Prostate%20cancer Diagnosis

Key Examinations for the Diagnosis of Prostate Cancer

• Prostate-specific antigen (PSA) level
• Digital rectal examination (DRE)
• Prostate biopsy

• Determines the extent of cancer upon diagnosis
• Important factor in the choice of treatment and provides information about the prognosis of the disease

Tumor, Nodes and Metastasis (TNM) System

• Developed by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC)

Clinical T (cT)
T - Primary Tumor
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
T1		Clinically inapparent tumor not palpable or visible by imaging
	T1a	Tumor incidental histological finding in 5% or less of tissue resected
	T1b	Tumor incidental histological finding in more than 5% of tissue resected
	T1c	Tumor identified by needle biopsy (secondary to elevated PSA level)
T2		Tumor confined within the prostate gland (by needle biopsy)
	T2a	Tumor involves 1/2 of one lobe or less
	T2b	Tumor involves >1/2 of one lobe but not both lobes
	T2c	Tumor involves both lobes
T3		Tumor extends through the prostatic capsule
	T3a	Extracapsular extension (unilateral or bilateral)
	T3b	Tumor invades the seminal vesicle(s)
T4		Tumor fixed or invades adjacent structures other than the seminal vesicles (bladder, rectum, levator muscles, and/or pelvic wall)
Pathological T (pT)
T - Primary Tumor
T2		Confined in the organ
T3		Positive extension extraprostatically
	T3a	Unilateral or bilateral extraprostatic extension
	T3b	Tumor invades seminal vesicle(s)
T4		Fixed tumor or invades adjacent structures other than the seminal vesicles (ie external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)
N - Regional Lymph Nodes
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Regional lymph node metastasis present
M - Distant metastasis1
M0		No distant metastasis
M1		Distant metastasis
	M1a	Non-regional lymph node(s)
	M1b	Bone(s)
	M1c	Other site(s) with or without bone disease
1The most advanced category (M1c) should be used when >1 metastasis site is present Adapted from: TNM Staging System for Prostate Cancer (8th ed., 2017) in National Comprehensive Cancer Network. NCCN guidelines: prostate cancer version 2.2021. NCCN. Feb 2021; European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Geriatric Oncology (SIOG) guidelines on prostate cancer-2020 update. 2021.

Staging

• Should be based on the PSA level, tumor grade, and positive prostate biopsies

Stage	Tumor	Node	Metastasis	PSA	Grade Group
I	cT1a-c	N0	M0	PSA <10	1
	cT2a	N0	MO	PSA <10	1
	pT2	NO	MO	PSA <10	1
IIA	cT1a-c	N0	M0	PSA  ≥10<20	1
	cT2a	N0	MO	PSA ≥10<20	1
	pT2	NO	MO	PSA ≥10<20	1
	cT2b	NO	MO	PSA <20	1
	cT2c	NO	MO	PSA <20	1
IIB	T1-2	N0	M0	PSA <20	2
IIC	T1-2	N0	MO	PSA <20	3
	T1-2	NO	MO	PSA <20	4
IIIA	T1-2	NO	MO	PSA ≥20	1-4
IIIB	T3-T4	N0	M0	Any PSA	1-4
IIIC	Any T	N0	MO	Any PSA	5
IVA	Any T	N1	M0	Any PSA	Any
IVB	Any T	Any N	M1	Any PSA	Any
Adapted from: National Comprehensive Cancer Network. NCCN guidelines: prostate cancer. Version 2.2021. NCCN.  Feb 2021; American Cancer Society. Prostate cancer staging. Aug 2019.

Risk Stratification

• Based on the PSA level, biopsy, Gleason score, and TNM classification
• Helps in decision making for the management of patients diagnosed with prostate cancer

