Benign and Malignant Diseases of Prostate

 Benign and malignant changes in the prostate increase with age.

 men in the 8th of life show hyperplastic changes in >90% and malignant changes in >70% of individuals.

ANATOMY AND PATHOLOGY

 Prostate: the pelvis and is surrounded by the rectum, the bladder, the periprostatic and dorsal vein complexes and neurovascular bundles (for erectile function) , urinary sphincter ( passive urinary control).
 The prostate is composed of branching tubuloalveolar glands arranged in lobules surrounded by fibromuscular stroma.
 The acinar unit includes an epithelial compartment made up of epithelial, basal, and neuroendocrine cells
and separated by a basement membrane, and a stromal compartment that includes fibroblasts and smooth-muscle cells.
 Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) prod by epithelial cells.
 Both prostate epithelial cells and stromal cells express androgen receptors (ARs) = depend on androgens for growth.
 Testosterone, the major circulating androgen, is converted by the enzyme 5α-reductase to dihydrotestosterone in the gland.
 periurethral portion of the gland increases in size at puberty and after the age of 55 years (growth of nonmalignant cells in the transition zone of the prostate that surrounds the urethra).
 Most cancers develop in the peripheral zone, palpated during a digital rectal examination (DRE).
 1 in 6 men will be dx with prostate cancer
Prostate  the second leading cause of cancer deaths in men, only 1 man in 30 DIAGNOSIS AND TREATMENT BY CLINICAL STATE
Cancer with prostate cancer will die of his disease.
 The prostate cancer continuum—from the appearance of a preneoplastic and invasive lesion that is localized to the gland,---> metastatic
EPIDEMIOLOGY lesion causing symptoms---> mortality—can span decades.
 RISK: increases 2.5-fold :one first-degree relative is affected and  CIinical States
fivefold if two or more are affected.  defined operationally on the basis of whether or not a cancer diagnosis
 40% of early-onset and 5–10% of all prostate cancers are hereditary. has been established and, for those with a diagnosis, whether or not
 African-American males have a higher incidence , more advanced metastases are detectable on imaging studies and the measured level
stage with higher-grade, more aggressive tumors. of testosterone in the blood.
 high risk in families has been linked to the HPC1 (hereditary  . For those with a prostate cancer diagnosis, the clinical states model : considers the probability of developing symptoms or dying
prostate cancer 1) susceptibility locus in RNASEL. from the disease.
 single-nucleotide polymorphisms (SNPs) in the vitamin D receptor in  cure—the elimination of all cancer cells (primary therapeutic objective of treatment for most cancers)
African-Americans and variants in the AR, CYP3A4 ---> involved in Cancer control: tempo of the illness is determined to be so slow or has been altered where it is unlikely to cause symptoms, tometastasize, or to
the deactivation of testosterone, as well as CYP17, which is involved shorten a patient’s life expectancy.
in steroid biosynthesis.
Risk factors
 environmental and dietary factors may play a role in prostate cancer
growth and progression.
 High consumption of dietary fats, such as α-linoleic acid or
polycyclic aromatic hydrocarbons ( form when red meats are
cooked): increase risk.
 risk of prostate cancer in Asian men increases when they move
to Western environments.

Protective factors
 consumption of the isoflavonoid genistein (which inhibits 5α-
reductase),
 cruciferous vegetables with isothiocyanate sulforaphane,
 Lycopene (tomatoes)
 inhibitors of cholesterol biosynthesis (e.g., statin drugs).
 Not smoking, regular exercise, and maintaining a healthy body
weight: reduce the risk of progression

