Week 2 - Prostate, Renal, Urinary Tract

Question 1

Outline urinary tract infections (UTIs).

Answer 1

• Urethritis, cystitis, prostatitis, pyelonephritis,
• 90% by Escherichia coli*, recurrence (40%).
- Recurrent UTIs common.
• Uropathogenic strains (UPEC). P fimbriae or pili - bind to urothelium.
- Caused by uropathogenic strains of E. coli - P fimbriae or pili specialised in these bacteria bind to urothelium - grow in urinary tract.
• Colonise colon spread to urinary tract.
- Due to close anatomic location.
• Staph., Saprophyticus, Proteus, Klebs., Enterococci, Ureaplasma - Rare.
- Staph, Saprophyticus ~5%.
- Other bacteria ~5%.
• Commonest entry point through urethra but can also enter through blood supply (systemic spread - less common).

Question 2

Identify the clinical features of UTIs.

Answer 2

• Females, anatomy, sexual activity, urinary tract abnormality/obstructions e.g. stones, tumours - all predispose to infections.
- Females more common due to short urethra and closer proximity to colon.
• Clinically presents as dysuria, low grade fever (or no fever), frequency, urgency.
• Flank pain, high fever - pyelonephritis.
- When present with high fever and flank pain - more typical of pyelonephritis.

• Complications - E. coli septicaemia* endotoxins → DIC*, prostatitis, prostatic abscess.

• E. coli septicaemia common.
• Endotoxin raised causing DIC.

Question 3

Outline the diagnosis of UTIs.

Answer 3

• Blood - leukocytosis - neutrophilia.

• Midstream clean catch urine specimen*
- Urine usually cloudy and see RBCs after centrifugation.

• Dipstick - leukocyte esterase and nitrite +ve - suggestive of infection.
- Leukocyte esterase only present in neutrophils so if the patient has lymphocytes, it won’t show up on the dipstick.

• Urine - pyuria, neutrophils, bacteria.
- Urine dipstick and MCS.

• MacConkey agar* selective, indicator media.
- 24h, 37˚C, aerobic environment, pink colony (lactose ferment → acid → pH indicator).
• Lactose in agar plate with pH indicators.
• E. coli forms pink colonies - ferment the lactose and release acid → pH indicators in the medium turn bright pink.
- Beta-haemolytic on blood agar.

Microscopy gram stain:
• Gram negative (pink) Bacilli, lactose fermenting.
• Also Enterococci.. and Klebsiella ferment lactose.
- Difficult to distinguish between bacteria - many tests to confirm/differentiate bacteria.
• Further tests to confirm - E. coli → urease -ve (unlike Klebsiella and Proteus +ve).
- E. coli urease negative and Klebsiella and Proteus urease positive.

Question 4

Describe the structure and function of the prostate.

Answer 4

• Periurethral, Fibromuscular gland.
• Function - semen, acid phosphatase. Sperm nutrition.
- Delivering semen and protecting the sperm with its nutrition. Important substance is acid phosphatase and prostate specific antigen.
• Hormone response - androgens, testosterone.
- Prostate responds to hormones - proliferative hormones.
• Prostatitis (infection/inflammation), BPH and cancer (most important clinically).
- Major disorders.
• Central zone - BPH.
- Central zone of prostate involved in BPH. Peripheral zone in cancer.
• Peripheral zone - cancer.

• Transitional zone in periuretheral area is the commonest site of BPH.
• Cancer usually located in peripheral zone - importance of DRE - can palpate hard gritty stoney swelling of cancer.
• BPH smooth firm enlargement.

Question 5

Describe the normal prostate histology.

Answer 5

1. Fibromuscular stroma.
   • Muscles.
2. Glands double layer epithelium.
   • Basal layer - flattened epithelium.
   • Columnar epithelium - secretory epithelium - secrete major component of semen.
3. Secretions (corpora amylaceae).
   • Protein aggregates - part of semen secretions.

Question 6

Identify the disorders of the prostate.

