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--Neoplasms of the Urinary System-- --Neoplasms of the Urinary System-- Urothelium composed of more than ___ cell laters must be considered abnormal 7 Zones of urothelium Superficial zone: Single layer of Umbrella cells (binucleated) Intermediate zone: 4-8 layers Basal zone: Single cuboidal layer von Brunn's nests Invaginations of urothelium into the lamina propria of the bladder Cystitis cystica von Brunn's nests with formation of a central lumen Cystitis glandularis Further enlargement of central lumen in Cystitis cystica, but with mucus-secreting columnar METAPLASIA Papilloma: Common or Rare? Benign or malignant? Papillomas are RARE and benign Can papillomas recur? Papillomas do not recur Does the STAGE or GRADE of Urothelial Carcinomas correlate with patient survival? **GRADE --every other neoplasm has been stage so far! Most common pattern of Urothelial Carcinoma Papillary Noninvasive Urothelial Carcinoma Thickening of the mucosa by proliferation of carcinoma cells, WITHOUT penetration of basement membrane How is a Carcinoma in situ different from a Noninvasive Urothelial Carcinoma? Carcinoma in situ--growth only the of the SURFACE Difference between Noninvasive and Invasive Urothelial Carcinoma Invasive carcinoma penetrates the BASEMENT MEMBRANE Do Papillary Carcinomas penetrate the basement membrane? "Penetration of basement membrane, infiltration of wall may or may not be present" Low grade Urothelial Carcinoma: -What is 5-year survival like? -Recurrences? -Excellent 5-year survival rate -May have multiple recurrences What is most important to Staging of Urothelial Carcinomas? -If seen, what should be the treatment? Mural muscle invasion is most important Presence generally dictate cystectomy as treatment All __________________ have a TENDENCY TO RECUR following excision, and usually the recurrence may exhibit greater anaplasia All transitional cell carcinomas What size must a mass be in order to be classified as a Papillary adenoma? <1 cm How do Renal Oncocytomas appear histologically? Polygonal cells with abundant eosinophilic cytoplasm What malignancy are Papillary Cortical Adenomas almost identical to? Renal cell carcinoma Radiographically and grossly, Angiomyolipomas resemble... Renal cell carcinoma Angiomyolipomas are seen in 25% of patients with... Tuberous sclerosis What are renal fibromas? Incidental small tumors present within the renal medulla, which are generally less than 1 cm. Renal cell carcinoma seen more in males or females? Male predominance What decades of life is Renal Cell Carcinoma more commonly seen? 6th-7th decades of life Risk factors for Renal Cell Carcinoma Tobacco, obesity, hypertension, unopposed estrogen therapy, environmental Renal cell carcinoma inherited? Generally sporadic, rarely hereditary (von Hippel-Lindau syndrome, hereditary clear cell carcinoma, hereditary papillary carcinoma) Classic triad of Renal Cell Carcinoma Pain, palpable flank mass, hematuria -More frequently asymptomatic until very large Paraneoplastic syndromes caused by Renal Cell Carcinoma Polycythemia, hypercalcemia, hypertension, hepatic dysfunction, feminization, masculinization, Cushing's syndrome, eosinophilia, leukemoid reactions and amyloidosis Most common sites of metastasis for Renal Cell Carcinoma Lungs, bones, regional lymph nodes, liver, adrenal glands, brain Most common type of Renal cell carcinoma Clear cell carcinoma What are the cells in Clear Cell Carcinoma clear? Abundant lipids and GLYCOGEN Gross color of: 1) Clear cell carcinoma 2) Papillary carcinoma 1) Yellow 2) Tan What 2 things can be found in the papillary cores of Papillary Carcinomas? Interstitial foam cells and psammoma bodies What do chromophobe renal cell carcinoma cells look like? Pale eosinophilic cells with distinct cell borders and perinuclear clear Chromophobe Renal Cell Carcinoma - significance May mimic oncocytoma Hobnail pattern Collecting duct carcinoma (a type of Renal cell carcinoma) May be associated with sickle trait Collecting duct carcinoma Collecting duct carcinoma also known as "medullary carcinoma" when associated with sickle trait In 98% of CLEAR CELL carcinomas, there is a deletion or unbalanced translocation resulting in the loss of chromosome ___, containing ____ gene 3 VHL gene (von Hippel-Lindau syndrome) PAPILLARY renal cell carcinomas are associated with Trisomy 7(familial & sporadic), 16, 17 and loss of Y chromosome What is encoded on chromosome 7 and 1 in the familial form of Papillary renal cell carcinoma? 