2. Prostate
The prostate gland is a male reproductive organ whose main
function is to secrete prostate fluid, one of the components of
semen.
The muscles of the prostate gland also help propel this
seminal fluid into the urethra during ejaculation .
One component of prostate fluid an enzyme called Prostate
Specific Antigen (PSA) also aids in the success of sperm by
liquefying semen that has thickened after ejaculation.
This thinning action allows sperm to swim more freely,
according to the medical reference book "Prostate Specific
Antigen" (Informal Health Care, 2001).
3. Prostate and Bladder obstruction
Unfortunately, while the prostate is in a great location for delivering this
important fluid and squeezing things along when the time is right, its
position around the urethra can be a liability if the gland swells or
grows.
A swollen prostate compresses the urethra and irritates the walls of the
bladder, interfering with normal urination.
More than half of men in their 60s suffer from a growth of the prostate called
Benign Prostatic Hyperplasia (BPH), according to the OSU Medical Center.
By age 70 or 80, a man's chance of suffering BPH jumps to 90 percent.
Symptoms include frequent urination, dribbling or leaking urine and a
stuttered or weak stream.
A growing prostate can also signal cancer. It is estimated that more than
200,000 men will be diagnosed with prostate cancer in 2010, according to
the National Cancer Institute.
4. Prostate: anatomy and histology
Prostate weighs 20 grams in normal adult
Retroperitoneal organ ,encircling the neck
of bladder and urethra
Devoid of a distinct capsule
Four distinct zones
Tubulvalveolar organ
Glands lined two layers of cells, basal
cells and columnar secretory cells
5. Adult prostate
The normal prostate contains
several distinct regions,
including a central zone (CZ),
a peripheral zone (PZ), a
transitional zone (TZ), and a
periurethral zone.
Most carcinomas arise from
the peripheral glands of the
organ and may be palpable
during digital examination of
the rectum.
Nodular hyperplasia, in
contrast, arises from more
centrally situated glands and
is more likely to produce
urinary obstruction early than
is carcinoma.
6. Histologically the prostate is
composed of glands lined by
two layers of cells.
A basal layer of low cuboidal
epithelium covered by a layer
of columnar secretory cells.
In many areas there are small
papillary infoldings of the
epithelium.
These glands are separated
by abundant fibromuscular
stroma.
Testicular androgens control
the growth and survival of
prostatic cells.
Castration leads to atrophy of
the prostate caused by
widespread apoptosis.
8. Benign Prostatic Hyperplasia BPH
Extremely common lesion in men over age 50
Hyperplasia of glands and stroma
Fairly large ,well delined nodules
20% in men over age 40,up to 70% by age 60,
and 90% by age 70
Related to the action of androgen
9. BPH and the role of DHT
DHT ,Dihydrotestesterone is the ultimate mediator for prostatic growth.
The main component of the “hyperplastic” process is impaired cell death
resulting in the accumulation of senescent cells in the prostate.
Androgens not only increase cellular proliferation, but also inhibit cell death.
The main androgen in the prostate, constituting 90% of total prostatic
androgens, is dihydrotestosterone (DHT).
It is formed in the prostate from the conversion of testosterone by the
enzyme type 2 5α-reductase, located almost entirely in stromal cells;
Epithelial cells of the prostate do not contain type 2 5α reductase, with the
exception of a few basal cells. Thus stromal cells are responsible for
androgen-dependent prostatic growth.
10. Other sources of DHT
Type 1 5α-reductase is not detected in the
prostate, or is present at very low levels.
However this enzyme may produce DHT
from testosterone in liver and skin, and
circulating DHT may act in the prostate by an
endocrine mechanism.
Nodular hyperplasia is not considered to be a
premalignant lesion
11. Mechanism of DTH induced growth
DHT binds to the nuclear androgen receptor (AR) present in
both stromal and epithelial prostate cells.
DHT is more potent than testosterone because it has a higher
affinity for AR and forms a more stable complex with the
receptor.
Binding of DHT to AR activates the transcription of androgen-
dependent genes.
DHT is not a direct mitogen for prostate cells, instead DHT-
mediated transcription of genes results in the increased
production of several growth factors and their receptors.
12. Growth factors
Most important among these are members of the fibroblast
growth factor (FGF) family, and particularly FGF-7
(keratinocyte growth factor;).
