JC72 (Surgery) - Hematuria, Kidney stones, PSA, BPH, Prostate Cancer Flashcards
Renal causes of haematuria
- Glomerular:
Glomerulonephritis
2. Tubular and parenchymal: Polycystic kidney Pyelonephritis Renal infarction RCC
Classical triad of presentation for RCC
flank pain (rare), painless haematuria and palpable flank mass (rare)
Post-renal causes of haematuria
Stone: Urolithiasis
Infection: UTI (rare)
Tumor: CA bladder, prostate
Trauma: Blunt trauma, iatrogenic e.g. catherization, TURP…etc
BPH
Non-infectious cystitis: previous radiation, chemotherapy
Exercise-induced hematuria: transient
Non-renal causes of haematuria
Benign idiopathic hematuria (rare): a/w exercise, febrile illness or vaccination, familial
Bleeding tendencies (rare): hematological disorders, anti-coagulants…etc
Define gross vs microscopic hematuria
□ Gross: visibly bloody or brown urine (as little as 1mL of blood/L urine)
□ Microscopic: >3 RBC per high-power field in ≥2 of 3 freshly voided, clean catch samples
False mimics of gross and microscopic hematuria
Gross:
→ Food: beetroot (anthrocyanins) → red urine
→ Drugs: levodopa (dark), senna, rifampicin, pyridium (orange)
→ Diseases: porphyria, alkaptonuria, bilirubinuria
Microscopic:
→ Menstruation (F)
→ Dehydration (concentrates urinary RBCs)
→ Heme in urine (also have peroxidase activity)
- Myoglobinuria due to rhabdomyolysis
- Haemoglobinuria due to intravascular haemolysis
List false positives and false negatives of dipstick hematuria
False positive: menstrual blood, hemoglobinuria, myoglobinuria, dehydration
False negative: Urine with high solute gradient, High ascorbic acid level, Nitrites (UTI), pH <5.0, Proteinuria
Define significance of initial stream, terminal stream and whole stream hematuria/ Timing of hematuria
□ Initial stream → anterior urethra (distal to urogenital diaphragm)
□ Terminal stream → bladder neck or posterior urethra
□ Throughout → bladder and upper urinary tract
Differentiate extraglomerular and glomerular hematuria
- Color
- Clots
- Proteinuria
- Urine microscopy
Hallmarks of nephrological causes of microscopic hematuria
- RBC cast - RBC extravasated into tubular lumen and complex with Tamm-Horsfall protein matrix)
- Dysmorphic RBC - RBC passage through defective basement membrane with osmotic damage
- Proteinuria
List nephrological causes of microscopic hematuria
Autoimmune diseases: - Berger's disease/ IgA nephropathy - Henoch-Scholein purpura/ IgA Vasculitis (lower limb purpura, arthralgia, hypertension) - Goodpasture syndrome/ Anti-GBM disease (autoimmune disease vs kidneys and lungs) Acute interstitial nephritis (mostly from infection or allergic drug reactions) Acute nephritic syndrome Alport's syndrome (SN deafness, Lens dislocation, mutation in collagen type IV)
Define irritative and obstructive LUTS
Irritative symptoms: frequency, urgency/urge incontinence, nocturia
→ Indicates storage problem (bladder pathology)
Obstructive symptoms: hesitancy, weak stream ± straining, terminal dribbling, incomplete emptying
→ Indicates voiding problem (urethral obstruction)
Dysuria: indicates ongoing infection or inflammation → UTI
Ddx painful and painless hematuria
Painful:
→ Loin pain → pyelonephritis, renal infarct, rarer causes (RCC, renal stones, GN)
→ Ureteric colic → ureteric stone or bleeding with clot colic in upper tract
→ Suprapubic pain → cystitis
→ Perineal pain → prostatitis
Painless: classically, painless gross haematuria in >35y/o = malignancy
→ Malignancy (esp if in advanced age)
→ Renal parenchymal diseases, eg. glomerulonephritis
Risk factors for urological malignancies
□ Male, advanced age (>35y), smoker118
□ Occupational exposure to chemicals or dyes (esp jobs involving plastic, petroleum, organic solvents)
□ Drugs, eg. aristoochic acid in TCM, cyclophosphamide, analgesic abuse
□ Hx of prior urinary sympotoms: gross haematuria, urological disease, irritative urinary symptoms, chronic UTI
□ Previous surgical/ medical: chronic indwelling FB, Radiation
□ FHx of renal cell carcinoma (FHx of urothelial CA is NOT a/w ↑risk)
□ FHx of kidney diseases, eg. polycystic kidney disease, stone disease
Outline P/E for hematuria
What to look for?
