Glomerular Diseases - PDF

Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Pathology Department, FMHS, Omdurman Islamic University, Sudan.  Outlines Introduction Anatomy and Physiology of the Kidney Classification of Glomerular Diseases Diagnosis Types  Intro...

Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Pathology Department, FMHS, Omdurman Islamic University, Sudan.  Outlines Introduction Anatomy and Physiology of the Kidney Classification of Glomerular Diseases Diagnosis Types  Introduction: Definition of glomerular diseases A group of conditions that damage the glomeruli—the kidney's microscopic filtration units responsible for removing waste and excess fluids from the blood. Damage to the glomeruli impairs kidney function, leading to issues such as proteinuria (excess protein in urine), hematuria (blood in urine), reduced glomerular filtration rate (GFR), and, in severe cases, chronic kidney disease or kidney failure.  Introduction: Significance of glomerular diseases The significance of glomerular diseases lies in their potential to cause substantial morbidity and mortality. They can lead to complications like hypertension, nephrotic syndrome, and end- stage renal disease, necessitating dialysis or kidney transplantation. Early detection and appropriate management are crucial to prevent progression and improve patient outcomes. Renal Anatomy 6 7 8  * Classification of glomerular diseases: I. Primary G.N (the disease affects kidney only): Minimal change glomerular disease (Lipoid nephrosis). Acute diffuse proliferative G.N: – Post-streptococcal G.N. – Non-post-streptococcal GN. Rapidaly progressive G.N. Membraneous G.N. Membranoproliferative G.N. Chronic G.N. 9 II. Secondary G.N (the disease affects kidney and other organs): – Systemic lupus erythematosus (SLE). – Polyarteritis nodosa (PAN). – Wegener granulomatosis. – Diabetes mellitus (diabeteic nephropathy). – Goodpasture syndrome. – Amyloidosis. 10 11 12 13 Normal: H&E Endothelial cells Mesangial cells Visceral epithelial cells (podocytes) Normal: PAS Endothelial cells Mesangial cells Visceral epithelial cells (podocytes)  Diagnosis of glomerular diseases To study any glomerular disease, a renal biopsy is taken and examined by 3 types of microscopes: 1. Light microscope: to examine the structure of glomeruli, tubules and interstitium. 2. IF (immune flourescent microscope): to detect the type of deposited immunoglobulin in the glomeruli. 3. EM (electron microscope): to detect the site of immune complex, either sub-epithelial, sub- endothelial, mesangial or basement membrane.. 16 17 *Etiology & pathogenesis: Chemical change in the glomerular basement membrane causing protein loss. 18 * Grossly: Mild bilateral kidney enlargement. * LM (Light microscope): No abnormalities. * IF (Immunoflurescence): No immune deposits. * EM (Electron microscope): Fusion of the foot processes of the epithelial cells (podocytes). 19 EM of normal glomerulus 20 EM of minimal change glom. disease 21 * CP (Clinical picture): Affect children and young adults. Cause nephrotic syndrome. * Fate: The disease has excellent prognosis and most patients respond to corticosteroids with complete resolution of proteinuria. 22 23  Immune complex reaction; (nephrotegenic strains of group A beta haemolytic streptococci + Ig G), the complex is deposited in the glomeruli with subsequent complement activation acute inflammation. 24 * Grossly: Mild bilateral kidney enlargement with petechial haemorrhages. 25 * LM (Light microscope): a. Glomeruli: Proliferation of endothelial and mesangial cells. Glomerular capillaries contain neutrophils. Bowman’s space shows: neutrophils, RBCs, some albumin. b. Tubules: The lining cells are swollen. The lumens show casts (RBCs casts, neutrophil casts & hyaline casts). c. Interstitium: Acute inflammatory reaction…... 26 Normal kidney 27 Normal kidney 28 Post-streptococcal GN 29  Post-streptococcal GN Diffuse, proliferative, exudative glomerulonephritis Neutrophils in capillary lumens (acute exudate) Post-streptococcal GN Red blood cell casts * IF (Immunoflurescence): Deposition of Ig G and C3. 32  Post-streptococcal GN Granular C3, IgG Positive Ig G and C3 34 * EM (Electron microscope): Subepithelial immune complex deposit (humps). 