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Clinical and Pathological Features of Hereditary Prostate Cancer
0022-5347/96/1556-184 1$03.00/0 % JOURNAL OF UROLOGY Copyright 0 1996 by A M E R I C A N UROLOCICAL ASSOCIATION, INC.
Vol. 155,1841-1843. June 1996 Printed in U S A
Original Articles CLINICAL AND PATHOLOGICAL FEATURES OF HEREDITARY PROSTATE CANCER DAVID W. KEETCH,” PETER A. HUMPHREY, DEBORAH S. SMITH, DAVID STAHL WILLIAM J. CATALONA
AND
From the D ~ V I S ~ofO Urologic I~S Surgery and Anatomic Pathology, Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
Purpose: We determined whether the clinical and pathological features of hereditary prostate cancer differ from those of sporadic prostate cancer. Materials and Methods: We compared the clinical and pathological features of radical prostatectomy specimens from 50 men with and 50 without a family history of prostate cancer who were matched for age and date of surgery. Results: Median serum prostate specific antigen concentration was not significantly different in the 2 groups. Mean Gleason score plus or minus standard deviation in the 50 men with sporadic prostate cancer was 6.2 5 1 compared to 5.6 5 0.9 in those with hereditary disease (p = 0.008). Of the 50 hereditary and 50 sporadic prostate cancers 35 (70%) and 33 (66%), respectively, were pathologically organ confined (p = 0.69). Median percentage of carcinoma within the gland (determined morphometrically) in men with hereditary disease was 11.4 -t 8.3 compared to 10.9 2 8.9 for those with sporadic cancer ( p = 0.63). Conclusions: In our study population hereditary prostate cancers have significantly lower Gleason scores compared to sporadic carcinomas. Otherwise, there appear to be no substantial clinical or pathological differences. KGy
WORDS:prostatic neoplasms, hereditary diseases
A positive family history is currently considered a significant risk factor for t h e development of prostate With regard to family history, prostate cancer is believed t o occur i n 3 forms: 1) sporadic-occurring randomly in the population, 2 ) familial-the unpredictable clustering of disease in families a n d 3) hereditary-early onset of disease and strong clustering i n individual families.7 I t is believed that the hereditary form of prostate cancer is characterized by mendelian inheritance of a highly penetrant, autosomal dominant gene.H To date, limited data are available comparing the clinical and pathological features of sporadic and hereditary prostate cancer.3.7.8 To evaluate further the potential clinical and pathological differences between these 2 forms of prostate cancer we compared t h e tumors from 50 men with and 50 without a family history of prostate carcinoma. MATERIALS AND METHODS
From our study of familial prostate cancer we retrospectively identified 50 men who presented to our institution with newly diagnosed disease, and underwent bilateral pelvic lymphadenectomy a n d radical retropubic prostatectomy between July 1988 a n d February 1994. These 50 men were classified a s having hereditary prostate cancer because the family pedigree consisted of either 3 successive generations affected with prostate cancer, a clustering of 3 or more prostate cancer cases i n a nuclear family, or 2 men with early age Accepted for publication December 8, 1995. * Requests for reprints: Division of Urology, 1040 N. Mason Rd., Suite 122, St. Louis, Missouri 63141.
at disease onset (younger than 55 years).’ These 50 men with hereditary prostate cancer were compared to 50 age and date of surgery matched controls who were retrospectively selected randomly from the surgical logs of 1 of us (W. J. C . ) , and who underwent radical prostatectomy between March 1988 and July 1994. All men in both groups h a d clinically localized prostate cancer as judged by serum prostatic acid phosphatase, bone scan, chest radiography and computerized tomography. Both groups were compared with respect to age a t diagnosis of prostate cancer, prevalence of suspicious digital rectal examination, and serum prostate specific antigen (PSA) concentration. Rectal examination results were missing for 1 man and serum PSA results were missing for 3 in the hereditary cancer group. The radical prostatectomy specimens from all 100 men were reviewed retrospectively by 1pathologist ( P . A. H.).The specimens were not completely embedded a t operation and initial processing. For the retrospective analysis the standardized, representative sections obtained from each quadrant of each specimen were reviewed. Each specimen was analyzed for Gleason score, organ confined versus nonorgan confined cancer, incidence of seminal vesicle and lymph node involvement, and percentage of specimen replaced by malignancy. Tumor was identified a s unilateral or bilateral. Intraglandular tumor extent was reported as the percentage of carcinoma in the gland using a grid morphometric technique.’” The percent of prostate involved by tumor and the actual tumor volume in radical prostatectomy specimens
1841
ANALYSIS OF HEREDITARY PROSTATE CANCER
1842
were shown to be highly correlated, with correlation coefficients of 0.81 to 0.88.11.1* Age at cancer diagnosis and Gleason score in both groups were compared using Student’s t tests. The prevalence of suspicious digital rectal examination, rate of organ confined cancer and rate of bilateral cancer were compared using chi-square statistics. Serum PSA values and percent cancer determinations were nonnormally distributed and, therefore, were compared using Wilcoxon’s nonparametric tests. Percent cancer measurements also were compared for men with organ confined versus nonorgan confined cancer in both groups.
