Neoplasms of the Prostate Gland

Neoplasms of the Prostate Gland

Prostate gland Made of two lobes, enclosed by an outer layer of tissue
Located in front of the rectum and just below the bladder, where urine is stored Blood supply: internal iliac artery -inferior vesical artery -middle rectal artery Venous drainage: dorsal venous complex IJV Innervation: pelvic plexus

Prostate Gland Peripheral zone 70% -Prostate cancer Central zone 25%
Transition zone 5% -BPH

Benign Neoplasms

Benign Prostatic Hyperplasia
Most common benign tumor in men Incidence is age related 20% in men aged 41-50 50% in men aged 51-60 >90% in men aged >80 Risk Factors: -genetic : autosomal dominant -racial differences

Pathology: BPH develops in the transition zone Results from increase in cell number Microscopic: nodular growth pattern, varying amounts of stroma and epithelium Compress the outer zones of the prostate (surgical capsule) bladder outlet resistance due to mechanical obstruction

Clinical Findings: Symptoms: Obstructive -hesitancy -decreased force and caliber of stream -sensation of incomplete bladder emptying -double voiding Irritative -urgency -frequency -nocturia

Signs P.E., DRE and focused neurologic exam Size and consistency Smooth, firm, elastic enlargement -PSA -TRUS -biopsy

Laboratory findings Urinalysis- to exclude infection or hematuria Serum creatinine measurement- to assess renal function Serum PSA- optional , increased ability to detect CaP DRE- general idea of the size and condition of the gland Imaging Upper tract imaging ( Intravenous pyelogram or renal ultrasound)- recommended only in presence of concomitant urinary tract disease

Prostate Biopsy Cytoscopy- to determine the size of the gland and identify the location and degree of the obstruction. Additional Tests: cystometrograms and urodynamin profiles.

Microscopic examination of different types of prostate tissues (stained with immunohistochemical techniques): A. Normal (non-neoplastic) prostatic tissue (NNT). B. Benign prostatic hyperplasia. C. High-grade prostatic intraepithelial neoplasia (PIN). D. Prostatic adenocarcinoma (PCA).

Differential Diagnosis -urethral stricture hx of urethral instrumentation, - bladder neck contracture urethritis, trauma -bladder stone: hematuria and pain -Prostate Cancer -UTI: do urinalysis and culture -neurogenic bladder disorders: history of neurologic disease, stroke, DM

Treatment -mild symptoms: watchful waiting -surgical indications: recurrent UTI refractory urinary retention recurrent gross hematuria bladder stones renal insuficiency large bladder diverticula

Medical Therapy 1. Alpha blockers -prostate and bladder contains alpha-1-adrenoreceptors - improvement in signs and symptoms - Phenoxybenzamine, prazosin 2. Alpha reductase inhibitors -Finasteride -blocks conversion of testosterone to dihydrotestosterone -reduce size of gland and improvement of symptoms

Medical Therapy 3. Combination Therapy - 5-alpha reductase inhibitor + alpha blocker 4. Phytotherapy - use of plants or plant extracts -popular in Europe and US

Conventional Surgical Therapy
Transurethral Resection of the Prostate (TURP) Transurethral Incision of the Prostate Open simple prostatectomy

Transurethral resection of the Prostate
Superior symptom score and flow rate improvement than minimally invasive therapy Longer length of confinement Risks: Retrograde ejaculation Impotence Incontinence

TURP An enlarged prostate can cause urinary problems due to its location around the male urethra (A). In TURP, the physician uses a cystoscope to gain access to the prostate through the urethra (B). The prostate material that has been restricting urine flow is cut off in pieces, which are washed into the bladder with water from the scope (B). (Illustration by GGS Inc.)

Transurethral Resection of the Prostate
Complications : Bleeding Urethral stricutre or bladder neck contracture Perforation of the prostate capsule with extravasation TUR syndrome  hypervolemic, hyponatremic state due to absorption of the hypotonic irrigating solution

TUR syndrome Nausea Vomiting Confusion Hypertension Bradycardia
Visual disturbances *risk increases with resection time >90 minutes Tx : diuresis Hypertonic saline administaration

Transurethral incision of the prostate
Moderate to severe symptoms Small prostate * posterior commissure hyperplasia: elevated bladder neck More rapid Less morbid Lower rate of retrograde ejaculation(25%)

Transurethral Incision of the Prostate
Technique Collin’s knife 5 and 7 o’clock positions Incision distal to the ureteral orifices and are extended outward to the verumontanum

