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Pathological features of hereditary prostate
cancer.
Bastacky SI, Wojno KJ, Walsh PC, Carmichael MJ, Epstein
JI
Department of Pathology, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21287-2101.
J Urol 1995 Mar;153(3 Pt 2):987-92
The aim of this study was to characterize the pathological
features of hereditary prostate cancer, a recently recognized
variant of prostate cancer with an autosomal dominant
inheritance of a rare highly penetrant gene associated with
early onset of disease. We compared the histology at radical
prostatectomy of clinical stage T2 prostate cancer, including
its relationship to prostatic intraepithelial neoplasia, in
men with a family history of prostate cancer to those without
a family history of prostate cancer. Three cohorts
(hereditary, familial and sporadic) were identified based on
pedigree analysis. A hereditary subgroup (28 patients) met 1
of the following 3 criteria: 1) cluster of greater than 3
affected relatives within the nuclear family, 2) occurrence of
prostate cancer in each of 3 generations in either the proband
paternal or maternal lineage, or 3) a cluster of 2 relatives
affected at an early age of less than 55 years. This subgroup
was compared to an age-matched subgroup with family history of
prostate cancer (26 patients) yet the aforementioned
conditions for inclusion within the hereditary subgroup were
not met and to a sporadic subgroup without a family history of
prostate cancer (27 patients). All parameters were
statistically similar among the groups except that hereditary
and familial group multifocal tumors were of lower grade (p =
0.0001), sporadic cases had a greater proportion of small
multifocal cancers associated with prostatic intraepithelial
neoplasia (p = 0.02) and the familial group had a weaker
correlation between total tumor volume and grade. In
conclusion, our analysis failed to demonstrate substantial
pathological differences among hereditary, familial and
sporadic forms of prostate cancer. Rather, our data are
remarkable for the wide range of all parameters studied in
each group. Even the sporadic cases had features, such as
increased numbers of precursor lesions and tumor
multifocality, which in other organs are commonly associated
with either hereditary cancer or cancer arising in a field
effect due to diffuse exposure to a carcinogen.
Familial risk factors for prostate cancer.
Carter BS, Steinberg GD, Beaty TH, Childs B, Walsh PC
Department of Epidemiology, School of Hygiene and Public
Health, Johns Hopkins Medical Institutions, Baltimore,
Maryland 21205.
Cancer Surv 1991;11:5-13
This chapter describes the application of the genetic
epidemiological approach to the study of human prostate
cancer. We review the evidence for the familial clustering of
prostate cancer and the Mendelian nature of this aggregation.
The nature of this clustering is such that the closer
genetically a man is to an affected relative and the greater
number of relatives affected in a man's family, the greater
his risk of prostate cancer. A complex segregation analysis of
the 691 prostate cancer families showed that prostate cancer
clustering can be explained by Mendelian inheritance of a rare
autosomal gene producing prostate cancer at an early age. A
model of inherited prostate cancer in the setting of multistep
carcinogenesis is presented. The implications of these data
for clinicians who diagnose and treat prostate cancer are also
discussed.
Mendelian inheritance of familial prostate
cancer.
Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC
Department of Epidemiology, Johns Hopkins School of Hygiene
and Public Health, Baltimore, MD.
Proc Natl Acad Sci U S A 1992 Apr
15;89(8):3367-71
Previous studies have demonstrated familial clustering of
prostate cancer. To define the nature of this familial
aggregation and to assess whether Mendelian inheritance can
explain prostate cancer clustering, proportional hazards and
segregation analyses were performed on 691 families
ascertained through a single prostate cancer proband. The
proportional hazards analyses revealed that two factors, early
age at onset of disease in the proband and multiple affected
family members, were important determinants of risk of
prostate cancer in these families. Furthermore, segregation
analyses revealed that this clustering can be best explained
by autosomal dominant inheritance of a rare (q = 0.0030)
high-risk allele leading to an early onset of prostate cancer.
