Diseases of the liver and pancreas


Tubulointerstitial Nephritis - Pyelonephritis (PN) and UTI



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Tubulointerstitial Nephritis - Pyelonephritis (PN) and UTI
Pyelonephritis: Renal disorder affecting tubules, interstitium and renal pelvis

  • Is one of the most common diseases of the kidney

  • Occurs in two forms:

  • Acute PN –

  • Caused by bacterial infection

  • Renal lesion associated with urinary tract infection

  • Chronic PN is a more complex disorder:

  • Bacterial infection plays a dominant role

  • Other factors (vesicoureteral reflux, obstruction) are also involved

  • Urinary tract infection (UTI): Implies involvement of either

  • Bladder (cystitis) or

  • Kidneys and their collecting systems (pyelonephritis), or

  • Both

  • UTIs are extremely common disorders.

Ascending Infection:



  • 85% of cases of UTI are: Gram-negative

bacilli that are normal inhabitants of the intestinal tract

  • Most common is Escherichia coli, followed by

Proteus, Klebsiella, and Enterobacter

Hematogenous Infection: Occurs



  • In presence of ureteral obstruction

  • In debilitated patients

  • Immunosuppressive therapy

  • With non-enteric organisms:

  • Staphylococci and certain fungi.

Vesico-Ureteric Reflux

(A) Intra vesical portion of the ureter is oblique – closes during micturition

(B) VUR occurs due to complete or partial absence of intra-vesical ureter

Acute Pyelonephritis


  • Is an acute suppurative inflammation of the kidney caused by bacterial infection–whether

  • Hematogenous/induced by septicemic spread

  • Ascending and associated with VUR

  • Hallmarks of acute PN are

  • Patchy interstitial suppurative inflammation. May occur as:

  • Discrete focal abscesses involving one or both kidneys

  • Large, wedge-shaped areas of coalescent suppuration

  • Tubular necrosis

  • Characteristically, glomeruli are resistant to infection

  • Destruction of glomeruli takes place:

  • With large areas of severe necrosis

  • Fungal PN (e.g., Candida)

Complications

Papillary necrosis:

  • Seen in diabetics + in those with urinary tract obstruction

  • Is usually bilateral

  • One or all of the pyramids of the affected kidney involved

  • On cut section, the tips or distal two-thirds of the pyramids have gray-white to yellow necrosis that resembles infarction

Pyonephrosis

  • Is seen when there is total or almost complete obstruction, particularly when it is high in the urinary tract.

  • Suppurative exudate is unable to drain > fills the renal pelvis, calyces, and ureter > pyonephrosis

Perinephric abscess

  • Extension of suppurative inflammation through the renal capsule into the perinephric tissue.

Papillary necrosis




Predisposing Conditions For Acute Pyelonephritis

  • Urinary obstruction, either congenital or acquired.

  • Instrumentation of the urinary tract, most commonly catheterization.

  • Vesicoureteric reflux.

  • Pregnancy

  • Patient’s sex and age.

  • Upto 1st year Males> Females (Congenital anomalies more evident)

  • Upto around 40 years, infections are much more frequent in females

  • With increasing age, males > females due to the development of prostatic hypertrophy and frequent instrumentation.

  • Pre-existing renal lesions, causing intrarenal scarring and obstruction.

  • Diabetes mellitus, in which acute PN is caused by

  • More frequent instrumentation

  • General susceptibility to infection

  • Neurogenic bladder dysfunction

  • Immunosuppression and immunodeficiency.

Clinical Features

  • Sudden onset pain at the costovertebral angle

  • Evidence of systemic infection, such as fever and malaise.

  • Indications of bladder/urethral irritation - dysuria, frequency, and urgency.

  • Urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower UTI.

  • Finding of leukocyte casts (pus casts) indicates renal involvement, because casts are formed only in tubules.

  • Diagnosis of infection: Urine culture.


Clinical Course

  • Uncomplicated acute PN usually follows a benign course, and the symptoms disappear within a few days after the institution of appropriate antibiotic therapy.

  • In the presence of unrelieved urinary obstruction, diabetes mellitus, and immunocompromise, acute PN may be more serious, leading to repeated septicemic episodes.

  • Superimposition of papillary necrosis often leads to acute renal failure.


Chronic Pyelonephritis (CPN) and Reflux Nephropathy

  • CPN is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial

inflammation and renal scarring are associated with pathologic involvement of

the calyces and pelvis

  • Pelvocalyceal damage is important in that many diseases produce chronic

tubulointerstitial alterations, but except for CPN and analgesic nephropathy,

none affects the calyces



  • CPN is an important cause of end-stage kidney disease

  • CPN can be divided into two forms:

  • Chronic obstructive

  • Chronic reflux-associated.


Chronic Obstructive PN

  • Obstruction predisposes kidney to infection. Recurrent infections > recurrent bouts of renal inflammation and scarring> CPN

  • Disease can be

  • Bilateral: as with obstructive anomalies of the urinary tract (e.g., posterior urethral valves)

  • Unilateral: such as occurs with calculi and unilateral obstructive anomalies of the ureter



Reflux Nephropathy

  • Is the more common form of chronic pyelonephritic scarring.

  • Occurs early in childhood, as a result of superimposition of a urinary infection on congenital VUR and intrarenal reflux

  • Reflux may be unilateral or bilateral

  • VUR occasionally causes renal damage in the absence of infection (sterile reflux), but only in the presence of severe obstruction.



Morphology-Chronic Pyelonephritis

  • Gross:

  • Kidneys usually are irregularly scarred

  • If bilateral, the involvement is asymmetric.

  • This contrasts with chronic glomerulonephritis, in which the kidneys are diffusely and symmetrically scarred.

  • The hallmark of CPN is the coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx

  • Microscopic:

  • Changes involve predominantly tubules and interstitium.

  • Tubules show atrophy in some areas and hypertrophy in others, or dilatation.

