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Prostate cancer

Prostate cancer is the most common form of cancer in men, accounting for around 25% of cases. However, it causes only 9% of all cancer deaths, which shows that it has a low mortality. This is owed mostly to regular screening of PSA levels and digital rectal examination and that we have relatively effective treatment. Prostate cancer is mostly a disease of elderly. About 1 in 8 men will be diagnosed with prostate cancer at some point of their lives, but autopsy studies have shown that many more than this actually develop prostate cancer, but that it remains too small to be significant.

Management may involve local radiotherapy, radical prostatectomy, or "active surveillance" (giving no treatment but monitoring closely for progression). Prostate cancer is usually not aggressive and has a good prognosis, which allows for the watchful waiting approach. A commonly known saying is that "more men die with prostate cancer than because of it".

Risk factors

The following are risk factors for developing prostate adenocarcinoma:

  • Age > 50 years
  • Positive family history
  • African-American ethnicity
  • Scandinavian ethnicity
  • Obesity
  • Diet high in animal fat

Benign prostatic hyperplasia is not a risk factor for prostate cancer.

Importantly, because the peripheral zone is not removed during simple prostatectomy or TUR-P, prostate cancer can still develop after these procedures (which are used for BPH).

Pathology

95% of prostate cancers are acinar adenocarcinomas, the remaining neuroendocrine tumours and sarcomas. Adenocarcinomas develop from the peripheral zone. The cells of the cancerous prostatic glands have prominent nucleoli and show atypia. These glands are small and are also not surrounded by basal cells, unlike the healthy prostatic glands. Prostate cancer has a long doubling time.

Prostate cancer, like BPH, depends heavily on androgens. Most cases of prostate cancer regress temporarily after anti-androgen therapy. This often leads to the cancer developing a mutation that allows it to function even in the absence of androgens.

Fusion of the genes TMPRSS2 and ETS occurs in 50% of prostate cancers. Inactivating mutations of the tumor suppressor PTEN is also frequent.

Metastasis

Prostate cancer is relatively indolent, generally not metastasising often. When it does, metastasis to bone and liver are most common.

Gleason grading

Grading depends on the Gleason system, which assigns each case a “score” based on their histology. Prostate cancers are divided into 5 grades, depending on the glandular architecture (and not the nuclear atypia). In grade 1 the glands look almost like normal glands while in grade 5 there are only a few or no glands (correspond to anaplasia).

Most prostatic adenocarcinomas show more than one pattern of differentiation. A grade is assigned to the pattern there is most of on a histological slide, and another grade is assigned to the pattern there is second most of. These two numbers are then combined to give a Gleason score. For example, if 60% of a prostate adenocarcinoma is grade 3 and 30% is grade 5, the combined score will be (3 + 5) = 8. The worst possible score is 10 and the best possible score is 2.

Gleason 2-6 is considered low grade, Gleason 7 is considered intermediate grade, and Gleason 8-10 is considered high grade.

Prostatic intraepithelial neoplasia

Prostatic intraepithelial neoplasia (PIN) is the precancerous lesion for prostate cancer. We distinguish two types: low-grade PIN and high-grade PIN. Low-grade PIN is found in a large number of adults, even young adults. This form virtually never progresses into prostate cancer.

High-grade PIN is associated with an increased risk of prostate cancer. It involves a disrupted basal layer of the prostatic glands, prominent nucleoli and increased density of the chromatin of the glandular cells.

Autopsy studies

Autopsy studies have shown that more than 50% of men at the age of 90 or more had prostate cancer at the time of death. For the age group 60-70 and 70-80 the numbers were 25% and 31%, respectively. However, most of these cases are not symptomatic and are therefore not detected before the autopsy. This shows the relatively high subclinical prevalence which is much higher than the clinical prevalence.

Clinical features

Prostate cancer usually does not cause symptoms in the early stages. As most (70 – 80%) prostate cancer grows in the peripheral zone of the prostate, lower urinary tract symptoms are rarely seen until the later stages, when the cancer has grown. Advanced-stage prostate cancer may present with general cancer symptoms like fatigue and loss of appetite.

Prostate cancer most frequently metastasizes into the spine, especially the lumbosacral part, causing lower back pain. It also metastasizes to parailiac lymph nodes.

Diagnosis and evaluation

The diagnosis may be suspected based on digital rectal examination (DRE) and serum PSA. Those 70 – 80% of cancers that occur in the peripheral zone may be discovered during routine digital rectal examination screening; most prostatic cancers aren’t palpable on DRE though. Definitive diagnosis is based on needle biopsy of the prostate.

Multiparametric MRI (mp-MRI) is a form of MRI which combines multiple MRI modalities to assess the prostate for cancer better than a "regular" MRI can.

Transrectal ultrasound may be used in the evaluation of prostate cancer to calculate the prostate volume and to guide biopsy.

