07. prostate cancer

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)



Fig. 7.1. Prostate after McNeal a. – peripheral zone; b – central zone; c –

transition zone; d - fibro-muscle stroma


• 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



Fig. 7.2. Limphnode groups interested in PC


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.




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




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.




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.



Fig. 7.3. Transrectal prostate biopsy.


• 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.




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.



Fig. 7.4. Digital rectal examination


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.




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.




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




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




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.




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.




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.

07. prostate cancer

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