  • Dilated tubules may be filled with colloid casts - thyroidization


Tubulointerstitial Nephritis (TIN) Induced by Drugs and Toxins

  • Toxins and drugs produce renal injury in three ways:

  • Trigger an interstitial immunologic reaction

  • Eg, acute hypersensitivity nephritis induced by methicillin

  • Cause ARF

  • Cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency

  • Eg., analgesic abuse nephropathy, detected only after onset of chronic renal insufficiency


Acute Drug-Induced Interstitial Nephritis

  • This is a well-recognized adverse drug reaction

  • Most frequently occurs with

  • Synthetic penicillins (methicillin, ampicillin)

  • Other synthetic antibiotics (rifampin)

  • Diuretics (thiazides)

  • Nonsteroidal anti-inflammatory agents (phenylbutazone)

  • Miscellaneous drugs (phenindione, cimetidine)

  • Disease begins about 15 days after exposure to the drug

  • Characterized by

  • Fever

  • Eosinophilia

  • Skin rash in about 25% of patients

  • Renal abnormalities

  • Hematuria

  • Mild proteinuria

  • Leukocyturia (including eosinophils).

  • A rising serum creatinine level or ARF with oliguria develops in about 50% of cases, particularly in older patients.


Analgesic Abuse Nephropathy

  • Is a form of chronic renal disease

  • Caused by excessive intake of analgesic mixtures

  • Characterized morphologically by chronic tubulointerstitial nephritis with renal papillary necrosis

  • The renal damage was first ascribed to phenacetin

  • Analgesic mixtures consumed often contain, in addition, aspirin, caffeine, acetaminophen (a metabolite of phenacetin), and codeine

  • Patients who develop this disease usually ingest large quantities of analgesic mixtures (more than 2 kg of aspirin or phenacetin over 3 years)

Grossly:

  • Kidneys are either normal or slightly reduced in size

  • Cortex exhibits depressed and raised areas, the depressed areas representing cortical atrophy overlying necrotic papillae.

  • The papillae show various stages of necrosis, calcification, fragmentation, and sloughing.

  • This gross appearance contrasts with the papillary necrosis seen in diabetic patients, in which all papillae are at the same stage of acute necrosis.

Microscopically:

  • Papillary changes may take one of several forms:

  • In early cases: Patchy necrosis

  • In the advanced form: Entire papilla is necrotic

  • Cortical changes consist of loss and atrophy of these tubules, and interstitial fibrosis and inflammation.

  • The small vessels in the papilla and submucosa of the urinary tract exhibit characteristic PAS-positive basement membrane thickening (analgesic microangiopathy).

Clinical Course

  • Women > men

  • Particularly prevalent in individuals with recurrent headaches and muscular pain, in psychoneurotic patients, and in factory workers.

  • Early renal findings include inability to concentrate the urine, as would be expected with lesions in the papilla.

  • Acquired distal renal tubular acidosis contributes to the development of renal stones.

  • Headache, anemia, gastrointestinal symptoms, and hypertension are common accompaniments of analgesic nephropathy.

  • The anemia in particular is out of proportion to the renal insufficiency, owing to damage to red cells by the phenacetin metabolites.

  • Urinary tract infection complicates about 50% of patients.

  • Occasionally, entire tips of necrotic papillae are excreted, and these may cause gross hematuria or renal colic due to obstruction of the ureter by necrotic fragments.

  • Progressive impairment of renal function may lead to chronic renal failure, but with drug withdrawal and proper therapy for infection renal function may either stabilize or actually improve.

  • Rarely can develop transitional papillary carcinoma of the renal pelvis


Diseases of Blood Vessels

  • Benign Nephrosclerosis

  • Malignant Phase of Hypertension (Malignant Nephrosclerosis)

  • Renal Artery Stenosis

  • Thrombotic Microangiopathies


Benign Nephrosclerosis

  • It is the term used for the kidney associated with sclerosis of renal arterioles and arteries

  • Resultant effect: Focal ischemia of the renal parenchyma supplied by the thickened narrowed arteriole

  • Pathogenesis: Two processes induce the arterial changes -

  • Medial and intimal thickening of the arterioles

  • Hyaline deposition in arterioles

Grossly:

  • Kidneys are either normal/moderately reduced in size

  • Cortical surfaces have a fine, even granularity that resembles grain leather

  • On section, the loss of mass is due mainly to cortical narrowing.

Histologically:

  • Narrowing of the lumina of arterioles and small arteries, caused by thickening and hyalinization of the walls

  • Larger interlobular and arcuate arteries exhibit a characteristic lesion called Fibroelastic hyperplasia

  • Consists of reduplication of the elastic lamina + increased fibrous tissue in the media, with resultant luminal narrowing.

  • Consequent to the hyaline vascular narrowing, there is patchy ischemic atrophy,

which consists of :

  • Foci of tubular atrophy and interstitial fibrosis

  • A variety of glomerular alterations

  • Collapse of glomerular basement membranes

  • Deposition of collagen within Bowman’s space

  • Periglomerular fibrosis

  • Total sclerosis of glomeruli.

  • Uncomplicated benign nephrosclerosis alone

  • Rarely causes renal insufficiency or uremia

  • Only moderate reductions in renal plasma flow

  • Normal or slightly reduced GFR

  • Mild proteinuria occasionally

  • Renal failure may supervene in 5% of patients with prolonged benign hypertension

  • In most patients however results from the development of the malignant or accelerated phase of hypertension


Malignant nephrosclerosis

  • It is the form of renal disease associated with the malignant or accelerated phase of hypertension

  • Occasionally develops in previously normotensive individuals

  • Often is superimposed on:

  • Pre-existing essential benign hypertension

  • Secondary forms of hypertension

  • Underlying chronic renal disease

  • Glomerulonephritis

  • Reflux nephropathy

  • Is uncommon, occurring in 1-5% of all patients with elevated blood pressure

  • Usually affects younger individuals

  • Males > Females

  • Commoner in blacks

Morphology

  • Grossly:

  • Kidney size is dependent on the duration and severity of the hypertensive disease.

  • “flea-bitten” appearance - Small, pinpoint petechial hemorrhages on the cortical surface from rupture of arterioles or glomerular capillaries

  • Histologically:

  • Two characteristic alterations of blood vessels

  • Fibrinoid necrosis of arterioles.

  • Hyperplastic arteriolitis, also referred to as “onionskinning”

  • Intimal thickening caused by proliferation of elongated, concentrically arranged cells, smooth muscle cells plus with fine concentric layering of collagen specially in the interlobular arteries and arterioles

  • Sometimes the glomeruli become necrotic and infiltrated with neutrophils, and the glomerular capillaries may thrombose (necrotizing glomerulitis).

