Prostate cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

Prostate cancer is the development of cancer in the prostate, a gland in the male reproductive system. It was first described in 1536 by Niccolò Massa. On microscopic histopathological analysis, increased gland density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of prostate cancer. It must be differentiated from benign prostatic hypertrophy, renal cancer, renal stones, bladder cancer, and cystitis. In 2012, the prevalence of prostate cancer was estimated to be 2,800 cases per 100,000 men in the United States. The incidence of prostate cancer is approximately 137.9 per 100,000 individuals worldwide. Common symptoms of prostate cancer include changes in bladder habits, hematuria, hematospermia, and painful ejaculation.^[1]

Prostate cancer was first described in 1536 by Niccolò Massa. In 1983, radical retropubic prostatectomy^[2] was first developed by Patrick Walsh to treat prostate cancer. In 1941, the first use of estrogen was developed by Charles B. Huggins to oppose testosterone production in men with metastatic prostate cancer. In the early 20th, radiation therapy was first developed to treat prostate cancer. In the 1970s, systemic chemotherapy was first studied to treat prostate cancer.^[3]

On microscopic histopathological analysis, increased gland density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of prostate cancer.

There are no established causes for prostate cancer. To review risk factors for the development of prostate cancer click here.

Prostate cancer must be differentiated from benign prostatic hypertrophy, renal cancer, renal stones, bladder cancer, and cystitis.

In 2021, there were an estimated 3,399,229 men living with prostate cancer in the United States. In 2012, the prevalence of prostate cancer was estimated to be 2,800 cases per 100,000 men in the United States.In 2022, there were 1,466,680 new cases of prostate cancer in men worldwide. The incidence of prostate cancer is approximately 109.8 per 100,000 individuals worldwide. It usually affects individuals of the African American race. Asian, Hispanic, and White individuals are less likely to develop prostate cancer. The incidence of prostate cancer increases with age; the median age at diagnosis is 66 years.^[4]

Common risk factors in the development of prostate cancer are Age, Ethnicity, Diet (Animal fat, vegetables, Lycopene and tomato-based products, Soy intake), omega 3-fatty acids, caffeine, Vitamins and minerals (Multivitamins, Folic acid and Vitamin B12, selenium, zinc, Calcium and Vitamin D), Cigarette Smoking, Hormones levels and Obesity (Sex hormones, Insulin and Insulin-like growth factor, Physical activity), Other factors like 5 Alpha reductase inhibitor, Prostatitis, Trichomonas Vaginalis infection, Environmental Carcinogen(Agent Orange, Choldecon, Bisphenol A), NSAIDS, Vasectomy, Ultraviolet light exposure, EBRT for rectal cancer.

According to the U.S. Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for prostate cancer. According to the American Cancer Society (ACS) guidelines, screening for prostate cancer by prostate specific antigen (PSA) and digital rectal exam (DRE) is recommended once among individuals age 50 years, age 45 years for African-American men and men with a family history of prostate cancer, and age 40 years for men with a very strong family history of prostate cancer.They should be retested every year if the prostate specific antigen is 2.5ng/ml or more and once every 2 years if less than 2.5mg/ml. According to the American Urological Association (AUA) guidelines, screening for prostate cancer by PSA is recommended every 2 years among individuals age 50 to 69 years, or younger than 50 years for individuals with high risk.^[5]

Prognosis of prostate cancer is generally good, and the 5-year survival rate is approximately 98.9%. The prognosis varies with the stage of tumor; Localized and regional tumors have the most favorable prognosis.

Common symptoms of prostate cancer include changes in bladder habits, hematuria, hematospermia, and painful ejaculation.^[6]

Common physical examination findings of prostate cancer include cachexia, pallor, anesthesia in the lower limbs, paresis in the lower limbs, lower-extremity lymphedema, bony tenderness, suprapubic palpation of the bladder, and an asymmetrical boggy mass with the change of texture may be palpated in the anterior wall of the rectum.^[7]

Prostate cancer may be classified into several subtypes based on TNM system and UICC.

Laboratory findings consistent with the diagnosis of prostate cancer include elevated serum prostate-specific antigen level, low red blood cell count, elevated blood urea nitrogen, and elevated serum creatinine. Some patients may have elevated concentration of serum calcium and alkaline phosphatase, which is usually suggestive of bone metastases.

There are no X-ray findings associated with prostate cancer.

There are no CT scan findings associated with in situ prostate cancer. CT scan may be helpful in the diagnosis of bone metastasis of prostate cancer.

MRI may be helpful in the diagnosis of prostate cancer. On an MRI scan, prostate cancer is characterized by a low signal within a normally high signal peripheral zone on T2-weighted images.

