PROSTATIC CANCER Prostate specific antigen (PSA).

Università degli Studi di Pavia
AA 2010 - 2011
Corso Integrato di Clinica Medica
Insegnamento di Oncologia Medica
IL TUMORE DELLA PROSTATA. I.
BIOLOGIA E CLINICA
Prof. Alberto Riccardi
BENIGN AND MALIGNANT DISEASE
IN PROSTATE. I.
* with aging,↑
frequency of both benign and
malignant prostatic diseases, from uncontrolled
growth of both stromal and epithelial components;
- from autopsies, hyperplastic and malignant
changes in > 90 and > 70%, respectively, in men >
70 yrs (not diagnosed during lifetimes);
* high prevalence of these diseases in elderly
population with competing causes of morbidity
and mortality mandates a risk - adapted approach
to diagnosis and treatment
BENIGN AND MALIGNANT DISEASE IN PROSTATE. II.
* risk - adapted approach to diagnosis and treatment
achieved by considering these diseases as series of
states;
* each state = distinct clinical milestone for which
intervention(s) recommended based on presence of risk
of developing symptoms or death from disease in given
time frame
BENIGN AND MALIGNANT DISEASE
IN PROSTATE. III.
* the high prevalence of prostate diseases, of
comorbid conditions and of competing causes of
death mandate careful consideration of risk / benefit
ratio of any proposed intervention:
* e.g., for benign proliferative disorders, symptoms
(urinary frequency, infection and potential for
obstruction) weighed against side effects and
complications of medical or surgical therapy;
* e.g., for prostate malignancies, risks of
developing disease, symptoms or death from cancer
balanced against morbidities of interventions
recommended and preexisting comorbid conditions
PROSTATE CANCER
ANATOMY
ANATOMY OF PROSTATE. I.
* in pelvis,
surrounded by rectum,
bladder,
dorsal and
periprostatic
venous complexes,
musculature of
pelvic wall,
urethral sphincter
(responsible for
passive urinary
control), pelvic plexus
and cavernous nerves
(innervating pelvic
organs and corpora
cavernosa)
ANATOMY OF PROSTATE. Ibis.
* in pelvis,
surrounded by rectum,
bladder,
dorsal and
periprostatic
venous complexes,
musculature of
pelvic wall,
urethral sphincter
(responsible for
passive urinary
control), pelvic plexus
and cavernous nerves
(innervating pelvic
organs and corpora
cavernosa)
ANATOMY OF PROSTATE. II.
- a peripheral (P) zone (from
which arise most PC), a
central (C) and a transition (T)
zone (were non - malignant
proliferation mainly occurs);
- anterior surface covered by
fibromuscular stroma
(UD = distal urethral segment; E =
ejaculatory duct stromal core)
T
T
ANATOMY OF PROSTATE. III.
* composed of branching
tubuloalveolar glands arranged
in lobules and surrounded by
stroma;
* glandular acinus (=
functional unit) including
(separated by basement
membrane):
- epithelial compartment
(epithelial, basal and
neuroendocrine cells), and
- stromal compartment
(fibroblasts and smooth muscle cells)
ANATOMY OF PROSTATE. IV.
* epithelial cells produce prostate specific antigen (PSA)
and prostate - specific acid phosphatase;
* both stromal and epithelial cells express androgen
receptors and depend on androgens for growth;
- testosterone = major circulating androgen, converted to
active form (dihydrotestosterone) by 5α - reductase
* paracrine growth regulatory signals between epithelial
and stromal cells contributes to growth of PC in primary and
metastatic sites
ANATOMY OF PROSTATE. V.
* changes in prostate size during two periods:
- in puberty → diffuse enlargement, and
- after 55 yrs → in focal regions in periurethral
area
ANATOMY OF PROSTATE. VI.
* most PC develop in peripheral zone
(often palpable by digital rectal
examination, DRE);
* non - malignant growth predominantly in
transition zone around urethra
EPIDEMIOLOGY
PROSTATIC CANCER
EPIDEMIOLOGY. I.
* most common cancer diagnosis and 2nd cause of cancer
death in men
INCIDENCE
MORTALITY
PROSTATIC CANCER
EPIDEMIOLOGY. II.
* in USA (2007), ~ 218,890 prostate cancers
diagnosed and 27,050 men died from prostate
cancer = paradox of management = although
prostate cancer 2nd leading cause of cancer deaths
in men, only 1 / 8 pts die of disease;
* absolute no. of prostate cancer deaths ↓ in past 5
yrs, ?due to widespread use of PSA - based
detection strategies
PROSTATIC CANCER
EPIDEMIOLOGY. III.
