PATHOLOGY OF THE MALE GENITAL SYSTEM
THE PENIS
Malformations of the Penis
Hypospadias is the most common malformation (1 in 250 live male births). It refers to
the abnormal location of the distal urethral orifice along the ventral aspect of the penis.
The urethral orifice is sometimes constricted, resulting in urinary tract obstruction.
Epispadias: the urethral orifice is situated on the dorsal aspect of the penis. Like
hypospadias, epispadias may produce lower urinary tract obstruction or incontinence.
Inflammatory Lesions of the penis
Balanitis refer to local inflammation of the glans penis; it may be associated with
inflammation of the overlying prepuce. Most cases occur due to poor local hygiene in
uncircumcised males, with accumulations of smegma (desquamated epithelial cells,
sweat, and debris) that acts as a local irritant. The distal penis is typically red, swollen,
and tender; a purulent discharge may be present.
Phimosis refers to the difficulty of retracting the prepuce over the glans. It may be
congenital but most cases are acquired from scarring of the prepuce secondary to
previous balanitis.
Genital candidiasis is particularly common in patients with diabetes mellitus.
Candidiasis presents as a painful, intensely pruritic erosions involving the glans penis,
scrotum, and adjacent intertriginous areas. Scrapings or biopsy specimens of the lesions
reveal characteristic budding yeast forms & pseudohyphae within the superficial
epidermis.
Penile Neoplasms
Squamous cell carcinomas of the penis are relatively uncommon. Most cases occur in
uncircumcised patients older than 40 years of age. Etiological factors include poor
hygiene that expose the area to potential carcinogens in smegma, smoking, and infection
with human papillomavirus (HPV), particularly types 16 and 18. These carcinomas are
generally preceded by dysplastic changes termed intraepithelial neoplasia that may
culminate in carcinoma in situ. Clinical variants of carcinoma in situ, all strongly
associated with HPV infection, occur on the penis
1. Bowen disease (Erythroplasia of Queyrat) a solitary, erythematous, plaque-like lesion
on the shaft of the penis that displays microscopically malignant cells throughout the
epidermis. It may progress to invasive carcinoma in one third of the cases. (Fig. 9-1)
2. Bowenoid papulosis presents as multiple reddish brown papules on the shaft, glans or
scrotum; it is and most often transient, with only rare progression to carcinoma. (Fig. 9-2)
Gross features of invasive Squamous cell carcinoma
This tumor appears as a gray, crusted, papular lesion, most commonly on the glans
penis or prepuce.
In many cases, the carcinoma infiltrates the underlying connective tissue to produce an
indurated, ulcerated lesion with irregular margins (Fig. 9-3).
Microscopic features
SCC is usually a keratinizing with infiltrating margins.
Verrucous carcinoma is very well differentiated variant of squamous cell carcinoma
characterized by a papillary architecture & rounded, pushing margins.
Most cases of squamous cell carcinoma of the penis are indolent. Regional metastases are
present in the inguinal lymph nodes in approximately 25% of patients at the time of
diagnosis. Distant metastases are relatively uncommon. The overall 5-year survival rate
averages 70%.
SCROTUM
The skin of the scrotum may be affected by several inflammatory conditions, including
local fungal infections and systemic dermatoses.
Squamous cell carcinoma, the most common of the generally rare scrotal tumors, but
represents the first observed human malignancy associated with environmental influences
i.e. a high incidence in chimney sweeps.
Hydrocele is an accumulation of serous fluid within the tunica vaginalis & represents the
most common cause of scrotal enlargement. It may arise in response to neighboring
infections or tumors, or it may be idiopathic.
Hematoceles & chyloceles, represent accumulations of blood or lymphatic fluid within
the tunica vaginalis respectively. In extreme cases of lymphatic obstruction, caused, for
example, by filariasis, the scrotum and the lower extremities may enlarge to dreadful
proportions, a condition termed elephantiasis.