Vitals: fever (pyelonephritis), HTN (nephritic syndrome)
General examination: pallor (anaemia), oedema (GN), rashes (vasculitis, CTD), bruises (bleeding tendency)
Abdominal examination:
□ Loin tenderness → renal pathology
□ Ballotable renal mass → RCC (rare), polycystic kidney, gross hydronephrosis (rare)
□ Renal bruit → renal artery stenosis (infarction)
□ Distended bladder → bladder outflow obstruction
DRE and external genitalia:
□ DRE for pelvic mass and prostatic enlargement
□ Varicocele may be due to large Lt RCC extending into renal vein
□ Urethra for urethral bleeding, clots
± other systems:
□ CVS: new murmurs (endocarditis)
□ Lungs: crackles, wheezes (Goodpasture’s syndrome)
First-Investigations for hematuria (excluding imaging)
Blood:
□ CBC: anaemia (uncommon in haematuria alone), leukocytosis (UTI)
□ RFT: renal impairment and electrolyte abnormalities
Urinalysis
1. Repeat dipstick to confirm haematuria and detect other pathologies
2. Biochemistry for protein and glucose
3. Microscopy: centrifuged
→ Confirm presence and delineate morphology of RBC
→ Detect WBC (pyuria = >5WBC/HPF) and organisms
4. Microbiology:
→ Culture and sensitivity → exclude UTI
→ EMU × AFB → exclude urinary tract TB
5. Cytology for malignant cells
2 mandatory investigations for gross hematuria
Cystoscopic exam of bladder
Upper tract imaging
List all imaging modalities for Ix of hematuria
Cystoscopy (standard)
Upper tract imaging (standard): Non-contrast CT, Ultrasound, CT urogram*, MR urogram, IV urogram
XR kidney, ureter and bladder (KUB)
Invasive:
- Retrograde pyelogram
- Ureteroscopy
Flexible cystoscopy
- Indication
- Function
- Field of examination
Indication: ALL patients with gross non-glomerular haematuria
Direct visualization of pathology, biopsy for histopathology
Field: Anterior and posterior urethra, entire bladder
USG for Ix of hematuria
- Indication
- Advantage
- Disadvantage
Indication:
Bedside screening for hydronephrosis, renal mass, renal stones
Advantage:
- Detect renal and bladder lesions
- Allow prostate size measurement
Disadvantage:
- Cannot detect ureter lesions e.g. ureteral stones
- Indirect evidence of obstruction
- No functional information
IV urogram
- Indication
- Advantages
- Disadvantages
Indication:
Upper tract imaging
Advantage:
- Direct evidence of obstruction
- Functional assessment
Disadvantage:
- Contrast anaphylaxis, nephrotoxicity
- Miss small parenchymal tumors
- No coronal and sagittal imaging
MR urogram
- Indications
- Advantages
- Disadvantages
Indications: pregnancy, contrast allergy, children, renal impairment
Advantage: No radiation
Disadvantage: image inferior to CT scan, poor images for stones, expensive
Invasive urogenital imaging
- Examples
- Indications
suspicious of serious pathology, eg. cancer, strictures
□ Eg. retrograde pyelogram: injection of contrast by catheterization of lower ureter via cystoscopy
□ Eg. ureteroscopy for brush cytology
Risk stratification system for microscopic haematuria
Investigations of low, intermediate and high risk patients
AUA microhematuria risk stratification system:
Low risk: repeat urinalysis in 6 months or Cystoscopy + USG kidneys
Intermediate risk: Cystoscopy + USG kidneys
High-risk: Cystoscopy + CT urogram
Urine cytology for malignant cells
- Recommended or not? Why?
