OF HEPATITIS C AND PROSTATE CANCER, INVERSE CORRELATION OF BASAL CELL
HYPERPLASIA OR PROSTATITIS AND EPIDEMIC SYPHILIS OF UNKNOWN DURATION
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TARANG SAFI, WILLIAM M. BRIGGS, MURRAY D. SCHWALB
and Mental Health Center, Department of Urology, New York Medical College,
Valhalla, NY, USA
Vol. 37 (2): 223-230, March - April, 2011
The accuracy of prostate specific antigen (PSA) to detect prostate cancer
has not yet been determined. Autopsy evidence suggests one-third of men
have evidence of prostate cancer. Correlation between prostate cancer
and sexually transmitted infection is indeterminate.
Materials and Methods: A retrospective database
was created of all men who underwent transrectal ultrasound guided prostate
biopsy over 3 years. Men were 49% African or African Caribbean, and 51%
Central or South American. Information about prostate specific antigen,
cholesterol, hepatitis A, B and C, human immunodeficiency virus, syphilis,
tuberculin skin testing and histology were collected.
Results: Hepatitis C antibody detection
correlated with prostate cancer OR 11.2 (95% CI 3.0 to 72.4). The odds
of prostate cancer increased annually (p = 0.0003). However, no correlation
was found between prostate cancer and the following: PSA, biopsy date,
repeat biopsy, more than 12 cores at biopsy, total cholesterol, high density
lipoprotein, triglycerides, low density lipoprotein, risk measure reported
with free and total PSA, hepatitis B surface antibody, high grade prostatic
intraepithelial neoplasia or atypical small acinar proliferation. Histologic
prostatitis and basal cell hyperplasia were inversely correlated with
prostate cancer. Syphilis of unknown duration occurred in 17% of men with
indeterminate correlation to prostate cancer.
Conclusion: In inner city men of African
and African-Caribbean, or Central and South American descent, prostate
specific antigen levels did not correlate with prostate cancer. Hepatitis
C antibody detection correlates significantly with prostate cancer. One
prostate biopsy is sufficient to diagnose statistically significant prostate
cancer. Histologic prostatitis and basal cell hyperplasia decrease odds
of prostate cancer. Atypical small acinar proliferation may not correlate
to prostate cancer and is pending further investigation. Men should be
screened for epidemic syphilis of unknown duration.
words: prostatic neoplasm; hepatitis c antibodies; biopsy; prostate;
syphilis; prostate specific antigen
Int Braz J Urol. 2011; 37: 223-30
The second leading cause of cancer death in men is prostate cancer (1).
Prostate-specific antigen (PSA) testing, digital rectal examination and
family history are the mainstays of screening (2). The accuracy of PSA
to detect prostate cancer has not been determined (2-9). Combining digital
rectal examination with PSA testing has not been shown to increase survival
(10). Autopsy evidence suggests nearly one-third of men have evidence
of prostate cancer of unknown clinical significance (11). There are indeterminate
correlations between prostate cancer and sexually transmitted infections
Objectives: A retrospective review was conducted
on all men who underwent transrectal ultrasound guided prostate biopsy
(TRPB) at an inner city hospital over 3 years to identify potential risk
factors for prostate cancer and improve selection criteria for TRPB.
MATERIALS AND METHODS
retrospective database was created of all men who underwent transrectal
TRPB at Lincoln Medical and Mental Health Center from January 1, 2007,
through December 31, 2009. The cross-sectional study “Risks, Benefits
and Selection Criteria for Transrectal Ultrasound Guided Prostate Biopsy:
A Study of Men in the Bronx Community”, was approved by the Institutional
Review Board. According to 2006 statistics, the patient population consisted
of approximately 49% African or African Caribbean, and 51% Central or
South American patients. Information about PSA, cholesterol, hepatitis
A, B and C, human immunodeficiency virus (HIV), syphilis, tuberculin skin
testing and histology were collected. Histology specimens suspicious for
or containing adenocarcinoma underwent additional central pathology review
at Memorial Sloan-Kettering Cancer Center. Completeness and accuracy of
data entry into the database was ensured by double data entry and follow-up
comparison with additional random checks. Receiver operating and skill
curve analysis (ROC) were used to interpret PSA data. Skill curves were
used to assess PSA for optimal diagnosis cut-off. Skill measure compared
the diagnostic ability of PSA beyond random guessing. Skill-based cut-off
was equivalent to the cut-off indicated by optimizing posterior odds in
accordance with Bayesian decision theory. Confidence intervals for the
cut-off point were constructed (13,14). Chi-squared analysis was used
to interpret serologic data. Standard statistical methods were used to
report confidence intervals. Logistic regression was used to analyze prostate
cancer risk and age.
was no correlation between PSA levels and prostate cancer in 462 of 473
men with 2899 PSA results (range 38.8 to 91.7 years). Eleven men were
excluded from PSA analysis due to prior prostate cancer diagnoses with
treatment. The American Cancer Society recommendation for prostate biopsy
in men with PSA level 4 ng/mL or more (2) served as a reference point
for analysis (Figure 1A-C).
