Renal Pathology. SCBM342 Systemic Pathology 19 February Lecturer: Niwat Kangwanrangsan, Ph.D.

Transcription

1 SCBM342 Systemic Pathology 19 February 2018 Renal Pathology Lecturer: Niwat Kangwanrangsan, Ph.D. Department of Pathobiology Faculty of Science, Mahidol University

2 Outline I: Kidney diseases & associated syndromes A) Clinical manifestations of renal diseases B) Glomerular diseases C) Diseases affecting tubules and interstitium D) Diseases involving blood vessels E) Chronic kidney diseases F) Cystic Dieseases G) Urinary outflow obstruction H) Congenital and developmental anomalies I) Neoplasms 2

3 Outline II: Diseases of lower urinary tract (Ureter&Bladder) J) Ureter K) Urinary bladder 3

4 Urinary System Urinary Tract -Kidney 1) Glomeruli 2) Tubules 3) Interstitium 4) Blood vessels - Lower urinary tract 1) Ureter 2) Bladder 3) Urethra (diseases associated with reproductive tract) 4

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7 Blood Flow in Kidney 7

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12 12 1) Glomeruli 2) Tubules 3) Interstitium 4) Blood vessels

13 Lower Urinary Tract MALE FEMALE 1) Ureter 2) Bladder 13 3) Urethra associated with reproductive system

14 Technical terms Nephrosis non-inflammatory disease of kidney Nephritis inflammatory disease of kidney Nephrolith kidney stone Urethritis inflammation of urethra * final pathway for urine in both sexes & * common pathway for urine & semen in male Nocturia frequently getting up & urinating during the night Enuresis involuntary release of urine, most often in reference to bedwetting. 14

15 Oliguria / Anuria decrease / no urine flow Glomerulopathies non-inflammatory & inflammatory glomerular diseases Hereditary glomerulopathy(congenital disease) Neoplasm(tumor & cancer) Systemic diseases -tubulo-interstitial & vascular diseases 15

16 Azotemia Elevation of blood urea nitrogen (BUN) and creatinine level Usually reflects a decreased glomerular filtration rate (GFR) Decrease of GFR may come from intrinsic renal disease or extrarenal causes Prerenal azotemia encountered when there is hypoperfusion of kidney (uaually due to reduce extracellular fluid volume). Postrenalazotemia occurred when urine outflow is obstructed Azotemia gives rise to clinical manifestation and systemic biochemical abnormalities, it is termed uremia. 16

17 Uremia characterized by failureof renal excretory function and also by metabolic and endocrine functions that incident to renal damage may involved with -uremic gastroenteritis - peripheral neuropathy - uremic fibrinous pericarditis 17

18 A: Clinical manifestations and syndromes 1. Nephrotic syndrome 2. Nephritic syndrome 3. Asymptomatic hematuria 4. Rapid progressive glomerulonephritis (RPGN) 5. Acute kidney injury 6. Chronic kidney disease 7. End stage renal disease (ESRD) 8. Urinary tract infection (UTI) 9. Nephrolithiasis two most common syndromes associated with glomerular diseases 18

19 A1: Nephrotic Syndrome can be characterized by Proteinuria daily protein loss in urine >3.5 g in adult Hypoalbuminemia plasma albumin <3.0 g/dl Generalized edema, Anasarca fluid retention Hyperlipidemia / Lipiduria cholesterol >200 mg/dl/ oval fat body in urine 19

20 derangement in capillary walls of glomeruli increase in permeability of glomerular basement membrane (GBM) - Proteinuria - Hypoalbuminemia -leakage of fluid from blood into extravascular spaces -increase release of renin from juxtaglomerular cells, promote retention of water and salt by the kidney resulting in edema 20 this onset, there are little or no azotemia, hematuria, or hypertension

21 Primary glomerular lesions that related to nephrotic syndrome 1. Focal segmental glomerulosclerosis - more important in adults 2. Minimal-changes disease - more important in children 21

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24 Minimal-change disease 24

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28 A2: Nephritic Syndrome can be characterized by Hematuria red cells and red cell casts in urine Proteinuria with in sub-nephrotic range with or without edema Azotemia Hypertension 28