On ultrasound, prostate cancer is characterized by hypoechoic areas.^[8]

Radionuclide may be helpful in the diagnosis of the bone metastasis of prostate cancer.

There are no other diagnostic study findings associated with prostate cancer.

Biopsy may be helpful in the diagnosis of prostate cancer. Findings on biopsy suggestive of prostate cancer include increased gland density, small circular glands, basal cells lacking, and cytological abnormalities.

The predominant therapy for prostate cancer is surgical resection. Adjunctive chemotherapy, radiation^[9], hormonal therapy, bisphosphonates, and analgesics may be required. Metastatic prostate cancer is managed according to hormone sensitivity or castration resistant cancer.

Surgery is the mainstay of treatment for prostate cancer.

Effective measures for the primary prevention of prostate cancer include healthy diet and maintaining a healthy weight.

There are no specific secondary preventive measures available but healthy lifestyle practices may decrease the overall mortality in prostate cancer patients.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

Prostate cancer was first described in 1536 by Niccolò Massa. In 1983, radical retropubic prostatectomy was first developed by Patrick Walsh to treat prostate cancer. In 1941, the first use of estrogen was developed by Charles B. Huggins to oppose testosterone production in men with metastatic prostate cancer. In the early 20th, radiation therapy was first developed to treat prostate cancer. In the 1970s, systemic chemotherapy was first studied to treat prostate cancer.

Although the prostate was first described by Venetian anatomist Niccolò Massa in 1536, and illustrated by Flemish anatomist Andreas Vesalius in 1538, prostate cancer was not identified until 1853.^[1]

Surgery

• The first treatments of prostate cancer were surgeries to relieve urinary obstruction.^[2]
• In 1904, the first performence of the removal of the entire gland (radical perineal prostatectomy) was done by Hugh H. Young at Johns Hopkins Hospital.^[3]
• Transurethral resection of the prostate (TURP) replaced radical prostatectomy for symptomatic relief of obstruction in the middle of the 20th century because it could better preserve penile erectile function.
• Radical retropubic prostatectomy was developed in 1983 by Patrick Walsh.^[4] This surgical approach allowed for removal of the prostate and lymph nodes with maintenance of penile function.

Medical therapy

• In 1941 Charles B. Huggins published studies in which he used estrogen to oppose testosterone production in men with metastatic prostate cancer. This discovery of “chemical castration” won Huggins the 1966 Nobel Prize in Physiology or Medicine.^[5] The role of the hormone GnRH in reproduction was determined by Andrzej W. Schally and Roger Guillemin, who both won the 1977 Nobel Prize in Physiology or Medicine for this work.
• Receptor agonists, such as leuprolide and goserelin, were subsequently developed and used to treat prostate cancer.^[6][7]
• Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiation became more popular as stronger radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds was first described in 1983.^[8]
• Systemic chemotherapy for prostate cancer was first studied in the 1970s. The initial regimen of cyclophosphamide and 5-fluorouracil was quickly joined by multiple regimens using a host of other systemic chemotherapy drugs.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Steven C. Campbell, M.D., Ph.D. Syed Musadiq Ali M.B.B.S.[2]

Prostate cancer may be classified into several subtypes based on TNM system and UICC.

Evaluation of the (primary) tumor (‘T’)^[1]

T	Definition
TX	Cannot evaluate the primary tumor
T0	No evidence of tumor
T1	Tumor present, but not detectable clinically or with imaging
T1a	Tumor was incidentally found in less than 5% of prostate tissue resected (for other reasons)
T1b	Tumor was incidentally found in greater than 5% of prostate tissue resected
T1c	Tumor was found in a needle biopsy performed due to an elevated serum PSA
T2	Tumor can be felt (palpated) on examination, but has not spread outside the prostate
T2a	Tumor is in half or less than half of one of the prostate gland’s two lobes
T2b	Tumor is in more than half of one lobe, but not both
T2c	Tumor is in both lobes
T3	Tumor has spread through the prostatic capsule (if it is only part-way through, it is still T2)
T3a	Tumor has spread through the capsule on one or both sides
T3b	Tumor has invaded one or both seminal vesicles
T4	Tumor has invaded other nearby structures

Evaluation of the regional lymph nodes (‘N’)

N	Definition
NX	Cannot evaluate the regional lymph nodes
N0	There has been no spread to the regional lymph nodes
N1	There has been spread to the regional lymph nodes

Evaluation of distant metastasis (‘M’)

M	Definition
M0	There is no distant metastasis
M1	There is distant metastasis

The UICC further groups the TNM data into the stages listed in the table below:^[2]

• Stage I

T	N	M	Definition
T1, T2a	N0	M0	Tumor involves half a lobe or less

• Stage II

T	N	M	Definition
T2b, T2c	N0	M0	Tumor involves more than half a lobe but is limited to the prostate

