17 - Prostate Cancer Flashcards
Most common cause of cancer in American men
Prostate Cancer
Second leading cause of cancer deaths in the USA
Prostate Cancer
Lifetime risk of men in this country developing prostate cancer
16%
Prostate Cancer - Risk Factors
Age (65 - 74, mean 66)
Ethnicity (African American men higher risk)
Genetics (Men with ≥1 first degree relative have 2x risk. Men with 2 - 3 first degree relatives have 5 - 11x risk) BRCA 1 (1.8-fold risk in men
Screening tests for prostate cancer
PSA (prostate specific antigen) Digital rectal exam PSA velocity PSA density Free to total PSA ratio PCA3
Prostate Specific Antigen (PSA)
Glycoprotein enzyme produced in prostate epithelial cells
Tissue barrier between prostate lumen and blood are disrupted in cancer
Used as screening tool now
PSA Performance
Cut off of 4.0 ng/mL Sensitivity 21% for any cancer, 51% for high grade Specificity 91% Positive predictive value 30% Negative predictive value 85%
Can be false positives or false negatives
Benign settings for an elevated PSA
Benign Prostatic Hyperplasia (BPH) Bacterial Prostatitis Acute urinary retention Ejaculation Digital rectal exam Prostate biopsy
Digital Rectal Exam (DRE)
Can detect tumors in posterior and lateral aspects Poor inter-observer agreement Sensitivity 59% Specificity 94% PPV 5 - 30%
Prostate Cancer Screening considerations
Not all men will die from it
Lifetime risk of prostate cancer 16%
Lifetime risk of dying from prostate cancer
Prostate Cancer Screening Recommendations
USPSTF recommends against PSA screening
ASCO says that if you have >10 year life expectancy, discuss risks/benefits of PSA testing
ACS and AUA - Recommendations to discuss PSA testing depend on age, life expectancy and clinical risk
Prostate Cancer - Presentation
80% of men are asymptomatic and diagnosed with elevated PSA. THey undergo a prostate biopsy
Symptoms: Urinary frequency Urgency Nocturia Hesitancy Hematuria Hematospermia (uncommon) Bony pain in metastatic setting
Prostate Cancer - Diagnosis
Transrectal Ultrasound Guided Biopsy
Evenly distributed but random samples of the prostate
6 core biopsies previously
Now we do 12
How much does a normal prostate weigh?
20 g
Zones of the prostate
1 - Peripheral
2 - Central
3 - Transitional
4 - Anterior Fibromuscular Stroma
Site for benign prostatic hyperplasia
3 (Transitional zone)
Site for carcinoma
1 (Peripheral zone)
Prostate Histo findings you might encounter
Inflammation - Prostatitis
Benign nodular enlargement, Benign prostatic hyperplasia
Intraepithelial lesion - High grade prostatic intraepithelial neoplasia
Invasive cancer
Benign Prostatic Hyperplasia
Extremely common over the age of 50
20% of men ages 40 have it
70% of men age 60 have it
Hyperplasia is almost EXCLUSIVELY in the transition zone
Forms large nodules in the periurethral region
Benign Prostatic Hyperplasia - Clinical Picture
Partial or complete urethral obstruction Urinary frequency Nocturia Difficulty in starting and stopping urine stream Overflow dribbling Dysuria and infections
May lead to:
bladder hypertrophy and distension
Benign Prostatic Hyperplasia - Pathological Exam
Prostate weighs 60 - 100g (3 - 5 times as much as before)
Most common specimen - Transurethral resection of prostate (TURP)
Grossly - the nodule of BPH vary from soft yellow pink to tough pale grey, depending on percentage of glands
Microscopically - BPH consists of nodules with variable amount of glandular and stromal component
High Grade Prostatic Intraepithelial Neoplasia (HGPIN)
Preserved normal architecture
Basal cell layer present
Luminal cells: Multilayered, nuclear enlargement and prominent nucleoli
HGPIN
Putative precursor lesion
Unclear whether HGPIN inevitably progresses into prostate cancer
Prostate cancer
Most common - Adenocarcinoma
Other cancers in prostate: Sarcoma, lymphoma
Prostate adenocarcinomas
Arise in the peripheral zone
Needle core biopsy transrectally
If it’s negative for carcinoma:
Is there inflammation? (acute/chronic)
Are there precursor lesions? (HGPIN)
If it’s positive for carcinoma:
It’s cancer
Prostate Adenocarcinoma - Histologic features
Small, crowded and infiltrative glands
Only one layer of cells (basal cell layer absent)
Nuclei are large with prominent nucleoli
Gleason Score
Grades:
1 - Not used in clinical practice
2 - Not used in clinical practice
3 - You can draw an outline around each individual gland
4 - You can see some lumens, but the glands have begun to fuse, so you can’t outline each gland anymore
5 - No more glands, only infiltrating cells
If there are two scores present in different parts, you add them up. (4 & 3 = 7)
If there is only one score uniformly all around, you just double it (3 & 3 = 6)
Extent of cancer
of core biopsies involved
Percentage of sampled tissue
Perineural invasion present
Interpreting Gleason Scores
4 is the most common Gleason grade
3 is the second most frequent Gleason grade
6 is the score with the best prognosis
7 has an intermediate prognosis
8 - 10 are the worst prognoses
New Grading System
Grade Group 1 - Gleason score of 6
Grade Group 2 - Gleason score of 7 (3 + 4), with predominantly 3 (not many fused glands)
Grade Group 3 - Gleason score of 7 (4 + 3), with predominantly 4 (mostly fused glands)
