ill).
RESULTS Of the 160 patients who underwent radical prostatectomy for clinical prostate cancer, 45 were excluded because they had had neoadjuvant hormonal therapy before surgery. The median age was not significantly different between the two groups. The median age was 64 years in the prostatectomy group and 68 years in the cystoprostatectomy group. The median prostate-specific antigen (PSA) level was 9.6 ng/mL (mean ⫾ SD, 12.8 ⫾ 9.1) in the prostatectomy group and 1.5 ng/mL (mean ⫾ SD, 2.0 ⫾ 1.7) in the cystoprostatectomy group. All patients who underwent cystoprostatectomy had normal age-adjusted PSA levels, except for one. One patient with muscleinvasive bladder cancer was excluded because he had a high PSA level and had been diagnosed with prostate cancer by prostate biopsy before surgery. Of the 29 patients who underwent cystoprostatectomy, 15 (51.7%) had prostate cancer. Table 1 shows the clinical and UROLOGY 70 (6), 2007
Pathologic stage T2 T3a T3b T4 Gleason score 4 5 6 7 ⱖ8 Tumor volume (cm3) ⬍0.5 ⱖ0.5 Perineural invasion Present Absent Surgical margin status Positive Negative LN metastasis Present Absent
RP Group (n ⫽ 115)
CP Group (n ⫽ 15)
72 (62.6) 35 (30.4) 7 (6.1) 1 (0.9)
15 (100) 0 (0) 0 (0) 0 (0)
0 (0) 3 (2.6) 41 (35.7) 54 (46.9) 17 (14.8) 0 (0) 115 (100)
3 (20.0) 3 (20.0) 7 (46.7) 1 (6.6) 1 (6.6) 5 (33.3) 10 (66.7)
67 (58.3) 48 (41.7)
0 (0) 15 (100)
49 (42.6) 66 (57.4)
0 (0) 29 (100)
4 (3.5) 111 (96.5)
0 (0) 29 (100)
RP ⫽ radical prostatectomy; CP ⫽ cystoprostatectomy; LN ⫽ lymph node. Data in parentheses are percentages.
Table 2. Prevalence of HGPIN and prostate cancer in both groups Variable PCa Significant PCa Insignificant PCa HGPIN* In benign prostates In insignificant PCa In significant PCa
RP Group (n ⫽ 115)
CP Group (n ⫽ 29)
115 (100) 115 (100) 0 (0) 81 (70.4)
15 (51.7) 5 (17.2) 10 (34.5) 8 (27.6) 3/14 (21.4) 4/10 (40.0) 1/5 (20.0)
HGPIN ⫽ high-grade prostatic intraepithelial neoplasia; PCa ⫽ prostate cancer; other abbreviations as in Table 1. Data in parentheses are percentages. * P ⬍0.001, chi-square test.
pathologic characteristics of the patients with prostate cancer in both groups. High-grade prostatic intraepithelial neoplasia was present in 81 (70.4%) of 115 patients who underwent radical prostatectomy and in 8 (27.6%) of 29 patients who underwent cystoprostatectomy (Table 2). This difference was statistically significant (P ⬍0.001). Of the patients who underwent cystoprostatectomy, HGPIN was present in 5 (33.3%) of the 15 patients with prostate cancer and in 3 (21.4%) of the 14 patients with no evidence of prostate cancer. In addition, HGPIN was found in only 1 (20%) of 5 patients with significant prostate cancer, but it was noted in 4 (40%) of 10 patients with nonsignificant prostate cancer. The presence of HGPIN had no correlation with PSA level, 1101
Table 3. Incidence of HGPIN found in whole prostates from radical prostatectomy or cystoprostatectomy Study Western countries McNeal and Bostwick,20 1986 Troncoso et al.,28 1989 Quinn et al.,21 1990 Abbas et al.,29 1996 Qian et al.,22 1997 Wiley et al.,23 1997 Prange et al.,30 2001 Kim et al.,31 2002 Truskinovsky et al.,24 2004 Asian countries Yang et al.,16 1999 Shin et al.,18 2000 Desai et al.,1 2002 Song et al.,19 2003 Present study
RP Group Population Men* (n) PIN Rate (%) USA USA USA USA USA USA German USA USA
100 — 40 — 195 64 — — 78
Taiwanese Japanese Indian Korean Korean
— 17 61 132 115
82 — 100 — 86 95 — — 100 — 76 85.2 65.2 70.4
Specimen
CP Group Men (n) PIN Rate (%) Specimen
RP — RP — RP RP — — RP
— 66
— 83.3
— CP
40 — 48 85 61 —
47.5 — 83 99 75 —
CP — CP CP CP —
— RP RP, TURP, CP RP RP
47 — 49 — 29
37.7 — 0 — 21
CP — CP, TURP — CP
HGPIN ⫽ high-grade prostatic intraepithelial neoplasia; TURP ⫽ transurethral resection of prostate; other abbreviations as in Table 1. * Men who did not undergo neoadjuvant hormonal therapy.