  • The arteriolar and arterial lesions result in considerable narrowing of all vascular lumina, with ischemic atrophy and infarction distal to the abnormal vessels.


Clinical Course

  • The full-blown syndrome of malignant hypertension is characterized by

  • Diastolic pressures > 130 mm Hg

  • Papilledema retinopathy

  • Encephalopathy

  • Cardiovascular abnormalities

  • Renal failure.

  • “Hypertensive crises” are sometimes encountered, characterized by episodes of loss of consciousness or even convulsions.

  • At the onset of rapidly mounting blood pressure

  • Marked proteinuria

  • Microscopic / macroscopic hematuria

  • But no significant alteration in renal function

  • Soon, however, renal failure makes its appearance.

Treatment:

  • The syndrome is a true medical emergency

  • Aggressive and prompt antihypertensive therapy before the development of irreversible renal lesions

Prognosis:

  • Before introduction of the new antihypertensive drugs, malignant hypertension was associated with a 50% mortality rate within 3 months of onset, progressing to 90% within a year.

  • At present, however, about 75% of patients will survive 5 years, and 50% survive with precrisis renal function.


Renal Artery Stenosis

  • Uncommon cause of hypertension( 2 to 5% of cases)

  • BUT it is the most common curable form of hypertension

  • Surgical treatment being successful in 70 to 80% of carefully selected cases

  • The classic experiments of Goldblatt in 1934 showed that constriction of one renal artery in dogs results in hypertension

  • The hypertensive effect is due to stimulation of renin secretion by cells of the juxtaglomerular apparatus > production of the vasoconstrictor angiotensin II.

  • Other factors, however, play a role in the maintenance of renovascular hypertension including sodium retention and, possibly, inhibition of medullary vasodepressor substances.

Morphology

  • Males > Females

  • Incidence increases with advancing age and DM

  • Causes of renal artery stenosis:

  • Occlusion by an atheromatous plaque at the origin of the

renal artery (70% of cases)

  • The plaque is usually concentrically placed, and

superimposed thrombosis often occurs.

  • Fibromuscular dysplasia of the renal artery

  • Fibrous or fibromuscular thickening

  • May involve the initima, the media (commonest), or the adventitia of the artery

  • Lesions may:

  • Consist of a single well-defined constriction, or

  • Series of narrowings, usually in the middle or distal portion of the renal artery.

  • Involve segmental branches

  • Be bilateral.

  • The ischemic kidney:

  • Usually reduced in size

  • Shows signs of diffuse ischemic atrophy

  • Crowded glomeruli

  • Atrophic tubules

  • Interstitial fibrosis

  • Focal inflammatory infiltrate.

  • Ipsilateral kidney: Only mild arteriolosclerosis

  • Ischemic kidney are usually protected from the effects of high pressure

  • Contralateral nonischemic kidney: Hyaline arteriolosclerosis

  • Depending on the severity of the preceding hypertension.

Clinical Course

  • In general these patients resemble those presenting with essential hypertension

  • Occasionally, a bruit can be heard on auscultation of the kidneys.

  • Diagnosis:

  • Elevated plasma or renal-vein renin

  • Response to ACE inhibitors (captopril)

  • Renal scans

  • Intravenous pyelography

  • Arteriography is required to localize the stenotic lesion.

  • Treatment: Surgical

  • Prognosis: Cure rate after surgery in

  • Fibromuscular dysplasias ~ 80%

  • Atherosclerotic stenosis ~ 60 - 75%


Urinary Tract Obstruction (Obstructive Uropathy)

  • Recognition of urinary obstruction is important because of:

  • Increased susceptibility to infection

  • Increased susceptibility to stone formation

  • Unrelieved obstruction almost always leads to permanent renal atrophy, termed hydronephrosis or obstructive uropathy


Causes of Urinary Tract Obstruction

  • Congenital anomalies

  • Posterior urethral valves and urethral strictures

  • Meatal stenosis

  • Bladder neck obstruction

  • Ureteropelvic junction narrowing or obstruction

  • Severe vesicoureteral reflux

  • Urinary calculi

  • Benign prostatic hypertrophy

  • Tumors

  • Carcinoma of the prostate

  • Bladder tumors

  • Contiguous malignant disease (retroperitoneal lymphoma)

  • Carcinoma of the cervix or uterus

  • Inflammation

  • Prostatitis

  • Ureteritis

  • Urethritis

  • Retroperitoneal fibrosis

  • Sloughed papillae or blood clots

  • Normal pregnancy

  • Uterine prolapse and cystocele

  • Functional disorders:

  • Neurogenic (spinal cord damage)

  • Other functional abnormalities of the ureter or bladder (often termed dysfunctional obstruction)




  • Hydronephrosis: Dilatation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine

Hydronephrosis of the Kidney

  • Marked dilation of the pelvis and calyces

  • Thinning of renal parenchyma

Morphology

  • When the obstruction is sudden and complete

  • Reduction of glomerular filtration

  • Usually leads to mild dilatation of the pelvis and calyces

  • Sometimes to atrophy of the renal parenchyma

  • When the obstruction is subtotal or intermittent, glomerular filtration is not suppressed, and progressive dilatation ensues

  • Depending on the level of urinary block, the dilation may affect first the bladder or ureter and then the kidney.

  • Grossly, the kidney may have slight-to-massive enlargement.

  • Histologically,

  • Cortical tubular atrophy with interstitial fibrosis.

  • Progressive blunting of the apices of the pyramids occurs, and eventually these become cupped.

  • In far-advanced cases, the kidney may become transformed into

  • A thin-walled cystic structure having a diameter of up to 15 to 20 cm

  • Striking parenchymal atrophy

  • Total obliteration of the pyramids

  • Thinning of the cortex.

Clinical Course

Acute obstruction



  • May provoke pain attributed to distention of the collecting system or renal capsule.

  • Most of the early symptoms are produced by the basic cause of the hydronephrosis.

  • Thus, calculi lodged in the ureters may give rise to renal colic, and prostatic enlargements to bladder symptoms.