- Specificity and sensitivity
Not recommended
- Only positive in HIGH grade cancer
- Negative in most low grader bladder cancer
- Poor sensitivity (50%) for bladder cancer
- Dependent on cytopathologist experience
List 2 iatrogenic causes of cystitis
Associated history/ diseases
Irradiation cystitis
Context:
→ Usually delayed for a few years after irradiation for pelvic malignancies
→ Seen in patient with cervical and colorectal cancer after irradiation
Haemorrhagic cystitis:
□ Context: pt with haematological malignancy with chemo
□ Cause: viral cystitis (immunocompromised), drug-related (cyclophosphamide, ifosfamide)
List primary renal neoplasms
Renal cell carcinoma (80-85%) from renal tubular cells
Urothelial carcinoma (~8%) from renal pelvis
Nephroblastoma (Wilms’ tumour, 5-6%) from embryonic nephrogenic tissues in children
Others (rare): oncotyoma, collecting duct tumours, renal sarcomas
Renal cell carcinoma
- Risk factors
Smoking
HTN and obesity
Acquired PKD (chronic dialysis) Toxin/ carcinogen exposure: e.g. asbestos, cadmium, aspirin, NSAID, chemotherapy, kidney irradiation
Medical diseases: Chronic Hep C, Sickle cell disease, Kidney stones
Genetic:
- Von Hippel-Lindau disease (VHL)
- Hereditary papillary RCC (HPRCC) with mutated MET protooncogene
- Tuberous sclerosis complex
Renal cell carcinoma
Clinical presentation: local, regional and systemic manifestations
Asymptomatic in early stages
Local symptoms: classical triad of flank pain + painless haematuria + renal mass only in <9%
Regional venous involvement:
→ Scrotal varicoceles (*classically left-sided, kidney tumour obstructing gonadal vein)
→ IVC involvement: LL oedema, ascites, Budd-Chiari syndrome, pulmonary embolus, dilated veins on abdomen
Systemic:
→ Metastatic symptoms: commonly lungs, LNs, bone, liver, brain
→ Constitutional symptoms
Renal cell carcinoma
Clinical presentation: local, regional and systemic manifestations
Asymptomatic in early stages
Local symptoms: classical triad of flank pain + painless haematuria + renal mass only in <9%
Regional venous involvement:
→ Scrotal varicoceles (*classically left-sided, kidney tumour obstructing gonadal vein)
→ IVC involvement: LL oedema, ascites, Budd-Chiari syndrome, pulmonary embolus, dilated veins on abdomen
Systemic:
→ Metastatic symptoms: commonly lungs, LNs, bone, liver, brain
→ Constitutional symptoms
→ Paraneoplastic syndrome
Renal cell carcinoma
Histological subtypes
Paraneoplastic symptoms associated
Subtypes:
Clear cell (70%)
Papillary (15%)
Chromophobe (10%)
- Anaemia (29-88% advanced ds): disproportionately severe, ACD pattern
- Pyrexia of unknown origin (20%): intermittent, a/w night sweats, anorexia, weight loss, fatigue
- Hypercalcaemia (15%) due to production of PTHrP or lytic bony mets
- Polycythaemia (1-5%) due to production of EPO
- Others: hepatic dysfunction (Stauffer syndrome), AA amyloidosis,
thrombocytosis, polymyalgia rheumatica, hypertension (renin)
Renal cell carcinoma
First-line investigations and typical findings
Contrast CT abdomen (Renal protocol)***
- Structure: complex cystic, thickened/irregular walls
- Contrast: 20-70HU ± necrosis, calcification on plain film, hyperenhancing (>10-15HU) on post-contrast phase
Ultrasound: diff. renal mass and cysts
- Cystic cancer: irregular, thickened walls, complex structure with septa
(CT-guided core biopsy: traditionally NOT done due to risk of tumour seeding)
Ddx benign and malignant renal masses
Benign masses:
→ Angiomyolipoma: fat attenuation, a/w Tuberous sclerosis
→ Oncotyoma
→ Simple renal cyst
→ Infectious, eg. renal abscess, focal pyelonephritis
Malignant:
→ Renal metastasis
→ Lymphoma
→ Other primary renal neoplasm, eg. Wilm’s tumour, sarcoma, urothelial carcinoma
Renal cell carcinoma
Localized RCC treatment options
- Surgical resection: Partial or Total/ radical nephrectomy
- Ablative therapies: Radio-frequency ablation, Cryotherapy
Renal cell carcinoma
Metastatic RCC treatment options
Local: Cytoreductive nephrectomy, Metastasectomy
Systemic:Targeted therapy options
Immune checkpoint inhibitors: Eg: nivolumab (anti-PD-1), ipilimumab (anti-CTLA4)
Antiangiogenic therapy:
- Small molecule TKIs, eg. sunitinib, pazopanib, cabozantinib, axitinib, sorafenib
- Anti-VEGF mAb, eg. bevacizumab
mTOR inhibitor, eg. temsirolimus, everolimus
Urothelial carcinoma
Sites of involvement
S/S
Dx and Ix
Most commonly arise from bladder, other sites of urinary tract incl renal pelvis, ureter, urethra (less common)