* diagnosed PC ↑ dramatically in early 90s from use
of serum prostate - specific antigen (PSA) (with
several “asymptomatic cancers” never producing
symptoms = lead - time bias);
* USA data: in 1996 = 352,000 (41,400 deaths) and
in 2004 = 230,000 (29,900 deaths) new diagnosed
cases;
* paradox = PC is 2nd cause of cancer deaths in
men → 8 : 1 ratio in incidence to PC - specific
mortality → majority of men do not die of PC
PROSTATIC CANCER
EPIDEMIOLOGY. IV.
Incidence and deaths
PROSTATIC CANCER
EPIDEMIOLOGY. V.
Incidence of and mortality from prostate cancer
in USA, with PSA for early diagnosis
PROSTATIC CANCER
EPIDEMIOLOGY. VI.
* incidence ↑ with advancing age (rare <
age 50) and ↑ among blacks than whites;
- for 50 - yr - old man, lifetime risk of
developing, of being diagnosed and of
dying of PC = 42, 9.5 and 2.9%, respectively
PROSTATIC CANCER
EPIDEMIOLOGY. VII. Incidence by age
SEER incidence rates 1973 - 1995
PROSTATIC CANCER
EPIDEMIOLOGY. VIII. Incidence and mortality by race
PROSTATIC CANCER
EPIDEMIOLOGY. IX.
* matched for age, in African - American
males ↑ no. of precursor prostatic
intraepithelial neoplasia (PIN, highly unstable
and typically multifoca) lesions and larger
tumors than in white males;
- ↑ levels of testosterone?;
- polymorphic variants of androgen receptor
gene? of cytochrome P450 C17 gene? of
steroid 5α - reductase type II (SRD5A2) gene?
PROSTATIC CANCER
EPIDEMIOLOGY. X.
- from epidemiology, risk of being diagnosed with
PC ↑ by a factor of 2 if one 1st - degree relative
affected and by 4 if ≥ 2 affected (from current
estimates, 40% of early - onset and 5 - 10% of all PC
are hereditary)
PROSTATIC CANCER
EPIDEMIOLOGY. XI.
* incidence of autopsy - detected cancers similar
around world, while incidence and deaths ≠ in
different parts of world and in different ethnic
groups;
- deaths / 100,000 men / yr: Sweden = 22; USA = 14;
Japan = 7;
* however, as for breast cancer in Asian women,
risk of prostate cancer in Asian men ↑ when they
move to Western environments (role for
environmental factors?)
PROSTATIC CANCER. EPIDEMIOLOGY. XII.
* favouring environmental factors cold include:
- high consumption of dietary fats, e.g., α - linoleic
acid) and polycyclic aromatic hydrocarbons (from
cooked red meats);
* protective factors could include:
- consumption of isoflavinoid genistein (in lupin
fava beans, soybeans, inhibiting 5α - reductase),
cruciferous vegetables (cauliflower, cabbage, cress,
bok choy, broccoli and similar green leaf vegetables,
containing isothiocyanate sulforaphan), retinoids
(e.g., lycopene in tomatoes), inhibitors of cholesterol
biosynthesis (e.g., statin drugs), antioxidants (α tocopherol, vitamin E) and selenium
PROSTATIC CANCER
EPIDEMIOLOGY. XIII.
* development of PC is multistep process;
- one early change = hypermethylation of GSTP1
(Glutathione S - Transferase P1) gene promoter
(playing important role in detoxification by
catalyzing conjugation of many hydrophobic and
electrophilic compounds with reduced
glutathione) → loss of function of a gene
detoxifiyng carcinogens
EPIGENETIC SILENCING OF GENE EXPRESSION
* DNA methyl - transferases carry
out methylation of CpG dinucleotides,
which triggers process of gene
silencing by binding methyl binding
demain and histone deacetylases
(HDAC) to bind to methylated DNA →
histone deacetylation and chromatin
condensation → loss of transcription
factor binding and repression of
transcription
silenced genes in
prostate cancer
PROSTATIC CANCER
EPIDEMIOLOGY. XIV.
* role for inflammation from finding that many
prostate cancers occur adjacent to a lesion
termed PIA (proliferative - inflammatory atrophy)
= a role for oxidative damage
PROSTATIC CANCER
EPIDEMIOLOGY.
XIVbis.
