PROSTRATE CANCER

Dr N K Mishra
 EMBRYOLOGY
• ENDODERM
• CLOACA
• URO RECTAL SEPTUM
• VENTRAL- UROGENITAL SINUS
• PROSTATIC BUD
 CYTODIFFERENTIATION
• 3 -COMPONENT
• EPITHELIUM
• EXTRACELLULAR MATRIX
• STROMA
 EPITHELIUM
• LUMINAL EPITHELIAL SECRETORY CELL(AP&
PSA)
• BASAL CELL
• INTERMEDIAT CELL
• NEURO ENDOCRINE CELL
 PROSTRATE ZONE
• ANTERIOR FIBROMUSCULAR- 30% of
prostrate, no glandular element.
• PERIPHERAL ZONE- Largest, 75% 0f glandular
tissue.
• CENTRAL ZONE-Surround ejaculatory duct,
25% of glandular element.
• TRANSITION ZONE-smallest, surround upper
urethral complex.
ENDOCRINE CONTROL OF PROSTRATE
 ENDOCRINE CONTROL OF PROSTRATE
• Testosteron- <1% adrenal
-peripheral coversion
-testis(major source)
-prostrate by its own
 TESTOSTERON
• <2% is free
• 98% in bound form
• 40% to s. albumin
• 57% to SHBG
• 1% to corticosteroid binding globulin(CBG)
• Normally large percentage of SHBG is
saturated and only small CBG and albumin is
used
• But when s. testosterone level increase in
plasma, saturation of protein proceeds from
SHBG to CBG & ALBUMIN
• So binding of androgen is a dynamic
equilibrium.
• Amount of testosterone binding depends on
two factor.
• 1-affinity
• 2-capacity
 S.ALBUMIN vs SHBG
ALBUMIN SHBG

