Urinary system outflow obstruction and urinary system tumors

1. Urinary system outflow obstruction and urinary system tumors Doç. Dr. Işın Doğan Ekici

2. URINARY OUTFLOW OBSTRUCTION

3. Renal Stones • Urolithiasis is calculus formation at any level in the urinary collecting system, but most often the calculi arise in the kidney. • They occur frequently, as is evidenced by the finding of stones in about 1% of all autopsies. • Symptomatic urolithiasis is more common in men than in women. • A familial tendency toward stone formation has long been recognized.

4. Pathogenesis • About 80% of renal stones are composed of either calcium oxalate or calcium oxalate mixed with calcium phosphate. • Another 10% are composed of magnesium ammonium phosphate, and 6% to 9% are either uric acid or cystine stones. • In all cases, there is an organic matrix of mucoprotein that makes up about 2.5% of the stone by weight

5. Pathogenesis • The cause of stone formation is often obscure, particularly in the case of calcium-containing stones. • Probably involved is a confluence of predisposing conditions. • The most important cause is increased urine concentration of the stone's constituents, so that it exceeds their solubility in urine (supersaturation).

6. 50% of patients who develop calcium stones have hypercalciuria that is not associated with hypercalcemia. • Most in this group absorb calcium from the gut in excessive amounts (absorptive hypercalciuria) and promptly excrete it in the urine, and some have a primary renal defect of calcium reabsorption (renal hypercalciuria).

7. In 5% to 10% of persons with this diagnosis there is hypercalcemia (due to hyperparathyroidism, vitamin D intoxication, or sarcoidosis) and consequent hypercalciuria. • In 20% of this subgroup, there is excessive excretion of uric acid in the urine, which favors calcium stone formation; presumably the urates provide a nidus for calcium deposition. • In 5% there is hyperoxaluria or hypercitraturia, and in the remainder there is no known metabolic abnormality. A high urine pH favors crystallization of calcium phosphate and stone formation.

8. The causes of the other types of renal stones are better understood. Magnesium ammonium phosphate (struvite) stones almost always occur in persons with a persistently alkaline urine due to UTIs. • In particular, the urea-splitting bacteria, such as Proteus vulgaris and the staphylococci, predispose the person to urolithiasis. • Moreover, bacteria may serve as particulate nidi for the formation of any kind of stone. In avitaminosis A, desquamated cells from the metaplastic epithelium of the collecting system act as nidi.

9. Gout and diseases involving rapid cell turnover, such as the leukemias, lead to high uric acid levels in the urine and the possibility of uric acid stones. • About half of the individuals with uric acid stones, however, have neither hyperuricemia nor increased urine urate but an unexplained tendency to excrete a persistently acid urine (under pH 5.5).

10. This low pH favors uric acid stone formation-in contrast to the high pH that favors formation of stones containing calcium phosphate. • Cystine stones are almost invariably associated with a genetically determined defect in the renal transport of certain amino acids, including cystine. • In contrast to magnesium ammonium phosphate stones, both uric acid and cystine stones are more likely to form when the urine is relatively acidic.

11. Urolithiasis may also result from the lack of substances that normally inhibit mineral precipitation. Inhibitors of crystal formation in urine include Tamm-Horsfall protein, osteopontin, pyrophosphate, mucopolysaccharides, diphosphonates, and a glycoprotein called nephrocalcin, but no deficiency of any of these substances has been consistently demonstrated in individuals with urolithiasis.

12. Morphology • Stones are unilateral in about 80% of patients. Common sites of formation are renal pelves and calyces and the bladder. • Often, many stones are found in one kidney. They tend to be small (average diameter 2-3 mm) and may be smooth or jagged. • Occasionally, progressive accretion of salts leads to the development of branching structures known as staghorn calculi, which create a cast of the renal pelvis and calyceal system. These massive stones are usually composed of magnesium ammonium phosphate.

13. Stones may be present without producing either symptoms or significant renal damage. • This is particularly true with large stones lodged in the renal pelvis. • Smaller stones may pass into the ureter, producing a typical intense pain known as renal or ureteral colic, characterized by paroxysms of flank pain radiating toward the groin. • Often at this time there is gross hematuria. • The clinical significance of stones lies in their capacity to obstruct urine flow or to produce sufficient trauma to cause ulceration and bleeding. In either case, they predispose the sufferer to bacterial infection. Fortunately, in most cases the diagnosis is readily made radiologically.