• Stage III

T	N	M	Definition
T3	N0	M0	Tumor has spread beyond the prostatic capsule or into the bladder neck or seminal vesicles

• Stage IV

T	N	M	Definition
T4	N0	M0	Tumor has become fixed to adjoining structures like the rectum or pelvic wall
any T	N1	M0	Tumor has spread to regional lymph nodes
any T	any N	M1	Tumor has spread to distant sites such as lungs or liver

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

In prostate cancer, the cells of these prostate glands mutate into cancer cells.The prostate gland require male hormones, known as androgen,to work properly. Androgens include testosterone, which is made in the testes, dehydroepiandrosterone,made in the adrenal gland; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass. Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen screening prostate gland cells mutate into cancer cells. On microscopic histopathological analysis, increased gland density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of prostate cancer. Androgen is required to activate a sufficient number of androgen receptors so that transcription of death-signaling gene is expressed. Multiple genes like RNASEL, MSR1, AR, CYP17, SRD5A2, ZIP1, RUNX2 is involved in pathogenesis.

• Prostate cancers can be lethal because they heterogeneously contain both androgen-dependent and androgen-independent malignant cells^[1]
• For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs) so that transcription of death-signaling gene is expressed
• Androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death
• Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelial and androgen-dependent prostate cancer cells
• Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents

• Rare autosomal dominant alleles account for a substantial proportion of cases of inherited, early-onset prostate cancer (defined as cancer occurring before 55 years of age)^[2]
• In families with men in whom prostate cancer is diagnosed at an older age, an X-linked allele may be responsible.^[3]
• The first molecular genetic study of familial prostate cancer in which polymorphic markers were used identified several regions of linkage; the chromosomal region 1q24–25, designated the locus of the hereditary prostate cancer (HPC1) gene, has been the most thoroughly investigated^[4]
• Some analyses have confirmed a link between HPC1 and prostate cancer, but others have failed to detect an association^[5]

• The RNASEL gene encodes a widely expressed latent endoribonuclease that participates in an interferon-inducible RNA-decay pathway that is thought to degrade viral and cellular RNA^[6]
• RNASEL has been linked to HPC1. In one family, four brothers with prostate cancer carried a disabling mutation of RNASEL, and in another family, four of six brothers with prostate cancer carried a base substitution affecting the RNASEL initiator methionine codon^[7]

• The macrophage-scavenger receptor 1 (MSR1) gene, located at 8p22, has also emerged as a candidate prostate–cancer–susceptibility gene^[8]
• It encodes subunits of a macrophage-scavenger receptor that is capable of binding a variety of ligands, including bacterial lipopolysaccharide and lipoteichoic acid, and oxidized high-density lipoprotein and low-density lipoprotein in the serum^[9]
• Germ-line MSR1 mutations have been linked to prostate cancer in some families with hereditary prostate cancer, and one mutant MSR1 allele has been detected in approximately 3 percent of men with non-hereditary prostate cancer but only 0.4 percent of unaffected men (P=0.05)^[10]

• Polymorphic variants of three genes involved in androgen action, the androgen-receptor (AR) gene, the cytochrome P-450c17 (CYP17) gene, and the steroid-5-α-reductase type II (SRD5A2) gene, have been implicated in modifying the risk of prostate cancer in genetic epidemiologic studies. In the case of AR, which encodes the androgen receptor, polymorphic polyglutamine (CAG) repeats have been described^[11]
• Functional studies have suggested that shorter polyglutamine repeats may be associated with increased androgen-receptor transcriptional transactivation activity^[12]
• Black Americans, who have a relatively high risk of prostate cancer, tend to have shorter androgen-receptor polyglutamine repeats, whereas Asians, who have a relatively low risk of prostate cancer, tend to have longer androgen-receptor polyglutamine repeats. Several genetic epidemiologic studies have shown a correlation between an increased risk of prostate cancer and the presence of short androgen-receptor polyglutamine repeats, but other studies have failed to detect such a correlation^[13]
• Polymorphic polyglycine (GGC) repeats are also characteristic of AR and may also influence the risk of prostate cancer^[14]
• CYP17 encodes cytochrome P-450c17α, an enzyme that catalyzes key reactions in sex-steroid biosynthesis. A variant CYP17 allele has been subjected to both population and genetic-linkage analyses to determine its association with prostate cancer, with inconsistent results^[15]
• SRD5A2 encodes the predominant isozyme of 5-α-reductase in the prostate, an enzyme that converts testosterone to the more potent dihydrotestosterone. Two common polymorphic variant SRD5A2 alleles have been described^[16]
• The alleles that encode enzymes with increased activity have been associated with an increased risk of prostate cancer and with a poor prognosis for men with prostate cancer^[16]

