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Overview of Carcinoma Prostate and Genetics
1.
2. Anatomy Of Prostate
• The prostate is a walnut-sized gland located in
front of the rectum and below the bladder.
• It surrounds the urethra, the tube-like channel
that carries urine and semen through the
penis.
• The primary function of the prostate is to
produce seminal fluid, the liquid in semen that
protects, supports, and helps transport sperm.
3. Base of the Prostate
The base is directed
upward near the
inferior surface of the
bladder. The greater
part of this surface is
directly continuous
with the bladder wall.
Apex of the Prostate
The apex is directed downward
and is in contact with the superior
fascia of the urogenital diaphragm.
Anatomy Of Prostate
4. Anatomy Of Prostate
• Blood supply
– Inferior vesical artery
• Derived from the internal iliac artery
• Supplies blood to the base of the bladder and prostate
• Capsular branches of the inferior vesical artery
– Help identify the pelvic plexus
• Nerve supply
– Neurovascular bundle
• Lies on either side of the prostate on the rectum
– Derived from the pelvic plexus , arising from the S2-4 and
T10-12 nerve roots
– Important for erectile function.
5. Prostatic Zonal Anatomy
• There are four zones
of the prostate :
the peripheral zone
(PZ) ,
transition zone (TZ) ,
Central zone, and
anterior fibromuscular
stroma zone.
6. • Peripheral zone (PZ)
– 70% of cancers
• Transitional zone (TZ)
– 20%
• TZ prostate cancers are
relatively nonaggressive
• PZ cancers are more
aggressive
– Tend to invade the peri-
prostatic tissues.
9. Metastatic Lymph Nodes
• Distant lymph nodes lie outside the confines of the
true pelvis.
• The distant lymph nodes include the following:
• Aortic (paraaortic lumbar)
• Common iliac
• Inguinal, deep
• Superficial inguinal (femoral)
• Supraclavicular
• Cervical
• Scalene
• Retroperitoneal
10. Epidemiology
Second leading cause of cancer death in men from western
countries
It is one of the 10 leading cancer sites in males in India,
accounting for about 4 % all male cancers
Age-adjusted annual incidence 176 per 100,000 in USA, whereas
only 7.1 in Mumbai and 4.3 in Bangalore (NCRP 1990-96)
11. Etiology
• Family history: 2-3 fold increased risk in men with a first
degree relative.
• Hereditary association: Early onset of disease and a
Mendelian autosomal dominant inheritance– accounting for
<10% of all cases but 40% in younger men in <55 years.
• Racial Factors: Striking differences in incidence and mortality
between the Black and White population, more common in
blacks.
• Environmental Factors: also responsible for ethnic differences,
as Asians migrating to USA have higher incidence of prostate
cancer.
12. Etiology
• Diet: one of the most important modifiable risk factors -- high
fat intake increases risk whereas diets rich in carotenoids
(tomato based products containing lycopene) and vitamin-E
are protective.
• No association with cigarette smoking, alcohol use, height
and weight and blood group.
• No data regarding viral origin.
• No convincing evidence that Vasectomy increases risk of
prostate cancer
13. Pathology
• Adenocarcinoma
– 95% of prostate cancers
• Developing in the acini of prostatic ducts
• Rare histopathologic types of prostate carcinoma
– Occur in approximately 5% of patients
– Include
• Small cell carcinoma
• Mucinous carcinoma
• Endometrioid cancer (prostatic ductal carcinoma)
• Transitional cell cancer
• Squamous cell carcinoma
• Basal cell carcinoma
• Adenoid cystic carcinoma (basaloid)
• Signet-ring cell carcinoma
• Neuroendocrine cancer
14. CLINICAL MANIFESTATIONS
• EARLY STAGE
• Asymptomatic
• Cancer is in the peripheral
zone
• LOCALLY ADVANCED DISEASE
• Obstructive / irritative
voiding
Hesitancy
Intermittent urinary stream
Decreased force of stream
--- May have growth into
the urethra or bladder
neck
• Retention of urine
• Hematuria
• Hematospermia
• Renal failure
• Pelvic pain
• ADVANCED DISEASE (spread
to the regional pelvic lymph
nodes)
• Edema of the lower
extremities
• Pelvic and perineal
discomfort
• METASTATIC DISEASE
• Bone pain
• Spinal cord
compression symptoms
• Paraperesis
18. T1a: Tumor with an incidental histologic finding in 5% or less of tissue
resected
T1b: Tumor with an incidental histologic finding in more than 5% of
tissue resected
19. T2a: Tumor that involves one-half of one side or less
T2b: Tumor that involves more than one-half of one side but not both
sides
T2c: Tumor that involves both sides
21. T4: Tumor is fixed or invades adjacent structures other than seminal
vesicles such as
● external sphincter
● rectum
● bladder
● levator muscles and/or
● pelvic wall
22.