Answer 6

1. Inflammations - infections - prostatitis.
2. Benign Prostatic Hyperplasia*
   • Starts in central periuretheral area, benign tumour, smooth, encapsulated - enlarges into the bladder because this is the only place that the gland can easily break through (the rest of the area is fibromuscular - hard). Grows into bladder obstructing urinary opening (internal meatus).
3. Neoplasms - prostatic carcinoma*
   • Peripheral zone posteriorly - hard gritty tumours → DRE.

Question 7

Outline the 4 types of prostatitis.

Answer 7

• Inflammation, oedema, rectal pain, obstruction/dysuria.
- Pain and discomfort in prostatic area/rectum, obstruction to urinary flow - patient tries to pass urine but causes pain due to inflammation.

4 major types:
• Acute suppurative prostatitis 5%
- E. coli, rarely Staph or N. gonorrhoeae.
- 5% of cases (not common) commonly due to E. coli.

• Chronic non bacterial AKA chronic pelvic pain sy.

• 90% chronic inflammation, symptoms, no pathogens.
• Most common.

• Asymptomatic inflammatory prostatitis.

• Only WBC, no symptoms, no pathogens.
• Rare - not very common.

• Granulomatous prostatitis.

• BPH, infarction, post TURP, idiopathic, TB or allergic (eosinophilic).
• Usually post surgery or idiopathic, TB, allergic - rare.

Question 8

Describe the diagnosis and morphology of prostatitis.

Answer 8

Diagnosis:
• Fluid examination after prostatic massage.
• Needle aspiration study of prostatic tissue (fine needle aspiration biopsy).

Morphology:
• Microscopy - oedema and plenty of inflammatory cells in between the gland.

Question 9

Outline benign prostatic hypertrophy (BPH).

Answer 9

• Non-neoplastic, androgen → hyperplasia. Castration → no BPH.

• Non-neoplastic, androgen induced hyperplasia (excess hormones or excess response to the hormones) - hyperplasia following androgen stimulation.
• Prostatic cancer and prostatic hyperplasia in old age where complete therapy is contraindicated → patients undergo castration - reduces BPH symptoms.

• Testosterone → DHT → hyperplasia.
- Testosterone gets converted to DHT (through the enzyme 5α reductase) → acts on nucleus to release growth factors → growth factors stimulate cells to divide → hyperplasia.

• Common, 75% of men 70-80 years. Only few symptomatic.
• Involves periurethral transitional zone.

Morphology:
• Nodular hyperplasia of glands and stroma (like in breast, thyroid etc.)
- Hormone induced hyperplasia.
• Stromal and gland hyperplasia. Cystic glands, secretions, double layer maintained.
- Glands are cystic with secretions and maintaining the normal double layer epithelium.
• BPH is NOT a precursor to carcinoma.
- Patients may have BPH and prostatic cancer but BPH is not a known precursor of carcinoma.

Question 10

Describe the morphology of BPH.

Answer 10

Gross: grey white, nodular hyperplasia, periuretheral zone.
Microscopy: hyperplastic cystic glands, normal double layer epithelium.

Gross:
• Periuretheral zone markedly enlarged with nodules.
• Cut section - white nodules compressing urethra.
• Well demarcated.
• Enlarges into the bladder - explains all the clinical features. When patients try to force urine → blocks more.

Microscopy:
• Nodules of hyperplastic glands that are cystic and with secretions.
• Hyperview - plenty of glands, stroma outside, double layer epithelium.
• Double layer important microscopically because in cancer, it will be a single layer.

Question 11

Identify the complications of BPH.

Answer 11

• Enlarged prostate.
- Enlarged prostate with the formation of the median lobe ball valve. Median lobe of prostate becomes a ball obstructing the opening.
- Marked thickening of the bladder wall.
- Prominent mucosal folds.
- Retention of urine leading to recurrent infections - inflamed mucosa, stone.
• Median lobe - ball valve*

1. Urinary obstruction.
2. Urine retention
3. Inflammation/infections
4. Hypertrophy of wall.
5. Mucosal trabeculations (due to hypertrophy of bladder wall).
6. Urolithiasis - stones (due to retention of urine - usually triple phosphate stones).

Question 12

Outline prostate cancer.

