Prostate Cancer

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Several men with prostate cancer are asymptomatic. Late-stage cancer can present with bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, urinary symptoms, and/or weight loss. Most cases of prostate cancer are identified based on diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests to determine prostate-specific antigen (PSA) levels and are confirmed based on image-guided transrectal biopsy. Management of prostate cancer depends on age, life expectancy, comorbidities, risk stratification, and preferences of the patient. Management options include active surveillance, androgen deprivation therapy, radiotherapy, chemotherapy, and radical prostatectomy.

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Overview

Epidemiology

  • Worldwide:
    • 2nd most common cancer in men
    • > 1.3 million cases diagnosed annually
  • In the United States:
    • 3rd leading cause of cancer in men
    • Approximately 192,000 cases diagnosed annually
    • The lifetime risk of being diagnosed with prostate cancer is 11%.
    • The lifetime risk of dying from prostate cancer is 2.5%.
  • 5-year survival after diagnosis:
    • Localized disease or regional spread: nearly 100%
    • Distant metastatic disease: 31%

Risk factors

Inherent factors (major):

  • Age
    • Rare in men < 40 years of age
    • Peaks in men between 65 and 74 years of age
  • More common, and earlier onset in African Americans
  • Family history of prostate cancer, particularly in 1st-degree relatives diagnosed at < 65 years of age
  • Family history of other heritable cancers
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer, BRCA1 and BRCA2 gene mutations
    • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer, Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
    • Pancreatic cancer

Medical factors:

  • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
  • 5-alpha-reductase inhibitors (e.g., finasteride)
    • ↓ PSA levels
    • ↑ High-grade risk of prostate cancer
  • Trichomonas vaginalis infection

Social and environmental factors:

  • High-fat, low-vegetable diet
  • Smoking
  • Exposure to Agent Orange
    • Herbicide and defoliant chemical used during the Vietnam War between 1965 and 1972
    • Associated with more aggressive cancer
  • Exposure to chlordecone 
    • Insecticide used between 1973 and 2003 in the Caribbean
    • Binds to estrogen receptors and contributes to malignancy

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Pathophysiology

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands gland and zonal anatomy

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands gland:

  • An organ under the bladder
  • Primarily composed of glandular tissue that secretes fluid into the ejaculate (which makes up semen, together with sperm and seminal fluid)

Zonal anatomy:

  • Peripheral zone: 
    • Comprises > 70% of the prostate gland
    • Approximately 70% of prostate cancers are in the peripheral zone.
    • Closest to the rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal 
  • Central zone: 
    • 15%‒20% of prostate cancers are in the central zone. 
    • Surrounds the ejaculatory ducts
  • Transitional zone: 
    • 10%‒15% of prostate cancers are in the transitional zone. 
    • Surrounds the proximal urethra
    • Key area of concern for benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia (BPH)
  • Fibromuscular stroma:
    • Cancer in the fibromuscular stroma is rare.
    • Does not contain glandular tissue
    • Surrounds the apex of the prostate
Prostate gland and main prostate zones

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands gland and main prostate zones: peripheral, transitional, and central zones in relation to other structures of the male genitourinary system

Image: “Zones of the prostate” by Mikael Häggström. License: CC0

Tumorigenesis

Under the influence of the factors listed below, prostate epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium → prostate intraepithelial neoplasia (precursor lesion) → localized adenocarcinoma → metastasis and androgen-resistant cancer

  • Adenocarcinoma accounts for > 90% of cases: develops primarily from a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the glandular tissue
  • Development of prostate cancer is affected by:
    • Environmental factors
      • Diet
      • Smoking
    • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
      • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer cells rely on testosterone for growth and survival.
      • Testosterone dependence is seen with antiandrogen therapy.
      • Mechanisms develop to overcome androgen blockade and eventually lead to androgen resistance.
    • Inherited genetic factors 
      • 2-fold ↑ risk in men with 1st-degree relatives with the disease
      • Germline MYC (oncogene in prostate cancer) variants
      • Other rare variants include BRCA2 and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure mismatch repair genes (part of Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome).
    • Acquired genetic factors
      • TMPRSS-ETS fusion gene is the most common gene alteration in prostate cancer (noted in 50% of cases).
      • Silencing of the gene encoding p27 (a protein controlling cell growth and division)
      • Amplification of MYC and deletion of PTEN: ↑ cell growth and ↑ androgen resistance
Pathogenesis of prostate cancer

