Diagnosis Of Prostate Cancerdocx

=== Diagnosis of prostate cancer ===

University Of Medicine And Pharmacy

Necolai Testmiteanu

Of Republic Of Moldova

DIAGNOSIS OF PROSTATE CANCER

Presented by : Neime Alaeddin

Chisinau – 2016

1.1 The Prostate

1.1.1 Anatomy

The prostate is the male sexual accessory gland. It is located on the floor of the pelvis and surrounds the neck of the bladder and urethra (see Figure 1.1). In men, the urethra serves two purposes; urination and ejaculation. It runs from the bladder through the prostate and to the tip of the penis. The section of the urethra running through the prostate is known as the prostatic urethra. After being produced in the testicles, sperm moves into a coiled mass, known as the epididymis for maturation. It then goes into two muscular tubes known as the vas deferens, which coil around the bladder and seminal vesicles. The seminal vesicle can house the sperm for several days until ejaculation. During ejaculation, the prostate muscles contract and expel the sperm into the prostatic urethra towards the tip of the penis.

Figure 1.1 The Prostate Gland

The average weight of a healthy prostate is approximately 11grams, ranging between 7 and 16grams . It is encapsulated by a fibroelastic tissue layer, leading to septa extending inwards and dividing the prostate into different lobes. The lobes accommodate nearly 50 irregularly branched saccular glands, excretory ducts, stroma (connective tissue cells), blood vessels and nerves. The glands are lined with two epithelial cell layers, the outer layer is composed of cuboidal epithelia (simple cube shaped) and the inner layer is composed of tall columnar epithelia. This transitional epithelium or urothelium has the ability to contract and expand according to the volume of fluid within.

The main male hormone is testosterone and is produced in the testicles. The prostate is regulated by dihydrotestosterone. Dihydrotestosterone is synthesized from testosterone in the peripheral tissue.

1.1.2 Prostate Function

The primary function of the prostate gland is to store part of seminal fluid and assist ejaculation during sexual activity. The smooth muscles in the prostate help to expel semen during ejaculation. The slightly alkaline fluid produced by the prostate makes up 25% of seminal fluid and allows sperm motility and viability. The vaginal tract is acidic therefore the alkalinity of the semen neutralizes the environment to allow the sperm to stay viable. A major constituent of prostatic secretion is prostate specific antigen (PSA), along with citrate (18.7 mg/ml), zinc (488 µg/ml), spermine (243 mg/ml) and cholesterol (78 mg/ml).

1.1.3 Prostate Structure

The prostate can be classified by two different systems; zones or lobes. The zonal classification is used more in pathology; classifying the prostate into four different regions. The peripheral zone (PZ) forms about 70% of the prostate and surrounds the urethra. Nearly 80% of prostatic cancers develop in the PZ. The central zone (CZ) surrounds the ejaculatory ducts and forms 25% of the prostate. Only 2.5% of prostatic cancers arise in this region, however the cancers that do develop here are more aggressive . The transition zone (TZ) accounts for around 20% of prostatic cancers and surrounds the proximal urethra. The TZ grows larger over time; benign prostatic enlargement originates in this region. The final region, the anterior fibro-muscular zone consists of muscle and fibrous tissue only.

The lobe classification system also divides the prostate into four different regions, the anterior lobe (roughly the same as the TZ), posterior lobe (comparable to the PZ), lateral lobes (spans all zones) and the median or middle lobe (CZ). This classification is usually used when describing the anatomy of the prostate.

1.2 Prostate Carcinogenesis

Cancers are described as unregulated growth and consequent spread of cells to other parts of the body. All types of cells can undergo such malignant changes and become cancers, however only epithelial cells can become carcinomas. The normal cell cycle is disrupted and the new “tumour” cells overgrow in a localised region at first, then spread to surrounding tissue and finally to other parts of the body via the lymphatic system and vascular system .

In the process of carcinogenesis, normal cells are transformed into cancer cells due to an uncontrolled cell division. Normal cell division maintains a balance between proliferation and cell death with tightly regulated processes. Mutations in DNA can disturb these processes, leading to the cell to rapidly divide and therefore proliferate at a much higher rate. The resulting mass can either be benign, which does not spread to other parts of the body, or be malignant which can invade other organs and spread to distant locations.

A possible precursor of prostatic carcinoma is prostatic intraepithelial neoplasia (PIN). PIN involves the abnormal development of the epithelial cells which line the prostate glands. Low grade PIN is characterized by crowded and irregularly spaced epithelial cells where the nuclei are hyperchromatic (with elevated chromatin) and pleomorphic (where there is variation in size and shape). In high grade PIN, a higher level of hyperchromatisms and pleomorphism exists. PIN is distinguished from adenocarcinoma by the involvement of a cluster of rounded cells, resembling a raspberry shape, known as acini . Presence of PIN suggests an increased risk for adenocarcinoma however it can be up to 10 years before prostate carcinoma presents

.