FGF-7, produced by stromal cells, is probably the most
important factor mediating the paracrine regulation of
androgen-stimulated prostatic growth.
Other growth factors produced in BPH are FGFs 1 and 2, and
TGFβ, which promote fibroblast proliferation.
Although the ultimate cause of BPH is unknown, it is believed
that DHT-induced growth factors act by increasing the
proliferation of stromal cells and decreasing the death of
epithelial cells.
13. Simplified scheme of
the pathogenesis of
prostatic hyperplasia.
The central role of
the stromal cells in
generating
dihydrotestosterone
(DHT) should be noted.
DHT may also be
produced in skin and
liver by both type 1 and
2 5α-reductase.
14. BPH , Morphology
The prostate weighs between 60 and 100 grams
Enlargement occurs almost exclusively in the inner aspect of
the prostate gland
Nodules ,vary in color and consistency
Histologic hallmark of BPH is nodularity due to glandular
proliferation or dilation and to fibrous or muscular proliferation
Aggregation of small to large and cystically dilated glands
Needle biopsy don’t sample the transitional zone BPH occur
15.
16.
17. Clinical features
The increased size of the gland, and the smooth muscle-mediated
contraction of the prostate cause urethral obstruction.
The increased resistance to urinary outflow leads to bladder hypertrophy
and distension, accompanied by urine retention.
The inability to empty the bladder completely creates a reservoir of residual
urine that is a common source of infection.
Increased urinary frequency, nocturia, difficulty in starting and stopping the
stream of urine, overflow dribbling, dysuria (painful micturition).
Increased risk of developing bacterial infections of the bladder and kidney.
In many cases, sudden, acute urinary retention appears for unknown
reasons that requires emergency catheterization.
18. Management
Decreasing fluid intake, especially before bedtime;
moderating the intake of alcohol and caffeine containing
products; and following timed voiding schedules.
α-blockers, which decrease prostate smooth muscle tone via
inhibition of α1-adrenergic receptors.
Inhibitors of 5-α-reductase.
Transurethral resection of the prostate (TURP).
High-intensity focused ultrasound, laser therapy,
hyperthermia, transurethral electro vaporization, and
transurethral needle ablation using radiofrequency.
20. Epidemiology
Cancer of the prostate is a disease of men over age 50 and
adenocarcinoma is the most common form.
One in six lifetime probability of being diagnosed with prostate
cancer.
Prostatic cancer is uncommon in Asians and occurs most
frequently among blacks.
Increased consumption of fats has been implicated.
Dietary products suspected of preventing or delaying prostate
cancer development include lycopenes (found in tomatoes),
selenium, soy products, and vitamin D.
21. Prostate Cancer Risk Factors
Established
• Advancing age
• Presence of androgens
• Family history (1st
degree relative)
• African ancestry
Potential
• High dietary fat
• Obesity
• Inherited mutations (BRCA1 or BRCA2 genes)
• Vitamin D or E deficiency
• Selenium deficiency?
22. Screening Recommendations
• Discuss with the patient and if he decides to be screened
• Annual PSA and DRE
• Age 50-70 yrs (with at least 10 yr life expectancy)
• Begin screening at age 40 if risk factors
• African ancestry
• First degree relative(s) with prostate cancer
• A shared decision-making approach to PSA screening
seems most appropriate
23. Prostate Cancer: Screening with PSA
No clear cut-point between normal and abnormal PSA levels.
Even PSA cut-off of 1.1 ng/ml misses up to 15% of prostate
cancer (The Cancer Prevention Trial – 2003)
Positive predictive value for PSA > 4ng/ml = 30% (i.e. About 1 in
3 men with elevated PSA have prostate cancer detected at time
of biopsy
PPV increases to 45-60% for PSA > 10ng/ml
Nearly 75% of cancers detected in the grey zone (PSA 4-10) are
organ confined; potentially curable.
<50% of prostate cancers organ confined if PSA >10
24. What is PSA (Prostate Specific
Antigen)?
A Serine protease
(enzyme) found in the
prostate
Secreted by prostate
epithelial cells
Found in ejaculate
As diagnostic tool for:
Screening
Staging
Prognostic indicator
Surveillance
25. Other causes of an elevated PSA
1. Age
2. Prostate size (BPH)
3. Infection/inflammation
4. Recent instrumentation (biopsy, catheterization,
etc.)