1 low affinity for testosterone High affinity

2 high capacity because its in abundance Low capacity
3- 40% bound 57% bound
 TEST vs ESTROGEN
• Administration of testosterone decrease
SHBG.
• Administration of estrogen increase SHBG.
• Estrogen compete with testosterone for
binding to SHBG.
• But estrogen has only 1/3 the binding affinity
of testosterone.
• Administration of small amount of estrogen
increase the total concentration of SHBG and
this effectively increase the binding of
testosterone and that lower the free
testosterone plasma concentration.
• Testosterone is converted to DHT by 5 alpha
reductase type 2.
 5 ALPHA REDUCTASE
• Type 1
• Type 2
 EPIDEMIOLOGY
• m/c non cutaneous malignancy in US men.
• 27% of all such cancer.
• 1 in 7(15.3%) will be diagnosed with PCa.
• Incidence varies with race, ethnicity and age.
• 1989 to1992 incidence increased due to
screening by PSA.
• After 1992 incidence decreased due to “cull
effect”
 RISK FACTOR
• Environmental
• Ethnicity and racial
• Age
• Familial- increase risk with increase number of
family member affected.
• Genetic – BRCA gene, TMPRSS mutation,
HOXB13 gene
• Chronic inflammation
• Vitamin D
• Sexual activity
• Vasectomy
• Smoking( high risk of biochemical recurrence)
• Diet
• Obesity(high risk of biochemical failure)
 MOLECULAR EPIDEMIOLOGY
• Polymorphism in both synthesis and metabolic
gene including AR , 5 alpha reductase
inhibitor.
• Estrogen –may act as pro carcinogen.
• ILGF- this stimulate proliferation
• Leptin- development of advance disease.
Control body weight by appetite supression
 CHEMOPREVENTION
• Goal is to reduce incidence and treatment
related s/e and mortality.
• PRIMARY CHEMOPREVENTION
• 2NDRY CHEMOPREVENTION(HGPIN)
• TERTIARY PREVENTION
Prostrate cancer prevention
 PCa TUMOR MARKER
• BLOOD BASED BIOMARKER
 PSA
 Prostrate specific membrane antigen(PSMA)
 Human kallikrenin2(HK2)
 Endogalin
 Circulating tumor cell(CTC)
• URINE BASED BIOMARKER
 Prostrate cancer antigen 3(PCA3)
 Gene fussion (TMPRSS2+ERG or ETV1)
 Metabolomics.
 Anexxin 3 - inversely related
 Micro RNA
• TISSUE BASED MARKER
 Alpha methylacyl co-enzyme A racemase.
 Epigenetic modification.
 PSA(HK3)
• Begin as zymogen called pre pro PSA
cleaved
Pro PSA
Cleaved by HK2
PSA(active)
• It is organ specific but not cancer specific.
• Function is to liquefy semen by acting on
semenogelin and fibronectin.
 COMPLEXED PSA
• 70-80% is protein bound mostly to ACT
• PSA-ACT(alpha1 antichymotrypsin). Inactive
but detectable.
• PSA-A2M(alpha2 microglobulin)(5-10%)
• PSA-API( alpha1 protease inhibitor)1-2%
 FREE PSA
• Pro PSA
• BPSA(BPH-PSA)
• Intact PSA(IPSA)
• PSA level varies with age, race, prost vol
• Increased PSA are probably a disruption of
cellular architecture within prostrate gland.
• On per cell basis PSA expression is same in
benign and malignant prostrate cell.
• The loss of barrier( basal layer and basement
membrane) leads to egress of PSA into
circulation.
 PROSTRATE CANCER ANTIGEN 3
• PCA3 better in diagnosing Pca then PSA
specially when there is prior negative
prostrate needle biopsy.
 GENE FUSION
• TMPRSS2+ERG or ETV1 is 100% specific.
• Present in only 50 % of cases.
 PROSTRATE BIOPSY
• Digital direct prostrate biopsy-till 1980
• TRUS guided biopsy
• Systemic sextant
• Systemic double sextant
• Corpora amylacia highlight the plane between
PZ & TZ
 INDICATION OF TRUS
• Treatment planning and vol measurement
• Placement of RF marker for EBRT
• Evaluation of azospermia
• Diagnose prost cancer.
• Extensive PIN.
• Positive urinary PCA3.
 CONTRAINDICATION BIOPSY
• Coagulopathy
• Immunosupression
• Acute prostatitis
• Color and power Doppler elastography -
improve cancer detection.
• TRUS with MRI- improved result
 PATHOLOGY
• PIN – architectural benign prostatic acini or
duct lined by atypical cell.
• LGPIN
• HGPIN
 LGPIN
• Diagnostic report should not comment on
LGPIN because
 Pathology cant distinguish b/w LGPIN and
benign prostrate tissue.
 LGPIN patient are not at greater risk of having
carcinoma on repeat biopsy.
 HGPIN
• Precursor lesion to intermediate to high grade
adenocarcinoma.
• HGPIN on single core biopsy- then repeat
biopsy is not indicated on 1st year in absence
of other risk factor.
• HGPIN on 2 or more core – repeat biopsy
within an year.
 GRADE OF TUMOR
• Most differentiated -grade 1
• Undifferentiated – grade 5
• Most common and highest grade on a given
core were added to reasult in gleasons score.
• Gleasons score – min 2 & maxm 10
• Gleason score 2-4 is not recommended for
adenocarcinoma (uropathologist/
reproducibility, not favorable for radical
prostatectomy)
• Gleason 6 is the lowest score assigned on
biopsy material.
 GRADING BASED ON SCORE
Gleasons score Grade group Chemical risk free
<=6 1 97%