• Prostate cancer is classified as an adenocarcinoma, or glandular cancer. The region of prostate gland where the adenocarcinoma is most common is the peripheral zone.^[17]

• Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in situ or prostatic intraepithelial neoplasia (PIN).^[18]

• Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time these cancer cells begin to multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor.^[18]

• Eventually, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or the rectum, or the tumor cells may develop the ability to travel in the blood stream and lymphatic system.^[18]

• Prostate cancer is considered a malignant tumor because it is a mass of cells which can invade other parts of the body. This invasion of other organs is called metastasis. Prostate cancer most commonly metastasizes to the bones, lymph nodes, rectum, and bladder.^[18]

• Prostate gland is a zinc-accumulating, citrate-producing organ^[19]
• The protein ZIP1 is required for the active transport of zinc into prostate cells
• Zinc have important role to change the metabolism of the cell in order to produce citrate, an important component of semen.
• The process of zinc accumulation and citrate production is energy inefficient and prostate cells sacrifice enormous of energy (ATP) in order to complete this task.
• Prostate cancer cells are generally devoid of zinc. This allows prostate cancer cells to save energy not making citrate, and utilize the new abundance of energy to grow and spread.
• The absence of zinc is thought to occur via a silencing of the gene that producing the transporter protein ZIP1.
• ZIP1 is now called a tumor suppressor gene product for the gene SLC39A1.The cause of epigenetic silencing is unknown.
• Zinc inhibits BF-kB pathways, is anti-proliferative,and induces apoptosis in abnormal cells.
• Unfortunately, oral ingestion of zinc is not effective because high concentrations of zinc into prostate cells is not possible without the active transporter ZIP1.
• RUNX2 is a transcription factor that prevents the cancer cells from undergoing apoptosis thereby contributing to the development of prostate cancer.
• The androgen receptor helps prostate cancer cells to survive and is a target for many anticancer research studies; so far, inhibiting androgen receptor.
• Prostate specific membrane antigen(PSMA) stimulates the development of prostate cancer by increasing folate levels for cancer cells to use to survive and grow.
• PSMA increases available folate for use by hydrolyzing glutamate folate.

Prostate cancer is uncommonly apparent on gross.^[20]

Major criteria:^[21][22]

• Architecture

• Increased gland density
• Small circular glands

• In rare subtypes – large branching glands

• “Infiltrative growth” pattern – malignant glands between benign ones

• Basal cells lacking

• Cytological abnormalities:

• Nuclear enlargement (subtle)
• Nucleoli (prominent)

Minor criteria:

• Nuclear hyperchromasia
• Wispy blue mucin
• Pink amorphous secretions
• Intraluminal crystalloid
• Amphophilic cytoplasm
• Adjacent High-grade prostatic intraepithelial neoplasia (HGPIN)
• Mitoses – quite rare

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• See Gleason score

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

There are no established causes for prostate cancer. To review risk factors for the development of prostate cancer click here.

There are no known direct causes for prostate cancer. To review risk factors for the development of prostate cancer click here.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2] Syed Hassan A. Kazmi BSc, MD [3] Amandeep Singh M.D.[4]

Prostate cancer must be differentiated from benign prostatic hypertrophy, renal cancer, renal stones, bladder cancer, and cystitis.

Prostate cancer must be differentiated from:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]}

• Benign prostatic hypertrophy (BPH)
• Renal cancer
• Renal stones
• Bladder cancer
• Cystitis
• Glomerulonephritis
• Prostatitis
• Pyelonephritis