14. Hydronephrosis • Hydronephrosis refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine. • The obstruction may be sudden or insidious, and it may occur at any level of the urinary tract, from the urethra to the renal pelvis. • The most common causes are as follows

15. Congenital: Atresia of the urethra, valve formations in either ureter or urethra, aberrant renal artery compressing the ureter, renal ptosis with torsion, or kinking of the ureter • Acquired: • Foreign bodies: Calculi, necrotic papillae • Tumors: Benign prostatic hyperplasia, carcinoma of the prostate, bladder tumors (papilloma and carcinoma), contiguous malignant disease (retroperitoneal lymphoma, carcinoma of the cervix or uterus) • Inflammation: Prostatitis, ureteritis, urethritis, retroperitoneal fibrosis • Neurogenic: Spinal cord damage with paralysis of the bladder • Normal pregnancy: Mild and reversible

17. Bilateral hydronephrosis occurs only when the obstruction is below the level of the ureters. • If blockage is at the ureters or above, the lesion is unilateral. • Sometimes obstruction is complete, allowing no urine to pass; usually it is only partial.

18. Pathogenesis • Even with complete obstruction, glomerular filtration persists for some time, and the filtrate subsequently diffuses back into the renal interstitium and perirenal spaces, whence it ultimately returns to the lymphatic and venous systems. • Because of the continued filtration, the affected calyces and pelvis become dilated, often markedly so. • The unusually high pressure thus generated in the renal pelvis, as well as that transmitted back through the collecting ducts, causes compression of the renal vasculature. • Both arterial insufficiency and venous stasis result, although the latter is probably more important. • The most severe effects are seen in the papillae, because they are subjected to the greatest increases in pressure.

19. Accordingly, the initial functional disturbances are largely tubular, manifested primarily by impaired concentrating ability. • Only later does glomerular filtration begin to diminish. • Experimental studies indicate that serious irreversible damage occurs in about 3 weeks with complete obstruction, and in 3 months with incomplete obstruction. • However, functional impairment can be demonstrated only a few hours after ureteral ligation. • The obstruction also triggers an interstitial inflammatory reaction, leading eventually to interstitial fibrosis.

20. Morphology • Bilateral hydronephrosis (as well as unilateral hydronephrosis when the other kidney is already damaged or absent) leads to renal failure, and the onset of uremia tends to abort the natural course of the lesion. • In contrast, unilateral involvements display the full range of morphologic changes, which vary with the degree and speed of obstruction. • With subtotal or intermittent obstruction, the kidney may be massively enlarged (lengths in the range of 20 cm), and the organ may consist almost entirely of the greatly distended pelvicalyceal system. • The renal parenchyma itself is compressed and atrophied, with obliteration of the papillae and flattening of the pyramids.

21. On the other hand, when obstruction is sudden and complete, glomerular filtration is compromised relatively early, and as a consequence, renal function may cease while dilation is still comparatively slight. • Depending on the level of the obstruction, one or both ureters may also be dilated (hydroureter).

22. Microscopically the early lesions show tubular dilation, followed by atrophy and fibrous replacement of the tubular epithelium with relative sparing of the glomeruli. • Eventually, in severe cases the glomeruli also become atrophic and disappear, converting the entire kidney into a thin shell of fibrous tissue. • With sudden and complete obstruction, there may be coagulative necrosis of the renal papillae, similar to the changes of papillary necrosis. • In uncomplicated cases the accompanying inflammatory reaction is minimal. • Complicating pyelonephritis, however, is common

24. Bilateral complete obstruction produces anuria, which is soon brought to medical attention. When the obstruction is below the bladder, the dominant symptoms are those of bladder distention. • Paradoxically, incomplete bilateral obstruction causes polyuria rather than oliguria, as a result of defects in tubular concentrating mechanisms, and this may obscure the true nature of the disturbance. • Unfortunately, unilateral hydronephrosis may remain completely silent for long periods unless the other kidney is for some reason not functioning. • Often the enlarged kidney is discovered on routine physical examination. Sometimes the basic cause of the hydronephrosis, such as renal calculi or an obstructing tumor, produces symptoms that indirectly draw attention to the hydronephrosis. Removal of obstruction within a few weeks usually permits full return of function; however, with time the changes become irreversible.