Answer 12

• Adenocarcinoma, most common male cancer, elderly (>50y).
- Most common male cancer, significantly high compared to all other cancers.
- Although cases of prostate cancer are high, death due to cancer is low.
• But second common cause of cancer death in males (next to lung).
• Many prostatic carcinomas are small and clinically insignificant (or do not progress).
• If tested, seen in many elderly dying of other causes* (incidental cancer).
- Find many prostate cancers which were not identified before.
• But some are rapidly fatal, no specific test to detect early*
• Population screening of PSA - controversial - now discouraged*
- Only available test is PSA but this is controversial. Lack of specificity.
• % of free PSA to total PSA is lower in men with prostate cancer.

Question 13

Describe the morphology of prostate cancer.

Answer 13

Gross:

1. Irregular, stony hard (hard, gritty/stoney)
2. Peripheral/posterior.

• Common in the posterior part/peripheral zone - near rectum → DRE. BPH grows anteriorly into bladder, cancer grows posteriorly.
• Hard gritty tumours without much haemorrhage or necrosis (unlike other cancers).
• When it spreads - starts as multiple nodules initially within capsule → later spreading out.
• Peripheral zone → invades capsule of prostate to extend beyond it to the surrounding structures such as the seminal vesicle.

Question 14

Explain the aetiopathogenesis of prostate cancer.

Answer 14

• Aetiology - ?Androgens, genes (ETS, PTEN) and ?env/diet (Not BPH).

• Like many cancers, unknown - androgens have been implicated.
• Castration decreases swelling/tumour growth → androgen dependent.
• Recent discovery of mutations in tumour suppressor genes - ETS, PTEN → provided more understanding.
• Environmental and dietary factors have also been implicated but not proven.
• BPH is not a known precursor of cancer although both disorders occur in older age.

• Patients (54%) lacking both PTEN and ETV had ‘good prognosis’ (85.5% alive at 11 years)* - localised cancer without killing
- Significant proportion of prostatic cancers do not kill.

• Pathogenesis - dysplasia → PIN → cancer.
• Same as other epithelial malignancies.
• Initial irritation → dysplasia → mutations → transforming into cancer but localised - in situ cancer (prostatic intraepithelial neoplasia - PIN) → later progresses to cancer.
• Normal (double layered epithelium) → PIN (mutations and cancer initially remain within the gland ) → Invasion → Metastasis.

Question 15

Outline prostate specific antigen (PSA).

Answer 15

• PSA* proteolytic enzyme, liquefies semen. Not cancer specific. Normal serum PSA <4.0ng/L. Increase in prostate damage/malignancy.
- Prostate specific antigen - most commonly used diagnostic marker.
- Proteolytic enzyme - functions as a liquefier.
- Not cancer specific - part of normal prostate. Simple prostatic massage can increase PSA levels.
• Lower in non malignant conditions but significant overlap*
- Issue of using PSA as a screening test.

Question 16

Describe prostate cancer microscopy.

Answer 16

1. Pleomorphic cells.
2. Single layer glands.
3. No secretions.

• Microscopic features very characteristic unlike other cancers.
• Normal - irregular gland with papillary projections, double layer (inner columnar cells and outer flat cells) with secretions.
• Cancer - more irregular looking (pleomorphic cells), single layered glands.
• Hyperview
- Normal - regular arrangement of nuclei at the base, functional.
- Cancer - irregular nuclei, clustering, single layer glands/irregular clusters, no flattened basal cells, non-functional (no vacuolations).

Question 17

Outline the Gleason scoring for prostate cancer.

Answer 17

• Biopsy microscopy study.
• 2 prominent areas.
• Add the values (2-10 max.).
E.g. 3 + 4 = 7

• Gleason scoring based on 2 prominent areas in a microscopic slide.
• Look under microscope, check all areas and pick 2 common areas - grade each area and add the values.
• Method used to add more accuracy.

1. Low grade - single layer cell, cancerous glands in one place.
2. Glands more spaced, more irregular, infiltrating away.
3. Unusual cells without any forming glands.

• Limitations - depends on accuracy of biopsy.

Question 18

Prostate cancer summary.

