Prostate Pathophysiology

Charles L. Hitchcock, MD PhD

Associate Professor - Clinical Department of Pathology

Learning Objectives

• Primary Objective:• Discuss benign and cancerous growth of the prostate

gland.

• Secondary Objectives: • Discuss screening and diagnosis of prostatic tumors. • Describe clinical and histological features of benign

prostatic hyperplasia (BPH) and prostate cancers, their identification and treatments.

• Identify issues related to prostate cancer screening and modifiable behaviors that impact its development

Objective 1

• Discuss screening and diagnosis of prostatic tumors.

Prostatic Zones

• B: bladder• U: prostatic urethra• SV: seminal vesicle• 1: Peripheral zone

• 65% glands• 2: Central zone

• 30% glands• 3: Transitional zone

• 5% of glands• 4: Anterior fibromuscular zone

Nonglandular Tissue

• Capsule• Sphincters• Fibromuscular tissue

Digital Rectal Exam DRE For Detecting Prostate Cancer

Benign Nodular Hyperplasia

Transrectal US + Biopsy

Screening For Prostate Cancer

Prostate Specific Antigen PSA

• PSA is a 33 kDa serine protease • Normally produced by prostatic glandular

epithelium. • Functions in liquefaction of the seminal

coagulum

What does a PSA Value Mean

• A PSA value between 4 ng/ml and 10 ng/ml do not distinguish between a benign and a neoplastic process, but does indicate a 20-25% risk for prostate cancer.

• The most common benign processes include: glandular hyperplasia, prostatitis, trauma, and DRE.

• The risk of prostate cancer >50% for PSA values > 10 ng/mL, and then increases as the PSA level rises.

Key Points

• Transition zone around the urethra – most common site of BPH.

• Peripheral zone = most common site of cancers

• DRE - poor screen for cancer

• Cystoscopy good for BPH diagnosis

Key Points

• Elevated PSA is not diagnostic of cancer.

• PSA and DRE should be used together for screening.

• Cannot distinguish between a clinically indolent and aggressive carcinoma.

• Leads to increased biopsies and risk of infection and bleeding.

• PSA should not be performed without a patient’s informed consent.

Objective 2

• Describe clinical and histological features of benign prostatic hyperplasia (BPH) and prostate cancers, their identification and treatments.

Clinical Presentations of Prostate Tumors – Early Onset

• Frequency• Urgency• Hesitancy• Incomplete emptying• Straining• Decrease force• Dribbling• Nocturia• Hematuria

Benign Prostatic Hyperplasia

Prostate Cancer

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

No Yes

Clinical Features of Prostatic Tumors

• Late onset BPH• Bladder diverticula

• Hydronephrosis

• Pyelonephritis

• Late onset prostatic cancer• Metastatic disease

• Bone pain – low back

• Weight loss

Key Points

• Clinical presentation of BPH and prostatic cancer may be identical when early.

• Normal glandular tissue has two cell layers• Fibromuscular stroma propel secretions out

of the gland.

Glandular Tissue

• Ducts and acini have a similar caliber and appearance.

• Columnar secretory epithelial cells

• Underlying basal cells• Basement membrane

NeuroendocrineCell

Normal Prostate

Fibromuscular Stroma

Gland

GlandGland

Fibromuscular Stroma

Normal ProstateFibromuscular

Stroma

Secretory Cells

BasalCells

Benign Prostatic Hyperplasia

Normal Prostate Hyperplasia Nodules

Urethra Urethra

Benign Prostatic Hyperplasia

Benign Prostatic Hyperplasia

Fibromuscular HyperplasiaGlandular Hyperplasia

Dihydrotestosterone and BPH

Treatment of BPH

Treatment of BPH

Laser PVP

TURP

Prostate Carcinoma

Prostate CarcinomaCapsular Invasion

Perineural Invasion Lymphatic Invasion

Adenocarcinoma

Score 1-2 – 10x Score 5 – 10x

Gleason Grading

Prostatic Carcinoma TNM Staging

Prostatic Carcinoma Treatment

• Watchful waiting or active surveillance

• Surgery: • Lymphadenectomy

• Radical prostatectomy, cryosurgery

• TURP

• Complications: impotence, shortening of the penis, incontinence of urine and/or stool, inguinal hernia

