Download Path Lecture 2: Disease of the Ureters, Bladder, and Urethra

Path Lecture 2: Disease of the Ureters, Bladder, and Urethra
 Ureters
o Congenital anomalies
 Ureteral duplication: most common anomaly of UT
 Ureterocele – a congenital saccular dilation of the terminal portion of the ureter
and often assoc. w/complete ureteral duplication
 Inflammation
o Ureteritis cystica
 Different names based on location
 Rare
 Morph: Von Brunn’s Nests
 Von Brunn’s Nests = solid nodules in transitional epithelium
 Imaging: multiple, small constant filling defects most numerous in upper ureter w/
“PUNCHED OUT DEFECTS IN LUMEN”
 Obstructive Lesions
o Retroperitoneal fibrosis
 Define: extensive fibrosis throughout the retroperitoneum, often centered over the
anterior surface of 4th and 5th LUMBAR VERTEBRAE
 Fibrosis  entrapment & obstruction
 Men
 Most common cause = use of particular drugs
 Can be 2nd to malignant or infections or from sclerosing effects of radiation, or
autoimmune
 Micro: fibroblastic proliferation & sclerosis and inflammatory cell infiltrate (+HLA-DR)
 Urinary Bladder
o Congenital anomalies
 Bladder diverticula
 Mostly acquired b/c persistent urethral obstruction
 Can have urinary stasis  infection & bladder calculi
 Extrophy
 Severe defect
 Define: anterior midline defect of abdominal wall, pelvis, UT, genitalia due to
overall deficiency of mesoderm to infraumbilical region
 Epispadias – mildest. Urethra opens as groove on dorsal penis w/urinary
incontinence
 Classic bladder extrophy – MOST COMMON. Bladder open to lower abd.
 Cloacal extrophy – omphalocele. Severe
 Risk of malignancy = 700 x higher for bladder carcinoma
 Inflammation
o Acute & chronic Cystitis
 Most common UTI – E.coli!
 Risk factors for young women: hx of previous episodes of cystitis & frequent/recent
sexual activity & use of spermicide use
 Risk factors for men: bladder outlet obstruction b/c prostatic hyperplasia, catheters
 Triad of ssx: lower abd. Pain, dysuria, micturition w/voids every 15-20 min
 Micro:
 Acute: stromal edema, hemorrhage, neutrophilic infiltrate
 Chronic: NO INFLAMMATION, mostly lymphocytes & fibrosis of lamina prop.
o Painful Bladder Syndrome/Intestinal cystitis (PBS-IC)
Define: suprapubic pain w/bladder filing assoc. w/increased urinary frequency in
absence of proven UTI
 Female 40 yo
 Etiology:
 Infection, leaky urothelium (def. GAG layer), immunological response (SLE,
Scleroderma, Sjogren w/most having anti-bladder Ab, ANA Ab), mast cell
involvement
 Dx: cystoscopy w/overdistention
 Morph: ulcerative (Hunner ulcer = hallmark of classic cystitis), non-ulcerative
(raspberry-like lesions)
o Malacoplakia
 Define: rare granulomatous disease due to E.coli
 Middle aged women
 More common w/DM & immunocompromised
 Gross hematuria
 Etiology: E.coli w/impaired host defenses & defective phagocystosis  MichaelisGutmann bodies
 Morph: soft, flat yellow-brown plaques or nodules, papillary lesions, hemorrhagic
masses, necrotic ulcerations
 Micro: Von Hansemann cells(aggregates of granular histocytes) w/M-G bodies
Urethra
o Inflammation
 Urethritis
 Assoc. w/Reiter syndrome
o Triad: arthritis, conjunctivitis, urethritis
 Urethral caruncle
 Define: inflammatory lesion that is small, red, painful mass at external urethral
meatus
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Path Lecture 3: Cystic Diseases of the Kidney
 Cystic Kidney Diseases
o Multicystic Renal Dysplasia
 Cause: persistence of abnormal structures in kidney
 Kidney enlarged, extremely irregular, multicystic
 Histo: flattened epithelium, islands of undiff. Mesenchyme, often w/cartilage and
immature collecting ducts
o ADPKD
 Most common inherited kidney disease
 One parent usually affected
 Basic defect is a disruption in the regulation of intracellular Ca levels due to mutation
in the genes
 Morph: HALLMARK – massively enlarged kidneys caused by sustained expansion of
innumerable fluid-filled cysts
 Surgical removal of cysts improves HTN
 Polycystic liver disease: MOST COMMON extrarenal manif.