23.
24. DIAGNOSTIC WORK-UP
• Laboratory
– Complete blood cell count, blood biochemistry
– Serum PSA (total, free, percentage free)
– Plasma acid phosphatases (prostatic/total)
• Radiographic imaging
– Transrectal ultrasonography (for biopsy guidance)
– Biopsy/Needle biopsy of prostate (transrectal,
transperineal)
– Chest radiograph (high risk for metastatic disease)
– Computed tomography of pelvis.
– Radioisotope bone scan
– Magnetic resonance imaging.
– PET CT Scan for metastasis in high risk cases
25. Diagnosis
• Signs and symptoms of Prostatism
• Abnormal DRE: although correlates poorly with the
volume and extent of cancer, an integral part of the
algorithm.
• Serum PSA: usually > 4 ng/ml
With increasing PSA level, chance of getting cancer
increases, but less likely to be organ confined.
• TRUS guided Biopsy:
1) to establish the diagnosis.
2) to report extent and grade of cancer in each core.
3) to document presence of PNI or ECE.
26. LABORATORY INVESTIGATIONS
• PROSTATE SPECIFIC ANTIGEN
– Serine protease glycoprotein secreted by prostatic epithelium
– Carcinoma specific
– Normal : 0.4 - 4 ng/ml (upper limit 2.6 ng/ml)
– t1/2 : 2.2― 3.2 ±0.1 days
– Mild elevation 4 ― 10 ng/ml
– Significant elevation >10 ng/ml
– Sensitivity ― 85%
– Specificity – 65-70%
– Estimated rate of cancer detection by PSA screening ― 1.8-
3.3%
– Carcinoma with normal PSA ― 25%
27. • Age specific PSA :
– Age PSA
40-50 0-2.5
60-70 0-4.5
70-80 0-6.5
• Pretreatment serum PSA is also predictive of EPE and
SVI :
PSA Rate of organ-confined disease
– 4 -10 ng/ml 53% - 70%
10 -20 ng/ml 31% - 56%
• Roach’s Probability of ECE, SVI and LNI:
– ECE+ = 3/2×PSA +(GS-3)×10
– SVI+ = PSA +(GS-6)×10
– LNI+ = 2/3×PSA +(GS-6)×10
28. PSA density (PSAD)
• The PSAD was introduced particularly for men with
normal DRE and PSA levels of 4–10 ng/mL in order
to differentiate between BPH and prostate cancer.
• The PSAD is calculated by dividing the serum PSA
level by the prostate volume, as measured by
TRUS.
• The threshold level of 0.15 or above indicates
prostate cancer, while 0.15 or below indicates
benign disease.
29. PSA Velocity (PSAV)
• The concept of the PSAV was developed to aid
the early diagnosis of nonpalpable organ-
confined cancer, since such cases show high
PSA changes in a short period of time (i.e.,
increased PSAV).
• The PSAV is calculated using a formula that
incorporates at least three PSA levels measured
at 6 month (or more) intervals.
30. PSA Bounce Phenomenon
• The PSA bounce is a temporary rise in PSA level after
radiation therapy.