Source: Harrison’s ShiennaMarie Page 1 of 7

  The development of prostate cancer is a multistep process.
Pathophysio  Early change: hypermethylation of the GSTP1 gene
promoter, ---> loss of function of a gene that detoxifies
carcinogens. Cancers develop adjacent to a lesion termed
PIA (proliferative inflammatory atrophy) ==role for
inflammation
Prevention
 No agent is currently approved for the prevention of
prostate cancer.
No Cancer
 5α-reductase inhibitors (5ARI) :predominant therapy to reduce
DIagnosis the future risk of a prostate cancer diagnosis.
 The Prostate Cancer Prevention Trial (PCPT), men aged >55 years
( 5ARI finasteride), : 25% reduction in prostate cancer incidence
(from 24% with placebo to 18% with finasteride): Finasteride
iinhibits type 1 isoform
REDUCE (Reduction by Dutasteride of Prostate Cancer Events trial)=
dutasteride: a reduction in incidence from 25% with placebo to 20%
with dutasteride (Dutasteride inhibits both the type 1 and type 2 5ARI
isoforms.)
Screening/Early Detection and Diagnosis
 Considerations for whether to pursue a diagnosis include :
 symptoms,
 an abnormal DRE, OR
 a change in or an elevated serum PSA.
 Genetic risk
I. HISTORY
- focus on symptoms of outlet obstruction, continence, potency, or
change in ejaculatory pattern
II. PHYSICAL EXAMINATION
 DRE focuses on
 prostate size and
 consistency and
 abnormalities within or beyond the gland.
- @ peripheral zone and may be palpated on DRE.
- Carcinomas: charac hard, nodular, and irregular, while
induration may also be due to benign prostatic
hyperplasia (BPH) or calculi.
= 20–25% of men with an abnormal DRE have prostate
cancer.
Source: Harrison’s
III. PROSTATE-SPECIFIC ANTIGEN IV. SECOND-LINE SCREENING TESTS
 PSA (kallikrein-related peptidase 3; KLK3): serine protease that causes liquefaction of seminal  The 4Kscore® Test (OPKO Lab,
coagulum. Nashville, TN): measures four
 It is produced by both nonmalignant and malignant epithelial cells = prostate-specific, (not prostate-specific kallikreins
prostate cancer– specific)  (total PSA,
 Serum levels INCREASE:  free PSA,
 Cancer  intact PSA, and
 from prostatitis and  human kallikrein 2).
 BPH.  The results are combined with
 cystoscopy or prostate biopsy can increase PSA levels up to tenfold for 8–10 weeks. clinical information: estimates an
 PSA circulating in the blood is inactive and mainly occurs as a complex with the protease inhibitor individual’s percent risk of being
α1-antichymotrypsin and as free (unbound) PSA forms. found to harbor an aggressive
 Free PSA is rapidly eliminated from the blood by glomerular filtration with an estimated half-life prostate cancer ---> opt for a
of 12–18 h. prostate biopsy
 Elimination of PSA bound to α 1-antichymotrypsin is slow (estimated half-life of 1–2 weeks) as it Prostate Health Index (PHITM,
too is largely cleared by the kidneys. Innovative Diagnostic Laboratory,
 Levels should be undetectable after about 6 weeks if the prostate has been completely removed Richmond, VA) : blood test that
(radical prostatectomy). estimates the risk of having prostate
 Immunohistochemical staining for PSA can be used to establish a prostate cancer diagnosis. cancer. combination of the free PSA,
 Most (90%) prostate cancer deaths: men with PSA levels in the top quartile (>2 ng/mL), total PSA, and the [-2]proPSA isoform of
minority of men with PSA >2 ng/mL will develop lethal prostate cancer. free PSA. combined in a formula that
NOTE: They concluded that the quality of evidence for the benefits of screening was moderate for men calculates the PHI score. The PHI score is
aged 55–69 years. For men outside this age range, evidence was lacking for benefit, but the harms of a better predictor of prostate cancer
screening, including overdiagnosis and overtreatment, remained. than the total PSA test alone or the free
The AUA recommends : shared decision-making for men aged 55–69 years considering PSAbased PSA test alone.
screening, a target age group for whom benefits may outweigh harms.
Recommendation: shared decision-making for men aged 55–69 and do not recommend screening for V. PROSTATE BIOPSY
men aged ≥70;  DX of cancer: imageguided
has reduced the risks of screening. needle biopsy.
 Direct visualization by transrectal
THREE GUIDELINES ultrasound (TRUS), magnetic
resonance imaging (MRI)
 avoid PSA tests in men with little to gain.
 There is no rationale in asymptomatic men with a short life expectancy. Hence, men  prostate biopsy: sampling error
aged >75 years should only be tested in special circumstances,( higher than median PSAs  = men with abnormal PSA and
measured before age 70 or excellent overall health) negative biopsy are frequently
 men with low PSAs, ( <1 ng/mL): testing less frequently, every 5 years, with screening advised to
possibly ending at age 60 if the PSA remains at ≤1 ng/mL. undergo additional testing
 Second, do not treat those who do not need treatment (4Kscore Test, PHI, prostate MRI,
 Third, refer men who do need treatment to high-volume centers. and/or repeat biopsy)
ShiennaMarie Page 2 of 7
 For Prostate BIOPSY
- cutpoint for prostate biopsy (a total PSA ≥4 ng/mL), most men with a PSA elevation do not have
histologic evidence of prostate cancer at biopsy.
In addition, many men with PSA levels below this cut-point harbor cancer cells in their prostate.
Information from the Prostate Cancer Prevention
- Patients with symptomatic prostatitis should have a course of antibiotics before biopsy
- the routine use of antibiotics in an asymptomatic man with an elevated PSA level is strongly
discouraged.