 Vascular: berry aneurysms
 Cardiac: mitral valve prolapse
 Diverticular: colonic diverticulosis & diverticulitis
o ARPKD
 MOST COMMON heritable cystic renal dz in infancy & childhood
 Parents unaffected
Defect in PKDHD1 (fibrocystin/polyductin)  ciliary dysfxn
Morph: non-obstructive, B/L, symmetric dilation & elongation of renal collecting ducts
and B/L enlargement of kidneys
 Pathogenesis: hyperplasia of epithelial change from absorptive to secretory
 Kidney & renal involvement
Cystic Diseases of the Renal Medulla
o Medullary Sponge Kidney
 Define: multiple cystic dilations of collecting ducts in medulla
 Renal fxn norm, found often incidentally
 Papillary ducts in medulla dilated
o Nephrolithiasis – Medullary Cystic Kidney Dz Complex
 Define: inherited, B/L small cysts in medulla, usually concentrated at corticomedullary
jxn
 Kidneys normal or small w/tubulointerstitial sclerosis  ESRD
 Nephrolithiasis (NPH)
 AR
 Juvenile – (NPH1)
o MOST COMMON FORM
o Onset ESRD 13 yo
 Infantile (NPH2)
o Onset ESRD 1-3 yo
 Adolescent (NPH3)
o Onset ESRD 19 yo
 MCKD
 AD
 Presents 3rd-4th decades w/terminal renal failure in adult
o Acquired (Dialysis-assoc) Kidney Disease
 Pts w/prolonged dialysis  develop cortical & medullary cysts
 Cysts contain calcium oxalate crystals
 Most severe complication: RCC
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Path Lecture 4: Renal Calculi Hydronephrosis
 Urinary tract stones
o Crystalline components and organic matrix
o Calcareous stones – most
 Calcium oxalate = dark brown, jagged, extremely hard
 Calcium oxalate + calcium phosphate = dirty white, smooth, easily break
o Struvite stones “infection stones”
 Magnesium ammonium phosphate
o Uric Acid stones = yellow or pink
 Common in pts w/hyperuricemia
o Crystaline stones
 Genetic defect in renal absorption of cysteine
o Stone formation
 Supersaturation
 Urine pH
o Acidic pH – cysteine, uric acid, calcium oxalate stone
o Alkaline pH – calcium carbonate, calcium phosphate, magnesium
phosphate stones
 Hypercalciuria: ex. Hyperparathyroidism
 Low urine citrate: calcium citrate acts as an inhibitor of crystallization
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 Metastability
 Precipitation
 Crystal growth
 Crystal aggregation
Nephrolithiasis
o Hypercalciuric nephrolithiasis
 Idiopathic
 Renal hypercalciuria
 Hormonal hypercalciuria
o Hyperuricosuric calcium nephrolithiasis
 >800 mg uric acid per day
 uricosuria + urine pH 5.5  calcium oxalate
o Hyperoxaluric calcium nephrolithiasis
 Calcium oxalate insoluble & MOST COMMON chemical compound found in kidney
stones
o Hypocitraturic calcium nephrolithiasis
 Citrate is inhibitor of stone formation
o Hypomagnesiuric calciumnephrolithiasis
 Mg & citrate important inhibitors of stone formation in UT
o Uric Acid nephrolithiasis
 Caused by hyperuricemia and gout. Persistent acidic urine
o Struvite nephrolithiasis
 UT infected w/proteus, klebsiella, or providentia (urease bacteria) NO E.COLI
 Staghorn calculi = upper UT stones that extend into at least 2 calices
o Cysteine stones
 Rare, uncommon AR disease – cystinuria
Bladder Stones “Vesicle Calculi”
o Define: usually assoc. w/urinary stasis from bladder outlet obstruction
o Men >50 yo w/enlarged prostates
o Morph: struvite + calcium oxalate or calcium phosphate
Urinary Tract Obstruction
o Morph: possibly a gradually increasing dilation of the renal pelvis & an increase in weight &
volume of kidney
 Weight increased b/c edema
 Dilation occurs 2-6 hrs post obstruction
o Micro: changes in 1-2 mo
 Sclerotic glomeruli
 Apoptosis of tubule cells
 Edema & collage deposition in interstitium
Path Lecture 5: Tubulointerstitial Nephritis
 Define: kidney diseases that involve renal structures outside glomerulus
 Biopsy req for dx
 MOST COMMON form: immunologic
 Most frequent causes:
o Drug-induced
o Infection-assoc.