S/S: haematuria (70-80%), obstructive flank pain (20-40%), LUTS, constitutional Sx (<10%)
Dx: urinary tract imaging, ureterorenoscopy + cystoscopy
Bladder cancer
Major histological subtypes
Urothelial (90%) arise from transitional cell epithelium of bladder
Non-urothelial (<5%):
→ Adenocarcinoma (1%) from remnant of urachus in bladder fundus/ metastasis
→ SCC (7-9%) from metaplasia due to chronic irritation by stones or infection
Secondary, eg. colon, rectum, prostate, uterine cervix
Risk factors of bladder cancer
Smoking: most important risk factor
Occupational carcinogen exposure
Drugs/toxins:
→ Aristolochic acid in TCM
→ Cyclophosphamide
→ Chronic analgesic abuse
Prior urological conditions:
→ Chronic cystitis (SCC)
→ Chronic urinary catheter placement for >10y
→ HPV infection
→ Upper tract urothelial CA
→ Bladder augmentation: a/w ~1% risk of CA bladder
→ RT to pelvis
List occupational risks a/w Bladder cancer
Examples: paint components, polycyclic aromatic hydrocarbons, diesel exhausts, benzene, hair dye, aniline-containing dyes,…
Occupations affected: textile workers, dye workers, tyre rubber and cable workers, petrol workers, leather workers, shoe manufacturers and cleaners, painters, hairdressers, lorry drivers, drill press operators, chemical workers, rodent exterminators and sewage workers
Bladder cancer
Clinical presentation
Painless gross haematuria (90%)
- Typically intermittent and present throughout micturition
LUTS: commonest in carcinoma in situ
→ Irritative (~1/3): frequency, urgency ± incontinence, nocturia
→ Obstructive (less common): strangury, intermittence, weak stream, incomplete voiding
Pain: usually indicates at least muscle-invasive disease
→ Flank pain
→ Suprapubic pain
Constitutional symptoms
Bladder cancer
Invasion/ metastatic complications
Complications:
Local due to fistula formation by extension to other organs
- Vesicocolic fistula → pneumaturia
- Vesicovaginal fistula → incontinence
Systemic due to metastasis
Bladder cancer
First-line investigations
Urinalysis for microscopy (confirm haematuria)
Urine cytology ×3: very insensitive (34%) but very specific (>98%)
Cystoscopy + Bx: gold-standard for diagnosis + staging
- flexible cystoscopy ± fluorescence
Urinary tract imaging: CTU, IVU, USG kidneys/bladder
Transurethral resection of bladder tumor (TURBT)***: for dx + staging ± Tx
- histopathology (final dx) + assess tumour invasion (T staging) [imaging may not be accurate] ± as primary therapy (in non-muscle invasive disease)
Non- Muscle invasive bladder cancer
- 2 subgroups with high recurrence and progression rate
- Treatment options
High risk subgroups:
- T1HG disease
- Cis disease
Tx:
- Intravesical BCG: instillation of BCG + NS into bladder via catheter
- Intravesical chemotherapy: mitomycin C (MMC), gemcitabine
- Radical cystectomy with pelvic LNectomy + urinary diversion
Muscle invasive bladder cancer
- Treatment options
Radical cystectomy (RC) with urinary diversion + pelvic LNectomy + Neoadjuvant chemotherapy: cisplatin-based
Multimodality treatment (MMT) = maximal TURBT + chemoirradiation
Metastatic/ unresectable bladder cancer
- Treatment option
Metastatic or unresectable bladder cancer (stage IV):
→ Cisplatin-based chemotherapy (1st line): PGC, GC or MVAC ± G-CSF
→ Immunotherapy (2nd line): pembrolizumab, atezolizumab
→ Other chemotherapy (2nd line): carboplatin-based, vinfluine
Upper tract urothelial carcinoma
- Risk factors
- Standard Tx
RF:
- Smoking
- Aristolochia fangchi (Chinese herb nephropathy)
- Arsitolochic acid (Balkin endemic nephropathy)
- Arsenic poisoning (Blackfoot disease)
- Hereditary: Lynch syndrome, HNPCC
Tx:
- Nephroureterectomy
- Partial ureterectomy with reconstruction
Urolithiasis
Risk factors
Diet:
- Low fluid
- Excessive calcium supplement
- Dietary oxalate: Tea, spinach, beets…etc
History of prior stones
Family history of stones
Recurrent UTI (struvite stone)
Medical:
- Malabsorptive conditions
- Urinary pH change - chronic diarrhea, T1RTA
- DM, obesity, HTN
- Gout
- Crohn’s
- Hyperparathyroidism
5 compositions of kidney stones, respective morphology
- Calcium (70%) - Calcium oxalate, phosphate: Irregular mulberry stones with sharp projections
- Urate (5%) - hard, smooth, ligh brown
- Struvite (1%) - Smooth, dirty white, Staghorn
- Cystine (2%) - multiple, very hard
- Xanthine and pyruvate stones
Struvite kidney stones
Risk factors