Answer 18

• Staging: stage 1 (90% 5 year survival) to stage 4 (10% survival).
- Stage 1 - within one area in the gland.
- Stage 2 - spread out.
- Stage 3 - touching the capsule.
- Stage 4 - beyond the capsule spread (poor prognosis).
• Adenocarcinoma, commonest male cancer.
• Two clinical types - good and bad prognosis.
• Many cancers are small, non palpable (DRE can miss), asymptomatic, only discovered on needle biopsy following raised PSA level*
- Many of these cancer usually don’t progress. Controversy over whether to start invasive treatment or just monitor PSA levels.
• 20-40% of localised prostate cancer have normal PSA value.
• PSA is useful but imperfect marker*
- Not cancer specific.
• Progressive increase in PSA is more useful in monitoring.
- Unlike benign conditions, PSA rapidly increases when the cancer is spreading.
• Low grade, localised cancers best managed by wait and watch.
- As many of them do not progress.

Question 19

Outline lithiasis.

Answer 19

Urolithiasis = stone outside kidney.
Nephrolithiasis = stone within kidney.

• Calcium stones (80%): oxalate/phosphate/urate salts (alkaline urine). Stone first, obstruction later. Small, spiky, haemorrhage.
- Hypercalciuria (familial 54%), increased gut absorption. Commonest aetiology is hypercalcuria (mostly familial) where there is increased gut absorption and increased excretion in the urine. (Serum Ca2+ is normal).
- Rarely defective tubular reabsorption of Ca+ (AKA renal hypercalciuria).
- UTI, common risk factor, hyperparathyroidism rare (<10%).
• Commonest clinically are calcium stones - oxalate, phosphate or urate salts of calcium. Usually form in alkaline urine. Small (1-3mm), spiky, cause haemorrhage.

• Struvite stones (15%): magnesium ammonium phosphate (triple phosphate stones). Staghorn stone - obstruction first, stone later.
- Chronic UTI with gram negative rods (split urea) pH > 7
- Urea splitting Proteus, Klebsiella etc. (not E. coli).
• Obstruction to urine flow and secondary infection occurs first.

• Uric acid stones (6% - rare):
- pH <5.5, high protein (meats), malignancy, gout (25%) - causes.

• Cystine stones (2%): genetic - failure of reabsorption.

Question 20

Outline urinary colic - calcium oxalate.

Answer 20

• Clinically caused by the small stones of the calcium group. Pain starts in the loin and radiates to the front.
• Unilateral, small 1-3mm, Ca oxalate stones.
• Passage causing paroxysmal, intense colicky pain in the loin, radiation to anterior (renal or ureteral ‘colic’) - ‘writhing in pain’ + haematuria (no casts).
- Stone formed in renal pelvis → pass through ureter → get stuck in the upper, middle or lower end.
- Spiky stones cause severe pain, spasmodic, intense - writhing pain.

Clinical symptoms based on level of obstruction:
1. Pelvis/ureteropelvic junction - deep flank pain, no radiation. Stretching of renal capsule.
• Rare. No radiation due to stretching of renal pelvis capsule.
2. Ureter - acute, severe, colicky pain in the flank, radiation to the testes/vulva. Nausea/vomiting. Most common clinically - ureteric obstruction.
a. Upper ureter - DDx cholecystitis.
b. Middle - DDx appendicitis.
c. Distal ureter - DDx pelvic inflammatory disease
3. Uretrovesical junction - irritative voiding/dysuria (characteristic feature).
• Pain in tip of penis/vulva.

Question 21

Outline Staghorn/triple phosphate/struvite stones.

Answer 21

• 15% of urolithiasis. Stone forms in Alk. pH >7.
• Obstruction → urine retention → infection → stone form.
- Obstruction due to some other cause happens first → secondary infection by urea splitting organism → causes stone formation - stones usually huge and fill the spaces available as the initial obstruction causes hydronephrosis (dilation).
- Usually not with severe pain like the calcium oxalate.
• Proteus, pseudomonas etc. Urea → ammonia (alk. phos).
• Large stone molds to pelvis and calyceal system (staghorn shape).
• Triple (struvite) phos. - magnesium ammonium phosphate.
• Chronic irritation, sq metaplasia and sq ca. rarely occur.