disease stage, tumor volume, tumor grade, lymphovascular invasion, or surgical margin status.
COMMENT High-grade prostatic intraepithelial neoplasia is a common pathologic abnormality identified in men who live in Western countries. However, information is limited on the prevalence of HGPIN in Asia.1,16 –19 The studies20 –26 of Western populations have reported that HGPIN is present in 82% to 100% of prostates from radical prostatectomy. However, the studies1,18,19 of Asian populations, including our results, have reported HGPIN in 65% to 85%, which is similar but slightly lower than the Western prevalence (Table 3). Several reports on HGPIN have suggested that HGPIN is present with clinically significant prostate cancer, regardless of the ethnic differences. The slightly lower prevalence of HGPIN in Asian men could have resulted because a greater number of Asian patients who underwent radical prostatectomy had been diagnosed with locally advanced prostate cancer. HGPIN lesions can be destroyed by advanced prostate cancer. This finding has been supported by Sakr and Grignon,27 who suggested a reciprocal relationship among the grade, volume, and extent of HGPIN. In addition, McNeal and Qian reported that the PIN was more extensive in lowerstage tumors, presumably owing to an overgrowth or obliteration of PIN by larger high-stage tumors. The prevalence of HGPIN in patients without clinical evidence of prostate cancer has not been thoroughly evaluated. Troncoso et al.,28 in a study of 66 men who underwent cystoprostatectomy, reported that HGPIN was present in 83.3% of cases. Subsequent studies performed in Western countries have shown similar results.23,29 –31 In contrast, only two Asian studies have reported on the prevalence of HGPIN in cystoprostate1102
ctomy specimens. Yang et al.,16 in a study of 47 Taiwanese men, reported HGPIN in 37.7% of cystoprostatectomy specimens, and Desai and Borges,1 in a study of 110 Indian men, reported that HGPIN was not present in any of the 49 prostatectomy specimens obtained from patients without prostate cancer, although whole prostate specimens were not embedded in their study. Our results showed that HGPIN was present in 0% to 38% of Asian men who underwent cystoprostatectomy, unlike Western studies, which have reported a frequency of 47% to 99% (Table 3). HGPIN seems to be less frequent in Asian men with incidental prostate cancer, in contrast to the findings in Western men, although no large studies of Asian populations and HGPIN have been done to confirm these findings. We found that prostate cancer, identified in the prostate glands of patients undergoing cystoprostatectomy, had the following characteristics. The serum PSA levels were most commonly in the normal range; many of the cancers were clinically insignificant (67%), and most patients had disease characterized by low-stage, low-grade, and small tumor volume. These characteristics suggest that quite a number of prostate cancers in cystoprostatectomy specimens were relatively early cancers or were cancers with different characteristics from the prostate cancer found in prostatectomy specimens. The relatively low prevalence of HGPIN in the cystoprostatectomy specimens suggests that factors associated with the prevention of further progression of the prostate cancer might be present during the transformation from incidental prostate cancer to clinically overt prostate cancer in Asian men or factors that promote progression might be present in Western men. Such a difference could explain the variation in prevalence of prostate cancer in Western and Asian men. UROLOGY 70 (6), 2007
In contrast, Epstein et al.32 suggested that the relationship between HGPIN and a centrally located Stage A tumor might not be a direct one because of the lack of a close spatial association between the two. Therefore, HGPIN could be a predisposing lesion, together with incidental prostate cancer and increasing age. However, we could not investigate this because the multifocality and zonal distributions of HGPIN were not available. More meticulous evaluations or molecular or genetic comparisons of HGPIN in Asian populations are necessary for confirmation of these issues.