Presentation
Risk factors:
Upper urinary tract infection with urease-positive organism (eg. Proteus, Klebsiella): produces ammonium (from urea) → ↑pH→ ppt of NH4PO4
Prior oxalate stones: predisposes to infection → forming mixed stones
Presentation:
Rarely classical renal colic,
usually UTI, mild flank pain or haematuria with alkaline pH (>8)
Calcium renal stones
Risk factors
Clinical presentation
Risk factors:
- High Calcium: supplement, hyperPTH, chronic acidosis, idiopathic or familial
- High Oxalate: dietary oxalate, bile acid malabsorption, idiopathic/primary
- Low citrate: chronic metabolic acidosis, high animal protein diet, idiopathic/primary
- High urine pH: e.g. urease- producing bacteria UTI
Presentation:
Early, symptomatic, sharp flank pain due to sharp shape of stones
Urate renal stones
Risk factors
Radiological feature
↑urine uric acid: hyperuricaemia, uricosuric drugs
↓urine pH (5-5.5): DM/metabolic syndrome, IEM, distal RTA (↓pH → ↑ppt of uric acid)
Radiolucent stones, usually seen as filling defects on CT
Pathogenesis of different types of renal stones
- Calcium/ urate/ cysteine
- Struvite
- Drug-induced
Calcium/ urate/ cysteine:
- Supersaturation of urine constituents»_space; precipitate and form crystals
- Calcium phosphate crystals form in renal medullary interstitium first and forms Randall’s plaque, more calcium compounds deposit on the nidus
Struvite: urinary tract infection with urease-positive organisms, produce ammonia
Drug-induced: precipitation of medication or their metabolites in urine
Clinical presentation of renal stones
Obstructive symptoms: result in loin pain or ureteric colic
→ Occurs only when lodging at pelviureteric junction (PUJ), ureter and at bladder neck
→ Site of obstruction determines location of pain
Ulcerative symptoms → haematuria (gross or macroscopic haematuria)
Predisposition to infection: pyelonephritis, pyonephrosis, urosepsis
Passing of stones: painful
Compare the presentation between renal, ureteric and bladder stones
Renal: usually asymptomatic if only in renal calyces (only painful when pass distally)
→ Renal pain occur if stone lodged in PUJ, hydronephrosis ± pyonephrosis
Ureteric stones: usually symptomatic
→ Ureteric colic: agonising pain a/w N/V
→ Radiates from loin downward around waist obliquely across abdomen just above inguinal ligament to genitals
→ Gross or microscopic haematuria (95%)
→ Bladder irritation (in distal ureter): dysuria, urgency, frequency
Bladder stones: usually asymptomatic
→ Irritative symptoms: frequency, urgency
→ Obstructive symptoms: sometimes BOO
→ Haematuria: esp occur at end of micturition
Renal stone management
Stone factors
Patient factors
Surgeons factors
Stone: Size, number, composition, unilateral/ bilateral
Patient:
Anatomy, Fitness for anesthesia, bleeding tendency, susceptibility for radiation, renal function
Surgeon: technology, expertise
First-line investigations for renal stones
General: CBC, CRP ± clotting if surgical procedure is planned
RFT: bilateral obstruction only
Calcium and urate
Imaging:
Non-contrast CT Abdomen + Pelvis***
X-ray KUB (screening)
USG kidney/bladder (preferred in pregnancy or children)
CT urogram: gross hematuria or renal mass
First-line emergency treatment options for renal stones
Supportive Tx:
→ Pain control: NSAIDs (1st line), opioids (hydromorphine, pentazocine, tramadol)
→ α-blockers can help reduce recurrent colic
→ Abx if complicated by infection
Urgent decompression by JJ stent (under fluoroscopy) or percutaneous nephrostomy (PCN)
→ Indication: uncontrolled sepsis, progressively worsening renal function,
Conservative Tx and medical expulsion therapy (MET): wait for spontaneous passage with supportive treatment
Definitive treatment options for renal stones
Extracorporeal shock wave lithotripsy (ESWL): US/XR-guided shock waves aimed at stones → crystalline stones disintegrate under impact of shock waves
Percutaneous nephrolithotomy (PCNL): flexible cystoscopy for ureteral cannulation → nephroscope passed into kidney by percutaneous technique → retrieval of stone in whole or in fragments after laser/USG/electrohydraulic lithotripsy
Ureterorenoscopy (URS): for lithotripsy (ureteric) or retrograde intrarenal surgery (RIRS) (renal): ureteroscope introduced transurethrally across the bladder into the ureter to remove stones directly or after laser lithotripsy
Treatment options for different sizes of renal stones
10, 10-20, 20mm?