An estimate of the frequency of PSA values
for men with and without cancer was made. Considerable overlap demonstrated
PSA values were equivalent for men with and without cancer. Cancer was
not more common than non-cancer until PSA values surpassed 150 ng/mL (Figure-1A).
Standard receiver operating characteristic (ROC) plot confirmed PSA could
not predict cancer (Figure-1B). The skill curve suggested the cut off
value for PSA to diagnose prostate cancer was not appreciated until levels
were above 400 ng/mL. Negative skill indicated PSA usefulness to detect
prostate cancer below 400 ng/mL was worse than chance diagnoses (Figure-1C).
The latest free and total PSA values for
111 patients were used to assess the risk value reported with these tests.
Risk measurement was not found to be predictive of cancer OR 1.01 (95%
CI 0.98 to 1.06). The risk of prostate cancer increased annually with
age (p = 0.0003, Table-1).
was no correlation observed between cholesterol and prostate cancer in
359 of 473 men with available test results: Total cholesterol OR 1.0 (95%
CI 0.99 to 1.01); high density lipoprotein OR 1.0 (95% CI 0.99 to 1.02);
triglycerides OR 1.0 (95% CI 0.99 to 1.01); low density lipoprotein OR
1.0 (95% CI 0.99 to 1.01).
all patients had serologic markers available for analysis. This limitation
is acknowledged. Hepatitis C antibody testing in 172 men correlated with
prostate cancer OR 11.2 (95% CI 3.0 to 72.4).
Inconclusive correlation was observed as
follows: Syphilis IgG testing with reflex microhemagglutination Treponema
pallidum test (MHATP) in 404 men OR 1.8 (95% CI 1.1 to 3.0); rapid plasma
reagin test in 243 men OR 1.8 (95% CI 0.9 to 3.7); HIV antibody testing
in 222 men OR 1.6 (95% CI 0.3 to 8.2).
Hepatitis B surface antibody testing in
176 men and tuberculin skin testing with purified protein derivate in
223 men did not correlate with prostate cancer OR 0.9 (95% CI 0.5 to 1.8)
and OR 1.2 (95% CI 0.7 to 2.1), respectively. Hepatitis B surface antibody
measurements after documentation of vaccination were excluded from analysis
in 3 patients.
There was not enough data to perform statistical
correlation for hepatitis B surface antigen, hepatitis B e antigen or
antibody, hepatitis B core antibody or antigen, hepatitis B polymerase
chain reaction or hepatitis A antibodies.
the 3 year study period 473 men had 537 TRPBs. All TRPB histology reports
at our institution for 7 years prior to the study period were examined
for a total of 717 TRPBs in 473 men. There was no correlation between
the date of TRPB and prostate cancer diagnosis OR 0.64 (95% CI 0.49 to
There was no correlation between prostate
cancer and atypical small acinar proliferation (ASAP) OR 0.88 (95% CI
0.48 to 1.55) or high grade prostatic intraepithelial neoplasia (HGPIN)
OR 0.99 (95% CI 0.33 to 2.72) on initial or repeat TRPB. With initial
or repeat biopsy there was an inverse correlation between prostate cancer
and prostatitis OR 0.35 (95% CI 0.21 to 0.56) with a similar result between
prostate cancer and basal cell hyperplasia (BCH) OR 0.30 (95% CI 0.09
Prostate cancer was found in 37.8% (175/463)
of undiagnosed men as follows: First TRPB 31.7% (147/463), second TRPB
diagnosed an additional 4.75% (22/144), third 0.6% (3/60) and fourth 0.6%
(3/22). No prostate cancers were detected on fifth, sixth, seventh or
eighth biopsy. There was no correlation between repeat TRPB and finding
statistically significant prostate cancer OR 0.64 (95% CI 0.49 to 0.81).
Our institution used a protocol of 12 cores as the minimum standard number
of specimens during the study period. There was no correlation between
increased number of prostate specimens over 12 and finding statistically
significant prostate cancer on initial TRPB OR 0.93 (95% CI 0.89 to 0.97)
or repeat TRPB OR 0.95 (95% CI 0.89 to 0.99).