29 about nephritic syndrome usually has an acute onset usually caused by inflammatory lesions of glomeruli infiltration of leukocytes inflammatory reaction damages the capillary walls -blood pass to the urine = hematuria -reduction of GFR = oliguria, edema, azotemia 29

30 A3: Asymptomatic hematuria nonnephroticproteinuria combination of theses 2 clinical presentation - IgA nephropathy - Alport syndrome - other early presentations of glomerular diseases A4: Rapid progressive glomerulonephritis (RPGN) rapid loss of renal function (a few days or weeks) histologic finding is crescent (crescentic GN) can progress to renal failure within weeks or months 30

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33 A5: Acute kidney injury acute increase in serum creatinine often associated with oliguria or anuria can be come from -glomerular injury - interstitial injury - vascular injury (thrombotic microangiopathy) - acute tubular epithelial cell injury A6: Chronic kidney disease progressive scarring of kidney various metabolic and electrolyte abnormalities e.g. hyperphosphatemia, dyslipidemia, metabolic acidosis often asymptomatic until uremia develop 33

34 A7: End-stage renal disease (ESRD) irreversible loss of renal function requirement of dialysis or transplantation typically due to progressive scarring of kidney A8: Urinary tract infection (UTI) bacteriuria and pyuria (bacteria and leukocytes in urine) symptomatic or asymptomatic affect to kidney (pyelonephritis) or bladder (cystitis) only A9: Nephrolithiasis formation of stone in collecting system, manifested by renal colic and hematuria (without RBC casts) 34

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41 Kidney Dialysis 41

42 UTI 42

43 UTI 43

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45 Glomerulus -an anastomosing network of capillaries invested by two layers of epithelium - Bowman capsule / Bowman space - fenestrated endothelial cells ( nm in diameter) - glomerular basement membrane (GBM) -podocytes - mesangial cells -permeability cut-off at molecular size and charge of albumin 45 (70,000 kda)

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47 B: Glomerular diseases immune mechanism underlie most of primary glomerular diseases and many of secondary glomerular diseases Two possible mechanisms of antibody deposition in glomerulus 1) deposition of circulating immune complex 2) immune complexes form in situ + complement system + cell-mediated immune mechanism 47

48 Antibody-mediated glomerular injury 48

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50 Patterns of immune complex deposition by immunofluorescence microscopy A) Granular, characteristic of circulation immune complex deposition B) Linear, characteristic of in situ immune complex deposition 50

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53 Minimal-change disease 53

54 Focal and segmental glomerulosclerosis PAS staining 54

55 Membranous nephropathy PAS staining 55

56 Membranoproliferativeglomerulonephritis 56

57 Poststreptococcalglomerulonephritis 57

58 IgA nephropathy 58

59 Crescentic glomerulonephritis silver stain 59

60 Non-immune mechanism of glomerular injury Podocyte injury -can be induced by toxin (or Ab to podocyte Ag) - morphological changes - effacement of foot process - vacuolization -detachment of cell from GBM -associated with proteinuria Nephron loss - scarring of glomerulus (glomerulosclerosis) - glomeruli hypertrophy to maintain the renal function -maladaptive changes increase in single-nephron GFR, blood flow, and transcapillary pressure (capillary hypertension) 60

61 C: Diseases Affecting Tubule and Interstitium most of tubular injuries also involve the interstitium the diseases can be characterized by 1) inflammatory involvement tubulointerstitialnephritis 2) ischemic or toxic injury acute tubular necrosis acute kidney injury 61

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63 TubulointerstitialNephritis (TIN) glomeruli may be affected only in late stage usually caused by non-bacterial in origin e.g. drugs, hypokalemia, irradiation, viral infection, and immune reaction pyelonephritis can be described in cases of TIN caused by bacterial infection - acute pyelonephritis - chronic pyelonephritis pyelo = pelvis 63

64 Pathways of renal infection 1) ascending infection from combination of - bladder infection - vesicoureteral reflux 2) hematogenous infection 64

65 Acute pyelonephritis the most important manifestation of UTI principal pathogens are enteric gram-negative bacteria, the most common is E. coli, the other important pathogens are Proteus, Klebsiella, Enterobacter, and Pseudomonas uncommon pathogens are Staphylococciand Streptococci ascending infection is frequent route commonly affects females (the close proximity of urethra and rectum) vesicoureteral reflux (VUR) aloe bacteria to ascend the ureter into pelvis 65