<10mm: ESWL
10-20mm: ESWL for non-lower pole or PCNL for lower pole
> 20mm: PCNL
Medical expulsive therapy for renal stones
Supportive: ask pt to strain urine, adequate hydration (IV not necessary), observation
Oral chemolysis, eg. alkalinization of urine (uric acid stone) or acidification (struvite stones)
MET: best for distal ureteric + >5mm stones (presence of large numbers of α1-receptors in distal ureter)
→ Regimen: α-blocker tamsulosin
Ureteric stones
Choice of therapy for upper and lower ureteric stones depending on size?
Upper:
<5mm = watchful waiting (WW)
5-10mm = URSL/ ESWL
>10mm = URSL
Distal:
<5mm = WW
5-10mm = URSL
>10mm = URSL
PSA
- physiological function
- Production process
Production: produced as proenzyme (proPSA) by prostatic acini → active PSA produced by removing propeptide → soon inactivated into inactive PSA by proteolysis
Physiological function: a protease that dissolves the coagulum (fibronectin, semenogelin) that traps sperm → release sperm in vagina after ejaculation
Serum PSA
- Half-life
- Process of release into serum
- Different forms of PSA in serum
Release into serum: half-life = 3 days (takes 7 cycles to clear → check PSA ≥3-4w after acute episode)
Active PSA diffuse directly into circulation → become rapidly bound by protease inhibitor (complexed PSA)
Inactive PSA diffuse into circulation → form free portion of PSA in blood
Elevated serum PSA in cancer
Pathophysiology
In prostate cancer, there is disruption of basement membrane
PSA release due to disruption of cellular architecture within prostate
Destroyed basal cells → ↑release of PSA into blood together with its precursors (proPSA)
Less proteolysis → ↑release of active PSA into blood → Lower %free PSA
Causes of elevated PSA
□ CA prostate: cancer tissue produces serum PSA 10× that of benign tissue
□ Benign prostatic conditions:
→ BPH: due to ↑prostate vol and ↑PSA/unit vol
→ Prostatitis ± infection
□ Trauma or mechanical stimulation:
→ Procedure-related: biopsy, TURP, prostate massage, PR exam, cystoscopy
→ AROU: important to defer PSA for 2-6w after acute AROU
→ Other mechanical stimulation: after ejaculation, perineal trauma, vigorous cycling
Natural, non-modifiable determinants of basal PSA level
Age: Increase 0.04ng/mL per year
Race: Black ethnicity has higher, White ethnicity has lower
Prostate volume
Traditional/ arbitrary cut-offs for serum PSA levels and risk of prostate cancer
Which level indicates prostate biopsy?
<4ng/mL → considered normal (high false-negative rate)
4-10ng/mL → 15-20% risk of CA prostate → consider biopsy
> 10ng/mL → >50% risk of CA prostate → biopsy definitely indicated
Additional PSA test metrics with higher diagnostic accuracy
- Age-specific PSA
- %free PSA = free PSA / total PSA
- PSA velocity = rise in PSA level / year
- PSA density = PSA / estimated volume of prostate (on TRUS)
- Prostate health index (PHI)
Other indices:
→ PSA doubling time (PSADT)
→ PSA transitional zone density
→ Supersensitive PSA
Define cut-off values for Age-specific PSA
% free PSA
Principle function of this metric
%free PSA = free PSA / total PSA
→ Principle: CA prostate gives ↑bound PSA than free
→ Finding: no agreed cutoff, usually used for stratification of ‘gray zone (4-10ng/mL)
Non-PSA tests for diagnosis of prostate cancer
PCA3 test: gene-based urine test for PCA3/PSA mRNA ratio
→ Principle: PCA3 highly over-expressed (66×) in almost ALL CA prostate, but not in benign diseases
Fusion gene (TMPRSS2-ERG) detection in urine sample of pt w/ CA prostate
Circulating tumour cells in metastatic disease
Genomic tests with scoring for aggressiveness of tumour
Risks of over-diagnosis and over-treatment of high serum PSA levels
From excess medication, protoscopy, biopsy, surgery…
erectile dysfunction, incontinence, bowel dysfunction, sepsis
Prostate cancer
Risk factors
Non-modifiable: Ethnicity: Blacks > Caucasians > Asians Old age Family history Hereditary mutations: eg. BRCA1/2, ATM, CHEK2, Lynch syndrome (HNPCC)
Hormonal: growth stimulated by androgens
Obesity
Outline history taking and P/E for elevated PSA
- Intention of PSA testing
- True elevation or not: r/o confounding factors - prostatitis from STD, iatrogenic damage, history of BPH and Prostate CA, Perineal injury…etc
- Symptoms suggestive of prostate cancer: Hematuria, Bone pain, Lower limb weakness, Weight loss
P/E:
- General: signs of uremia (lower urinary tract obstruction causing obstructive nephropathy)
- Metastatic symptoms, incl. lower limb weakness, weight loss, spinal pain (Batson plexus)…
- Abdominal: ballotable kidneys, bladder distension (lower urinary tract obstruction)
- DRE:
- Anal tone (nerve invasion)
- Size, consistency of prostate
- Surface, induration of prostate/ median groove present or not
Follow-up investigations after elevated serum PSA
- Prostate biopsy after r/o confounding factors