* role for
inflammation from
finding that many
prostate cancers
occur adjacent to
lesion termed PIA
(proliferative inflammatory atrophy)
= a role for oxidative
damage
PROSTATIC CANCER. EPIDEMIOLOGY. XV.
Risk in carriers and non carriers
of BRCA1 and BRCA2 mutations
PROSTATIC CANCER. EPIDEMIOLOGY. XVI.
Risk in carriers and non carriers of BRCA1 and BRCA2
mutations (by specific gene mutations)
PROSTATIC CANCER
EPIDEMIOLOGY. XVII.
Survival by time of diagnosis
DIAGNOSIS AND TREATMENT
BY CLINICAL STATE
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. I.
* prostate disease continuum can span decades, from
appearance of preneoplastic and invasive lesion
localized to prostate to metastatic lesion resulting in
symptoms and, ultimately, mortality;
- management at all points centered on “competing
risks” defined by considering disease as series of
clinical states
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. II.
* clinical states framework considers risk of morbidity
from enlarging but non - malignant gland, probability
that a clinically significant PC is present in individual
with or without urinary symptoms, and, for those with
PC diagnosis, probability of developing symptoms or
dying from disease
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. III.
* states operationally defined on basis of whether or
not cancer diagnosis established and, for those already
diagnosed, whether or not metastases detectable on
imaging studies and measured level of testosterone in
blood
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. IV.
* with this approach, an individual resides in only one
state and remains in that state until progression;
- at each assessment, decision to offer treatment and
specific form of treatment based on risk posed by
cancer, relative to competing causes of mortality present
in individual pt → more advanced the disease, greater
need for treatment
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. V.
* for individuals without cancer diagnosis, decision to
detect cancer based on probability that “clinically
significant” cancer be present;
- for pts with prostate cancer diagnosis, clinical state
model considers probability of developing symptoms or
dying from disease:
- e.g., pt with localized prostate cancer with all cancer
removed surgically remains in state of localized disease
as long as PSA remains undetectable
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. VI.
* time within a state = measure of efficacy of
intervention on natural history of disease (benign or
malignant in etiology and recognizing that impact may
not be assessable for yrs);
* as many men with active cancer not at risk for
metastases, symptoms or death state model also allows
≠ between “cure” (= elimination of all cancer cells =
primary therapeutic objective when treating most
cancers → “pt cured”) and “cancer control” (in which
tempo of illness modulated and symptoms controlled
until pt dies of other causes = “pt controlled”);
[“other causes” = equivalent therapeutically, from pt
standpoint, if pt not experienced symptoms of disease
or with treatment needed to control it]
DIAGNOSIS AND TREATMENT BY CLINICAL STATE. VII.
* management of PC unique;
- even with documented recurrence, immediate
therapy not always necessary
→ to be considered, as at time of diagnosis, need
for intervention based on tempo of illness → relative
risk : reward ratio of therapy
NO CANCER DIAGNOSIS
PREVENTION
PROSTATIC CANCER
PREVENTION
* several agents under investigation for their potential to ↓
risk of clinically significant prostate cancer;
- Prostate Cancer Prevention Trial = double - blinded,
randomized multicenter trial to investigate ability of
finasteride (5α - reductase inhibitor) to prevent development
of PC in men ≥ 55 yrs;
- PC detection rate = 18.4% (803 / 4364) for finasteride and
24.4% (1147 / 4692) for placebo - treated men;
- however, more of PC detected in finasteride group were
high - grade [37% (280 / 757) vs 22% (237 / 1068 cancers) for
placebo];
- no effect on survival detected;
* vitamin E and selenium (SELECT study) being tested as
preventive agents
DIAGNOSIS
PROSTATIC CANCER
* diagnosis of PC based on:
- symptoms and / or
- abnormal digital rectal examination (DRE)
and / or
-↑ serum PSA
SYMPTOMS
PROSTATIC CANCER
Symptoms. I.
* urologic history focused on symptoms of
outlet obstruction, continence, potency or
change in ejaculatory pattern (most frequent in
benign than in malignant prostate disease)
PROSTATIC CANCER
Symptoms. II. Obstructive symptoms.