Diseases		Clinical manifestations									Para-clinical findings		Gold standard
		Symptoms						Physical examina
											Lab Findings	Diagnosi
		Low back pain	Fever	Nausea/ Vomiting	Urinary symptoms			Hypertension	Pitting edema	Other
					Dysuria	Frequency	Oliguria
Disease		Low back pain	Fever	Nausea/ Vomiting	Dysuria	Frequency	Oliguria	Hypertension	Pitting edema	Other	Lab Findings	Diagnosis method	Gold standard
Nephrolithiasis[16][17]		+	±	+	±	±	±	–	–	Radiating pain to groin	Hypercalciuria Hyperoxaluria Hypocitraturia Hyperuricemia Hyperuricosuria	Ultrasound: Hydronephrosis +/- Abdominal CT scan without contrast	Abdominal CT scan without contrast
Malignancy	Renal cell carcinoma (RCC)[18][13]	–	–	–	–	–	–	±	±	Flank mass	Anemia Hematuria	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work-up and follow-up of patients with renal cell carcinoma. The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.	–
	Bladder cancer[19][20][21]	–	–	–	–	±	±	–	–	Suprapubic pain	Anemia Hematuria	Ultrasound, CT scan, Biopsy	Biopsy
	Prostate cancer[22][23]	±	–	–	–	±	±	–	–	–	Anemia Hematuria	Ultrasound, CT scan, Biopsy	Biopsy
Lower urinary tract diseases	Benign prostatic hyperplasia	+/-	–	–	+	+	–	–	–	Nocturia Other voiding symptoms Slow urinary stream Splitting or spraying of the urinary stream Intermittent urinary stream Hesitancy Straining to void Terminal dribbling	Urinalysis to rule out UTI Elevated BUN/Cr High PSA values	Urine cytology to screen for bladder cancer Biopsy to rule out cancer	Biopsy
	Urolithiasis[24][25][26]	+	+/-	+	+	+	+	–	–	Flank Groin pain	Urine analysis High Cr	Abdominppelvic CT scan without contrast	Abdominppelvic CT scan without contrast
Infectious diseases	Pyelonephritis[27][28]	+	+	+	+	+	+	–	–	Delirium Headache	Positive leukocyte esterase test and nitrite test. Blood/urine cultures	CT and ultrasound: Enlarged kidneys Round swollen kidneys Hypodense appearance Abscesses may not be present	–
	Cystitis[29][30]	–	–	–	+	+	+	–	–	Dyspareunia Supra pubic tenderness	Pyuria: > 5-10 WBC/hpf or 27 WBC/microliter Positive leukocyte esterase test and nitrite test. Positive urine/blood cultures	Ultrasound: Presence of gas in the bladder wall. Also, help to detect the presence of a tumor or a stone.	Urine culture
	Prostatitis[31][32]	–	+	–	+	+	+	–	–	Body aches	Increased leukocytes (>10 per high power field) on CBC Bacteria seen on urine culture Elevated C-reactive protein Transiently elevated PSA (prostate specific antigen) levels	Ultrasound: Focal hypoechoic region located in the peripheral part of the prostate CT scan: Edema of the prostate gland with diffuse enlargement,.	–

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2] Muhammad Saad, M.B.B.S.[3] Syed Musadiq Ali M.B.B.S.[4] Kavya Keerthi Vadlamudi, M.B.B.S.[5]

In 2022, there were 1,466,680 new cases of prostate cancer in men worldwide. In 2020, there are expected to be approximately 191,930 new prostate cancer diagnoses and approximately 33,330 prostate cancer deaths. The number of deaths was 19.0 per 100,000 men per year. These rates are age-adjusted and based on 2013-2018 cases and deaths. Approximately 12.1 percent of men will be diagnosed with prostate cancer at some point during their lifetime, based on 2013-2017 data. In 2017, an estimated 3,170,339 men were living with prostate cancer in the United States.

• In 2021, there were an estimated 3,399,229 men living with prostate cancer in the United States.^[1]
• In 2017, there were an estimated 3,170,339 men living with prostate cancer in the United States.^[2]
• Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States.^[3]

• In 2022, there were 1,466,680 new cases of prostate cancer in men worldwide.^[4]
• In 2020, there are expected to be approximately 191,930 new prostate cancer diagnoses and approximately 33,330 prostate cancer deaths^[5].
• Prostate cancer is second only to non-melanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in United States men.
• In 2022, there were an estimated 1,466,680 new cases of prostate cancer and 396,792 prostate cancer deaths, making it the second most commonly diagnosed cancer in men and cancer death^[6][4].

• The incidence of prostate cancer increases with age; the median age at diagnosis is 67 years.^[1]

• Shown below is an image depicting the incidence of prostate cancer by age and race in the United States between 1975 and 2015.^[7]

• The annual incidence rate of prostate cancer is 173.0 cases per 100,000 Black men vs 97.1 per 100,000 White men.^[8][9]
• It usually affects individuals of the African American race. Asian, Hispanic and White individuals are less likely to develop prostate cancer.
• Shown below is a table depicting the age-adjusted rate of prostate cancer by race in 2015 in the United States.^[7]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	19.5 per 100,000	18.2 per 100,000	39.9 per 100,000	8.8 per 100,000	16.2 per 100,000

• Shown below is an image depicting the incidence of prostate cancer by race in the United States between 1975 and 2015.^[10]

• Prostate cancer is highly hereditable
• More than 50% of prostate cancer risk is attributable to genetic factors, as shown by studies performed in Northern Europe.^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Syed Musadiq Ali M.B.B.S.[2]

Common risk factors in the development of prostate cancer are family history, African American men, dietary factors, obesity, elevated blood levels of testosterone, inherited gene mutation, inflammation of the prostate, tall adult height, exposure to pesticides, and occupational exposures.

