07. Prostate Cancer
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8/2/2019 07. Prostate Cancer
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Urology course –– Prostate cancer
Statistically, it is the most common cancer of men (exceeding the lung and coloncancer) and it represents 32% of all cancers. Its occurrence is correlated with the natural
phenomenon of aging. It is very rare in men under 40 years, but it reaches its maximum
frequency in the eighth decade of life.
We have to mention that the incidence of occult cancers (shown in autopsy) is
much higher than those manifested clinically. The latter ones are characterized by a large
variability in their natural evolution (and therefore the potential for metastasis), leading to
various controversies regarding appropriate therapy attitude, depending on the evolution
of the disease. Therefore, the treatment that may evolve from a simple monitoring to
aggressive surgery (total prostatectomy) depends on the age of the patient, grading and
the clinical stage and last but not least on the protocols and therapy possibilities of each
medical center.
INCIDENCE
The incidence, namely the rate of morbidity / year / 100.000 population ranges
from 1.3 in China, 3.4 in Japan and 30 in Germany. In the U.S.A, this rate is 60 in the
white population and 95 in the black population. In Europe, it is the second cause of
death after lung cancer and bronchitis, approximately at the same level with colorectal
tumors. In Germany, there are 40.000 new cases / year. 40-60% of men of 70 years suffer
of prostate cancer, mostly well-differentiated, of small dimensions. These prostate
cancers found incidentally at autopsy are known as latent prostate cancers. Prostate
cancer grows slowly; the doubling time of tumor mass is 2-4 years.
The increased incidence of occult cancers may be explained by the fact that this
cancer may occur in advanced ages, and as it grows slowly, it does not manifest
clinically, as the individuals die from other morbid causes associated.
ETIOPATHOGENESIS
Epidemiological studies emphasize the involvement of factors in the etiology of
PC:
7. Prostate cancer (PC)
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Fig. 7.1. Prostate after McNeal a. – peripheral zone; b – central zone; c –
transition zone; d - fibro-muscle stroma
Urology course –– Prostate cancer
• Genetic predisposition (if a sibling or parent suffers of PC, the risk of PC is at
least double);
• Hormone causes (the involvement of steroid hormone is clear because PC does
not occur in eunuchs; cancer cells depend on hormones and increase rapidly in the
presence of androgens; castration causes a dramatic regression in the evolution of
cancer. Neoplasia occurs in the active prostate glands, not in those inactive by age).
On the other hand, in patients with prostate cancer we may notice aberrations in the
steroid metabolism;
• Environmental and diet factors (the second and third generation of Japanese living
in America have the same incidence of PC as the rest of the population, while in
Japan it is only 10% of the incidence in the U.S.);
• Local infections (due to the direct relationship between prostate gland and urethra,
it is possible that some viral or venereal infections to be involved in prostate cancer;
these data are controversial).
PATHOLOGY
According to the studies of McNeal, the prostate, a gland, is divided into several
areas (fig. 6.1), into the rectum, related to its anterior part, is found in the peripheral
area, the origin for 75%
of all prostate
carcinomas.
In less than 5%
of cases, prostate cancer
originates in the central
area, which is located
around ejaculation
channels (fig. 7.1),
which open at the level
of the seminal
colicullus. Around the proximal urethra, the transitional area is found, the place of origin
of BPH. About 20% of all prostate cancers occur in this area.
a
b
c d
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Fig. 7.2. Limphnode groups interested in PC
Urology course –– Prostate cancer
Prostate glands have their own channels that open in the seminal colicullus
channels that are covered with cubic epithelial cells. Around the prostate gland, there is a
stroma rich in connective tissue.
In 98% of the cases, prostate cancer originate in the glandular epithelium, and the
remaining of 2% originate in the epithelium of the tubes of the prostate gland. Very rarely
we may also find sarcomas, which originate in the stroma of the glandular tissue,
especially in young people.
Local-regional evolution. Prostate cancer grows in the direction of the apex of the
prostate gland. Following the development of the prostate cancer, the prostate capsule is
infiltrated, the perineural spaces being particularly affected at the entry and exit of the
nerves. The capsular penetration and seminal vesicles are signs indicating locally
advanced prostate cancer.
Metastasis. The most comon metastasis of prostate cancer are at the lymph node
and bone.