66 Clinical features for uncomplicated acute pyelonephritis pain, chills, fever, nausea, malaise, dysuria, frequency and urgency turbid urine (pyuria) usually is unilateral and do not develop renal failure may become recurrent or chronic 66

67 Acute pyelonephritis - abscesses (focal pale) - congestion (dark vessels) 67

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69 Chronic pyelonephritis common in patients with history of UTI marked by uneven scarring and deformity of pelvicalyceal system uneven interstitial fibrosis, infiltration of lymphocytes, plasma cells, and occasionally neutrophils, dilation or contraction of tubules with thyroidization, atrophy of epithelial lining important cause of chronic kidney disease there are 2 forms -chronic obstructive pyelonephritis - chronic reflux-associated pyelonephritis 69

70 Chronic obstructive pyelonephritis obstruction predisposes the kidney to infection inflammation and scarring unilateral or bilateral Chronic reflux-associated pyelonephritis most common cause of chronic pyelonephritis resulted from superimposition of UTI on congenital vesicoureteral reflux and intrarenal reflux may develop secondary glomerulosclerosis 70

71 Typical coarse scars (found in vesicoureteral reflux ) 71

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73 Drug-induce tubulointerstitialnephritis also called acute drug-induced TIN drugs in associated with disease including penicillins, riflampin, diuretics, proton pump inhibitors, non-steroidal anti-inflammatory agents, immune checkpoint inhibitors drugs act as haptenthat can bind to cytoplasmic or extracellular components of tubular cells clinical feature related with immune mechanism (increase in serum IgE with eosinophilia suggested Type I Hypersensitivity) in others cases might be Type IV hypersensitivity reaction 73

74 prominent eosinophilic and mononuclear cells infiltration 74

75 Acute tubular necrosis/injury (ATN/ATI) but necrosis is rarely observed in the kidney biopsy, so later use ATI most common cause of kidney injury damage of tubular cells with an acute decline in kidney function decrease GFR, elevation of serum creatinine, oliguria (urine output <400 ml/day) shedding of tubular casts and tubular cells into urine 2 forms of ATI which differ in underlying cause 1) Ischemic ATI -a period of inadequate blood flow (hypotension/ shock) 2) Nephrotoxic ATI -a variety of poisons e.g. heavy metals (mercury), organic solvents (CCl 4 ), gentamycin and other antibiotics 75

76 ATI 76

77 ATI - tubular epithelial cell injury - blebbing into the lumen - detachment of tubular cells - proteinaceous casts - interstitial edema 77

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80 Postulate sequence in ischemic or toxic tubular injury 80

81 D: Diseases Involving Blood Vessels Nearly all diseases of the kidney affect the renal blood vessels secondarily. Systemic vascular diseases, such as various forms of vasculitis, also involve renal blood vessels, and often produce clinically important effects on renal function. kidney is intimately involved in the pathogenesis of both essential and secondary hypertension. This part covers the renal lesions associated with hypertension. 81

82 Nephrosclerosis refers to sclerosis of small renal arteries and arterioles that is strongly associated with hypertension morphological changes of the small arterioles are called hyaline arteriolosclerosis cause ischemia, which leads to various combinations of interstitial fibrosis, tubular atrophy, and focal global glomerulosclerosis frequency and severity of the lesions are increased at any age when hypertension or diabetes are present 82

83 Two processes participate in the arterial lesions of nephrosclerosis: 1. Medial and intimal thickening, as a response to hemodynamic changes, aging, genetic defects, or some combination of these 2. Hyalinization of arteriolar walls, caused by extravasation of plasma proteins through injured endothelium and by increased deposition of basement membrane matrix 83

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85 hyaline arteriosclerosis 85

86 Malignant hypertension defined as blood pressure usually greater than 200/120 mm Hg may present with severe acute kidney injury and renal failure renal changes are confined to the vasculature and may include thrombotic microangiopathy resulting from long-standing hypertension causes increased permeability of the vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition, leads to the appearance of fibrinoidnecrosis of arterioles and small arteries and intravascular thrombosis mitogenicfactors from platelets (e.g., platelet-derived growth factor) and plasma cause intimal hyperplasia of vessels, resulting in hyperplastic arteriosclerosis 86

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88 fibrinoid necrosis of afferent arteriole hyperplastic arteriosclerosis onion-skin lesion 88