TABLE2 Unilateral versus bilateral organ confined cancer in men wtth hereditary disease and controls No ConfinedTotal No t l r ) Ca Group
Bilat Ca
p Value
0.06 21/36 (58) 12/14 (86) Control 25/39 ( 64 ) 0.08 Hereditary 10/11(91) There was no significant difference between the hereditary and control groups.
TABLE3. Median percent organ confined versus nonorgan confined intraglandular tumor extent in men with hereditary prostate cancer and controls
RESULTS
There were 47 white men in each group, while 3 in the hereditary group and 2 in the control group were black, and 1 in the control group was Asian. Mean age plus or minus standard deviation at prostate cancer diagnosis was 61.3 2 6.4 years in the hereditary group compared to 61.4 2 6.2 in the control group ( p = 0.94). The prevalence of a suspicious digital rectal examination was similar in the hereditary (29 of 49 patients or 59%) and control (34 of 50, or 68%) groups (p = 0.36). Median serum PSA concentration was 6.8 ng./ml. (semi-interquartile range 2 4.4) in the hereditary group and 5.9 ng./ml. (semi-interquartile range 2 2.0) in the control group (p = 0.92). The pathological characteristics of the cancers in both groups are shown in table 1. The rate of organ confined cancer was approximately the same in both groups (70 versus 66%).Two men in each group demonstrated seminal vesicle invasion. Two men in the hereditary group had metastatic cancer within lymph nodes compared to none in the control group. Of 50 cancers in the control group 36 (72%)were bilateral compared to 39 of 50 (78%)in the hereditary group (p = 0.48). Unilateral cancers tended to be more often pathologically organ confined than bilateral cancers in both groups, although this did not reach statistical significance (table 2). The intraglandular tumor extent, reported as percentage of specimen involvement, was approximately the same in both groups (11.4 versus 10.970, table 1). The intraglandular tumor extent was significantly higher in men with nonorgan confined compared to organ confined cancer in both groups (table 3). Mean Gleason score was significantly higher (6.2 2 1) in the control group compared to the hereditary group (5.6 2 0.9).The distribution of Gleason scores was notably different between the 2 groups. Of 50 men in the hereditary group 42 (84%)had Gleason score 5 or 6 tumors compared to only 29 of 50 (58%)in the control group (p = 0.004), while Gleason score 7 tumors were found in 17 (34%)and 3 (6%),respectively (p = <0.0001), and Gleason scores 8 to 10 (poorly differentiated) cancers in only 2 (4%)and 3 (6%),respectively.
Unilat Ca
Mean Pathological Stage Ca Group
Organ Confined Ca
Nonorgan Confined Ca
p Value
18.7 I 8.7 13-44) 7.1 z 4.4 (0.1-72.6) Control 0.05 9.5 t 6.3 ( 0 . M 1 . 2 ) 22.6 ? 14.9 (6.3-85.1, 0.001 Hereditary There was no significant difference between the hereditary and control groups.