Cryptorchidism
This refers to failure of testicular descent into the scrotum leading to malposition of the
gonad anywhere along its migration pathway. Normally, the testes descend from the
coelomic cavity into the pelvis and then through the inguinal canals into the scrotum
during intrauterine life. The diagnosis of cryptorchidism is difficult before 1 year of age,
because complete testicular descent into the scrotum is not invariably present at birth. By
1 year of age, cryptorchidism is present in 1% of the males and in 10% of these cases is
bilateral. Several influences may interfere with testicular descent including
1. Hormonal abnormalities
2. Intrinsic testicular abnormalities
3. Obstruction of the inguinal canal
4. Congenital syndromes.
In the vast majority of cases, however, the cause is unknown.
Complications of cryptorchidism include
1. Sterility in bilateral cases.
2. Atrophy of the cryptorchid testis and even of the contralateral descended gonad.
3. Malignancy of the cryptorchid testis (up to 5 times increased risk). An increased risk is
also noted in the contralateral, normally descended testis, suggesting that some intrinsic
abnormality, rather than simple failure of descent, may be responsible for the increased
cancer risk.
Surgical placement of the undescended testis into the scrotum (orchiopexy) before
puberty decreases the likelihood of testicular atrophy and reduces, but does not
eliminate, the risk of cancer and infertility. The cryptorchid testis may be of normal size
early in life, although some degree of atrophy is usually present by the time of puberty
with microscopic evidence of tubular atrophy, fibrosis & hyalinization. Loss of tubules is
usually accompanied by hyperplasia of Leydig cells. Foci of intratubular germ cell
neoplasia may be present in cryptorchid testes and may be the source of subsequent
cancers developing in these organs.
Other causes of testicular atrophy (apart from cryptorchidism) include (Fig. 9-4)
1. Chronic ischemia
2. Trauma
3. Radiation
4. Antineoplastic chemotherapy
5. Conditions associated with elevation in estrogen levels (e.g., cirrhosis)
Inflammatory Lesions of the testis & epididymis
Inflammatory lesions are more common in the epididymis than in the testis. Causes
include venereal diseases, nonspecific epididymitis and orchitis, mumps, and
tuberculosis.
Nonspecific epididymitis and orchitis usually begin as a primary UTI with subsequent
climbing infection of the testis through the vas deferens or lymphatics of the spermatic
cord. The involved testis is typically swollen and tender and contains a predominantly
neutrophilic inflammatory infiltrate.
Orchitis complicates mumps infection in roughly 20% of infected adult males but rarely
occurs in children. The affected testis is edematous and congested and contains a
predominantly lymphoplasmacytic inflammatory infiltrate. There may be an associated
considerable loss of seminiferous epithelium with resultant tubular atrophy, fibrosis, and
sterility.
Granulomatous orchitis may be due to infections and autoimmune injury. Of these,
tuberculosis is the most common. Testicular tuberculosis generally begins as an
epididymitis, with secondary involvement of the testis. The histologic changes include
granulomatous inflammation and caseous necrosis, identical to that seen in active
tuberculosis in other sites.
TESTICULAR NEOPLASMS
Testicular neoplasms are the most important cause of firm, painless enlargement of the
testis. The peak incidence is between the ages of 20 and 34 years. In adults, 95% of
testicular tumors arise from germ cells, and all are malignant. Neoplasms derived from
Sertoli or Leydig cells (sex cord/stromal tumors) are uncommon and, in contrast to
tumors of germ cell origin, usually pursue a benign clinical course.
The etiology of testicular neoplasms is not known.
The following are risk factors
1. Cryptorchidism: a history of this condition is present in 10% of testicular cancer.
2. Intersex syndromes, including androgen insensitivity syndrome and gonadal
dysgenesis.
3. Genetic & ethnic influences as manifested by
a. Family history: the risk of neoplasia is increased in siblings of males with testicular
cancers.
b. Cancer in one testis is associated with a markedly increased risk in the contralateral
testis.
A wide range of abnormalities in testicular germ cell neoplasms have been detected, the
most common of which is an isochromosome of the short arm of chromosome 12.
However, the role of such aberrations remains unclear.
c. Whites are affected more commonly than blacks.