Risk Group	Clinical Stage		PSA		Grade Group or Gleason Pattern		Others
Clinically Localized
Very Low	T1c	and	<10 ng/mL	and	Grade group 1	and	<3 prostate biopsy fragments/cores positive, with ≤50% cancer in each fragment/core and PSA density <0.15 ng/mL/g
Low	T1-T2a	and	<10 ng/mL	and	Grade group 1
Intermediate	T2b-T2c	or	10-20 ng/mL	or	Grade group 2-3
Intermediate - Favorable	T2b-T2c	or	10-20 ng/mL	or	Grade group 1 or 2	and	1 intermediate risk factor (IRF) and percentage of positive biopsy core <50%
Intermediate - Unfavorable	T2b-T2c	or	10-20 ng/mL	or	Grade group 3	and/or	2 or 3 IRF and/or percentage of positive biopsy cores ≥50%
High	T3a	or	>20 ng/mL	or	Grade group 4 or Grade group 5		Exactly 1 high-risk feature
Locally Advanced
Very High	T3b-T4	or	Any	or	Primary Gleason pattern 5 or Grade group 4 or 5 in >4 cores		2 or 3 high-risk features
Regional	Any T, N1, M0
Metastatic	Any T, any N, M1
Adapted from: National Comprehensive Cancer Network. NCCN guidelines: prostate cancer version 2.2021. NCCN. Feb 2021; EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. 2021; European Society for Medical Oncology. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Jun 2020.

Cancer of the Prostate Risk Assessment (CAPRA)

• A straightforward scoring system (0-10) that predicts likelihood of metastasis, cancer-specific mortality, and overall survival
• Based on the patient’s age, PSA levels, Gleason score, clinical stage, and percent of malignant biopsy cores
• Also predicts disease recurrence after radical prostatectomy

• Key determinant of primary treatment for patients diagnosed with prostate cancer include life expectancy estimation, family history and risk for germline mutations

Life Expectancy Estimation

• A key determinant of primary treatment for prostate cancer when considering observation or active surveillance
• Done using life tables such as the Memorial Sloan Kettering Male Life Expectancy tool, the Minnesota Metropolitan Life Insurance Tables, the Social Security Administration Life Insurance Tables, or the WHO’s Life Tables by Country, and computed based on patient’s health status

Genetic Testing
Germline Testing

• Recommended for prostate cancer patients with any of the following: Family history of prostate cancer, high-risk, very high-risk, regional or metastatic prostate cancer, intermediate-risk prostate cancer with intraductal/cribriform histology, or Ashkenazi Jewish ancestry 
• Should include MLH1, MSH2, MSH6, PMS2, BRCA2, BRCA1, ATM, PALB2 and CHEK2
  •  Cancer predisposition next-generation sequencing (NGS) panel testing which includes above genetic mutations except for PALB2 may be considered
• Recommended for very low-, low- and intermediate-risk groups if patient has strong family history of prostate cancer or with intraductal/cribriform histology
• Genetic counseling is needed before germline testing

Molecular Assays

• Provide a more personalized or precise approach to treatment
• Available tumor-based molecular assays include Decipher, Oncotype DX Prostate, Prolaris and ProMark
• Recommended somatic tests for the following patients:
  • Regional or metastatic prostate cancer: Tumor testing for somatic homologous recombination gene mutations which includes MLH1, MSH2, MSH6, PMS2, BRCA2, BRCA1, ATM, CHEK2 and microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) (to check for Lynch syndrome)
    • Cancer predisposition NGS panel testing which includes BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2 should be considered
  • Low- and favorable intermediate-risk prostate cancer with life expectancy ≥10 years: Decipher, Oncotype DX Prostate, Prolaris, and ProMark
  • Unfavorable intermediate- and high-risk prostate cancer with life expectancy ≥10 years: Decipher and Prolaris tumor-based molecular assays
  • PSA resistance/recurrence after radical prostatectomy: Decipher molecular assay to be used during counseling for risk stratification
• For post-prostatectomy patients, Decipher molecular assay is recommended if not previously done to test for adverse features 
• For patients with history of Abiraterone/Enzalutamide therapy for metastatic CRPC, androgen receptor splice variant 7 (AR-V7) testing in circulating tumor cells may be considered to help with treatment decision making
• Tumor testing for MSI-H or dMMR is recommended for patients with mCRPC and can be considered in those with regional or castration-naive metastatic prostate cancer
• Decipher molecular assay is recommended post-prostatectomy to decide on adjuvant treatment if adverse factors are present

Gleason Score

• Useful in determining tumor grade, prognostic risk, and management strategies

Gleason Score	Definition
Gleason X	Gleason score cannot be assessed
Gleason <6	Well differentiated (slight anaplasia)
Gleason 7	Moderately differentiated (moderate anaplasia)
Gleason 8-10	Poorly differentiated/undifferentiated (marked anaplasia)

Grade Group

• New histologic grading system developed by the International Society of Urological Pathology (ISUP) that assigns grade groups based on the Gleason score and thereby provides better management strategies