Common risk factors in the development of prostate cancer include:

• Age
• Ethnicity
• Diet

• Animal fat
• Vegetables
• Lycopene and tomato based products
• Soy intake
• omega 3-fatty acids
• caffeine

• Vitamins and minerals

• Multivitamins
• Folic acid and Vitamin B12
• selenium
• zinc
• Calcium and Vitamin D

• Cigarette Smoking
• Hormones levels and Obesity

• Sex hormones
• Insulin and Insulin like growth factor
• Obesity
• Physical activity

• 5 alpha reductase inhibitor
• Prostatitis
• Trichomonas vaginalis infection
• Environmental Carcinogen

• Agent Orange
• Choldecone
• Bisphenol A

• NSAIDS
• Vasectomy
• Ultraviolet light exposure
• EBRT for rectal cancer

• Prostate cancer has strongest relationships between age and any human malignancy.
• Prostate cancer rarely occurs before the age of 40.
• The incidence rises rapidly and the annual incidence of new cases of prostate cancer in white men in 1995 was approximately 0.1, 0.6, and 1 percent in men in their 50s, 60s, and 70s, respectively^[1].

• Prostate cancer is more common in black than white or Hispanic men.^[2]
• African American men have higher serum PSA levels, worse Gleason scores, and more advanced stage of disease at the time of diagnosis^[3].

• The association between intake of nutrients and the risk of prostate cancer are available^[4].

• Animal fat —
  • A diet high in animal fat may be an important factor in the development of prostate cancer^[5].
  • Intake of large amounts of alpha-linolenic acid and low amounts of linoleic acid appear to be associated with increased risk^[6].
• Vegetables —
  • A diet low in vegetables may be another risk factor for prostate cancer^[7].
  • There is higher prostate cancer risk in men who consume fewer than 14 servings of vegetables weekly.^[7].
  • There was no association between fruit and/or vegetable consumption and the risk of prostate cancer^[8]
• Lycopene and tomato based products —
  • Tomato-based products are rich in lycopene has potent anti-oxidant properties.
  • There is only limited evidence to support an association between tomato consumption and reduced prostate cancer risk^[9].
  • Dietary intake of lycopene is associated with a lower incidence of prostate cancer and a decreased risk of lethal prostate cancer^[10].
• Soy intake —
  • Phytoestrogens (flavones, isoflavones, lignans) are naturally occurring plant compounds that have estrogen-like activity.
  • Phytoestrogens found in soy foods may reduce prostate cancer risk either via their inherent estrogenic properties, or by inhibition of the enzyme 5-AR.

• Omega-3 fatty acids —
  • High levels of omega-3 fatty acids, such as [[fish oil], were associated with an increased risk of high grade prostate cancer^[11].
• Coffee —
  • Increasing consumption of coffee appears to be associated with a decreased risk of lethal prostate cancer.^[12]

• Multivitamins—
  • The regular use of multivitamins does not appear to affect the risk of early or localized prostate cancer^[13].
  • There is increased risk of advanced or fatal prostate cancer in men using relatively large amounts of multivitamins^[14].
• Folic acid and B12 —
  • High serum folic acid and B12 levels is associated with a small increase in the risk of prostate cancer.
• Selenium —
  • High blood levels of selenium is associated with lower risk of aggressive disease (advanced-stage disease).
• Zinc —
  • Studies have showed an association between zinc supplement use and prostate cancer risk. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer.^[15]
• Calcium and vitamin D —
  • Intake of dairy products and calcium and a higher risk of prostate cancer risk has been suggested.^[16].
  • Higher levels of vitamin D is associated with increased aggressiveness in those men diagnosed with prostate cancer (Gleason score ≥7 or stage III or IV disease)^[17].

• Cigarette smoking may have an effect on both the risk of developing prostate cancer and its prognosis once a diagnosis is established.
• There is increased risk for prostate cancer in smokers^[18].
• There are consistent data on the association of smoking at the time of diagnosis with risk of a cancer recurrence and cancer-related mortality^[19].
• Men with prostate cancer should be strongly encouraged to stop smoking.

• Sex hormones and Insulin like growth factor–
  • Relationship between serum sex hormone levels and prostate cancer come from a pooled analysis of 18 prospective trials.^[20].
  • Serum concentrations of testosterone, dihydrotestosterone (DHT), and other active androgen derivatives obtained prior to diagnosis are not associated with an increased risk of subsequent prostate cancer.
  • There is no association seen with pre-diagnosis serum levels of estrogens (estradiol, free estradiol).
  • Testosterone supplementation as a treatment for hypogonadism does not appear to be associated with an increased risk of prostate cancer.
  • There is modest increased risk of prostate cancer in men with the highest circulating levels of IGF^[21].