• It may occur anywhere between about 1 and 3 years
after treatment
• The magnitude of the bounce lies in the range 0.5–2
ng/mL and may last from a few months to around a year
• The reason for the bounce is not known
• Testosterone recovery after hormonal treatment may
cause a PSA bounce in patients receiving androgen
ablation therapy along with radiotherapy
31. PSA Relapse
PSA relapse definition after RT
• ASTRO consensus → three consecutive increases in
PSA is the definition of biochemical failure after radiation
therapy. The date of failure should be the midpoint
between the post-RT nadir PSA and the first of the three
consecutive rises.
• Phoenix definition →
– (1) a rise by 2 ng/mL or more above the nadir PSA should be
considered the standard definition for biochemical failure after
external RT with or without hormonal treatment;
– (2) the date of failure should be determined “at call” (not
backdated).
32. Digital Rectal Examination
• Cornerstone of the physical examination/ instrumental in staging
• Sim’s lateral position.
– Organ palpation:
• Craniocaudal and transverse dimension
• Consistency / Mobility
• Any firm/ elevated area and its size.
• Typical finding ca prostate- Hard, nodular, asymmetrical, may
or may not be raised above the surface of gland and is
surrounded by compressible prostatic tissue.
– Prostatic induration - BHP nodule/ calculi/ infection/
granulomatous prostatitis / infarction
– Specificity- 50% and Sensitivity- 70%
– Only 25-50% of men with an abnormal DRE have cancer.
– DRE + PSA specificity 87%
35. Gleason’s Score
• Donald F. Gleason in 1966 created a unique
grading system for prostatic carcinoma based
solely on the architectural pattern of the
tumor.
36.
37. Gleason’s Score
• Prostate cancer has a pronounced morphological
heterogeneity and usually more than one
histological pattern is present.
• The primary and secondary pattern, i.e. the most
prevalent and the second most prevalent pattern
are added to obtain a Gleason score or sum.
• Gleason Score= Predominant pattern (1-5) +
Secondary pattern (1-5)
• Best Score=2, Worst Score=10
42. CT SCAN
• Primary role
– Size determination of the gland
– Assess pelvic LN metastasis
– Treatment planning in RT
– Extra Prostatic Extension:
• Loss of periprostatic fat planes
• Bladder base deformity
• Obliteration of the normal angle b/w the SV and post. aspect of UB
– LN involvement
• Abnormality in size
• Sensitivity 25%
• Reserved for patients with higher PSA values (>20-25 ng/ml)
• CT guided FNAC
43. MRI
• Superior to CT in defining prostate apex, NVB and anterior rectal wall
• Better delineation of periprostatic fat involvement
– T1w- provides high contrast b/w water density
structures i.e. Prostate, SV and fat, NVB, perivesical
tissue and LNs
– T2w fast spine echo- zonal anatomy, architecture of
SV
• Ca Prostate: A focal, peripheral region of decreased signal intensity
surrounded by a normal(high intensity) peripheral zone
• BHP: centrally located nodules of similar signal
• Primary staging sensitivity- 69%
• Endorectal surface coil MRI- accuracy of 54-72% staging the primary
and detects SVI and ECE
44. • Indications: High likelihood of capsular invasion and LN metastasis
– Abnormal DRE
– PSA>20
– Poorly differentiated ca
• Sensitivity to locate gland tumor- 79% and specificity- 55%
• LN detection- Low sensitivity but high specificity
45. 99Tc BONE SCAN
• Clinically apparent metastatic disease limited to bone in 80-85%
of patients of metastatic ca prostate
• Osteoblastic secondaries
• MC sites of metastasis
– Vertebral column- 74%
– Ribs- 70%
– Pelvis- 60%
– Femora- 44%
– Shoulder girdle-41%
Indications: Pretherapy
– Early stage disease-T1-T2 with
• PSA > 20 ng / ml
• GS≥ 8
• Bony pain
– T3-T4 –Symptomatic patients
– High grade tumor
– Base line: Elderly, patients with h/o arthritis, to document degenerative
changes that may later be interpreted as metastatic osseous disease and to
assess t/t effectiveness
46. What is a Prostate-Specific
Membrane Antigen (PSMA) study?