CONCLUSIONS The prevalence of HGPIN in Korean men with clinical prostate cancer was as great as that of Western men. Previous studies, including our results, have shown a lower prevalence of HGPIN in Asian men who underwent cystoprostatectomy compared with the prevalence in Western reports. The different prevalence of HGPIN found in incidental prostate cancer, between Asian and Western men, suggests that factors could be present that prevent the progression of prostate cancer or the characteristics of prostate cancer might be different in Asian populations.
12. 13. 14.
15.
16.
17.
18.
19.
20. 21.
22.
References 1. Desai SB, and Borges AM: The prevalence of high-grade prostatic intraepithelial neoplasia in surgical resection specimens: an Indian experience. Cancer 94: 2350 –2352, 2002. 2. Sakr WA: Prostatic intraepithelial neoplasia: a marker for high-risk groups and a potential target for chemoprevention. Eur Urol 35: 474 – 478, 1999. 3. Hsing AW, Tsao L, and Devesa SS: International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 85: 60 – 67, 2000. 4. Ministry of Health and Welfare: 2004 Annual Report of the Central Cancer Registry in Korea. Goyang, Ministry of Health and Welfare, 2005. 5. Steiner MS, and Bostwick DG: High-grade prostatic intraepithelial neoplasia, in Mydlo JH, and Godec CJ (Eds): Prostate Cancer: Science and Clinical Practice. San Diego, Academic Press, 2003, pp 34 – 43. 6. Sakr WA, Billis A, Ekman P, et al: Epidemiology of high-grade prostatic intraepithelial neoplasia. Scand J Urol Nephrol 205: 11–18, 2000. 7. Sakr WA, Grignon DJ, Crissman JD, et al: High-grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20 – 69: an autopsy study of 249 cases. In Vivo 8: 439 – 443, 1994. 8. Sakr WA, Haas GP, Cassin BF, et al: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 150: 379 –385, 1993. 9. Sakr WA, Grignon DJ, Crissman JD, et al: Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 30: 138 –144, 1996. 10. Sakr WA, Grignon DJ, Haas GP, et al: Epidemiology of high-grade prostatic intraepithelial neoplasia. Pathol Res Pract 191: 838 – 841, 1995. 11. Argani P, and Epstein JI: Inverted (hobnail) high-grade prostatic intraepithelial neoplasia (PIN): report of 15 cases of a previously
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undescribed pattern of high-grade PIN. Am J Surg Pathol 25: 1534 –1539, 2001. Bostwick DG, Liu L, Brawer MK, et al: High-grade prostatic intraepithelial neoplasia. Rev Urol 6: 171–179, 2004. Bostwick DG, and Qian J: High-grade prostatic intraepithelial neoplasia. Mod Pathol 17: 360 –379, 2004. Epstein JI, Walsh PC, CarMichael M, et al: Pathological and clinical findings to predict tumor extent of non-palpable (stage T1c) prostate cancer. JAMA 271: 368 –374, 1994. Carter HB, Sauvageot J, Walsh PC, et al: Prospective evaluation of men with stage T1c adenocarcinoma of the prostate. J Urol 157: 2206 –2209, 1997. Yang CR, Ou YC, Ho HC, et al: Unsuspected prostate carcinoma and prostatic intraepithelial neoplasm in Taiwanese patients undergoing cystoprostatectomy. Mol Urol 3: 33–39, 1999. Watanabe M, Fukutome K, Kato H, et al: Progression-linked overexpression of c-Met in prostatic intraepithelial neoplasia and latent as well as clinical prostate cancers. Cancer Lett 141: 173–178, 1999. Shin M, Takayama H, Nonomura N, et al: Extent and zonal distribution of prostatic intraepithelial neoplasia in patients with prostatic carcinoma in Japan: analysis of whole-mounted prostatectomy specimens. Prostate 42: 81– 87, 2000. Song SY, Kim SR, Aha G, et al: Pathologic characteristics of prostatic adenocarcinoma: a mapping analysis of Korean patients. Prostate Cancer Prostatic Dis 6: 143–147, 2003. McNeal JE, and Bostwick