tate cancer probands have a t least 1 other affected male relative.3.4. l3 Familial prostate cancer is the simple clustering of disease within families. Hereditary prostate cancer is believed to be a subtype of familial prostate cancer, and is characterized by either 3 successive generations being affected with the disease, a clustering of 3 or more men with prostate cancer in a nuclear family, or 2 men with early age at onset of disease (younger than 55 years) in the same family. The hereditary form of prostate cancer has been reported to comprise only 5 to 6% of all prostate cancer cases.7.13 It usually occurs 10 years earlier than sporadic prostate cancer, and is believed to be transmitted in a mendelian pattern of inheritance by a highly penetrant, autosomal dominant gene.7 It is also believed to account for 43%of all early onset prostate cancer^.^.^ Steinberg et al evaluated the characteristics of disease in 29 men with and 80 without a family history of prostate cancer, and found no difference in the clinical and pathological stages.3 Carter et a1 compared the clinical and pathological features of prostate cancers from 33 men with hereditary, 144 with familial and 496 with sporadic prostate cancer.7 They found no difference in serum PSA concentration, PSA density, prostate weight, Gleason score or rate of organ confined cancer among the 3 groups. However, it must be remembered that all patients in these 3 groups were treated with radical prostatectomy and, therefore, represent a select group. Bastacky et a1 performed whole-mount analysis on the prostatectomy specimens from 27 men with sporadic, 26 with familial and 28 with hereditary prostate cancer.9 The rates of organ confined disease, seminal vesicle invasion and lymph node involvement, as well as mean number of tumor nodules and mean tumor volume were not different among the 3 groups. The only significant differences were that small, mulDISCUSSION tifocal carcinomas in the familial and hereditary groups had Several studies demonstrated a clustering of prostate can- a lower Gleason score compared to those in the sporadic cer cases in certain families.’-6 Between 13 and 26%of pros- group, and a greater proportion of the sporadic prostate cancers were small, multifocal and associated with prostatic intraepithelial neoplasia. We found few differences in the characteristics of herediTABLE1. Pathological characteristics of hereditary prostate cancers tary versus sporadic prostate cancers. Mean serum PSA concompared to controls centration and prevalence of suspicious rectal examination Hereditary Group Control Group were no different in the 2 groups. The rate of organ confined I50 pts. 1 (50 pts. J cancer, seminal vesicle invasion and percent intraglandular Mean Gleaeon score r 5.6 r 0.9 (4-8) 6.2 r 1.014-9, 0.008 tumor extent were the same in both groups. The rate of SD (range) bilateral cancer, a gross indicator of multifocality, was not No. organ confined C d 35/50 1701 33/50 (661 0.69 different between the 2 groups. The only significant differtotal Nn. ( ? I Median ? (:a semi- 11.4 f 8.3 10.4-85.11 10.9 * R.9 ( 0 1-72.61 0.63 ence between our 2 groups, as in the study of Bastacky et aL9 interquartile range was that Gleason score was simificantlv lower amone men ( rangc I with hereditary prostate cancer. Also, there was a hvigher +
ANALYSIS OF HEREDITARY PROSTATE CANCER
proportion of Gleason score 7 disease in our sporadic cancer group, which may represent a selection bias since our control group was retrospectively selected based only on patient age and date of surgery. It should be emphasized that our men constitute a select group, since all were considered surgical candidates. I t is possible that if all stages of hereditary prostate cancer were compared to a full spectrum of sporadic prostate cancers significant clinical and/or pathological differences may be noted. Further studies are needed to examine this issue fully. Based on currently available data, it appears that after radical prostatectomy clinically localized, hereditary prostate cancers exhibit many of the same pathological characteristics as clinically localized sporadic prostate cancers. However, these pathological changes occur at earlier ages in men with hereditary prostate c a n ~ e r . ~Germline .~ deoxyribonucleic acid alterations in genes involved in cellular growth and differentiation that control the promotion and/or inhibition of aberrant cellular growth are most likely the basis for this early expression of disease in these select cases. Environmental factors may or may not influence these apparent genetic abnormalities. Further studies characterizing possible genetic aberrations are needed to delineate this matter. In conclusion, except for lower histological grade, there appear t o be no substantial clinical or pathological differences in hereditary versus sporadic prostate cancers.