• PSMA studies are performed on newly diagnosed prostate
cancer patients to determine if the disease has spread to
pelvic lymph nodes.
• The study is also performed on patients who have had their
prostate gland removed and have an increase in prostate-
specific antigen (PSA) blood levels.
• PSMA is a membrane glycoprotein which is overexpressed
manifold on prostate cancers, and the expression increases
with Tumor Aggressiveness,
Androgen-independence,
Metastatic Disease,
Disease recurrence
47. • Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing
PSMA antigen with excellent sensitivity & specificity, thereby
detecting lesions remaining unidentified by conventional
methods.
• The study involves a special molecule called a monoclonal
antibody developed in a laboratory and designed to bind to
the prostate-specific membrane antigen on cancer cells. This
antibody is paired with a radioactive material called
Gadolinium 68 that can be detected by a gamma camera.
When injected into the patient’s bloodstream, the radioactive
antibody travels and attaches to cancer cells.
• The gamma camera then produces three-dimensional images
of the tumor and its location inside the body.
48. This 73-year-old man was recently diagnosed with prostate
cancer and has an elevated PSA. PET/CT shows the intense
activity in the prostate cancer (arrow) and the spread to the
left pelvic bone (b).
50. INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR
CLINICALLY LOCALIZED DISEASE
Risk Group
Clinical/Pathologic Features
Very low
Has all of the following:
• cT1c
• Grade Group 1
• PSA <10 ng/mL
• Fewer than 3 prostate biopsy fragments/cores positive, ≤50%
cancer in each fragment/core
• PSA density <0.15 ng/mL/g
Low
Has all of the following but does not qualify for very low risk:
• cT1–cT2a
• Grade Group 1
• PSA <10 ng/mL
Has all of the Has all of the following:
• 1 IRF
• Grade Group 1 or 2
• <50% biopsy cores positive (eg, <6
of 12 cores)
Intermediate
following:
• No high-risk group features
• No very-high-risk group features
• Has one or more intermediate
risk
Favorable
intermediate
Has one or more of the following:
• 2 or 3 IRFs
• Grade Group 3
• ≥ 50% biopsy cores positive (eg, ≥ 6
of 12 cores)
factors (IRFs):
cT2b–cT2c
Grade Group 2
or 3
PSA 10–20 ng/mL
Unfavorable
intermediate
High
Has no very-high-risk features and has exactly one high-risk feature:
• cT3a OR
• Grade Group 4 or Grade Group 5 OR
• PSA >20 ng/mL
Very high
Has at least one of the following:
• cT3b–cT4
• Primary Gleason pattern 5
• 2 or 3 high-risk features
• >4 cores with Grade Group 4 or 5
51. Life Expectancy Options
< 10years Observation
10 to 20years Active Surveillance
> 20 years Active Surveillance
RT
Surgery
Very Low Risk
53. Life Expectancy Initial Therapy Adjuvant Therapy
< 10years Observation
RT ADT (short course)
> 10years RT ADT (short course)
Surgery RT if adverse
features ADT
if LN positive
Intermediate Risk
54. Initial Therapy Adjuvant Therapy
RT ADT (long course)
Surgery RT if adversefeatures
ADT (long course) if LN
positive
High Risk
55. Initial Therapy Adjuvant Therapy
RT ADT (long course)
Surgery RT if adverse features
ADT (long course) if LN
positive
Treat like metastatic
disease, with ADT alone
(selectedpatients)
Very High Risk
56. ACTIVE SURVEILLANCE (AS) AND WATCHFUL WAITING (WW)
• AS generally consists of DRE and PSA every 3–6 months
with routine repeat biopsy in 1–2 yrs with definitive
treatment given if disease progresses.
• The goal of AS is to avoid or defer therapy (and side
effects) until necessary.
• WW watches for symptoms that may arise from prostate
cancer rather than regimented PSA, DRE, and biopsy,
typically in men not suitable for aggressive treatment.