25. Hydroureter

26. Bladder and urethra-non-neoplastic diseases

27. CYSTITIS • Infection with enteric bacteria • Women > men (short urethra!) • Predisposing factors • Pregnancy • Calculi • Medical procedures (catheter) • Diabetes • Chemotherapy • Tumors

28. Risk Factorof Cystitis (FIVE Cs) Coitus related (including pregnancy) Calculi Catheter Cancer Chemotherapy

29. Formsof Cystitis • Acute – bacterial • Chronic – bacterial • Chronic interstital – unknown etiology (women) • Malakoplakia – E. coli + macrophages • Iatrogenic • Cystitis is usually of bacterial origin, and has the same story as common pyelonephritis, which it precedes. • Urosepsis still kills many adults of both sexes.

30. Pathology of Cystitis • Neutrophils abound in the acute phase. • In longstanding disease, there is a chronic inflammatory infiltrate and there may be much fibrosis. • Polypoid cystitis is not a tumor at all, but a reactive overgrowth (collagen and/or extra ground substance) in response to ongoing inflammation. • S. hematobium : Squamous metaplasia in endemic areas usually results from infestation with S. hematobium. • The bladder can be ruined by all the eggs in the muscularis propria.

31. Chemotherapy cystitis results from cyclophosphamide ("Cytoxan") or busulfan ("Myleran") administration, and radiation to the pelvic area can also produce a vicious cystitis. • Giant cell cystitis" is a non-disease, merely describing the presence of giant cells in patients who have had radiation or chemotherapy. • Hunner's interstitial / ulcerative cystitis is a poorly-understood process in which all three layers of the bladder become chronically inflamed.

32. Acute cystitis

33. Malakoplakia is a curious macrophage-rich response to E.coli/Proteus infections. • The cells seem to have some problem phagocytizing the bacteria. • Grossly, soft ("malakos" in Greek) yellow plaques. • Microscopy: foamy, lipid-laden (von Hensemann's) macrophages with calcified spherules (Michaelis-Gutmann bodies).

34. Malakoplakia

35. URETHRA • Posterior stricture: • Males • Often congenital • Urethral caruncle: • Female • Near the opening of the urethra • Begins with plugging of the ducts of the glands • Mixed inflammation of the lamina propria, and often with pseudoepitheliomatous hyperplasia of the overlying squamous epithelium

36. Urethral caruncule

37. Urinary tract tumors Renal Tumors Urothelial Tumors

38. Renal Tumors of Childhood • Nephroblastic tumors:● Nephroblastoma     ● Favorable histology     ● Unfavorable histology (diffuse / focal anaplasia)● Nephrogenic rests and nephroblastomatosis● Cystic nephroma and cystic partially differentiated nephroblastoma● Metanephric tumors     ● Metanephric adenoma     ● Metanephric adenofibroma     ● Metanephric stromal tumorMesoblastic nephroma:● Clear cell carcinoma● Rhabdoid tumor of kidney● Renal epithelial tumors of childhood:● Papillary renal cell carcinoma● Renal medullary carcinoma● Translocation associated RCC (Xp11.2 / t(6;11) translocations)Rare tumors:● Ossifying renal tumor of infancy● Angiomyolipoma

39. Renal tumors of Adult • ● Renal cell carcinoma● Renal cortical adenomaMetanephric tumors:● Metanephric adenoma● Metanephric adenofibroma● Metanephric stromal tumor● Metanephric adenosarcoma● OncocytomaRare tumors with epithelial / parenchymal differentiation:● Carcinoid tumor● Small cell carcinoma● Primitive neuroectodermal tumor● Juxtaglomerular cell tumor● Teratoma● Nephroblastoma and other “pediatric” renal tumors● Multilocular cyst (cystic nephroma)● Mixed epithelial and stromal tumor● SpiradenocylindromaMesenchymal tumors:● Angiomyolipoma● Epithelioid angiomyolipoma● Medullary fibroma● Leiomyoma.......

40. Many types of benign and malignant tumors occur in the urinary tract. • In general, benign tumors such as small (<0.5 cm) cortical papillary adenomas or medullary fibromas (interstitial cell tumors) have no clinical significance. • The most common malignant tumor of the kidney is renal cell carcinoma, followed in frequency by nephroblastoma (Wilms tumor) and by primary tumors of the calyces and pelvis. • Other types of renal cancer are rare and need not be discussed here. • Tumors of the lower urinary tract are about twice as common as renal cell carcinomas.

41. Oncocytoma ● 4-7% of adult renal epithelial tumors ● Adults age 50+; 2/3 men; usually incidental ● May co-exist with renal cell carcinoma ● Rarely associated with renal failure due to multiple tumors or large bilateral tumor. Macroscopy: Well defined borders, mahogany brown tumor with stellate central fibrous scar Micro: Benign tumor of uniform round / polygonal cells with abundant, intensely eosinophilic and granular cytoplasm with uniform small, round and central nuclei with evenly dispersed chromatin.