Pathology  Each Core of the biopsy: examined for the presence of cancer Staging TNM
 amount of cancer is quantified: based on length of the cancer
And Staging
within the core and the percentage of the core involved.
 >95% of cancers are adenocarcinomas; Categories
 rest are squamous or transitional cell tumors or, rarely,  the basis of an abnormal PSA (T1c)
carcinosarcomas.  palpable but clinically confined to the gland (T2),
 Metastases: rare, may include colon cancers or transitional  extended outside the gland
cell tumors of the bladder via direct extension.
 Gleason grading system, in which the dominant and secondary TRUS is the imaging technique most frequently used to assess the primary
glandular histologic patterns are scored from 1 tumor, chief use is directing prostate biopsies, not
(well-differentiated) to 5 (undifferentiated) staging.
 summed to a total score of 2–10 for each tumor. Computed tomography (CT) lacks sensitivity and specificity to detect
 The most poorly differentiated area of tumor (i.e., the area extraprostatic extension and is inferior to MRI in visualization of lymph
with the highest histologic grade) = biologic behavior. nodes.
 The presence or absence of perineural invasion and MRI is superior to CT to detect cancer in the prostate and to assess local
extracapsular spread are also recorded. disease extent.
 a new 5-grade group system has been developed: - useful for the planning of surgery and radiation therapy.
Grade Group 1 (Gleason score ≤6) T1-weighted MRI produces a high signal in the periprostatic fat, periprostatic
Grade Group 2 (Gleason score 3+4 = 7) venous plexus, perivesicular tissues, lymph nodes, and bone marrow. T2-
Grade Group 3 (Gleason score 4+3 = 7) weighted MRI demonstrates the internal architecture of the prostate and
Grade Group 4 (Gleason score 4+4 = 8) seminal vesicles.
Grade Group 5 (Gleason scores 9 and 10) Most cancers have a low signal, while the normal peripheral zone has a high
signal
 lowest risk as Grade Group 1
 predicts prognosis Radionuclide bone scans
(bone scintigraphy)
evaluate spread to
osseous sites. True-
positive bone scans are
uncommon when the PSA
is <10 ng/mL unless the
tumor is high-grade

Source: Harrison’s ShiennaMarie Page 3 of 7

 Radical Prostatectomy
Treatment  Patients with clinically localized disease: radical prostatectomy, radiation therapy, or active
surveillance.  Goal: excise the cancer completely with a clear margin,
Choice of therapy : factors  to maintain continence by preserving the external sphincter,
 the presence of symptoms,  and to preserve potency by sparing the autonomic nerves in neurovas bundle
 the probability that the untreated tumor will adversely affect the quality or duration of survival
 probability that the tumor can be cured by single-modality therapy directed at the prostate versus INDICATION
requiring both local and systemic therapy to achieve cure.  patients with a life expectancy of 10 years or more

After radical surgery to remove all prostate tissue, PSA should become undetectable in the blood within 6 PERFORMED via a retropubic or perineal approach, or via a minimally invasive robotic-assisted or hand-held
weeks. laparoscopic approach.
= PSA remains/detectable after radical prostatectomy, the patient is considered to have persistent or
recurrent disease. Outcomes : predicted using postoperative nomograms (pretx factors and pathology