3+4=7 2 88%

4+3=7 3 69%

8 4 63%

9-10 5 34%
 DIAGNOSIS AND STAGING
• Rarely symptomatic at early stage
• Presence of symptom suggest advanced or metastatic stage
• Obst urinary symptom
• Haematospermia
• Decrease ejeculatory volume
 METASTATIC SYMPTOM
• Bone pain
• Pathological #
• Anemia
• b/l L/L oedema
 DIAGNOSIS
• DRE
• PSA
• CLINICAL RISK ASSESMENT
• TRUS
• MRI
• METASTATIC workup
STAGING
 RIST STRATIFICATION
risk criteria
Low risk PSA<10ng/dl
GS <7
T1-2a
Intermediate risk PSA 10-20
GS=7
T2b
High risk PSA >20
GS>7
T2c
Locally advance Any PSA
Any GS
T3-T4 &Nx
 MANAGEMENT OF LOW RISK DISEASE
(A) watchfull waiting (ww)
Asymptomatic patient
Life expectancy <10year
(B) Active survillance (AS)
To patient suitable for curative treatment with low risk
Pca
Perform multiparametric MRI(mMRI)
Follow up on DRE+PSA+repeat biopsy
Councell patient on possibility of needing further
treatment
C) Active treatment-
 surgery and RT
 No PLND- risk of node is <5%
(D) RT
 Low dose rate (LDR) brachytherapy- no previous TURP
with good IPSS and prost vol <50ml
 IMRT (74-80gy)without androgen deprivation
(E) Others
 Cryotherapy
 HIFU
 INTERMEDIAT RISK
(A)Active survillance (AS)-
highly selected patient(10% pattern 4)
Accepting the potential increased risk of further
metastasis.
(B) Radical prostetectomy
Life expectancy >10 year
Nerve sparing surgery for low risk and extra
capsular disease
Extended PLND to be performed
(C)RT
LDR brachy- no previous turp with good IPSS
and prost vol <50ml
EBRT+short term neoadjuvent+ ADT(4-
6month)
 if not willing for ADT then esclate the dose of
EBRT in combination with brachytherapy
 HIGH RISK LOCALISED DISEASE
(A)Radical prostatectomy + RPLND
 Don’t depent on frozren section whether to
proceed with RPLND or not
(B) RT
 EBRT+ADT(2-3year) OR
 EBRT+Brachytherapy boost(HDR or LDR)+
ADT
 LOCALLY ADVANCED DISEASE
(A)Radical prostretectomy
 To highly selected patient
 cT3b-T4 N0 or any T N1
 As part of multimodal treatment
 EPLND to be done
(B)RT
In N0- RT+ADT(2-3years)
(C)Others
No focal treatment
ADT as monotherapy-
 when unwilling or unable to resist any form of local
treatment
 when PSA doubling time of 12 month
 PSA>50
 Poorly differentiated tumor
ADJUVENT TREATMENT AFTER RP
• When post op PSA>0.1ng/ml
• No adjuvent theraoy in pN0 patient
• EBRT- when increased risk of local relaps(pT3pN0
with +Ve margin or invason of seminal vesicle)
• For pN+ after EPLND-
 ADT For N+
 ADT with Additional RT
 Observation(<=2 node with microscopic involvement/
PSA<0.1/ absence of extranodal extension.
 PALLIATIVE TREATMENT
(A) Localised disease
 Watchful waiting- asymptomatic pnt not eligible for
local curative treatment
 While on ww base the decision to start non
curative treatment on symptom and disease
progression
(B) Localy advanced disease
 ADT monotherapy to M0 asymptomatic pnt with
PSA-DT>12m, PSA <50 and well differentiated
tumor.
(C) Metastatic tumor
M1 symptomatic- immediat systemic
treatment to palliat symptom.
M1 asymptomatic- immediat systemic
treatment to imrove survival OR discuss
defered castration, provided the patient is
closely monitored(lowers treatment side
effect)
(D)All M1 patient
LHRH antagonist- impending spinal cord
compression
Pnt treated with LHRH agonist- short term
administration of anti androgen to stop “flare up”
phenomena.
Docetaxel+ castration when fit enough to tolerate
docetaxel.
Doce + castration +abireteron acetate+ prednisolon
FOLLOW UP AFTER CURATIVE TREATMENT

• Disease specific history

• DRE
• PSA( 3,6,12 month then every six month until
3 year and then annually)
• If s/o recurrence-only imaging to detect
recurrence.
• No routine bone scan.
 FOLLOW UP DURING HORMONAL
TREATMENT
• Evaluate at 3, 6 month after initiation of
treatment.
• M0- F. up after 6 month with- history + PSA +
DRE.
• M1- F.up, every 3-6 month- history + DRE+ PSA
+ Hb+ Creat+ Alkaline phosphates.
Testosterone level to be chkd during first year.