o Immune-mediated
 Ssx: renal failure, generalized hypersensitivity syndrome (triad = low grade fever, skin rash,
arthralgias)
 Acute Tubulointerstitial Nephritis
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o Reactive interstitial nephritis
 Define: acute inflamm. Of renal interstitum during general infection (scarlet fev)
 Morph: enlarged kidneys
 No medulla involvement
 Clinical: transient acute renal failure, abnormal urinalysis
 Path: delayed type hypersensitivity or cytokines released during infection
o Drug-induced
 Define: well-organized adverse rxn to drugs
 NSAIDs, SMX-TPM, PCNs, PPIs, H2 blockers, TZD, tetracycline, allopurinol
 Enlarged kidneys
 IF: fibrin in renal interstitium
 Clinical: transient renal failure, triad of allergic rxn (low-grade fever, skin rash,
arthralgia), eosinophilia
o Immunologically-mediated
 Anti-TBM Ab-mediated
 Autoimmune dz, Abs against tubular BM
 Linear IgG deposits along tubular BM
 Immune complex deposits on BM
 Granular immunoglobulin deposits
 T-lymphocyte-mediated
 Granulomas formed in renal interstitium
 Sarcoidosis
 Etiology: LUPUS MOST COMMON DZ
 Clinical: maculopapular rash, fever, eosinophilia, abrupt onset renal dysfxn
Chronic Tubulointerstitial Nephritis
o Define: common final response pattern of kidney to variety of insults
o Clinical: HTN, or asymptomatic
o Lab: increased Cr, decreased renal acid secretion/metabolic acidosis, excessive loss of
substance in urine, mild proteinuria
o Morph: tubular atrophy & dilation and hyalinized casts “thyroidization”
Analgesic Nephropathy
o Define: MOST COMMON category of chronic interstitial nephritis worldwide
o Long-term phenacetin, aspirin, caffeine, phenacetin-acetaminophen, NSAIDs
o Associated w/papillary necrosis
o Clinical: HTN, renal insufficiency, papillary necrosis (gross hematuria & flank pain)
o Kidneys slightly smaller
o Cortex w/depressed areas overlying necrotic papillae
NSAID Nephropathy
o Adverse rxns of NSAIDs by inhibition of prostaglandins
o Prostaglandins maintain renal blood flow and GFR
o 15% of all cases of drug-induced renal failure
Aristolochic Acid Nephropathy (AAN)
o Define: rapidly progressive tubulointerstitial nephritis  ESRD
o Herb: aristolochia fangchi is cause
o Proximal tubular cells main target
o Shrunken, asymmetric kidneys
o Cause of Balkan nephropathy
Urate Nephropathy
o Acute uric acid nephropathy: pts w/leukemia & lymphomas w/chemo
o Chronic uric acid nephropathy: pts w/hyperuricemia & gout. Can induce chronic renal injury
independent of crystal formation
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Hypercalcemia & Nephrocalcinosis
o Define: calcification of renal parenchyma
o Morph: purplish-blue tinge or stippling on H&E = calcifications
Path Lecture 6: Acute Tubular Necrosis (ATN)
 Define: destruction of tubular epithelial cells & acute diminution of renal fxn
 Pts die b/c of serious involvement of other systems – NOT KIDNEY
 Acute renal failure
o Pre-Renal ARF
 MOST COMMON FORM OF KIDNEY INJURY
 Adaptive to hypotension & volume depletion  structurally fxn intact nephrons
 Oliguria & azotemia
o Intra-Renal ARF
 Injury to kidney
 Acute tubular necrosis MOST COMMON FORM OF INTRARENAL ARF
o Post-renal ARF
 Due to bladder outlet syndrome
 ATN occurs after ischemic or toxic event
o Ischemic
 Hypoperfusion lasts for long time
 Pre-renal azotemia
o Nephrotoxic
 Exogenous nephrotoxins  ATN
 Aminoglycosides
o Presents w/non-oliguric renal failure
o 7-10 days post therapy
 Amphotericin B
o Affects proximal tubule, medullary ascending loop of Henle, collecting
ducts
 Radiographic contrast media
o Non-oliguric renal failure
o 24-48 hrs post
 Cyclosporine & tacrolimus
o Decrease in dosage reverse renal insufficiency
o Present w/HTN
 Acyclovir, Indinavir, Sulfa Drugs
o Crystal formation
 Endogenous nephrotoxins  ATN
 Myoglobinuria from rhabdomyolysis
 Hemoglobinuria from transfusion rxn
 Ischemic Acute Tubular Necrosis
o Initiation
o Maintenance
 Few days to several weeks
