Download The Prostate

BPH
Benign Prostatic Hyperplasia
PROSTATE GLAND
• a walnut-sized gland found in
the true pelvis of males just
behind the symphysis pubis.
• composed of several regions
or lobes that are enclosed by
an outer layer of tissue
(capsule)
• Three distinct zones:
– peripheral zone (PZ)
– central zone (CZ)
– transitional zone (TZ)
PROSTATE GLAND
• Benign prostatic
hyperplasia uniformly
arise in the
transitional zone
• 60-70% of carcinomas
originate in the
peripheral zone
– 10-20% in the TZ
– 5-10% in the CZ
Benign Prostatic Hyperplasia
• Characterized by hyperplasia of prostatic stromal and
epithelial cells, resulting in the formation of large, fairly
discrete nodules in the periurethral region of prostate
• With sufficient growth the nodules can compress the
urethral canal causing partial, or sometimes complete
obstruction of urethra inhibiting urine flow
• Not considered as a premalignant tumor
[ PSA]
Incidence & Epidemiology
•
•
•
•
•
Most common benign tumor in men
Incidence is age-related
20% - men aged 41-50
50% - men aged 51-60
90% - men older than 80
ETIOLOGY
• Risk factors are poorly understood [multifactorial]
• BPH involves both the stromal and epithelial elements of
the prostate undergoing hyperplastic changes
• Seems strongly tied to endocrine control [levels of free
testosterone and estrogen]
• As men age the androgen receptors of the prostate
becomes increasingly sensitive/hormonally dependent on
testosterone and dihydrotestosterone (DHT) production
Dihydrotestosterone (DHT)
• In both cell types (stroma/epithelial), DHT binds
to nuclear androgen receptors and signals the
transcription of growth factors that are mitogenic
• Though testosterone can also bind to androgen
receptors and cause growth stimulation, DHT is
10x more potent because it dissociates from
androgen receptors more slowly
PATHOLOGY
• BPH originates from
the transition zone
• Hyperplastic process
resulting from
increase number of
cells
PATHOLOGY
• Nodular growth
pattern composed of
stroma and
epithelium
• BPH nodules in the
transition zone
enlarge and compress
the outer zones of the
prostate  formation
of surgical capsule
PATHOPHYSIOLOGY
• Symptoms are either obstructive or secondary
response of the bladder to the outlet
resistance
• As enlargement ensues, mechanical
obstruction may result from intrusion into the
uretheral lumen or bladder neck  high
bladder outlet resistance
PATHOPHYSIOLOGY
• Stroma composed of smooth mm and
collagen is rich in adrenergic nerve supply 
autonomic stimulation sets a tone to the
prostatic urethra
• Irritative voiding complaints are secondary
response of the bladder to increased outlet
resistance
Clinical Findings of BPH
Symptoms
• Obstructive
• Hesitancy
•  Force and caliber of
stream
• Sensation of incomplete
bladder emptying
• Double voiding
• Straining to urinate
• Post-void dribbling
•
•
•
•
Irritative
Urgency
Frequency
Nocturia
Symptoms
• AUA (American Urological Association) Symptom
Score questionnaire
– Single most important tool to evaluate patients with
BPH
– Recommended for all patients before initiating
therapy
– Self-administered
– Identifies the need to treat
– Monitors therapeutic response
– Scoring: 0-35
Source:
Smith’s General
Urology, 17th ed.
Signs
• Physical examination
• DRE
• Focused neurologic examination
Signs
• Size and consistency
• Smooth, firm, elastic enlargement of the
prostate=BPH
• Induration=CA?
– Further evaluation: PSA, transrectal US, biopsy
Laboratory Findings
• Assessment of renal function
– Urinalysis
– Serum creatinine
• Renal insufficiency:
– 10% of patients with prostatismupper-tract
imaging
–  Risk of postoperative complications from
surgical intervention for BPH
• Serum PSA: Optional
Imaging
• Upper-tract imaging
(intravenous
pyelogram or renal
US)
– Recommended only
in the presence of
concomitant urinary
tract disease or
complications from
BPH
Cystoscopy
• Not recommended
to determine need
for treatment
• Assist choosing
surgical approach for
invasive therapy
Additional Tests
• Cystometrograms and urodynamic profiles
– Tests for bladder capacity & pressure, and lower
urinary tract symptoms (bladder, urethra)
respectively
– Suspected neurologic disease
– Failed prostate surgery
• Flow rate measurement, post-void residual
urine, pressure-flow studies
– Optional
Differential Diagnosis:
• Urethral Stricture
• Bladder Neck Obstruction
– hx of previous urethral instrumentation, urethritis or
trauma
• Bladder Stones- Hematuria and pain
• UTI- Mimics the irritative symptoms of BPH
– Urinalysis and culture
• Neurogenic Bladder- hx of neurologic problems,
stroke, dm, or back injury.