Unilateral, complete, or partial hydronephrosis

  • May remain silent for long periods of time, since the unaffected kidney can maintain adequate renal function.

In bilateral partial obstruction

  • Earliest manifestation is that of inability to concentrate the urine, reflected by polyuria and nocturia.

  • Some patients will have acquired distal tubular acidosis, renal salt wasting, and secondary renal calculi, and a typical picture of tubulointerstitial nephritis with scarring and atrophy of the papilla and medulla.

  • Hypertension is common in such patients.

Complete bilateral obstruction

  • Results in oliguria or anuria

  • Is incompatible with long survival unless the obstruction is relieved.


Urolithiasis (Renal Calculi, Stones)

  • Stones may form at any level in the urinary tract, but most arise in the kidney

  • Urolithiasis is a frequent clinical problem, affecting 5 to 10% of Americans in their lifetime

  • Males are affected more often than females

  • Peak age at onset is between 20 and 30 years.

  • Familial and hereditary predisposition to stone formation has long been known

  • Many of the inborn errors of metabolism, such as gout, cystinuria, and primary hyperoxaluria, provide good examples of hereditary disease characterized by excessive production and excretion of stone-forming substances.

Cause and Pathogenesis

  • There are four main types of calculi:

  • Calcium oxalate, or mixed with calcium phosphate (75%)

  • “Triple stones” or struvite stones, composed of magnesium ammonium phosphate (15%)

  • Uric acid stones (6%)

  • Cystine (1-2%)

  • An organic matrix of mucoprotein, making up 1 to 5% of the stone by weight, is present in all calculi.

  • Although there are many causes for the initiation and propagation of stones, the most important determinant is an increased urinary concentration of the stones’ constituents, such that it exceeds their solubility in urine (supersaturation).

  • A low urine volume in some metabolically normal patients may also favor supersaturation.

Urolithiasis (Renal Calculi, Stones)



Calcium Oxalate stones

  • Hypercalciuria

  • Hypercalcemia

  • Hyperuricosuria

  • Hyperoxalauria

  • Hypocitraturia




  • Calcium oxalate stones are associated

  • With both hypercalcemia and hypercalciuria (5% of patients)

  • Hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states.

  • Hypercalciuria without hypercalcemia (~ 55%)

  • Absorptive hypercalciuria - hyperabsorption of calcium from the intestine

  • Renal hypercalciuria - an intrinsic impairment in renal tubular reabsorption of calcium

  • Idiopathic fasting hypercalciuria with normal parathyroid function.

  • ~ 20% are associated with increased uric acid secretion (hyperuricosuric calcium nephrolithiasis), with or without hypercalciuria.

  • The mechanism of stone formation in this setting involves “nucleation” of calcium oxalate by uric acid crystals in the collecting ducts.

  • ~ 5% associated with hyperoxaluria, either hereditary (primary oxaluria) or, more commonly, acquired by intestinal overabsorption in patients with enteric diseases.

  • The latter, so-called “enteric hyperoxaluria,” also occurs in vegetarians, because much of their diet is rich in oxalates.

  • Hypocitraturia associated with acidosis and chronic diarrhea of unknown cause may produce calcium stones.

  • In a variable proportion of patients with calcium stones no cause can be found (idiopathic calcium stone disease).



Magnesium ammonium phosphate stones:

  • Are formed largely following infections by urea-splitting bacteria (e.g., proteus and some staphylococci), which convert urea to ammonia.

  • The resultant alkaline urine causes the precipitation of magnesium ammonium phosphate salts.

  • These form some of the largest stones, as the amounts of urea excreted normally are huge.

  • Staghorn calculi are almost always associated with infection.


Uric acid stones:

  • Are common in patients with hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as the leukemias.

  • In contrast to the radiopaque calcium stones, uric acid stones are radiolucent.

Cystine stones:

  • Are associated with a genetically determined defect in the renal transport of certain amino acids, including cystine

General

  • Stones are unilateral in about 80% of patients.

  • The favored sites for their formation are

  • Within the renal calyces and pelves

  • In the bladder

  • If formed in the renal pelvis:

  • Tend to remain small

  • Have an average diameter of 2 to 3 mm

  • May have smooth contours or

  • may take the form of an irregular, jagged mass of spicules.

  • Occasionally, progressive accretion of salts leads to the development of branching structures known as staghorn stones, which create a cast of the pelvic and calyceal system.

Clinical Course

  • Stones are of importance when they obstruct urinary flow or produce ulceration and bleeding.

  • They may be present without producing any symptoms or significant renal damage.

  • In general, smaller stones are most hazardous, as they may pass into the ureters, producing pain referred to as colic (one of the most intense forms of pain) as well as ureteral obstruction.

  • Larger stones cannot enter the ureters and are more likely to remain silent within the renal pelvis.

  • Commonly, these larger stones first manifest themselves by hematuria.

  • Stones also predispose to superimposed infection, both by their obstructive nature and by the trauma they produce.

Nephrolitihiasis





  • Large stone impacted in the renal pelvis



Malignant Tumors

  • Renal Cell Carcinoma (Hypernephroma, Adenocarcinoma of Kidney)

  • Urothelial Carcinomas of Renal Pelvis


Renal Cell Carcinoma (Hypernephroma, Adenocarcinoma of Kidney)

  • Renal cell carcinomas represent about 1 to 3% of all visceral cancers and account for 85 to 90% of all renal cancers in adults.

  • Occur most often in older individuals, usually in the sixth and seventh decades of life,

  • A male preponderance in the ratio of 3:1.

  • Because of their gross yellow color and the resemblance of the tumor cells to clear cells of the adrenal cortex, they are also called hypernephroma.

  • These tumors arise from tubular epithelium and are therefore renal adenocarcinomas.

  • A greater frequency of adenocarcinoma of the kidney in cigarette, pipe, and cigar smokers.

  • Genetic factors also play a role

  • Nearly two-thirds of patients with the von Hippel-Lindau syndrome (VHL), characterized by hemangioblastomas of the central nervous system and retina, develop bilateral, often multiple renal cell carcinomas.

Morphology

  • May arise in any portion of the kidney, but more commonly it affects the poles, particularly the upper one.

  • Usually these neoplasms occur as solitary unilateral lesions.

