Carcinoma Of The Prostate (cap)

Carcinoma of the Prostate (CaP) Solis, Ma. Rachelle So-Reyes, Jamil Laurence Sto. Domingo, Braulio II Suller, Armida Section IIID

Incidence & Epidemiology Prostate Cancer (CaP)  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%

Incidence & Epidemiology Risk factors: Increasing age Age

Probability

> 40

1/10,000

40 - 59

1/103

60 - 79

1/8

Race → African American > whites

Incidence & Epidemiology (+) family history Age of onset in the family member diagnosed with CaP 70

Relative risk of patient

60

5X

50

7X

4X

Incidence & Epidemiology High dietary fat intake Exposure to cadmium - cigarette smoke - alkaline batteries - welding

Etiology 

Gene responsible for familial CaP resides in chromosome 1



Regions of the human genome that have been identified as possible areas that harbor tumor suppressor genes: 8p, 10q, 13q, 16q, 17p, 18q

Pathology 

>95%: adenocarcinomas



5%: transitional cell carcinomas (90%), neuroendocrine (“small cell”) carcinomas or sarcomas

Pathology Cytologic characteristics:  hyperchromatic, enlarged nuclei, w/ prominenent nucleoli 

cytoplasm abundant (NC ratio not often helpful in Dx) & slightly blue-tinged or basophilic



absent basal cell layer - HMW keratin immunohistochemical staining

Pathology Prostatic Intraepithelial Neoplasia (PIN)  precursor to invasive CaP  basal cell layer of the glandular architecture is present Classifications: High grade PIN (HGPIN)  associated with invasive CaP in ~5080% of cases  Low grade PIN (LGPIN)  ~20%

Pathology Prostatic Intraepithelial Neoplasia (PIN) This example of highgrade PIN shows all the classic histologic features: intermediate-to-large size preexisting glands displaying nuclear and nucleolar enlargement and fragmented basal cell layer

Pathology Origin of CaP:  



70% - peripheral zone 10-20% - transitional zone 5-10% - central zone

Grading & Staging Gleason grading system  most

commonly employed grading system in the US  relies upon the low power appearance of the glandular architecture under the microscope  pathologists assign a primary grade to the pattern of cancer that is most commonly involved & a secondary grade to the second most commonly observed pattern

Grading & Staging Gleason score or Gleason sum  primary grade + secondary grade  Gleason grades: 1- 5  Gleason scores: 2 - 10 Tumor

Grade

Well-differentiated

2-4

Moderately-differentiated

5-6

Poorly-differentiated

8-10

Grading & Staging Gleason grades 1 & 2  small,

uniformly shaped glands, closely packed, w/ little infiltrating stroma

Grading & Staging Gleason grade 1

The most important difference between Gleason pattern 1 and 2 is the presence or absence of circumscription respectively.

Grading & Staging Gleason grade 2

The focus of cancer is not circumscribed. The glands are round to oval and uniformly placed. There are no sharply-angulated or distorted glands.

Grading & Staging Gleason grade 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

Grading & Staging Gleason grade 3

Gleason grade 3 is the most commonly seen pattern. Even at low magnification, one can easily appreciate the variation in size, shape, and spacing of glands. Many small glands have occluded or abortive lumens. There is no evidence of glandular fusion.

Grading & Staging Gleason grade 3

This example of Gleason grade 3 cancer shows abundant amphophilic cytoplasm, enlarged nuclei with prominent nucleoli

Grading & Staging Gleason grade 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

Grading & Staging Gleason grade 4

The glands are fused and there is no intervening stroma. Glandular fusion is a hallmark of Gleason grade 4.

Grading & Staging Gleason grade 4

Higher magnification view of the previous slide. Most glands have occluded lumens. The nuclei are hyperchromatic.

Grading & Staging Gleason grade 5  single infiltrating cells, no gland formation or lumen appearance comedocarcinoma  cribriform glands w/ central areas of necrosis

Grading & Staging Gleason grade 5

Tumor cells are arranged in solid sheets with no attempts at gland formation.

Grading & Staging 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 system for prostate cancer 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

*T2a & b – confined to prostate

TNM staging system for prostate cancer 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.