 Reduction in GFR, salt and water overload (edema), rising BUN & Cr
o Recovery
 Regeneration of tubular epithelial cells
 Polyuria
o Micro: tubular necrosis is patchy & affects single cells
o Urinary Sediment
 Epithelial cell casts = MOST COMMON FORM
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 Hyaline casts = tamm-horsfall mucoprotein solidified
 Granular casts
 Muddy brown casts = HALLMARK
Toxic Acute Tubular Necrosis
o Caused by dose-dependent toxic renal injury
o Extensive tubular cell necrosis uniformly involving all nephrons
o Casts present in collecting ducts w/extensive necrosis along proximal tubule segment at 3
days
o 7 days = necrotic debris has disappeared from proximal tubules
o 10 days = cells are regenerating, which mature at 15 days
Path Lecture 7: Pyelonephritis
 Acute Pyelonephritis
o Define: tubulointerstitial component of the kidneys affected
o E.coli
o Female
o Ascending infection: MOST COMMON cause of clinical pyelonephritis
o Morph: kidneys enlarged, red-congested w/yellow areas of focal abscess formation. Renal
papillae are flat or diffusely blunted
o Micro: areas of inflammation are well circumscribed & separated y zones of parenchyma that
are fine. Abscesses form in cortex w/destruction of all the renal parenchymal elements in
their center
 Acute Non-Complicated Pyelonephritis
o By 3 weeks, interstitial fibrosis develops & scar contraction is evident in kidney poles
o Lab: Pyuria, white cell casts, nitrite tests
o E.coli most common, Klesbiella 2nd
 Acute Complicated Pyelonephritis
o XGP
 Rare, serious complication characterized by an infectious renal phegmon
 Immunocompromised w/assoc. urolithiasis, UTI, DM
 Histo: lipid-laden macs
 E.coli or Proteus infection
o Emphysematous pyelonephritis (EPN)
 Severe necrotizing infection causes gas formation
 Common in DM
o Pyonephros = pus
o Papillary necrosis
 Coagulative necrosis of renal medullary pyramids & papillae
 DM and persons w/UT obstructions
 Pyramids have white or yellow necrosis
 Chronic Pyelonephritis
o Define: chronic interstitial inflammation induced by recurrent or persistent pyelonephritis
o Often in pts w/major anatomic anomalies that keep infection alive
o Major cause of ESRD throughout the world
o Female and more often in infants and young children
o Classification:
 Chronic non-obstructive pyelonephritis
 MOST COMMON SUBTYPE
 Pts w/VUR
 Chronic obstructive pyelonephritis
 Old male w/bladder stones, BPH, or carcinoma of prostate
 Women complication of cervical & endometrial carcinoma
o Morph: coarse segmental scarring of kidneys, diffuse pelvicaliceal dilation & parenchymal
thinning
o Dx: intravenous urography
Path Lecture 8: Amyloidosis
 Stains w/congo red that is orange brick in light and apple green birefringence (B-sheets of
amyloid) in polarized light
 AL Amyloidosis – txt w/chemo
o MOST COMMON FORM OF AMYLOIDOSIS IN US & EU
o All patients have plasma cell dyscrasia
 Multiple myeloma (MM)
 Malignant plasma cells in bone marrow producing M protein
 Monoclonal gammopathies of undetermined significance (MGUS)
 Monoclonal Ig (M grotein) in serum or urine in persons w/out myeloma
 Lamda chains
o Clinical: amyloid deposition in virtually every system BUT CNS, fatigue & weight loss
 Renal amyloidosis
 Cardiac amyloidosis – rt sided heart failure
 Peripheral amyloid neuropathy – spinal nerves
 GI amyloidosis – constipation or constipation/diarrhea
 Others – easy bruising – “raccoon eyes”
o Always progressive
 AA Amyloidosis – txt by controlling underlying inflammatory dz
o MOST COMMON form of systemic amyloidosis worldwide
o Fibrils composed of serum amyloid A (SAA) which is secreted during acute inflammation
 Liver major site synthesis
o Clinical: Liver & spleen where amyloid A FIRST deposits BUT kidney is common clinical
presentation
 RACCOON EYES, ORTHOSTATIC HTN = NOT FEATURES
 ATTR Amyloidosis
o Senile systemic amyloidosis (SSA) – affects elderly
o Deposition of amyloid mainly in heart of TTR molecules
o Dx: TTR
 B2M Amyloidosis
o Hemodialysis assoc.