  • They are spherical masses, 3 to 15 cm in diameter, composed of bright yellow—gray-white tissue that distorts the renal outline.

  • Commonly there are large areas of ischemic, opaque, gray-white necrosis, foci of hemorrhagic discoloration, and areas of softening.

  • The margins are usually sharply defined and confined within the renal capsule

  • However, small satellite nodules are often found in the surrounding substance, providing clear evidence of the aggressiveness of these lesions.

  • As the tumor enlarges, it may bulge into the calyces and pelvis and eventually may fungate through the walls of the collecting system to extend even into the ureter.

  • One of the striking characteristics of this tumor is its tendency to invade the renal vein and grow as a solid column of cells within this vessel.

  • Further extension produces a continuous cord of tumor in the inferior vena cava and even in the right side of the heart.




  • Histologically, the growth pattern varies from papillary to solid, trabecular (cord-like), or tubular (resembling tubules).

  • In any single tumor, all variations in patterns of growth may be present.

  • The most common tumor cell type (70% of cases) is the clear cell, having a rounded or polygonal shape and abundant clear cytoplasm

  • Fifteen per cent are papillary, composed of either clear cells or granular cells (granular cell renal carcinoma).

  • Have a moderately eosinophilic cytoplasm, grow in sarcomatoid pattern, and have a decidedly worse prognosis.

  • Most tumors are well differentiated (grades I and II), but some (grade IV) show marked nuclear atypia with formation of bizarre nuclei and giant cells.

  • The stroma is usually scanty but highly vascularized.

Clinical Course

  • The three classic diagnostic features of unfortunately appear in only 10% of cases.

  • costovertebral pain,

  • palpable mass, and

  • hematuria

  • The most reliable of the three is hematuria, which eventually appears in about 90% of cases.

  • However, the hematuria is usually intermittent and may be microscopic

  • Generalized constitutional symptoms, such as fever, malaise, weakness, and weight loss.

  • This pattern of asymptomatic growth occurs in many patients, so that the tumor may have reached a diameter of more than 10 cm when it is discovered.

  • Renal cell carcinoma is classified as one of the great “mimics” in medicine, because it tends to produce a diversity of systemic symptoms not related to the kidney. In addition to the fever and constitutional symptoms mentioned earlier, renal cell carcinomas produce a number of paraneoplastic syndromes ascribed to abnormal hormone production, including polycythemia, hypercalcemia, hypertension, hepatic dysfunction, feminization or masculinization, Cushing’s syndrome, eosinophilia, leukemoid reactions, and amyloidosis.

  • One of the common characteristics of this tumor is its tendency to metastasize widely before giving rise to any local symptoms or signs.

  • In 25% of new patients with renal cell carcinoma, there is radiologic evidence of metastases at presentation.

  • The most common locations of metastasis are the lungs (over 50%) and bones (33%), followed in order by the regional lymph nodes, liver and adrenals, and brain.

  • In 10 to 15% of cases, the primary tumor metastasizes across the midline to the opposite kidney.

  • It is essential that renal cell carcinomas be diagnosed at the earliest possible stage, which is usually accomplished during the investigation of hematuria in a middle-aged or an elderly patient.

  • Renal ultrasonography, nephrotomography, computed tomography scanning, and intravenous pyelography aid in the differential diagnosis of a simple cyst from a tumor.

  • Urinary cytology may also be helpful in identifying tumor cells.

  • The average 5-year survival of patients with renal cell carcinoma is about 45%, and up to 70% in the absence of distant metastases.

  • With renal vein invasion or extension into the perinephric fat, the figure is reduced to approximately 15 to 20%.

  • Nephrectomy is the treatment of choice.



Urothelial Carcinomas of Renal Pelvis

  • ~ 5 to 10% of primary renal tumors occur in the renal pelvis

  • These tumors span the range from apparently benign papillomas to frank papillary carcinomas, but, as with bladder tumors, the benign papillomas are difficult to differentiate from the low-grade papillary cancers.

  • Renal pelvic tumors usually become clinically apparent within a relatively short time because they lie within the pelvis and, by fragmentation, produce noticeable hematuria. They are almost invariably small when discovered.

  • These tumors are almost never palpable clinically; however, they may block the urinary outflow and lead to palpable hydronephrosis and flank pain.

  • Occasionally, urothelial tumors may be multiple, involving the pelvis, ureters, and bladder.

  • Infiltration of the wall of the pelvis and calyces is common, and renal vein involvement likewise occurs.

  • For this reason, despite their apparently small, deceptively benign appearance, the prognosis for these tumors is not good.

  • Five-year survival rates vary from 50 to 70% for low-grade superficial lesions to 10% with high-grade infiltrating tumors.


WILMS TUMOR

DEFINITION:



  • An embryonal renal neoplasm characterized usually by an abdominal mass.

EPIDEMIOLOGY:

  • Prevalence:

  • 1/12,000 live births

  • 2nd most common extracranial solid tumor in children

  • makes up 7% of all childhood cancers

  • Peak age of onset:

  • 6 months - 10 years (greatest in first 5 years)

  • Risk factors:

  • familial - autosomal dominant (in some families)

  • chrom.#: 11p13

  • M = F

  • Most common renal cancer in children

Pathogenesis

  • Tumor origin - kidney (bilateral in only 5%)

  • Wilms' tumor is a nephroblastoma which can arise by a variety of pathogenic pathways from primitive metanephric blastema

  • The gene for Wilms' tumor (WT2-1) is located at 11p13

  • Encodes a DNA-binding protein that is expressed

  • Primarily in the fetal kidney

  • In tissue that gives rise to the genitourinary system

  • Inactivation of this gene may be responsible for the occurrence of a Wilms' tumor


Wilms Tumor associated anomalies

1. WAGR Syndrome



  • Wilms' tumor

  • Aniridia

  • lack or defect of the iris

  • Genitourinary Anomalies

  • gonadal dysgenesis, hypospadias, cryptorchidism, duplication of collecting system