Open Simple prostatectomy
Prostate is too large to be removed endoscopically Open enucleation “large” vary depending on the surgeon’s experience with TURP >100 grams Concomitant bladder diverticulum Bladder stone Dorsal lithotomy positioning is not possible Can be Simple suprapubic prostatectomy or Simple retropubic prostatectomy

Open Simple Prostatectomy
Simple suprapubic prostatectomy Performed transvesically, operation of choice if with concomitant bladder pathology Semicirucular incision in the bladder mucosa., distal to the trigone Hemostasis attained with suture ligature Urethral and suprapubic catheter – before closure

Open Simple prostatectomy
Simple retropubic prostatectomy Bladder not entered Transverse incision made in the surgical capsule of the prostate Urethral catheter - end of the procedure

Open Simple Prostatectomy

Minimally Invasive Therapy
1. Laser therapy 2. Transurethral electrovaporization of the prostate 3. Hyperthermia 4. Transurethral needle ablation of the prostate 5. High-intensity focused ultrasound 6. Intraurethral stents

1. Laser Therapy Two main energy sources – Nd:YAG and holium:YAG
Techniques: a. Coagulation necrosis technique b. Visual contact ablative technique c. Intersitial laser therapy

Coagulation Necrosis Techniques
Transurethral laser-induced prostatectomy (TULIP) with TRUS guidance Do not create an immediate visual defect in the prostatic urethra Tissue sloughed : several weeks – 3 months following the procedure

Visual Contact Ablative techniques
More time consuming Fiber placed in direct contact with the prostate tissue Immediate defect is obtained

Interstitial laser therapy
Fibers directly into the prostate, cystoscopic control Laser is fired  submucosal coagulative necrosis Urethral mucosa is spared prostate tissue is reabsorbed by the body  ↓ irritative voiding symptoms

ADVANTAGES Minimal blood loss Rare instaces of TUR syndrome
Ability to treat patients receiving anticoagulation therapy Ability to be done as an outpatient procedure

DISADVANTAGE Lack of availability of tissue for pathologic examination
Longer postoperative catheterization time More irritative voiding complains High cost of laser fibers and generators

2. Transurethral Electrovaporization of the Prostate
Use standard resectoscope – grooved rollerball High current densities cause heat vaporization of tissue cavity in the prostatic urethra Takes longer than a standard TURP

Transurethral Microwave Thermotherapy
3. Hyperthermia TUMT Microwave hyperthermia – delivered with a transurethral catheter Deliver microwave energy to the prostate,high temperatures  kill prostate cells Sensors on the catheter and on a tube in the rectum enable monitoring of the temperatures throughout the procedure, and a cooling system circulates water within the catheter to protect the urethra.

4. Transurethral needle ablation of the Prostate (TUNA)
Specially designed urethral catheter where radio frequency needles are deployed coagulative necrosis Not adequate in treating bladder neck and median lobe enlargement

5. High-intensity focused ultrasound Thermal ablation
Dual-function ultrasound probe (rectum) Transrectal imaging of the prostate Delivers short bursts high-intensity focused ultrasound energy Coagulative necrosis Bladder neck and median lobe enlargement are not adequately treated

6. Intraurethral Stents Endoscopically placed in the prostatic fossa
Keep the prostatic urethra patent For patients with limited life expectancy, not appropriate candidates for surgery or anesthesia

Intraurethral Stent

Carcinoma of the PROSTATE
Most common cancer detected in American men Second leading cause of cancer death in men, mortality rates have been declining since the mid-1990’s Major health-care concern unless more effective forms of prevention and treatment are identified Prevalence increases most rapidly with age

CaP continues to increase with advancing age Lifetime risk of a 50-year-old man for: Latent: 40% Clinically apparent: 9.5% Death from - : 2.9% Many prostate cancers are indolent and inconsequential to the patient while others are virulent, and if detected too late or left untreated, they result in a patient’s death

Risk factors: Increasing age < 40 : 1 in 10,000 40-59: 1 in 103 60-79: 1 in 8 (+) Family Hx Age of disease onset in the family member affects patient’s relative risk 70 y/o : 4x 60 y/o: 5x 50 y/o: 7x BRCA1 and BRCA2 genes have two to five times higher risk of prostate cancer. African American > white Diet Total fat, animal fat, red meat, Vitamin D and Calcium - ↑ Fish, lycopene selenium, omega03 FA, Vitamin E - ↓

Molecular Genetics and Pathobiology
Molecular profiling of human tissues Diagnostic, prognostic and therapeutic markers have been discovered Chromosomal rearrangements or copy number abnormalities described in Prostate CA 8p, 10q, 11q, 13q, 16q, 17q, and 18q Specific loss at 8p23.2 and/or gain at 11q13.1 : predictive of prostate CA progression

Molecular Genetics and Pathobiology
Inflammation may be related to prostate CA development Candidate- inherited susceptibility genes for prostate CA including familial cancer: RNASEL: encoding an interferon inducible ribonuclease MSR1: encoding subunits of the macrophage scavanger receptro

Pathology ~95% : Adenocarcinoma ~5% : nonadenocarcinoma
90% : transitional cell carnicomas 10% neuroendocrine (“small cell”) carcnomas or sarcoma Histology: heterogenous, arising from stromal epithelial, or ectopic cells.