35 Glomerular basement Neutrophils membrane Deposits Subepithelial “humps” GBM Epithelial cell “hump”-like deposit 38 * CP (Clinical picture): In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cocoa-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients exhibit red cell casts in the urine, mild proteinuria (usually less than 1 mg/day), peri-orbital edema, and mild to moderate hypertension. 39  Hematuria (coca cola colored urine) RBCs cast 40  In adults, the onset is more likely to be atypical, with the sudden appearance of hypertension or edema, frequently with elevation of serum creatinine. Important laboratory findings include elevations of anti-streptococcal antibody (ASO) titers and a decline in the serum concentration of C3 (consumed). 41  More than 95% of affected children eventually recover totally with conservative therapy aimed at maintaining sodium and water balance. A small minority of children (perhaps less than 1%) do not improve, become severely oliguric, and develop a rapidly progressive glomerulonephritis. Some of the remaining patients may undergo slow progression to chronic glomerulonephritis. 42  In adults, the prognosis is bad. Most of the patients pass to rapidly progressive glomerulonephritis or chronic renal failure. 43  Membranous glomerulopathy Capillary wall Diffuse thickening only subepitheli if deposits are al deposits big enough Granular loop deposits of IgG always present but not specific  Conditions associated with membranous nephropathy Primary/idiopathic – most have antibodies against podocyte antigen Phospholipase A2 receptor (PLA2R) Malignancy: solid tumors Infection: hepatitis B/C, malaria, syphilis Drugs: penicillamine, gold Autoimmune diseases: SLE Sarcoidosis.  Membranoproliferative Glomerulonephritis (MPGN) (type I) Mesangial and endocapillary proliferation with lobular accentuation and double contoured capillary walls  Diabetic glomerulosclerosis Visible by GBM light thickening microscopy and only if mesangial advanced matrix enough increase  Amyloidosis Amorphous material by Haphazardly light arranged microscopy 10nm fibrils Commonly light chain - associated with myeloma but does not have to be confused with it. Amyloidosis: Congo red stain under polarized light  Anti-GBM disease (Goodpasture’s syndrome) Clinical presentation: RPGN If associated hemoptysis and dyspnea: Goodpasture’s syndrome. Pathogenesis: circulating auto- antibodies against non-collagenous domain of 3 chain of collagen type IV (cross reacting with glomerular and alveolar basement membranes). Goodpasture’s syndrome Glomeruli Fibrinoid Necrosis Glomerular necrosis  Goodpasture’s syndrome Fibrin extravasation, cellular crescent Crescent Normal glomerular tuft Fibrin  Goodpasture’s syndrome Linear IgG; No deposits in EM EM: No deposits Goodpasture’s syndrome Alveolar hemorrhage Blood Alveolar septa  Anti-GBM disease: Clinical Course Steroids, cytotoxic agents and plasmapheresis : Resolves pulmonary hemorrhages Renal function improves if intervened early (sCr 4-5 mg/dl). Irreversible renal failure if therapy is delayed. May recur in renal transplants (anti- GBM antibody titers monitored).  IgA Nephropathy Clinical presentation: – Recurrent gross/microscopic hematuria – Proteinuria usually non-nephrotic range. – No systemic disease (vs Henoch- Schönlein Purpura). – Acute nephritic syndrome in 5-10% of cases. – Hematuria often preceded by respiratory and gastrointestinal infections.  IgA Nephropathy LM: – mesangioproliferative most common – endocapillary proliferative and/or sclerosing lesions may be seen. – Segmental crescents can be present. IF: defining feature – Dominant /co-dominant IgA stain (IgA /= IgG); C3, K, L + EM: Mesangial deposits;  segmental subendothelial deposits.  IgA Nephropathy Mesangial Proliferation Expanded, hypercellular mesangium  IgA Nephropathy Fibrocellular crescent Less cellular, Crescent “Fibrous” areas Cellular areas  IgA Nephropathy Mesangial IgA, C3  IgA Nephropathy Mesangial deposits GBM Mesangial immune complex  Henoch-Schönlein Purpura Most common in children (3-8 yrs), but also occurs in adults. Syndrome: systemic vasculitis – Purpuric skin rash (extensor surfaces of extremeties) – Abdominal pain, vomiting, melena – Arthralgias – Renal manifestations (IgA nephropathy).  Systemic Lupus Erythematosus Multisystem disease of autoimmune origin Predominantly seen in women of childbearing age (F: M=9:1), > severe in AA, Hispanics. Acute or insidious in onset; chronic remitting and relapsing course. Primary target organs: skin, joints, kidney, serosal membranes.  