* at diagnosis, both early and advanced PC may be
asymptomatic;
* ≠ benign proliferative disorders [early
encroaching urethra → symptoms of outlet
obstruction (hesitancy, difficult and intermittent
voiding, diminished stream, postvoid leakage,
incomplete emptying) and anatomic changes in
urinary apparatus];
* in symptomatic pt, history focused on urinary
tract to identify other causes of voiding dysfunction
PROSTATIC CANCER
Symptoms. III. Obstructive symptoms
* over time, resistance to flow of urine reduces
compliance of detrusor muscle, resulting in
obstructive complaints including:
- nocturia;
- difficulty in voiding;
- bladder instability;
- complete urinary retention (possibly
precipitated by infection, tranquilizing drugs,
antihistamines or alcohol)
PROSTATIC CANCER
Symptoms. IV. Obstructive symptoms
* in severe cases, bladder may be palpable;
- however, relationship between obstructive
signs and symptoms and prostate size not
straightforward (= a small gland does not
exclude significant blockage)
PROSTATIC CANCER
invading bladder,
peritoneum and rectum
LOCALLY ADVANCED
PROSTATIC CANCER
PROSTATIC CANCER
Symptoms. V. Irritative symptoms
* frequency, dysuria, or urgency occur in PC
but also with prostate calculi and with
infectious or inflammatory diseases (acute or
granulomatous prostatitis);
- differentiating PC from prostatitis usually
needs histology (with a biopsy performed
after trial of antibiotics);
* high suspicion for PC in all men > 40 yrs
PROSTATIC CANCER
Symptoms. VI. Evaluation
* self - administered American Urological
Association (AUA) Symptom Index
classifies symptoms as mild, moderate or
severe from 7 questions, useful as
baseline and in follow - up
AUA System Index
For AUA Symptom Score, circle one no. each line. I.
AUA Symptom Score
(Circle 1 Number on Each Line)
Not
at
All
Less than
1 Time in
5
Less than
Half the
Time
About
Half the
Time
More than
Half the
time
Almost
Always
Over the past month, how often you have had a sensation of
not emptying your bladder completely after you finished
urinating?
0
1
2
3
4
5
Over the past month, how often have you had to urinate again
less than 2 h after you finished urinating?
0
1
2
3
4
5
Over the past month, how often have you found you stopped
and started again several times when you urinated?
0
1
2
3
4
5
Over the past month, how often have you found it difficult to
postpone urination?
0
1
2
3
4
5
Questions to Be Answered
AUA System Index
For AUA Symptom Score, circle one no. each line. II.
AUA Symptom Score
(Circle 1 Number on Each Line)
Not
at
All
Less than
1 Time in
5
Less than
Half the
Time
About
Half the
Time
More than
Half the
time
Almost
Always
Over the past month, how often have you had a weak urinary
stream?
0
1
2
3
4
5
Over the past month, how often have you had to push or strain
to begin urination?
0
1
2
3
4
5
Over the past month, how many times did you most typically
get up to urinate from the time you went to bed at night until
the time you got up in the morning?
(0)
1 time
2 times
3 times
4 times
5 times
Questions to Be Answered
Sum of 7 circled numbers (AUA Symptom Score):
Note: AUA, American Urological Association.
Barry MJ et al: J Urol 148:1549, 1992. Used with permission. http://www.lww.com
AUA System Index
Circle one no. each line
PROSTATIC CANCER
Symptoms. VII. Late symptoms
* hematospermia or erectile dysfunction (especially
with tumor extended outside gland);
* pain secondary to bone metastases (but many pts
asymptomatic despite extensive spread);
- less common presentations (from extensive
disease): myelophthisic disorders, disseminated
intravascular coagulation, pulmonary emboli, spinal
cord compression, scrotal and / or lower extremity
lymphedema secondary to infiltration of pelvic
lymph nodes (extensive disease);
* % of diagnoses at late stages ↓ significantly from
PSA - based detection strategies
METASTASES FROM
PROSTATIC CANCER
BONE SCAN
BONE METASTASES
FROM PROSTATIC CANCER
(Christmas tree - like pattern)
BONE SCAN
BONE METASTASES FROM PROSTATIC CANCER
(Christmas tree - like pattern)
BONE METASTASES FROM PROSTATIC CANCER
X - ray of
multiple sclerotic
metastases
at lumbar spine
and pelvis
PHYSICAL EXAMINATION
DIGITAL RECTAL EXAMINATION
(DRE)
PROSTATIC CANCER
Physical examination.
Digital rectal examination (DRE). I.
* focuses on size, consistency and
abnormalities, within or beyond gland;
* many cancers easily palpable on
posterior surfaces of lateral lobes;
* PC in 20 - 25% of men with abnormal
digital rectal examination
PROSTATIC CANCER
Physical examination. Digital rectal examination. II.
