Prostate Cancer Study Notes

PROSTATE CANCER

Presenter

  • Dr. Honoratha, RSD3

Objectives

  • Discuss prostate cancer in terms of:

    • Risk factors

    • Pathology and presentation.

  • Describe various treatment options for prostate cancer.

  • Explain clinical presentations of seminal vesicle cancer.

  • Discuss the management of seminal vesicle cancer.

Epidemiology

  • Most common visceral malignancy in men.

  • Third highest cause of cancer-related deaths (following lung and colon cancers).

  • Second most commonly diagnosed cancer in men.

  • Peak incidence occurs between ages 70-74, with 85% of diagnoses after age 65.

  • Lifetime risk of prostate cancer is approximately 1 in 6 (~17%) for Caucasians and 1 in 5 for African Americans.

  • Lifetime risk of death from prostate cancer is about 1 in 36 (~3%) for Caucasians and 1 in 21 for African Americans.

  • Rarely diagnosed in men younger than 50, accounting for only 2% of all cases.

  • Increase in incidence of local-regional disease, contrasted by a decrease in metastatic disease since the introduction of PSA testing.

Risk Factors

General Factors

  • Specific causes of prostate cancer initiation and progression remain unknown; however, genetics and environment are considered influential.

Specific Risk Factors

  • Obesity: Higher BMI correlates with increased prostate cancer risk due to elevated oxidative stress.

  • Race: Increased risk in African Americans and decreased risk in Asians.

  • Diet: Fatty diets, particularly high in polyunsaturated fats, are linked with increased risk of prostate cancer.

  • Prostatitis or chronic inflammation: Leads to cellular hyperproliferation, heightening risk.

  • Sexually transmitted diseases (STDs): Associated with proliferative inflammatory atrophy, leading to defects in cellular defenses and increased oxidative stress.

  • Molecular and hormonal factors:

    • Low androgen exposure may be protective.

    • Mutation in the SRD5A2 gene increases enzyme activity, correlating with poor prognosis.

    • Genes involved in testosterone biosynthesis are implicated in prostate cancer risk.

  • Estrogens: Potentially protective against prostate cancer by inhibiting prostate epithelial cell growth.

  • Insulin-like growth factor (IGF): High IGF levels may be associated with increased prostate cancer risk.

  • Leptin: Elevated levels may promote cancer risk by stimulating cell migration via VEGF and FGF pathways.

  • Vitamin D: Low levels associated with increased prostate cancer risk, particularly in populations with limited sun exposure.

  • Dietary factors: High calcium intake from dairy may reduce Vitamin D levels, increasing cancer risk. In contrast, diets rich in fish (high in Vitamin D) lead to low prostate cancer rates, as seen in Japan.

  • Familial and hereditary factors:

    • Familial: Two first-degree relatives diagnosed at any age, or one first-degree and two second-degree relatives.

    • Hereditary: Three or more prostate cancer cases in the same family, cases in three successive generations, or two cases diagnosed under the age of 55.

Pathology

Prostatic Intraepithelial Neoplasia (PIN)

  • Comprises architecturally benign acini or ducts lined by atypical cells, classified into low-grade and high-grade neoplasias.

  • Pathologists refrain from commenting on low-grade PIN in diagnoses for two primary reasons:

    • Difficulty in reproducibly distinguishing low-grade PIN from benign tissue.

    • No increased risk of carcinoma upon rebiopsy for patients with low-grade PIN compared to those with benign findings.

High-grade PIN (HGPIN)

  • Considered a precursor to some prostate carcinomas. Evidence supporting this includes:

    • Increased size and number of HGPIN foci in prostates containing cancer.

    • Higher number of multifocal carcinomas with increasing amounts of HGPIN.

    • Both HGPIN and carcinoma show preferential involvement of the peripheral zone, with similar biomarkers and molecular changes.

    • Approximately 20% of HGPIN lesions harbor the TMPRSS2-ERG fusion gene, commonly detected in prostate cancers.

Atypical Small Cell Acinar Proliferation (ASAP)

  • Characterized by small cell proliferation with cytologically abnormal cells.

  • EAU recommends a repeat biopsy due to high progression probability to prostate cancer, with required surveillance via PSA monitoring.

Adenocarcinoma

  • Accounts for 95% of prostate cancers, arising in prostatic gland ducts.

  • Typically multifocal in 85% of cases.

Spread of Prostate Cancer

  • Direct Spread:

    • Invasion of periprostatic tissues (lacks a capsule).

    • Perineural invasion along planes of decreased resistance.

    • Involvement of seminal vesicles via perivesicular soft tissues or ejaculatory ducts.

    • Spread to the rectum via Denonvillier fascia.

  • Metastasis:

    • Most frequent sites: lymph nodes and bones.

    • Secondary sites include the Virchow’s node, lungs, bladder, liver, and adrenal glands.