1997 Revised Criteria for SLE Classification (4 required for diagnosis) 1. Malar rash 8. Neurological disorder 2. Discoid rash 9. Hematological disorder 3. Photosensitivity 10. Immunological disorder: Anti-dsDNA 4. Oral ulcers Anti-Sm Ab 5. Arthritis Antiphospholipid Ab 6. Serositis 7. Renal disorder 11. Antinuclear Ab (ANA)  Systemic Lupus Erythematosus Role of antibodies in the diagnosis: – ANA is highly sensitive , but not very specific. – Anti-dsDNA and anti-Smith (anti-Sm) antibodies are less sensitive but more specific. Etiology and pathogenesis: – Genetic factors – Environmental factors eg. Drugs – Immunological factors (dysregulation & loss of self tolerance).  SLE and Kidney The morphological changes in lupus nephritis (LN) are extremely variable. The lesions result from deposition of immune complexes (Ag-AB). The clinical presentation, course and prognosis of various lesions differ. – Nephrotic, nephritic-nephrotic, RPGN.  SLE and Kidney Endocapillary proliferation Too many cells and loss of capillary lumens SLE and Kidney “Wire loops” (large subendothelial deposits)  SLE and Kidney Intraluminal hyaline thrombi  SLE and Kidney Cellular crescent  SLE and Kidney Different case: Membranous LN (nephrotic syndrome) Diffusely thickened, Lumpy-bumpy capillary walls SLE and Kidney IgG, IgM, IgA, C3, C1q, K, L: “full house”  SLE and Kidney Mesangial deposits Deposit GBM  SLE and Kidney Subendothelial deposits Deposit GBM Deposit  SLE and Kidney Subepithelial deposits GBM Deposits  SLE and Kidney Tubuloreticular inclusions  CLASSIFICATION OF Lupus Nephritis Class LM IF EM I normal mesangial mesangial deposits II mesangial mesangial mesangial hypercellularity deposits III focal proliferative GN mesangial + capillary Mes + subendo (< 50% glomeruli) wall dep IV diffuse proliferative (> mesangial + capillary Mes + subendo 50% glomeruli) wall dep V Membranous capillary wall (+/- Subepithelial mesangial) +/- mes VI Advanced sclerosis +/- +/-  Chronic Glomerulonephritis Chronic end-stage damage to glomeruli, tubules and blood vessels. Bilateral kidneys symmetrically contracted. Associated with hypertension. Clinical features of chronic renal failure and uremia develop. Chronic Glomerulonephritis Globally sclerosed glomeruli Atrophic tubules Atrophic tubules Chronic Glomerulonephritis Robbins.. 82 Nephrotic and Nephritic Syndromes Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Pathology Department, FMHS, Omdurman Islamic University, Sudan. Outlines  Filtration Membrane  Nephrotic syndrome  Nephritic syndrome Filtration Membrane – Electron Micro. 3 - A syndrome formed of: 1. Proteinuria (i.e. >3.5g/24 hrs). 2. Hypoproteinaemia (i.e. 80% of cases are due to glomerulonephritis.  Nephrotic Syndrome: Pathophysiology  In this syndrome, there is damage to podocytes. It was once thought that this allowed albumin to leak out into the tubule, thus causing proteinuria and hypoalbuminemia, and leading to reduced plasma oncontic pressure and peripheral oedema. The damage to the podocytes was thought not to be significant enough to allow RBCs through the gaps thereby rendering haematuria unlikely.  Nephrotic Syndrome: Pathophysiology  Recently, this theory has come under scrutiny as it has been discovered that the aforementioned situation does not cause a change in oncotic pressure, confirming the presence of an alternative pathology causative of oedema. Nephrotic Syndrome: Clinical signs  Pitting oedema, particularly in the limbs and around the eyes;  may also cause genital oedema and ascites.  Possible hypertension.  Nephrotic Syndrome: Causes  Primary causes – these are diagnoses of exclusion that are only made if secondary causes cannot be found: o Minimal change disease (MCD) o Focal segmental glomerulosclerosis o Membranous nephropathy.  Nephrotic Syndrome: Causes  Secondary causes – note that these fall into the same three categories as above: o Minimal change disease – Hep B, SLE, diabetes M, sarcoidosis, syphilis, malignancy o Focal segmental glomerulosclerosis –HIV, obesity, diabetes M, hypertensive nephrosclerosis o Minimal change disease –drugs, malignancy, particularly Hodgkin’s lymphoma.  Nephrotic Syndrome: Differential diagnoses  Cardiac failure, i.e. increased JVP, pulmonary oedema and mild proteinuria, and  liver disease, i.e. reduced serum albumin.  