The obturator lymph nodes represent
the first station. In case of radical
prostatectomy, they are the lymph nodes
indicating the lymphatic invasion or its
absence. The pre-sacral and inguinal lymph
nodes are the next lymph node stop, then the
common iliac lymph nodes and then paraaortic
lymph nodes (fig. 7.2). The mediastinal and
supraclavicular lymph nodes are subsequently
infiltrated.
Hematogenous metastases are usually
found at the level of the skeleton (osteoblastic
metastases), they are found in 85% of the
patients dying of this condition.
Visceral metastases are rare; the lung, liver and adrenal glands may be involved.
Generally, hematogenous metastasis follows the lymph metastasis. Most PC develop
heterogeneous and multicentric.
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Urology course –– Prostate cancer
The "grading" system most commonly used is the Gleason system, which notes
from 1 to 5, based on glandular appearance (and not smear!), two most frequent focal
tumors. The score resulted is interpreted as follows: 2-4 well differentiated, 5-7
moderately differentiated, 8-10 poorly differentiated. It is one of the most important
clinical indicators for assessing PC prognosis. The stage of the PC staging is determined
according to the TNM system of UICC.
TNM staging system
T - tumor
Tx- primary tumor cannot be identified
T0 - no primary tumor
T1 –tumor not clinically apparent
T1a - tumor found incidentally at histological examination, representing <5% of
the tissue obtained through TURP
T1b - tumor discovered incidentally at the histological examination, representing >
5% of the tissue obtained through TURP
T1c - impalpable tumor, identified by biopsy (elevated PSA)
T2 – tumor localized in the prostate
T2a – the tumor occupies half or less of a lobe
T2b – the tumor occupies more than half of one lobe, but not both
T2c –the tumor occupies both lobes
T3 – extracapsular extended tumor
T3a - extracapsular (unilateral or bilateral) extension with microscopic bladder
neck invasion
T3b – the tumor invades the seminal vesicles
T4 – the tumor is fixed or invades the adjacent structures others than the seminal vesicles:
external sphincter, rectum, elevator muscle of the anus or pelvis.
N - Lymph nodes
Nx - the lymph nodes cannot be evaluated
N0 - no metastases in the regional lymph nodes
N1 –metastasis in regional lymph nodes
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Urology course –– Prostate cancer
M - Metastasis
Mx - the existence of metastases cannot be evaluated
M0 - no distant metastases
M1 - distant metastases
M1a - metastasis to lymph nodes other than the regional lymph nodes
M1b. - Bones
Mlc - Other tissues or organs
Symptoms
Currently, PC is most commonly found in asymptomatic phase or by elevated
PSA, or DRE. These investigations should be applied to all patients over 45 years, as
screening. Thanks to the aggressive screening policies in countries like USA, Austria,
England, France, the mortality due to this pathology decreased. At the same time, PC
may also be discovered incidentally on the pathological examination of the tissue
obtained by transurethral resection of the prostate adenoma, for example.
The localized PC rarely generates symptoms. Sometimes, the occurrence of bone
metastases orients the clinical examination toward a suffering prostate, where cancer, by
then asymptomatic, is detected.
Sometimes, even from the early stages of disease, the development of the tumoral
process in the cervical - trigonal region leads to the occurrence of the dysectasia
syndrome, characterized by dysuria, pollakiuria and urination pain. In the prostate cancer
it is usual that dysuria worsens rapidly, the patient sometimes suffering of acute urinary
retention or chronic incomplete retention with bladder distension, in a few months.
Initially, terminal hematuria, then total hematuria, but low-intensity and
persistent, is frequently added to the dysectasia syndrome in PC, unlike prostate
adenoma. Some patients may present hemospermia. Very rarely, PC occurs in a
hemorrhagic syndrome due to fibrinolysis.
In extended prostate cancer, the general condition is also influenced;patients lose
weight, paleness due to anemia also occurs, sometimes due to persistent hematuria less
abundant, but persistent, as well as by the inhibitory action of the neoplastic process on
the bone marrow.
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Urology course –– Prostate cancer
CLINICAL EXAMINATION
Digital rectal examination has a major role in the diagnosis of PC, which may
detect the lesion even before clinical manifestation.