43. Renal Cell Carcinoma • These tumors are derived from the renal tubular epithelium, and hence they are located predominantly in the cortex. • Renal carcinomas represent 80% to 85% of all primary malignant tumors of the kidney, and 2% to 3% of all cancers in adults. • This translates into about 30,000 cases per year; 40% of patients die of the disease. Carcinomas of the kidney are most common from the sixth to seventh decades, and men are affected about twice as commonly as women. • The risk of developing these tumors is higher in smokers, hypertensive or obese patients, and those who have had occupational exposure to cadmium. • Smokers who are exposed to cadmium have a particularly high incidence of renal cell carcinomas. • The risk of developing renal cell cancer is increased 30-fold in individuals who develop acquired polycystic disease as a complication of chronic dialysis. • The role of genetic factors in the causation of these cancers is discussed below.

44. Renal cell cancers were formerly classified on the basis of morphology and growth patterns. • However, recent advances in the understanding of the genetic basis of renal carcinomas have led to a new classification based on the molecular origins of these tumors. • The three most common forms are as follows:

45. Clear cell carcinomas • These are the most common type, accounting for 70% to 80% of renal cell cancers. Histologically, they are made up of cells with clear or granular cytoplasm. • Whereas the majority of them are sporadic, they also occur in familial forms or in association with von Hippel-Lindau (VHL) disease. • It is the study of VHL disease that has provided molecular insights into the causation of clear cell carcinomas. • VHL disease is autosomal dominant and is characterized by predisposition to a variety of neoplasms, but particularly to hemangioblastomas of the cerebellum and retina.

46. Hundreds of bilateral renal cysts and bilateral, often multiple, clear cell carcinomas develop in 40% to 60% of individuals. • Those with VHL syndrome inherit a germ-line mutation of the VHL gene on chromosome 3p25 and lose the second allele by somatic mutation. • Thus, the loss of both copies of this tumor suppressor gene gives rise to clear cell carcinoma. • The VHL gene is also involved in the majority of sporadic clear cell carcinomas. • Cytogenetic abnormalities giving rise to loss of chromosomal segment 3p14 to 3p26 are often seen in sporadic renal cell cancers. • This region harbors the VHL gene (3p25.3).

47. The second, nondeleted allele is inactivated by a somatic mutation or hypermethylation in 60% of sporadic cases. • Thus, homozygous loss of the VHL gene seems to be the common underlying molecular abnormality in both sporadic and familial forms of clear cell carcinomas. • The VHL protein is involved in limiting the angiogenic response to hypoxia; thus, its absence may lead to increased angiogenesis and tumor growth. • An uncommon familial form of clear cell carcinoma unrelated to VHL disease also involves cytogenetic abnormalities involving chromosome 3p.

48. Papillary Renal Cell Carcinomas • These comprise 10% to 15% of all renal cancers. As the name indicates, they show a papillary growth pattern. • These tumors are frequently multifocal and bilateral and appear as early-stage tumors. • Like clear cell carcinomas they occur in familial and sporadic forms, but unlike these tumors, papillary renal cancers have no abnormality of chromosome 3. • The culprit in the case of papillary renal cell cancers is the MET proto-oncogene, located on chromosome 7q31. • The MET gene is a tyrosine kinase receptor for the growth factor called hepatocyte growth factor.

49. It is an increased gene dosage of the MET gene due to duplications of chromosome 7 that seems to spur abnormal growth in the proximal tubular epithelial cell precursors of papillary carcinomas. • In keeping with this, trisomy of chromosome 7 is seen commonly in the familial cases. • In these individuals, along with increased gene dosage there are activating mutations of the MET gene. • By contrast, in sporadic cases there is duplication or trisomy of chromosome 7 but there is no mutation of the MET gene. • Another chromosomal translocation, involving chromosome 8q24 close to the c-MYC gene, is also associated with some cases of papillary carcinoma.

50. Chromophobe Renal Carcinomas • These are the least common, representing 5% of all renal cell carcinomas. • They arise from intercalated cells of collecting ducts. • Their name denotes the observation that the tumor cells stain more darkly (i.e., they are less clear) than cells in clear cell carcinomas. • These tumors are unique in having multiple losses of entire chromosomes, including chromosomes 1, 2, 6, 10, 13, 17, and 21. • In general, chromophobe renal cancers have a good prognosis.