89 E: Chronic Kidney Diseases a broad term that describes the final common pathway of progressive nephron loss resulting from any type of kidney disease remaining intact nephrons are ultimately maladaptive and cause further scarring eventually results in an end-stage kidney with sclerosedglomeruli, tubules, interstitium and vessels unless the disorder is treated with dialysis or transplantation, death from uremia, electrolyte disturbances, or other complications of endstage renal disease results 89

90 Pathogenesis destroys more and more nephrons makes adaptive mechanisms are initated that try to maintain renal function glomerular hyperfiltrationtends to compensate for decreased glomerular filtration rate resulting from the loss of nephrons increased plasma creatinine, decreased tubular reabsorption (for sodium, phosphate, and calcium), or increased tubular secretion (for potassium and hydrogen ions) helps to maintain homeostasis until the late stages of chronic kidney disease, however, renal function often deteriorates progressively even when the original insult is controlled Uncontrolled hypertension, regardless of the etiology, results in more rapid renal functional decline 90

91 Clinical Features chronic kidney disease may develop insidiously and be discovered late in its course, because it is often asymptomatic. frequently, renal disease is first detected by the discovery of proteinuria, hypertension, or azotemia on routine medical examination. in patients with glomerular disease resulting in nephrotic syndrome, as the glomeruli undergo sclerotic changes and result in nephron loss, the avenue for protein loss is progressively lessened, and the nephrotic syndrome thus becomes less severe with advanced disease some degree of proteinuria, however, is present in almost all cases hypertension is very common. microscopic hematuria is usually present, grossly bloody urine is infrequent at this late stage 91

92 chronic glomerulonephritis, Masson s trichrome stain 92

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95 F: Cystic Diseases of the Kidney comprising of 1) hereditary, 2) developmental, and 3) acquired disorders often present diagnostic problems for clinicians, radiologists, and pathologists and can occasionally be confused with malignant tumors 95

96 Simple cysts generally innocuous lesions that occur as multiple or single cystic spaces of variable size commonly, they are 1 to 5 cm in diameter; translucent; lined by a gray, glistening, smooth membrane; and filled with clear fluid microscopic examination, these membranes are seen to be composed of a single layer of cuboidal or flattened cuboidal epithelium cysts usually are confined to the cortex. common postmortem finding that has no clinical significance the main importance of cysts lies in their differentiation from kidney tumors, when they are discovered either incidentally or during evaluation of hemorrhage and pain radiographic studies show that in contrast with renal tumors, renal cysts have smooth contours, are almost always avascular, and produce fluid rather than solid tissue signals on ultrasonography 96

97 Autosomal Dominant (Adult) Polycystic Kidney Disease characterized by multiple expanding cysts affecting both kidneys that ultimately destroy the intervening parenchyma approximately found 1 in individuals and accounts for 10% of cases of chronic kidney disease genetically heterogeneous. It can be caused by inheritance of one of at least two autosomal dominant genes of very high penetrance. 97

98 Pathogenesis in 85% to 90% of families, PKD1,on the short arm of chromosome 16, is the defective gene, this gene encodes a large (460-kDa) and complex cell membrane associated protein called polycystin-1 Polycystin-1 localizes to the primary cilium of tubular cells, giving rise to the concept of renal cystic diseases as a type of ciliopathy Cilia serve as mechanosensorsof fluid flow. Current evidence suggests that polycystin mutations produce defects in mechanosensing in turn, alters downstream signaling events involving calcium influx, leading to dysregulation of cell polarity, proliferation, and cell cell and cell matrix adhesion increase in intracellular calcium is thought to stimulate proliferation and secretion from the tubular epithelial cells, which together lead to the formation of cysts cyst formation and interstitial fibrosis are characteristic of progressive polycystic kidney disease tumor suppressor genes, a second somatic hit is required for cyst development 98

99 Clinical Features does not produce symptoms until the fourth decade of life, by which time the kidneys are quite large. most common presenting complaint is flank pain or a heavy, dragging sensation. Acute distention of a cyst, either by intracystichemorrhage or by obstruction, may cause excruciating pain. Sometimes attention is first drawn to the lesion on palpation of an abdominal mass. intermittent gross hematuria commonly occurs most important complications are hypertension and urinary infection hypertension of variable severity develops in about 75% of individuals although the disease is ultimately fatal, the outlook is generally more favorable than with most chronic kidney diseases. The condition progresses very slowly. End-stage renal disease occurs at about 50 years of age, but there is wide variation in the course 99