  • mental Retardation

  • deletion of chromosome 11p13

  • tumor develops at a younger age

  • increased incidence of bilateral tumor

2. Beckwith-Wiedemann Syndrome

  • rearrangement of chromosome 11p15

  • hemihypertrophy

3. Drash Syndrome

  • Wilm's Tumor

  • Nephropathy - hypertension, proteinuria, renal failure

  • Genitourinary Anomalies - ambiguous genitalia

4. Perlman Malformation Syndrome



Table exam:

0-4 years

Leukemia:

Retinoblastoma

Neuroblastoma

Wilms tumor
5-9 years

Leukemia

Retinoblastoma

Wilms tumor

Ewings tumor
10-14 years:

hepatocarcinoma

osteogenic sarcoma

thyroid carcinoma

hodgkins

Pathology of Wilms Tumor



  • Macroscopic

  • usually confined to the kidney

  • most of affected kidney usually replaced

  • may be cystic

  • Histologic Types

  • Phasic

  • Classic histology is triphasic: blastemal, epithelial, and/or stromal elements

  • constitute 90% of tumors: favourable prognosis

  • Anaplastic

  • constitute 10% of tumors: unfavourable prognosis

Pathology of Wilms Tumor



  • Usually confined to the kidney

  • Most of affected kidney usually replaced

Pathology of Wilms Tumor


Triphasic histology of Wilms Tumor


  • Stromal, less cellular area (left)

  • Spindle and epithelial cells (center)

  • Blastemal cells (Tightly packed blue cells)

Pathology of Wilms Tumor


  • Tumor shows attempts at formation of primitive glomerulus and tubules


CLINICAL FEATURES

  • Primary Tumor

  • Abdominal mass

  • Abdominal pain

  • Hematuria - gross or microscopic, painless, in up to 25%

  • Hypertension - in 25% (due to renin-secreting tumor or renovascular hypertension)

  • Others - fever, malaise, anemia, weight loss, left varicocele

  • Syndromes - aniridia, hemihypertrophy, etc.

  • Metastases

  • Lung (10% have metastasis at time of diagnosis, isolated or multiple)

  • Lymph nodes

  • Liver

  • Brain

  • Rare - bone, skin, pleura, heart, epidural space

Investigations

Imaging Studies

  • Tumor

  • Abdominal X-Ray (rim-ring calcification)

  • Abdominal Ultrasound (intra- or extrarenal, uni- or bilateral, uni- or multi-focal, solid or cystic)

  • Abdominal CT

  • IVP - internal compression of calyceal system

  • For Metastases

  • Chest X-Ray

  • CT Chest



STAGING

  • National Wilms' Tumor Society (NWTS)

  • Stages I -> V

  • Staging system has prognostic significance

  • Stage I

  • The tumor is limited to the kidney.

  • Stage II

  • The tumor extends beyond the kidney.

  • Stage III

  • Residual non-hematogenous tumor is present, and confined to the abdomen.

  • Stage IV

  • Hematogenous metastases (lung, liver, bone, brain, etc.)

  • Lymph node metastases outside the abdomino-pelvic region

  • Stage V

  • Bilateral renal involvement is present at diagnosis.

PROGNOSTIC INDICATORS:

1. Stage


  • extent of tumor

2. Histology

  • favourable or unfavourable

3. Basic Fibroblast Growth Factor (bFGF)

  • a heparin-bound blood vessel-generating peptide associated with the growth and spread of bladder, prostate, and kidney cancer

  • measured as pg/g creatinine in the urine

  • for those with Stage III or IV, preoperative bFGF levels are 25x higher than in those with Stage I or II

  • for those with persistent or recurrent Wilms' tumor, post-operative bFGF levels are 100x higher than in those who remain disease-free

  • there is a 1.6x greater chance of tumor recurrence in those with elevated postoperative bFGF levels

MANAGEMENT

  • Surgery

  • Primary and second-look operations

  • Removal of involved kidney with evaluation and biopsy of the opposite kidney

  • Explore for extension, lymph node involvement, liver metastases

  • Chemotherapy

  • Actinomycin-D and vincristine +/- Doxorubicin

  • Prognosis

  • Greater than 85% cure rare with current therapy

  • Stage - Cure Rate

  • I - 98%

  • II - 95%

  • III - 90%

  • IV - 80%




Diseases of the Lower Urinary Tract


  • Ureters

  • Congenital Anomalies

  • Inflammations

  • Tumors/ tumor-like conditions

  • Obstructive Lesions

  • Urinary Bladder

  • Congenital Anomalies

  • Inflammations

  • Neoplasms

  • Obstructions

  • Urethra

Congenital Anomalies of the Ureter

Double and bifid ureters:



  • Derived from a double or split ureteral bud

  • Almost invariably associated either with

  • Totally distinct double renal pelves

  • Anomalous development of a very large kidney, having a partially bifid pelvis terminating in separate ureters

  • May pursue separate courses to the bladder but commonly are joined within the bladder wall and drain through a single ureteral orifice.

Ureteropelvic junction obstruction (UPJ):

  • A congenital disorder

  • Results in hydronephrosis

  • Usually presents in male infants

  • More common in the left ureter

  • For unknown reasons, there is agenesis of the contralateral kidney

Diverticula:

  • Saccular outpouchings of the ureteral wall

  • Congenital / acquired

  • Are of importance as pockets of stasis and secondary infections

Hydroureter:

  • Dilatation, elongation, and tortuosity of the ureters

  • Congenital / acquired

  • Reflects some neurogenic defect in the innervation of the ureteral musculature

Megaloureter:

  • Massive enlargement of the ureter

  • Due to a functional defect of ureteral muscle.


Diverticula

  • A pouch-like eversion or evagination of the bladder wall

  • Congenital/ acquired due to persistent urethral obstruction

  • with prostatic enlargement (hyperplasia or neoplasia)

  • Usually consists of a round-to-ovoid, sac-like pouch that varies from <1 cm to 5-10 cm in diameter.

  • Clinical significance:

  • Constitute sites of urinary stasis

  • Predispose to

  • Infection

  • Formation of bladder calculi.

  • Vesicoureteric reflux

  • Rarely, carcinomas may arise in bladder diverticuli

Acute cystitis

  • Secondary to bacterial infection (usually E. coli)

  • Other pathogens include Proteus, Klebsiella, Staphylococcus saprophyticus, and Enterobacter spp.