7:MET proto-oncogene (a tyrosine-kinase receptor for hepatocyte growth factor) 1: PRCC gene, which is associated with sporadic tumors in children What are Tumor grading and staging for in Renal Cell Carcinoma Grading - prognosis Staging - Course of treatment How are Urothelial carcinomas of the renal pelvis different from renal cell carcinomas? Urothelial carcinoma of the renal pelvis tends to become apparent earlier in the disease course, since they sit right in the collecting system and more often produce gross hematuria when they fragment. How do patients with Urothelial carcinomas of the renal pelvis present? Hematuria, Renal colic, hydronephrosis What has worse prognosis and why? Urothelial carcinoma of renal pelvis or bladder urothelial carcinoma? Urothelial carcinoma of RENAL PELVIS because they are more commonly infiltrative Wilms' tumor is a cancer derived from Embyronic renal blastema Wilms' tumors most commonly occur between the ages of _________ -90% of cases before the age of 2 and 4 90% before age 6 Most common presenting symptom of Wilms' tumor Palpable abdominal mass +/- hematuria Development of Wilms' tumor is linked to what chromosomal loci? What kind of genes are they? WT1 and WT2, both located on short arm of chromosome 11. Both are tumor suppressor genes Histologically, Wilms' tumors are characterized by what three main components? 1) Blastema 2) Epithlium 3) Stroma What does BLASTEMA look like in Wilms' tumor? Undifferentiated small cells with hyperchromatic nuclei, scant cytoplasm and frequent mitotic figures arranged in a serpinginous, trabecular, diffuse or nodular pattern What are the most common sites of metastasis from Wilms' tumor? regional Lymph nodes, Lungs, Liver What is the prognosis for Wilms' tumor? Good! What are poor prognostic factors for Wilms' tumors? -Age greater than 2 years -High stage at presentation -Diffuse anaplasia Goljan: Child with unilateral flank mass and hypertension Wilms' tumor --Developmental diseases, Tubulointerstitial and Vascular disease of Kidney-- --Developmental diseases, Tubulointerstitial and Vascular disease of Kidney-- What is the definitive renal precursor? What does it arise from The metanephros, arises from mesenchyme What two things must connect to achieve complete development of the kidney? Metanephros and ureteric bud What other system is often also abnormal if the kidney is abnormal and why? Internal genital system is also often abnormal because of the close proximity of the two systems How is Renal agenesis inherited? NOT inherited--is usually sporadic! However, 2x more common in males than females What 2 things occur when there is UNIlateral agenesis of the kidneys? 1. Adaptive hypertrophy of the remaining normal kidney 2. Unilateral absence of the vas deferens or fallopian tube A decreased amount of amniotic fluid, think Bilateral agenesis If born, what do babies with Bilateral agenesis usually die of? They die due to inability to breath in sufficient amount of oxygen (pulmonary hypoplasia) Is renal hypoplasia more commonly a bilateral or unilateral defect? More commonly a UNILATERAL defect What are most cases of Renal Hypoplasia really due to? Most Renal Hypoplasia represents acquired SCARRING from infection, vascular or other parenchymal diseases What does a true hypoplastic kidney show? No scars and a reduced number of renal lobes and pyramids How does a Horseshoe kidney usually manifest clinically? Usually no clinical importance, but in some, the fact that the ureters must actually run over the fused lower poles of the kidney have cause an increased risk of infection and obstruction of the kidneys Where can ectopic kidneys be found? At pelvic brim or within the pelvis What problem may ectopic kidneys present? Kinking or tortuosity of the ureters may cause some obstruction to urinary flow, which predisposes to bacterial infections Prevailing theory on the origin of Cystic Renal Dysplasia Obstruction of the ureter or bladder increased pressure within the collecting duct, thus distorting the developing kidney How does Cystic Renal Dysplasia appear histologically? ARRESTED DEVELOPMENT, with simple ducts and often the presence of CARTILAGE How does a person with Cystic Renal Dysplasia present? Usually asymptomatic unless UTI