After radiation therapy, in contrast, PSA does not become undetectable because the remaining nonmalignant PSA failure is usually defined as a value >0.1 or 0.2 ng/mL.
elements of the gland continue to produce PSA even if all cancer cells have been eliminated.
Neoadjuvant hormonal treatment with gonadotropin-releasing hormone (GnRH) agonists/antagonists: to
 T1, T2, and T3 disease:cancers with a range of prognoses improve the outcomes of surgery for high-risk pt. FOR 3 or 8 months of androgen depletion before surgery
 Some T3 tumors are curable with therapy directed solely at the prostate, and some T1 lesions have a showed that serum PSA levels decreased by 96%, prostate volumes decreased by 34%, and margin positivity
high probability of systemic relapse that requires the integration of local and systemic therapy to rates decreased from 41 to 17%. Not been shown to improve PSA relapse–free survival.
achieve cure.
Adverse effect
prognostic models or nomograms that use a combination of the initial clinical T stage, biopsy Gleason score,  Incontinence
the number of biopsy cores and baseline PSA. older age and
 discrete cut-points (PSA <10 or ≥10 ng/mL; Gleason score of ≤6, 7, urethral length
or ≥8); The skill and experience of the surgeon

Recommend: radical surgery for a younger patient with a low probability of cure. recovery of erectile fxn, assoc w:
 younger age,
adverse events  quality of erections before surgery, and
 radical prostatectomy: incontinence 2 to 47% and impotence 25 to 89%. After surgery,  absence of damage to the neurovascular bundles.
impotence is immediate but may reverse over time, while with radiation therapy impotence is  erectile function begins to return about 6 months after surgery if neurovascular
not immediate but may develop over time. tissue has been preserved.
 Of greatest concern to patients are the effects on continence, sexual potency, and bowel function Potency is reduced by half if at least one neurovascular bundle is sacrificed.
- drugs such as sildenafil, intraurethral inserts of alprostadil, and intracavernosal injections of vasodilators:
recover satisfactory sexual function.