Men were staged according to the current
American Joint Committee on Cancer staging system. Staging information
was available for 167 men: Stage I 1.2% (2/167, average age 78.4 years);
stage II 85.6% (143/167, age range 42.3 to 86.7, average age 66.0 years);
stage III 6.0% (10/167, age range 54.0 to 70.3, average age 63.1 years);
and stage IV 7.8% (13/167, age range 56.6 to 86.5, average age 65.7 years).
Two of the men included as stage II had suspicious findings for metastatic
lesions. One of the patients had diffuse spinal uptake on bone scan without
evidence of lesions on MRI. Another man had a lytic lesion on the iliac
crest, which had a non-diagnostic biopsy, and was thought to be a bone
island by radiographic interpretation. He also had a sacral mass thought
to represent a schwannoma. Of note, 28 men classified as stage II had
prostatectomy, with 39.3% (11/28) reclassified after surgery: 10 stage
III and 1 stage IV.
population studied was considered vulnerable secondary to educational
and economic disparities and consisted of approximately 49% African or
African Caribbean, and 51% Central or South American men. This cross-sectional
study was instituted as a quality control measure. One objective was to
identify PSA selection criteria for improved screening. All men had PSA
testing. The utility of PSA to predict prostate cancer was worse than
chance diagnosis (Figure 1A-C). A recent longitudinal study also supports
this observation (15).
PSA testing has not achieved positive and
negative likelihood ratios typically required to meet statistical standards
for population based screening tests (15). However, American Cancer Society
guidelines consider PSA of 4.0 ng/mL a reasonable threshold for further
evaluation and suggests that providers consider individualized decision
making when PSA levels fall in the indeterminate range of 2.5 to 4.0 ng/mL
(2). Evidence-based medicine has proven that prostate cancers, including
high grade cancers are not rare in men with PSA levels below 4.0 ng/mL
(16). Autopsy observation suggests nearly one-third of men under the age
of 80 have prostate cancer of unknown significance (11). These findings
suggest prostate cancer occurs ubiquitously.
The hypothesis that prostate cancer is caused
by an ubiquitous or communicable factor is not novel. A total of 37.8%
of men were diagnosed with prostate cancer. Syphilis of unknown duration
occurred in 17% (69/404) of men tested suggesting an epidemic. Indeterminate
correlation to prostate cancer was congruent with previously published
data (17). Increased rates of both syphilis (18) and prostate cancer (19)
in Jamaica suggested a circumstantial correlation, although sexually transmitted
infections have been extensively studied without an identified causative
agent (12). Hepatitis C is communicable by sexual contact and has not
been established as a risk factor for prostate cancer, although there
are no studies which have investigated hepatitis C antibody in a prospective
trial. This observational study suggests the odds ratio for hepatitis
C antibody is 11.2 (95% CI 3.0 to 72.4). This finding suggests a common
molecular modulation may exist between hepatitis C and prostate cancer.
This correlation is novel and would be best investigated by prospective
trials and experiments focusing on immune modulation. Not all men had
hepatitis C testing since this was an observational trial. It is possible
that some men would have had more serologic testing if their physician
suspected cancer and this limitation is acknowledged.
The risk of prostate cancer increased with
age OR 1.03 (95% CI = 1.02 to 1.05, p = 0.0003). The odds ratio is multiplicative
and applies to each year of age. For instance, a man 20 years old has
odds of 20*1.03 (minus a constant) and a man 60 years old has odds 60*1.03
(minus a constant). Overall, a man 60 years old will have three times
the odds of a man 20 years old (Table-1).
One 12 core biopsy was sufficient to detect
prostate cancer. Additional cores or repeat TRPBs were unlikely to find
statistically significant cancers. Although not statistically significant,
15% (22/144) of second biopsies diagnosed prostate cancer, a finding of
clinical significance. Recent evidence which suggests 48 men with prostate
cancer need to be treated to prevent 1 prostate cancer associated death
(20) implies 461 repeat TRPBs would be needed to prevent 1 death.
There was no correlation on initial or repeat TRPB between prostate cancer
and high grade prostatic intraepithelial neoplasia supporting recommendations
for repeat biopsy on these men is not indicated (21). However, lack of
correlation between atypical small acinar proliferation and prostate cancer
in these men on initial or repeat biopsy was incongruent with current
recommendations (21). Specimens suspicious for adenocarcinoma receive
a central pathology review at Memorial Sloan-Kettering Cancer Center.
