Prostate Cancer: A Comprehensive Overview

1. Epidemiology

• Harrison's Principles of Internal Medicine 22e (2025), p. 741

2. Etiology and Risk Factors

Genetic/Hereditary Factors

• Risk increases 2.5-fold with one affected first-degree relative, and even more with two or more affected relatives.
• ~40% of early-onset and 5-10% of all prostate cancers are hereditary.
• Genome-wide association studies (GWAS) have identified multiple susceptibility loci; mutations in BRCA1/BRCA2 are associated with aggressive disease.

Racial Disparities

• African-American men have a higher incidence, present at a more advanced stage, and develop higher-grade, more aggressive cancers compared to other ethnic groups. Genetic, environmental, and societal factors are all implicated.

Androgen Dependence

• Both prostate epithelial and stromal cells express androgen receptors (ARs) and depend on androgens for growth. Testosterone is converted by prostatic 5α-reductase to dihydrotestosterone (DHT), a more potent androgen, which is the dominant growth driver. This underpins the rationale for androgen deprivation therapy (ADT).

Other Risk Factors

• Age (incidence rises sharply after 50)
• Diet high in animal fat
• Obesity and components of the metabolic syndrome
• Family history of breast or prostate cancer
• Hypertriglyceridemia (associated with prostate cancer risk in elderly men)
• Harrison's Principles of Internal Medicine 22e, p. 741; Campbell-Walsh-Wein Urology

3. Pathology

Gross and Microscopic Features

• The prostate is composed of branching tubuloalveolar glands arranged in lobules, surrounded by fibromuscular stroma.
• The acinar unit contains epithelial, basal, and neuroendocrine cells separated by a basement membrane.
• >95% of prostate cancers are adenocarcinomas arising from the acinar epithelium. Rare types include squamous cell carcinoma, transitional cell tumors, carcinosarcoma, and small-cell (neuroendocrine) carcinoma.
• Peripheral zone is the site of origin for ~70% of cancers.
• Transition zone is the site of BPH and ~20-30% of cancers.

Precursor Lesion

• Prostatic Intraepithelial Neoplasia (PIN), particularly high-grade PIN, is considered a precursor to invasive adenocarcinoma.

Patterns of Spread

• Bailey and Love's Short Practice of Surgery, 28th Ed., p. 1554; Harrison's Principles of Internal Medicine 22e

4. Classification

A. Gleason Grading System

B. ISUP/WHO Grade Groups (2016 reform)

C. TNM Staging System (AJCC)

D. D'Amico Risk Stratification (widely used)

• Harrison's Principles of Internal Medicine 22e, p. 741; Campbell-Walsh-Wein Urology; Bailey and Love's 28th Ed.

5. Diagnosis

Clinical Presentation

• Early disease: Often asymptomatic. Symptoms, when present, overlap with BPH: urinary frequency, urgency, nocturia, dysuria, and acute urinary retention.
• Advanced disease: Bone pain, weight loss, anemia, hematuria, and symptoms of ureteric obstruction (anuria if bilateral).

Digital Rectal Examination (DRE)

• Stony hard, irregular induration of the prostate; obliteration of the median sulcus suggests carcinoma.
• Extension to the seminal vesicles or bladder base is diagnostic of locally advanced disease.

Prostate-Specific Antigen (PSA)

• PSA is organ-specific but not cancer-specific -- also elevated in BPH, prostatitis, UTI, and after urinary retention or catheterization.
• PSA >10 ng/mL strongly favors malignancy.
• PSA velocity (rate of rise over time) and free-to-total PSA ratio improve specificity.
• Adjunct markers: 4Kscore (total PSA, free PSA, intact PSA, hK2), Prostate Health Index (PHI) (total PSA + free PSA + [-2]proPSA), urine-based tests (ExoDx exosome test, Select-MDx).