Source: Harrison’s ShiennaMarie Page 4 of 7

 Radiation Therapy
- given via external beam,
- by radioactive sources implanted into the gland,
- or by a combination of the two techniques.
1. External beam radiation therapy
 external beam intensity-modulated radiation therapy (IMRT)
permits shaping of the dose, and
allows the delivery of higher doses to the prostate and a
dramatic reduction in normal tissue
 safe administration of doses >80 Gy
Cancer control after radiation therapy , criteria:
 decline in PSA to <0.5 or 1 ng/mL,
 “nonrising” PSA values, and
 Neg biopsy of the prostate 2 years after completion
of treatment.
biochemical failure a rise in PSA by ≥2 ng/mL higher than the
lowest PSA achieved.
androgen deprivation therapy (ADT) in combination with radiation.
 intermediate-risk prostate cancer= short-course ADT (6 months),
PLUS external beam radiotherapy : improvements in overall
survival.
 highrisk disease: longer courses of ADT (18–36 months)
Neoadjuvant hormone therapy before radiation therapy:
 to decrease the size of the prostate and,
 to reduce the exposure of normal tissues to full-dose radiation,
 to increase local control rates, and
 to decrease the rate of systemic failure.
 Short-term hormone therapy =reduce toxicities and improve
local control rates
 long-term treatment (2–3 years) : to prolong the
time to PSA failure and lower the risk of metastatic disease in
men with high-risk cancers.
Source: Harrison’s
2. Brachytherapy
 direct implantation of radioactive sources (seeds) into the
prostate.
 Goal:
 deliver intensive irradiation to the prostate,
 minimizing the exposure of the surrounding tissues.
 Performed transperineally as an outpatient procedure with real-
time imaging.
 INDICATION: pt with good or intermediate prognostic features.
 SE: urinary frequency and urgency that can persist for several
months.
 Incontinence 2–4%
 Proctitis <2%
Active surveillance
 described previously as watchful waiting or deferred therapy
 INDICATIN: patients with cancers of low aggressiveness that can
be safely monitored at fixed intervals with DREs, PSA
measurements, imaging (usually prostate MRI), and repeat
prostate biopsies as indicated until histopathologic or serologic
changes correlative of progression warrant treatment with
curative intent.
 criteria includes men with clinical T1c tumors that are biopsy
Gleason grade 6 (Grade Group 1) involving 3 or fewer cores, each
core having <50% involvement by tumor, and a PSA density of
<0.15.
ShiennaMarie
RISING PSA AFTER DEFINITIVE LOCAL THERAPY
 pt with sole manifestation of disease is a rising PSA after surgery
and/or radiation therapy. there is no evidence of disease on
imaging studies.
 central issue: whether the rise in PSA results from persistent
disease in the primary site, systemic disease, or both.
 The decision to recommend radiation therapy after
prostatectomy is guided by the pathologic findings at surgery and
an MRIof the prostate or prostate bed
 Or with biopsy of the urethrovesical anastomosis before
considering radiation.
 Factors that predict for response to salvage radiation therapy:
 positive surgical margin,
 lower Gleason score in the radical prostatectomy specimen,
 long interval from surgery to PSA failure,
 slow PSA doubling time, and
 low (<0.5–1 ng/mL) PSA value at the time of radiation
treatment.
Radiation therapy: NOTrecommended if the PSA was persistently
elevated after surgery (disease had spread outside of the area of
the prostate bed and is unlikely to be controlled with radiation therapy).
Page 5 of 7
 METASTATIC DISEASE: NONCASTRATE
noncastrate metastatic disease =men with
metastases visible on an imaging study at the time of
diagnosis or after local therapy(ies), and noncastrate
levels of testosterone (>150 ng/dL).
Symptoms: pain from osseous spread
Less common are symptoms related to marrow
infiltration by tumor
(myelophthisis), coagulopathy, or spinal cord
compression.
- Treatment: to deplete/lower androgens by medical
or surgical (least acceptable)
- antiandrogens
 combination of ADT plus docetaxel, OR ADT
plus abiraterone plus prednisone
Testosterone-Lowering Agents
 lower testosterone levels: GnRH agonists/antagonists,
17,20-lyase inhibitors, CYP-17 inhibitors, and estrogens
such as diethylstilbestrol (DES)
 DES: risk of vascular complications such as fluid retention,
phlebitis, emboli, and stroke.
 GnRH agonists/antagonists (leuprolide acetate and
goserelin acetate) = produce a rise inLH and FSH--->
downregulation of receptors in the pituitary gland--->
chemical castration.
 relatively contraindicated in men with significant
obstructive symptoms, cancer-related pain, or spinal
cord compromise.
 Pure androgen antagonists such as bicalutamide can
be used to prevent flare.
 GnRH antagonists such as degarelix = castrate levels
of testosterone within 48 h without the initial rise in
serum testosterone and may be associated with a
lower risk of cardiovascular
complications.
 SE: androgendeprivation syndrome ( hot flushes,
weakness, fatigue, loss of muscle mass, anemia,
change in personality, and depression. Changes in
lipids, obesity, and insulin resistance, increased risk
of diabetes and CV, decrease in bone density
(fractures)
 Baseline fracture risk can be assessed using the FRAX
scale,
 patients are advised calcium and vitamin D
supplementation, along with a bisphosphonate,
RANK-ligand inhibitor (denosumab), or torimefene.
Antiandrogens
 Nonsteroidal first-generation
antiandrogens (bicalutamide and
nilutamide)= block the ligand binding
to the AR .
 When antiandrogens are given alone,
testosterone levels increase (cause
fewer hot flushes, less of an effect on
libido, less muscle wasting, fewer
personality changes, and less bone
loss)
 Gynecomastia: problem. Prev by
tamoxifen or prophylactic breast
irradiation.
 use of these first-generation: limited
to the first 2–4 weeks of treatment,
to protect against the flare (combined
to GNRH analogue or surg
orchiectomy)
Intermittent Androgen Deprivation Therapy
(IADT)
 To reduce the side effects of androgen
depletion
 way to prevent the selection of cells that
are resistant to androgen depletion.
 allowing endogenous testosterone levels
to rise
---> the cells that survive androgen depletion
will induce a normal differentiation pathway-->
surviving
cells that are allowed to proliferate in the
presence of androgen will
retain sensitivity to subsequent androgen
depletion.
 androgen depletion is continued for 2–6
months beyond the point of maximal
response.
 Once stopped, endogenous
testosterone levels increase, and the
symp assoc with hormone treatment
abate. PSA levels also begin to rise, and
at some level treatment is restarted.