In the beginning, the tumor lesion is represented by an intra-prostate nodule,
difficult to differentiate from an inflammatory one. The prostate nodule inflammation
protrudes at the surface of the gland and has precise limits; the cancerous nodule is
inserted in the gland, tough, well-defined and painless. Sometimes the whole lobe or
entire gland is affected, which in case of tumor is hard, with irregular surface, painless,
well confined. Most of the times, the median ditch is maintained. In advanced stages, the
gland is fixed on tissues and bones surrounding sacral excavation. In this phase, at the
DRE, a hard, woody mass is found, occupying all the pelvis, where the prostate cannot
be detected; frozen pelvis.
Any hard, painless prostate nodule requires clarification by biopsy.
DIAGNOSIS
1. Transrectal ultrasound. Today there are special ultrasound probes with
appropriate frequency of 7,5 MHz or more for rectal or vaginal examination. Typically,
the PC node occurs as a hypoechogenic area. This sign is not specific, since HBP, blood
vessels, cysts, inflammatory processes appear as hypoechogenic areas. If they are located
in the peripheral area of the prostate, they should also be investigated by biopsy. The
main advantage of the transrectal prostate biopsy compared to the supra-symphyseal or
transurethral biopsy is that of sampling ultrasound guided biopsies, by adjusting the
needle guidance system for transrectal ultrasound probe, which allows adequate sampling
of biopsies from suspicious areas. This will enable pathologist to determine the stage and
grading, which are the most important factors in determining prognosis. The limit of the
transrectal ultrasound is the lower accuracy of magnetic resonance imaging (MRI) in
assessing extracapsular extension, failure to appreciate the regional lymph node invasion
and make differential diagnosis with other hypoecogenic images due to adenoma or
prostatitis (specificity 78-99%).
2. Prostatic biopsy puncture needles have been much improved by adapting them
to biopsy guns.
• Prostate biopsy. It may be transrectal, transperineal or transurethral biopsy.
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Fig. 7.3. Transrectal prostate biopsy.
Urology course –– Prostate cancer
• Transrectal biopsy. It is carried out by means of transrectal ultrasound (fig.
7.3). Currently, it is the most
used technique in asymptomatic
patients with elevated PSA. 12
biopsies are performed under
ultrasound guidance. In addition,
the ultrasound guidance may
identify hypoechogenic areas
(pathognomonic for PC) that are
not detected in DRE and may
guide the biopsies to the
transition area located above the
prostate and that is not accessible
to DRE. Rarely, it may be performed without ultrasound guidance. The palpating finger
(index) feels the node and the biopsy needle is inserted in the lesion. Tru-Cut biopsy
needles (Travenol) are used.
• Transperineal biopsy. It is performed with the same type of needle, but only
preceded by local anesthesia.
3. PSA values. Prostate specific antigen (PSA) is a glycoprotein secreted by prostate, which prevents sperm clotting. PSA may be determined from serum by radio- or
immunoassay methods, with elevated values both in HBP and in PC. But appearance of
the PC tissue increases the serum value of PSA 10 times more than the same quantity of
BPH tissue. However, 20% of the PC found are accompanied by normal levels of PSA.
Generally, the maximum normal value of PSA is 3,2 ng / ml. PSA is an extremely useful
value for incipient and early prostate cancer diagnosis. PSA has a special value in the
control and monitoring therapy.
We may conclud that PSA is a useful marker for post-therapy screening and
tracking. Thus, the total acid phosphatase, prostatic acid phosphatase and alkaline
phosphatase are no longer used in the diagnosis and therapy monitoring of the prostate
cancer.
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Urology course –– Prostate cancer
4. CT examination is not an appropriate examination to evidence PC metastases
in lymph nodes. CT may detect these lymphatic invasions only in the case of massive
node invasion, with lymph nodes having a diameter larger than 1.5 cm. Even in assessing
local tumor invasion (T staging) CT is an investigation with modest results.
5. Bone scintigraphy. It is the most important investigation for highlighting bone
metastases. Sensitivity of the method in detecting these metastases is approximately
100%. All processes of bone healing after fractures, inflammation, etc., may cause
similar changes in osteoblastic metastases.