– PE: diminished perineal or lower extremity
sensation or alteration in bulbocavernous reflex
Treatment:
• Mild symptoms (score 0-7)- watchful waiting
• Surgical indications
– refractory urinary retention
– recurrent UTI
– recurrent gross hematuria
– bladder stones
– renal insufficiency
– large bladder diverticula
Medical Therapy:
• Alpha blockers
– alpha-1-adrenoreceptors located in the prostate and
bladder
– Contractile response of prostate to agonists
– Selective blockade of α1a receptors = fewer A.E.
• 5α-reductase inhibitors (Finasteride)
– blocks conversion of testosterone to
dihydrotestosterone
– ↓ size of prostate
– Improvement of symptoms (>40cm)
Medical Therapy:
• Combination therapy
– Alpha blockers + 5α-reductase inhibitors
• Phytotherapy
– use of plants or plant extracts for medicinal
purposes
– MOA, efficacy and safety unknown
Conventional Surgical Therapy:
• Transurethral resection of the prostate (TURP)
–
–
–
–
Done endoscopically
Symptom score and flow rate improvement
Longer hospital stay
TUR syndrome
• Transurethral incision of the prostate
– More rapid less morbid
• Open Simple Prostatectomy
– Done when the prostate is too large to be removed
endoscopically
Conventional Surgical Therapy:
• Open Simple
Prostatectomy
– Glands >100g
– With concomitant
bladder diverticulum
or bladder stone or
dorsal lithotomy
position is not
possible
Conventional Surgical Therapy:
– Simple Suprapubic Prostatectomy
• Procedure of choice in dealing with concomitant
bladder pathology
– Simple Retropubic Prostatectomy
• The bladder is not entered
Minimally Invasive Therapy:
• Laser Therapy
• Transurethral
Electrovaporization of the
Prostate
• Hyperthermia
• Transurethral Needle
Ablation of the Prostate
• High Intensity Focused
Ultrasound
• Intraurethral Stents
• Transurethral Balloon
• Dilation of the Prostate
Prostate Cancer
Molecular genetics, Pathophysio
Prostate Cancer
Prostate Cancer
most common cancer
diagnosed & is the 2nd leading
cause of cancer death in American
men
Incidence continues to  with
advancing age (no peak)
Lifetime risk of a 50-yr old man
for latent CaP: 40%; clinically
apparent: 9.5%; death from CaP:
2.9%
•
•
•
•
•
•
Risk factors:
Increasing age
Race
Family history
High dietary fat intake
Exposure to chemicals (e.g. cadmium)
Molecular genetics
• Chromosome 1
– Gene responsible for familial prostatic cancer
• Tumor suppressor genes (8p, 10q, 13q, 16q,
17p, 18q)
•
Found in the regions human genome
•
Pathology
• Nature :
• More than 95% are adenocarcinomas
• 5% are transitional cell carcinomas
– 90% are neuroendocrine (“small cell”) carcinomas
or sarcomas
Histologic characteristics
•
- hyperchromatic, enlarged nuclei, w/
prominenent nucleoli
•
- cytoplasm abundant & slightly bluetinged or basophilic
•
- absent basal cell layer
•
- HMW keratin immunohistochemical
• Origin of Prostatic cancer
• Peripheral zone- 70%
• Transitional zone- 10 to 20%
• Central zone- 5 to 10%
• Prostatic Intraepithelial Neoplasia (PIN)
•
•
- Precursor to invasive prostatic cancer
- Basal cell layer of the glandular
architecture is present
• Classifications:
• High grade PIN
•
- associated with invasive Prostatic cancer
Prostatic Intraepithelial Neoplasia
(PIN)
classic histologic
features:
- intermediate-to-large
size preexisting glands
displaying nuclear and
nucleolar enlargement
and fragmented basal
cell layer
Grading and Staging
•
•
•
•
•
•
•
•
Gleason score or Gleason sum
primary grade + secondary grade
Gleason grades: 1- 5
Gleason scores: 2 - 10
Tumor Grade
Score
Well-differentiated
2-4
Moderately-differentiated
5-6
Poorly-differentiated
8-10
• Gleason grades 1 & 2
• - small, uniformly shaped glands, closely
packed, w/ little infiltrating stroma
Gleason 1
• The most important
difference between
Gleason pattern 1 and 2
is the presence or
absence of
circumscription
Gleason 2
•
The glands are
round to oval and
uniformly placed. There
are no sharplyangulated or distorted
glands.