  • Other causes of cystitis include:

  • Adenovirus

  • Instrumentation

  • Cyclophosphamide therapy (hemorrhagic cystitis)

  • Most commonly due to ascending infection from urethra (women > men)

  • Secondary to trauma during intercourse

  • Organisms originate from fecal flora in women and prostate in men

  • Clinical features:

  • Frequency of urination, dysuria, sense of urgency, discomfort over the bladder (suprapubic); fever is uncommon

  • Urinalysis:

  • Pyuria, hematuria sometimes

  • Positive dipstick for nitrite and leukocyte esterase

  • WBC casts would indicate acute pyelonephritis



Malakoplakia

  • Chronic inflammatory cystitis characterized by yellow plaques, nodules, or polyps in the bladder mucosa.

  • Microscopically:

  • Accumulations of macrophages filled with round, laminated concretions (Michaelis-Gutman bodies) which stain positive with PAS, calcium, and iron stains.

  • Is most commonly found in the bladder; also found in renal pelvis, ureter, prostate, epididymis, colon, and lungs

  • Related to chronic bacterial infection, mostly E.coli



  • Large macrophages with granular PAS positive cytoplasm

  • Several dense round Michaelis Gutman bodies

Bladder Neoplasms

  • Increasing incidence

  • Around 10,000 deaths in the US annually

  • ~95% are epithelial in origin

  • 90% are composed of urothelial (transitional) cell type

  • ~5% are mesenchymal tumors


Urothelial (Transitional) cell Tumors

Classified into two major categories:



  • Low grade urothelial tumors

  • Always papillary

  • Non-invasive

  • Recurrent

  • Excellent prognosis

  • High grade urothelial carcinoma

  • Maybe papillary / nodular or both

  • Exhibit pleomorphism and anaplasia

  • Frequently metastasize

  • Poor prognosis

Grading of Urothelial Tumors

  • WHO Classification (1972)

  • Papilloma

  • TCC Grade I

  • TCC Grade II

  • TCC Grade III

  • ISUP Consensus (International Society of Urological Pathology-1998)

  • Urothelial Papilloma

  • Urothelial neoplasm of low malignant potential

  • Urothelial Carcinoma, low grade

  • Urothelial Carcinoma, high grade



Urothelial (Transitional) cell Tumors

  • 50% of all bladder tumors are high grade lesions

  • Most arise from the posterior/ lateral wall of the base of the bladder

  • Gross appearance of all vesical cancers may be described as:

  • Papillary – exophytic polypoid lesions attached by a stalk to the mucosa. Penetration of the basement membrane by the neoplastic cells may or may not be present.

  • Flat lesions – growing as plaque-like thickenings of the mucosa without the formation of well-defined papillary structures

  • May be in situ or invasive (more often the latter)

  • More anaplastic than the papillary lesions.

  • Noninvasive – thickening of the mucosa by proliferation of cancer cells, but without penetration of the basement membrane.

  • Invasive – penetrating the mucosal basement membrane into the bladder wall, and possibly into contiguous structures.

Morphologic patterns of Bladder Carcinoma

TEST: PICTURE

Papilloma of Urinary Bladder

  • Small branching structure

  • Individual finger-like papillae have a central core of loose

fibrovascular tissue covered by normal-appearing transitional

cells seven or fewer layers in thickness



  • Cells recapitulate the normal architecture of

transitional urinary tract epithelium

Normal Transitional Epithelium of the Bladder




Morphology of Urothelial Tumors
GRADE I:

  • Tumor cells display some atypia

  • But are well differentiated

  • Closely resemble normal transitional cells

  • Mitoses are rare

  • There is a significant increase in the number of layers of cells, that is, more than seven layers but only slight loss of polarity

Grade I (Low Malignant Potential Tumor)

GRADE II


  • Tumor cells are still recognizable as of transitional origin.

  • The number of layers of cells is increased (often more than ten),

  • Number of mitoses is increased

  • There is greater loss of polarity

  • Greater variability in cell size, shape, and chromaticity is present.

GRADE III

  • Tumor cells are barely recognizable as of transitional origin

  • All the changes of grade II are more aggravated

  • Disarray of cells with loosening and fragmentation of the superficial layers of cells.

  • Sometimes the cells tend to flatten out, and the lesions come to resemble squamous cell carcinomas

  • Alternatively, foci of glandular differentiation may be present.

Grade III (High Grade)

Carcinoma In Situ



  • Carcinoma in situ (CIS) is a high-grade flat abnormality confined to the bladder mucosa

  • Usually occurs as a diffuse area of mucosal reddening, granularity, or thickening without producing an evident intraluminal mass

  • In some instances the in situ changes involve most of the bladder surface and may even extend into the ureters and urethra



Other Types of Bladder Carcinoma

  • Squamous cell carcinomas represent about 3 to 7% of bladder cancers.

  • Arise in areas of squamous metaplasia of the bladder mucosa

  • Adenocarcinomas of the bladder are rare.

  • Rare variants are

  • Highly malignant signet cell carcinoma

  • Mixed adenocarcinoma and transitional cell carcinomas.

Epidemiology and Pathogenesis

  • The incidence of carcinoma of the bladder resembles that of bronchogenic carcinoma

  • Males > females (3:1)

  • Industrialized > developing nations

  • Urban > rural dwellers

  • About 80% of patients are between the ages of 50 and 80 years.


Factors implicated in the causation of TCC

  • Cigarette smoking is clearly the most important influence

  • Risk increased three- to sevenfold

  • Depends on the pack-years and smoking habits

  • Industrial exposure to arylamines, particularly 2-naphthylamine

  • Cancers appear 15 to 40 years after the first exposure.

  • Schistosoma haematobium infections are an established risk

  • Ova deposited in the bladder wall > brisk chronic inflammatory response > progressive mucosal squamous metaplasia, dysplasia and neoplasia

  • ~ 70% of the cancers are squamous cell in type, the remainder being TCC.

  • Long-term use of phenacetin, implicated also in analgesic nephropathy

  • Heavy long-term exposure to cyclophosphamide induces hemorrhagic cystitis

  • Increases the risk of bladder cancer almost tenfold after 12 years of exposure


Clinical Course of Bladder Cancer

  • All bladder tumors classically produce painless hematuria

  • Their dominant and sometimes only clinical manifestation.