1843
EDITORIAL COMMENT
Prostate cancer has been divided into 3 epidemiological categories (sporadic, familial and hereditary) based on the presence or absence of familial clustering of disease and patient age at onset (reference 7 in article). The majority of prostate cancers occur after age 65 years in the setting of no family history of disease (sporadic) and are believed to be associated primarily with environmentally induced or spontaneously occurring genetic alterations. Approximately 1 5 4 of men with prostate cancer have a family history of disease (familial prostate cancer). This familial aggregation is stronger than the familial aggregation present in breast and colon cancers, and may result from combinations of environmentally induced, spontaneous and inherited genetic alterations. Hereditary prostate cancer can be defined clinically but not yet by the inheritance of any specific genetic alteration. Since tumorigenesis is believed to result from a pathway of multiple genetic alterations, inheritance of an important early alteration along this pathway would more likely lead to the earlier age at onset of disease, compared to acquisition of the alteration later in life. Strong evidence for an inherited form of prostate cancer is based on 3 findings: 1) relatives of patients with prostate cancer younger than 55 years are at increased risk for cancer compared to relatives of older patients with prostate cancer, 2)there is stronger familial clustering among families with early age at onset of disease, and 3) the number of affected family members and age at onset of prostate cancer are the most important determinants of prostate cancer risk among relatives. Statistical analysis (segregation analysis) suggests that mendelian inheritance of an autosomal dominant gene best explains the observed familial clustering and early age a t onset of disease (reference 8 in article). REFERENCES The authors evaluated the clinical features of prostate cancer to 1. Morganti, G., Gianferrari, L. and Cresseri, A,: Recherches clini- determine if there are differences between hereditary and sporadic costatistiques et genetiques sur les neoplasies de la prostate. cancers. Hereditary prostate cancer is defined as prostate cancer Acta Generacae Med. Gemellogogiae, 6 304, 1956. affecting multiple family members ( 3 or more) within the same 2. Woolf, C. M.: An investigation of the familial aspects of carci- nuclear family, cancer in 3 generations (paternal or maternal linnoma of the prostate. Cancer, 1 3 739, 1960. eage) or cancer in 2 relatives before age 55 years. This is a clinical 3. Steinberg, G. S., Carter, B. S., Beaty, T. H., Childs, B. and definition based on observed disease clustering that was developed to Walsh. P. C.: Familv historv and the risk of Prostate cancer. identify families in whom inheritance of a genetic defect most likely Prostate, 17: 337, 1990. has a role in development of prostate cancer (reference 8 in article). 4. Sritz. M. R.. Currier, R. D., Fueger, J. J., Babaian, R. J. and If hereditary prostate cancer, clinically defined, is associated with 'Newell, G. R.: Familial patter& of prostate cancer: a case- inheritance of a mutated tumor suppressor gene a s in other heredicontrol analysis. J. Urol., 1 4 6 1305, 1991. tary neoplasms, one might expect to find a difference in clinical or 5. Cannon, L., Bishop, D. T., Skolnick, M., Hunt, S., Lyon, J. L. and pathological features between hereditary and sporadic cancers. HowSmart, C. R.: Genetic epidemiology of prostate cancer in the ever, the striking finding in this and other studies (references 7 and Utah Mormon genealogy. Cancer Surv., 1: 47, 1982. 9 in article) is the similarity between hereditary and sporadic can6. Apnkian, A. G.. Bazinet, M., Plante, M., Meshref, A., Trudel, C., Aronson, S., Nachabe. M., Peloquin, F., Dessurealt, J., Narod, cers with respect to clinical and pathological features. Digital rectal S.. Bemn. L. and Elhilali, M. M.: Family history and the risk of examination findings, PSA levels, tumor grade, intraglandular tuprostatic carcinoma in a high risk group of urological patients. mor extent and multifocality, presence of precursor lesions (prostatic intraepithelial neoplasia), presence and extent of extraprostatic disJ Urol., 154: 404, 1995. 7. Carter. B. S.. Bova. G. S.. Beatv. T. H., Steinberg, G. D., Childs, ease, and progression atter radical prostatectomy have all been comB., Isaacs,W. B. and Walsh, P. C.: Hereditary prostate cancer: pared between hereditary and sporadic prostate cancers either in epidemiological and clinical features. J. Urol., 1 5 0 797, 1993. this study or previous analyses. The only significant difference in the 8. Carter, B. S., Beaty, T. H., Steinberg, G. D., Childs, B. and present study is the finding that Gleason score is lower among men Walsh, P. C.: Mendelian inheritance of familial prostate can- with hereditary prostate cancer compared to sporadic disease, which was previously described for small multifocal cancer nodules 1 refercer. Proc. Natl. Acad. Sci., 8 9 3367, 1992. 