Metastatic disease METASTATIC DISEASE: CASTRATE Pain Management

Castration-resistant prostate cancer (CRPC), disease that progresses while the measured levels of
Castrate
testosterone in the blood are 50 ng/mL or lower---> complications
 The most common manifestation: rising PSA, frequently cooccurring with progression in
bone.
 Nodal and/or visceral spread: lessnfrequent
 Pain secondary to osseous metastases = complication and major cause of morbidity, worsened by the narcotics
needed to control symptoms.
 Management requires accurate diagnoses because non-cancer etiologies including degenerative disease, spinal
stenosis, and vertebral collapse secondary to bone loss are common.
 Neurologic symptoms that are suggestive of base of skull disease or spinal cord compromise= emergency
evaluation= neuro symtoms or neuro fxn loss = external beam radiation

 docetaxel : only FDA-approved life-prolonging therapy for CRPC.
 NOW, recognized that the majority of mCRPCs continue to express the AR = overexpression
of the receptor itself and the enzymes in the androgen biosynthesis pathways
 = next-generation antiandrogen enzalutamide
and the CYP-17 inhibitor abiraterone acetate (PLUS prednisone),= prolong life and
are FDA-approved for use in CRPC in both the pre- and post-chemotherapy setting
 Diffuse symptoms in the absence of neurologic deficits = bone-seeking radioisotopes such as
radium-223 or the beta emitter 153Sm-EDTMP, or mitoxantrone, or abiraterone acetate, enzalutamide, and
docetaxel.
 Radium-223: indicaion: patients with symptoms
 153Sm-EDTMP and mitoxantrone: for palliation of pain but not shown to prolong life.
 Abiraterone, enzalutamide, and docetaxel = palliate pain

Source: Harrison’s ShiennaMarie Page 6 of 7

 BENIGN BENIGN PROSTATIC HYPERPLASIA Diagnostic Procedures and Treatment
 BPH ---> Dev of lower urinary tract symptoms - LUTS: American Urological Association’s Symptom Index (AUASI), also adopted as the International Prostate Symptom Score (IPSS)
DISEASE
(LUTS) in men.  Asymptomatic : do not require treatment
 LUTS, further subdivided into:  Inability to urinate, gross hematuria, recurrent infection, or bladder stones: may require surgery.
 obstructive symptoms  In patients with symptoms, uroflowmetry : identify those with normal flow rates who are unlikely to benefit from treatment, and
 urinary hesitancy,  bladder ultrasound: identify those with high postvoid residuals who may need intervention
 straining,  Cystoscopy : hematuria is documented and to assess the urinary outflow tract before surgery.
 weak stream,  Imaging of the upper tracts: patients with hematuria, a history of calculi, or prior urinary tract problems.
 terminal dribbling,
 prolonged voiding,
 incomplete emptying)
 irritative symptoms
 urinary frequency,
 urgency,
 nocturia,
 urge incontinence,
 small voided volumes).
- LUTS: combination of the mass effect, prostatic
enlargement and age-related detrusor dysfunction.

TREATMENT
 Goal: symptomatic relief
 Alpha-adrenergic receptor antagonists : treat dynamic aspect of BPH by reducing sympathetic tone of the bladder outlet, --> decreasing resistance and
improving urinary flow.
 5ARIs treat the static aspect of BPH by reducing prostate volume. Also, in the prevention of BPH progression, as measured by prostate volume, the risk of
developing acute urinary retention, and the risk of having BPH-related surgery.
 The use of an alpha-adrenergic receptor antagonist PLUS 5ARI as combination therapy: symptomatic relief while preventing progression of BPH.
 phosphodiesterase-5 (PDE5) inhibitors: tx erectile dysfunction
 sildenafil, vardenafil, tadalafil, and avanafil
 The use of PDE5 inhibitors is not without controversy, however, given the fact that short-active phosphodiesterase inhibitors such
 Antivholinergics: tx overactive bladder
 Surgical therapy: second-line therapy and is usually reserved for patients after a trial of medical therapy.
goal: to reduce the size of the prostate, effectively reducing resistance to urine flow.
Surgical approaches: TURP, transurethral incision, or removal of the gland via a retropubic, suprapubic, or perineal approach, transurethral ultrasound-
guided laser-induced prostatectomy (TULIP), stents, and hyperthermia.

Source: Harrison’s ShiennaMarie Page 7 of 7