Gleason Grading System

  • Introduced by Donald Gleason in 1960, categorizes prostate cancer based on glandular architecture using grades 1 through 5:

    • Score: Sum of the most common and second most common tumor patterns, theoretically ranging from 2 to 10, though scores of 2-5 are rarely assigned.

    • Score of 6 indicates low-grade, 7 indicates intermediate, and scores of 8-10 indicate high-grade cancers.

Gleason Grade Groups (ISUP Classification)

  • Grade Group 1: Gleason score ≤ 6

  • Grade Group 2: Gleason score 7 (3+4)

  • Grade Group 3: Gleason score 7 (4+3)

  • Grade Group 4: Gleason score 8

  • Grade Group 5: Gleason score 9-10

  • Notable Risks: Grades 1, 2, and 3 signify low to intermediate risk; grades 4 and 5 indicate high risk.

Variants of Prostatic Carcinoma

  • Epithelial Variants:

    • Mucinous carcinoma: Rare and aggressive, associated with significant bone involvement.

    • Neuroendocrine differentiation: Includes small cell carcinoma, mixed small cell and adenocarcinoma (50% mix), presenting a poor prognosis.

  • Non-epithelial Variants:

    • Sarcomas: Rare (0.1-0.2%), mainly rhabdomyosarcoma, and leiomyosarcoma, with lymphoma also noted.

Clinical Presentation

  • Early stages of prostate cancer typically cause no symptoms; symptoms suggest locally advanced or metastatic disease.

  • Locally advanced symptoms include:

    • Urinary symptoms

    • Ureteral obstruction causing renal failure

    • Hematospermia or decreased ejaculate volume.

  • Metastatic disease symptoms include:

    • Bone pain

    • Pathological fractures

    • Anemia

    • Lower extremity edema

    • Less common: malignant retroperitoneal fibrosis, paraneoplastic syndromes, disseminated intravascular coagulation (DIC).

  • Due to widespread PSA screening, locally advanced and metastatic presentations are uncommon.

Diagnostic Modalities

  • Triad of Diagnosis:

    • Digital Rectal Examination (DRE): 50% of suspicious lesions may have cancer on biopsy; biopsy is recommended irrespective of PSA levels for abnormal DRE findings, as 25% of patients may have PSA < 4 ng/ml.

    • Prostate-Specific Antigen (PSA): A serine protease from the kallikrein gene family, produced by prostatic epithelial and peri-urethral glands.

    • Transrectal Ultrasound (TRUS) + Biopsy: Standard approach in diagnosis.

  • PSA Derivatives:

    • PSA Density (PSAD): Ratio of PSA to gland volume; biopsy may only be recommended if PSAD exceeds 0.1 or 0.15.

    • PSA Velocity: Rate of change > 0.75 ng/ml/year as a cancer marker. A rising PSA of 0.75 ng/mL/year indicates an increased risk of cancer.

    • PSA Doubling Time (PSADT): Time required for PSA levels to double.

PCA3

  • Prostate Cancer Gene 3: A prostate-specific non-coding mRNA expressed at 100 times normal levels in 95% of prostate cancer cases; used to improve detection and assist TRUS biopsies, potentially distinguishing clinically significant from indolent disease.

New Markers for Prostate Cancer Detection

  • Human Kallikrein 2: Predictor of extracapsular extension and seminal vesicle invasion.

  • Others include Prostate-Specific Antibodies, Urokinase Type Plasminogen Activator Receptor (uPAR), Early Prostate Cancer Antigen (EPCA), GSTP-1 hypermethylation.

Imaging Techniques

  • Bone X-rays: Insensitive; requires over 50% bone density involvement for detection. Useful for confirmation only.

  • Bone Scans: Most sensitive; valuable baseline prior to radical prostatectomy.

  • TRUS: Less sensitive for local extension but complements DRE findings.

  • Pelvic CT/MRI: Detects local extensions and lymph node metastasis; indicated for high-risk patients.

  • Multiparametric MRI:

    • T2-weighted images: Offer good zonal anatomy differentiation.

    • Diffusion-weighted images: Indicate increased cellularity of malignant tissue, decrease in apparent diffusion coefficient (ADC) values.

    • Dynamic contrast-enhanced images: Showcase early and active enhancement of blood supply with quick contrast washout.

    • MRI spectroscopic imaging allows assessment of tumor aggressiveness based on size and vascularization.

Staging of Prostate Cancer

Primary Tumor (T)

  • TX: Primary tumor cannot be assessed.

  • T0: No evidence of primary tumor.

  • T1: Clinically undetectable, not palpable. Includes T1a (incidental finding in ≤5% of tissue), T1b (results from needle biopsy due to elevated PSA).

  • T2: Tumor confined within the prostate. Includes T2a (involves ≤50% of one lobe), T2b (involves >50% of one lobe), T2c (involves both lobes).

  • T3: Tumor extends through the prostate capsule (T3a = unilateral, T3b = bilateral).

  • T4: Tumor invades seminal vesicles or adjacent structures (rectum, bladder, etc.).

Regional Lymph Nodes (N)

  • NX: Nodes not assessed.