Causes and complications:
• Ureteral stricture, infection, sepsis.
• Obstruction → hydronephrosis* → CRF.
• Pyelonephritis, abscess.
- Secondary infection spreads to kidney - pyelonephritis.
- Perirenal abscess.

Question 22

Outline hydronephrosis.

Answer 22

Any obstruction leading to dilation of renal pelvis and calyces with atrophy of parenchyma.

• Dilation of renal pelvis and calyces with atrophy of parenchyma. Secondary to obstruction*

• Congenital - ureteric atresia, kinks, torsion etc.
• Acquired - calculi, tumours, inflammation, stricture, foreign body, neurogenic, pregnancy. (Acquired most common).

Stone can cause hydronephrosis and hydronephrosis can cause stones.

• Bilateral hydronephrosis - obstruction at or below the bladder (usually partial).
• Dilation of ureter → hydroureter.
• Bilateral partial → polyuria.
- Bilateral partial hydroureters can cause polyuria due to defective tubular function.
• Unilateral complete/partial → may be asymptomatic (one of the kidneys is still functioning).

Complications:
• Infection, lithiasis (triple phosphate).
• Atrophy, CRF (due to pressure atrophy).

Question 23

Outline cystic kidney disease.

Answer 23

• Kidney is pack of million nephrons.
- Lots of tubules - cystic kidneys common.
• Cysts form due to misconnection.
- Any misconnection, congenital or acquired leads to cysts.
- Commonest is polycystic kidney disease - adult type. Simple cysts also common but they don’t produce many clinical symptoms.
• Genetic/Acquired.

Genetic PKD:
• Adult Polycystic Kidney (ADPKD) - autosomal dominant.
• Infantile Polycystic Kidney (ARPKD) - autosomal recessive.
• Uraemic Medullary Cysts.
• Renal Dysplasia.
• Medullary sponge kidney.

Acquired PKD:
• Simple cysts*
- Usually no clinical significance.
• Dialysis associated cysts.
- Multiple cysts in chronic kidney/renal failure.

Question 24

Outline Autosomal Dominant PKD/Adult/ADPKD

Answer 24

• Common, Autosomal Dominant ~40y.
- 1 in 700 people. Usually present around 40 with symptoms.
• Partial lack of tubular development.
- Kidneys function partially but gradually develop chronic renal failure.
• Bilateral, large, cystic kidneys.
- Almost size of football.

Clinical features:
• Flank pain, mass, haematuria and UTI.
- Recurrent UTIs.
• Minor trauma → haematuria*
- Most commonly patients present with haematuria following a minor trauma.
• CRF ~50y, common cause of dialysis.
• PKD-1 gene (polycystin) mutation 85%. PKD-2 in 15%, PKD 3 rare.
- Commonest mutation is PKD-1 gene (polycystin) on chromosome 16.

Other associations:
• Liver, splenic, pancreatic cysts (30%).
- Associated with cysts in other organs.
• Cerebral Berry aneurysms (20%).
• Diverticulosis coli.

Question 25

Outline Autosomal Recessive PKD/Infantile/ARPKD

Answer 25

• Autosomal Recessive PKD: Infantile, rare 1:30,000.
- 100% abnormality of development.
• PKHD 1 Rare, complete disorganisation, small cysts (sponge kidney) normal size → renal failure.
- Young kids present with multiple small cysts - known as sponge kidney. Develop renal failure at young age.
• Associated with liver cysts. Perinatal, infantile and juvenile forms.

Question 26

Outline renal tumours.

Answer 26

RCC most common, benign tumours rare.

Benign: <3cm
• Adenoma, angiomyolipoma (rare).
- Blood vessels, smooth muscle, fat cells.

Malignant: >3cm.
• Renal cell carcinoma* (common - adults).
• Wilm’s/Nephroblastoma (childhood).
- Common tumour of childhood - <10y.
• Transitional cell carcinoma of renal pelvis.
- More common in urinary bladder but can also occur in renal pelvis.