Classification and Histogenesis of Testicular tumors
The WHO classification is the most widely used. In this, germ cell tumors of the testis are
divided into two broad categories, based on whether they contain
1. A single histologic pattern (60% of cases) or
2. Multiple histologic patterns (40% of cases).
Germ cell tumors of the testis arise from primitive cells that may either differentiate
along gonadal lines to produce seminomas or transform into a totipotential cell
population, giving rise to nonseminomatous germ cell tumors. Such totipotential cells
may remain largely undifferentiated to form embryonal carcinomas, may differentiate
along extra-embryonic lines to form yolk sac tumors & choriocarcinomas, or may
differentiate along somatic cell lines to produce teratomas. This proposed histogenesis is
supported by the high frequency of mixed histologic patterns among nonseminomatous
germ cell tumors.
Most testicular tumors arise from in situ lesions designated intratubular germ cell
neoplasia. Such in situ lesions are seen in adjacent to a testicular germ cell tumor in
virtually all cases.
Seminomas
This is the most common testicular germ cell neoplasm, accounting for 50% of these
tumors. The peak incidence is between 34 to 45 years, which is about 1 decade later than
that of most other GCTs. Before puberty, seminoma is extremely rare; in fact, it does not
occur in the first decade of life especially in children younger than 5 years. Most patients
present with a typically painless testicular enlargement.
Gross features
They are soft, well-demarcated, usually homogeneous, gray-white or pale tumors that
bulge from the cut surface of the affected testis (Fig. 9-5 A).
The neoplasms are typically confined to the testis.
Large tumors may contain foci of coagulation necrosis, usually without hemorrhage.
Microscopically
Seminomas are composed of large, uniform cells with distinct cell borders, clear,
glycogen-rich cytoplasm, and round nuclei with conspicuous nucleoli (Fig. 9-5 B).
The cells are often disposed in small lobules with intervening fibrous septa.
A lymphocytic infiltrate is usually present.
A granulomatous inflammatory reaction may also be present.
In as many as 25% of cases, cells staining positively for human chorionic gonadotropin
(hCG) can be seen. Some of these hCG-expressing cells are morphologically similar to
syncytiotrophoblasts, and they are presumably the source of the elevated serum hCG
concentrations that may be encountered in some males with pure seminoma.
Spermatocytic seminoma: is a much less common morphologic variant of seminoma
that tend to occur in older patients. It contains cells with round nuclei with spiral
deposition of chromatin that are reminiscent of secondary spermatocytes. The cytoplasm
of tumor cells is eosinophilic and does not contain glycogen .A high mitotic activity is
often present. (Fig. 9-6) It typically occurs in men older than 50 years of age (median, 55
years)
Embryonal carcinoma occurs most frequently between 25 and 35 years of age, which is
10 years earlier than the age range for seminoma. It is rare after the age of 50 years and
does not occur in infancy. Most patients present with a painless unilateral enlarging
testicular mass. Approximately two thirds of cases have retroperitoneal lymph node or
distant metastases at the time of diagnosis.
Gross features
Is an ill-defined, invasive tumor that contains foci of hemorrhage and necrosis (Fig. 9-
7 A)
The primary lesions may be small, even in patients with systemic metastases.
Larger lesions may invade the epididymis and spermatic cord.
Microscopic features (Fig. 9-7 B).
The constituent cells are large and primitive (undifferentiated) looking, with basophilic
cytoplasm, indistinct cell borders, and large nuclei with prominent nucleoli. Mitoses
are frequent including abnormal ones
The neoplastic cells are disposed in solid sheets that may contain glandular structures
and irregular papillae
In most cases, other germ cell tumors (e.g., yolk sac tumor, teratoma, choriocarcinoma)
are admixed with the embryonal carcinoma. In fact, pure embryonal carcinomas are
quite rare.
Yolk sac tumors (YST) (endodermal sinus tumors)
These are the most common primary testicular neoplasm in children younger than 3 years
of age. In adults, yolk sac tumors are most often seen admixed with embryonal
carcinoma. Yolk sac tumors represent endodermal sinus differentiation of totipotential
neoplastic cells.
Grossly, these tumors are often large and may be well demarcated.
Microscopy discloses low cuboidal to columnar epithelial cells forming microcysts,
sheets, glands, and papillae, often associated with eosinophilic hyaline globules. A
distinctive feature is the presence of structures resembling primitive glomeruli, the so-
called Schiller-Duvall bodies. α-fetoprotein (AFP) can be demonstrated within the
cytoplasm of the neoplastic cells by immunohistochemical techniques. (Fig. 9-8)
Choriocarcinomas represent differentiation of pluripotent neoplastic germ cells along
trophoblastic lines.