2. Spurious high PSA should follow-up with PSA test 4 weeks later
Prostate cancer
Major histological subtype
Pre-malignant lesions subtypes
Adenocarcinoma (95%): 70-80% arise from peripheral zone
Other variants:
eg. ductal adenocarcinoma, mucinous adenocarcinoma, signet cell CA, small cell CA
Premalignant lesions: often identified in TURP for BPH or Bx
→ Prostatic intraepithelial neoplasia (PIN): architecturally benign prostatic acini and ducts lined by atypical cells
→ Others: atypical adenomatous hyperplasia, intraductal carcinoma of prostate
Prostate cancer
Clinical presentation
Asymptomatic (80%): elevated PSA or abnormal DRE or on TURP specimens
Urinary symptoms: → LUTS → Haematuria or haemospermia (<1%) → Obstructive uropathy / renal failure due to ureteric/trigone invasion → Malignant priapism
Metastatic symptoms:
→ Vertebral metastasis (commonest): bone pain, pathological fractures, cord compression, hyperCa (via Batson’s plexus)
→ Other metastasis:
- Direct: stromal invasion through prostatic capsule, urethra, bladder base, seminal vesicles
- Lymphatics: sacral, iliac, para-aortic nodes
- Haematogenous: lungs, liver, bones
DRE for prostate cancer
- Features elicited
DRE: insensitive (cannot detect small cancers and cancer in other areas) and non-specific (30% PPV only)
→ Asymmetric induration
→ Frank hard irregular nodule fixed to pelvic wall
→ Obliteration of median groove
→ Theoretically can obtain T staging via DRE
Prostate biopsy
- Indications
- Approaches (3)
- Process of biopsy
Indication:
→ Abnormal DRE suggestive of CA prostate
→ Elevated PSA if would affect Tx decision (>10y life expectancy)
→ Clinically metastatic disease if diagnosis doubtful
Approach:
- Transrectal (TR): traditional, worse infection rate and access
- Transperineal (TP) **: newer approach, allows access to all areas + better cancer detection rate
- MR/USG Fusion-Targeted Biopsy **
Process:
- Antimicrobial prophylaxis, topical/ local periprostatic anesthesia
- Imaging guidance: majority TRUS-guided
- 12-core or 26 core systemic biopsy with labelling from different areas of prostate
- Targeted biopsy only done after imaging localisation
Prostate biopsy
Complications
Fever (1/4): common despite prophylactic Abx
Bleeding (1%): PR bleed, haematochezia, haematospermia, haematuria
Urosepsis (1%)
Transient LUTS
Rare, serious complications:
Vasovagal syncope
Acute urinary retention
Post-biopsy infection
Post-prostate biopsy infection
Definition
Pathophysiology
Infection rate and ICU care rate
Fever +/- chills and rigor as a result of prostate biopsy
Within 24hours to 1 week of biopsy
Associated with septic shock and multi-organ failure
Pathophysiology:
- Local bacteria in rectum enters systemic circulation during transrectal biopsy»_space; resistant bacteria triggers sepsis and SIRS
- Biopsy complicated by AROU»_space; uropathogens cause sepsis
Post-biopsy infection rate = 4.3%, of which 11% needed ICU care
Multiparametric prostate scan
- Mechanism
- Benefit
- Targeted biopsy using multi-sequences of MRI and real-time TRUS imaging
- Higher cancer detection rate, lower sepsis rate
Prostate biopsy
- 2 approaches associated with higher cancer detection rate and lower sepsis rate
Multiparametric MRI prostate
Transperineal Ultrasound guided biopsy (TPUS)
Define metrics for Clinical staging of prostate cancer (c.f. pathological staging)
Function of clinical staging
Clinical staging:
- Nomograms: pre-treatment parameters to predict possibility of ECE, LND, SVI
- Serum PSA
- Gleason scores
- Clinical T stage by DRE
- Positive and negative biopsy core numbers - Additional Radiological imaging (optional)
- Pelvic lymphadenectomy (optional)
Function:
- Risk stratification of prostate cancer - predict prognosis and guide Tx
- Extent of disease before treatment
Outline the clinical risk stratification system for prostate cancer
D’Amico stratification system
Low risk:
- cT1 to T2a and PSA =< 10ng/mL and Gleason score < 6
Intermediate risk:
- cT2b and/or PSA 10-20ng/mL and/or Gleason score 7
High risk:
- cT2c or PSA >20ng/mL or Gleason 8-10
Gleason score
- Function
- System for scoring
Function: quantify prostate cancer’s clinical behavior and mortality rates
Scoring: based on architectural features of CA cells from histological samples
primary (most prevalent histological pattern) + secondary (2nd most prevalent pattern)
Example: composite GS = 3 + 4 (or 7) = primary pattern 3, secondary pattern 4
Additional radiological imaging for clinical staging of prostate cancer
- 2 aims
- 3 modalities
Aims:
- Accurately stage disease, r/o metastasis
- Treatment planning
Modalities:
- R/o metastasis: Whole body bone scan (Tc-99m methylene disphosphonate); PSMA-PET scan (antigen against prostate-sepcifc-membrane-antigen PSMA)
- Treatment planning: Multiparametric MRI scan
MRI prostate
- Features attainable from scan?