or abdominal mass detects it What genes/chromosomes are affected by APCKD? Chromosome 16 - PKD1 polycystin 1 Chromosome 4 - PKD2 polycystin 2 What are the most common presenting symptoms of APCKD? Hematuria, hypertension, vague abdominal pain What parts of the nephron can APCKD affect? Can affect ANY part of the nephron How can APCKD cause renal failure? The cysts can cause compression atrophy of the remaining normal renal tissue ****What associated finding is most important in APCKD? Berry aneurysm Besides Berry aneurysms, what other finding can be associated with APCKD? -Mitral valve prolapse -Hepatic cysts What gene/chromosome regions are involved in CPCKD? PKHD1 gene, which maps to chromosome region 6p21-p23 What does PKHD1 gene encode? Fibrocystin, a large protein that has a role in collecting duct and biliary differentiation What organs does CPCKD affect and in what pattern? -Affects kidney and liver, usually in inverse proportions What happens in the most common form of CPCKD? Affected children present with renal failure at birth or soon after -May have symptoms similar to bilateral renal agenesis, but have markedly enlarged kidneys palpable at birth How are the cysts different in APCKD vs CPCKD? APCKD - Cysts all over nephron CPCKD - Cysts limited to collecting ducts What does Medullary Sponge Kidney affect? Cystic dilation of collecting ducts in the MEDULLA How do patients with Medullary Sponge Kidney present? Asymptomatic! Usually an incidental finding from radiographs, infections, hematuria, or urinary calculi What are the cystic diseases of the medulla? 1. Medullary Sponge Kidney 2. Nephronophthisis Does Medullary Sponge Kidney affect adults or kids? Adults Where are the cysts found in Nephronophthisis Corticomedullary junction How does Nephronophthisis begin? Initial injury to the distal tubules with tubular basement membrane disruption, followed by chronic and progressive tubular atrophy and interstitial fibrosis and eventually renal insufficiency What are the three variants of nephronophthisis disease? 1) Sporadic, nonfamilial 2) Familial juvenile 3) Renal-retinal dysplasia How are the familial forms of nephronophthisis inherited? Autosomal recessive Most common genetic cause of end-stage renal disease in children and young adults Nephronophthisis How do children affected by nephronophthisis present? Why? Polyuria and Polydipsia which reflect a marked defect in the concentrating ability of the renal tubules. Sodium wasting and tubular acidosis are also prominent Extrarenal associations of juvenile nephronophthisis Ocular motor abnormalities Retinal dystrophy Liver fibrosis Cerebellar abnormalities What genes are mutated in the juvenile forms of nephronophthisis? NPH1, NPH2, NPH3 What genes have been identified as causing medullary cystic disease associated with progression to end-stage kidney disease in adult life? MCKD1 and MCKD2 Which forms of nephronophthisis are autosomal recessive and which are autosomal dominant? Autosomal recessive - Familial juvenile nephronophthisis Autosomal dominant - Adults ***Just like Polycystic Kidney disease!! Adults - Dominant Kids - Recessive What can patients on dialysis for > 10 years develop? Acquired cysts How are dialysis-associated cysts different from other cystic diseases? The cysts often contain calcium oxalate crystals. They probably form as a result of obstruction of tubules by interstitial fibrosis or by oxalate crystals How do patients with Acquired (dialysis-associated) cystic disease present? Asymptomatic! However, sometimes the cysts bleed, causing hematuria. What are patients with Acquired Cystic Disease at increased risk of? Renal cell carcinoma What are simple cysts? Usually multiple cortical cysts filled with clear fluid, of no clinical significance Most common cause of acute renal failure Acute tubular nephropathy Two major causes of Acute tubular nephropathy -Renal ischemia -Toxic damage How will someone with Acute Tubular Necrosis present? Oliguria Are the structural changes seen in Acute Tubular Necrosis reversible or irreversible? BOTH! Gross pathology of Acute Tubular Necrosis: -Gross appearance -Section appearance -Pallor Gross appearance: Kidney enlarged, often tense, often PALE Section: Parenchyma appears to bulge out of capsule Pallor: Cortex is pale, medulla is dark, with exaggeration of the cortico-medullary junction Is widespread necrosis of tubular epithelium