The estimated cumulative risk of prostate cancer for carriers
revealed that the allele was highly penetrant: by age 85, 88%
of carriers compared to only 5% of noncarriers are projected
to be affected with prostate cancer. The best fitting
autosomal dominant model further suggested that this inherited
form of prostate cancer accounts for a significant proportion
of early onset disease but overall is responsible for a small
proportion of prostate cancer occurrence (9% by age 85). These
data provide evidence that prostate cancer is inherited in
Mendelian fashion in a subset of families and provide a
foundation for gene mapping studies of heritable prostate
cancer. Characterization of genes involved in inherited
prostate cancer could provide important insight into the
development of this disease in general.
Family history and the risk of prostate
cancer.
Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC
Brady Urological Institute, Johns Hopkins Hospital,
Baltimore, MD 21205.
Prostate 1990;17(4):337-47
A case-control study was performed to estimate the relative
risk of developing prostate cancer for men with a positive
family history. Extensive cancer pedigrees were obtained on
691 men with prostate cancer and 640 spouse controls. Fifteen
percent of the cases but only 8% of the controls had a father
or brother affected with prostate cancer (P less than .001).
Men with a father or brother affected were twice as likely to
develop prostate cancer as men with no relatives affected. In
addition, there was a trend of increasing risk with increasing
number of affected family members such that men with two or
three first degree relatives affected had a five and 11-fold
increased risk of developing prostate cancer. Recognizing that
9-10% of U.S. men will develop prostate cancer in their
lifetime, men with a family history of prostate cancer should
be advised of their significantly increased prostate cancer
risk and should undergo appropriate screening measures for
this disease.
Familial patterns of prostate cancer: a
case-control analysis.
Spitz MR, Currier RD, Fueger JJ, Babaian RJ, Newell GR
Department of Cancer Prevention and Control, University of
Texas M.D. Anderson Cancer Center, Houston.
J Urol 1991 Nov;146(5):1305-7
Epidemiological data have not yet enabled physicians to
look beyond age and race to identify men at increased risk for
prostate cancer. We conducted a hospital-based case-control
study of familial patterns of prostate cancer with
self-reported data from a risk-factor questionnaire. There
were 385 patients with histologically confirmed prostate
cancer, and 385 race and age-matched (+/- 5 years) controls
with other cancers. Family history, available for 378 patients
and 383 controls, was positive for prostate cancer in 13.0%
versus 5.7%, respectively. The difference was significant at p
= 0.01. The over-all age-adjusted risk estimate for men with a
first-degree relative with prostate cancer was significantly
elevated (odds ratio of 2.41), as were the individual risk
estimates for having a father or brother with prostate cancer
(odds ratio of 2.24 and 2.66). Having a second-degree relative
(grandfather or uncle) with prostate cancer also conferred
elevated but not statistically significant risk. These data
accord well with the few previously published case-control
studies of familiarity of prostate cancer. On the basis of
these findings, one should consider recommending participation
in early detection programs for prostate cancer in a man whose
father or brother has had the disease.
Family history and prostate cancer risk.
Lesko SM, Rosenberg L, Shapiro S
Slone Epidemiology Unit, School of Public Health, Boston
University School of Medicine, Brookline, MA 02146, USA.
Am J Epidemiol 1996 Dec 1;144(11):1041-7
The authors examined the relation between family history of
prostate cancer and the risk of this cancer in a
population-based case-control study conducted in Massachusetts
between December 1992 and October 1994. Cases were all
incident cases of prostate cancer in men younger than 70 years
(n = 563); controls were men with no history of the disease
matched to the cases on age and town of residence (n = 703).
Prostate cancer risk was increased among men who reported a
history of this cancer in either their fathers or brothers
(odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.7-3.3).