DG: Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol 17: 64 –71, 1986. Quinn BD, Cho KR, and Epstein JI: Relationship of severe dysplasia to stage B adenocarcinoma of the prostate. Cancer 65: 2328 – 2337, 1990. Qian J, Wollan P, and Bostwick DG: The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 28: 143–148, 1997. Wiley EL, Davidson P, McIntire DD, et al: Risk of concurrent prostate cancer in cystoprostatectomy specimens is related to volume of high-grade prostatic intraepithelial neoplasia. Urology 49: 692– 696, 1997. Truskinovsky AM, Sanderson H, and Epstein JI: Characterization of minute adenocarcinomas of prostate at radical prostatectomy. Urology 64: 733–737, 2004. Oyasu R, Bahnson RR, Nowels K, et al: Cytological atypia in the prostate gland: frequency, distribution and possible relevance to carcinoma. J Urol 135: 959 –962, 1986. Qian J, Wollan P, and Bostwick DG: The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 28: 143–148, 1997. Sakr WA, and Grignon DJ: Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia: relationship to pathologic parameters, volume and spatial distribution. Anal Quant Cytol Histol 20: 417– 423, 1998. Troncoso P, Babaian RJ, Ro JY, et al: Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinoma in cystoprostatectomy specimens. Urology 34: 52–56, 1989. Abbas F, Hochberg D, Civantos F, et al: Incidental prostatic adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder cancer. Eur Urol 30: 322–326, 1996. Prange W, Erbersdobler A, Hammerer P, et al: High-grade prostatic intraepithelial neoplasia in cystoprostatectomy specimens. Eur Urol 39: 30 –31, 2001. Kim HY, and Yang XJ: Prevalence of high-grade prostatic intraepithelial neoplasia and its relationship to serum prostate specific antigen. Int Braz J Urol 28: 413– 417, 2002. Epstein JI, Cho KR, and Quinn BD: Relationship of severe dysplasia to stage A (incidental) adenocarcinoma of the prostate. Cancer 65: 2321–2327, 1990.
1103
RESULTS
CONCLUSIONS
To evaluate the prevalence of high-grade prostatic intraepithelial neoplasia (HGPIN) and its association with prostate cancer in Korean men. A total of 160 patients who underwent radical prostatectomy for clinical prostate cancer were included as study subjects and 29 patients who underwent radical cystoprostatectomy for muscle-invasive bladder cancer were included as controls. Each intact prostate gland was serially sectioned at 3-mm intervals perpendicular to the posterior surface. The presence and prevalence of prostate cancer and HGPIN were assessed and their association evaluated. High-grade prostatic intraepithelial neoplasia was present in 81 (70.4%) of 115 patients who underwent radical prostatectomy and in 8 (27.6%) of 29 patients who underwent cystoprostatectomy. This difference was statistically significant (P ⬍0.001). Among the patients who underwent cystoprostatectomy, HGPIN was present in 5 (33.3%) of 15 patients with prostate cancer and in 3 (21.4%) of 14 patients with no evidence of prostate cancer. The presence of HGPIN had no correlation with prostate-specific antigen level, disease stage, tumor volume, grade, lymphovascular invasion, or surgical margin status. The prevalence of HGPIN in Korean men with clinical prostate cancer was as great as that of Western men. Previous studies, and our results, had demonstrated a lower prevalence of HGPIN in Asian men who underwent cystoprostatectomy. The different prevalence of HGPIN found in incidental prostate cancer, between Asian and Western men, suggests that factors could be preventing the progression of prostate cancer or different characteristics of the prostate cancer in Asian populations. UROLOGY 70: 1100 –1103, 2007. © 2007 Elsevier Inc.