seen in ATN? NO! How do the proximal convoluted tubules appear in ATN? Dilated with flattening of individual epithelial cells and loss of the brush border (distalization) Goljan audio: What two parts of the nephron are most at risk of Acute Tubular Necrosis? Straight segment of Proximal convoluted tubule (most susceptible to hypoxia) Thick ascending limb Most common drugs to cause ATN Aminoglycoside antibiotics Radiologic contrast dyes Mechanism of toxic ATN Direct toxicity against tubular epithelial cells, with most toxins affecting the proximal portion of the nephron How do Ischemic and Toxic ATN differ in where they preferentially affect the nephron? Ischemic: Patchier and more preferentially involves the Thick Ascending Loop of Henle Toxic: Proximal portion of nephron Treatment for ATN Supportive until tubular function returns Poor prognostic signs for Acute Tubular Necrosis Severe oliguria, prolonged renal impairment, advanced age, multi-system organ failure Dominant pathologic feature of Interstitial Nephritis Interstitial inflammation Capsular petechiae may be present Interstitial nephritis Gross pathology of Interstitial Nephritis: -Gross appearance -Section appearance Gross: Symmetrically enlarged kidneys with tense RED-GRAY capsule Section: Cut surface shows pale cortex with blurring of cortico-medullary junction Interstitial Nephritis - Treatment Identify and remove causative agent Interstitial Nephritis - Prognosis Favorable! Most patients recover full renal function What medication can be used for Interstitial Nephritis? Corticosteroids Pyelonephritis affects what parts of the nephron? Tubules, interstitium and renal pelvis How does pyelonephritis usually arise? Usually from an ascending infection ****Papillary necrosis Acute pyelonephritis Microabscesses in cortex, pale streaks extending into medulla Acute Pyelonephritis Papillary necrosis as a complication of Acute Pyelonephritis: -Seen mainly in... -Usually unilateral or bilateral? -Seen mainly in diabetics and patients with UT obstruction -Usually bilateral Pyonephritis Suppurative filling of renal pelvis, calyces and ureter with pus Perinephric abscess Extension of suppurative inflammation through the renal capsule into the perinephric tissue Vesicoureteral and renal pelvic reflux cause CHRONIC pyelonephritis Thyroidization CHRONIC pyelonephritis ****Costovertebral angle pain, bladder symptoms, systemic evidence of infection Acute Pyelonephritis Kidney size in Analgesic Abuse Nephropathy Normal or slightly reduced ****Early sign of Analgesic Abuse nephropathy Inability to concentrate urine ****Bence Jones protein Multiple myeloma --Glomerular Disorders-- --Glomerular Disorders-- The earliest manifestation of glomerular basement membrane damage is The presence of proteinuria Crescent formation seen in Rapidly progressive glomerulonephritis What causes crescentic formation? Glomerular inflammation --> capillary loops are disrupted--> cytokines and chemokines pour into Bowman's space. This activates and proliferates Parietal epithelial cells and inflammatory cells, forming a crescent. Goljan: Immune cells seen in NEPHRITIC syndrome Neutrophils Antibodies to glomerular basement membrane seen in Goodpasture's syndrome Goljan: Immune cells seen in NEPHROTIC syndrome Cytokines Focal vs Diffuse Focal: < 50% of glomeruli in a kidney involved Diffuse: > or = 50% of glomeruli in a kidney involved Segmental vs Global Segmental: Only part of an individual glomerulus is involved Global: All parts of an individual glomerulus is involved The term "membranous" refers to... Involvement of the capillary BASEMENT MEMBRANE, often leading to an increase in thickness of the loop Antibodies that are directed against antigens that are normally present in the glomerulus will form whereas Antibodies to antigen-antibody complexes that are trapped in the kidney will produce Linear pattern of fluorescence Granular fluorescent pattern Edema in Nephritic or Nephrotic syndrome? BOTH! Edema is non-specific Minimal change disease in ADULTS can be caused by Hodgkin lymphoma or NSAID use Proteinuria in Minimal change disease -Abrupt onset -Massive ****SELECTIVE -Predominantly albumin (no globulins!) Underlying defect in Minimal change disease Loss of negative charge of basement membrane, allowing protein leakage Minimal change disease - morphology Light: Normal IF: Normal EM: Widespread fusion or effacement