5. Physiological variation
6. Recent ejaculation
26. Free/Total PSA Ratio:
A Way to Improve Specificity
Prostate cancer maybe
associated with more
protein-bound PSA
(less free PSA) than in
BPH
F/T ratio is lower in
patients with prostate
cancer
Can improve test
specificity
Useful when total PSA
in 4-10 ng/ml range
BPH
Prostate Ca
29. Prostate Cancer: Presentation
Early stages usually asymptomatic
Most cases detected by serum PSA screening
Palpable nodule or firmness on DRE
Advanced stages
Urinary retention/renal failure
Bone pain
Anemia
Weight loss, fatigue
Spinal cord compression
30. Prostate Cancer: Diagnosis
Indications for trans rectal ultrasound (TRUS) guided biopsy
Palpable nodule on DRE
Elevated serum PSA
Biopsy involves 10-18 needle cores taken mostly from the
peripheral zone of the prostate
Transrectal ultrasound alone/CT scan/MRI not sensitive
enough to make the Diagnosis
31. The 2016 and 2004 WHO
classifications of prostatic carcinoma
32. Adenocarcinoma of Prostate
The most common form is
adenocarcinoma
Three variants
1. Acinar adenocarcinoma
2. Intraductal carcinoma
3. Ductal adenocarcinoma
33. Variants of acinar adenocarcinoma (AC) of
the prostate in the 2016 WHO classification
34. Adenocarcinoma: Gross Morphology
70% arises in the peripheral zone of the
gland
Palpable in rectal exam
Gritty and firm
Spread by direct local invasion and
through blood stream and lymph
Local extension most commonly involves
the seminal vesicles and the base of the
urinary bladder
35.
36.
37. Adenocarcinoma
Well defined gland pattern
Histologic diagnosis in some cases is one
of the most chalenges for pathologists
Peri-neural invasion is common and
typical
38. Adenocarcinoma: microscopic
pathology
Well-defined, readily demonstrable gland patterns, that are
typically smaller than benign glands.
Lined by a single uniform layer of cuboidal or low columnar
epithelium.
Cancer glands are more crowded, and characteristically lack
branching and papillary infolding.
The outer basal cell layer typical of benign glands is absent.
39. Adenocarcinoma: microscopic
pathology
The cytoplasm of the tumor cells ranges from pale-clear as
seen in benign glands to a distinctive amphophilic
appearance.
Nuclei are large and often contain one or more large nucleoli.
There is some variation in nuclear size and shape, but in
general pleomorphism is not marked.
Mitotic figures are uncommon.
α-methylacyl-coenzyme A-racemase (AMACR) is up-
regulated in prostate cancer and can be detected by
immunohistochemistry
46. Adenocarcinoma ,Clinical Course
Microscopic cancers are asymptomatic,
discovered incidently
Patients with clinically localized disease
do not have urinary symptoms
Most arise peripherally ,away from
urethra, therefore ,urinary symptoms
occur late.
Prognosis depends mainly on the extent
of the disease at the time of the diagnosis.
47. Prostate Cancer
Prognostic factors
Depends upon grade, stage and
treatment
Early stage/well-differentiated Ca treated
by radical prostatectomy:
85% + 10 year survival
Metastatic disease
<10% 5 year survival
48. Adenocarcinoma: Gleason’s Grading
Gleason grading system is the best known
for grading
Five grades on the basis of glandular pattern
and degree of differentiation as seen under
low magnification
Grading is of particular important in prostate
cancer, because it is the best marker ,along
with the stage ,for predicting prognosis
49. Adenocarcinoma: Gleason’s Grading
Gleason grade is from 1-5 based on glandular
architecture
Gleason score is the total primary grade (1-5) +
secondary grade (1-5) = 2-10
4-6/10=well-differentiated
7/10=moderately differentiated
>8/10=poorly differentiated
50.
51.
52.
53.
54. Grading and grouping
Grade Group 1 (Gleason score ≤6) – Only individual discrete well-
formed glands
Grade Group 2 (Gleason score 3+4=7) – Predominantly well-formed
glands with a lesser component of poorly-formed/fused/cribriform
glands.