* PC typically hard, nodular and irregular
(induration also due to fibrous areas in benign
hyperplasia or to calculi);
- midline furrow between lateral lobes obscured
by either benign or malignant disease;
- detection of local extension into seminal
vesicles
PROSTATIC CANCER
DIGITAL RECTAL
EXAMINATION
BENIGN
PROSTATIC
HYPERTROPHY. I.
median bar obstruction
with markedly distended,
atonic, thin - walled
bladder
BENIGN
PROSTATIC
HYPERTROPHY. II.
initially hypertrophic
bladder
BENIGN
PROSTATIC
HYPERTROPHY. III.
hydro - ureteronephosis
PROSTATE SPECIFIC
ANTIGEN
(PSA)
PROSTATIC CANCER
Prostate specific antigen (PSA). I.
* Kallikrein - like serine protease (causing
liquefaction of seminal coagulum) produced by
both non - and malignant epithelial cells = prostate
specific but not PC specific (↑ in prostatitis, non malignant enlargement of gland, PC and after
prostate biopsy, with level not affected by DRE);
- PSA values may fluctuate for no apparent
reason → an isolated abnormal value be confirmed
before proceeding with further testing;
- performance of prostate biopsy can ↑ PSA levels
up to 10 - fold for 8 - 10 wks
PROSTATIC CANCER
Prostate specific antigen (PSA). Ibis.
PROSTATIC CANCER
Prostate specific antigen (PSA). II.
* in serum, circulates as inactive complex with
two protease inhibitors (α1 - antichymotrypsin and
β2 - macroglobulin), usually measured by
radioimmunoassay (T 1 / 2 = 2 - 3 days);
- levels undetectable with prostate completely
removed;
* PSA immunostaining used to establish a PC
diagnosis
PROSTATIC CANCER
Prostate specific antigen (PSA). III.
* PSA testing approved for early detection in 1994;
* initially, recommended (American Cancer Society,
American Urologic Association) on annual basis (along
with DRE) for men > 50 yrs (with anticipated survival >
10 yrs, including men ≤ 76 yrs);
* American College of Physicians recommends
physicians "describe potential benefits and known
harms of screening" and "individualize decision to
screen"
* ↑ PSA levels in African American men without PC, but
with 50% ↑ risk of PC (no explanation for this racial
difference);
- for African Americans and men with family history,
testing advised from 40 yrs
PROSTATIC CANCER
Prostate specific antigen (PSA). IV.
* PSA criteria to recommend diagnostic prostate
biopsy evolved over time;
- goal = ↑ sensitivity of test for younger men more
likely to die of disease and ↓ frequency of detecting
cancers of low malignant potential in elderly men
more likely to die of other causes;
- age - specific reference ranges ↓ upper limit of
normal for younger men and ↑ it for older men
PROSTATIC CANCER
Prostate specific antigen (PSA). V.
* initially, normal range = < 4 ng / mL;
- for values > 4, sensitivity for PC
detection = 57 - 79%, specificity = 59 - 68%
and positive predictive value = 40 - 50%;
- PC in < 20% of men with PSA in normal
range
PROSTATIC CANCER
Prostate specific antigen (PSA). VI.
* further testing aimed at ↑ sensitivity for young
men more likely to die of PC, while ↓ frequency of
diagnosing PC of low biologic potential in elderly
(more likely to die of other causes):
- age - specific reference ranges;
- free and complexed PSA;
- ratios of free to total, complexed to total and free
to complexed PSA
- PSA density (PSAD);
- PSA velocity
PROSTATIC CANCER
Prostate specific antigen (PSA). VII.
Age - specific reference ranges
* e.g., 4 ng / mL threshold for biopsy ↓ to 2.6 ng /
mL for men < 60 yrs, based on finding that ~ 50% of
men with PSA reaching this level ↑ to 4 within
relatively short (4 - yr) time frame, and that, once
diagnosed, nearly 1 / 3 cancer has spread beyond
confines of gland
PROSTATIC CANCER
Prostate specific antigen (PSA). VIII. Age - specific
reference ranges
* age - specific
reference ranges (=
lower and higher
normal “upper limits”
for younger and older
individuals,
respectively)
PROSTATIC CANCER
Prostate specific antigen (PSA). IX.
Free and complexed PSA
* most PSA complexed to α1 - chymotrypsin (ACT),
with only small percentage being "free“
- “free PSA” lower in PC;
- e.g., in men with PSA of 4 - 10, risk of cancer <
10% with free PSA > 25% but as high as 56% with
free PSA < 10%
PROSTATIC CANCER
Prostate specific antigen (PSA). X.