9. Bastacky, S. I., Wojno, K. J., Walsh, P. C., Carmichael, M. J. and ence 9 in article).The finding of overlapping clinical and pathological Epstein, J. I.: Pathological features of hereditary prostate can- features in hereditary and sporadic prostate cancers may be the result of a selection bias. Only radical prostatectomy candidates cer. J. Urol., part 2, 153: 987, 1995. 10. Humphrey, P. A. and Vollmer, R. T.: Intraglandular tumor ex- were evaluated and not the full spectrum of patients with prostate tent and prognosis in prostatic carcinoma: application of a grid cancer. Also, the definition of hereditary prostate cancer presently is method to prostatectomy specimens. Hum. Path., 21: 799. clinical and not molecular. Identification of the genetic alterations 1990. that are important for prostate cancer development may allow more 11. Epstein. J. I . , Carmichael. M., Partin, A. W. and Walsh, P. C.: IS precise molecular classification of men with prostatic cancer. tumor volume an independent predictor of progression followPresently, the most significant clinical application of the descriping radical prostatectomy? A multivariate analysis of 185 clin- tion of hereditary prostate cancer is the recognition of increased ical stage B adenocarcinomas of the prostate with 5 years of prostate cancer risk in men who should be encouraged to pursue followup. J. Urol., 149: 1478, 1993. aggressive screening, especially in the setting of a history of early 12. Humphrey, P. A., Baty. J. and Keetch, D. W.: Relationship be- onset of disease. The only other risk factor associated more stmngly tween serum prostate specific antigen, needle biopsy findings, with prostate cancer development is patient age. and histopathologic features of prostatic carcinoma in radical H . Ballentine Carter prostatectomy tissues. Cancer, 75: 1842, 1995. Department of Urology 13. Keetch, D. W., Rice, J. P., Suarez, B. K. and Catalona, W. J.: The Johns Hopkins Hospital Familial aspects of prostate cancer: a case control study. J Baltimore, Maryland Urol.. 1&1: 2100, 1995. I
Vol. 155,1841-1843. June 1996 Printed in U S A
Original Articles CLINICAL AND PATHOLOGICAL FEATURES OF HEREDITARY PROSTATE CANCER DAVID W. KEETCH,” PETER A. HUMPHREY, DEBORAH S. SMITH, DAVID STAHL WILLIAM J. CATALONA
AND
From the D ~ V I S ~ofO Urologic I~S Surgery and Anatomic Pathology, Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
Purpose: We determined whether the clinical and pathological features of hereditary prostate cancer differ from those of sporadic prostate cancer. Materials and Methods: We compared the clinical and pathological features of radical prostatectomy specimens from 50 men with and 50 without a family history of prostate cancer who were matched for age and date of surgery. Results: Median serum prostate specific antigen concentration was not significantly different in the 2 groups. Mean Gleason score plus or minus standard deviation in the 50 men with sporadic prostate cancer was 6.2 5 1 compared to 5.6 5 0.9 in those with hereditary disease (p = 0.008). Of the 50 hereditary and 50 sporadic prostate cancers 35 (70%) and 33 (66%), respectively, were pathologically organ confined (p = 0.69). Median percentage of carcinoma within the gland (determined morphometrically) in men with hereditary disease was 11.4 -t 8.3 compared to 10.9 2 8.9 for those with sporadic cancer ( p = 0.63). Conclusions: In our study population hereditary prostate cancers have significantly lower Gleason scores compared to sporadic carcinomas. Otherwise, there appear to be no substantial clinical or pathological differences. KGy
WORDS:prostatic neoplasms, hereditary diseases
A positive family history is currently considered a significant risk factor for t h e development of prostate With regard to family history, prostate cancer is believed t o occur i n 3 forms: 1) sporadic-occurring randomly in the population, 2 ) familial-the unpredictable clustering of disease in families a n d 3) hereditary-early onset of disease and strong clustering i n individual families.7 I t is believed that the hereditary form of prostate cancer is characterized by mendelian inheritance of a highly penetrant, autosomal dominant gene.H To date, limited data are available comparing the clinical and pathological features of sporadic and hereditary prostate cancer.3.7.8 To evaluate further the potential clinical and pathological differences between these 2 forms of prostate cancer we compared t h e tumors from 50 men with and 50 without a family history of prostate carcinoma. MATERIALS AND METHODS
From our study of familial prostate cancer we retrospectively identified 50 men who presented to our institution with newly diagnosed disease, and underwent bilateral pelvic lymphadenectomy a n d radical retropubic prostatectomy between July 1988 a n d February 1994. These 50 men were classified a s having hereditary prostate cancer because the family pedigree consisted of either 3 successive generations affected with prostate cancer, a clustering of 3 or more prostate cancer cases i n a nuclear family, or 2 men with early age Accepted for publication December 8, 1995. * Requests for reprints: Division of Urology, 1040 N. Mason Rd., Suite 122, St. Louis, Missouri 63141.