Grade Group 4 - Gleason score of 8
Grade Group 5 - All else
Prostatic Adenocarcinoma - Immunohistochemistry
Markers for basal cell layer
PIN4 immunostain
P63 and HMWCK basal cell markers
Prostatic Adenocarcinoma - Resection specimens
Margins: Positive or Negative
Spread to periprostatic soft tissue, seminal vesicles, bladder neck
Perineural invasion
Metastases
Prostatic Adenocarcinoma - Metastasis
First spreads via lymphatics to obturator nodes
Then spreads to para-aortic nodes
Hematogenous spread is mainly to bones
Osteoblastic lesions in the lumbar spine, proximal femur, pelvis, thoracic spine, ribs
Prostate Cancer - Stage I/II
T1 - Tumor not palpable/detectable (detected by PSA)
T2 - Palpable, confined to prostate
Prostate cancer - Stage III/IV
T3 - Through prostate capsule or involving seminal vesicles
N0 - Negative nodes
M0 - No distant metastases
T4 - Invading other structures
N1 - Positive nodes
M1 - Distant metastases
Prostate Cancer - Stage at Presentation
81% - Localized (confined to primary site) [100% 5 year survival]
12% - Regional (Regional lymph nodes involved) [100% 5 year survival]
4% - Distant (Cancer has metastasized)
3% - Unknown (Unstaged)
Prostate Cancer - Local Treatment
Surgery
Radiation (External beam or Brachytherapy)
Observation (Active surveillance)
Surgery - Prostatectomy
Retropubic or perineal approach
Open or minimally invasive
Nerve sparing approach - Preservation of autonomic cavernous nerves in neurovascular bundle
Advantages:
Pathologic staging, pelvic nodes accessible
Risks:
Impotence 59% at 2 months, 43% at 2 years
Incontinence 52% at 2 months, 15% at 2 years
Surgical risks
Prostate Cancer Treatment - Radiation
External beam radiation:
In combination with hormonal therapy, depending on risk
No direct comparison to surgery, but outcomes thought to be equivalent
Side effects: Radiation proctitis, enteritis, cystitis, sexual dysfunction, low risk for urinary incontinence
Brachytherapy:
Radioactive seed implants
Can be given with external beam radiation with higher risk prostate cancer
Side effects: Urinary retention, proctitis, sexual dysfunction
Prostate Cancer Treatment - Active Surveillance
Observation rather than immediate treatment for patients with low risk prostate cancer
PSA
Prostate Cancer Treatment - Metastatic
Androgen Deprivation Therapy
Old school: Surgical Orchiectomy
Quick, cost-effective, no compliance issues
More modern: Medical orchiectomy
GnRH agonists (overstimulation downregulates GnRH receptors, decreasing LH & FSH levels)
Add antiandrogen threapy (Bicalutamide) to counter “flare”
GnRH agonists
Goserelin
Leuprolide
Buserelin
Triptorelin
All injectible
Goal: Testosterone level down to 50
GnRH antagonist
Degarelix
Blocks GnRH receptors
Hormone Sensitive vs Castrate Resistant
Hormone sensitive prostate cancer develops resistance to hormonal therapy after about 2 years
This is called “Castrate Resistant Prostate Cancer” (CRPC)
Metastatic CRPC is lethal
Castrate Resistant Prostate Cancer - Treatment
Chemotherapy (Docetaxel, Cabazitaxel)
Secondary hormonal manipulation (Abiraterone, Enzalutamide)
Immune therapy
Radium 223
Chemotherapy - Docetaxel - Mechanism of action
Taxane - Inhibits depolymerization of tubulin, stabilizes microtubules
IV every 3 weeks
Hepatic metabolism
Chemotherapy - Docetaxel - Side effects
Cytopenias Peripheral neuropathy Alopecia Darkening of skin and nails Nausea/Vomiting Taste alteration Edema
Chemotherapy - Cabazitaxel - Mechanism of action
Taxane - Inhibits depolymerization of tubulin, stabilizes microtubules
IV every 3 weeks
Works for metastatic CRPC after docetaxel treatment has failed to halt the progression
Chemotherapy - Cabazitaxel - Side effects
Cytopenias
Diarrhea
Nausea/Vomiting
Fatigue
Abiraterone
CYP-17 Hydroxylase Inhibitor
Reduces the production of testosterone even further. Can reach undetectable levels or
Abiraterone - Effects
4 extra months overall survival
Improves pain
Improves quality of life
Improves time before needing chemo
Abiraterone -Side Effects
Blocking androgen formation leads to upstream metabolites to pile up. One of those is aldosterone.
Mineralicorticoid excess: Hypertension Hypernatremia Hypokalemia Fluid retention
Enzalutamide
Novel anti-androgen
Can block every step of the process from androgen’s extracellular binding to DNA transcription regulation
Taken PO
Enzalutamide - Effects
Improves overall survival
Improves quality of life
Improves pain
Improves time to needing chemo
Enzalutamide - Side Effects
Fatigue
Hypertension
Decreased appetite
Sipuleucel-T
Immune Therapy
Patients get leukocytes pheresed from their blood
Monocytes isolated
Monocytes exposed to growth factor and prostate cancer proteins
Monocytes re-infused as APCs that present the cancer proteins
Sipuleucel-T - Effects
Improves overall survival
Does not affect PSA or radiographic imaging
Sipuleucel-T - Side Effects
Infusion-related reactions (chills, fatigue, fever, nausea, headache)
Radium 223
Hones to osteoblastic regions, since it’s in the same family as calcium
Given IV monthly for 6 months
Improves overall survival
Improves time to symptomatic skeletal event
Radium 223 - Side effects
Low rates of myelosuppression
Minimal toxicities