Size of prostate
Prostate configuration
Invasion:
- Extra-prostatic invasion
- Seminal vesicle invasion
- Rectal wall
- Lymph node
- Pelvic bone
Prostate cancer
Treatment options
Indication for each option
Treatment for recurrence
Localized/ locally advanced
- Radical prostatectomy
- External Beam Radiotherapy
Advanced, systemic, metastatic:
- Combination therapy (Androgen-Deprivation therapy (ADT) + docetaxel or abiraterone + prednisolone)
- ADT monotherapy/ Surgical or medical castration
- Cytotoxic chemotherapy: Docetaxel, Abiraterone
- Androgen-targeted agent
Recurrence:
- Post RARP BCR: Salvage RT
- Post-RT recurrence: Salvage RARP
Radical proctectomy
- Extent of excision
- Technique
- Complications
Involves:
- Resection of prostate, prostatic urethra, seminal vesicles, part of ureter
- ± ePLND: obturator fossa, external iliac up to aortic bifurcation
Technique: nerve-sparing technique to prevent ED
Complications:
- General: GA risk, mortality
- Erectile dysfunction
- Urinary incontinence , bladder neck (anastomotic) strictures
- Others: bleeding, rectal injury, infection
Radiotherapy for prostate cancer
- Indications for local and metastatic PC
- 2 forms
- Complications
Indications for local:
- Localized or locally advanced
Indications for metastasis:
- Urgent treatment for spinal cord compression by tumor
- Pathological fracture with fixation surgery
- Local symptom control, pain relief
Forms: EBRT/IMRT (common) or interstitial brachytherapy (rare)
Complications:
- Erectile dysfunction: up to 30%
- Cystitis, proctitis: up to 10%
Treatment options for locally advanced prostate cancer
Radical proctectomy + Post-operation radiotherapy/ Androgen-deprivation therapy (ADT)
Neoadjuvant androgen-deprivation therapy + radiotherapy
Androgen deprivation therapy for prostate cancer
- Rationale/ mechanism
- Modalities
- Treatment for castration-refractory PC
Rationale: >90% of prostate tumour has testosterone-dependent growth
→ Suppression of testosterone secretion or inhibiting its effect at androgen receptor → ↓growth of prostatic tumour
Options:
- Surgical castration by bilateral orchiectomy
- Medical castration by hormonal therapy:
- GnRH agonist, eg. Zoladex (goserelin), Lupron (leuprolide)
- GnRH antagonist, eg. degarelix
Refractory:
- Cytotoxic chemotherapy
- AR-targeted agents (enzulutamide, abiraterone)
- Radium-223
- Sipuleucel-T
S/E of androgen-deprivation therapy
Sexual dysfunction in majority: loss of libido in first few months, followed by ED
Osteoporosis and bone fractures: should measure baseline BMD
- Tx: lifestyle modification, osteoclast inhibition (bisphosphonate, denosumab)
Vasomotor symptoms, eg. hot flashes, nausea, sweating
↓lean body mass, ↑body fat, ↓muscle strength
↑risk of cardiovascular disease and ↑insulin resistance
Population-wide PSA screening
Consensus?
Provisions of PSA screening?
No consensus
Screen if:
- Shared decision between patient and doctor
- Benefits and shortcomings of PSA testing in asymptomatic patient explained clearly before testing
