Acinar adenocarcinoma of the prostate is a common malignancy, particularly in the developing world. Radiotherapy plays an increasingly important role in the management of this disease and it is one of the most common problems seen in the radiation oncology clinic.
Geographical and Genetic Variations
Australia has an incidence of prostate cancer of 100 per 100,000 people per year, making it the most common cancer of men. Mortality rates are significantly lower at about 17 per 100,000 per year. There are significant differences in populations worldwide:
- Western Europe and North America, with similar populations to Australia, have a similar rate of prostate cancer
- China and Japan have very low rates of prostate cancer
- Blacks who live in the Americas have very high rates of prostate cancer. Sub-saharan Africa also has high age-adjusted incidence and mortality rates, whereas northern Africa has relatively low rates of the disease.
Migrants form an interesting cohort. Some groups develop a much higher rate of disease compared to their home country (West Africans); others retain their low risk (Japanese).
In all groups, the risk of prostate cancer is very low before the age of 50. The incidence of disease increases rapidly after this age.
The incidence of prostate cancer over time has been complicated by two factors:
- The introduction of transurethral resection of prostate as a treatment for benign prostatic hypertrophy
- The introduction of PSA as a screening test
Incidence of prostate cancer doubled in the 1980's as TURP became a well established procedure, and increased the incidental findings of localised prostate cancer. Incidence rates have fallen since the 1990's, presumably due to earlier detection of prostate cancers in the 1980's. Mortality rates have fallen in most nations, although the role of screening with PSA tests has been questioned.
Aetiology and Pathogenesis
Genetic factors are very important in the development of prostate cancer, but do not completely explain the differences seen between different geographical groups. This difference does not seem to relate to diet or other factors. Men with two first degree relatives have a tenfold risk of developing the cancer themselves, again supporting a strong genetic basis for the disease.
Testosterone is thought to be a major factor in the development of prostate cancer. When bound to its receptor, testosterone is transported to the nucleus where it induces transduction of various genes, including those related to cell division and survival. There is a suggestion that variations in the androgen receptor gene may account for differences seen between geographical and racial groups.
Other factors do not seem to play a role (such as sexual activity or occupation).
The natural history of acinar adenocarcinoma is of a slowly progressive tumour with a long subclinical phase. The posterior portion of the gland is most commonly involved, which does not lead to discernible symptoms.
There is often an asymptomatic period where the tumour is localised to the prostate gland. The gland may be focally involved (with a nodule), or is more commonly diffusely infiltrated by the cancer. As the disease advances it may penetrate outside the prostate and spread into periprostatic fat. This is most commonly achieved by perineural invasion but tumours can also directly invade outside the prostate.
The seminal glands are the most commonly involved extraprostatic tissue (and have their own staging category, T3b). They are involved via direct extension, lymphovascular spread or via spread along the ejaculatory ducts.
Metastases may develop in otherwise asymptomatic patients, and are usually skeletal. Visceral metastases are seen late in the course of the disease.
Many patients are asymptomatic. Most patients are diagnosed by detection of an elevated Prostate Specific Antigen (PSA) level. Some patients may be diagnosed on digital rectal examination. Less commonly, patients present with symptoms of urinary obstruction (about 5% of trans-urethral resections of prostate for presumed benign prostate hypertrophy). Locally advanced disease can present with rectal bleeding or obstruction; this is, however, rare. Metastatic disease often presents with back pain or symptoms localised to the involved organ.
Many prostate cancers retain the gene kallekrein peptidase 3 (KLK3). It codes for a peptidase that is secreted by prostate cells as a component of semen. This peptidase is detectable in the blood as Prostate Specific Antigen or PSA. The role of KLK3 in the development of prostate cancer is not well understood; it may simply be a residual function that the prostate cancer cells retain, or it may be involved in tumorigenesis and aggressiveness.
Within the blood, PSA is usually bound one of two serum proteins, α-1-anti-chromotrypsin (ACT) or α-2-macroglobulin (AMG). All PSA tests use immunoassay techniques - ie: a monoclonal antibody that binds to specific parts of the PSA molecule. PSA is undetectable in the blood when bound to AMG as all potential binding sites are hidden by the larger AMG molecule. When bound to ACT, only part of the PSA molecule is hidden and it is therefore detectable. Some PSA is not bound to either protein and is known as 'free PSA'. This gives rise to the following concepts:
- Total PSA: PSA that is either free or bound to the ACT molecule.
- Bound PSA: PSA that is bound to the ACT molecule
- Free PSA: PSA that is not bound to either ACT or AMG
The free PSA component is higher in men without cancer; a low level is suggestive of malignant disease.
Other important blood tests include:
- LFT - to detect possible liver involvement or bony metastases
- FBE/UEC - to assess suitability for surgery
- Calcium - may be elevated in advanced disease
Several imaging studies should be considered:
- Ultrasound is useful in both biopsy of the prostate gland (trans-rectal ultrasound or TRUS) and in assessing obstruction of the urinary tract
- CT can detect nodal metastases and give an accurate estimate regarding prostate size. It is also useful for assessment of distant, non-bony metastases
- WBBS is extremely helpful in excluding osteoblastic bony metastases, the most common kind seen in prostate cancer
- MRI is a developing modality in prostate cancer. Advocates claim it allows detection of extraprostatic extension and visualisation of the tumour within the gland; however the diagnostic gain from the test has not been fully established.