6. Magnetig resonance imaging (MRI). An expensive and time-consuming
investigation. It is superior both to transrectal ultrasound in assessing extracapsular
invasion, and to the CT in assessing lymph nodes invasion, especially when MRI with
endo-rectal probe is performed. It is restricted to young patients, where the preservation
of the peri-prostate vascular-nervous packages is needed (their bilateral intraoperatory
cutting generates erectile dysfunction).
7. UIV and renal ultrasound show urethral obstruction by the infiltration of
terminal ureters at the level of the bladder, in a PC with local invasion.
The most important diagnostic measure before radical prostatectomy is a local
lymphadenectomy for the nodes in the obturator fossa (6-9 lymph nodes on each side). If
these nodes are invaded, we may assume with a probability of 90% that there are distance
lymphatic metastases.
DIFFERENTIAL DIAGNOSIS
There are other prostate disorders that may mimic a PC such as prostate adenoma,
chronic prostatitis, prostatic tuberculosis, fibrosis caused by previous biopsies, cysts and
prostate stones. The occurrence of PSA decreased the number of patients undergoing
prostate biopsy.
1. Prostate adenoma is usually associated with a long history of obstructive
symptoms and the prostate volume is usually higher than in CP.
2. Prostatic tuberculosis is often associated with damages of epididymis, history
of pulmonary tuberculosis, fever and sterile pyuria.
3. Chronic prostatitis has a long history, and leukocytes are identified in urine or
prostatic secretion.4. Prostate cysts or stones are easily identified at transrectal ultrasound.
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Fig. 7.4. Digital rectal examination
Urology course –– Prostate cancer
5. The differential diagnosis of Paget's disease is taken into consideration in
asymptomatic patients with bone metastases who present increased values acid
phosphatase and alkaline phosphatase.
STAGING
The assessment of the clinical stage of cancer can be made by DRE, transrectal
ultrasound, computed tomography or magnetic resonance imaging. DRE (fig. 7.4) may
assess the extracapsular extension, seminal vesicle attachment, extension to pelvic wall or
the rectum. The examination depends on the experience of the examiner; it cannot
identify the T stage and it cannot clearly differentiate the prostate conditions described
above.
Transrectal ultrasound may diagnose 60% of the PC because of their
hypoechogenic aspect (40% are isoechogenic or hyperechogenic) and it also serves to the
eco-guiding of the biopsies (the guidance allows adequate sampling of biopsies of
suspicious areas, which allows the pathologist to assess the stage and grading, the most
important factors in determining the prognosis). The limit transrectal ultrasound is
accuracy, lower magnetic
resonance imaging (MRI) in
assessing the extracapsular
extension, failure to
appreciate the regional lymph
node invasion and the
differential diagnosis with
other hypoechogenic images
due to adenoma or prostatitis
(specificity 78-99%).
TREATMENT
1. Treatment of localized PC (T1 ,T2, NX – N0 ,M0)
1.a. Monitoring of the patient (Watchful waiting - WW).
Watchful waiting may be considered in patients with localized PC, but with a
reduced life expectancy or elderly patients with less aggressive tumors.
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Urology course –– Prostate cancer
The current treatment for T1 and T2 stages is the radical prostatectomy or
radiotherapy, both with a long-term survival of 80-90% and mortality less than 1%.
1.b. Total prostatectomy may be transperitoneal and / or retropubic.
Laparoscopic lymph node dissection allows perineal approach in obese patients, without
the need for another suprapubic incision. In this intervention, besides the removal of the
prostate, the seminal vesicles will also be removed and the bilateral lymphadenectomy
will be performed.
The survival rate from 10 to 15 years, in T2 patients, is 68%, respectively 62%
respectively.
Similar results (in terms of oncology) with open radical prostatectomy were
obtained by laparoscopic radical prostatectomy, or even robotics.
The immediate complications of total prostatectomy are intraoperative bleeding,
injury of the obturator nerve, the ureter or rectum. Immediate postoperative
complications include: venous thrombosis, pulmonary embolism, symptomatic pelvic
lymphocele, wound or urinary tract infections, etc.. The incidence of these complications
is less than 3%.
Long-term complications are urinary incontinence and erectile dysfunction.
PSA level after radical prostatectomy should be 0 ng / ml at about 6 weeks.
