Diseases Of The Prostate
The prostate is the organ of the body most frequently afflicted by disease in males over 50 years of age. The single most common pathologic process is benign prostatic hyperplasia (BPH). At least 70% of 70-year-old men develop BPH; 40% develop some symptom of bladder outflow obstruction.
Epidemiology and symptoms
Age is a risk factor for BPH. Data suggesting that black race puts men at increased risk appear to be poorly controlled for socioeconomic status and access to health care.
BPH causes urethral obstruction severe enough to warrant medical intervention in about 30% of elderly men. Interestingly, the overall size of the prostate does not correlate with either the presence or the severity of outflow obstruction. The fibromuscular hypertrophy that occurs with BPH can partially denervate prostatic and surrounding tissues, leading to urethral irritation and producing frequency and urgency of micturition, urge incontinence and nocturia.
BPH is characterized by a gradual increase in both the glandular and fibromuscular tissue in the periurethral and transition zones of the prostate that surround the urethra at its origin from the bladder and midsegment, respectively. Nodular hyperplasia is the characteristic microscopic change of BPH. It involves cellular hyperplasia plus associated changes in the architecture of the ducts and acini. Nodular hyperplasia in the transition zone is characterized by large amounts of glandular tissue that arise through budding and branching of pre-existing ducts. This latter type of hyperplastic proliferation is a highly unusual finding in adult human tissues, whether normal or diseased. It is felt that this anomalous development results from a reversion of the tissue to more embryonic behaviors.
Transition and central zones of the adult prostate gland seem to be of Wolffian duct derivation while the peripheral zone arises from the urogenital sinus (Chapter 6). These diverse embryological origins may explain why BPH occurs within the transition and central zones while prostatic adenocarcinoma originates within the peripheral zone (Fig. 41.1a).
The prostate glandular tissue is unique among the internal genitalia in that it requires dihydrotestosterone (DHT) for normal embryologic development and for maintenance. Testosterone acts as a prohormone. It isconvertedlocallytothemorepotentandrogen DHTby 5α-reductase. DHT potency rests on the higher affinity of the prostatic nuclear androgen receptor for DHT than for testosterone (see Chapter 2).
Differentiation and growth of prostatic epithelium is dependent on androgen-sensitive factors produced in the underlying stroma (embryological mesenchyme). Candidate growth factors increase mitosis in prostatic epithelial cells in vitro and include epidermal growth factor (EGF), insulin-like growth factors (IGFs) and basic fibroblast growth factor (bFGF). Expression of bFGF increases in BPH.
Development of BPH requires a normally functioning testis and 5α-reductase. Individuals lacking 5α-reductase have a vestigial prostate and never develop BPH or prostate cancer. Men with BPH have raised 5α-reductase activity and possibly an increase in prostate androgen receptors, making the “aging” prostate more susceptible to androgen stimulation. There may be a protective role for estrogens in BPH.
Estradiol production slowly increases in older men when the testes become less responsive to luteinizing hormone (LH) so that more LH is required to maintain androgen production. High LH levels disproportionately stimulate estrogen production. Elevated circulating estrogens increase hepatic sex hormone-binding globulin (SHBG) synthesis and elevations in SHBG reduce concentrations of free testosterone in the circulation. This decreases the amount of testosterone available to be converted to DHT in the prostatic stroma.
It is believed that the clinical symptoms of BPH are not caused simply by an increase in urethral resistance due to enlargement of the prostate. Many of the symptoms formerly thought to be secondary to BPH are related to age-related bladder dysfunction, generally referred to as lower urinary tract symptoms (LUTS).
Treatment of BPH and LUTS
Medical treatment is now the preferred treatment for BPH. It focuses on shrinking the prostate using 5α-reductase inhibitors and on symptomatically treating obstructive symptoms with α-adrenergic agents. The latter are effective because of the large proportion of smooth muscle containing adrenergic receptors in BPH. Because the symptoms of BPH are also caused by bladder dysfunction, antimuscarinic agents that act on bladder muscle receptors are used in select cases.
Surgical treatment of BPH includes transurethral prostatectomy (TURP), treatment of BPH tissue using laser technology and microwave therapy to the prostate.
Prostate cancer (PCa) is the most common noncutaneous malignancy in the USA and Europe. It will certainly grow in frequency as the population ages. Autopsy series have consistently found incidental PCa in 30–80% of older men.