100 Autosomal dominant adult polycystic kidney 100

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103 Autosomal Recessive (Childhood) Polycystic Kidney Disease this is a rare autosomal recessive disorder that is genetically distinct from adult polycystic kidney disease. occurs in approximately 1 in 20,000 live births perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on age at presentation and the presence of associated hepatic lesions all types result from mutations in the PKHD1gene, coding for a putative membrane receptor protein called fibrocystin. Fibrocystinis found in cilia in tubular epithelial cells, but its function remains unknown serious manifestations usually are present at birth, and young infants may die quickly from hepatic or renal failure. Patients who survive infancy develop liver cirrhosis (congenital hepatic fibrosis) 103

104 Medullary Diseases with Cysts There are two major types of cystic disease affecting the medulla: 1) medullary sponge kidney, a relatively common and usually innocuous condition, occasionally associated with nephrolithiasis, which will not be discussed further, and 2) nephronophthisis-medullary cystic disease complex, which is almost always associated with renal dysfunction. Nephronophthisisusually begins in childhood. Four variants are recognized on the basis of the timing of onset: infantile, juvenile (most common), and adolescent nephronophthisis, and medullary cystic disease developing later in adult life. 15% to 20% of children with juvenile nephronophthisishave extrarenal manifestations, often appear as retinal abnormalities, including retinitis pigmentosa, and even early-onset blindness At least nine gene loci (NHP1 to NHP9) have been identified for the autosomal recessive forms of the nephronophthisiscomplex. 104

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106 G: Urinary Outflow Obstruction G1: Renal stones (Urolithiasis) G2: Hydronephrosis 106

107 G1: Renal Stones (Urolithiasis) among the parts of urinary system, most of stones arise in the kidney symptomatic diseases are common in men, unilateral 3 major types: 1) calcium oxalate /or mixed with calcium phosphate, 2) magnesium ammonium phosphate, 3) uric acid or cysteine 2.5% of stone weight is mucoprotein most important cause is supersaturation of urine, other causes can be changes in urine ph, or bacterial infections progressive accretion of salts leads to branching structure (staghorn) stones may present without symptoms or significant renal damage smaller stone may pass into urine, that can make intense pain known as renal colic characterized by paroxysm of flank pain radiation toward the groin, gross hematuria can cause trauma resulting ulceration and bleeding Gout and leukemia lead to high uric acid levels can be the cause of 107 uric acid stones

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110 G2: Hydronephrosis dilation of real pelvis and calyces atrophy of parenchyma from obstruction of outflow of urine obstruction can occur at any parts of the urinary system most common causes are 1) congenital 2) acquired - foreign bodies - proliferative lesions - inflammatory lesions - neurogenic - normal pregnancy bilateral hydronephrosisoccurs only when obstruction is below the level of ureter, complete bilateral hydronephrosis can make anuria incomplete bilateral obstruction cause polyuria rather than oliguria before irreversible stage, removal of obstruction usually permits full return of function within a few weeks 110

111 dilation of pelvis and calyces thin of renal cortex 111

112 H: Congenital and Developmental Anomalies represent the most common cause of end-stage renal disease in individuals younger than 21 years of age and account for 40% to 50% of pediatric renal failure worldwide abnormalities can affect the kidney (dysplasia, agenesis, hypoplasia), collecting system (duplicated collecting system, hydronephrosis, megaureter), bladder (ureteroceleand vesicoureteral reflux), or urethra (posterior urethral valves) may present as an isolated feature or as part of a syndrome in association with extrarenalmanifestations. Most result from sporadic developmental defects of unknown cause. Others are caused by germline mutations in genes that impact the development of the kidney and especially the ureteric bud. 112

113 Multicystic dysplasia the most common form of renal cystic disease in childhood a developmental rather than a preneoplasticlesion. Because renal dysplasia is often associated with obstruction in the lower urinary tract, increased hydrostatic pressure in the developing kidney is thought to play a role in its development. kidneys are usually grossly distorted; the cysts range from microscopic to several centimeters in diameter. The histologic hallmarks are ducts and tubules lined by epithelial cells and surrounded by cuffs of cellular mesenchyme. 113