Otherwise, it is considered tumor residue or metastasis (PSA remains high or increases
rapidly after prostatectomy) or tumor recurrence (PSA to 0 ng / ml and then increases).
Other surgical techniques which may be applied to these patients, but that have no
intention of oncology treatment are represented by cryotherapy or ablation with high
frequency ultrasound (HIFU), perineal or transrectal techniques.
1.c. Radiotherapy. Brachytherapy and external conformational therapy seem
to have similar results with the surgery. Since in this case, the staging is only clinical and
imaging (not pathological), the comparative studies between the two methods are difficult
to perform.
Transperineal brachytherapy is the transperineal implantation in prostate of
radioactive seed under ultrasound control (fig. 7.5). It is reserved for the patients with
small prostate, low PSA and low Gleason score.
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Urology course –– Prostate cancer
Relapse-free survival after radiotherapy is modest, 54% at 5 years and 36% at 10
years.
2. Treatment of locally advanced PC with or without metastases (T3, T4, N1,
M1)
Prostate carcinomas are heterogeneous tumors composed of hormone sensitive
and hormone resistant cells. The degree of hormone sensitivity will determine the initial
response to androgen deprivation. Although dihydrotestosterone (DHT) is the active
metabolite necessary for the
normal prostate cell growth, PC
may use other hormone
precursors for its growth (ex.
those from the adrenal gland).
After androgen
deprivation, approximately
40% of the patients experience
the cessation of the disease
progression, while 20% of the
cancers will continue to grow
and evolve. Treatment results
are modest, over time they
become ineffective due to the
proliferation of certain
hormone resistant tumor cells.
The average survival time of
patients with metastases is 2
years. Approximately 80% of
them die within the first 5
years.
Hormone therapy (fig 7.6)
Estrogens. Until recently, estrogens (diethylstilbestrol - DES) and orchiectomy
have been the most important alternatives to hormone therapy. DES, at a dose of 3
Fig.7.6 Hypothalamus-pituitary-gonadal axis
LH
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Urology course –– Prostate cancer
mg/day, acts by suppressing LH and probably, also by a minor effect (little known) in
cancer cells. The efficacy of estrogen use is similar to orhiectomy, but combining the two
methods (orchiectomy + estrogen) is not superior and life expectancy does not change.
Estrogens tend now to be abandoned because 20-30% of the patients present lethal
cardiac or pulmonary complications, as thromboembolism, peripheral edema and fluid
retention, in the first 3 months (at the mentioned dose). Painful gynecomastia is another
complication that is resolved by radiotherapy.
Orchiectomy is the cheapest and safest method of blending testicular androgens.
At present, local anesthesia may be given, requiring 1-2 days of hospitalization. It is
difficult for patients to accept it, because it is psychologically traumatizing. Usually,
surgery is accompanied by hot flashes, which decrease at the administration of
Cyproterone acetate, DES (diethylstilbestrol) 1 mg twice / week or monthly injections of
depot progesterone preparations.
LH-RH agonists. Also known as analogues (leuprorelin, goserelina, buserelin,
etc.) work by stimulating the production of pituitary gonadotropins, for 2-3 weeks, then
inhibiting it. Their effecacy is similar to the estrogens and orhiectomy (they reduce
testosteronemia to the castrating level) and they are administered as subcutaneous
injections or as depot at 1, 2, 3 or 6 months. Side effects include hot flashes 50%, nausea
5% and gynecomastia 3%. Currently, depot preparations of gosereline (Zoladex) or
difereline, with monthly administration (3,75 mg) and more recently at 3 months (1 l,
25mg) are manufactured.
LH-RH antagonists
In contrast to LH-RH agonists, LH-RH antagonists bind rapidly to LH-RH
receptors in the pituitary gland, resulting in rapid decrease in LH, FSH and testosterone.
Studies on this type of hormone therapy are still at beginning. There are no such forms as
depot as for LH-RH agonists. As representatives, we may mention abarelix, degarelix.
Antiandrogens include drugs that act either a) by the inhibition of androgen
synthesis, or b) by blocking their action in the target organ.
a) androgen synthesis inhibitors include spironolactone, aminoglutethimide and
ketoconazole and block the synthesis both at testicular and adrenal level. Ketoconazole,
imidazole derivative, initially conceived as antifungal, has significant side effects
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Urology course –– Prostate cancer
including: hepatotoxicity, gastrointestinal intolerance, gynecomastia and hypocalcaemia.