Pathogenesis of prostate cancer:
Normal prostate gland comprises basal and luminal cells. Majority of prostate cancers arise from the peripheral zone. Under the influence of diet, androgens, and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation caused by genetic variants, precursor lesions (prostatic intraepithelial neoplasia) develop. As further genetic or epigenetic alterations occur, the lesions progress to adenocarcinoma. Tumors initially regress with antiandrogen therapy, but eventual androgen resistance occurs.

Image by Lecturio.

Clinical Presentation

  • The majority of diagnosed patients are identified by screening for prostate cancer.
  • Usually asymptomatic in early stages
  • Manifestations in later stages:
    • Bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain (most common site of disseminated prostate cancer)
    • Weakness from spinal-cord compression
    • Weight loss
    • Fatigue
    • Urinary retention
    • Hematuria
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
    • Hydronephrosis Hydronephrosis Hydronephrosis is dilation of the renal collecting system as a result of the obstruction of urine outflow. Hydronephrosis can be unilateral or bilateral. Nephrolithiasis is the most common cause of hydronephrosis in young adults, while prostatic hyperplasia and neoplasm are seen in older patients. Hydronephrosis 

Diagnosis

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands-specific antigen

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands-specific antigen levels are determined to detect early cancer.

Background:

  • Protein produced by prostate cells (but not specific to malignancy)
  • A small amount enters the bloodstream in healthy individuals.
  • ↑ Serum PSA level in prostate cancer is due to:
    • ↑ Number of cells producing PSA, despite malignant cells synthesizing less PSA
    • Disruption in the normal architecture and basement membrane, allowing ↑ levels of PSA to enter the bloodstream

Interpretation:

  • PSA ≥ 4 ng/mL is considered positive and the most widely accepted standard, which balances the trade-offs between sensitivity and specificity.
  • Long-term use of 5-alpha-reductase inhibitors:
    • Associated with ↓ PSA levels with long-term medication use
    • Correction factor should be applied for accurate interpretation.
    • If there is an ↑ in PSA level, the patient should be referred to urology.
  • Other urological conditions that can elevate PSA levels:
    • BPH
    • Prostatitis Prostatitis Prostatitis is inflammation or an irritative condition of the prostate that presents as different syndromes: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain, and asymptomatic. Bacterial prostatitis is easier to identify clinically and the management (antibiotics) is better established. Prostatitis
    • Urinary retention
    • Urological procedures (e.g., catheter placement, cystoscopy) 
  • Repeat testing is recommended in the case of ↑ PSA (after addressing factors possibly influencing the elevation)

Clinical variables to interpret PSA levels:

  • General age-adjusted PSA (ng/dL) thresholds are as follows: 
    • 40‒49 years of age: 2.5
    • 50‒59 years of age: 3.5
    • 60‒69 years of age: 4.5
    • 70‒79 years of age: 6.5
  • PSA density:
    • Ratio of PSA to prostate volume (measured using imaging studies)
    • Value ≥ 0.15 ng/mL/g is an indication for prostate biopsy
  • PSA velocity: 
    • Cancer grows faster and the increase in PSA levels is more rapid.
    • At least 3 measurements should be obtained over a 2-year period.
  • Free and complexed PSA: 
    • 2 forms of PSA: free, and complexed to protease inhibitors
    • In cancer: ↑ in PSA complexed to protease inhibitors

Digital rectal examination (DRE)

  • No longer recommended for asymptomatic patients
  • Low sensitivity and specificity
  • However, if an abnormality (e.g., nodule, asymmetry) is detected on rectal exam, evaluation should be conducted.

Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands biopsy

  • Confirmatory test required for diagnosis
  • Biopsy is performed using an image-guided (transrectal ultrasound or MRI) transrectal approach.
  • Considerations before pursuing biopsy:
    • Age and ethnicity of the patient
    • Life expectancy of the patient
    • Comorbidities
    • Immediate and long-term risks of biopsy, and possible treatment options

Imaging studies

  • Evaluation of the extent of prostate cancer and volume determination:
    • MRI
    • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands Imaging Reporting and Data System (PI-RADS) 
      • Used to report the likelihood of cancer in a suspicious area
      • 5-point scale, with 1 representing high unlikeliness and 5 indicating high likeliness of cancer
  • To determine extra-prostatic extension and distant metastasis:
    • CT or MRI of the abdomen and pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis
    • PET: Images may be superimposed with CT and MRI.
    • Bone scan
Imaging of a patient with metastatic prostate cancer

Imaging of a patient with metastatic prostate cancer:
(A) Magnetic resonance imaging (MRI) demonstrates the seminal vesicles (SV), the prostate lesion (tumor), and extracapsular extension (ECE).
(B) Bone scan shows solitary L5 vertebral body metastasis.

Image: “Rationale for stereotactic body radiation therapy in treating patients with oligometastatic hormone-naïve prostate cancer” by O. Bhattasali et al. License: CC BY 3.0

Staging

Parameters

The following elements are crucial determinants of outcome and are used for risk stratification in selecting a treatment approach:

  • Extent of tumor (T)
  • Spread to lymph nodes (N)
  • Metastasis (M) 
  • Pretreatment PSA levels
  • Histological grade group (based on the Gleason score)

Tumor-nodes-metastases staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

The TNM staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis is based on the 8th-edition staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis guidelines by the American Joint Committee on Cancer. There are 2 categories of staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis:

  1. Clinical staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis: based on physical exam, imaging, and biopsy
  2. Pathological staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis: based on findings after prostatectomy
Table: Tumor staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
Tumor clinical stage (cT) Description
cTX Primary tumor cannot be assessed.
cT0 No evidence of primary tumor
cT1 No palpable disease on DRE
  • T1a: cancer incidentally found in ≤ 5% of tissue obtained in a surgery for benign disease
  • T1b: cancer incidentally found in > 5% of tissue obtained in a surgery for benign disease
  • T1c: cancer found during biopsy for elevated PSA
cT2 Palpable disease on DRE, but confined within the prostate
  • T2a: ≤ 50% on 1 side of the prostate
  • T2b: > 50% on 1 side of the prostate
  • T2c: both sides affected
cT3 Palpable outside the prostate laterally, or involving the seminal vesicles
  • T3a: extra-prostatic extension (through the capsule)
  • T3b: extension to the seminal vesicles
cT4 Tumor is fixed, or it can invade the adjacent structures (external sphincter, rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal, bladder, levator ani, or pelvic wall).
DRE: digital rectal examination
PSA: prostate-specific antigen
Table: Tumor staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
Tumor pathological stage (pT)* Description
pT2 Organ confined
pT3 Extra-prostatic extension
  • pTsa: unilateral or bilateral extension or microscopic bladder neck invasion
  • pT3b: invades seminal vesicles
pT4 Tumor is fixed or invades other adjacent structures (external sphincter, rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal, bladder, levator ani, or pelvic wall).
*There is no pathological T1 classification.
Table: Lymph node (N) staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
Clinical node stage (cN) Description
cNX Regional lymph nodes not assessed
cN0 No regional lymph-node involvement
cN1 Metastasis in regional lymph node(s)
Table: Metastasis (M) staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis
Metastasis stage Description
M0 No distant metastasis
M1 Distant metastasis to:
  • M1a: non-regional lymph node(s)
  • M1b: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones(s)
  • M1c: other sites (with or without bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones disease)

Histological grading Grading Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

Grade group is based on the Gleason score.