Free and total PSA
* free and total PSA
measures, to determine need
of biopsy when PSA is 4 - 10
ng / mL;
- free PSA lower in PC;
* ratios of free to total,
complexed to total and free
to complexed PSA:
- in one series, specificity ↑
by 20% with “normal
ranges”: free / total PSA >
0.15; complexed / total PSA <
0.70 and free / complexed
PSA > 0.25
PROSTATIC CANCER
Prostate specific antigen (PSA). XI. PSA density
* PSA density (PSAD) measurements developed to
correct for contribution of benign prostatic
hyperplasia (BPH) to total PSA level;
- PSAD = measured PSA value corrected for
influence of benign prostatic hyperplasia, by
dividing serum PSA level by estimated prostate
weight (from transrectal ultrasonography, TRUS);
- values < 0.10 and > 0.15 ng / mL consistent with
hyperplasia and PC, respectively (PSAD ↓ with age)
PROSTATIC CANCER
Prostate specific antigen (PSA). XII. PSA density
Kaplan - Meier survival curves for death from PC for three
PSA / TTV (Total Tumor Volume) density groups: Group I, <
0.7 ng / ml; Group II, 0.7 - 6.0 ng / ml and Group III, > 6.0 ng/ml
PROSTATIC CANCER
Prostate specific antigen (PSA). XIII. PSA velocity
* PSA velocity = rate of
change in PSA over time
(PSA doubling time,
especially useful for men
with values rising in
seemingly "normal" range);
- with PSA > 4, ↑
> 0.75 ng /
mL / yr suggestive of PC;
- with PSA < 4, ↑
> 0.50 ng /
mL / yr advise biopsy (e.g., ↑
from 2.5 to 3.2 in 1 - yr
warrants further testing (even
if level is still in “normal
range”)
PROSTATIC CANCER
Prostate specific antigen (PSA). XIV. PSA velocity
* PC progression for 3 groups based on different rates of PSA doubling
time (PSADT): 1) (PSADT = 6 mos) generally requires earlier hormone
theapy, short - term relief of PSA and subsequent failure; 2) (PSADT = 11
mos): slower PSA rise prior to hormonal intervention, maintained for
much ↑ periods: 3) (PSADT = 30 mos) slowly rising PSA values and may
not reach a threshold for hormonal intervention for > a decade
PROSTATIC CANCER
PSA - based detection strategies
* PSA - based detection strategies changed clinical
spectrum of disease, with newly diagnosed cancers:
- 95 - 99% clinically localized;
- 40% not palpable (70% of these pathologically
organ - confined);
- drawback of widespread PSA use = detection and
treatment of PCs with low malignant potential that
do not shorten survival or produce symptoms
during pt's lifetime;
* side effects of treatment (including impotence,
incontinence and bowel dysfunction) unacceptable
for these pts
PROSTATIC CANCER
PSA - based detection strategies
- ongoing formal clinical trials to assess value
of screening on PC morbidity and mortality;
- until available results, men advised for
informed decision about undergo testing
Prostate cancer
diagnostic
algorithm based
on digital rectal
examination
and PSA
* overall, biopsy recommended with abnormal DRE and / or PSA
(cancer in 25% men with PSA > 4 ng / mL and abnormal DRE and in
17% of with a PSA of 2.5 - 4.0 ng / mL and normal DRE)
SCREENING
PROSTATIC CANCER
Management by states
Screening (no cancer diagnosis)
* annual rectal examination and PSA
determination for men 50 - 79 yrs (45 yrs for
individuals with 1st - degree relative with PC or
African Americans):
- probably (no controlled trials), significant ↑ in %
of clinically localized tumors, ↓ % of nodal spread
and ↓ % of osseous disease at presentation;
* risks of screening = unnecessary morbidity or
mortality from overdetection and overtreatment
Prostate cancer diagnosis and treatment after the introduction of
Prostate-Specific Antigen
screening: 1986 – 2005
H. Gilbert Welch HG and AlbertsenPC J Natl Cancer Inst 2009;101: 1 – 5
• Background Although there is uncertainty about the effect
of prostate-specific antigen (PSA) screening on the rate of
• prostate cancer death, there is little uncertainty about its
effect on the rate of prostate cancer diagnosis.
• Systematic estimates of the number of men affected,
however, to our knowledge, do not exist.
• Methods We obtained data on age-specific incidence and
initial course of therapy from the National Cancer
• Institute ’ s Surveillance, Epidemiology, and End Results
program. We then used age-specific male population
• estimates from the US Census to determine the excess (or
deficit) in the number of men diagnosed
Screening for PC: update of evidence
for U.S. Preventive Services Task Force Purpose: examining the
Screening for Prostate Cancer
evidence of benefits of
screening and earlier treatment.