• Radiation - external & internal• Complications: impotence, incontinence, and increased risk

for bladder and rectal cancers

Prostatic Carcinoma Treatment

• Hormonal

• Orchiectomy

• Estrogen

• GnRH analogs (leuprolide) - suppresses LH-RH synthesis

• Antiandrogens (flutamide) - inhibits androgen uptake & nuclear binding

• Adrenal androgen synthesis blockade (ketoconazole)

• Complication: hot flashes, impaired sexual function , osteoporosis, diarrhea, pruritus

• Chemotherapy

• Immunotherapy

Prostatic Carcinoma Treatment

• Radiation - external & internal

• Complications: impotence, incontinence, and increased risk for bladder and rectal cancers

• Hormonal

• Orchiectomy

• Estrogen

• GnRH analogs (leuprolide) - suppresses LH-RH synthesis

• Antiandrogens (flutamide) - inhibits androgen uptake & nuclear binding

• Adrenal androgen synthesis blockade (ketoconazole)

• Complication: hot flashes, impaired sexual function , osteoporosis, diarrhea, pruritus

• Chemotherapy

• Immunotherapy

Key Points

• Clinical presentation of BPH and prostatic cancer may be identical with early onset.

• Normal glandular tissue has two cell layers.

• Fibromuscular stroma propels secretions out of the gland.

• The incidence of BPH increases with age.• Glandular and stromal hyperplasia

commonly occurs in the transitional zone.

• TX: Watchful waiting, hormonal blockade, surgery

Key Points – 2 Prostate Cancer

• Often multifocal – separate tumors• Adenocarcinomas• Gleason grading system• TNM Staging – incidental (I) to metastatic (IV)• Six methods of treatment

Objective 3

• Identify issues related to prostate cancer screening and modifiable behaviors that impact its development.

Risk Factors – Nodular Prostatic Hyperplasia

• Age – incidence increases with age, with 70% of men over 60 having it.

• Family history – does increase the risk• Obesity• High BP• Low HDL• Diabetes• Peripheral vascular disease• Poor diet and lack of exercise

Heart DiseaseRisk Factors

Risk Factors – Prostate Cancer

• Gender• Most common malignancy in U.S. men• >217,000 new cases in 2013 (25% of new cancers in men)• 2nd leading cause of death among men• >32,000 deaths in 2013. • ~1/6 lifetime death risk• mortality African-American men is 2x > Caucasian men• Incidence increased in 1988-92 but has declined in 1992-95,

and has leveled off since 1995

Risk Factors – Prostate Cancer

• Age• Incidence of latent carcinoma is:

• 20% in men 50-59• ~70% in 70-80

• 64% of all prostate cancers are diagnosed in men > 65 years

• Ethnicity and Race• incidence in AA 1.5 - 2x > Caucasian men

• U.S. >> Asia and South America• High fat diet - ?

Risk Factors – Prostate Cancer

• Hereditary form in ~ 10% of all cases and up to 40 percent of early onset disease.

• Family history of prostate carcinoma• Hereditary prostate cancer gene 1, or HPC1, linked

in prostate cancer families to the RNASEL gene.

Prostate Screening

PSA – Key Points

• “The PSA test measures the blood level of PSA, a protein that is produced by the prostate gland. The higher a man’s PSA level, the more likely it is that he has prostate cancer. However, there are additional reasons for having an elevated PSA level, and some men who have prostate cancer do not have elevated PSA.

• The PSA test has been widely used to screen men for prostate cancer. It is also used to monitor men who have been diagnosed with prostate cancer to see if their cancer has recurred (come back) after initial treatment or is responding to therapy.

• Some advisory groups now recommend against the use of the PSA test to screen for prostate cancer because the benefits, if any, are small and the harms can be substantial. None recommend its use without a detailed discussion of the pros and cons of using the test.”

http://www.cancer.gov/cancertopics/factsheet/detection/PSA

Key Points – Prostate Cancer

• Prostate cancer is primarily a disease of older men.

• African-American men have up to twice the incidence and mortality of Caucasian men.

• The RNASEL gene is associated with hereditary forms of prostate cancer.

• Early onset may be asymptomatic, or associated with hematuria or dysuria; whereas bone pain is a common symptom of late onset.

• DRE detection of prostatic cancer is derived from the fact that 70% arise in the peripheral zone.

Prostate Cancer Quiz

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