o Clinical: osteoarticular sites
 Hereditary Systemic Amyloidosis
o Familal Mediterranean Fever = periodic disease – txt w/colchicine
 Brief episodes of peritonitis, pleuritis, and arthritis assoc. w/fever
 MEVF gene codes for pyrin or marenostrin (AR)
o Familial Amyloidotic Polyneuropathy – txt w/liver transplant
 Liver produces mutated TTR & affects peripheral nerves
 Diagnosis of Amyloidosis
o Renal & hepatic biopsy – high positive yield in most forms of systemic amyloidosis
o Recta mucosa – biopsy site of choice
Path Lecture 9: Renal Vascular Disorders
 Benign Nephrosclerosis
o Define: focal ischemia of parenchyma from sclerosis of renal arterioles & small aa.
o Older blacks
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o Can be w/out HTN, but HTN & DM = increased incidence & severity
o Medial & intimal thickening & hyaline deposition in arterioles
o Normal or moderately decreased kidney size
o Cortical surface: resembles grain leather
o Micro: hyaline arteriosclerosis – patchy ischemic atrophy
Malignant HTN Nephrosclerosis
o Younger AA men
o Hyperplastic arteriosclerosis & increased levels of angiotensin & renin = TYPICAL
o Morph: “flea-bitten” appearance b/c of pinpoint petechial hemorrhages
o Micro: fibrinoid necrosis of arterioles & onion-skin lesion of arterioles
o Clinical: HTN, papilledma, retinal hemorrhage, encephalopathy, CV abnormalities, renal failure
Renal Artery Stenosis (RAS)
o Potentially curable form of HTN w/surgical txt
o Atherosclerotic RAS = MOST COMMON CAUSE OF RENO-VASCULAR HTN
 Important cause of chronic renal insufficiency & ESRD
 Proximal 1/3 of main renal artery
 Older men
o Fibromuscular Dysplasia (FMD)
 Deformation in renal artery wall  stenosis
 Younger women
 NO INFLAMMATION
 Thickening of arterial wall occurs
 Distal 2/3 of artery = string of beads
o Kidneys small w/signs of diffuse ischemic atrophy
Atheroembolic Renal Disease
o Emboli are cholesterol crystals appearing as rhomboid clefts
Sickle cell disease nephropathy
o Hematuria & hypothenuria (decreased ability to concentrate)
Diffuse Cortical Necrosis
o Most often after an obstetric emergency
o Massive ischemic necrosis limited to cortex
o Clinical: sudden anuria, terminating rapidly in uremic death
Renal Infarcts
o Result of embolized thrombi often from MI
o Most renal infarcts are of the “white” anemic variety
Path Lecture 10: Tumors of the Kidney
 Benign tumors of the kidney
o Renal papillary adenoma
 Epithelial lesions of the renal cortex w/a tubular/papillary architecture
 Small, solid, well circumscribed, yellow-tan tumors in cortex
o Angiomyolipoma
 Varying components of blood vessels, smooth m., and adipose tissue
 Pts w/tuberus sclerosis could get this in teens
o Oncocytoma
 Cells w/granular & acidophilic cytoplasm – eosinophilia due to abundant mito
 Men >50 yo
 Mahogany brown w/central steallate scar
 Differentiate from RCC which is yellow-orange
 Malignant Tumors
o RCC
Large cells w/clear to granular cytoplasm & prominent vasculature
MOST COMMON CANCER OF KIDNEY
Smoking, obesity, HTN, enviro & occupational, acquired renal cystic disease w/ESRD
Inherited forms:
 RCCa related to von Hippel-Lindau disease