Grade Group	Gleason Score	Risk Group	Description
1	≤6 (≤3+3)	Very low	Only individual, discrete, well-formed glands
2	7 (3+4)	Intermediate	Predominantly well-formed glands with lesser component of poorly formed/fused/cribriform/glomeruloid glands
3	7 (4+3)	Intermediate	Predominantly poorly formed/fused/cribriform/glomeruloid glands with lesser component of well-formed glands
4	8 (4+4, 3+5, 5+3)	High	Only poorly formed/fused/cribriform/glomeruloid glands or Predominantly well-formed glands and lesser component lacking glands or Predominantly lacking glands with lesser component of well-formed glands
5	9 (4+5, 5+4) or 10 (5+5)	Very high	Lack of gland formation with or without poorly formed/fused/cribriform glands

• Criteria that signify strong family history of prostate cancer and should prompt genetic testing include:
  • Brother, father or >1 family member ≤60 years old diagnosed or who passed away due to prostate cancer
  • Ashkenazi Jewish ancestral lineage: Associated with germline mutations in BRCA2 or BRCA1
  • ≥3 cancers of the following carcinomas present on the same side of the family, especially if diagnosed ≤50 years of age: Breast, bile duct, colorectal, endometrial, gastric, renal, ovarian, melanoma, pancreatic, prostate, urothelial, small intestines

Digital Rectal Examination (DRE)

• Detects prostatic enlargement with volume of >0.2 mL
• Abnormal DREs are associated with high Gleason scores and may be considered for prostate biopsy

Prostate-Specific Antigen (PSA) Level

• A kallikrein-like serine protease produced by prostatic epithelial cells
• Organ specific but not specific to cancer and may be elevated in benign conditions (eg benign prostatic hypertrophy, prostatitis)
• Risk for prostate cancer increases with increasing level of PSA and may warrant a prostate biopsy
• Predicts extension outside the prostate gland, seminal vesicle invasion, and lymphadenopathies
• Baseline results should be obtained prior to starting treatment as it is also a good measurement for therapeutic efficacy
• Other parameters (PSA testing derivatives) include free PSA level, PSA velocity and PSA density

Prostate Biopsy

• Most common method used in diagnosing prostatic carcinoma
• Should only be offered if PSA levels and DRE highly suggest prostate cancer
• Transrectal ultrasound (TRUS)-guided core-needle prostate biopsy is highly recommended for men with PSA levels of >4 ng/mL
• Indications:
  • Increased risk for prostate cancer and with PSA levels of 2.5-4 ng/mL
  • Increased PSA levels of >0.35 ng/mL within 1 year from baseline of <4 ng/mL
  • Increased PSA levels of >0.75 ng/mL within 1 year from baseline of 4-10 ng/mL
  • PSA levels too high for age range

• Obtaining a minimum of 10-12 cores are recommended
• Should be done under antibiotic coverage
• The perineal approach (transperineal 3D prostate mapping biopsy) is a useful option for special circumstances (eg rectal amputation)
• Transperineal biopsies are favored compared to TRUS-guided biopsies due to reduced risk of infection
• Confirmatory prostate biopsy, with or without multiparametric MRI (mpMRI), may be considered if active surveillance is being considered for very low-risk patients, and with or without molecular tumor analysis in low- to favorable intermediate-risk patients
• Indications for repeat biopsy after previously negative results:
  • Persistently elevated and/or increasing PSA levels
  • Suspicious DRE
  • Positive mpMRI findings

Other Biomarker Tests

• Have been associated with prostate cancer diagnosis but are not routinely performed
• Biomarkers other than PSA that are used for prostate cancer include apoptosis markers [eg B-cell lymphoma 2 (Bcl-2), BCL2 Associated X Protein (Bax)], proliferation rate markers (eg Ki67), p53 mutation/expression, p27, E-cadherin, deoxyribonucleic acid (DNA) plody, p16
• Other biomarker tests recommended by the National Comprehensive Cancer Network (NCCN) include percent free PSA (%f PSA), Prostate Health Index (PHI), four kallikrein (4K) score^®, EPI, prostate specific antigen 3 (PCA3), ConfirmMDx and ExoDx Prostate(IntelliScore) (EPI) test
• Tests that are currently being studied include Mi-Prostate Score (MiPS) and SelectMDx 
• An increase in serum acid phosphatase levels may indicate poor prognosis in patients with localized and disseminated disease