114 Renal agenesis Bilateral agenesis is incompatible with life and usually is encountered in stillborn infants often associated with other congenital disorders (e.g., limb defects, hypoplasticlungs). Unilateral agenesis is uncommon and compatible with normal life if no other abnormalities exist. Hypoplasia may occur bilaterally, resulting in renal failure in early childhood, but is more commonly encountered as a unilateral defect the hypoplastickidney shows no scars and has a reduced number of renal lobes and pyramids, usually six or fewer. 114

115 I: Neoplasms of Kidney there are many types of benign and malignant neoplasms occur in urinary tract the most common malignant neoplasm of the kidney is renal cell carcinoma, followed in frequency by nephroblastoma (Wilms tumor) and by primary neoplasms of the calyces and pelvis other types of renal cancer are rare neoplasms of the lower urinary tract are about twice as common as renal cell carcinomas I1: Oncocytoma I2: Renal cell carcinoma I3: Wilm Tumor 115

116 I1: Oncocytoma benign neoplasm arise from intercalated cells of collecting ducts associated with loss of Chr.1 and Y characterized by plethora of mitochondria, providing the basis of their tan color and finely granular eosinophilic cytoplasm 116 tubolocystic pattern

117 I2: Renal cell carcinoma derived from renal tubular epithelium locate predominantly in the cortex represent 80-85% or primary malignant neoplasms of kidney men are affect twice as commonly as women risk groups: smokers, hypertensive or obese patients, people with cadmium exposure closely relate with acquired polycystic disease as a complication of kidney dialysis classified by morphology and growth pattern 1) clear cell carcinoma (most common) 2) papillary renal cell carcinoma 3) chromophobe renal carcinoma 117

118 clear cell pattern 118

119 I3: Wilms tumor (nephroblastoma) common renal cancer in children at the age <10 year-old the cancer mass contains cells and tissues derived from mesoderm typically large, solitary, well-circumscribed mass relate with congenital malformation 1) WAGR syndrome 2) Denys-Drashsyndrome 3) Beck-with-Wiedemann syndrome 119

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121 J: Ureter Ureteropelvic junction obstruction congenital disorder, usually found in infancy or childhood result in hydronephrosis Retroperitoneal fibrosis uncommon cause of ureteral obstruction inflammatory process causing hydronephrosis Malignant tumor pathologically similar to those are found in renal pelvis, calyces, or bladder most are urothelial carcinoma 121

122 K: Urinary bladder K1: Nonneoplasticconditions K2: Neoplasms 122

123 K1: Nonneoplasticconditions Bacterial cystitis common in women coliform bacteria Hemorrhagic cystitis occur in patients receiving cytotoxic antitumor drugs sometimes complicates adenovirus infection Interstitial cystitis causes chronic pelvic pain syndrome suprapubic pain when bladder filling and relieved by bladder empty hematuria and dysuria can be occurred later develop to contracted bladder 123

124 Malakoplakia uncommon inflammatory disease defect of phagocytic or degradative function of macrophages undigested bacteria accumulation within phagosomes macrophages contain laminated mineralized concretions known as Michaelis-Gutmann bodies Polypoid cystitis caused by inflammation condition resulting from irritation of bladder mucosa submucosal edema 124

125 K2: Neoplasms majority of bladder cancer is urothelial carcinoma the latter is squamous cell carcinoma, which related with urinary schistosomiasis (e.g. in Egypt) precursor of invasive urothelial carcinoma: 1) noninvasive papillary tumor (most common) 2) carcinoma in situ 125

126 Morphologic patterns of urothelial neoplasia 126

127 Papillary urothelial tumor, resembling coral within bladder 127

128 Noninvasive low-grade papillary urothelial carcinoma 128

129 Carcinoma in situ, hyperchromatic nuclei and a mitotic figure (arrow) 129

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132 References 1. Robbins Basic Pathology (2018) 10 th Edition, Vinay Kumar, AbulK. Abbas, Jon C. Aster. Elsevier. 2. Rubins Pathology: Clinicopathologic Foundations of Medicine (2012) 6 th Edition, Raphael Rubin, David Strayer, Emanuel Rubin. Lippincott Williams & Wilkins 132