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.
Pathogenesis
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
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.
Epidemiology
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.
Pathogenesis
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
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.