• Should be based on age, risk, PSA results, Gleason score, and patient’s health status
• Pelvic and/or abdominal imaging is recommended for high-risk to very high-risk patients and for intermediate-risk patients with >10% probability of pelvic LN involvement in nomogram
• Imaging may be considered in symptomatic very low-, low- and intermediate-risk patients
• Bone imaging should be performed for any patient with symptoms consistent with bone metastases

Plain Film Radiography

• May be used to assess for presence of bone pathologies in symptomatic patients

Ultrasonography

• Transrectal ultrasound (TRUS) may be used to assess the prostate gland if PSA levels and DRE results are inconclusive
• Also used as a guide during transrectal prostate biopsies
• Considered in patients with suspected recurrence after surgery

Computed Tomography (CT) Scan

• May be used to assess for presence of bone pathologies, gross extracapsular disease, nodal metastatic disease, and/or visceral metastatic disease
• May be used for pelvic and/or abdominal examination as part of initial evaluation and for follow-up evaluation for recurrence or progression
• May be used for lymph node staging in asymptomatic patients at intermediate-high risk (PSA level >10 ng/ mL, Gleason score >8, or clinical stage >T3)

Magnetic Resonance Imaging (MRI)

• Multiparametric MRI (mpMRI) by diffusion-weighted imaging or hydrogen 1 (H1)-spectroscopy may be done to assess if repeat prostate biopsy is needed in patients with negative results in TRUS
  • Detects large and poorly differentiated tumors and extracapsular extension, used for staging of pelvic lymph nodes, and detects bone metastases (98-100% sensitivity and specificity)

• May be used for pelvic and/or abdominal examination as part of initial evaluation and for follow-up evaluation for recurrence or progression 
• Sensitivity at >2 cc: 67-75% for Gleason <6; 97% for Gleason 7; 100% for Gleason >8
• mpMRI is preferred over CT for abdominal/pelvic staging 
• Positive results may suggest repeat prostate biopsy

Radionuclide Bone Scan

• A conventional technetium-99m-methylene diphosphonate (MDP) bone scan is used to assess for possible bone involvement
• May be performed for symptomatic patients with PSA results of >10 ng/mL, Gleason score >8, long life expectancy, higher T stage and those with decreasing PSA doubling time (PSADT)
• May be considered in patients with increasing PSA or positive DRE post-radiotherapy who may benefit from additional local or systemic therapy
• Recommended for patients at high- to very-high risk and in patients at intermediate risk with T2 and PSA of >10 ng/mL

 Positron Emission Tomography (PET)/CT Scan and PET/MRI

• F-18 sodium fluoride, C-11 choline, and F-18 fluciclovine PET/CT or PET/MRI may be considered after bone scan for further evaluation of the bones with equivocal bone scan results 
• Gallium-68 prostate-specific membrane antigen (⁶⁸Ga-PSMA) PET/CT scan demonstrates high sensitivity with histopathological diagnosis, and has better sensitivity and specificity compared to CT or bone scan for the detection of recurrences at lower prostate-specific antigen (PSA) levels
  • Can be utilized in staging prostate cancer
• Consider C-11 choline or F-18 fluciclovine PET/CT or PET/MRI for soft tissue and bone evaluation if other work-ups did not show any evidence of metastasis

• 45-75 years of age at average risk for prostate cancer
• 40-75 years of age at high risk for developing prostate cancer: African descent, germline mutations, with 1st- or 2nd-degree relatives diagnosed with metastatic prostate, ovarian, breast (female at ≤45 years of age), colorectal, endometrial (≤50 years of age) or pancreatic cancer, ≥2 1st- or 2nd-degree relatives diagnosed with prostate, breast, colorectal or endometrial cancer at any age 
• Very healthy >75 year-old individuals with minimal or no comorbidities 
• With previous PSA level of >1 g/mL at 40 years old or >2 ng/mL taken at 60 years old
• With initial screening which includes PSA and DRE
• With negative results but at risk for prostate cancer, repeat screening should be done depending on the PSA and DRE results:
  • PSA <1 ng/mL with normal DRE = 2- to 4-year intervals
  • PSA 1-3 ng/mL with normal DRE = 1- to 2-year intervals
  • PSA >3 ng/mL in 40-75 years old and/or very suspicious DRE and PSA ≥4 ng/mL in >75 years old or very suspicious DRE = PSA, DRE if not done, mpMRI; consider biomarkers
  • PSA <4 ng/mL with normal DRE and no other indications for biopsy = 1- to 4-year intervals