Grossly, they are often small, nonpalpable lesions, even with extensive systemic
metastases. Microscopically, they are composed of sheets of small cuboidal cells
intermingled with large, eosinophilic syncytial cells containing multiple dark,
pleomorphic nuclei; these represent cytotrophoblastic and syncytiotrophoblastic
differentiation, respectively (Fig. 9-9). The hormone hCG can be identified with
immunohistochemical staining.
Teratomas represent differentiation of neoplastic germ cells along somatic cell lines.
Grossly There are firm masses that on cut surface often contain cysts and recognizable
areas of cartilage. (Fig. 9-10)
Microscopically, three major variants of pure teratoma are recognized:
1. Mature teratomas contain fully differentiated tissues from one or more germ cell
layers (e.g., neural tissue, cartilage, adipose tissue, bone, and epithelium) in a haphazard
array.
2. Immature teratomas, in contrast, contain immature somatic elements reminiscent of
those in developing fetal tissue.
3. Teratomas with somatic-type malignancies are characterized by the development of
frank malignancy in preexisting teratomatous elements, usually in the form of a
squamous cell carcinoma or adenocarcinoma.
Pure teratomas in prepubertal males are usually benign. In adults, teratomas metastasize
in as many as one third of cases. As with other germ cell tumors, testicular teratomas in
adults often contain other malignant germ cell elements and therefore should be generally
regarded as malignant neoplasms.
Mixed germ cell tumors account for 40% of all testicular germ cell neoplasms.
Combinations of any of the described patterns may occur in mixed tumors, the most
common of which is a combination of teratoma, embryonal carcinoma, and yolk sac
tumors.
Clinically, testicular germ cell tumors are divided in to two broad categories:
1. Seminomas and
2. Non-seminomatous tumors
These two groups of tumors have somewhat distinctive clinical presentation and natural
history. Individuals with testicular germ cell neoplasms present most frequently with
painless testicular enlargement. However, some tumors, especially nonseminomatous
germ cell neoplasms, may have widespread metastases at diagnosis, in the absence of a
palpable testicular lesion. Seminomas often remain confined to the testis for prolonged
intervals and may reach considerable size before diagnosis. Metastases are most
commonly encountered in the iliac and para-aortic lymph nodes. Hematogenous
metastases occur later. In contrast, nonseminomatous germ cell neoplasms tend to
metastasize earlier, by both lymphatic and hematogenous routes. Hematogenous
metastases are most common in the liver and lungs.
Testicular germ cell neoplasms are staged as follows:
Stage I: Tumor confined to the testis
Stage II: Regional lymph node metastases only
Stage III: Nonregional lymph node and/or distant organ metastases
Assay of tumor markers secreted by tumor cells is important in the clinical evaluation
and staging of germ cell neoplasms.
1. hCG, produced by neoplastic syncytiotrophoblastic cells, is always elevated in patients
with choriocarcinoma. Other germ cell tumors, including seminoma, may also contain
syncytiotrophoblastic cells without cytotrophoblastic elements and hence up to 25% of
seminomas secrete hCG.
2. AFP is normally synthesized by the yolk sac and several other fetal tissues. Germ cell
tumors containing elements of yolk sac (endodermal sinus) often produce AFP; in
contrast to hCG, the presence of AFP is a reliable indicator of the presence of a
nonseminomatous component to the germ cell neoplasm, because yolk sac elements are
not found in pure seminomas.
Because mixed patterns are common, most nonseminomatous tumors have elevations of
both hCG and AFP. In addition to their role in the primary diagnosis and staging of
testicular germ cell tumors, serial determinations of hCG and AFP are useful for
monitoring patients for persistent or recurrent tumor after therapy.
THE PROSTATE
PROSTATITIS may be acute or chronic.
1. Acute bacterial prostatitis is caused by the same organisms associated with acute
UTIs, particularly Escherichia coli. Most patients with acute prostatitis also have
concomitant acute urethritis and cystitis. In these cases, organisms may reach the prostate
by direct extension from the urethra or urinary bladder. Alternatively prostatitis may
complicate infections from distant sites through the blood.