Specimens containing ASAP are not reviewed by an external institution.
On first biopsy ASAP was seen in 25.5% of men (118/463). Cancer and ASAP
were seen on first biopsy in 7.6% of men (35/463). In men with ASAP on
first biopsy, cancer was seen on second biopsy in 17.3% of men (9/52)
which was not statistically different from the overall cancer rate on
second biopsy of 15.2% (22/144). We will continue to investigate this
discrepancy by obtaining external histology review and continuing data
collection to generate a larger number of patients.
Inverse correlation of microscopic inflammation
or prostatitis with prostate cancer confirmed previous observations (22).
Statistically, prostatitis showed some protection against prostate cancer
as 21% of men in this study with prostatitis had prostate cancer, which
was lower than the overall rate of 37.8% of men diagnosed. This finding
while statistically significant is not clinically satisfactory given a
rate of cancer of 21% in men with this finding. A similar relationship
between basal cell hyperplasia (BCH) and prostate cancer was observed.
Statistically, BCH had an inverse correlation to prostate cancer, however,
16% of men with BCH had prostate cancer, which again was much lower than
the overall rate of 37.8% in this population. Basal cell hyperplasia has
been linked to a rare form of prostate cancer (23) and the clinical importance
of this finding is not understood. Overall, lower rates of prostate cancer
were seen in men with prostatitis and BCH, suggesting there is some protective
inner city men of African, African-Caribbean, South or Central American
descent, PSA levels do not correlate with prostate cancer. One 12 core
prostate biopsy can diagnose statistically significant cases of prostate
cancer. Repeat prostate biopsy was positive in 15% of cases, a finding
clinically, but not statistically significant. High grade prostatic intraepithelial
neoplasia on initial or repeat prostate biopsy does not correlate statistically
to prostate cancer. On going investigation is pending concerning lack
of correlation concerning prostate cancer and atypical small acinar proliferation.
Prostatitis and basal cell hyperplasia have an inverse correlation with
prostate cancer. Men should be screened for epidemic syphilis of unknown
duration. The presence of prostate cancer is increased with hepatitis
C antibody detection. Prospective trials and experiments focusing on hepatitis
C antibody detection and immune modulation are needed to investigate this
Ana Osansky for her excellent record keeping, and librarian Inna Lipnitskaya
for her support.
CONFLICT OF INTEREST
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August 10, 2010
Dr. Annika Krystyna
Lincoln Medical and Mental Health Center
Department of Urology, 2A7
c/o Ana Osansky
234 E. 149th Street
New York, NY 10452, USA
Fax: (718) 579-4673
this manuscript by Krystyna et al., the authors conducted a retrospective
review of all men who underwent a transrectal ultrasound guided prostatic
biopsy at a community hospital in New York over a 3 year period. The study
population consisted predominantly of American men of African/African-Caribbean
or South/Central American descent. The authors concluded that among inner
city men of such ethnic background, prostate specific antigen (PSA) levels
did not correlate with prostate cancer. Hepatitis C antibody detection
correlated significantly with the detection of prostate cancer. Furthermore,
the authors concluded that one prostate biopsy is sufficient to diagnose
significant prostate cancers in the majority of their study population.
Atypical small acinar proliferation (ASAP) did not correlate with prostate
cancer. The authors as well propose that men should be screened for epidemic
syphilis of unknown duration. The pathophysiology underlying prostate
cancer remains poorly understood particularly in such minority groups.
In this regard, I applaud the efforts of the authors in addressing this
important clinical question. This intriguing possible association between
hepatitis C and prostate cancer will require validation in subsequent
prospective studies and a causal relationship between hepatitis C and
prostate cancer must be demonstrated for this hypothesized association
to have clinical merit. However, several conclusions made by the authors
namely the adequacy of a single prostate biopsy to diagnose prostate cancer
in the majority of patients, lack of correlation between PSA and prostate
cancer, and the inability to demonstrate an association between ASAP and
prostate cancer may all reflect their retrospective study design, study
population characteristics, and limited statistical power in view of their
relatively small sample size.
As we strive to advance the field of cancer
research, one must always critically evaluate the results and conclusions
of such studies which must be contrasted to those of prior peer reviewed
scientific papers on the subject matter and in reference to our fundamental
understanding of cancer biology. Failure to do so may result in confounding
clinical messages and conclusions.
Assistant Professor of Urologic Oncology
H. Lee Moffitt Cancer Center
Tampa, FL, USA