Gleason 3
• - Variable-sized glands that percolate between
normal stroma
• Cribriform pattern
•
- a small mass of cells is perforated by
several gland lumens w/ no intervening
stroma  cookie-cutter-like
appearance of cell nests
•
- smooth border
This example of Gleason grade 3 cancer shows abundant
amphophilic cytoplasm, enlarged nuclei with prominent
nucleoli.
Higher magnification view of the previous slide. Most glands
have occluded lumens. The nuclei are hyperchromatic.
Gleason 4
• - Incomplete gland formation
• Several histological appearances:
• - sometimes glands appear fused, sharing a
common cell border
• - sheets of cell nests or long cords of cells
• - cribriform glands (large masses, ragged
borders w/ infiltrating fingerlike projections
The glands are fused and there is no intervening stroma.
Glandular fusion is a hallmark of Gleason grade 4.
Higher magnification view of the previous slide. Most glands
have occluded lumens. The nuclei are hyperchromatic.
Gleason 5
• - single infiltrating cells, no gland formation or
lumen appearance
• comedocarcinoma
•
 cribriform glands w/ central areas of
necrosis
• - Tumor cells are
arranged in solid sheets
with no attempts at
gland formation.
• TNM staging system
• - Primary tumor categorization (T stage) uses
the results of the digital rectal examination
(DRE) & transrectal ultrasound (TRUS) but not
the results of biopsy
TNM staging
T – Primary tumor
Tx
Cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ (PIN)
T1a
5% of tissue in resection for benign disease has cancer, (N) DRE
T1b
>5% of tissue in resection for benign disease has cancer, (N) DRE
T1c
Detected from elevated PSA alone, (N) DRE & TRUS
T2a
Tumor palpable by DRE or visible by TRUS on one side only
T2b
Tumor palpable by DRE or visible by TRUS on both sides
T3a
Extracapsular extension on one or both sides
T3b
Seminal vesicle involvement
T4
Tumor directly extends into bladder neck, sphincter, rectum, levator
muscles, or into pelvic sidewall
N – Regional lymph nodes (obturator, internal iliac, external iliac, presacral lymph
nodes)
Nx
Cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a regional lymph node or nodes
M – Distant metastasis
Mx
Cannot be assessed
M0
No distant metastasis
M1a
Distant metastasis in non-regional lymph nodes
M1b
Distant metastasis to bone
M1c
Distant metastasis to other sites
Patterns of Progression
• - The likelihood of local extension outside the
prostate (extracapsular extension) or seminal
vesicle invasion & distant metastasis increases
w/ tumor volume & more poorly
differentiated cancers.
•
• - Penetration of the prostatic capsule by
cancer is common & occurs along the
perineural spaces
• - Seminal vesical invasion – associated with a
high likelihood of regional or bladder disease
• - Socally advanced prostatic cancer may
invade the bladder trigone  ureteral
obstruction
• Lymphatic metastases:
•
•
•
•
- Obturator lypmh node chain (most common)
- Common iliac
- Presacral
- Periaortic lymph nodes
• Axial skeleton
• most usual site of distal metastases (lumbar
• - Vertebral body involvement w/ significant
tumor masses extending into the epidural
space  cord compression
• - Visceral metastases: lung, liver, adrenal gland
• - CNS involvement usually a result of direct
extension from skull metastasis
Grading & Staging
Gleason Grading System
• Most commonly employed grading system in
the US
• Low-power appearance of the glandular
architecture under the microscope
• Primary grade = most common observed
pattern
• Secondary grade = second most common
• Grade range from 1 to 5
• Only one pattern present = 1° and 2° grade
Gleason Score or Gleason Sum
• Obtained by adding the primary and
secondary grade together
• Range from 2 to 10
• Gleason sum 2-4 = well-differentiated tumor
•
Gleason sum 5-6 = moderately
differentiated
•
Gleason sum 7 = moderate - poor
•
Gleason sum 8-10 = poorly differentiated
Gleason Grade
• Gleason grade 1 and 2
– Small, uniformly shaped glands, closely packed
with little intervening stroma
• Gleason grade 3
– Variable-sized glands that percolate between
stroma
– Cribriform pattern = variant of Gleason grade 3;
cookie-cutter-like appearance of cell nests
• Gleason grade 4
– Incomplete gland formation
– Glands appear fused; common cell border
• Gleason grade 5
– Single infiltrating cells
– No gland formation or lumen appearance
– Comedocarcinoma = unusual variant; appearance
of cribriform glands with central areas of necrosis
TNM Staging System for CaP
CaP Chemoprevention
• Ideal tx intervention = arrest disease
progression during latent period and decrease
incidence of clinical disease
• Ideal agent = nontoxic and low cost
• Ideal patient = one at high risk of the disease