Methods: from MEDLINE and
Cochrane Library → questions
representing a logical chain
between screening and
reduced mortality.
Data synthesis → no
conclusive direct evidence that
screening reduces PC mortality
(some screening tests detect
PC at an earlier stage than
clinical detection, but no study
examined additional benefit of
earlier treatment after detection
by screening) (especially, men
Conclusions: net benefit of screening with life expectancy < 10 yrs
cannot be determined
unlikely benefit from screening
even under favorable
Harris R and Lohr KN
assumptions)
Ann Intern Med 2002; 137: 917 - 29
Interval cancers in PC screening: comparing 2 - and 4 - yr screening
intervals in European Randomized Study of Screening for PC (ERSPC),
Gothenburg and Rotterdam. I.
Roobol MJ et al JNCI 2007, 99: 1296 - 303
Background: incidence of PC ↑
substantially since common practice
to screen asymptomatic men. In 1993,
ERSPC initiated to determine how
PSA screening affects PC mortality.
Variations in screening algorithm,
e.g., interval between screenings,
likely influence morbidity, mortality
and quality of life of screened
population.
Methods: comparing no. of detected PC, interval cancers [defined as those
diagnosed during screening interval but not detected by screening, in men in
screening arm of ERSPC aged 55 - 65 yrs at time of first screening and
participating through two centers of ERSPC: Gothenburg (2 - yr interval, n = 4202)
and Rotterdam (4 - yr interval, n = 13301)] and of potentially life - threatening
(aggressive) interval cancer defined as one with ≥ 1 of following characteristics at
diagnosis: stage N1 or M1, plasma PSA concentration > 20.0 ng / mL, or Gleason
score > 7
Interval cancers in PC screening: comparing
2- and 4- yr screening intervals in European
Randomized Study of Screening for PC. II.
Roobol MJ et al JNCI 2007, 99: 1296 – 303
Results: 10 - yr cumulative incidence of all PC
in Rotterdam (4 yrs) vs Gothenburg (2 yrs) =
1118 (8.41%) vs 552 (13.14%) (p < .001),
cumulative incidence of interval cancer = 57
(0.43%) vs 31 (0.74%) (p = .51) and cumulative
incidence of aggressive interval cancer = 15
(0.11%) vs 5 (0.12%) (p = .72).
Conclusion: with 2 - yr screening interval ↑
detection rates than 4 - yr interval but did not
lead to significantly lower rates of interval
and aggressive interval PC
Kaplan - Meier estimates of outcomes in screening arms
of Rotterdam and Gothenburg centers of ERSPC. Center
1 = Rotterdam, Center 2 = Gothenburg. A) estimated %
of men free from PC, p < .001; B) estimated % of men
free of interval PC, p = .51; C) estimated % of men free of
aggressive interval PC; p = .72. Outer lines = 95% CI
Randomised prostate cancer screening trial: 20 yr follow - up. I.
Sandblom G et al BMJ 2011; 342: d1539
Objective: to assess whether screening for PC ↓ PC specific
mortality.
Design: population based, randomised controlled trial.
Participants: men aged 50 - 69 yrs in Sweden, identified in 1987 in
National Population Register
Intervention: from study population, 1494 men randomly allocated
to be screened by including every sixth man from a list of dates of
birth:
- invited to be screened every third yr from 1987 to 1996.
- on first two occasions, screening done by digital rectal
examination only;
- from 1993, this was combined with prostate specific antigen
testing (4 µg / L as cut off)
- on fourth occasion (1996), only men aged ≤ 69 yrs invited;
- prostate cancer specific mortality up to 31 December 2008
Randomised prostate cancer screening trial: 20 yr follow - up. II.
Sandblom G et al BMJ 2011; 342: d1539
Results: in the 4 screenings from 1987 to 1996 attendance =
1161 / 1492 (78%), 957 / 1363 (70%), 895 / 1210 (74%), and 446 / 606
(74%), respectively;
- there were 85 cases (5.7%) of PC diagnosed in screened and 292
(3.9%) in control group;
- risk ratio for death from PC in screening group was 1.16 (95%
confidence interval = 0.78 to 1.73);
- in Cox proportional hazard analysis comparing prostate cancer
specific survival in control group with in screened group, hazard
ratio for death from PC = 1.23 (0.94 - 1.62; P = .13);
- after adjustment for age at start of study, hazard ratio = 1.58
(1.06 - 2.36; p = .024).