Grade Group 3 (Gleason score 4+3=7) – Predominantly poorly-
formed/fused/cribriform glands with a lesser component of well-
formed glands.
Grade Group 4 (Gleason score 8) - Only poorly-
formed/fused/cribriform glands or - Predominantly well-formed
glands with a lesser component lacking glands†† or - Predominantly
lacking glands with a lesser component of well-formed glands.
Grade Group 5 (Gleason scores 9-10) – Lacks gland formation (or
with necrosis) with or w/o poorly-formed/fused/cribriform glands.
55. Prostate Cancer:
Staging
Can spread to adjacent organs (seminal
vesicles, bladder), lymph nodes, bone
Most bone mets are osteoblastic
Prior to initiating treatment consider
Bone scan (PSA>10, Gleason Score >7)
CT scan pelvis/abdomen (PSA >10, Gleason
Score >7))
These tests are typically not required in
asymptomatic men with low risk prostate cancer
56. Adenocarcinoma
Grading and Staging
Staging in prostate cancer depends on
the TNM system .
Clinical staging includes combined clinical
and radiological findings and PSA levels.
Pathological staging includes tumor extent
on biopsy and Gleason's grade.
AJCC staging combines the both.
59. N and M
Status of Regional Lymph Nodes (N)
N0 NO REGIONAL NODAL METASTASES
N1 METASTASIS IN REGIONAL LYMPH NODES
Distant Metastases (M)
M0 NO DISTANT METASTASES
M1 DISTANT METASTASES PRESENT
M1a Metastases to distant lymph nodes
M1b Bone metastases
M1c Other distant sites
60.
61. Prostate Cancer – Treatment - Survival
Considerations
Patient’s age
Co-morbid health
conditions
Tumor stage
Tumor grade (Gleason
score)
Often a patient choice
Surgery and
62. Adenocarcinoma
Treatment
Surgery ,radiotherapy ,and hormonal therapy
90% of treated patients expected to live for 15
years
Currently the most acceptable treatment for
clinically localized cancer is radical surgery
Too locally advanced cancers can be treated by
radiotherapy
Hormonal therapy (Antiandrogen therapy) could
induce remission .
63. Early Stage Prostate Cancer
Treatment
Early stage Cancer
1. Radical Prostatectomy
2. External Beam Radiotherapy
3. Radioactive Seeds (Brachytherapy)
4. Active Surveillance
5. Observation – Watchful Waiting
67. Spinal Cord Compression
Metastatic prostate cancer is a
common cause of spinal cord
compression
Clinical recognition is critical
Signs and symptoms
Back pain
Neurological symptoms in
saddle distribution
Lack of rectal tone, fecal and
urinary incontinence
Paraplegia below the level of
compression
MRI is diagnostic
68. Spinal Cord Compression
Treatment
Emergency decompression laminectomy
by spinal surgeons
Emergency radiation to affected level
Dexamethasone/steroids
Emergency bilateral orchidectomies if
patient not already on androgen
deprivation
70. Prostate Cancer Prevention
Two major studies using 5 α reductase inhibitors
vs placebo
Similar reduction in prostate cancer diagnosis
in the treatment arms (23-24%)
Not currently approved by Health Canada for
prostate cancer prevention
PCPT (Thompson et al NEJM 2003)
Finasteride
Reduce (Andriole et al NEJM 2010)
Dutasteride
Notas do Editor
2x risk if one 1st degree family relative
2x risk if 1st degree relative with prostate cancer; 9x risk if 2 or more relatives with prostate cancer
PSA is involved in liquefaction of the seminal fluid- essential for sperm function. Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), is a glycoprotein enzyme encoded in humans by the KLK3 gene. PSA is a member of the kallikrein-related peptidase family and is secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen in the seminal coagulum and allows sperm to swim freely.[5] It is also believed to be instrumental in dissolving cervical mucus, allowing the entry of sperm into the uterus.[6]
PSA is present in small quantities in the serum of men with healthy prostates, but is often elevated in the presence of prostate cancer or other prostate disorders.[7] PSA is not a unique indicator of prostate cancer, but may also detect prostatitis or benign prostatic hyperplasia.
Prostate biopsy not a good gold standard
Morbidity from a biopsy (pain, UTI, sepsis)
Prostate biopsy not a good gold standard. Possible morbidity from a biopsy (pain, UTI, sepsis)