carcinoma of prostate in brief

1. Moderator: Dr.Sitharamaiah
Mch Urology
Presentor: Dr K. Meena Reddy
GS 2nd yr PG

2.  It is the 2nd most common cancer and sixth leading cause of cancer deaths
among men worldwide.
 Incidence by age
◦ Carcinoma prostate is strongly related to age with
 incidents rate ↑from 50 – 54 years
 Peak in 75 – 79 years
 Subsequent drop in 80-84 years later increase steadily
 Incidence by ethnicity
◦ African Americans are at higher risk than whites

3.  Advanced age
 Ethnicity
 Positive family history
◦ Age of disease onset in family member affects patients relative risk
 70 years – RR ↑ 4 fold
 60 years – RR ↑ 5 fold
 50 years – RR ↑ 7 fold
 Total fat intake, animal fat & red meat intake are associated with increased
risk
 Obesity – associated with ↑ risk of advanced Ca & high recurrence after Rx
 Vit D & Ca - ↑risk
 Previous vasectomy - ↑risk (?)
 (Lycopene, selenium, w-3 FAs (fish), Vit E – Protective)

4. ◦ 95% of prostate cancers are Adenocarcinomas
◦ 5% are Heterogenous - Arising from stromal/ epithelial/ ectopic cells
 Non Adeno Carcinomas
i. Epithelial variants
 Endometrioid
 Mucinous
 Adenoid cystic
 Signet ring
 Adenosquamous
 Squamous cell
 Transitional cell
 Neuroendocrine
 Comedo carcinoma

5. ii. Non epithelial variants
◦ Rhabdomyosarcoma
◦ Leiomyosarcoma
◦ Osteosarcoma
◦ Angiosarcoma
◦ Carcinosarcoma
◦ Malignant lymphoma
iii. Others – Metastatic neoplasms

6.  Cytologic characteristics of Ca Prostate include
◦ Hyperchromatic enlarged nuclei with prominent nucleoli, abundant basophilic
cytoplasm
◦ *Basal cell layer is absent in Ca Prostate (Present in normal gland, BPH gland,
precursor lesions)
so HMW keratin immunostaining is helpful for diagnosis in doubtful cases.
 Precursor lesions
◦ PIN (Prostate intraepithelial neoplasia)
◦ ASAP (Atypical small acinar proliferation) – high risk
◦ HGPIN

7.  Site: approximately
◦ 60 – 70% Ca. Prostate originate in peripheral zone
◦ 10 – 20% in transitional zone
◦ 5 – 10% in central zone
 Ca. Prostate is usually multifocal
 Spread
◦ Local
 Penetration of prostate capsule along perineural space
 Seminal vesical invasion
 Bladder trigone involvement
 Rarely – Rectal invasion (one way Denonvilliers fascia barrier)
◦ Lymphatic – LN chains of obturator, EIxternal, Internal, Common Iliac, pre sacral and periaortic
lymphnodes

8.  Haematogenous
◦ Axial skeleton is usual site for distant mets
 Lumbar spine
 Proximal femur
 Pelvis
 Thorasic spine
 Ribs, Sternum
 Skull
 Humerus
◦ Bone lesions of metastatic Ca. Prostate – Typically Osteoblastic
◦ Visceral mets most commonly involve lung, liver and adrenal gland
◦ Epidural space involvement – direct extension from vertebral body
◦ CNS involvement – direct extension from skull metastasis

9.  Chromosomal rearrangements at 8p, 10q, 11q, 13q, 16q, 17p, 18q described
in prostate cancer.
 Specific loss at 8p 23.2 &/ or gain at 11q 13.1 are predictive of prostate
cancer progression.
 Molecular events are not always spontaneous, but the product of
environmental influences (inflammation).
 Over expression of transcription factors like ERG and Etv1 are seen in Ca. P
 TMPRSS2 was fused with these genes suggesting fusion accounted for over
expression
◦ TMPRSS2: ERG fusion identified in 50% of tumors- represents early molecular event in
carcinogenesis.
 Men with family h/o breast and ovarian Cancer – Offered a genetic test of
family specific BRCA 1 or 2 mutations as they are at ↑risk of breast &
prostate carcinoma

10.  Symptoms
◦ Early stage Ca.P – asymptomatic
◦ Symptoms often suggest locally advanced/ metastastic disease
 Obstructive or irritating voiding complaints
 Bone pain & pathological #
 Symptoms of cord compression – Paresthesias, LL weakness, urinary or fecal
incontinance
 Signs
◦ DRE – induration or nodularity
◦ Bulky lymphadenopathy may lead to lymphedema of lower extremities
◦ Weakness/ spasticity of lower limbs and hyper reflexic bulbo cavernous reflex are
related to level of cord compression.