  • Standard measure of differentiation of prostate cancer
  • 5 patterns graded from 1–5: 
    • 1 being closest to the normal tissue
    • 5 being the most abnormal
  • Biopsy specimen is examined under low magnification to identify the most common (1st number) and 2nd most common (2nd number) patterns. 
  • The 2 numbers are added to obtain the Gleason score.
  • Gleason score is used to predict clinical behavior and outcome.
    • Lower score and grade group: Cancer is likely to grow and spread slowly.
    • High score and grade group: Cancer is likely to grow and spread rapidly.
    • Order is as important as the total score in predicting prognosis (e.g., 3 + 5 = 8 has a more favorable prognosis than 5 + 3 = 8).
Grade group Gleason score Pattern
1 Gleason ≤ 6 Well-differentiated tumors
2 Gleason 3 + 4 = 7 Predominantly well-formed glands with few poorly formed glands
3 Gleason 4 + 3 = 7 Predominantly poorly formed glands with less well-formed glands
4 Gleason 8 Only poorly formed glands or predominantly well-formed glands; a lesser component with a lack of glands 
5 Gleason 9‒10 Advanced; lacks gland formation or exhibits necrosis 

Prognostic stage

The TNM stage, PSA, and histological grade group can be used to determine the prognostic stage group.

Table: Criteria for prognostic stage group
Stage Tumor (T) Node (N) Metastasis (M) PSA (ng/mL) Grade group
I cT1a‒c, cT2a, pT2 N0 M0 < 10 1
II IIA cT1a‒c, cT2a, pT2 N0 M0 ≥ 10, < 20 1
cT2b–c < 20
IIB T1‒T2 N0 M0 < 20 2
IIC T1‒T2 N0 M0 < 20 3‒4
III IIIA T1‒T2 N0 M0 ≥ 20  1‒4
IIIB T3‒T4 N0 M0 Any 1‒4
IIIC Any N0 M0 Any 5
IV IVA Any N1 M0 Any Any
IVB Any Any M1 Any Any
PSA: prostate-specific antigen

Risk stratification

Information regarding tumor stage, grade group, Gleason score, and PSA level is used to determine clinical-risk categories.

  • Risk may be assessed as:
    • Very low
    • Low
    • Intermediate
    • High
    • Very high 
  • Use of risk-evaluation guides:
    • Appropriateness in ordering imaging studies (e.g., do not obtain CT or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones scans in very low-/low-risk patients)
    • Treatment options

Management

Principles of treatment

  • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer is associated with slow growth and may not be clinically significant during the lifetime of a patient.
  • Definitive treatments are associated with substantial side effects that impact the quality of life.
  • Multiple factors are considered in treatment:
    • Age and life expectancy
    • Overall health and comorbidities
    • Characteristics of the cancer and risk stratification
    • Patient preferences

Management options

Active surveillance:

  • Deferred treatment with monitoring:
    • Serial PSA and DREs over regular intervals
    • Repeat biopsies
    • MRI
  • Intention to treat for disease progression or change in patient preference
  • Preferred in patients with very low- or low-risk cancer

Radiation therapy (RT):

  • External beam RT (EBRT): can cause erectile dysfunction and radiation proctitis
  • Brachytherapy:
    • Radioactive seed implants 
    • Can cause bladder irritation

Surgery (radical prostatectomy):

  • Options:
    • Open surgery 
    • Laparoscopy Laparoscopy Laparoscopy is surgical exploration and interventions performed through small incisions with a camera and long instruments. Laparotomy and Laparoscopy with or without robotic assistance
  • Removal of the prostate gland, seminal vesicles, and pelvic lymph nodes, followed by reconstruction (reconnecting the bladder neck and the urethra)
  • Can cause erectile dysfunction and stress urinary incontinence Urinary incontinence Urinary incontinence (UI) is involuntary loss of bladder control or unintentional voiding, which represents a hygienic or social problem to the patient. Urinary incontinence is a symptom, a sign, and a disorder. The 5 types of UI include stress, urge, mixed, overflow, and functional. Urinary Incontinence 

Androgen deprivation therapy (ADT):