Risk varied with the number of relatives affected and their
relationship to the case. For a history of prostate cancer in
one relative, the OR was 2.2 (95% CI 1.5-3.2); if two or more
relatives were affected, it was 3.9 (95% CI 1.7-5.2). For
prostate cancer in the father, the OR was 1.9 (95% CI
1.2-3.0); for prostate cancer in a brother, it was 3.0 (95% CI
1.8-4.9). Risk was inversely related to the subject's age and
to age at diagnosis of prostate cancer in his affected
relative. Among probands younger than 60 years, the OR was 5.3
(95% CI 2.5-12); for those 60-64 years of age, the OR was 2.7
(95% CI 1.3-5.5); and for those 65 years of age and older, the
OR was 1.6 (95% CI 1.0-2.5). For prostate cancer diagnosed in
a relative before age 65, the OR was 4.1 (95% CI 2.3-7.3); for
detection of the disease after age 74, the OR was 0.76 (95% CI
0.38-1.5). The association was present both among men with
local and advanced stage disease and among men whose prostate
cancer was detected either by screening or because of
symptoms. These data provide evidence that after controlling
for diet and other potential confounders, familial factors are
significantly associated with the risk of prostate cancer.
Combination of screening and preoperative endocrine
therapy: the potential for an important decrease in prostate
cancer mortality.
Labrie F, Cusan L, Gomez JL, Diamond P, Candas B
Prostate Cancer Research Unit, CHUL Research Center, Le
Centre Hospitalier de l'Universite Laval, Quebec,
Canada.
J Clin Endocrinol Metab 1995 Jul;80(7):2002-13
Prostate cancer is the second cause of cancer death in men
in the Western world; its medical and social impact is
comparable to that of breast cancer in women. Although it is
well recognized that early treatment is the only possibility
for reducing the high rate of death from prostate cancer,
screening and even early treatment are controversial issues
due mainly to arguments based upon old literature and lack of
awareness of the significant advances recently made in this
field. As it is well known that surgical removal of
organ-confined prostate cancer cures the disease, and it has
been demonstrated that annual screening with prostate-specific
antigen coupled with digital rectal examination followed, when
indicated, by transrectal ultrasonography of the prostate more
than doubles the proportion of organ-confined disease,
screening alone offers the possibility of at least doubling
the number of patients curable from prostate cancer or the
potential for a cure to an estimated 45% of prostate cancer
patients compared to a maximum of 20% in the absence of
screening. It is important to mention that screening does not
detect small and insignificant cancers, especially when random
biopsies are not performed routinely. The critical volume of
prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in
diameter, if spherical. Such a tumor should increase serum
prostate-specific antigen by 0.5 ng/mL. Contrary to the belief
that screening detects cancers that are too small, the fact is
that screening detects prostate cancer too late or nonorgan-
or nonspecimen-confined cancer in 35-50% of cases. There is,
thus, a narrow window when prostate cancer can be detected at
a curable stage, and even the best available screening
techniques cannot succeed in all cases. It should be mentioned
that the recent improvements of the technique of radical
prostatectomy have markedly improved the acceptability of
surgery. Concerning the recent publicity related to watchful
waiting, it is essential to indicate that all such reports
support the notion that prostate cancer grows slowly, but
steadily and irremediably, with increasing malignancy and risk
of distant metastases and death if sufficient time is allowed.
Another serious limitation of watchful waiting is that the
available prognostic factors have a large margin of error and
cannot predict with certainty the rate of progression of the
tumor.
Diagnosis of advanced or noncurable prostate cancer
can be practically eliminated by prostate-specific
antigen.
Labrie F, Candas B, Cusan L, Gomez JL, Diamond P, Suburu R,
Lemay M
Prostate Cancer Clinical Research Unit, CHUL Research Center,
Quebec, Canada.
Urology 1996 Feb;47(2):212-7
OBJECTIVES: To determine the percentage of localized and
potentially curable prostate cancers diagnosed at follow-up
screening visits compared with the first screening visit.