Multiparametric MRI (mpMRI)

1. T2-weighted imaging
2. Diffusion-weighted imaging (DWI)
3. Dynamic contrast-enhanced (DCE) imaging
4. (Optionally) spectroscopic imaging

• PI-RADS 1-2: Low risk - biopsy can often be safely deferred
• PI-RADS 3: Equivocal
• PI-RADS 4-5: High risk - targeted biopsy recommended

Prostate Biopsy

• Gold standard for diagnosis.
• Image-guided (TRUS, MRI, or MRI-TRUS fusion) needle biopsy.
• Extended-pattern 12-core biopsy including peripheral zone sampling and targeted sampling of suspicious lesions.
• MRI-guided biopsy is superior to ultrasound-guided biopsy for accuracy.

Staging Investigations

• Bone scan (Tc-99m MDP): Recommended when PSA >20 ng/mL (T1), PSA >10 ng/mL (T2), Gleason 8-10, T3/T4 disease, or bone symptoms. Detects osteoblastic metastases (Fig. 84.19 -- pelvic osseous metastases).
• CT scan (chest, abdomen, pelvis): Evaluates lymphadenopathy in high-risk patients.
• PSMA PET/CT (68Ga-PSMA): Increasingly used for detection of recurrence at low PSA levels and primary staging in high-risk disease. PSMA is overexpressed on prostate cancer cells, including in castration-resistant and metastatic disease.
• 11C-choline / 18F-fluorocholine PET/CT: Established for biochemical recurrence but has largely been superseded by PSMA PET in many centers.

Laboratory Tests

• In advanced disease: Leukoerythroblastic anemia (marrow infiltration), thrombocytopenia, DIC, elevated alkaline phosphatase (bone/liver metastases).
• Harrison's 22e, pp. 741-743; Bailey and Love's 28th Ed., pp. 1554-1556; Tietz Textbook of Laboratory Medicine 7th Ed.; Campbell-Walsh-Wein Urology

6. Treatment

A. Active Surveillance (AS)

• Recommended for low-risk disease (Grade Group 1, PSA <10, T1-T2a).
• Involves serial PSA measurements, repeat biopsies, and mpMRI monitoring.
• Defers definitive treatment unless progression is detected, minimizing side effects in men with indolent cancers.

B. Radical Prostatectomy (RP)

• Open, laparoscopic, or robot-assisted laparoscopic radical prostatectomy (RALP).
• Preferred in men with localized disease and >10-year life expectancy.
• Nerve-sparing technique aims to preserve erectile function.
• Complications: erectile dysfunction, urinary incontinence, climacturia (urinary incontinence at orgasm), dry ejaculation (retrograde ejaculation or loss of ejaculate).
• Prognostic factors post-RP: tumor grade, surgical margin status, extracapsular extension, seminal vesicle invasion, and lymph node involvement.

C. Radiation Therapy (RT)

• External beam radiotherapy (EBRT): Modern techniques (IMRT, VMAT) enable dose escalation with reduced toxicity.
• Brachytherapy (BT): Interstitial low-dose-rate (LDR) seeds (125I, 103Pd) or high-dose-rate (HDR) for localized disease.
• Combined EBRT + ADT used for intermediate/high-risk disease.
• Side effects: erectile dysfunction, reduced ejaculate, decreased libido, radiation cystitis, proctitis.

D. Androgen Deprivation Therapy (ADT)

• The backbone of treatment for locally advanced and metastatic disease.
• Achieves castrate testosterone levels (<50 ng/dL).
• Methods:
  • Surgical castration (bilateral orchiectomy) -- permanent.
  • LHRH agonists (e.g., leuprolide, goserelin [Zoladex]): Initial testosterone flare managed with short-term antiandrogens.
  • LHRH antagonists (e.g., degarelix): No testosterone flare.
  • Antiandrogens (bicalutamide, enzalutamide): Block androgen receptor directly.