2. Chronic prostatitis may follow episodes of acute prostatitis, or may develop
insidiously, without previous episodes of acute infection. In some cases of chronic
prostatitis bacteria can be isolated (chronic bacterial prostatitis). In other instances the
presence of an increased number of leukocytes in prostatic secretions confirms prostatic
inflammation, but bacteriologic findings are negative (chronic abacterial prostatitis),
which account for most cases of chronic prostatitis. Several nonbacterial agents
implicated in the pathogenesis of nongonococcal urethritis, including Chlamydia
trachomatis.
Pathological features
Acute prostatitis: there is an acute, neutrophilic inflammatory infiltrate, congestion, and
stromal edema. Neutrophils are initially within the prostatic glands but as the infection
progresses, they destroy glandular epithelium and extends into the surrounding stroma,
resulting in the formation of microabscesses. Grossly visible abscesses can develop with
extensive tissue destruction, e.g. in diabetic patients.
Chronic prostatitis: evidence of tissue destruction and fibroblastic proliferation, along
with the presence of inflammatory cells, such as lymphocytes & neutrophils, is required
for a histologic diagnosis of chronic prostatitis.
3. Granulomatous prostatitis is a variant of chronic prostatitis, it is not a single disease
but instead a morphologic reaction to a variety of insults. It may be seen
1. With systemic inflammatory diseases (disseminated TB, sacoidosis, fungal infections).
2. As a nonspecific reaction to inspissated prostatic secretions
3. After transurethral resection of prostatic tissue.
Microscopically, there are multinucleated giant cells and variable numbers of foamy
histiocytes, sometimes accompanied by eosinophils. Caseous necrosis is only seen in the
setting of tuberculous prostatitis.
Clinical features
Prostatitis is manifested as dysuria, frequency, lower back pain, and poorly localized
suprapubic or pelvic pain. The prostate may be enlarged and tender, particularly in acute
prostatitis with often fever and leukocytosis. Chronic prostatitis, even if asymptomatic,
may become a reservoir for organisms capable of causing UTIs. Chronic bacterial
prostatitis, therefore, is one of the most important causes of recurrent urinary tract
infection in men.
BENIGN PROSTATIC HYPERPLASIA (BPH) (Nodular hyperplasia of the
prostate)
The normal prostate consists of glandular and stromal elements surrounding the urethra.
The prostatic parenchyma can be divided into the following biologically distinct zones:
1. Peripheral
2. Central
3. Transitional, and
4. Periurethral zones (Fig. 9-11).
The types of proliferative lesions are different in each zone. For example, most
hyperplastic lesions arise in the inner transitional and central zones of the prostate, while
most carcinomas arise in the peripheral zones.
BPH is an extremely common & affects a significant number of men by the age of 40,
and its frequency rises progressively with age, reaching 90% by the eighth decade. BPH
is characterized by proliferation of both stromal and epithelial elements, with resultant
enlargement of the gland and, in some cases, urinary obstruction. Androgens have a
central role in the pathogenesis of BPH. Dihydrotestosterone. (DHT) is derived from
testosterone through the action of 5α-reductase & appears to be major hormonal
stimulus for stromal and glandular proliferation in men with nodular hyperplasia. DHT
binds to nuclear androgen receptors and, in turn, stimulates synthesis of DNA, RNA,
growth factors, and other cytoplasmic proteins, leading to hyperplasia. This is the base
for the current use of 5α-reductase inhibitors in the treatment of symptomatic nodular
hyperplasia. Local, intra-prostatic concentrations of androgens and androgen receptors
contribute to the pathogenesis of this condition. Age-related increases in estrogen levels
that may increase the expression of DHT receptors on prostatic parenchymal cells,
thereby functioning in the pathogenesis of nodular hyperplasia.
Gross features
BPH arises mostly in the inner, peri-urethral glands of the prostate, particularly from
those that lie above the verumontanum.
The affected prostate is enlarged.
The cut surface contains many well-circumscribed nodules (Fig. 9-12 A). The nodules
may have a solid appearance or may contain cystic spaces, the latter corresponding to
dilated glandular elements seen in histologic sections.