Nephrotic Syndrome: Complications  The condition causes an increased susceptibility to infection – partly due to loss of immunoglobulin in the urine. Patients tend to be prone to streptococcus infection, as well as bacterial peritonitis and cellulitis.  Nephrotic syndrome also increases the risk of thromboembolism and hyperlipidaemia.  Nephrotic Syndrome: Complications  The former is due to an increase in the synthesis of clotting factors and to platelet abnormalities, and the latter is a result of increased synthesis of these by the liver to counteract reduced oncotic pressure.  Nephrotic Syndrome: Investigations  These are the same as those carried out in GN.  Also, check for cholesterol as part of confirming the presence of hyperlipidemia.  Renal biopsy – order this for all adults. In children, because the main cause is minimal change GN, steroids are the first-line treatment. Therefore, in children, biopsy is necessary only if pharmaceutical intervention fails to improve the situation.  Nephrotic Syndrome  The hypercoagulant state seen in the nephrotic syndrome can be a risk factor for renal vein thrombosis. This can present as loin pain, haematuria, palpable kidney and sudden deterioration in kidney function. This should be investigated with Doppler US, MRI or even renal angiography.  Once diagnosed, give warfarin for 3 to 6 months.  Nephrotic Syndrome: Management  Generally, this involves treatment of the underlying condition which is usually GN. Therefore, fluid management and salt intake restriction are priorities. The patient is usually given furosemide along with an ACE inhibitor and/or an angiotensin II receptor antagonist. Prophylactic heparin is given if the patient is immobile. Hyperlipidaemia can be treated with a statin.  Nephritic Syndrome  Again, this is a term describing a set of symptoms and not a pathological condition in itself. Acute and chronic forms of the syndrome exist. The main difference between this and nephrotic syndrome is that in nephritic syndrome haematuria is present. There is also proteinuria, hypertension, uraemia, and possibly oliguria. The two standout features are hypertension and RBC casts. The urine will often appear ‘smoky’ in colour due to the presence of RBC casts. Very rarely, it may appear red  Nephritic Syndrome: Causes 1. Post-streptococcal 2. Primary:  Membranous glomerulonephritis  Rapidly progressive glomerulonephritis  IgA nephropathy (Berger’s disease) 3. Secondary  HSP  Vasculitis.  Nephritic Syndrome: CLINICAL FEATURES  Abrupt onset of :  glomerular haematuria (RBC casts or dysmorphic RBC).  non-nephrotic range proteinuria (< 2 g in 24 hrs).  oedema (periorbital, sacral).  hypertension.  transient renal impairment (oliguria, uraemia).  Nephritic Syndrome  Urinary casts – these are cylindrical structures produced by the kidney and present in the urine in certain renal diseases. They form in the DCT and collecting duct, dislodging and passing in the urine where they are detected by microscopy. RBC casts are usually associated with nephritic syndrome. The presence of RBCs within a cast is always pathologic and strongly indicative of glomerular damage. Nephritic Syndrome  The proteinuria present is often smaller than in nephrotic syndrome, thus a coexistent condition of nephrotic syndrome is not usually present.  Nephritic Syndrome  Encepelopathy may be present, particularly in children, due to electrolyte imbalances and hypertension. This type of presentation is indicative of glomerular damage, but requires renal biopsy to determine the exact problem. In this respect it is similar to nephrotic syndrome.  Overlapping of the two syndromes is possible as nephrotic syndrome may precede nephritic syndrome, although not vice-versa.  Nephritic Syndrome  Mechanisms of the syndrome vary according to cause; both primary and secondary causes exist.  Post-infectious GN is the classic illustration of nephritic syndrome, but the condition may be caused by other glomerulopathies and by systemic diseases such as connective tissue disorders.  