T
he prevalence of prostate cancer reportedly varies among different ethnic groups and populations.1,2 An increase in the prevalence of prostate cancer has been observed in Asian countries during recent decades.3 In Korea, the prevalence of prostate cancer is also increasing, but this increase has not been as great as that in Western countries.4 High-grade prostatic intraepithelial neoplasia (HGPIN) is accepted as a premalignant lesion that has the potential to progress to prostate adenocarcinoma.5 The prevalence of both HGPIN and prostate cancer inFrom the Urologic Oncology Clinic, Division of Specific Organs Cancer, National Cancer Center, Division of Specific Organs Cancer, Research Institute, National Cancer Center, Goyang, South Korea Reprint requests: Kang Hyun Lee, M.D., Ph.D., Urologic Oncology Clinic, National Cancer Center, 809 Madu-dong, Ilsan-dong-gu, Goyang-si, Gyeonggi-do 411769, Republic of South Korea. E-mail: [email protected] Submitted: February 22, 2007; accepted (with revisions): July 3, 2007
1100
© 2007 Elsevier Inc. All Rights Reserved
crease with patient age, and HGPIN precedes the onset of prostate cancer by less than one decade.6 –9 However, as with prostate cancer, the prevalence of HGPIN is reportedly different among ethnic groups and populations. Several studies have reported ethnic differences in the prevalence of HGPIN consistent with those of prostate cancer.9 –14 Ethnic differences for HGPIN showing similar patterns with the prevalence of prostate cancer have supported HGPIN as a premalignant lesion of prostate cancer. However, most studies of racial differences have compared African Americans and whites; few studies have investigated Asians. Therefore, we investigated the prevalence of HGPIN in the prostate glands of Korean patients who had undergone radical prostatectomy for prostate cancer and those who had undergone radical cystoprostatectomy for 0090-4295/07/$32.00 doi:10.1016/j.urology.2007.07.015
bladder cancer and compared these results with the reported Western prevalence data.
Table 1. Clinical and pathologic characteristics of patients with prostate cancer in both groups Characteristic
MATERIAL AND METHODS A total of 190 prostate glands were obtained from November 2001 to January 2007. The study subjects included 160 patients who had undergone radical prostatectomy for clinical prostate cancer; 30 patients who had undergone radical cystoprostatectomy for muscle-invasive bladder cancer were included as controls. Patients who had had androgen deprivation therapy before surgery were excluded. Insignificant prostate cancers included those with the following characteristics: size less than 0.5 cm3, disease confined to the prostate gland, seminal vesicles and lymph nodes negative for tumor, and an absence of Gleason pattern 4 or 5.14,15 All specimens included intact whole prostate gland specimens that had been totally embedded. Each prostate gland was serially sectioned at 3-mm intervals perpendicular to the posterior surface. Hematoxylin-eosin slides were reviewed by the pathologist for assessment of the tumor grade and stage. To assist with the diagnosis of malignancy, immunohistochemical staining with monoclonal antibodies to high-molecular-weight cytokeratin (34betaE12, Dako, Glostrup, Denmark) and p63 (4A4, Dako) was used to confirm the status of basal layers on atypical lesions. The PIN lesions were divided into low and high grade. The presence of prostate cancer and HGPIN was assessed. In addition, tumor stage, Gleason grade, tumor volume, tumor location, extraprostatic extension, perineural invasion, lymphovascular invasion, and surgical margin status were evaluated. Tumor stage was assessed according to the TNM system (American Joint Committee on Cancer, 2002) and tumor grade according to the Gleason grading system. Age was compared with the paired t test among each group. The prevalence was compared using the chi-square test. Correlations between several pathologic characteristics and the presence of HGPIN were assessed by logistic regression analysis. All tests were performed at the 5% significance level using the Statistical Package for Social Sciences, version 11.5, for Windows (SPSS, Chicago, Ill).