at disease onset (younger than 55 years).’ These 50 men with hereditary prostate cancer were compared to 50 age and date of surgery matched controls who were retrospectively selected randomly from the surgical logs of 1 of us (W. J. C . ) , and who underwent radical prostatectomy between March 1988 and July 1994. All men in both groups h a d clinically localized prostate cancer as judged by serum prostatic acid phosphatase, bone scan, chest radiography and computerized tomography. Both groups were compared with respect to age a t diagnosis of prostate cancer, prevalence of suspicious digital rectal examination, and serum prostate specific antigen (PSA) concentration. Rectal examination results were missing for 1 man and serum PSA results were missing for 3 in the hereditary cancer group. The radical prostatectomy specimens from all 100 men were reviewed retrospectively by 1pathologist ( P . A. H.).The specimens were not completely embedded a t operation and initial processing. For the retrospective analysis the standardized, representative sections obtained from each quadrant of each specimen were reviewed. Each specimen was analyzed for Gleason score, organ confined versus nonorgan confined cancer, incidence of seminal vesicle and lymph node involvement, and percentage of specimen replaced by malignancy. Tumor was identified a s unilateral or bilateral. Intraglandular tumor extent was reported as the percentage of carcinoma in the gland using a grid morphometric technique.’” The percent of prostate involved by tumor and the actual tumor volume in radical prostatectomy specimens
1841
ANALYSIS OF HEREDITARY PROSTATE CANCER
1842
were shown to be highly correlated, with correlation coefficients of 0.81 to 0.88.11.1* Age at cancer diagnosis and Gleason score in both groups were compared using Student’s t tests. The prevalence of suspicious digital rectal examination, rate of organ confined cancer and rate of bilateral cancer were compared using chi-square statistics. Serum PSA values and percent cancer determinations were nonnormally distributed and, therefore, were compared using Wilcoxon’s nonparametric tests. Percent cancer measurements also were compared for men with organ confined versus nonorgan confined cancer in both groups.
TABLE2 Unilateral versus bilateral organ confined cancer in men wtth hereditary disease and controls No ConfinedTotal No t l r ) Ca Group
Bilat Ca
p Value
0.06 21/36 (58) 12/14 (86) Control 25/39 ( 64 ) 0.08 Hereditary 10/11(91) There was no significant difference between the hereditary and control groups.