Renal glomerular syndromes corresponding glomerular pathology Nephritic (bleeding) Nephrotic (heavy Increased cellularity proteinuria) Mesangial Podocyte injury Crescents Foot process fusion Necrosis Subepithelial immune Immune complex deposits in complex deposits the mesangium and subendothelial space Segmental glomerular basement membrane Linear glomerular basement collapse membrane deposits  Nephrotic syndrome causes Children  Primary diseases (95%)  Membranous (5%) Notice that:  Minimal change (65%)  Secondary causes are rare in  FSGS (10%) children but common in adults  MPGN (10%)  Other proliferative GN (10%)  Secondary causes may  Secondary (5%) resemble the primary lesions  SLE, drugs, Infections, malignancy, hereditary nephritis, bee-sting allergy (e.g. malignancy associated  Adults membranous) or look nothing  Primary diseases (60%) like them (e.g. amyloid)  Membranous (30%)  In children, the most common  Minimal change (10%) primary lesion is minimal  FSGS (35%)  MPGN (10%) change nephrotic syndrome.  Other proliferative GN (15%) Because this is steroid  Secondary diseases (40%) responsive, children with NS  Diabetes, amyloidosis, SLE, drugs (gold, penicillamine, heroin), are treated empirically Infections (malaria, syphilis, hep. B, HIV), malignancy, bee-sting allergy THANKS Pyelonephritis and Acute Interstitial Nephritis Pro. Nazik Elmalaika Husain, MBBS, MSc, MD, MHPE, PhD. Professor, Pathology Dep., FMHS, OIU Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Professor, Pathology Department, FMHS, Omdurman Islamic University, Sudan. Infections of Urinary Tract Upper Urinary tract Pyelonephritis: Acute Chronic. Acute Interstitial Nephritis (AIN) Lower Urinary tract ureteritis cystitis urethritis.  Objectives  Upper urinary tract infections: pyelonephritis and Acute Interstitial Nephritis (AIN).  The pathophysiology  Complications. Pyelonephritis: Definition A disease affecting the tubules, interstitium and renal pelvis. Two forms: Acute: often due do bacterial infection. Chronic: complex, infection plays a role, but reflux and obstruction may also contribute.  Acute Pyelonephritis- general More common in women and men older than age 65. Sudden onset of costovertebral angle pain. Good, rapid response to antibiotics. Septicaemia is a complication in immunosuppressed patients. Acute Pyelonephritis- Symptoms Fever Nausea and vomiting Chills General malaise or Tachycardia and fatigue tachypnea Burning, urgency, or Flank, back, or loin pain frequency of urination Nocturia Tender costovertebral angle (CVA) Recent cystitis or treatment for urinary tract Abdominal, often colicky, discomfort infection (UTI) Routes of infection  Ascending infection This is the most common route of infection.  Hematogenous infection.  Predisposing conditions- acute pyelonephritis Urinary tract obstruction, either congenital or acquired. Instrumentation of the urinary tract Vesicoureteral reflux Pregnancy. Gender and age. Preexisting renal lesions, causing intra-renal scarring and obstruction Diabetes mellitus Immunosuppression and immunodeficiency.  PATHOPHYSIOLOGY Acute pyelonephritis is the active bacterial infection, whereas chronic pyelonephritis results from repeated or continued upper urinary tract infections or the effects of such infections. Chronic pyelonephritis often occurs with a urinary tract defect, obstruction, or, most commonly, when urine refluxes from the bladder back into the ureters.  PATHOPHYSIOLOGY In pyelonephritis, organisms move up from the urinary tract into the kidney tissue. Bacteria trigger the inflammatory response, and local edema results. Acute pyelonephritis involves acute tissue inflammation, tubular cell necrosis, and possible abscess formation. The infection is scattered within the kidney; healthy tissues can lie next to infected areas. Fibrosis and scar tissue develop from the inflammation. The calices thicken, and scars develop in the interstitial tissue.  PATHOPHYSIOLOGY Reflux of infected urine from the bladder into the ureters and kidney is responsible for most cases of chronic pyelonephritis. Inflammation and fibrosis lead to deformity of the renal pelvis and calices. Repeated or continuous infections create additional scar tissue, changing blood vessel, glomerular, and tubular structure. As a result, filtration, reabsorption, and secretion are impaired and kidney function is reduced. Acute Pyelonephritis: macro description  Kidney surface shows multiple discrete areas that corresponds to abscesses. Acute on chronic pyelonephritis with numerous septic foci present in an already scarred kidney.  