• WW may forgo possibility of curative treatment but
symptoms are addressed
60. Salvage Radiotherapy
• Post RP recurrent
disease
Radical Radiotherapy
• T1, T2, T3, T4a
• Uresectable,
• Elderly , frail, comorbid
condition
• Refusal for surgery
• Prohibitive morbidity
due to surgery
Post op Radiotherapy
• pT3/4
• Close & positive margins
• Extracapsular extension
• Invasion to
• Seminal vesicles
• Extraprostatic extension
• multiple nodes
• R1 resection
• Pre op PSA >10ng/ml
• Pre op PSA velocity >2 ng/
ml/year
61. Target Volumes
CTV = entire prostate +/- seminal vesicles +/- LN.
■ Low-risk prostate cancer CTV = entire prostate only.
■ Intermediate-risk prostate cancer CTV = prostate + proximal 1 cm
of the bilateral seminal vesicles.
■ High-risk prostate cancer CTV = prostate + proximal 2 cm of the
bilateral seminal vesicles (consider entire seminal vesicles if grossly
involved) +/- LN regions.
■ Definition of the PTV
■ PTV: With CBCT IGRT, an 8 to 10 mm expansion is used, except
posteriorly, where a 5 to 8 mm margin is used. The PTV expands into
the rectum, whereas the CTV does not.
GTV adenocarcinoma of the prostate is not visualized well and therefore is
not contoured separately.
TARGET LOW RISK INTERMEDIATE RISK HIG RISK
CTV1 PROSTAE +/-
PROXIMAL
SEMINAL
VESICLES
(74GY)
PROSTATE +PROX.
SEMINAL
VESICLE(76-78GY)
PROSTATE=GROSS ETRACAPSULAR
DISEASE &PROX.SEMINL VESICAL(76-
78GY)
CTV2 -- DISTAL SEMINAL
VESICALS(56 GY)
DISTAL SEMINAL VESICLES AND
LN(56 GY)
62. Dose/Fractionation
Regimen Preferred Dose/Fractionation
Moderate Hypofractionation
(Preferred)
3 Gy x 20 fx
2.7 Gy x 26 fx
2.5 Gy x 28 fx
2.75 Gy x 20 fx
Conventional Fractionation
1.8–2 Gy x 37–45 fx
2.2 Gy x 35 fx + micro-boost to
MRI-dominant lesion to up to 95 Gy (fractions up to
2.7 Gy)
SBRT
Ultra-Hypofractionation
9.5 Gy x 4 fx
7.25–8 Gy x 5 fx
6.1 Gy x 7 fx
6 Gy x 6 fx
63. Brachytherapy
It is also a dose escalation method when
combined with EBRT.
Low Risk Disease: Brachy only
High Risk Disease: EBRT + Brachy
64. LDR Brachy
• As Brachy only: I125 144 Gy, Pd103 125 Gy.
• After EBRT 40-50 Gy: I125 110 Gy, Pd103 90 Gy.
HDR Brachy
• As Brachy only: 9.5Gy twice daily for 2 days or
10.5Gy in 3# over one day.
• After EBRT: 9.5Gy in 2# over one session.
68. The androgen-signaling axis and
its inhibitors. Testicular androgen
synthesis is regulated by the
gonadotropin-releasing
hormone (GnRH)–LH axis,
whereas adrenal androgen
synthesis is regulated by the
corticotrophin-releasing
hormone (CRH)-ACTH axis. GnRH
agonists and corticosteroids
inhibit stimulation of the testes
and adrenals, respectively.
Abiraterone inhibits CYP17, a
critical enzyme in androgen
synthesis. Bicalutamide,
flutamide, and nilutamide
competitively inhibit the binding
of androgens to androgen
receptors; enzalutamide also
blocks the translocation
of the ligand bound AR complex to the nucleus and from binding to DNA. DHEA,
dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulphate; DHT,
dihydrotestosterone; AR, androgen receptor; ARE, androgen-response element.