Adenocarcinoma is a type of cancer arising from epithelial cells of the secretary glands lining the prostatic ducts. The cytological features include enlarged hyperchromatic nuclei, as in PIN

.

1.2.1 Molecular changes

Most of the human genome is non-coding DNA; therefore the majority of genetic changes are harmless. The coding DNA makes up approximately 3% of the genome and genes are also split into introns (non-coding) and exons (coding). Only mutations in the exon regions of the genome are subject to harmful changes which may affect protein composition .

Although the genetics of prostate cancer are poorly understood, we know cancers almost always arise from a single somatic cell, that undergoes a number of genetic changes which cause a change in gene activity and therefore phenotype . Cancer causing mutations usually arise in genes involved in the regulation of cellular growth or death . Since there are over 100 types of cancers and each tumour has a number of different subtypes, the complexity makes it difficult to pinpoint origin of disease. The past two decades have seen extensive research in the molecular, biochemical and cellular processes involved in the transformation of normal cells to malignant cancer cells. The vast majority of cancer cells have six different capabilities; self sufficiency in growth signals, insensitivity to anti growth signals, evasion of apoptosis, infinite replication ability, sustained angiogenesis and ability to invade tissue and metastasise . Normal cells monitor their external environment and stimulate cell division when necessary. Cancer cells, however, produce their own signals which liberate them from the growth limitations of normal cells. The second capability is insensitivity of anti-growth signals, which works in the same way as the previous stage, as cancer cells do not receive signals to inhibit growth. The third feature is the acquired capability of sustained growth. A normal cell usually stops replicating after 60 or 70 times, which is controlled by the telomeres. These segments of DNA are shortened by each round of

DNA replication, and eventually, when they are too short for another round of the cycle, the cell undergoes apoptosis (cell death). Cancer cells are able to maintain the length of their telomeres, allowing them replicate infinitely. The next feature is evasion of apoptosis, which is usually exerted by p53. In cancer cells, the p53 gene is often mutated and therefore apoptosis does not occur as normal. Angiogenesis is the formation of new blood vessels. These are essential for supplying the tumour with oxygen and nutrients. And the final capability is tissue invasion and metastasis, where cancer cells attach themselves to other cells and move around the body .

Cancer genes can be classified into three main categories; oncogenes, tumour suppressor genes and cells involved in DNA repair. Oncogenes were the first cancer causing genes identified and lead to unregulated cell growth . Most arise from genes known as proto oncogenes responsible for normal cell growth. They are generally dominant and common mutations include an increase in protein activity or loss of regulation, increase in protein concentration or chromosomal translocation causing gene expression of the different cell type.

Examples of oncogenes include ras (mutated in about 15% of cancers), myc and abl .

Tumour suppressor genes are also known as anti-oncogenes and are usually inactivated by loss of function mutations. In 1971, Knudson studied sporadic and familial retinoblastoma and formulated the two hit model of carcinogenesis which demonstrates the loss of function changes. In familial retinoblastoma, there is a 50% chance of a child inheriting the condition from an affected parent and in sporadic there is no additional risk . The inherited form is not known to cause a predisposition of tumour development due to germline mutations in one copy of the tumour suppressor gene . A somatic mutation of the second copy will cause

tumour progression. In sporadic retinoblastoma, two different “hits” are required within the same cell to develop a tumour. The p53 gene TP53 is one of the most important tumour suppressor genes involved in key cancer control pathways, such as cell cycle control, apoptosis, angiogenesis and genetic stability. And the final category is genes responsible for DNA repair mechanisms, which allow normal DNA replication. Mutations in this process often result in genetic instability leading to abnormal chromosome numbers or breaks .

A mutation specific for prostate cancer is yet to be identified. Also, common mutations in oncogenes and tumour suppression genes for various other cancers are surprisingly rare in primary prostate cancer .

1.2.2 Prostate Specific Antigen

Prostate specific antigen (PSA) is a glycoprotein produced by the prostate acinar cells and is unique to the prostate gland. The function of PSA is to dissolve the seminal clot after ejaculation in order to facilitate the transport of spermatozoa along the female reproductary tract. PSA may be complexed to serum proteins, when it is known as “complexed PSA” or it can be free, known as “free PSA”. Both complexed PSA and free PSA are combined to give a measure of total PSA. Although PSA is present in high concentrations in seminal fluid (0.5 to 2.0 mg/mL) it has a much lower concentration in the blood, almost 1000 times lower. Although the variations in concentration are independent of other proteins, it is sensitive to changes in serum testosterone levels . Age specific normal ranges are used to identify elevated levels; however these vary according to the assay used.