RESULTS Of the 160 patients who underwent radical prostatectomy for clinical prostate cancer, 45 were excluded because they had had neoadjuvant hormonal therapy before surgery. The median age was not significantly different between the two groups. The median age was 64 years in the prostatectomy group and 68 years in the cystoprostatectomy group. The median prostate-specific antigen (PSA) level was 9.6 ng/mL (mean ⫾ SD, 12.8 ⫾ 9.1) in the prostatectomy group and 1.5 ng/mL (mean ⫾ SD, 2.0 ⫾ 1.7) in the cystoprostatectomy group. All patients who underwent cystoprostatectomy had normal age-adjusted PSA levels, except for one. One patient with muscleinvasive bladder cancer was excluded because he had a high PSA level and had been diagnosed with prostate cancer by prostate biopsy before surgery. Of the 29 patients who underwent cystoprostatectomy, 15 (51.7%) had prostate cancer. Table 1 shows the clinical and UROLOGY 70 (6), 2007
Pathologic stage T2 T3a T3b T4 Gleason score 4 5 6 7 ⱖ8 Tumor volume (cm3) ⬍0.5 ⱖ0.5 Perineural invasion Present Absent Surgical margin status Positive Negative LN metastasis Present Absent
RP Group (n ⫽ 115)
CP Group (n ⫽ 15)
72 (62.6) 35 (30.4) 7 (6.1) 1 (0.9)
15 (100) 0 (0) 0 (0) 0 (0)
0 (0) 3 (2.6) 41 (35.7) 54 (46.9) 17 (14.8) 0 (0) 115 (100)
3 (20.0) 3 (20.0) 7 (46.7) 1 (6.6) 1 (6.6) 5 (33.3) 10 (66.7)
67 (58.3) 48 (41.7)
0 (0) 15 (100)
49 (42.6) 66 (57.4)
0 (0) 29 (100)
4 (3.5) 111 (96.5)
0 (0) 29 (100)
RP ⫽ radical prostatectomy; CP ⫽ cystoprostatectomy; LN ⫽ lymph node. Data in parentheses are percentages.
Table 2. Prevalence of HGPIN and prostate cancer in both groups Variable PCa Significant PCa Insignificant PCa HGPIN* In benign prostates In insignificant PCa In significant PCa
RP Group (n ⫽ 115)
CP Group (n ⫽ 29)
115 (100) 115 (100) 0 (0) 81 (70.4)
15 (51.7) 5 (17.2) 10 (34.5) 8 (27.6) 3/14 (21.4) 4/10 (40.0) 1/5 (20.0)
HGPIN ⫽ high-grade prostatic intraepithelial neoplasia; PCa ⫽ prostate cancer; other abbreviations as in Table 1. Data in parentheses are percentages. * P ⬍0.001, chi-square test.
pathologic characteristics of the patients with prostate cancer in both groups. High-grade prostatic intraepithelial neoplasia was present in 81 (70.4%) of 115 patients who underwent radical prostatectomy and in 8 (27.6%) of 29 patients who underwent cystoprostatectomy (Table 2). This difference was statistically significant (P ⬍0.001). Of the patients who underwent cystoprostatectomy, HGPIN was present in 5 (33.3%) of the 15 patients with prostate cancer and in 3 (21.4%) of the 14 patients with no evidence of prostate cancer. In addition, HGPIN was found in only 1 (20%) of 5 patients with significant prostate cancer, but it was noted in 4 (40%) of 10 patients with nonsignificant prostate cancer. The presence of HGPIN had no correlation with PSA level, 1101
Table 3. Incidence of HGPIN found in whole prostates from radical prostatectomy or cystoprostatectomy Study Western countries McNeal and Bostwick,20 1986 Troncoso et al.,28 1989 Quinn et al.,21 1990 Abbas et al.,29 1996 Qian et al.,22 1997 Wiley et al.,23 1997 Prange et al.,30 2001 Kim et al.,31 2002 Truskinovsky et al.,24 2004 Asian countries Yang et al.,16 1999 Shin et al.,18 2000 Desai et al.,1 2002 Song et al.,19 2003 Present study
RP Group Population Men* (n) PIN Rate (%) USA USA USA USA USA USA German USA USA
100 — 40 — 195 64 — — 78
Taiwanese Japanese Indian Korean Korean
— 17 61 132 115
82 — 100 — 86 95 — — 100 — 76 85.2 65.2 70.4
Specimen
CP Group Men (n) PIN Rate (%) Specimen
RP — RP — RP RP — — RP
— 66
— 83.3
— CP
40 — 48 85 61 —
47.5 — 83 99 75 —
CP — CP CP CP —
— RP RP, TURP, CP RP RP
47 — 49 — 29
37.7 — 0 — 21
CP — CP, TURP — CP
HGPIN ⫽ high-grade prostatic intraepithelial neoplasia; TURP ⫽ transurethral resection of prostate; other abbreviations as in Table 1. * Men who did not undergo neoadjuvant hormonal therapy.
disease stage, tumor volume, tumor grade, lymphovascular invasion, or surgical margin status.