  • N0: No regional lymph node metastasis.

  • N1: Metastasis in regional nodes.

Distant Metastasis (M)

  • M0: No distant metastasis.

  • M1: Distant metastasis present. Includes Ml for non-regional lymph nodes, M2 for bones, and other sites with or without bone disease.

Treatment Approaches to Prostate Cancer

Management Factors

  • Treatment Selection based on:

    • Clinical stage (TNM)

    • Risk category (Low / Intermediate / High)

    • Life expectancy and comorbidities

    • Patient preference

D’Amico Risk Stratification Parameters

  • Factors considered:

    • PSA level

    • Gleason Score

    • Clinical staging (TNM/NCCN)

Risk Group

PSA (ng/mL)

Gleason Score

Clinical Stage

Low

<10

≤6

T1-T2a

Intermediate

10-20

7

T2b-T2c

High

>20

8-10

T3-T4

Classification of Prostate Cancer

  • Localized Disease: T1/T2, No/Mo.

  • Locally Advanced Disease: T1/T2, N+, Mo; T3/T4, No/N+, Mo; proven M1.

  • Risk Groups:

    • Low: T1/T2a, Gleason grade 6, PSA < 10.

    • Intermediate: T2b, or Gleason grade 7, or PSA 10-20.

    • High: T3/T4, or PSA >20, Gleason ≥ 8.

1. Conservative Management
Watchful Waiting

  • Focus on palliative intent for elderly or patients with a life expectancy of <10 years.

  • Applicable to all risk groups; no routine biopsies; treatment only if symptoms arise (e.g., obstruction, pain).

Active Surveillance

  • Intended for curative treatment in low-risk disease and selected intermediate-risk patients.

  • Criteria: PSA <10 ng/mL, Gleason ≤ 6 (Grade Group 1).

  • Follow-up: PSA every 6 months, annual DRE, MRI ± repeat biopsies.

Recommendations for Low-Risk Disease

  • Patients with life expectancy < 10 years managed by watchful waiting.

  • Patients with life expectancy > 10 years and low-risk disease managed via active surveillance.

Recommendations for Intermediate-Risk Disease

  • Expectant management includes offering watchful waiting to asymptomatic patients with life expectancy < 10 years.

  • Offer active surveillance to selected ISUP grade group 2 patients meeting specific criteria.

  • Patients with ISUP grade group 3 disease excluded from active surveillance protocols.

Radical Prostatectomy (RP)

  • Implied for patients with > 10 years life expectancy. Delays (>3 months) in RP are often acceptable.

  • Nerve-sparing surgery considered for patients with low risk of extracapsular disease.

Radiotherapeutic Treatments

  • Low-dose rate (LDR) brachytherapy advised for patients with good urinary function and favorable intermediate-risk disease.

  • Intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) in combination with short-term androgen deprivation therapy (ADT).

  • Normofractionation versus moderate hypofractionation approaches proposed based on patient profiles.

High-Risk Localized Prostate Cancer

  • Definition: confined within the prostate but with high-risk features like PSA > 20 ng/mL

  • Preferred treatment:

    • Radical prostatectomy + Pelvic Lymph Node Dissection (PLND) in fit patients, often followed by adjuvant radiotherapy for positive margins or extracapsular extension.

    • Salvage radiotherapy for PSA recurrence.

Treatment of Locally Advanced Disease

  • EBRT + Long-Term ADT as a mainstay.

  • Selected patients may undergo radical prostatectomy, requiring extended lymph node dissection, often followed by adjuvant/salvage RT ± ADT.

Management of Biochemical Recurrence (BCR)

  • Biochemical recurrence defined as two consecutive PSA rises ≥ 0.2 ng/dL after achieving undetectable levels following RP.

  • Imaging Recommendations Post PSA Rise:

    • PSMA PET/CT as the first-line imaging technique once PSA exceeds ~0.2 ng/mL.

    • Conventional imaging (bone scan, CT) utilized based on PSA levels and clinical context.

Treatment Options for Castration-Resistant Prostate Cancer (CRPC)

  • Include systemic therapies like Abiraterone acetate + prednisone, Enzalutamide, Darolutamide.

    • Other therapies include chemotherapy (Taxane-based) like Docetaxel, and Cabazitaxel.

    • PARP Inhibitors for patients with HRR gene alterations and PSMA-targeted radioligand therapy.

Emotional and Physical Effects of Hormonal Therapy

  • Side effects include loss of libido, erectile dysfunction, obesity, dyslipidemia, gynecomastia, hot flashes, anemia, cognitive decline, and osteoporosis.

Mechanisms of Resistance in CRPC

  • AR-Dependent Mechanisms: Include mutations and ligand-independent activation.

  • AR-Independent Mechanisms: Proliferation of androgen-independent clones, inhibited apoptosis, mutation of oncogenes like p53.

Recommendations for Adjuvant Treatment

  • Recommendations based on pathologic findings post-RP, emphasizing tailored therapies based on individual risk factors and disease characteristics.