  • Luteinizing hormone-releasing hormone (LHRH) agonists:
    • Leuprolide acetate, goserelin, triptorelin, and histrelin
    • Initial release/surge of LH, then ↓ pituitary LH → ↓ testosterone
  • LHRH antagonists:
    • Degarelix, relugolix
    • ↓ Pituitary drive without an initial surge in LH → ↓ testosterone
  • Antiandrogens Antiandrogens Antiandrogenic drugs decrease the effect of androgens. Classes include androgen receptor blockers, 5-alpha-reductase inhibitors, and androgen synthesis inhibitors. Both men and women may use antiandrogens, which treat advanced prostate cancer, benign prostatic hyperplasia (BPH), alopecia, and hirsutism. Androgens and Antiandrogens:
    • Androgen receptor antagonists: flutamide, bicalutamide, apalutamide, and enzalutamide
    • Androgen synthesis inhibitors: abiraterone, ketoconazole, and aminoglutethimide
  • Surgical castration with simple orchiectomy (removal of the testicles Testicles The testicles, also known as the testes or the male gonads, are a pair of egg-shaped glands suspended within the scrotum. The testicles have multiple layers: an outer tunica vaginalis, an intermediate tunica albuginea, and an innermost tunica vasculosa. The testicles are composed of testicular lobules and seminiferous tubules. Testicles): ↓ testosterone levels
  • General side effects:
    • Reduced sexual desire
    • Impotence
    • Hot flashes
    • Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia and breast tenderness
    • Depression

Chemotherapy:

  • Docetaxel
  • Cabazitaxel

Immunotherapy:

  • Sipuleucel-T (Provenge) 
    • Vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination
    • Made from autologous mononuclear cells
    • Induces immunity against prostate cancer 
    • For metastatic ADT-resistant prostate cancer
  • Pembrolizumab:
    • Programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death receptor-1 ligand (PD-L1) inhibitor
    • For patients lacking the mismatch-repair (dMMR) mechanism, and for individuals with high levels of microsatellite instability (MSI-H)

Other therapies:

  • Targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted Therapy and Other Nontraditional Antineoplastic Agents 
    • Poly-ADP-ribose polymerase (PARP) inhibitors
    • For patients with germline or somatic DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (BRCA)
  • Radium-223
    • Emits alpha radiation
    • Prevents complications due to bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones metastasis

Management

The following management options are based on prognostic stage, and should be guided by the age, health, and preferences of the patient:

  • Stage I:
    • Active surveillance (preferred)
    • RT or surgery: considered in patients with a high probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of progression
  • Stage II:
    • Active surveillance
      • If no symptoms
      • In the elderly
      • If serious health issues
    • RT with or without ADT
    • Surgery with or without EBRT
  • Stage III:
    • Recurrence after treatment is more likely.
    • EBRT plus ADT: Brachytherapy may be added.
    • Surgery followed by RT and/or ADT
  • Stage IV:
    •  Lymph-node involvement:
      • RT plus ADT
      • In young individuals with minimal regional lymph-node spread, surgery followed by ADT with or without RT can be considered.
    • Metastatic disease: ADT plus chemotherapy
    • Other options: 
      • ADT-resistant cancer: immunotherapy or PARP inhibitors
      • Symptomatic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones metastasis without visceral disease: radium-223