PSA

Main article: PSA

Prostate-specific antigen (PSA) is an enzyme that is produced only by the prostatic glandular epithelium, which is why its level correlates to the number of prostatic glands in the body. Its level can also be increased in prostatitis or BPH, so it’s not specific for cancer. PSA is considered elevated above 4 ng/mL, but there is no level of PSA which is definitely associated with prostate cancer which requires treatment.

It is uncertain whether PSA screening actually decreases prostate-cancer related deaths. Elevated PSA might not necessarily correlate to a clinically active cancer, so its usefulness should be determined on a case-by-case basis. PSA does have great value in measuring the effectiveness of therapy though.

In addition to measuring the total level of PSA, one can also measure other parametres such as free PSA, PSA density, PSA velocity, complexed PSA, and percentage of [-2]proPSA (a precursor of PSA). While decreased free PSA is known to be more specific for prostate cancer than total PSA, the clinical utility of the other parametres is not yet established and so they're not much used.

Staging

  • T1 – incidental finding
    • Not palpable or visible on imaging
    • Present biochemically (as elevated PSA)
  • T2 – localized cancer
    • Localized to prostate
  • T3, T4 – locally advanced cancer
  • N+ or M+ – metastatic cancer

Treatment

In many cases of prostate cancer an “active surveillance” approach might be safer than outright treating the tumor. This is especially true for elderly people with comorbidities or people with a less than 10-year life expectancy, as the treatment might be worse than the disease.

For low-risk prostate cancer, active surveillance and surgery have the same outcome. For intermediate and high-risk disease, surgery has better outcome than surveillance. For intermediate-risk disease, radiotherapy and surgery have similar outcomes and odds of cure.

Metastatic prostate cancer cannot be cured. Palliative options include chemotherapy and hormonal therapy.

Active surveillance

Active surveillance is the preferred option for most prostate cancer which are low or low-intermediate risk. It involves routinely measuring PSA and repeating mp-MRI to assess for progression. If there is sign of progression, active therapy can be considered.

Active surveillance helps avoid cancer treatment which may be unneccessary, as low and low-intermediate risk prostate cancer may never metastasise or become symptomatic. However, the patient must live with the uncertainty that the cancer may progress.

Surgical therapy

Surgical treatment of the prostate involves laparoscopic radical prostactetomy (RP), the complete surgical removal of the prostate. Radical prostatectomy has better outcomes when performed robot-assisted. RP is only performed if one expects to achieve cure.

This surgery usually severs autonomic cavernous nerves which control erectile function, thereby almost always causing impotence as a side effect. Another common side effect is urinary incontinence, but this usually improves over time.

Radiotherapy

Radiotherapy is a potentially curative modality for prostate cancer, but prostate cancer requires a very high load of radiation for local control, up to 100 Gy total. Radiotherapy may be performed with external beam (EBRT) or high dose rate brachytherapy (HDBRT), but external therapy is most common.

Before radiotherapy, small seeds of gold are inserted into the prostate. Because these are clearly visible on imaging, this allows for more precise radiation planning.

Radiotherapy also has impotence as a common side effect.

Watchful waiting

Watchful waiting is different from active surveillance in that there is no routine evaluation for progression, and is an option for asymptomatic or mildly symptomatic prostate cancer. With watchful waiting, one undergoes no treatment but if symptoms occur or progress, one can consider palliative treatment.

Chemotherapy

Chemotherapy is indicated as palliation for metastatic prostate cancer. Commonly used drugs are docetaxel and cabazitaxel.

Castration/ADT

Castration, also known as androgen deprivation therapy (ADT), is the anatomical or functional loss of the testicals. It may be achieved by orchidectomy or by use of GnRH agonists or antagonists. ADT is usually combined with an antiandrogen like abiraterone or enzalutamide.

ADT is usually indicated as neoadjuvant therapy before curative radiotherapy as well as adjuvant therapy after. Hormones make the cancer cells more radiosensitive and decreases the tumour size. Common side effects include erectile dysfunction, as well as typical symptoms of menopause like hot flashes, night sweats, mood changes, and decreased libido. However, these side effects are reversible when hormonal therapy is finished. It may also be used as palliation for metastatic prostate cancer.

Screening

The efficacy of screening for prostate cancer is debated. The reason for this is that not all cases of prostate cancer are aggressive and fatal; many cases follow a very indolent course with few clinical symptoms. Screening (especially with PSA) can’t differentiate between prostate cancers that would become aggressive and those that wouldn’t, and so many people who would develop clinically indolent prostate cancer undergoes potentially life-changing treatment which may be worse than the symptoms of the cancer would have been. Indeed, prostate cancer is often found incidentally on autopsy, and more people die with prostate cancer than of prostate cancer.

In Norway, there is no national screening programme for prostate cancer. In Hungary, the lecture recommends annual DRE and PSA measurement for men older than 50, but there is no national screening programme (as far as I can see).