o Predisposition to retinal & cerebellar hemangiomas, clear cell renal
carcinomas, and pheochromocytomas
 RCCa Tumor Types
 Clear Cell carcinoma
o MOST COMMON TYPE
o Loss of VHL on chromosome 3
 Papillary carcinoma
o From distal collecting tubule
o Assoc. w/pts on chronic hemodialysis
o Tan brown cut surface, Psammoma bodies might be there
 Chromophobe renal cell carcinoma
o Pale eosinophilic cells w/perinuclear halos arranged in a solid sheet
o Plant-cell like
 Carcinoma of the collecting ducts of Bellini
o Arises in medulla
o Nests of malignant tumor cells mixed w/fibrotic stroma w/in medulla
 Renal medullary carcinoma
o Associated w/sickle cell
Wilms Tumor (Nephroblastoma)
o Ped malignant from metanephric blastema
o MOST COMMON TYPE OF RENAL MALIGNANCY IN KIDS
o Nephrogenic rests are precursor lesions
o Hereditary forms:
 WAGR syndrome
 Denys-Drash syndrome – WT1 mutation
 Beckwith-Wiedmann syndrome – WT2 mutation
o Solitary mass tan to tan-gray
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Path Lecture 11: Tumors of the Urothelium
 Benign Proliferative Urothelial Lesions
o Urothelial hyperplasia
 Marked thickened urothelium w/o cytologic atypia
 NO MALIGNANCY
o Von Brunn Nests
 Bulbous invaginations of surface urothelium encroaching into lamina propria
o Pyelitis, Ureteritis, Cystitis Cystica
 Von Brunn nests develop central lumen
 Pyelitis – in kidney
 Ureteritis – in ureter
 Cystitis cystica – in bladder & associated w/bladder carcinoma
o Squamous metaplasia
 Reactive process w/replacement of urothelial lining by squamous epithelium
o Neurogenic Adenoma
 Males
 Clustered small papillae assoc. w/small multiple tubule structures
 + Pax-2 transcription factor
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 Chronic infection
Epithelial Tumors of Urinary Bladder
o In Africa, increased b/c of Schistosoma hematobium
o Whites mostly in urban
o Papillary lesions – red & elevated
o Flat lesions – carcinomas extending along bladder surface. Multiple, red, velvety, flat patches
only mucosal surface = carcinoma in situ
o Urothelial papilloma – men >50 yo
o Urothelial carcinoma in situ – flat, non-invasive tumor all layers of urothelium
 Multiple red, velvety, flat patches confined to mucosal surface = CIS
o Papillary urothelial neoplasms of low malignancy potential (PUNLMP)
 Can’t invade or metastasize
o Low grade urothelial carcinoma
 Papillary low grade urothelial carcinoma
 Sea anemones
o High grade urothelial carcinoma
 Malignant neoplasm often invasive
 Epithelium of varying thickness
Non-Urothelial Carcinomas of the Bladder
o Squamous cell carcinoma
 Common in countries w/urinary schistosomiasis
 Squamous differentiation resembling epidermis
o Adenocarcinoma
 Glandular differentiation
 Mucin-secreting & trigone area
Mesenchymal (Soft tissue) tumors of the bladder
o Benign tumors
 MC – leiomyoma
o Sarcomas
 Rhabdomyosarcoma – resembles skeletal m. features
 MOST COMMON MALIGNANT BLADDER TUMOR IN KIDS
 Bladder trigone
 Leiomyosarcoma
 Malignant smooth muscle tumor
 MOST COMMON SARCOMA OF BLADDER IN ADULTS
 Dome of bladder & lateral wall
 Seen after txt w/cyclophosphamide