Acute Pyelonephritis: micro description Patchy acute interstitial and tubular inflammation (PMNs). Glomeruli are not usually involved. Acute pyelonephritis. There is a diffuse interstitial infiltrate with polymorphonuclear leukocytes. Acute pyelonephritis marked by an acute neutrophilic exudate within tubules and interstitial inflammation Acute pyelonephritis:Complications 1. Papillary necrosis 2. Pyonephrosis 3. Perinephric abscess. Chronic Pyelonephritis Chronic tubulo-interstitial inflammation and renal scarring associated with pathologic involvement of the calyces and pelvis. An important cause of end-stage kidney disease (10%-20% ). Chronic Pyelonephritis-types Divided into two forms: * reflux-associated (chronic reflux-associated pyelonephritis) * obstructive (chronic obstructive pyelonephritis). Chronic Pyelonephritis: types Reflux: more common, usually arises in childhood, unilateral or bilateral; damage often due to infection; associated with calyceal dilation (usually upper pole); you may see tubular atrophy and thyroidization, interstitial fibrosis Obstruction: associated with parenchymal scarring, usually not in children. Chronic Pyelonephritis: Symptoms Hypertension Inability to conserve sodium Decreased urine concentrating ability, resulting in nocturia Tendency to develop hyperkalemia and acidosis. Chronic Pyelonephritis: Lab/diagnostic tests Urinalysis shows leukocytes, bacteria, nitrites, and red blood cells; may see white blood cell casts. Urine culture identifies organism. Sensitivity shows which antibiotics the organism is most responsive to. CBC shows leukocytosis. Chronic Pyelonephritis: Radiologic tests An x-ray of the kidneys, ureters, and bladder (KUB) and IV urography are performed to diagnose stones or obstructions. A cystourethrogram is indicated for some patients. These procedures define urinary tract structures and identify any defects. U/S, CT scan. Chronic Pyelonephritis Radiologic findings Specific defects to be identified include foreign bodies, such as stones; obstruction to the outflow of urine, such as tumors, structural defects, or prostate enlargement; and urine reflux caused by incompetent bladder-ureter valve closure. Gross description Irregular scarred cortical surface usually at poles, dilated and blunted calyces. Dilated ureter; retraction and destruction of papillae with “U” shaped scars. A. Bilateral hydronephrosis with acute on chronic pyelonephritis in a child due to urinary tract obstruction. B. Hydronephrosis with thinned renal parenchyma in an adult kidney.  B. Healed pyelonephritis associated with vesicoureteral reflux has produced scarring of both poles of the kidney with calyceal distortion due to infection of the peripheral compound papillae. A. Scar of healed pyelonephritis  Micro descriptiom Tubular thyroidization (filled with colloid casts), Tubular atrophy. Interstitial fibrosis and inflammation (intense diffuse lymphoplasmacytic inflammatory infiltrate with germinal centers). Obliterative endarteritis of vessels, interstitial Tamm-Horsfall protein (amorphous, fibrillary, PAS+ material surrounded by inflammatory cells) Normal glomeruli early in disease course. Chronic pyelonephritis is a nonspecific interstitial infiltrate predominately with lymphocytes. Chronic pyelonephritis Chronic pyelonephritis: lymphocytes and plasma cells  Chronic pyelonephritis Both lymphocytes and plasma cells are seen in this case of chronic pyelonephritis. The plasma cells are most characteristic for chronic pyelonephritis. Chronic pyelonephritis  MEDICAL MANAGEMENT Antibiotics to treat infection- Broad spectrum initially then narrow spectrum when the results of the urine C&S are known. Antipyretics (Tylenol) for fever. (NSAIDS like Motrin are Nephrotoxic) Fluids for dehydration due to vomiting and diarrhea- at least 2 liters per day unless contraindicated. Phenazopyridine for relief of dysuria symptoms. Repeat urine culture after completion of antibiotic course.  Surgical management Surgical interventions can correct structural problems causing urine reflux or obstruction of urine outflow or can remove the source of infection. The surgical procedures may be one of these: Pyelolithotomy (stone removal from the kidney), Nephrectomy (removal of the kidney), ureteral diversion, or reimplantation of ureter to restore proper bladder drainage. Acute Interstitial Nephritis (AIN) Acute Interstitial Nephritis (AIN) Is an inflammatory condition that affects the interstitial tissue of the kidneys, which is the area surrounding the renal tubules. Patients with AIN may present with symptoms such as fever, rash, eosinophilia, and an abrupt decline in kidney function (acute kidney injury). Acute Interstitial Nephritis (AIN) Causes: AIN can be triggered