PSA was first described as a prostate cancer marker in 1982 and the first reports of its use as a screening test were in 1991 . The incidence of prostate cancer has had a gradual increase in most Western countries over the last 30 years, however the use of PSA testing caused a spike in new diagnoses in the USA in the early 1990s . A good screening test should be sensitive, safe, cheap and should be used for diseases in which early detection improves prognosis. There has been some debate over the last criterion for PSA testing, although it has been developed extensively in order to increase specificity and sensitivity . As benign prostatic enlargement can also be responsible for increasing PSA, an adjusted value called PSA density, is often used. For this measure, the serum PSA value is divided by prostate volume. The main advantage of this test is that it guides decision making for prostate biopsies. However, as a transrectal ultrasound (TRUS) is required for the measurement of prostate volume, it increases the discomfort for the patient and it is costly . Free PSA can be measured by a blood test and is usually lower in prostate cancer patients, however the reasons for this are unclear . Men with a free PSA of less than 15% have a higher risk of prostate cancer, yet in men with 25% or higher free PSA, the risk is significantly reduced .

As PSA increases with age, cut off values are age dependent (see Table 1.1). There are also different reference ranges for different ethnicities . Although these reference ranges are easy to use, they can fail to detect high grade prostate cancer in older men .

1.2.3 Symptoms and Diagnosis

Prostate tumours are usually slow growing and symptoms may not occur for many years. In the early stages of prostate cancer, there are often no symptoms. However, due to its location surrounding the urethra, symptoms for the disease most commonly affect urination. Prostate cancer symptoms include frequent urination, increased urination during the night, (nocturia), difficulty in maintaining a steady stream of urine, blood in the urine (hematuria) and painful urination (dysuria). It can also affect sexual function, for example difficulty in achieving erection or painful ejaculation. If the cancer is advanced, it can spread to other organs, causing bone pain in the pelvis or ribs. Many of the urinary symptoms also occur in other prostate diseases, such as benign prostate hyperplasia, along with an enlargement of the prostate. Prostate tumours are only felt in a small percentage of cases during a digital rectal examination (DRE). Diagnosis of prostate cancer must be confirmed by a needle biopsy. The International Classification of Diseases version 10 (ICD10) classifies malignant neoplasm of the prostate as code C61 .

1.2.4 Tumour staging

Once a patient has been diagnosed with a prostate tumour, the cancer must be staged to determine if it has spread beyond the prostate. Staging also provides a better insight into the risk of the disease spreading further so the correct treatment option is selected. The TNM stage was developed by the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) (32). It is used to evaluate the extent of the primary tumour (T), the affected regional lymph nodes (N) and if it has spread or metastasized (M). There are four stages; in stage I only a small part of the prostate is cancerous, most of the cells are normal

and the gland feels normal. In stage II, a lump can be felt in the prostate to the examining finger and a larger part of the prostate is affected. In stage III, the tumour has spread beyond the prostate and in stage IV; it has spread to lymph nodes or nearby organs. A more detailed view can be found in Table 1.2.

Table 1.2 Staging of Prostate Cancer

1.2.5 Tumour Grading

Tumours are graded to allow better predictions for prognosis. The Gleason Grading System is the most commonly used system, where cancers are scored according to their appearance under a microscope. During biopsy, a sample of the prostate tissue is obtained and prepared on microscope slides. Two grade scores are assigned for the two most common tumour patterns, and these scores added together for a final Gleason sum. Gleason scores range from 1 to 5, where 5 has the poorest prognosis and Gleason sums range from 2 to 10. The Gleason patterns are detailed Table 1.3. For the primary grade, pathologists identify which pattern corresponds with at least 50% of the tumour and the secondary grade represents the minority of the tumour.

The prognosis for prostate cancer can be variable. More aggressive tumours, with Gleason sum 8, 9 or 10, can lead to death in a short space of time, however lower grades, with Gleason sum of 6 or lower, may not see any clinical consequences . Albertsen et al conducted a series of studies on a cohort of 767 untreated cancer patients. Men with tumours of Gleason sum 5 had between 6% to 11% cancer mortality at 20 years. Patients with tumours with a higher Gleason sum had up to 70% (Gleason score 7 or 8) and 87% (Gleason score 10) rates of death from prostate cancer, with very few of the entire cohort surviving more than 15 years after diagnosis .

Table 1.3 Gleason Patterns

Pattern 1 The cancerous prostate cells closely resemble normal prostate cells. The glands are small, well-formed, and closely packed.

Pattern 2 The glands are larger and have more tissue between them

Pattern 3 The tissue still has recognizable glands, but the cells are darker. Some cells have left the glands and have started to invade the surrounding tissue.

Pattern 4 The tissue has few recognizable glands. Many cells are invading the surrounding tissue

Pattern 5 The tissue does not have recognizable glands. There are often just sheets of cells throughout the surrounding tissue.