• Obesity–
  • There is a small but statistically significant association between obesity and prostate cancer incidence^[22].
  • There is a clear relationship between obesity and disease aggressiveness.^[23].

• Physical activity–
  • There was no association overall between prostate cancer incidence and total, vigorous or non-vigorous physical activity in the entire population.
  • However, men over the age of 65 who were in the highest category of vigorous activity (more than three hours per week of vigorous activity) had a significantly lower risk of advanced prostate cancer.
  • Another report from the same investigators suggests that young lean men who are more physically active have an increased risk of developing metastatic disease and fatal prostate cancer if they had a high energy intake^[24].

• 5-alpha reductase inhibitors lower the prostate-specific antigen (PSA), they potentially increase the risk of high-grade prostate cancer.

• There is significant but modest increase (approximately 1.5- to 2-fold) in the risk of prostate cancer in men with prostatitis.^[25]

• Studies have shown an increased incidence of seropositivity for antibodies against trichomonas vaginalis in men who subsequently are diagnosed with prostate cancer^[26].
• This association was more pronounced in those with more advanced or higher Gleason grade tumors.

• Agent Orange —
  • Exposure to Agent Orange, an herbicide defoliant sprayed extensively in Vietnam between 1965 and 1971 that contained dioxins, appears to be associated with an increased incidence of prostate cancer.
  • The cases of prostate cancer arising in those exposed to Agent Orange appear to be more aggressive^[27]
• Chlordecone —
  • Chlordecone is an organochlorine insecticide with estrogenic properties, which was widely used in the West Indies from 1973 to 1993.^[28].
• Bisphenol A —
  • Exposure to abnormal concentrations of estrogen early in life may initiate changes in prostate stem cells.
  • These changes have been postulated to persist into later life and potentially contribute to the development of prostate cancer^[29].

• Intake of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) has been associated with a decreased risk of some cancers, particularly colorectal cancer.
• An inverse association between long-term NSAID use and prostate cancer risk has also been suggested.^[30].
• There is a decreased risk for the overall incidence of prostate cancer and for advanced prostate cancer.

• A prior vasectomy increases risk of getting prostate cancer is controversial, with some, but not all, studies showing a weak association.^[31].
• There was no statistically significant association between prior vasectomy and prostate cancer incidence or death.
• In a cohort study of almost 50,000 men in the Health Professionals Follow-up Study, 6023 men developed prostate cancer^[32].
• On multivariable analysis, vasectomy was associated with a statistically significant increase in the risk of high-grade, lethal, or advanced prostate cancer.
• A meta-analysis that incorporated data from multiple studies suggest that there is a weak association between vasectomy and prostate cancer^[33].

• In one case-control study exposure to ultraviolet (UV) light had a protective effect on the development of prostate cancer^[34].
• The mechanism behind this association is not clear but involvement of vitamin D and its receptor has been hypothesized^[35].

• External beam radiation therapy (EBRT) for prostate cancer is associated with an increased risk of rectal cancer.
• RT for rectal cancer has not been associated with an increased risk of subsequent prostate cancer.
• In a study based upon the Surveillance, Epidemiology, and End Results (SEER) database, the risk of prostate cancer was decreased by 72 percent in 1572 men who had previously received EBRT as a component of their treatment for rectal cancer^[36].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2] Muhammad Saad, M.B.B.S.[3]

According to the U.S. Preventive Services Task Force (USPSTF), there is insufficient evidence to recommend routine screening for prostate cancer and that the decision should be an individual choice after understanding that overdiagnosis and overtreatment can be significant side-effect in false positives. According to the American Cancer Society (ACS) guidelines, screening for prostate cancer by prostate specific antigen (PSA) and digital rectal exam (DRE) is recommended once among individuals age 50 years, age 45 years for African-American men and men with a family history of prostate cancer, and age 40 years for men with a very strong family history of prostate cancer. According to the American Urological Association (AUA) guidelines, screening for prostate cancer by PSA is recommended every 2 years among individuals age 50 to 69 years, or younger than 50 years for individuals with high risk.

Prostate cancer screening options include the digital rectal exam and the prostate specific antigen (PSA) blood test. Screening for prostate cancer is controversial because it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments.