TABLE3. Median percent organ confined versus nonorgan confined intraglandular tumor extent in men with hereditary prostate cancer and controls
RESULTS
There were 47 white men in each group, while 3 in the hereditary group and 2 in the control group were black, and 1 in the control group was Asian. Mean age plus or minus standard deviation at prostate cancer diagnosis was 61.3 2 6.4 years in the hereditary group compared to 61.4 2 6.2 in the control group ( p = 0.94). The prevalence of a suspicious digital rectal examination was similar in the hereditary (29 of 49 patients or 59%) and control (34 of 50, or 68%) groups (p = 0.36). Median serum PSA concentration was 6.8 ng./ml. (semi-interquartile range 2 4.4) in the hereditary group and 5.9 ng./ml. (semi-interquartile range 2 2.0) in the control group (p = 0.92). The pathological characteristics of the cancers in both groups are shown in table 1. The rate of organ confined cancer was approximately the same in both groups (70 versus 66%).Two men in each group demonstrated seminal vesicle invasion. Two men in the hereditary group had metastatic cancer within lymph nodes compared to none in the control group. Of 50 cancers in the control group 36 (72%)were bilateral compared to 39 of 50 (78%)in the hereditary group (p = 0.48). Unilateral cancers tended to be more often pathologically organ confined than bilateral cancers in both groups, although this did not reach statistical significance (table 2). The intraglandular tumor extent, reported as percentage of specimen involvement, was approximately the same in both groups (11.4 versus 10.970, table 1). The intraglandular tumor extent was significantly higher in men with nonorgan confined compared to organ confined cancer in both groups (table 3). Mean Gleason score was significantly higher (6.2 2 1) in the control group compared to the hereditary group (5.6 2 0.9).The distribution of Gleason scores was notably different between the 2 groups. Of 50 men in the hereditary group 42 (84%)had Gleason score 5 or 6 tumors compared to only 29 of 50 (58%)in the control group (p = 0.004), while Gleason score 7 tumors were found in 17 (34%)and 3 (6%),respectively (p = <0.0001), and Gleason scores 8 to 10 (poorly differentiated) cancers in only 2 (4%)and 3 (6%),respectively.
Unilat Ca
Mean Pathological Stage Ca Group
Organ Confined Ca
Nonorgan Confined Ca
p Value
18.7 I 8.7 13-44) 7.1 z 4.4 (0.1-72.6) Control 0.05 9.5 t 6.3 ( 0 . M 1 . 2 ) 22.6 ? 14.9 (6.3-85.1, 0.001 Hereditary There was no significant difference between the hereditary and control groups.
tate cancer probands have a t least 1 other affected male relative.3.4. l3 Familial prostate cancer is the simple clustering of disease within families. Hereditary prostate cancer is believed to be a subtype of familial prostate cancer, and is characterized by either 3 successive generations being affected with the disease, a clustering of 3 or more men with prostate cancer in a nuclear family, or 2 men with early age at onset of disease (younger than 55 years) in the same family. The hereditary form of prostate cancer has been reported to comprise only 5 to 6% of all prostate cancer cases.7.13 It usually occurs 10 years earlier than sporadic prostate cancer, and is believed to be transmitted in a mendelian pattern of inheritance by a highly penetrant, autosomal dominant gene.7 It is also believed to account for 43%of all early onset prostate cancer^.^.^ Steinberg et al evaluated the characteristics of disease in 29 men with and 80 without a family history of prostate cancer, and found no difference in the clinical and pathological stages.3 Carter et a1 compared the clinical and pathological features of prostate cancers from 33 men with hereditary, 144 with familial and 496 with sporadic prostate cancer.7 They found no difference in serum PSA concentration, PSA density, prostate weight, Gleason score or rate of organ confined cancer among the 3 groups. However, it must be remembered that all patients in these 3 groups were treated with radical prostatectomy and, therefore, represent a select group. Bastacky et a1 performed whole-mount analysis on the prostatectomy specimens from 27 men with sporadic, 26 with familial and 28 with hereditary prostate cancer.9 The rates of organ confined disease, seminal vesicle invasion and lymph node involvement, as well as mean number of tumor nodules and mean tumor volume were not different among the 3 groups. The only significant differences were that small, mulDISCUSSION tifocal carcinomas in the familial and hereditary groups had Several studies demonstrated a clustering of prostate can- a lower Gleason score compared to those in the sporadic cer cases in certain families.’