METHODS: Within the context of a prospective screening
study performed in randomly chosen men aged between 45 and 80
years, up to 6-year follow-up screening visits have been
performed with serum prostate-specific antigen (PSA)
measurement and digital rectal examination (DRE) followed by
transrectal ultrasonography of the prostate when PSA or DRE is
abnormal.
RESULTS: Of the 117 prostate cancers diagnosed at 14,554
annual follow-up visits, only 1 cancer (0.9%) was metastatic
compared with 8% (26/322) at 8029 first visits. Moreover, 97%
of the cancers detected at follow-up visits could be
identified by PSA alone compared with 86% at first visit. The
incidence of 0.8% per year during 15 years of screening
between the ages of 55 and 70 years would diagnose localized
prostate cancer in 12% of the population, a value not too
different from the 10% diagnosed with prostate cancer during
life-time in the absence of screening.
CONCLUSIONS: The present data show that annual screening
with PSA diagnoses clinically localized prostate cancer in
more than 95% of cases, thus almost completely eliminating the
diagnosis of metastatic prostate cancer. Moreover, the number
of prostate cancers diagnosed is not significantly increased
by screening.
Evaluation of prostAsure index in the detection of
prostate cancer: a preliminary report.
Babaian RJ, Fritsche HA, Zhang Z, Zhang KH, Madyastha KR,
Barnhill SD
Department of Urology, University of Texas M. D. Anderson
Cancer Center, Houston 77030, USA.
Urology 1998 Jan;51(1):132-6
OBJECTIVES: Although prostate-specific antigen (PSA) has
revolutionized the detection of prostate cancer, it has
definite limitations with respect to its clinical sensitivity
and specificity. Because a substantial number (20% to 40%) of
men undergoing radical prostatectomy have a PSA level of 4.0
ng/mL or less, any new test offering diagnostic improvement
must perform well in patients whose PSA level is less than or
equal to 4.0 ng/mL, as well as in patients whose PSA is
greater than 4.0 ng/mL. The performances of two tests, the
ProstAsure index and the percent free PSA test, were evaluated
in detecting cancer.
METHODS: We retrospectively analyzed serum samples from 225
men who were grouped into three categories: 94 men who had a
normal digital rectal examination and a serum PSA level of 4.0
ng/mL or less, 77 men who were clinically suspected of having
benign prostatic hyperplasia (BPH) with a serum PSA level of
4.0 ng/mL or less, and 54 men with localized prostate cancer.
The PSA assays were performed using the Hybritech and Tosoh
assays and the ProstAsure index was determined by Global
Health Net, Savannah, Ga. Receiver operator characteristic
(ROC) curves were constructed to evaluate the performance of
these two tests, and the areas under the curve were compared
for significance.
RESULTS: The sensitivity and specificity of detecting
prostate cancer using ProstAsure were 93% and 81%,
respectively. Using a cutoff value of 15%, the sensitivity and
specificity of detecting cancer for percent free PSA were 80%
and 74%, respectively (sensitivity increased to 93% and
specificity to 59% for free PSA at 19%). In men with a total
serum PSA level of 4.0 ng/mL or less, ProstAsure had a lower
false-positive rate compared to free PSA level at 19% for men
with or without clinical BPH as well as for men without
clinical BPH using a 15% free PSA threshold. ProstAsure left
fewer cancers undetected (7%) compared to free PSA at the 15%
cutoff (20%).
CONCLUSIONS: In this study of selected men, ROC curve
analysis shows a statistically significant advantage in
performance (P = 0.0023) for the ProstAsure index compared to
free PSA in detecting prostate cancer.
Prostate cancer detection in men with serum PSA
concentrations of 2.6 to 4.0 ng/mL and benign prostate
examination. Enhancement of specificity with free PSA
measurements.
Catalona WJ, Smith DS, Ornstein DK
Division of Urologic Surgery, Department of Surgery,
Washington University School of Medicine, St. Louis, Mo 63110,
USA.