Patterns of Progression seminal vesical invasion – associated with a high likelihood of regional or bladder disease 

locally advanced CaP may invade the bladder trigone ureteral obstruction

Patterns of Progression Lymphatic metastases: obturator lypmh node chain (most common) common iliac presacral periaortic lymph nodes Axial skeleton  most usual site of distal metastases

Patterns of Progression Sites of distal metastases: Lumbar spine (most common) Proximal femur Thoracic spine Ribs Sternum Skull Humerus

Patterns of Progression bone lesions typically osteoblastic  involvement of long bones fractures  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 

Clinical Findings

Symptoms  

       

early-stage CaP usually asymptomatic symptoms  suggests advanced or metastatic diseases Difficulty voiding or urinary retention Weak or interrupted flow of urine Frequent urination (especially at night) Pain or burning during urination. Increased urinary frequency Blood in urine Back pain Painful ejaculation

Symptoms obstructive or irritative voiding complaints  from local growth of the tumor into the trigone of the bladder metastatic disease of the vertebral column bone pain

Symptoms 

Metastatic disease to the vertebral column w/ impingement on the SC symptoms of cord compression (paresthesias, weakness of the lower extremities & urinary or fecal incontinence)

Signs Azotemia from bilateral ureteral obstruction (from direct extension into the trigone or from retroperitoneal lymphandenopathy) Specific signs of cord compression relate to the level of compression

Laboratory Findings Anemia – metastatic disease   alkaline phosphatase   serum acid phosphatase 

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) Serum PSA  combined w/ DRE & TRUS w/ systematic biopsy  not specific for CaP

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) PSA velocity PSA density Age-adjusted reference ranges for PSA Racial variations in CaP detection Molecular forms of PSA

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) PSA velocity  rate of change of serum PSA  annual PSA velocity > 2.0 ng/mL was associated significantly with disease recurrence, death from prostate cancer, and death from any cause1   PSA velocity significant only when several PSA assays are carried out by the same lab over a period of at least 18 mos

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) PSA density  ratio of the PSA to gland volume  Elevated ~ 0.12 ng/mL per g of BPH tissue Racial variations in CaP detection  black>white

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) Age-adjusted references for PSA  rate of change of serum PSA  serum PSA levels increase with age  traditional upper limit of reference range levels of PSA is 4 ng/mL

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) Age-specific PSA reference range levels2 (Oesterling et al) Patients Patients Patients Patients

aged aged aged aged

40-49 years, 50-59 years, 60-69 years, 70-79 years,

0-2.5 ng/mL 0-3.5 ng/mL 0-4.5 ng/mL 0-6.5 ng/mL

Tumor Markers PROSTATE-SPECIFIC ANTIGEN (PSA) Molecular forms of PFA Protein-bound  ~90% - α1-antitrypsin  others - α2-macroglobulin 

Free

Digital Rectal Exam (DRE) 





About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. Only 20% of men with abnormal DREs have cancer. About 60% of men who have prostate cancer have normal DRE results

Digital Rectal Exam (DRE)

The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities.

Prostate Biopsy Systematic sextant prostate biopsy  was the most commonly employed technique used in detecting CaP  biopsies obtained under TRUS guidance, from the apex, midsection, & the base of each side of the prostate at the midsagittal line halfway between the lateral border & midline of the gland  to predict extracapsular extension & risk of relapse following radical prostatectomy

Prostate Biopsy Systematic sextant prostate biopsy Indications: men over age 40 with elevated PSA abnormal digital rectal examination (DRE) abnormal ultrasound of the prostate (TRUS) urinary symptoms without an obstructive etiology of symptoms

Imaging TRUS  useful in performing prostatic biopsies & in providing local staging information if cancer is detected  allows uniform spatial separation & sampling of the regions of the prostate & also makes lesion-directed biopsies possible  CaP appears as a hypoechoic lesion in the peripheral zone

Imaging TRUS

Imaging TRUS  provides more accurate local staging than does DRE sonographic criteria for extracapsular extension:  bulging of the prostate contour or  angulated appearance of the lateral margin

Imaging TRUS sonographic criteria for seminal vesicle invasion: posterior bulge at the base of the seminal vesicle or asymmetry in echogenicity of the seminal vesicle associated w/ hypoechoic areas at the base of the prostate

Imaging TRUS

Axial transrectal ultrasonographic (TRUS) scan shows extensive hypoechoic area (arrows) in the right peripheral zone.

Imaging TRUS  enables measurement of the prostate volume (calculation of PSA density) PSA density = (π/6) X (AP diameter) X (transverse diameter) X sagittal diameter  cryosurgery

& brachytherapy

Imaging Endorectal MRI  staging accuracy: 51 – 92%  high image quality  operator-dependent  expensive

Imaging Axial imaging  selectively performed to exclude lymph node metastases in high risk patients who are thought to be candidates for definitive local therapy Criteria:  (-) bone scans  T3 cancers or a PSA>20ng/mL  Primary Gleason grade 4 or 5 cancers

Imaging Bone scan  can be omitted in patients w/ newly diagnosed, untreated prostate cancer who are asymptomatic & have serum PSA concentrations < 10 ng/mL

Imaging Bone scan

Imaging Molecular staging  detection of circulating levels prostate cells in the peripheral blood of men w/ CaP RT-PCR  uses peripheral blood samples & attempts to identify the presence of the mRNA to PSA (indirect evidence of prostate cells in the peripheral circulation)

Renal function tests (RFT) or Intravenous pyelogram (IVP)  may

be performed to detect kidney damage, especially after longstanding urethral obstruction and/or urinary retention

Differential Diagnosis      

Other Factors That Increase PSA BPH Urethral instrumentation Infection Prostatic infarction Vigorous prostate massage

Differential Diagnosis    

Other causes of induration of the prostate: Chronic granulomatous prostatitis Previous TURP or needle biopsy Prostatic calculi

Differential Diagnosis 

Paget’s Disease- PSA is usually normal and x-ray findings demonstrate subpriosteal cortical thickening.