Adenocarcinoma Cytologic characteristics of CaP:
Hyperchromatic. Enlarged nuclei with prominent nucleoli Cytoplasm, often abundant Slightly blue tinged or basophilic Basal cell layer is absent high molecular weight keratin immunohistochemical staining, preferentially stains basal cells Markers: AMACR or EPCA Useufl to identify those with the disease, but who have equivocal or negative biopsies on standard tissue staining

Prostatic Intraepithelial Neoplasia (PIN) and Atypical Small Acinar Proliferation (ASAP)
Either lesion, may be at an increased risk of prostate cancer and warrant repeat biopsy High-grad PIN (HGPIN) Cellular proliferations within preexisting ducts and glands, with nuclear and nucleolar enlargement similar to prostate cancer Retains a basal cell layer in immunohistochemistry

Adenocarcinoma 60-70% originate in the peripheral zone
10-20% originate in the transitional zone 5-10% originate in the central zone Prostate cancer most often thought to be multifocal, there is increasing detection of unifocal and smaller cancer Widespread screening and extended biopsy technique

Nonadenocarcinoma Epithelial Nonepithelial Endometrioid Mucinous
Singet-ring Adenoid cystic Adenosquamous Squamous cell Transitional cell Neuroendocrine may occur in response to prolonged androgen deprivation comedocarcinoma Nonepithelial Rhabdomyosarcoma Leiomyosarcoma Osteosarcoma Angiosarcoma Carcinosarcoma Malignant lymphoma Metastatic neoplasm

Grading and Staging Gleason Grading System
Relies on low-power appearance Primary grade – pattern most commonly observed Most important in placing patients in prognostic group Secondary grade – second most commonly observed However, if there is only one pattern present, primary and secondary grade are reported as the same grade Gleason grade range from 1 to 5

Gleason Grade Characteristic 1 and 2 Small, uniformly shaped glands, closely packed with little intervening stroma 3 Variable-sized glands that percolate between normal stroma Variant: Cribriform : small mass of cells is perforated by several gland lumens with no itervening stroma : cookie-cutter-like appearance of nest cells : smooth border 4 Incomplete gland formation. fused, sharing a common cell border Sheets of nest cells or long cords of cells Cribriform , cell masses are large and borders ragged with infiltrating finger-like projections 5 Single inflitrating cells, with no gland formation or lumen appearance Comedocarcinoma – appearance of cribriform but with central areas of necrosis

Gleason score obtained by adding the primary and secondary grades together Differentiation score Well-differentiated 2-4 Moderately-differentiated 5-6 Poorly-differentiated 8-10

TNM staging Primary tumor categorization (Tstage)
Clinical staging system uses results of DRE and TRUS STAGE SUB-STAGE DEFINITION T1 Clinically unapparent tumor, not detected by DRE nor visible by imaging T1a Incidental histologic finding; <5% of tissue resected during TURP T1b Incidental histologic finding; >5% of tissue resected during TURP T1c Tumor identified by needle biopsy due to elevated PSA T2 Confined within the prostate (detectable by DRE, not visible on TRUS) T2a Tumor involves half of the lobe or less T2b Tumor involves more than one half of one lobe but not both lobes T2c Tumor involves both lobes T3 Tumor extends through the prostate capsule but has not spread to other organs T3a Unilateral extracapsular extension T3b Bilateral extracapsular extension T3c Tumor invades seminal vesicle(s) T4 Tumor is fixed or invades adjacent structures other than seminal vesicles T4a Tumor invades bladder neck and/or external sphincter and/or rectum T4b Tumor invades levator muscles and/or is fixed to pelvic wall

STAGE SUB-STAGE DEFINITION Node (N) Regional lymph nodes N0 No lymph nodes metastasis N1 Metastasis in single lymph node <2 cm in greatest dimension N2 Metastasis in single lymph node >2cm but <5 cm in greatest dimension, or multiple lymph nodes, none >5 cm N3 Metastasis in lymph node >5 cm in greatest dimension Metastasis Systemic spread M0 No distant metastasis M1a Non-regional lymph node metastasis M1b Bone metastasis a) Axial skeleton only b) Extending to peripheral skeleton also M1c Metastasis at other sites