The urethra is usually compressed by the hyperplastic nodules, often to a slitlike
orifice.
In some cases, hyperplastic glandular and stromal elements lying just under the
proximal prostatic urethra may project into the bladder lumen as a pedunculated mass,
resulting in a ball-valve type of urethral obstruction.
Microscopic features
The hyperplastic nodules are composed of varying proportions of proliferating
glandular elements and fibromuscular stroma.
The hyperplastic glands are lined by tall, columnar epithelial cells and a peripheral
layer of flattened basal cells; crowding of the proliferating epithelium results in the
formation of papillary projections in some glands (Fig. 9-12 B).
The glandular lumina often contain inspissated, proteinaceous secretory material,
termed corpora amylacea.
The glands are surrounded by proliferating stromal elements.
Areas of infarction are frequent in advanced cases of BPH and are accompanied by
foci of squamous metaplasia in adjacent glands. (Fig. 9-13)
Clinical manifestations of BPH occur in only 10% of men with the disease. Because
nodular hyperplasia preferentially involves the inner portions of the prostate, its most
common manifestations are those of lower urinary tract obstruction. These include
difficulty in starting the stream of urine (hesitancy) and intermittent interruption of the
urinary stream while voiding. Some may develop complete urinary obstruction, with
resultant painful distention of the bladder and, if neglected, hydronephrosis. Symptoms of
obstruction are frequently accompanied by urinary urgency, frequency, and nocturia, all
indicative of bladder irritation. The combination of residual urine in the bladder and
chronic obstruction increases the risk of urinary tract infections.
CARCINOMA OF THE PROSTATE
This is the most common visceral cancer in males and the second most common cause of
cancer-related deaths in men older than 50 years of age, after carcinoma of the lung. The
peak incidence is around the age of 70 years. Hidden (Latent) cancers of the prostate are
even more common than those that are clinically apparent, with an overall frequency of
more than 50% in men older than 80 years of age.
Hormones, genes, and environment are thought to be of pathogenetic importance:
A. Androgens; their role in prostatic carcinogenesis is supported by the following
observations
1. Cancer of the prostate does not develop in males castrated before puberty.
2. The growth of many prostatic carcinomas can be inhibited by orchiectomy or by the
administration of estrogens such as diethylstilbestrol.
B. Hereditary & Racial contributions are supported by
1. The increased risk of the disease among first-degree relatives of patients with prostate
cancer.
2. Symptomatic carcinoma is more common and occurs at an earlier age in blacks &
Asians. Whether such racial differences occur as a consequence of genetic influences
&/or environmental factors remains unknown.
However, the frequency of latent (incidental) prostatic cancers is similar in all races,
suggesting that race is more importantly in the growth of established lesions than in the
initial development of carcinoma.
In familial cases, several susceptibility loci on chromosome 1 have been identified.
C. Environmental influences is suggested by the increased frequency of prostatic
carcinoma in certain industrial settings and by significant geographic differences in the
incidence of the disease. Carcinoma of the prostate is particularly common in
Scandinavian countries and relatively uncommon in Japan and certain other Asian
countries. Males immigrating from low-risk to high-risk areas maintain a lower risk of
prostate cancer; the risk of disease is intermediate in subsequent generations, in keeping
with an environmental influence on the development of this disease. A diet high in animal
fat has been suggested as a risk factor.
Gross features (Fig. 9-14 A)
The majority of prostate cancers (80%) arise in the outer (peripheral) glands and hence
may be palpable as irregular hard nodules by rectal digital examination. Because of the
peripheral location, prostate cancer is less likely to cause urethral obstruction in its initial
stages than is nodular hyperplasia.
Early lesions typically appear as ill-defined masses just beneath the capsule of the
prostate.
On cut surface, foci of carcinoma appear as firm, gray-white to yellow lesions that
infiltrate the adjacent native prostatic tissues with ill-defined margins.
Metastases to regional pelvic lymph nodes may occur early.
Locally advanced cancers often infiltrate the seminal vesicles and periurethral zones of
the prostate and may invade the adjacent soft tissues and the wall of the urinary
bladder. Denonvilliers fascia, the connective tissue layer separating the lower
genitourinary structures from the rectum, usually prevents growth of the tumor
posteriorly. Invasion of the rectum therefore is less common than is invasion of other
contiguous structures.