Question 27

Outline renal cell/clear cell carcinoma.

Answer 27

• ~60y, males 3:1.
- Usually disease of adult, males more common.
• Familial and sporadic types: VHL gene (Von Hippel-Lindau). VHL - familial carcinoma sy. - early age, bilateral.
- Familial about 10%, sporadic more common.
- Familial associated with VHL - multiple carcinomas, present at earlier age, bilateral.
• Sporadic - risk factors - tobacco, obesity.
- More common, single.
• Characterised by clear cells, well demarcated, grows in to renal vein

Question 28

Describe the morphology of renal cell carcinoma.

Answer 28

Gross:

1. Yellow well demarcated.
2. Necrosis, haemorrhage.
3. Renal vein extension.

• Tumour - looks like lipoma - well demarcated fat tissue with some areas of necrosis and some haemorrhage.
• Tumour extends into the vein because cancer cells are well cohesive.

Microscopy:
• Clear cells, uniform, no pleomorphism.
- Microscopy looks like lipoma not cancer. However, nucleus in centre, uniform and round (compressed at periphery in lipoma).
- High school appearance, JCU behaviour (destructive, damaging, spreads - poor prognosis).
• Papillary - in familial.

Question 29

Identify the clinical features of renal cell carcinoma.

Answer 29

• Triad: haematuria, flank pain and mass* (<10%).
- Seen in <10% of cases.
• Haematuria (50%) most common.
• Haematogenous spread*
• Paraneoplastic syndromes common (hormone) - RCC secretes hormones.
- PTH → hypercalcaemia.
- Erythropoietin → polycythemia.
- HPTN, amyloidosis, leukocytosis and eosinophilia - features also part of paraneoplastic syndrome.
• 5 year survival ~40%.

Question 30

Outline Wilms tumour.

Answer 30

• AKA Nephroblastoma.
• Childhood tumour (2-5y) 98% <10y, common.
- Kidney markedly stretched out by expanding tumour.
- Large tumour. Appears demarcated but with more haemorrhage.
- Commonest kidney tumour in young children.
• Asymptomatic, hypertension or haematuria.
- Ranges from asymptomatic to hypertension or haematuria.
• Sporadic, unilateral (80%) - like adult.
• Familial (10%), bilateral.
• Gross: large, bulky, haemorrhagic tumour.
• Microscopy: dark, blue, embryonic blast cells forming primitive tubules and glomeruli.
- Looks like inflammatory cells (lymphocytes) - trying to form tubules and glomeruli. Looks like an embryonic kidney but it is a cancer.

Question 31

Outline transitional cell neoplasms.

Answer 31

• Neoplasm of urothelium (tr. epithelium of renal pelvis, ureter, bladder and urethra - tumour can occur anywhere).
- Urinary bladder most common - produced papillary growth.
• 90% of bladder ca. Males 3:1, aged, 50-70y.
• Painless haematuria, malignant cells in urine*
- Characteristic presentation.
- Rare to see malignant cells in urine in RCC.
• Risk factors - β-naphthylamine, smoking, chronic cystitis, schistosomiasis (mostly squamous cell carcinomas in case of schistosomaisis).
• Papillary (low grade), flat → infiltrative (high grade).
- Benign papillary low grade → can become flat and infiltrative (high grade).
- Or can be flat carcinoma in situ that becomes invasive. Papillary to flat most common.
• Microscopy - pleomorphic cells but forming papillary structures.

Question 32

Differentiate between renal cell carcinoma and Wilms tumour.

Answer 32

Renal cell carcinoma:
• Adults, commonest.
• Clear cell carcinoma.
• Tubular epithelial tumour.
• Haematuria, flank pain and mass.
• Gross: large, yellow, haemorrhagic, invade renal vein.
• Microscopy: clear cells, uniform.

Wilms/Nephroblastoma:
• Children, common < 10y.
• Embryonic blast cell tumour.
• Mass, pain, vomiting, haematuria.
• Fever, anorexia.
• Gross: soft, grey, haemorrhagic.
• Microscopy: dark blue blast cells forming tubules and glomeruli.