  • Occasionally, frequency, urgency, and dysuria accompany the hematuria.

  • When the ureteral orifice is involved, pyelonephritis or hydronephrosis may follow.

  • When first discovered

  • ~60% neoplasms are single

  • ~70% localized to the bladder

  • Urothelial tumors, whatever their grade, have a tendency to recur following excision, and usually the recurrence exhibits a higher grade

  • ~50% of papillomas and low-grade carcinomas recur

  • ~80-90% of high grade tumors recur


Prognosis of Bladder Cancers

  • Papillomas and Grade I cancers (those of low malignant potentials)

  • 98% 10-year survival rate regardless of the number of recurrences

  • Grade III cancer

  • ~ 40% 10-year survival rate

  • Squamous cell carcinomas

  • ~70% mortality within a year

  • The prognosis depends on:

  • Histologic pattern

  • Grade of the tumor

  • Stage when first diagnosed

  • Other factors that may influence the prognosis:

  • Expression of blood group antigens by tumor cells

  • Tumor cells that express A, B, and H antigens have a better prognosis than those that do not or lose this capacity

  • Analogously, the detection of a T antigen, increased c-myc expression, and multiple chromosomal mutations all worsen the outlook.


Diagnosis of Bladder Cancers

  • The clinical challenge with these neoplasms is early detection and adequate follow-up

  • Cytoscopy and biopsy are the mainstays of diagnosis for regular neoplastic lesions

  • Difficult to detect lesions

  • Carcinoma in situ producing no or only subtle gross mucosal changes

  • Early small papillary lesions

  • Of value in these circumstances are

  • Cytologic examination

  • Flow cytometric analyses of urinary sediment specially for DNA content – differentiates the high-grade tumors from the benign ones


Mesenchymal Tumors

Benign:


  • Variety of benign mesenchymal tumors may arise in the bladder

  • Are rare

  • Most common is leiomyoma

  • All tend to grow as isolated, intramural, encapsulated, oval-to-spherical masses, varying in diameter up to several centimeters

Sarcomas:

  • Uncommon in the bladder

  • Produce large masses (10-15 cm in diameter) that protrude into the vesical lumen

  • Are soft, fleshy, gray-white in gross appearance

  • Rhabdomyosarcoma takes one of two forms:

  • “Adult” form occurs mostly in adults older than 40 years of age

  • Embryonal rhabdomyosarcoma, or sarcoma botryoides

  • Most common sarcoma in children

  • Present with grape-like masses

  • Protruding from the urethra in males (arise in the prostate) and vagina in females


Secondary Tumors

  • Most often by direct extension from primary lesions in nearby organs

  • Cervix

  • Uterus

  • Prostate

  • Rectum

  • Common sequelae:

  • Hemorrhage

  • Ureteral obstruction

  • Vesicovaginal fistulas


Obstruction of Urinary Bladder

  • Variety of intrinsic and extrinsic diseases of the bladder narrow the urethral orifice and cause partial or complete vesical obstruction.

  • In males: Most important lesion is enlargement of the prostate gland due either to nodular hyperplasia or to carcinoma

  • In females: Vesical obstruction is somewhat less common

  • Is most often caused by cystocele of the bladder

  • The more infrequent causes can be listed as:

  • Congenital narrowings or strictures of the urethra

  • Inflammatory strictures of the urethra

  • Inflammatory fibrosis and contraction of the bladder following varying types of cystitis

  • Bladder tumors –either benign or malignant–when strategically located

  • Secondary invasion of the bladder neck by growths arising in perivesical structures, such as the cervix, vagina, prostate, and rectum

  • Mechanical obstructions caused by foreign bodies and calculi

  • Injury to the innervation of the bladder causing neurogenic or cord bladder.

Morphology

  • In the early stages:

  • Some thickening of the bladder wall, presumably due to hypertrophy of the smooth muscle.

  • Mucosal surface may be entirely normal.

  • With progressive hypertrophy of the muscular coat:

  • Individual muscle bundles greatly enlarge

  • Produce trabeculation of the bladder wall

  • Crypts form and may then become converted into true acquired diverticula.

Obstruction of Urinary Bladder


Urethra-Inflammation

  • Urethritis is classically divided into

  • Gonococcal - Is one of the earliest manifestations of this venereal infection

  • Nongonococcal urethritis

  • Is very common

  • Caused by a variety of bacteria specially E. coli and other enteric organisms

  • Urethritis is often accompanied by cystitis in females and prostatitis in males.

  • Chlamydia trachomatis is responsible for 25 - 60%

  • Urethritis is also one component of Reiter’s syndrome – arthritis+ conjunctivitis+ urethritis.

  • May cause considerable

  • Local pain

  • Itching

  • Frequency



Tumors - Urethral caruncle

  • Is an inflammatory lesion presenting as a small, red, painful mass about the external urethral meatus in the female

  • Found at any age

  • More common in later life

  • Grossly:

  • A hemispheric, friable, 1-2 cm nodule

  • Occurs singly, either just outside or just within the external urethral meatus

  • May be covered by an intact mucosa

  • Is extremely friable, and the slightest trauma may cause ulceration of the surface and bleeding.

  • Histologically:

  • Composed of a highly vascularized, young, fibroblastic connective tissue, more or less heavily infiltrated with leukocytes

  • The overlying epithelium, where present, is either transitional or squamous cell in type

  • Treatment: Surgical excision


Tumors of the Urethra

Papillomas:



  • Occur usually just within or on the external meatus.

  • They may be of viral origin, analogous to those affecting the vulva.

Carcinoma of the urethra:

  • Is an uncommon lesion

  • It tends to occur in advanced age in women

  • Begins about the external meatus or on the immediately surrounding structures, such as the glans penis or the introitus in the female.

  • Appear as warty, papillary growths that at first resemble the sessile papillary carcinomas in the bladder.

  • As they progress, they tend to become ulcerated on their surfaces and to assume the characteristics of a fungating, ulcerating lesion

  • Most of these malignancies are squamous cell carcinomas.

  • Overall, they are more aggressive than bladder cancers, more often invasive, and more difficult to eradicate despite the fact that they seldom metastasize probably because most lead to death within a few years.



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