E. Castration-Resistant Prostate Cancer (CRPC)

• Abiraterone acetate (+ prednisone): Inhibits CYP17A1, blocking androgen synthesis in adrenals and tumor.
• Enzalutamide: Second-generation AR antagonist; blocks AR signaling at multiple levels.
• Docetaxel (chemotherapy): Indicated in CRPC and increasingly used upfront in metastatic hormone-sensitive disease.
• Cabazitaxel: Second-line after docetaxel failure.
• Radium-223 (223RaCl2): Alpha-emitting radionuclide for symptomatic bone metastases (improves overall survival).
• PARP inhibitors (olaparib, rucaparib): For patients with BRCA1/2 or homologous recombination repair mutations.
• 177Lu-PSMA-617: Radioligand therapy for PSMA-positive CRPC (increasingly available).

F. Treatment Summary by Stage

• Harrison's Principles of Internal Medicine 22e, pp. 742-744; Tietz 7th Ed.; Campbell-Walsh-Wein Urology; Bailey and Love's 28th Ed.

7. Prognosis

• Gleason grade / Grade Group: Strongest pathological predictor.
• Clinical stage: Extracapsular extension, seminal vesicle invasion, and lymph node status are major adverse prognostic factors.
• Serum PSA at diagnosis and post-treatment: PSA nadir and PSA velocity post-treatment predict recurrence.
• Surgical margins: Positive margins after RP confer higher biochemical recurrence risk.
• Nomograms: Integrate PSA, clinical stage, and Gleason score to predict outcomes (e.g., Partin Tables, Kattan nomograms, CAPRA score).

Most men diagnosed with prostate cancer will not die from their disease. The major clinical challenge remains distinguishing aggressive, lethal cancers from indolent ones that can be safely observed.

• Harrison's Principles of Internal Medicine 22e, p. 741; Tietz Textbook of Laboratory Medicine 7th Ed.; Campbell-Walsh-Wein Urology; Bailey and Love's Short Practice of Surgery 28th Ed.

Cervical Cancer: Etiology, Pathology, Classification, Diagnosis, Treatment, and Prognosis

1. Epidemiology

• Goldman-Cecil Medicine International Edition; Berek & Novak's Gynecology

2. Etiology and Risk Factors

Primary Cause: Human Papillomavirus (HPV)

• Of >200 HPV strains, ~40 infect the genital tract
• High-risk HPV types: 16, 18, 31, 33, 45, 52, 58 (15 high-risk subtypes total)
• HPV 16 and 18 alone cause ~70% of all cervical cancers
• HPV types 31, 33, 45, 52, and 58 account for an additional ~20%
• Low-risk HPV (types 6, 11) cause genital warts, not cancers
• HPV is sexually transmitted via genital-genital or genital-oral contact

Risk Factors Summary

Molecular Mechanism of HPV Carcinogenesis

• E6 protein: Binds to and degrades the p53 tumor suppressor, inhibiting apoptosis and contributing to cellular immortalization
• E7 protein: Binds to and degrades pRb tumor suppressor, disrupting the E2F transcription factor and causing unregulated cell cycle progression

• Most infections (~90%) are transient, asymptomatic, and clear within 1-2 years
• In ~10% of women, HPV causes persistent infection
• Persistent HPV infection -- either as an episome or integrated into host cell DNA -- is necessary for development of precancer and cancer
• Goldman-Cecil Medicine; Berek & Novak's Gynecology; Sabiston Textbook of Surgery

3. Pathology

Precursor Lesions

• CIN 1 is largely HPV cytopathic effect; most regress spontaneously
• CIN 2/3 carry significant risk of progression to invasion if untreated

Histological Subtypes of Invasive Cervical Cancer

• Most common (~70-80%), arises from ectocervical squamous epithelium
• Subtypes: large cell keratinizing, large cell non-keratinizing, small cell (distinct from neuroendocrine)
• Rates have been declining with widespread Pap smear use

• Arises from endocervical glandular epithelium; accounts for ~15-25% of cases
• Incidence increasing in younger women in some countries (including the US), likely due to inadequate Pap screening detection of glandular lesions
• HPV 18 is more commonly associated with adenocarcinoma than SCC
• More difficult to detect on cytology (higher false-negative rate)
• Has different carcinogenic pathways from SCC