11.  Azotemia
Due to bilateral Ureteral Obstruction
 Trigone inv
 Retroperitoneal adenopathy
 Anemia
 ↑ALP – bone mets
 ↑Sr Acid Phosphatase

12.  PSA is a serine protease of hk family produced by epithelial component
of benign/ malignant prostatic tissues
 Unbound/ bound form (to α1- Antichymotrypsin, α2- Marcoglobulins)
 Diagnostic (screening tool)/ risk stratifier in known Ca. P
Note: BPH, prostatitis, urethral instrumentation, perineal insults like prolonged bike ride –
elevate PSA  False +ve results. 5α reductase inhibitors can lower PSA
 Normal level ≤ 4 ng/ ml
◦ PP value of 4-10 ng/ml is 20-30%
(So Ca. P screening strategies done when ↑PSA associated with other risk factors
like family history, race, age)
◦ PP value of > 10 ng/ml is up to 70%

13.  Refining:
o PSA Velocity – Rate of change of Sr. PSA.
o PSA doubling time – time required for PSA to double
o PSA density-ratio of PSA to gland volume
 ↑Sr. PSA by 0.75 ng/ml/year ↑risk of Ca.
 Very rapid increase of PSA is suggestive of prostatitis rather than cancer
 PSA level ↑ on avgerage of 0.12 ng/ml per gram of BPH tissue
 biopsy advocated only if PSA density exceeds 0.1 or 0.15( has its own
drawbacks)

14.  Prostate Cancer Antigen 3
◦ Non coding prostate specific mRNA
◦ 66-fold upregulation seen in Ca. tissue compared with adjacent non Ca. tissue with
accuracy of 75%.
◦ Particularly useful in the evaluation of men with negative prior biopsy and a rising
PSA.

15. A. Prostate Biopsy
◦ Indications – elevated Sr. PSA, abnormal DRE or both
◦ Procedure
 ↓ LA, antibiotic prophylaxis (FQs)
 ↓ TRUS guidance with spring loaded biopsy device coupled to imaging probe
◦ Traditionally 6 biopsies are taken throughout peripheral zone along parasagittal
line with optional additional sampling
 Transitional zone biopsy
 Anterior commissure biopsy
◦ “Saturation biopsy” (extended pattern) & transperineal approach improve cancer
detection
◦ Complications: hematospermia, hematochezia, hematuria in 40-50% pts life
threatening sepsis.

16. B. Grading
◦ “Gleason system” is most commonly employed grading system. It relies on low-
power appearance of glandular architecture under microscope
◦ Gleason grader range from 1 to 5
 g-1,2 are rarely assigned
 g-3 – low grade disease (variable sized glands that percolate through normal stroma
and between normal glands)
 g-4 – Intermediate grade disease (incompletely formed glands with variable amount of
fusion and more infiltrative growth pattern)
 g-5 – high grade disease (single infiltrating cell with no gland formation)

17. ◦ Pathologist assign
 1° grade – pattern of tumor that is most commonly observed
 2° grade – 2nd most commonly observed pattern in specimen
represented as (3 +4)
◦ Gleason score or Gleason sum – Obtained by adding 1° & 2° grades
 Score 2-4 ≃ well differentiate tumor
 Score 5-7 ≃ moderately differentiate tumor
 Score 8-10 ≃ poorly differentiate tumor

18.  For T- stage (Primary tumor
Categorization) – Clinical staging
system uses results of DRE & TRUS, but
not the results of biopsy

21. D. Imaging
1. TRUS
 Carcinoma prostate appears as Hypoechoic lesion in peripheral zone &/or
hypervascularity seen on power doppler examination
 sonographic criteria for
 Extracapsular extension – bulging prostate contour/ angulated appearance of lateral margin
 Seminal vesicle invasion – posterior bulge at base of SV asymmetry in echogenicity of sv
 Elastography – differential compressibility of benign Vs malignant tissues
2. Endorectal MRI – high image quality but operator dependent, require
expertise

23. 3. Axial Imaging(CT,MRI)
 Neither modality is particularly accurate for local T Staging
 For detection of LN metastasis in high risk patients & for CT guided biopsies of LNs
4. Bone scan
◦ Most common site of Carcinoma Prostate metastasis is Bone
◦ Not done as inv in 1° evaluation if asymptomatic, T1T2 disease, PSA<20 ng/ml
5. Antibody imaging
◦ Not used routinely
◦ Used for initial staging & workup of recurrent disease
◦ ProstaScint (Murine monoclonal antibody) to prostate specific membrane antigen (PSMA) is
conjugated to 111 Indium
◦ After infusion of antibody, SPECT images are obtained at 30min, & at 72 – 120 hours

24. E. Multivariable Risk Assessment :
CAPRA (Cancer of the Prostate Risk
Assessment) Score
◦ 5 variable – PSA, Gleasons score, T-
Stage, % biopsy cores positive and age
 0-2 – Low risk disease
 3-5 – Intermediate risk
 6-10 – high risk