-6 Between 13 and 26%of pros- group, and a greater proportion of the sporadic prostate cancers were small, multifocal and associated with prostatic intraepithelial neoplasia. We found few differences in the characteristics of herediTABLE1. Pathological characteristics of hereditary prostate cancers tary versus sporadic prostate cancers. Mean serum PSA concompared to controls centration and prevalence of suspicious rectal examination Hereditary Group Control Group were no different in the 2 groups. The rate of organ confined I50 pts. 1 (50 pts. J cancer, seminal vesicle invasion and percent intraglandular Mean Gleaeon score r 5.6 r 0.9 (4-8) 6.2 r 1.014-9, 0.008 tumor extent were the same in both groups. The rate of SD (range) bilateral cancer, a gross indicator of multifocality, was not No. organ confined C d 35/50 1701 33/50 (661 0.69 different between the 2 groups. The only significant differtotal Nn. ( ? I Median ? (:a semi- 11.4 f 8.3 10.4-85.11 10.9 * R.9 ( 0 1-72.61 0.63 ence between our 2 groups, as in the study of Bastacky et aL9 interquartile range was that Gleason score was simificantlv lower amone men ( rangc I with hereditary prostate cancer. Also, there was a hvigher +
ANALYSIS OF HEREDITARY PROSTATE CANCER
proportion of Gleason score 7 disease in our sporadic cancer group, which may represent a selection bias since our control group was retrospectively selected based only on patient age and date of surgery. It should be emphasized that our men constitute a select group, since all were considered surgical candidates. I t is possible that if all stages of hereditary prostate cancer were compared to a full spectrum of sporadic prostate cancers significant clinical and/or pathological differences may be noted. Further studies are needed to examine this issue fully. Based on currently available data, it appears that after radical prostatectomy clinically localized, hereditary prostate cancers exhibit many of the same pathological characteristics as clinically localized sporadic prostate cancers. However, these pathological changes occur at earlier ages in men with hereditary prostate c a n ~ e r . ~Germline .~ deoxyribonucleic acid alterations in genes involved in cellular growth and differentiation that control the promotion and/or inhibition of aberrant cellular growth are most likely the basis for this early expression of disease in these select cases. Environmental factors may or may not influence these apparent genetic abnormalities. Further studies characterizing possible genetic aberrations are needed to delineate this matter. In conclusion, except for lower histological grade, there appear t o be no substantial clinical or pathological differences in hereditary versus sporadic prostate cancers.
1843
EDITORIAL COMMENT
Prostate cancer has been divided into 3 epidemiological categories (sporadic, familial and hereditary) based on the presence or absence of familial clustering of disease and patient age at onset (reference 7 in article). The majority of prostate cancers occur after age 65 years in the setting of no family history of disease (sporadic) and are believed to be associated primarily with environmentally induced or spontaneously occurring genetic alterations. Approximately 1 5 4 of men with prostate cancer have a family history of disease (familial prostate cancer). This familial aggregation is stronger than the familial aggregation present in breast and colon cancers, and may result from combinations of environmentally induced, spontaneous and inherited genetic alterations. Hereditary prostate cancer can be defined clinically but not yet by the inheritance of any specific genetic alteration. Since tumorigenesis is believed to result from a pathway of multiple genetic alterations, inheritance of an important early alteration along this pathway would more likely lead to the earlier age at onset of disease, compared to acquisition of the alteration later in life. Strong evidence for an inherited form of prostate cancer is based on 3 findings: 1) relatives of patients with prostate cancer younger than 55 years are at increased risk for cancer compared to relatives of older patients with prostate cancer, 2)there is stronger familial clustering among families with early age at onset of disease, and 3) the number of affected family members and age at onset of prostate cancer are the most important determinants of prostate cancer risk among relatives. Statistical analysis (segregation analysis) suggests that mendelian inheritance of an autosomal dominant gene best explains the observed familial clustering and early age a t onset of disease (reference 8 in article). REFERENCES The authors evaluated the clinical features of prostate cancer to 1. Morganti, G., Gianferrari, L. and Cresseri, A,: Recherches clini- determine if there are differences between hereditary and sporadic costatistiques et genetiques sur les neoplasies de la prostate. cancers. Hereditary prostate cancer is defined as prostate cancer Acta Generacae Med. Gemellogogiae, 6 304, 1956. affecting multiple family members ( 3 or more) within the same 2. Woolf, C. M.: An investigation of the familial aspects of carci- nuclear family, cancer in 3 generations (paternal or maternal linnoma of the prostate. Cancer, 1 3 739, 1960. eage) or cancer in 2 relatives before age 55 years. This is a clinical 3. Steinberg, G. S., Carter, B. S., Beaty, T. H., Childs, B. and definition based on observed disease clustering that was developed to Walsh. P. 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