Within the prostate gland, high grade tumour tumour is visible as distinct areas, often white or yellow. Lower grade tumours may be less distinct on macroscopic observation. There is usually microscopic extension beyond visibly involved prostate.
Normal prostate epithelium contains a secretory cuboidal/columnar layer and a regenerative basal layer. Prostate cancer is notable for lack of the basal layer of cells in all cases, although this is sometimes difficult to evaluate.
Glandular architecture forms the basis of the Gleason staging system; nuclear atypia is not included for staging purposes. Grades 1-3 form glandular lumen without a basal cell layer but with retained polarity; the lumen in grade 4 are less well formed and there is loss of polarity; and grade 5 tumours have minimal lumen formation.
- Grade 1 is very rare, and is formed by back to back lumens lined by polarised cells with no invasion into adjacent benign prostate
- Grade 2 is also rare, formed by more variable glands that may be separated to some degree. There is minimal invasion into prostate
- Grade 3 is the most common form, with small glands, often separated by stroma, that infiltrate through the normal prostate tissue. The glands are more angular than the lower grade lesions.
- Grade 4 is the second most common form, with fused, cribriform or poorly defined glandular structures.
- Grade 5 tumours form solid sheets of cells with minimal to no lumen seen. Single cells may invade through the stroma.
In summary, as the grade increases, the large (grade 1) to intermediate (grade 2) lumen become smaller (grade 3) and more deranged (grade 4) until they no longer exist (grade 5).
The final Gleason score is made by adding the two most prominent patterns together; eg, if the tumour is mostly pattern 4 with some pattern 3 it would be Gleason 7. For all cases, it is important to differentiate the prominent pattern as Gleason 3+4 carries a better prognosis than Gleason 4+3. Tertiary patterns are sometimes seen; this is only of importance for Gleason 7 disease where some recommend that the Gleason score be upgraded to include the pattern 5 (eg. Gleason 3+4 would become Gleason 3+5 and Gleason 4+3 would become Gleason 4+5); this is because tertiary pattern 5 carries an additional poor prognostic impact.
Nuclei are typically larger and have discernable nucleoli; the degree of nuclear atypia usually mirrors the architecture. The luminal border is well defined in carcinoma compared to a fluffier appearance in normal glands. Perineural invasion is diagnostic of prostate cancer.
Most prostate cancers stain positively for PSA. The staining is often heterogenous and less intense in higher grade tumours. PSA staining is seen in other sites, notably adenocarcinomas of the urethra or periurethral glands; adenocarcinoma of anal glands; and in salivary gland tumours. Other useful immunohistochemical stains include prostate specific acid phosphatase (PAP) in cases where PSA is negative, androgen receptor stains, or p63. Cytokeratin stains can detect basal cells and help to exclude benign from malignant processes.
The common genetic abnormalities seen in other cancers are not seen in prostate cancer. There are frequently losses or gains or chromosomal arms. The exact genes are under current investigation.
Prostate cancer is staged using the TNM system; prostate cancer is special in that it utilises the Gleason Score as well as the PSA when determining stage.
Clinical and pathological staging is different. Clinical stage refers to examination and imaging findings; pathological stage refers to a resected prostate. The most common stage is T1c; this is tumour that is undetectable clinically or on imaging but for which a needle biopsy was performed; this is usually in the setting of an elevated PSA.
Clinical T Stage
|T1a||Incidental finding in resected prostate tissue
(usually TURP), < 5% involved
|T1b||Incidental finding in resected prostate tissue, > 5% involved|
|T1c||Tumour detected by needle biopsy due to elevated PSA|
|T2a||Tumour nvolves less than one half of one lobe|
|T2b||Tumour involves over half of one lobe|
|T2c||Tumour involves both lobes|
|T3a||Extraprostatic extension of tumour|
|T3b||Involvement of seminal vesicles/glands|
|T4||Fixed to, or invasion of, adjacent organs
other than seminal vesicles/glands;
Pelvic wall involvement
Pathologic T Stage
There is no T1 stage.
|T2a||Involves less than one half of one lobe|
|T2b||Involves over one half of one lobe|
|T2c||Involves both lobes|
|T3a||Extraprostatic extension or
microscopic bladder neck invasion
|T3b||Seminal vesicle/gland involvement|
|T4||Invasion of adjacent structures or pelvic wall|
Nodal disease is a very poor prognostic sign and any nodal disease indicates stage IV.
|N1||Regional node involvement|
|M1a||Non-regional lymph nodes|
|M1c||Other sites with metastases|
The Gleason Score is the single most important prognostic factor for prostate cancer death. It is included in the TNM staging system because of this. The three categories are:
- Gleason ≤ 6
- Gleason 7
- Gleason ≥ 8
The PSA is another important indicator of death from prostate cancer. Similar to the Gleason Score, there are three groupings:
- PSA < 10
- PSA ≥ 10 but < 20
- PSA ≥ 20
The staging is quite complicated for prostate cancer given the additional information from the Gleason Score and PSA.
|N0||M0||G ≤ 6
G ≤ 6
|PSA < 10
PSA < 10
G ≤ 6
G ≤ 7
G ≤ 7
|PSA < 20
PSA < 20
PSA < 20
G ≥ 8
PSA ≥ 20
|III||T3||N0||M0||G Any||PSA Any|
|G Any||PSA Any|