Prostate cancer
Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Early prostate cancer causes no symptoms. Abnormal growth of prostate tissue is usually detected through screening tests, typically blood tests that check for prostate-specific antigen (PSA) levels. Those with high levels of PSA in their blood are at increased risk for developing prostate cancer. Diagnosis requires a biopsy of the prostate. If cancer is present, the pathologist assigns a Gleason score, and a higher score represents a more dangerous tumor. Medical imaging is performed to look for cancer that has spread outside the prostate. Based on the Gleason score, PSA levels, and imaging results, a cancer case is assigned a stage 1 to 4. A higher stage signifies a more advanced, more dangerous disease.
Prostate cancer
Prostate carcinoma
Typically none. Sometimes trouble urinating, erectile dysfunction, or pain in the back/pelvis.
Age > 40
Older age, family history, race
PSA test followed by tissue biopsy
Five-year survival rates range from 30–99%, depending on stage.[1]
Most prostate tumors remain small and cause no health problems. These are managed with active surveillance, monitoring the tumor with regular tests to ensure it has not grown. Tumors more likely to be dangerous can be destroyed with radiation therapy or surgically removed by radical prostatectomy. Those whose cancer spreads beyond the prostate are treated with hormone therapy which reduces levels of the androgens (male sex hormones) that prostate cells need to survive. Eventually cancer cells can grow resistant to this treatment. This most-advanced stage of the disease, called castration-resistant prostate cancer, is treated with continued hormone therapy alongside the chemotherapy drug docetaxel. Some tumors metastasize (spread) to other areas of the body, particularly the bones and lymph nodes. There, tumors cause severe bone pain, leg weakness or paralysis, and eventually death.
Prostate cancer prognosis depends on how far the cancer has spread at diagnosis. Most men diagnosed have tumors confined to the prostate; 99% of them survive more than 10 years from their diagnoses. Tumors that have metastasized to distant body sites are most dangerous, with five-year survival rates of 30–40%.
The risk of developing prostate cancer increases with age; the average age of diagnosis is 67. Those with a family history of any cancer are more likely to have prostate cancer, particularly those who inherit cancer-associated variants of the BRCA2 gene. Each year 1.2 million cases of prostate cancer are diagnosed, and 350,000 die of the disease,[2] making it the second-leading cause of cancer and cancer death in men. One in eight men is diagnosed with prostate cancer in his lifetime and one in forty dies of the disease.[3] Prostate tumors were first described in the mid-19th century, during surgeries on men with urinary obstructions. Initially, prostatectomy was the primary treatment for prostate cancer. By the mid-20th century, radiation treatments and hormone therapies were developed to improve prostate cancer treatment. The invention of hormone therapies for prostate cancer was recognized with the 1966 Nobel Prize to Charles B. Huggins and the 1977 Prize to Andrzej W. Schally.
Prevention[edit]
No drug or vaccine is approved by regulatory agencies for the prevention of prostate cancer. Several studies have shown 5α-reductase inhibitors to reduce the total incidence of prostate cancer; however, it is unclear as of 2022 whether they reduce any cases of dangerous disease.[35]
Prognosis[edit]
The prognosis of diagnosed prostate cancer varies widely based on the cancer's grade and stage at the time of diagnosis; those with lower stage disease have vastly improved prognoses. Around 80% of prostate cancer diagnoses are in men whose cancer is still confined to the prostate. These men can survive long after diagnosis, with as many as 99% still alive 10 years from diagnosis.[79] Men whose cancer has metastasized to a nearby part of the body (around 15% of diagnoses) have poorer prognoses, with five-year survival rates of 60–80%.[1] Those with metastases in distant body sites (around 5% of diagnoses) have relatively poor prognoses, with five-year survival rates of 30–40%.[1]
Those who have low blood PSA levels at diagnosis, and whose tumors have a low Gleason grade and less-advanced clinical stage tend to have better prognoses.[80] After prostatectomy or radiotherapy, those who have a short time between treatment and a subsequent rise in PSA levels, or quickly rising PSA levels are more likely to die from their cancers.[53] Castration-resistant metastatic prostate cancer is incurable,[81] and kills a majority of those whose disease reaches this stage.[61]
Cause[edit]
Prostate cancer is caused by the accumulation of genetic mutations to the DNA of cells in the prostate. These mutations affect genes involved in cell growth, replication, cell death, and DNA damage repair.[82] With these processes dysregulated, some cells replicate abnormally, forming a clump of cells called a tumor.[83] As the tumor grows, its cells accumulate more mutations, allowing it to stimulate the growth of new blood vessels to support further growth.[84] Eventually, a tumor can grow large enough to invade nearby organs such as the seminal vesicles or bladder.[85] In advanced tumors, cells can develop the ability to detach from their original tissue site, and evade the immune system.[84] These cells can spread through the lymphatic system to nearby lymph nodes, or through the bloodstream to the bone marrow and (more rarely) other body sites.[84] At these new sites, the cancer cells disrupt normal body function and continue to grow. Metastases cause most of the discomfort associated with prostate cancer, and can eventually kill the affected person.[84]