JAMA 1997 May 14;277(18):1452-5
OBJECTIVE: To determine the detection rate of prostate
cancer in a screening population of men with prostate-specific
antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign
prostate examination, to assess the clinicopathological
features of the cancers detected, and to assess the usefulness
of measuring the ratio of free to total PSA to reduce the
number of prostatic biopsies.
DESIGN: A community-based study of serial screening for
prostate cancer with serum PSA measurements and prostate
examinations.
SETTING: University medical center.
SUBJECTS: A total of 914 consecutive screening volunteers
aged 50 years or older with serum PSA levels of 2.6 to 4.0
ng/mL who had a benign prostate examination and no prior
screening tests suspicious for prostate cancer, 332 (36%) of
whom underwent biopsy of the prostate.
MAIN OUTCOME MEASURES: Cancer detection rate, clinical and
pathological features of cancers detected, and specificity for
cancer detection using measurements of percentage of free
PSA.
RESULTS: Cancer was detected in 22% (73/332) of men who
underwent biopsy. All cancers detected were clinically
localized, and 81% (42/52) that were surgically staged were
pathologically organ confined. Ten percent of the cancers were
clinically low-volume and low-grade tumors, and 17% of those
surgically staged were low-volume and low-grade or moderately
low-grade tumors (possibly harmless). Using a percentage of
free PSA cutoff of 27% or less as a criterion for performing
prostatic biopsy would have detected 90% of cancers, avoided
18% of benign biopsies, and yielded a positive predictive
value of 24% in men who underwent biopsy.
CONCLUSIONS: There is an appreciable rate of detectable
prostate cancer in men with serum PSA levels of 2.6 to 4.0
ng/mL. The great majority of cancers detected have the
features of medically important tumors. Free serum PSA
measurements may reduce the number of additional biopsies
required by the lower PSA cutoff.
Prospective longitudinal evaluation of men with
initial prostate specific antigen levels of 4.0 ng./ml. or
less.
Harris CH, Dalkin BL, Martin E, Marx PC, Ahmann FR
Section of Urology, University of Arizona College of Medicine
and Tucson Veterans Affairs Medical Center, USA.
J Urol 1997 May;157(5):1740-3
PURPOSE: We evaluated the 3-year longitudinal changes in
serial serum prostate specific antigen (PSA) levels in men
with an initial PSA of 4.0 ng./ml. or less and no suspicion of
prostate cancer.
MATERIALS AND METHODS: A total of 760 men with an initial
PSA of 4.0 ng./ml. or less plus a normal or suspicious digital
rectal examination and a benign prostate biopsy was enrolled
into an every 4-month PSA monitoring study.
RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml.
or less only 3 (0.5%) had a persistently abnormal PSA for 3
years and 1 cancer (0.2%) was detected, and 48 men had a PSA
velocity of 0.8 ng./ml. per year or more at year 1 but only 1
(2%) had a persistent rate of increase (2.4 ng./ml. Per year)
at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85
had an abnormal PSA but only 37 (43%) met the criteria for
biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the
201 men 24 had a PSA velocity of 0.8 ng./ml. Per year or more
at year 1 but only 4 had persistence for 3 years. All 4 men
had cancer but they were identified as at high risk by PSA
criteria.
CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at
low risk for an abnormal PSA or cancer within 3 years and
annual monitoring may not be necessary. However, annual
monitoring is clinically useful in men with an initial PSA of
2.1 to 4.0 ng./ml. Also, serial monitoring with interval
testing in men whose PSA becomes greater than 4.0 ng./ml. Is
beneficial in identifying a high risk group requiring biopsy.
Finally, PSA velocity did not add further to cancer detection
in this population.
Systematic 5 region prostate biopsy is superior to
sextant method for diagnosing carcinoma of the prostate.
Eskew LA, Bare RL, McCullough DL
Department of Urology, Bowman Gray School of Medicine of Wake
Forest University, Winston-Salem, North Carolina, USA.