• Contains both squamous and glandular elements
• Generally carries a worse prognosis than either pure SCC or adenocarcinoma alone

• Neuroendocrine carcinoma (small cell type): Very aggressive, often metastatic at presentation; treated like small-cell lung cancer
• Malignant melanoma of the cervix
• Sarcomas (e.g., carcinosarcoma)
• Metastases to the cervix (from colon, ovary, endometrium)

Patterns of Spread

• Berek & Novak's Gynecology; Goldman-Cecil Medicine

4. Classification and Staging

FIGO Staging System (2018 Revised)

D'Amico-equivalent Risk Grouping (simplified)

• Early-stage: Stages I-IIA -- surgical or radiation approaches; high cure rate
• Locally advanced: Stages IIB-IVA -- definitive chemoradiation
• Metastatic/recurrent: Stage IVB -- systemic chemotherapy + immunotherapy
• Goldman-Cecil Medicine International Edition; Berek & Novak's Gynecology; Sabiston Textbook of Surgery

5. Diagnosis

Clinical Presentation

• Early disease: Usually asymptomatic; detected by screening
• Symptomatic presentations:
  • Abnormal vaginal bleeding -- irregular, heavy, or postcoital bleeding (most common presenting symptom)
  • Malodorous vaginal discharge
  • Pelvic pain or pain with intercourse
  • Advanced disease: obstructive uropathy (hydronephrosis, uremia), bowel/bladder dysfunction, leg edema from lymphatic obstruction, weight loss

Physical Examination

• Speculum examination: Grossly visible exophytic, ulcerative, or endophytic cervical mass; cervix may be friable and bleed on contact
• Digital/bimanual examination: Firm, expanded cervix; parametrial nodularity indicates local extension
• Rectal examination: Best method for assessing parametrial involvement and cervical size in endocervical lesions
• Lymph node assessment: Supraclavicular, axillary, inguinofemoral nodes evaluated for metastases

Cervical Screening (Detection Before Symptoms)

1. Pap smear (Papanicolaou test): Cytological examination of cervical cells. False-negative rate up to 50% in invasive cancer -- a negative Pap should never be relied on in a symptomatic patient
2. HPV co-testing: More sensitive; primary HPV testing now recommended in many guidelines
3. Co-test (Pap + HPV): Recommended every 5 years in women aged 30-65

Colposcopy

• Abnormal blood vessels (looped, corkscrew, J-shaped)
• Irregular surface contour with loss of epithelium
• Color tone change (acetowhite areas)

Biopsy

• Punch biopsy of visible lesion = definitive diagnosis in most cases
• Colposcopic-directed biopsy + endocervical curettage (ECC) when no gross lesion
• Cone biopsy / LEEP if colposcopy is inadequate, diagnosis uncertain, or for therapeutic excision of early microinvasive disease

Staging Investigations

• MRI pelvis: Best for local disease extent, parametrial involvement, lymphadenopathy
• CT chest/abdomen/pelvis: Lymph node assessment, distant metastases
• PET-CT: Metabolically active nodes, distant disease (superior sensitivity for lymph node involvement)
• Examination under anesthesia (EUA), cystoscopy, proctoscopy: For advanced disease staging
• Renal function / KUB: Hydronephrosis from ureteral obstruction (upstages to IIIB)
• Chest X-ray: Lung metastases

Laboratory Tests

• Full blood count (anemia from bleeding/marrow invasion), LFTs, renal function
• No specific serum tumor marker for routine use (SCC antigen sometimes used in squamous cell cancer for monitoring)
• Berek & Novak's Gynecology; Goldman-Cecil Medicine; Sabiston Textbook of Surgery

6. Treatment

A. Preinvasive Disease (CIN 2/3, HSIL)

• LEEP (Loop Electrosurgical Excision Procedure): Outpatient; excises the transformation zone
• Cold Knife Conization (CKC): Operating room; better for glandular lesions or when LEEP margins are inadequate
• Ablative methods (cryotherapy, laser): Used in low-resource settings
• Goal: excise all diseased tissue with clear margins