COMMENT High-grade prostatic intraepithelial neoplasia is a common pathologic abnormality identified in men who live in Western countries. However, information is limited on the prevalence of HGPIN in Asia.1,16 –19 The studies20 –26 of Western populations have reported that HGPIN is present in 82% to 100% of prostates from radical prostatectomy. However, the studies1,18,19 of Asian populations, including our results, have reported HGPIN in 65% to 85%, which is similar but slightly lower than the Western prevalence (Table 3). Several reports on HGPIN have suggested that HGPIN is present with clinically significant prostate cancer, regardless of the ethnic differences. The slightly lower prevalence of HGPIN in Asian men could have resulted because a greater number of Asian patients who underwent radical prostatectomy had been diagnosed with locally advanced prostate cancer. HGPIN lesions can be destroyed by advanced prostate cancer. This finding has been supported by Sakr and Grignon,27 who suggested a reciprocal relationship among the grade, volume, and extent of HGPIN. In addition, McNeal and Qian reported that the PIN was more extensive in lowerstage tumors, presumably owing to an overgrowth or obliteration of PIN by larger high-stage tumors. The prevalence of HGPIN in patients without clinical evidence of prostate cancer has not been thoroughly evaluated. Troncoso et al.,28 in a study of 66 men who underwent cystoprostatectomy, reported that HGPIN was present in 83.3% of cases. Subsequent studies performed in Western countries have shown similar results.23,29 –31 In contrast, only two Asian studies have reported on the prevalence of HGPIN in cystoprostate1102
ctomy specimens. Yang et al.,16 in a study of 47 Taiwanese men, reported HGPIN in 37.7% of cystoprostatectomy specimens, and Desai and Borges,1 in a study of 110 Indian men, reported that HGPIN was not present in any of the 49 prostatectomy specimens obtained from patients without prostate cancer, although whole prostate specimens were not embedded in their study. Our results showed that HGPIN was present in 0% to 38% of Asian men who underwent cystoprostatectomy, unlike Western studies, which have reported a frequency of 47% to 99% (Table 3). HGPIN seems to be less frequent in Asian men with incidental prostate cancer, in contrast to the findings in Western men, although no large studies of Asian populations and HGPIN have been done to confirm these findings. We found that prostate cancer, identified in the prostate glands of patients undergoing cystoprostatectomy, had the following characteristics. The serum PSA levels were most commonly in the normal range; many of the cancers were clinically insignificant (67%), and most patients had disease characterized by low-stage, low-grade, and small tumor volume. These characteristics suggest that quite a number of prostate cancers in cystoprostatectomy specimens were relatively early cancers or were cancers with different characteristics from the prostate cancer found in prostatectomy specimens. The relatively low prevalence of HGPIN in the cystoprostatectomy specimens suggests that factors associated with the prevention of further progression of the prostate cancer might be present during the transformation from incidental prostate cancer to clinically overt prostate cancer in Asian men or factors that promote progression might be present in Western men. Such a difference could explain the variation in prevalence of prostate cancer in Western and Asian men. UROLOGY 70 (6), 2007
In contrast, Epstein et al.32 suggested that the relationship between HGPIN and a centrally located Stage A tumor might not be a direct one because of the lack of a close spatial association between the two. Therefore, HGPIN could be a predisposing lesion, together with incidental prostate cancer and increasing age. However, we could not investigate this because the multifocality and zonal distributions of HGPIN were not available. More meticulous evaluations or molecular or genetic comparisons of HGPIN in Asian populations are necessary for confirmation of these issues.
CONCLUSIONS The prevalence of HGPIN in Korean men with clinical prostate cancer was as great as that of Western men. Previous studies, including our results, have shown a lower prevalence of HGPIN in Asian men who underwent cystoprostatectomy compared with the prevalence in Western reports. The different prevalence of HGPIN found in incidental prostate cancer, between Asian and Western men, suggests that factors could be present that prevent the progression of prostate cancer or the characteristics of prostate cancer might be different in Asian populations.
12. 13. 14.
15.
16.
17.
18.
19.
20. 21.
22.
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