J Urol 1997 Jan;157(1):199-202; discussion 202-3
PURPOSE: The number of patients undergoing prostate biopsy
has dramatically increased due to prostate specific antigen
screening. The low specificity of this screening tool requires
prostate biopsy for diagnosis of prostate cancer. The sextant
biopsy technique has been used widely with success in
diagnosing carcinoma of the prostate. However, concern has
arisen that the original sextant method may not include an
adequate sampling of the prostate. For many years we have used
a method of prostate biopsy that, in addition to sextant
biopsies, takes additional biopsies in a systematic fashion,
which we call the 5 region prostate biopsy. We conducted a
prospective study to determine if our 5 region prostate biopsy
technique significantly increases the chances of finding
carcinoma of the prostate compared to the sextant biopsy
technique.
MATERIALS AND METHODS: A total of 119 patients underwent
transrectal ultrasound guided needle biopsy of the prostate.
In addition to sextant biopsies, cores were taken from the far
lateral and mid regions of the gland. Pathological findings of
the additional regions were compared to those of the sextant
regions.
RESULTS: Of the 48 patients with prostate cancer 17 (35%)
had carcinomas only in the additional regions, which would
have remained undetected had the sextant biopsy technique been
used alone (p < 0.05). Of these additional cancers 83% had
Gleason scores of 6 or more.
CONCLUSIONS: We introduce the 5 region technique of
prostate biopsy as a means of significantly increasing the
diagnostic yield of prostate biopsy in finding carcinoma of
the prostate. We have found this technique to be safe,
efficacious and superior to the sextant method of biopsy in
identifying prostate cancer at an early but significant stage.
The greatest use of the 5 region biopsy technique is in
patients who have prostate specific antigen levels between 4
and 10 ng./ml.
Family history of breast cancer as a predictor for
fatal prostate cancer.
Rodriguez C, Calle EE, Tatham LM, Wingo PA, Miracle-McMahill
HL, Thun MJ, Heath CW Jr
American Cancer Society, Epidemiology and Surveillance
Research, Atlanta, GA 30329-4251, USA.
Epidemiology 1998 Sep;9(5):525-9
To examine the relation between family history of breast
cancer in a mother or sister and a man's risk of fatal
prostate cancer, we analyzed data from a prospective mortality
study of adult men in the United States. During 12 years of
follow-up, there were 3,141 deaths from prostate cancer in a
cohort of 480,802 men who were cancer-free at study entry in
1982. Results from Cox proportional hazards models, adjusted
for other risk factors, showed a modest increased risk of
fatal prostate cancer associated with a family history of
breast cancer (in the absence of a family history of prostate
cancer) [rate ratio (RR) = 1.16; 95% confidence interval (CI)
= 1.01-1.33]. The association was stronger among men younger
than 65 years of age whose relatives were diagnosed with
breast cancer before age 50 years (RR = 1.65; 95% CI =
0.88-3.10) and among Jewish men (RR = 1.73; 95% CI =
1.00-2.97). The increased risks observed in these subgroups
may reflect genetic alterations underlying familial clustering
of prostate and breast cancer.
Genetic epidemiology of prostate cancer in the Utah
Mormon Genealogy.
Cancer Surv 1:47-69, 1982.
No abstract.
Dietary phytoestrogens and prostate cancer.
Proc Annu Meet Am Assoc Cancer Res 36:687, 1995.
No abstract
Familial clustering of cancers of the breast and
prostate in a population-based sample of postmenopausal
women.
Proc Annu Meet Am Assoc Cancer Res 35:A1724,
1994.
No abstract.
Hereditary prostate cancer: epidemiologic and
clinical features.
Carter BS, Bova GS, Beaty TH, Steinberg GD, Childs B, Isaacs
WB, Walsh PC
Department of Urology, Johns Hopkins Medical Institutions,
Baltimore, Maryland 21287-2101.
J Urol 1993 Sep;150(3):797-802
No abstract.
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