B. Microinvasive Disease (Stage IA1)

• Cone biopsy with clear margins: Fertility-sparing; adequate for IA1 without LVSI (lymphovascular space invasion)
• Simple (extrafascial) hysterectomy: Definitive treatment in women who do not desire fertility

C. Early Invasive Disease (Stages IA2-IIA)

• Radical hysterectomy (Wertheim's hysterectomy) -- removes uterus, cervix, upper vagina, parametria, and pelvic lymph nodes
• Open surgery is standard (minimally invasive approaches show worse disease-free survival, particularly for tumors >2 cm -- landmark LACC trial)
• Sentinel lymph node biopsy or formal pelvic +/- para-aortic lymphadenectomy
• Radical trachelectomy (cervix only, preserves uterus): Fertility-sparing option for carefully selected women with tumors <2 cm

• Positive margins, parametrial involvement, positive nodes: Chemoradiation
• Large tumor, deep stromal invasion, lymphovascular space invasion: Radiation +/- chemotherapy

• External beam radiotherapy (EBRT) to pelvis
• Brachytherapy (intracavitary): Delivers high local dose to cervix/vaginal vault
• Combined EBRT + brachytherapy achieves equivalent cure rates to surgery in early stages

D. Locally Advanced Disease (Stages IIB-IVA)

• Concurrent chemoradiation: Weekly cisplatin (radiation sensitizer) + EBRT + intracavitary brachytherapy
• Cisplatin + 5-fluorouracil (5-FU) regimens also used
• Para-aortic radiation if para-aortic nodes involved

E. Metastatic / Recurrent Disease (Stage IVB or Recurrence)

• First-line systemic therapy: Platinum-based doublet (cisplatin or carboplatin + paclitaxel)
• Bevacizumab (anti-VEGF antibody): Added to platinum-taxane doublet; provides incremental survival benefit in advanced/recurrent disease
• Pembrolizumab (anti-PD-1 checkpoint inhibitor): Combined with chemotherapy ± bevacizumab for PD-L1-positive tumors
• Pelvic exenteration: For selected patients with central pelvic recurrence after prior radiation; highly morbid but curative in 25-50% of cases
• Palliative radiotherapy: For symptom control (bleeding, bone pain)

F. HPV Vaccination (Prevention)

• Gardasil-9 (9-valent): Protects against HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
• Efficacy 97-100% for CIN 2/3 caused by HPV 16/18 in previously uninfected women
• WHO target: Vaccinate 90% of girls by age 15, screen 70% of women aged 35-45 twice, treat 90% of detected lesions -- projected to reduce incidence to <4 per 100,000
• Berek & Novak's Gynecology; Goldman-Cecil Medicine; Sabiston Textbook of Surgery

7. Prognosis

Key Prognostic Variables for Early-Stage Disease

• Lymph node involvement: Single most important adverse prognostic factor
• Parametrial involvement: Significantly worsens prognosis
• Surgical margins: Positive margins increase recurrence risk
• Tumor size: Tumors >4 cm have higher recurrence rates
• Lymphovascular space invasion (LVSI): Independent adverse factor
• Depth of stromal invasion
• Histologic subtype: Adenosquamous carcinoma and neuroendocrine carcinoma carry worse prognosis than SCC or pure adenocarcinoma

Special Prognostic Considerations

• Women managed by a gynecologic oncologist have statistically better survival outcomes
• Recurrent disease is generally not curable (except selected central pelvic recurrences amenable to exenteration), with median survival measured in months with systemic therapy
• HPV vaccination and screening represent the most powerful tools for reducing mortality from this disease

The overarching principle: cervical cancer is largely a preventable disease with a long preinvasive window of opportunity for intervention. Earlier diagnosis through screening dramatically improves outcomes across all histologic subtypes.

• Goldman-Cecil Medicine International Edition; Berek & Novak's Gynecology; Sabiston Textbook of Surgery, 21st Ed.