Microscopic features (Fig. 9-14 B)
Most carcinomas are adenocarcinomas with variable degrees of differentiation.
The better differentiated lesions are composed of small glands that infiltrate the
adjacent stroma in an irregular, haphazard fashion.
In contrast to normal and hyperplastic prostate, the glands in carcinomas
1. Lie "back to back" and appear to dissect sharply though the native stroma
2. Are lined by a single layer of cuboidal cells with conspicuous nucleoli; the basal cell
layer seen in normal or hyperplastic glands is absent.
With increasing degrees of anaplasia, irregular glandular, papillary or cribriform
epithelial structures, and, in extreme cases, sheets of poorly differentiated cells are
present.
Glands adjacent to areas of invasive carcinoma of the prostate often contain foci of
epithelial atypia, or prostatic intraepithelial neoplasia (PIN).
Because of its frequent coexistence with infiltrating carcinoma, PIN has been suggested
as a probable precursor to carcinoma of the prostate. PIN has been subdivided into high-
grade and low-grade patterns, depending on the degree of atypia. Importantly, high-grade
PIN shares molecular changes with invasive carcinoma, lending support to the argument
that PIN is an intermediate between normal and frankly malignant tissue.
A number of histologic grading schemes have been proposed for carcinoma of the
prostate. They are based on features such as the degree of glandular differentiation, the
architecture of the neoplastic glands, nuclear anaplasia, and mitotic activity. A commonly
used method for grading is the Gleason system, which has proved to correlate reasonably
well with both the stage of prostatic carcinoma and its prognosis.
Clinically, 10% of carcinomas are localized and discovered unexpectedly during
histologic examination of tissues removed for nodular hyperplasia. Because most cancers
begin in the peripheral regions of the prostate, they may be discovered during digital
rectal examination. More extensive disease may produce local discomfort and evidence
of lower urinary tract obstruction. PR exam. in such cases reveals a hard, fixed prostate.
Aggressive carcinomas may first come to attention through the presence of metastases.
Bone metastases, particularly to the axial skeleton, are common and may cause either
osteolytic (destructive) or, more commonly, osteoblastic (bone-producing) lesions. The
presence of osteoblastic metastases in an older male is strongly suggestive of advanced
prostatic carcinoma.
Assay of serum levels of prostate-specific antigen (PSA) has gained widespread use in
the diagnosis of early carcinomas. PSA is proteolytic enzyme produced by both normal
and neoplastic prostatic epithelium. Traditionally, a serum PSA level of 4.0 ng/L has
been used as the upper limit of normal. Cancer cells produce more PSA, but any
condition that disrupts the normal architecture of the prostate, including adenocarcinoma,
BPH, and prostatitis, may also cause an elevation in serum levels of PSA. Moreover, in
some cases of cancer of the prostate, especially those confined to the prostate, serum PSA
is not elevated. Because of these problems, PSA is of limited value when used as an
isolated screening test for cancer of the prostate. However, it has a much more value
when it is used in conjunction with other procedures, such as digital rectal examination,
transrectal sonography, and needle biopsy. In contrast to its limitations as a diagnostic
screening test, serum PSA concentration is of great value in monitoring patients after
treatment for prostate cancer, with rising levels after therapy indicative of recurrence
and/or the development of metastases.
Staging of the extent of disease has an important role in the evaluation and treatment of
prostatic carcinoma. The anatomic extent of disease and the histologic grade influence
the therapy for prostate cancer and correlate well with prognosis. Carcinoma of the
prostate is treated with various combinations of surgery, radiation therapy, and hormonal
manipulations. Most prostate cancers are androgen sensitive and are inhibited to some
degree by surgical or pharmacologic castration, estrogens, and androgen receptor-
blocking agents. These all have been used to control the growth of disseminated lesions.
The prognosis for patients with limited-stage disease is favorable: more than 90% of
patients with stage T1 or T2 lesions (localized to the prostate) survive 10 years or longer.
The outlook for patients with disseminated disease remains poor, with 10-year survival
rates in this group ranging from 10% to 40%.