Screening for CaP Disease is burdensome  PSA improves the detection of clinically important tumors  Most PSA detected tumors are curable  Mortality of prostate cancer is declining in areas where screening occurs =combination of DSE and serum PSA 

Treatment A. Localized Disease

1. General Considerations      

Treatment decisions are based on the: Grade and stage of the tumor Life expectancy of the patient Ability of therapy to ensure disease-free survival Morbidity Patient and physician preferences

2. Watchful waiting 

 

Therapeutic treatment of radical treatment for early stage prostate cancer-not yet proven Px are older maybe with other illness Small, well-differentiated prostate cancer-> very slow growth rates

3. Radical prostatectomy 





Understanding the anatomy of the pelvis resulted in lower rate of complications Prognosis treated by radical prostatectomy correlates with the pathologic stage of the specimen Px with adverse prognostic factors undergoing surgery is decreasing-> established normograms based on serum PSA, clinical DRE stage, and Gleason sum derived from biopsy

3. Radical protastectomy 



High grade tumors (Glial sum >7) high risk of progression Morbidity –related to the experience of the surgeon

3. Radical protastectomy Immediate intraoperative complications: =blood loss (more common in retropubic approach) =rectal injury (rare with retropubic approach, common in perineal approach, can be repaired) =ureteral injury (exceedingly rare.) 

3. Radical protastectomy 

= = = =

Perioperative complications: deep venous thrombosis pulmonary embolism lymphocoele formation wound infection

3. Radical protastectomy Late complications: = urinary incontinence = impotence 

4. Radiation therapy-external beam therapy Standard XRT = depend upon bony landmarks to define treatment borders or a single CT slice to define target volume =fail to provide adequate coverage of the target volume 

4. Radiation therapy-external beam therapy 3 dimensional conformal radiotherapy = ability to calculate dose in 3 dimensions = ability to generate 3 dimensional dose displays and dose volume histograms = less normal tissue is irradiated because of the use of multiple complex field =toxicity is reduced 

5. Radiation therapy-brachytherapy  

Place radioactive seeds under TRUS guidance With computer software- can preplan a precise dose of radiotherapy to be delivered by TRUS guidance

6. Cryosurgery   



Less invasive form for tx of localized CaP Use of subfreezing tissue to destroy tissue Freezing the prostate is carried out using a multiprobe cryosurgical device Multiple hollow-core probes are placed percutaneously under TRUS guidance

6. Cryosurgery 

Can result in negative post treatment prostatic biopsies and low or undetectable serum PSA levels

Treatment B. Locally advanced disease

1. Radiation therapy 

Most patients with T3 CaP are treated with neoadjuvant hormonal therapy followed by XRT.

Treatment C. Recurrent disease

1. Following Radical Prostatectomy 



Recurrence is related to : cancer grade, pathologic stage, and extent of extracapsular extension Recurrence more common: positive surgical margins, positive extracapsular extension, seminal vesicle invasion and high grade disease.

1. Following Radical Prostatectomy Systemic relapse =persistently detectable PSA immediately after surgery =PSA levels detectable in the early postoperative period =PSA levels that double rapidly 

1. Following Radical Prostatectomy Local recurrence =PSA levels undetectable initially then becoming detectable after a long time after radical protastectomy =PSA doubling time is prolonged 

2. Following Radiation Therapy 

 

Cancer recurrence= rising PSA levels following definitive radiation therapy Biopsies of prostate- identify local recurrence Imaging with bone scans and CT- identify distant recurrence

Treatment D. Metastatic disease

1. Initial endocrine therapy   

Most prostatic carcinomas are hormone dependent. 70-80% respond to androgen deprivation Free testosterone=> enters prostate cell => converted to DHT(major intracellular androgen) => binds a cytoplasmic receptor protein=> complex moves to nucleus=> transcription

1. Initial endocrine therapy 





LHRH agonist and orchiectomy-most common forms of primary androgen blockade used antiandrogen plus LHRH agonist or orchiectomy – suppressing both testicular and adrenal androgen=>better initial and longer response Antiandrogen=> competitively binding the receptor for DHT (responsible for prostatic growth and development)

2. Early manipulations for endocrine therapy failure 



Patients receiving complete androgen blockade therapy who demonstrate a rise in serum PSA levels-> discontinuation of antiandrogen PSA receiving monotherapy (LHRH agonist or orchiectomy whose PSA starts rising-> addition of an antiandrogen