Conclusions: after 20 yrs of follow-up, rate of death from PC did
not # significantly between men in screening group and those in
control group
Randomised prostate cancer screening trial: 20 yr follow - up. III.
Sandblom G et al BMJ 2011; 342: d1539
* left: Kaplan - Meier curves of overall survival for men
diagnosed with PC in control (n = 292) and in screened group
(n = 85) (p = 0.14)
* right: Kaplan - Meier curves of PC specific survival for men
diagnosed with PC in control (n = 292) and screened group (n
= 85) (p = 0.065)
PROSTATE BIOPSY
PROSTATIC CANCER
Biopsy. I.
* diagnosis of PC from
TRUS - or MRI - guided
needle biopsy (direct
visualization → all
areas of gland are
sampled)
PROSTATIC CANCER
Transrectal ultrasonography. I.
* most PC hypoechoic, but no single ultrasound
finding allows clear - cut distinction between PC
and benign conditions;
- small (< 5 - 7 mm), well differentiated cancers
(especially in transition zone) also difficult to
distinguish from normal prostate
PROSTATIC
CANCER
hypoechoic mass
on
ultrasonography
PROSTATIC CANCER
Transrectal ultrasonography. II.
* limited accuracy in assessing extent of
local disease (mainly in determining
invasion of seminal vesicles);
* used to determine size of gland for
calculation of PSAD and to guide biopsy
and placement of radioactive seeds
PROSTATIC CANCER
Biopsy. II.
* at least 6 separate cores (3 from right and 3 from
left) + biopsy of transition zone (if clinically
indicated);
- each core of biopsy examined for cancer, and
amount of cancer quantified based on length of
tumor within core and percentage of core involved;
- commonly, 12 - 14 cores ↑ diagnostic yield =
sensitivity = ~ 80% for detection of cancer;
* biopsy not advised in pt with prostatitis until
completing a course of antibiotics)
PROSTATIC CANCER
Biopsy. III.
* positive predictive value for PC:
= 21% with abnormal DRE;
= 25% with PSA > 4 ng / mL and abnormal DRE, and
= 17% with PSA = 2.5 - 4.0 ng / mL and normal DRE;
* individuals with abnormal PSA and negative
biopsy be advised to repeat biopsy
PATHOLOGY
Stepwise progression of prostate cancer
Pathology. I. Benign prostatic hyperplasia (BPH)
Stromal (left) and epithelial (right) forms
of benign prostatic hyperplasia
Pathology. II. Benign prostatic hyperplasia (BPH)
PROSTATIC CANCER
Pathology. III. Prostatic intraepithelial neoplasia (PIN)
* noninvasive
proliferation of
epithelial cells
within ducts;
- considered
as precursor
of PC (but not
all PIN develop
into invasive
PC);
- on a genetic
level, highly
unstable and
typically
multifocal
PROSTATIC CANCER
Pathology. IV. Prostatic intraepithelial neoplasia (PIN)
PROSTATIC CANCER
Pathology. V. Invasive cancers
* adenocarcinomas (> 95%) from prostatic
acini;
- other: squamous and transitional cell
tumors, and, rarely, carcinosarcomas;
* metastases to prostate rare;
* sometimes, transitional cell tumors from
bladder or colonic lesions directly invade
gland
PROSTATIC CANCER
Pathology. VI. Invasive
cancers
well differentiated
prostatic cancer
PROSTATIC CANCER
Pathology. VII. Invasive
cancers
poorly differentiated
prostatic cancer
PROSTATIC CANCER
Pathology. VIII. Invasive cancers
prostatic cancer with neuroendocrine features
(CHR = chromogranin stainin)
PROSTATIC CANCER
Pathology. IX. Adenocarcinoma
* each biopsy core evaluated for:
- presence or absence of cancer;
- differentiation grade;
- perineural invasion, and
- extracapsular extension
PROSTATIC CANCER
Pathology. X. Adenocarcinoma
* histologic grade most commonly assessed by
“Gleason system”:
- dominant and secondary glandular histologic
patterns independently assigned numbers from 1
(well - differentiated) to 5 (undifferentiated) and
summed to give a total grading score of 2 → 10;
- grading reproducible and correlated with clinical
outcome (most poorly differentiated area of tumor
often determines biologic behavior);
- presence or absence of perineural invasion and
extracapsular spread recorded
PROSTATIC CANCER
Pathology. XI. Gleason grading
Gleason grading
G1
G4
G2
G3
G5