69. Ablation of
androgen source
Inhibition of
LHRH or LH
Inhibition of androgen
synthesis
Antiandrogens
Orchiectomy DES
Leuprolide
Aminogluthemide Cyprotene acetate
Goserelin Ketoconazole Flutamide
Triptorelin Biclutamide
Histrelin Nilutamide
Cetrorelix
Abarelix
70. RT + SHORT-TERM ADT
Randomized trials of stADT vs. no ADT report that
adding 3–6-mo ADT improves bPFS by 10–25% and
CSS by 3–8%.
71. RT + LONG-TERM ADT
For high-risk men, long-term ADT improves DFS, CSS, and
OS vs. no ADT or 4–6-mo ADT.
Current standard for most high-risk men is 2–3 yrs ADT, but
18 months may be reasonable for those with limited high-
risk features or comorbidity.
73. Schedule Frequency
First follow up 4-6 weeks after RT
0-1 years Every 3-4 months
2-5 years Every 6 months
5+ years Annually
Examination
History & Physical
Examination
Complete History & Physical
Examination
Annual DRE
Laboratory Tests PSA every 6-12 months for 5
years and then annually
Imaging Studies Based on clinical indication
only
Follow Up
74. GERMLINE TESTING
Pre-test Considerations
The panel recommends inquiring about family and personal history of cancer, and
known germline variants at time of initial diagnosis.
Testing
• If criteria are met, germline multigene testing that includes at least BRCA1,
BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2 is
recommended
Post-test Considerations
Post-test genetic counseling is strongly recommended if a germline mutation
(pathogenic/likely pathogenic variant) is identified. Cascade testing for relatives is
critical to inform the risk for familial cancers in all relatives.
75. It is recommended in patients with a personal history of
prostate cancer in the following scenarios
• By prostate cancer stage or risk group (diagnosed at any
age)
• Metastatic, regional (node positive), very-high-risk
localized, or high-risk localized prostate cancer
GERMLINE TESTING
76. It may be considered in patients with a personal history of
prostate cancer in the following scenarios
• By prostate cancer tumor characteristics (diagnosed at
any age)
• Intermediate-risk prostate cancer with
intraductal/cribriform histology
• By prostate cancer AND a prior personal history of any of
the following cancers:
– exocrine pancreatic, colorectal, gastric, melanoma, upper tract
urothelial, glioblastoma, biliary tract, and small intestinal
GERMLINE TESTING
77. Germline testing is recommended in patients
with a personal history of prostate cancer in
the following scenarios
≥1 first-, second-, or third-
degree relative with:
→ Breast, colorectal or
endometrial cancer at age≤50y
→ Ovarian, male breast or
exocrine pancreatic cancer at
any age
→ metastatic, regional, very-high-
risk, or high-risk prostate
cancer at any age
≥1 first-degree relative (parent or
sibling) with prostate cancer at
age ≤60 y
≥2 first-, second-, or third-degree
relatives with breast and prostate
cancer at any age
≥3 first- or second-degree relatives
with:
→ Lynch syndrome-related cancers,
especially if diagnosed <50 y:
colorectal, endometrial, gastric,
ovarian, exocrine pancreas, upper
tract urothelial, glioblastoma,
biliary tract, and small intestinal
cancer
A known family history of familial
cancer risk mutation especially
in: BRCA1, BRCA2, ATM,
PALB2, CHEK2, MLH1, MSH2,
MSH6, PMS2, and EPCAM
78. SOMATIC TESTING
Pre-test Considerations
The panel recommends inquiring about family and personal history of
cancer, and known germline variants at time of initial diagnosis.
Testing
• Tumor testing for alterations in homologous recombination DNA
repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA,
RAD51D, CHEK2, and CDK12, is recommended
• TMB testing and Tumor testing for MSI-H or dMMR is recommended
in patients with metastatic or regional castration-resistant prostate
cancer
Post-test Considerations
Post-test genetic counseling to assess for the possibility of Lynch
syndrome is recommended if MSI-H or dMMR is found
Unenhanced CT scan in 78-year-old man with prostate cancer, Gleason score of 34 at biopsy, PSA level of 21 ng/mL, and palpable tumor shows enlarged prostate with evidence of gross tumor ECE (arrow) along left posterolateral
margin of the gland.