It is indicated that fast-acting drug in patients with bone pain and spinal cord
compression.
b) androgen antagonists act through a competitive mechanism of blocking the
androgen receptor. They may be steroid anti-androgens (cyproterone acetate – 200 – 300
mg/day Androcur) or non-steroid antiandrogens (flutamide - Eulexine 3x250 mg / day,
nilutamida - 2x150mg/zi, bicalutamide - Casodex 50-100 mg / day). The advantage of
these drugs is to preserve libido in most patients.
Maximum androgen blockade (CAB = complete androgen blockade) is an anti-
androgen in association with orchiectomy or LH-RH analogue. This association is based
on the idea that hormonal treatment failure is due to inadequate suppression of adrenal
androgens and not to the selection of the hormone resistant cancer cells. Recent studies
have not demonstrated the superiority of the method in terms of increased survival or
quality of life.
Minimal androgen blockade is the combination of a minimum non-steroid anti-
androgen 5 α reductase inhibitor (finasteride). By this combination the testosterone level
is low, without significant effects on sexual function.
The anti-cancer drugs may be used in metastasis hormone-resistant PC. Various
types of anti-cancer drugs have been studied: taxanes, mitoxantrone in combination with
corticosteroids, estramustin phosphate, cisplatin or carboplatin, etc.
Suramin, an anti-parasitic agent, is currently the subject of several studies. It
works by blocking growth factors (b FGF and EGF), having anti-enzymatic effects,
cytotoxic effects on PC cells and suppression effect on the corticosuprarenal gland, all
resulting in a decrease of plasma androgens. It determines a reduction in the oral tissue,
which persists on average 4-11 months (at 33-50% of hormone resistant patients). PSA
decreases by 75% to 29% of men receiving such treatment.
Recent phase III trials have shown encouraging results on the effects of the
treatment with certain Sipuleucel-T (Provenge) vaccines in patients suffering of hormone
resistant PC with metastases.
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Urology course –– Prostate cancer
The palliative treatment refers to the patients with bone metastases and to the
patients with subvesical obstruction. In the first case, we use radiotherapy or recently, the
administration of strontium 89.
The patients with subvesical obstruction are treated with orchiectomy, CAB and /
or transurethral resection, with the intention of removing the largest possible amount of
the tumor tissue, leaving a prostate lodge type cavity after the resection, being mandatory
to keep the striated sphincter.
CONCLUSIONS
Prostate cancer is a disease of older man. It is the most common urological
malignant tumor and it is the second as a cause of cancer death in men, after bronchial
carcinoma. Prostate cancer is an extremely slow growing adenocarcinoma that grows
very slowly and whose early forms noticed in the autopsy of the men over 70 years are
found in half of the autopsies.
The aggression of the tumor is closely correlated with its volume. From a tumor
volume (ex. 0,5 cm3), there is a clinically manifested tumor that may be palpated at DRE.
Up to a volume of 4 cm3, the tumor is almost always limited to the prostate. At higher
volumes, it penetrates the capsule and it metastasizes first to the lymph nodes (lymphatic
metastases), and then the bones (hematogenous metastases).
By the digital rectal examinations, we may discover prostate tumors clinically
relevant. Early detection of prostate cancer was much improved by determining the level
of the prostate specific antigen PSA. Transrectal ultrasound is the diagnostic method that
may be used to diagnose prostate cancer in early stage. The diagnosis of PC is determined
by histopathological examination of a tissue fragment taken by prostate biopsy,
ultrasound guided.
PC limited to the organ will be treated by radical prostatectomy. Radiation
therapy does not have a curative, but palliative role.
PC with metastases will be treated by one of the various forms of anti-androgenic
therapy.
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Urology course –– Prostate cancer
PSA is an organ-specific marker. After total prostatectomy, it becomes a tumor-
specific marker, very useful in monitoring the evolution of surgery. Based on serum PSA
values, the effect of radiotherapy or hormone therapy is monitored.
PC cannot be cured by means of current chemotherapy and immunotherapy. In
these cases, palliative measures will be applied to calm down pain.