25.  Screening: with DRE & PSA
◦ Undertaken at the age of 50, but started at the age of 40 for men with risk factors
◦ Interval – annual is recommended but if PSA level ≤ 1 ng/ml – screening at 2-3
year interval is done
 Chemoprevention
◦ 5α – Reductase inhibitors (Finasteride, Dutasteride)
(but associated with sexual side effects, whereas urinary symptoms are
significantly ameliorated)

26.  Primary disease
◦ Men with low risk disease – Active surveillance
◦ Low to intermediate risk – local monotherapy (surgery or radiation)
◦ High-risk disease – multimodality therapy (RT + HT or Surgery--> radiation depending
on pathology & PSA outcome)

27. 1. Active Surveillance
◦ Practiced in men with well characterized, early stage, low grade tumors because
disease specific mortality is low
◦ but they may progress (related to tumor grade), hence this procedure remains
underused as an initial management strategy
◦ Pt’s are followed up carefully with serial DRE & PSA assessments & follow up
TRUS guided biopsies to ensure stability of tumor

28. 2. Radical Prostatectomy
◦ Removal of prostate gland + seminal vesicles
◦ LN dissection if significant LN mets present
◦ Approaches
 Perineal
 Retropubic – disadvantage of injury to dorsal venous complex
 Laparoscopic and Robotic are minimally invasive extraperitoneal/ intraperitoneal
approaches
◦ Prognosis depends on grade of tumor, stage of specimen, PSA response
◦ PSA fall to undetectable levels with in 6 weeks
◦ All men with LN inv should be offered adjuvant androgen deprivation therapy

29. Radical Prostatectomy (Contd..)
◦ Pt’s with adverse pathological features (+ve margins, extra capsular extension,
seminal vesical invasion) should be offered adjuvant radiation
◦ Complication
 Intraop – blood loss, rectal & ureteral injury
 Perioperative – DVT, PTE, Lymphocele formation, wound infections
 Late – Urinary incontinence of impotence

30. 2. Radiation Therapy
a) EBRT
 6500 – 7000 cGy to prostate
 use of improved imaging & novel treatment planning (with three dimensional, better targeting, & by
shaping radiation volume, higher doses can be given
 Whole pelvic radiation(with androgen deprivation) associated with improved outcome.
 Androgen deprivation
 Short term – 3-4 months
 Long term – 24 months
 Side Effects
 Early obstructive, irritative voiding/ bowel symptoms
 Long term complications – urethral strictures, Rectourinary fistula, radiation cystitis
 Novel radiation approaches with steriotactic radiation (Cyberknife) & proton beam
radiation

32. 3. Radiation Therapy (Contd..)
b) Brachytherapy
 TRUS guided placement of radioactive seeds
 Seeds can be permanent (I 125, Palladium 103)
 Seeds are removable (Iridium 192)
 High risk disease pts should receive androgen deprivation therapy prior to
brachytherapy

34. 4. Cryosurgery
◦ Freezing of prostate using cryosurgical device ↓TRUS guidance complications
 Erectile dysfunction
 Very common

35.  Recurrent disease
◦ Diagnosed by rising PSA after treatment
◦ Persistently detectable Sr. PSA after surgery is considered as failure, i.e. raise of at
least 2 ng/ml greater than the nadir level
◦ If interval to PSA failure is < 3-6 years & post treatment PSADT < 3m place the pt at
↑risk of metastasis & Ca specific mortality.

36.  Metastatic disease
◦ Initial endocrine therapy
 Carcinoma Prostate is a hormone (Testosterone) dependent tumor
 Testosterone produced by leydig cells in testes (95%), some amount by peripheral
conversion of other steroids
 Free Testosterone enter prostate cell, converted to DHT which bind to cytoplasmic ®
complex & modulates transcription in nucleus.

37.  Androgen deprivation can be induced at several levels along pituitary gonadal axis
Level Agent
Pituitary Diethylstilbestrol
Goserelin
triptorelin
Leuprolide
Historeli
Degarelix
Adernal Ketoconazole
Aminoglutethimide
Abiraterone
Testicle Orchiectomy
Prostate Cell Bicalutamide
Flutamide
Nilutamide

38.  Early endocrine therapy has survival advantage
 All metastatic diseases (Symptomatic/ asymptomatic) should be started on
endocrine therapy
 Side effect – Hot flushes, anemia, loss of libido, cognitive changes, ↑Total
cholesterol, ↑CDL, & TG, low bone mineral density

39.  Hormone refractory Carcinoma Prostate
◦ 2° hormonal therapy aimed at androgen biosynthesis pathway (Ketoconazole,
abiraterone)
◦ Immunotherapy
◦ Taxane based chemotherapy
◦ RANK (® activator of NFkB) ligant antibody-Slow the devp & progression of bone
metastasis (Denosumab)