Risk factors for PCa include age, race, positive family history, dietary fat intake and circulating hormone concentrations. African-American men who consume a high-fat diet are at the highest risk for PCa. Asian men residing in the Far East who subsist on a low-fat diet carry the lowest risk. Changes in geography or eating habits profoundly modify these background racial differences. Plasma androgen concentrations at the high end of normal increase PCa risk, as do SHBG or estrogen concentrations at the lower end of the normal range.
As with most malignancies, PCa probably occurs due to environmental promoters in genetically susceptible tissues. For PCa, age and family history are predisposing factors and androgen is the promoter. Because the incidence of microscopic PCa appears independent of race and of geography despite very different incidence rates of clinically apparent disease, race may influence the progression of latent tumors to clinically evident tumors. Modest differences in androgen production among African-American, Asian and white men have been reported. These exposures over a lifetime may explain the influence of race on PCa.
The hereditary form is set apart from the more common form by an earlier age of onset. Hereditary PCa is rare, although positive family history confers significant risk for given individuals in that family.
Adenocarcinoma of the glandular epithelium of the peripheral zone of the prostate gland is the most common form of PCa. It results from androgen activity on a tissue with acquired oncogenic potential. Prostatic intraepithelial neoplasia (PIN) is the first sign of an evolving neoplastic process. It is characterized by proliferation and anaplasia of the cells lining the ducts and glandular acini of the peripheral zone and disruption of the architecture of the basal epithelial cell layers.
Like most malignancies, the prognosis in PCa is determined by the stage and grade of the tumor at detection. Patients with disease localized to the prostate have an 80% survival rate at 5 years. The presence of distant metastases at diagnosis significantly lowers 5-year survival. PCa spreads locally to the hypogastric and presacral chains of lymph nodes and hematogenously to bone.
The interaction between prostatic stroma and epithelium appears to have an important role in the development of PCa (Fig. 41.1b). Different stromal growth factors are overexpressed in PCa when compared with BPH. Specifically, the stroma of PCa contains more IGF, EGF and TGF-β, while that in BPH contains more bFGF. DHT and testosterone both stimulate production of EGF and TGF-β by the prostate gland. The androgen dependence of these growth factors probably also accounts for much of the hormonal dependence of the normal prostate gland.
Mutations in the ERBB2 oncogene cause increased EGF receptor (EGFR) activity in PCa. Similar ERBB2 mutations are found in breast cancers. In both diseases, the EGFR shifts from its normal position in the basal epithelial layer to the luminal epithelium as the disease progresses from hyperplasia to intraepithelial neoplasia to frank cancer. Hereditary PCa is associated with mutations in the BRCA1 or BRCA2 tumor suppressor genes. Similar gene mutations are also asso- ciated with breast and ovarian cancers.
Loss of heterogeneity studies have identified several chromosomal loci as potential sites for abnormal tumor suppressor activity in PCa. For instance, in PCa that metastasizes after therapy, there is a gain in genetic material at the site of the androgen receptor gene on the long arm of the X chromosome. The gene for the androgen receptor becomes amplified after androgen withdrawal treatment, an adaptation by the tumor that aids its survival under androgen-deficient conditions. This discovery sheds light on the molecular basis for the development of drug resistance by some cancer cells.
Prostate-specific antigen (PSA) is a protease secreted by the prostatic epithelium. Small amounts leak across the prostatic acini and into the plasma. PSA determinations may be used as a screening tool for PCa in asymptomatic men although the risk-benefit ratio of this approach remains unclear.
Treatment of locally contained PCa includes surgery, radiation therapy or active surveillance. Surgical treatment involves removing the prostate and seminal vesicles in an effort to completely remove all malignant prostate cancer cells. With radiation therapy, radiation is delivered to the prostate either externally or internally with seeds placed inside prostate. Active surveillance (following the prostate cancer without specific treatment) may be used for those men who have small volume disease of the prostate or those who have significant comorbidities. In these patients, it is felt that the prostate cancer could grow slowly enough that treatment is not necessary. Other less common treatments for localized prostate cancer include cryosurgery (freezing of the prostate) and high-intensity focused ultrasound to the prostate.
Treatment of metastatic PCa involves androgen withdrawal, which may be accomplished by orchidectomy (surgical removal of the testicles), by treatment with leuteinizing hormone (LH) aka gonadotropin releasing hormone (GnRH) agonists or antagonists (both ultimate-lysuppress LH release, or by treatment with an antiandrogen. Chemotherapy is used when hormonal withdrawal is not effective; it has modest success in treating metastatic PCa.