Differential Diagnosis

  • BPH: a condition caused by an increase in the number of stromal and epithelial cells within the prostate gland. Patients are usually > 50 years of age and present with symptoms of bladder obstruction and/or bladder-storage problems. Benign prostatic hyperplasia can lead to an increase in PSA levels. Diagnosis is based on history and invasive testing (cystoscopy, urodynamics, transrectal ultrasound imaging). Management is with medications and/or surgery.
  • Prostatitis Prostatitis Prostatitis is inflammation or an irritative condition of the prostate that presents as different syndromes: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain, and asymptomatic. Bacterial prostatitis is easier to identify clinically and the management (antibiotics) is better established. Prostatitis: a group of inflammatory conditions of the prostate gland. Patients may be asymptomatic or present with urinary symptoms, such as perineal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, increased urinary frequency and urgency, urinary obstruction, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. The diagnosis is generally clinical and supported by urinalysis and culture data. Management depends on the etiology, but can include antibiotics in cases of infection. Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands-specific antigen levels may be elevated. To differentiate prostatitis from prostate cancer, PSA levels are remeasured after the treatment of prostatitis.
  • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction (ED): the consistent inability to acquire or maintain an erection. Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction is associated with diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, heart disease, and certain drugs (e.g., antidepressants). Treatments for prostate cancer (RT, prostatectomy) can also result in ED. Management is with phosphodiesterase-5 inhibitors and vacuum-assisted erection devices.
  • Urinary incontinence (UI): the involuntary leakage of urine. There are many types of incontinence, including stress, urge, and mixed type. Radical prostatectomy can result in stress UI, which presents as urine leakage with exertion or as gravitational incontinence. Lifestyle intervention (Kegel exercises), medical therapy, and surgical procedures are options in managing post-surgical UI.

References

  1. American Urological Association. (2017). Clinically Localized Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands Cancer: AUA/ASTRO/SUO Guideline. https://www.auanet.org/guidelines/prostate-cancer-clinically-localized-guideline#x6911
  2. American Urological Association. (2020). Medical student curriculum: Prostate cancer screening Prostate cancer screening Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is around 11%, and the lifetime risk of dying from this condition is 2.5%. Prostate cancer is a slow-growing cancer that takes years (even decades) to develop into advanced disease, and many men remain asymptomatic and die from other medical conditions. Prostate Cancer Screening and management. https://www.auanet.org/education/auauniversity/for-medical-students/medical-students-curriculum/medical-student-curriculum/prostate-cancer/psa
  3. Kantoff, P., Taplin, M., Smith, J. (2020). Clinical presentation and diagnosis of prostate cancer. UpToDate. Retrieved Jan 21, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-prostate-cancer
  4. Kantoff, P., Taplin, M., Smith, J. (2020). Initial staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis and evaluation of men with newly diagnosed prostate cancer. UpToDate. Retrieved Jan 23, 2021, from https://www.uptodate.com/contents/initial-staging-and-evaluation-of-men-with-newly-diagnosed-prostate-cancer
  5. Klein, E. (2021). Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer: Risk stratification and choice of initial treatment. UpToDate. Retrieved Jan 23, 2021, from https://www.uptodate.com/contents/prostate-cancer-risk-stratification-and-choice-of-initial-treatment
  6. Netto, G., Amin, M. (2020). The Lower Urinary Tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract and Male Genital System. Kumar, V., Abbas, A., Aster, J., Robbins, S. Robbins and Cotran (Eds.) Pathologic Basis of Disease (10th ed., pp 977–983). Elsevier, Inc. 
  7. Posielski, M., Richards, K. (2020). Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis. Medscape. https://emedicine.medscape.com/article/2007051-overview
  8. Mark, J.R. (2019). Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer. [Online] MSD Manual Professional Version. https://www.msdmanuals.com/professional/genitourinary-disorders/genitourinary-cancer/prostate-cancer
  9. American Cancer Society (2019). Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands cancer stages and other ways to assess risk. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/staging.html
  10. American Cancer Society (2019). Initial treatment of prostate cancer, by stage. https://www.cancer.org/cancer/prostate-cancer/treating/by-stage.html
  11. Madan, R.A., Antonarakis, E.S., et al. (2020). Putting the pieces together: Completing the mechanism of action jigsaw for Sipuleucel-T. Journal of the National Cancer Institute, 112(6), 562–573. https://pubmed.ncbi.nlm.nih.gov/32145020/
  12. Antonarakis, E.S., Piulats, J.M., et al. (2020). Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: Multicohort, open-label phase II KEYNOTE-199 study. Journal of Clinical Oncology, 38(5), 395–405. https://pubmed.ncbi.nlm.nih.gov/31774688/
  13. Sandhu, S.K., Omlin, A., et al. (2013). Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. Annals of Oncology, 24(5), 1416–1418. https://pubmed.ncbi.nlm.nih.gov/23524863/

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