• The PSA is a kallikrein. A four kallikrein panel includes total PSA, free PSA, intact PSA and human kallikrein-related peptidase-2 (hK2) and improves accuracy of predicting high-grade cancer (Gleason ⩾7) at biopsy.^[1]
• According to the American Cancer Society (ACS) guidelines, screening for prostate cancer by PSA and DRE is recommended once among individuals age 50 years, age 45 years for African-American men and men with a family history of prostate cancer, and age 40 years for men with a very strong family history of prostate cancer.They should be retested every year if the prostate specific antigen is 2.5ng/ml or more and once every 2 years if less than 2.5mg/ml.^[2][3][4]

• The 2007 National Comprehensive Cancer Network (NCCN) guideline recommends offering a baseline PSA test and DRE at ages 40 and 45, and annual PSA testing and DRE beginning at age 50 (with annual PSA testing and DRE beginning at age 40 for African-American men, men with a family history of prostate cancer, and men with a PSA ≥ 0.6 ng/mL at age 40 or PSA > 0.6 ng/mL at age 45) through age 80, along with information on the risks and benefits of screening.
• According to the American Urological Association (AUA) guidelines, screening for prostate cancer by PSA is recommended every 2-4 years among individuals age 50 to 69 years and adapted recommendations for screening in high-risk populations.^[5][6]

Since there is no general agreement that the benefits of PSA screening outweigh the harms, the consensus is that clinicians use a process of shared decision-making that includes discussing with patients the risks of prostate cancer, the potential benefits and harms of screening, and involving the patients in the decision.^[7]

Benefits

• Screening tests are able to detect prostate cancer at an early stage, but it is not clear whether this earlier detection and consequent earlier treatment leads to any change in the natural history and outcome of the disease. Observational evidence shows a trend toward lower mortality for prostate cancer in some countries, but the relationship between these trends and intensity of screening is not clear, and associations with screening patterns are inconsistent. The observed trends may be due to screening, or to other factors such as improved treatment. Results from two randomized trials show no effect on mortality through 7 years but are inconsistent beyond 7 to 10 years.^[8]

Harms

• Based on solid evidence, screening with PSA and/or DRE detects some prostate cancers that would never have caused important clinical problems. Thus, screening leads to some degree of overtreatment. Based on solid evidence, current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men.

• mpMRI may be more accurate and is being studied with a four kallikrein panel in a randomized controlled trial of screening.^[9][10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. No long-term outcome data are available from the PSA era. Patients and clinicians therefore need to evaluate historic series in the context of contemporary practice. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%. Prognosis of prostate cancer is generally good, and the 5-year survival rate is approximately 98.9%. The prognosis varies with the stage of tumor; Localized and regional tumors have the most favorable prognosis. Malignant cells are widely disseminated in men with advanced prostate cancer. However, metastases preferentially develop in the bones of the axial skeleton, where red marrow is most abundant. Complications include pain requiring irradiation, pathologic fractures, spinal cord compression.

• Public health records document that men in the United States have a one in six lifetime risk of developing prostate cancer.^[1]
• Many men will die from competing medical hazards, not prostate cancer. Prostate cancer is often a slowly progressive disease.
• Men with newly diagnosed disease often face difficult choices regarding appropriate treatment. To make an informed decision, men require information concerning the natural history of prostate cancer, the impact of competing medical hazards, and the efficacy of treatment.
• During the last several decades, a number of researchers have contributed to the understanding of the natural history of prostate cancer. *Their work was performed in the era preceding widespread testing for prostate-specific antigen (PSA).
• Since the introduction of testing for PSA during the late 1980s, the incidence of prostate cancer has risen dramatically and mortality from this disease has declined.
• Unfortunately, no long-term outcome data are available from the PSA era. Patients and clinicians therefore need to evaluate historic series in the context of contemporary practice.
• Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55-69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%.^[2]
• A total of 17% of men with no visible lesion developed a visible lesion at a median follow up of 3.6 years.^[3]

• Between 2010 and 2016, the 5-year relative survival of patients with prostate cancer was 97.8%.^[4]

• When stratified by age, the 5-year relative survival of patients with prostate cancer was 99.1% and 98.8% for patients <65 and ≥ 65 years of age respectively.^[4]

• The survival of patients with prostate cancer varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of prostate cancer:^[4]

Stage	5-year relative survival (%), (2010-2016)
All stages	97.8%
Localized	100%
Regional	100%
Distant	30.2%
Unstaged	83.3%

• Shown below is an image depicting the 5-year conditional relative survival (probability of surviving in the next 5-years given the cohort has already survived 0, 1, 3 years) between 1975 and 2011 of prostate cancer by stage at diagnosis according to SEER. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[4]

• Most prostate cancers are diagnosed in the local stage and are asymptomatic.
• Prostate cancer may present with nonspecific urinary symptoms, hematuria, or hematospermia; however, these are usually due to non-malignant conditions. Among the six percent of patients whose prostate cancer is metastatic at the time of diagnosis, bone pain may be the presenting symptom. Bone is the predominant site of disseminated prostate cancer, and pain is the most common manifestation of bone metastases. other complication includes:^[5][6]
  • Sexual dysfunction
  • Fatigue
  • Pathologic fractures
  • Spinal cord compression
  • Hypercalcemia or Hypocalcemia
  • Anemia

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