STAGE SUB-STAGE DEFINITION Histopathologic Differentiation GX Grade cannot be assessed G1 Well differentiated (slight anaplasia) G2 Moderately differentiated (moderate anaplasia) G3 Poorly differentiated or undifferentiated (marked anaplasia)

PROSTATE CANCER CHEMOPREVENTION
Ideal therapeutic intervention : arrest disease progression (latency period) decrease the incidence of clinical disease. Ideal agent: nontoxic and low cost Ideal patient: one at high risk of the disease Agents: vitamin E, selenium, dutasteride , COX-2 inhibitors, dietary supplements, and toremifene, finasteride

Patterns of Progression
local extension outside the prostate seminal vesicle invasion Distant metastases tumor volume more poorly differentiated cancers. Small and well-differentiated cancers (grades 1 and 2) prostate large-volume (>4 cm3) poorly differentiated (grades 4 and 5) extensive or metastatic to regional lymph nodes or bone

Penetration of the prostatic capsule by cancer often occurs along perineural spaces. Seminal vesicle invasion→ regional/distant disease Lymphatic metastases→ obturator lymph node chain Advanced: ureteral obstruction. Rare Rectal Involvement

Distant metastases →The axial skeleton (lumbar spine) Bone lesions of metastatic CaP →osteoblastic Long bones involvement→ pathologic fractures Vertebral body involvement→ cord compression

Visceral metastases: lung liver adrenal gland Central nervous system involvement - skull metastasis.

SYMPTOMS Early: asymptomatic Symptoms = advanced/ metastatic disease
Obstructive/ irritative voiding complaints: local growth bone pain: Metastatic disease to the bones Metastatic disease to the vertebral - cord compression (paresthesias) - weakness of the lower extremities - urinary fecal incontinence.

SIGNS Physical examination (DRE) Induration
Advanced disease with bulky regional lymphadenopathy may lead to lymphedema of the lower extremities Cord compression relate to the level include weakness or spasticity of the lower extremities and hyperreflexic bulbocavernosus reflex.

LABORATORY FINDINGS Azotemia Anemia elevated Alkaline phosphatase
elevated Serum acid phosphatase

TUMOR MARKERS—PROSTATE-SPECIFIC ANTIGEN
a serine protease produced by benign and malignant prostate tissues Free / unbound Normal PSA values are those ≤4 ng/mL. Not specific for CaP 20–30%: ng/mL 42% to 71.4%: excess 10 ng/mL

TUMOR MARKERS—PROSTATE-SPECIFIC ANTIGEN
Increase PSA: BPH, urethral instrumentation, and infection Decrease PSA concentrations: LHRH agonists and antagonists 5-alpha-reductase high body mass indexes

Attempts at refining PSA
PSA velocity (change of PSA over time) PSA density (standardizing levels in relation to the size of the prostate) Age-adjusted PSA reference ranges (accounting for age- dependent prostate growth and occult prostatic disease) PSA forms (free versus proteinbound molecular forms of PSA).

PSA velocity the rate of change of serum PSA
increases by 0.75 ng/mL/y an increased risk harboring cancer the same laboratory over a period of at least 18 months. rapid PSA velocity (ie, PSA doubling times ≤6 months) ↑ risk of failure of initial treatment development of metastases prostate cancer specific mortality.

PSA density The ratio of PSA to gland volume
0.12 ng/mL/g of BPH tissue.: Enlarged glands due to BPH may have elevated PSA levels Biopsy exceeds PSA density 0.1 or 0.15 Problems with this approach include the facts (1) epithelial-stromal ratios vary from gland to gland and only the epithelium produces PSA (2) errors in calculating prostatic volume may approach 25%.