of visceral epithelial foot processes Most common cause of nephrotic syndrome in Caucasian adults Membranous nephropathy Nephrotic syndrome associated with Hepatitis B Membranous nephropathy Membranous nephropathy is the result of Slow accumulation of antigen-antibody complexes in the basement membrane ****Only Nephrotic syndrome with SELECTIVE proteinuria Minimal change What is thought to trigger Minimal change in children URI ****Treatment for Minimal Change in: -Kids -Adults Kids: Corticosteroids; if no response-->biopsy Adults: Biopsy to determine cause of nephrotic syndrome "Spike and Dome" on EM Membranous Membranous - Morphology Light: Diffuse thickening of basement membrane, NO INCREASE in cellularity IF: GRANULAR deposits of IgG and C3 EM: Spike and Dome What deposits are seen in the sclerotic areas of Focal Segmental Glomerulonephritis? IgM and C3 deposits IgM and C3 deposits FSG What is wrong in FSG? Loss of size selectivity and charge of basement membrane Which has INCREASED cellularity? Focal segmental, Membranous or both? Focal segmental only! Most common cause of end-stage renal disease in US Diabetic glomerulosclerosis What causes renal damage in Diabetic glomerulosclerosis? Glycosylation of basement membrane causes hemodynamic changes and thickening. Glycosylation of the efferent arteriole-->↑GFR-->mesangial damage & wire-looping. ****Kimmelsteil-Wilson nodules Diabetic glomerulosclerosis ****Wire-loop lesions Diabetic glomerulosclerosis How does Diabetic glomerulosclerosis appear on LM? Wire-loop lesions (Kimmelsteil-Wilson nodules) Amyloidosis is a manifestation of a number of different systemic diseases in which circulating serum proteins are deposited in tissues as Beta-pleated sheets In the US, the most common amyloidosis, AL amyloid, is related to Light chains produced by MULTIPLE MYELOMA or lymphoplastic lymphoma AA amyloid is derived from Serum protein (whereas AL amyloid is derived from polymerized immunoglobulin light chain) The cardinal features of Nephritic syndrome are ______________ GFR, salt and water ________________ and often ___________________ Decreased GFR Salt and water RETENTION HEMATURIA Most common cause of nephritic syndrome in children Post-streptococcal glomerulonephritis When does a Post-streptococcal glomerulonephritis usually occur? After a SKIN (or less commonly, throat) infection by Group A strep Post-streptococcal glomerulonephritis - pathogenesis (2 ways) Most likely: Circulating antigens are filtered by the glomerulus, but then become trapped and incite development of antigen-antibody complexes, inciting an inflammatory response in situ Less likely- Antigen-antibody complexes form in the circulation and then become trapped in the glomerulus Post-streptococcal glomerulonephritis - Morphology Light: Increase in number of cells in glomerulus, predominantly neutrophils. Tubulointerstitial compartment is spared! IF: Granular pattern of IgG and C3 EM: Subepithelial "humps" (epithelial side of basement membrane) Post-streptococcal glomerulonephritis - Prognosis Children usually recover completely What is found in all forms of lupus nephritis? Mesangial deposits Who is membranoproliferative glomerulonephritis seen in? Children and adolescents Tram-tracks Type 1 Membranoproliferative glomerulonephritis Clinical presentation can range from mild proteinuira to nephrotic to nephritic Membranoproliferative glomerulonephritis Morphology of Membranoproliferative glomerulonephritis (both types) TYPE I LM: Tram-tracks IF: C3 in coarse granular pattern EM: Subendothelial deposits TYPE2 LM: "Dense-deposits" IF: Faint or broken LINEAR C3 along GBM EM: Electron-dense deposits in GBM, Bowman's capsule, tubular BM Most common Glomerular disease WORLDWIDE IgA glomerulonephropathy How does IgA Glomerulonephropathy present? Asymptomatic hematuria or proteinuria What defect is responsible for Alport syndrome? Defect in Type IV collagen causes irregular BM thickening Glomerular disease that can cause lens dislocation and cataracts Alport syndrome Deficiency in alpha-Galactosidase A Fabry disease Accumulation of ceramide trihexoside Fabry disease Types of SLE I Nomal II Mesangial III Focal Proliferative IV Diffuse Proliferative V Membranous VI Advanced sclerosing Anti-glomerular basement membrane glomerulonephritis Goodpasture's syndrome Goodpasture's syndrome pattern on IF. What antibodies? LINEAR!! IgG and C3