• Agents currently being studied in clinical trials:
finasteride, dutasteride, vit E, selenium, COX-2
inhibitors, and SERMs
Patterns of Progression
• Grades 1 and 2
– Confined to the prostrate
• Grades 4 and 5 (plus large-volume)
– Locally extensive
– Metastatic to regional lymph nodes or bones
Clinical findings
Symptoms
• Early
– Asymptomatic
• Locally advanced/Metastatic
– symptomatic
Signs
• DRE --> induration --> further evaluation
• Locally advanced disease with bulky
lymphadenopathy
– Lymphedema of the LE
• Cord compression
– Weakness/spasticity of LE
– Hyperreflexic bulbocavernous reflex
Laboratory Findings
•
•
•
•
Azotemia
Anemia
ALP
ACP
Tumor Markers - PSA
•
•
•
•
•
Not specific
PSA velocity - 0.75 ng/mL/yr
PSA density - 0.12 ng/ml/g
Age adjusted PSA reference ranges
PSA forms
Prostate Biopsy
• Systemic sextant prostate biopsy
– Apex
– Midsection
– Base
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Imaging
• TRUS
– Biopsy and local staging
– Measures prostatic volume
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Prostatic carcinoma
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Extracapsular extension
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Seminal vesicle invasion
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• Endorectal MRI
– Low signal intensity area
– Right seminal vesicle invasion
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• Axial Imaging
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
• Bone scan
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see thi s picture.
Molecular Staging
• Circulating prostate cells in the peripheral
blood
• Not always indicative of metastatic disease or
treatment failure
Differential Diagnosis
Carcinoma of the Prostate
Elevated PSA
•
•
•
•
•
BPH
Urethral Instrumentation
Infection
Prostatic Infarction
Vigorous Prostate Massage
Induration of the Prostate
• Chronic Granulomatous prostatitis
• Previous TURP or needle biopsy
• Prostatic Calculi
Paget’s disease
• Sclerotic lesions on plain x-ray films and
elevated levels of alkaline phosphatase
• PSA levels are usually normal and x-ray
findings demonstrate subperiostealcortical
thickening
Screening for CaP
Carcinoma of the Prostate
CaP Screening
• PSA improves detection of clinically important
tumors without signifi cantly increasing the
detection of unimportant tumors
• most PSA-detected tumors are curable
• prostate cancer mortality is declining in
regions where screening occurs
• curative treatments are available
CaP Screening
• the use of both DRE and serum PSA is
preferable to either one used alone
• earlier screening starting at age 40
• men with very low serum PSA level (1 ng/ml)
may be able to be screened at less frequent
intervals (every 2 to 3 years)
CaP Screening
• Normal PSA = 4 ng/ml or less
• Normal values for all men of ages and prostate
volume
• Recent findings show a fall in prostate cancer
mortality due to early detection efforts
CaP Screening
• Screening should be undertaken in men who
are healthy enough to benefit from it
• Screening may be highly encouraged in certain
populations with a higher disease prevalence
and/or mortality such as African American
men and those with a strong family history of
the disease
Treatment : Localized Disease
Carcinoma of the Prostate
General Considerations
• treatment decisions are based on:
– the grade and stage of the tumor
– the life expectancy of the patient
– the ability of each therapy to ensure disease-free
survival
– its associated morbidity
– patient and physician preferences
Watchful Waiting and Active
Surveillance
• Low mortality with watchful waiting in early
stage prostate cancer
• A more modern concept of watchful waiting is
better termed active surveillance where men
with very well-characterized, early stage, and
low to intermediate grade cancer are followed
very carefully and treated at the first sign of
subclinical progression based on serial and
regular physical examinations, serum PSA
measurements, and repeat prostatic biopsy
Radical Prostatectomy
• An operation to remove the prostate gland
and some of the tissue around it
• May be done by open surgery or by
laparoscopic surgery through small incisions
• A few doctors now do it by guiding robotic
arms that hold the surgery tools - robotassisted prostatectomy
Radiation Therapy
External Beam Therapy
• Uses a linear accelerator, a high-energy x-ray
machine, to direct radiation to the prostate
tumor
• Radiation works more effectively on small and
moderately sized prostate glands
• Men with very large prostate glands often
undergo a 3- to 6-month course of hormone
therapy to shrink the prostate gland prior to
radiation therapy.