Age-adjusted reference ranges for PS
↑ PSA w/ ↑ age = prostate gland growth higher incidence of subclinical prostatitis cancer ↑ sensitivity: younger ↑ specificity: older

Molecular forms of PSA 90% serum PSA: alpha antichymotyrpsin
Less: free/ alpha 2-macroglobulins Prostate cancer patients demonstrate lower percent-age of free PSA >25% free PSA older patients were less threatening in terms of tumor grade and volume

PROSTATE BIOPSY Considered in men with elevated serum PSA, DRE, or combination of two Performed under TRUS guidance using a spring-loaded device coupled to imaging probe Peripheral zone of prostate 6 biopsies were taken along a parasagittal line between the lateral edge and the protatic midline at the apex, midgland, and base bilaterally

PROSTATE BIOPSY Local anesthesia and preprocedure antibiotoc prophylaxis 10-24% painful Local anesthesia: topically along the ant. Rectal wall, injected into or adjacent to the prostate, or combination Adverse Efects: hematospermia, hematuria, minor rectal bleeding , high fever

Combined Modality Risk Assestment
Better assessment of disease natural history Appropriate selection of initial treatment Normograms Probability tables incorporating serum PSA T stage Cancer volume Patient age

Imaging TRUS Endorectal magnetic resonance imaging (MRI)
Axial imaging (CT, MRI) Bone scan Antibody imaging

TRUS local staging information
allows uniform spatial separation and sampling of the regions of the prostate and also makes lesion-directed biopsies possible. CaP tends to appear as a hypoechoic lesion in the peripheral zone TRUS also enables measurement of the prostate volume, which is needed in the calculation of PSA density. cryosurgery and brachytherapy Color or power Doppler TRUS assesses blood flow

Endorectal magnetic resonance imaging (MRI) -Accurate assessment of cancer location and stage
Axial imaging (CT, MRI) - to exclude lymph node metastases Bone scan-bone (common site of metastasis ) - for men newly diagnosed of prostate cance - PSA 15 ng/mL or greater -locally advanced disease (T3B, T4) Antibody imaging -px that will undergo treatment - detect the site of recurrent disease

Differential Diagnosis
↑ PSA concentration BPH urethral instrumentation Infection prostatic infarction, vigorous prostate massage Induration chronic granulomatous Prostatitis previous TURP or needle biopsy prostatic calculi. Paget’s disease Sclerotic lesions on plain x-ray films ↑levels of alkaline phosphatase can PSA levels: normal x-ray:subperiosteal cortical thickening

Screening for CaP PSA improves detection of clinically important tumors without significantly increasing the detection of unimportant tumors the use of both DRE and serum PSA is preferable Recommend screening be undertaken at age 50 annual screening is most often recommend. very low serum PSA level (≤1 ng/mL) may be able to be screened at less frequent intervals (every 2 or 3 years).

Treatment: Neoplasms of the Prostate Gland

Localized Disease grade and stage of tumor life expectancy of patient
General Considerations Treatment decisions are based on: grade and stage of tumor life expectancy of patient ability of each therapy to ensure disease-free survival patient and physician preferences

Radical Prostatectomy
Major surgical procedure where the surgeon removes both the prostate gland and the seminal vesicles Generally performed with a lower abdomen incision (retropubic approach). Others prefer transperineal approach (region between the scrotum and anus) or transcoccigeal approach posteriorly. Pelvic lymph node dissection is generally performed for staging purposes at the time of surgery; more extended and meticulous dissection is advised.

Prostatectomy

Laparoscopic approach Performed through an extra- or transperitoneal approach Associated with reduced blood loss, shorter hospitalization, and return to normal activity

Laparoscopic Approach

Immediate Intraoperative Complications Blood loss (common with retropubic approach) Rectal injury (common with perineal approach) Ureteral injury (rare)

Perioperative Complications Deep vein thrombosis Pulmonary embolism Lymphocoele formation Wound infection

Late Complications Incontinence Impotence

Radiation Therapy External Beam Radiotherapy (XRT)
Delivery of cGy to the prostate Dose escalation more than or equal to 72 cGy appear to improve biochemical outcomes Radiation therapy may be improved with the use of neoadjuvant, concurrent, and androgen deprivation

Radiation Therapy External Beam Radiotherapy (XRT) Side effects:
Obstructive or irritative voiding or bowel syndromes Late onset of sexual dysfunction (18-24 months) especially with androgen deprivation therapy

External Beam Radiotherapy

Radiation Therapy Brachytherapy Radioactive seeds under TRUS Implants
- permanent (iodine 125, palladium 103) dose delivered over time wherein seeds are loaded in hollow- core catethers lower dose; higher total dose temporary higher dose; lower total dose

Brachytherapy

Cryosurgery and High-Intensity Focused Ultrasound
Freezing of prostate through multiprobe cryosurgical device Temperature is 0 C to -2 C HIFU Delivered through rectal probe Induces coagulative necrosis of benign and malignant prostatic tissue Complication: urinary retention

Metastatic Disease Initial Endocrine Therapy
Androgen Deprivation therapy through LHRH agonist Goserelin acetate Triptorelin pamoate Histrelin acetate Leuprolide acetate

Neoplasms of the Prostate Gland

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