Pathophysiology[edit]
Most prostate tumors begin in the peripheral zone – the outermost part of the prostate.[86] As cells begin to grow out of control, they form a small clump of disregulated cells called a prostatic intraepithelial neoplasia (PIN).[87] Some PINs continue to grow, forming layers of tissue that stop expressing genes common to their original tissue location – p63, cytokeratin 5, and cytokeratin 14 – and instead begin expressing genes typical of cells in the innermost lining of the pancreatic duct – cytokeratin 8 and cytokeratin 18.[86] These multilayered PINs also often overexpress the gene AMACR, which is associated with prostate cancer progression.[86]
Some PINs can eventually grow into tumors.[87] This is commonly accompanied by large-scale changes to the genome, with chromosome sequences being rearranged or copied repeatedly. Some genomic alterations are particularly common in early prostate cancer, namely gene fusion between TMPRSS2 and the oncogene ERG (up to 60% of prostate tumors), mutations that disable SPOP (up to 15% of tumors), and mutations that hyperactivate FOXA1 (up to 5% of tumors).[86]
Metastatic prostate cancer tends to have more genetic mutations than localized disease.[88] Many of these mutations are in genes that protect from DNA damage, such as p53 (mutated in 8% of localized tumors, more than 27% of metastatic ones) and RB1 (1% of localized tumors, more than 5% of metastatic ones).[88] Similarly mutations in the DNA repair-related genes BRCA2 and ATM are rare in localized disease but found in at least 7% and 5% of metastatic disease cases respectively.[88]
The transition from castrate-sensitive to castrate-resistant prostate cancer is also accompanied by the acquisition of various gene mutations. In castrate-resistant disease, more than 70% of tumors have mutations in the androgen receptor signaling pathway – amplifications and gain-of-function mutations in the receptor gene itself, amplification of its activators (for example, FOXA1), or inactivating mutations in its negative regulators (for example, ZBTB16 and NCOR1).[88] These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease.[88] Similarly, deletions of the tumor suppressor PTEN are harbored by 12–17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors.[88] Less commonly, tumors have aberrant activation of the Wnt signaling pathway via disruption of members APC (9% of tumors) or CTNNB1 (4% of tumors); or dysregulation of the PI3K pathway via PI3KCA/PI3KCB mutations (6% of tumors) or AKT1 (2% of tumors).[88]
Special populations[edit]
Transgender women and gender non-conforming people who have prostates can develop prostate cancer. Those who have undergone gender-affirming hormone therapy or gender-affirming surgery have reduced risk of developing prostate cancer, relative to cisgender men of similar age.[103] Screening tests in this group are complicated, as transgender women may have lower PSA levels than cisgender men due to their reduced testosterone levels.[104] PSA levels greater than 1 ng/mL are generally considered above normal by gender care specialists.[105] Digital rectal exams of the prostate are often impossible in women who have undergone vaginoplasty, as the length and rigidity of the new vagina can obstruct access to the prostate from the rectum.[105]
Society and culture[edit]
Prostate cancer screening and awareness have been widely promoted since the early 2000s by Prostate Cancer Awareness Month in September and Movember in November.[120] However, an analysis of internet searches suggests neither event changes the level of prostate cancer interest or discussion much, in contrast to the more established Breast Cancer Awareness Month.[120]
Research[edit]
Prostate cancer is a major topic of ongoing research. From 2016–2020, over $1.26 billion was invested in prostate cancer research, representing around 5% of global cancer research funds.[121] This places prostate cancer 10th among 18 common cancer types in funding per cancer death, and 9th in funding per disability-adjusted life year lost.[122]
Research into prostate cancer relies on a number of laboratory models to test aspects of the disease. Several prostate immortalized cell lines are widely used, namely the classic lines DU145, PC-3, and LNCaP, as well as more recent cell lines 22Rv1, LAPC-4, VCaP, and MDA-PCa-2a and −2b.[123] Research requiring more complex models of the prostate uses organoids – clusters of prostate cells that can be grown from human prostate tumors or stem cells.[124] Modeling tumor growth and metastasis requires a model organism, typically a mouse. Researchers can either surgically implant human prostate tumors into immunocompromised mice (a technique called a patient derived xenograft),[125] or induce prostate tumors in mice with genetic engineering.[126] These genetically engineered mouse models typically use a Cre recombinase system to disrupt tumor suppressors or activate oncogenes specifically in prostate cells.[127]