Radiation Therapy
External Beam Therapy
• Radiation is an outpatient procedure that
does not carry the standard risks or
complications that accompany major surgery,
such as surgical bleeding, post-operative pain,
or risk of stroke, heart attack or blood clot.
• The procedure itself causes no pain
• The risk of incontinence is minimal with
radiation therapy
•
Radiation therapy
Brachytherapy
• Also called seed implantation or interstitial
radiation therapy
• Uses small radioactive pellets, or "seeds,"
each about the size of a grain of rice and are
placed directly into your prostate
• Generally used only in men with early stage
prostate cancer that is relatively slow growing
• May not be as effective in men with large
prostate glands because many more seeds
may be needed
Cryosurgery
• A procedure in which the prostate gland is
frozen under controlled conditions in order to
kill cancer cells
• Works best on prostates 40 grams or less in
size as measured by ultrasound
• Special metal probes are inserted through the
perineum and directly into preselected
locations in the prostate gland
• Liquid nitrogen is then circulated through the
probes to freeze the entire gland.
High Intensity Focused Ultrasound
• Utilizes transrectal ultrasound that is highly
focused into a small area, creating intense
heat of 80-100° C, which is lethal to prostate
cancer tissue
• Can also be used to treat prostate cancer that
has begun to spread beyond the capsule
• allows the surgeon to precisely ablate the
prostate gland with pinpoint accuracy and
thereby preserve the adjacent structures.
Treatment of Prostate CA
Recurrent Disease
• Relapse
– Rising serum PSA after treatment
– 3 consecutive rises in serum PSA above nadir
(ASTRO)
– Modification: rise of at least 2ng/ mL greater than
the nadir level
– “PSA Bounce”- not indicative or recurrence
• Increase risk for metastasis
– Interval to PSA failure <3-6 years and a
posttreatment PSA doubling time <3 months
Following Radical Prostatectomy
• Related to cancer grade, pathologic stage, and
extent of extracapsular extension
• Likelihood for recurrence more likely in
patients with:
– Positive surgical margins
– Established extracapsular extension
– Seminal vesicle invasion
– High grade disease
– Persistenly detectable serum PSA levels
immediately after surgery
Following Radiation Therapy
• PSA levels continues to
rise after radiation
therapy
• Perform biopsy and CT
• Androgen deprivation
or androgen ablation
therapy
• Local recurrence:
brachytherapy,
cryosurgery, or salvage
prostatectomy
Metastatic Disease Therapy
• Initial endocrine therapy
– Most prostatic carcinomas are hormone
dependent
– LHRH agonists: goserelin acetate, triptorelin
pamoate, histrelin acetate and leuprolide acetate
by injection monthly
• Avoid the flare phenomenon
– Orchiectomy less commonly performed today
– Estrogen by feedback inhibition
– Ketoconazole for advanced prostate cancer with
SCC or DIC
Metastatic Disease Therapy
• Complete Androgen
Blockade
– Suppressing both
testicular and adrenal
androgens
– Combining antiandrogen with LHRH
agonists or orchiectomy
• Intermitent androgen
deprivation
– Delay in the appearance
of hormone- refractory
Manipulations for Hormone
Refractomy Prostate Cancer
• Patients who have a rise in serum PSA levels
• Complete androgen blockade therapysecondary rise in PSA levels
• Emergence of hormone- refractory state due
to mutations in the androgen receptor
– Some anti-androgens may stimulate a mutated
androgen receptor to produce more testosterone
• Discontinue the anti-androgen
Metastatic Disease Therapy
• Hormone refractory disease
– Patients with metastatic disease where hormonal
therapy failed
– Incurable
– Combination of agents are suggested:
• Mitoxantrone with prednisone
• Extramustine with taxane
Metastatic Disease Therapy
• Patients receiving
monotherapy (LHRH
agonist or orchiectomy)
may respond to
addition of an antiandrogen
– Additional use of
ketoconazole,
aminoglutethimide,
corticosteroids, and
estrogenic compounds
should be considered