by various factors, including: Medications: Antibiotics, nonsteroidal anti- inflammatory drugs (NSAIDs), and certain diuretics are common culprits. Infections: Some bacterial or viral infections can lead to AIN. Autoimmune Diseases: Conditions like systemic lupus erythematosus or Sjögren's syndrome. Acute Interstitial Nephritis (AIN) Histological Features: AIN is characterized by the presence of inflammatory cells such as lymphocytes, eosinophils, and sometimes plasma cells within the interstitium. Tubular damage and edema can also be observed. AIN. The mononuclear infiltrate is accompanyed by abundant eosinophils and may have a granulomatous appearance. AIN. Higher power of tubulitis demonstrating interstitial edema and invasion of the tubular epithelium by lymphocytes. Acute Interstitial Nephritis (AIN) AIN is significant as it is a potentially reversible cause of acute kidney injury, especially if the underlying cause (e.g., a specific medication) is identified and addressed promptly. THANKS Lower Urinary Tract Infections Prof. Nazik Elmalaika Husain, MBBS, MSc, MD, MHPE, PhD. Professor, Pathology Dep., FMHS, OIU, Sudan. Infections of Urinary Tract Upper Urinary tract Pyelonephritis: Acute Chronic. Acute Interstitial Nephritis (AIN) Lower Urinary tract ureteritis cystitis urethritis.  Objectives Lower Urinary tract Ureteritis Cystitis Urethritis.  UTI: Definition UTI:the finding of microorganisms in bladder urine with or without clinical symptoms and with or without renal disease. Significant bacteriuria: the number of bacteria in the voided urine exceeds the number that can be expected from contamination (i.e. ≥ 10⁵ cfu/ml).  Factors normally protecting against infection/UTI  Washing out bacteria during micturition.  Low pH/high osmolarity of urea.  Tamm-Horsfall protein (antibacterial) and other bactericidal secretions from uroepithelium.  Ureterovesical junction acts as valve.  Ureterovesical Junction (UVJ) Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014 Cystitis Bacterial (acute) cystitis Cystitis is an inflammation of the bladder. Bacterial (acute) cystitis Most common Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014 form of UTI.  Cystitis  Non-bacterial cystitis (Painful Bladder Syndrome/Interstitial Cystitis)  Not from infection; chronic.  Interstitial cystitis involves all layers of bladder.  Manifestations:  Most common in women 20 to 30 years old  Bladder fullness, frequency, small urine volume, chronic pelvic pain.  Mucosal (Hunner) ulcers.  Treatment  No single treatment effective, symptom relief. Clinical features of UTI: Cystitis Frequency Urgency Dysuria – painful voiding  suprapubic Pain Cloudy or foul-smelling urine. Acute and Chronic Cystitis: Etiology  Women are more likely to develop cystitis  Tuberculous cystitis is always a sequel to renal TB  Candida albicans  Schistosomiasis (Schistosoma haematobium)),  Chlamydia, and Mycoplasma may also cause cystitis. Acute and Chronic Cystitis: Predisposing factors  Bladder calculi, urinary obstruction, diabetes mellitus, instrumentation, and immune deficiency.  Irradiation of the bladder region gives rise to radiation cystitis.  Cystitis with malakoplakia Peculial inflammatory reaction chacakterized by soft, yellow, plaques 3-4 cm in diameter and histologically by foamy macrophages. Slide 22.6 Acute inflammation of the urinary bladder. Multiple acquired diverticula (arrows) lie between hypertrophied muscular bundles in a hypertrophied bladder of a patient who had severe prostatic hyperplasia. Any question? THANKS  Prof. Nazik Elmalaika Husain, MBBS, MSc, MD, MHPE, PhD. Professor, Pathology Dep., FMHS, OIU, Sudan.  Hydronephrosis- Dilation of the renal pelvis or calyces Obstructive uropathy- functional or anatomic obstruction of urine flow at any level of the urinary tract Obstructive nephropathy- when obstruction causes function or anatomic renal damage  Urinary Tract Obstruction Urinary tract obstruction – interference with the flow of urine at any site along the urinary tract. – Uni- or bilateral, partial/complete, sudden/insidious anywhere, from inside urinary tract or elsewhere. Severity and sequellae based on: 1. Location 2. Completeness 3. Involvement of one or both upper urinary tracts 4. Duration 5. Cause. Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014 Ref: Robins Pathological Basis of Diseases, 6th Ed. Urinary Tract Obstruction: Physiology  Urinary Tract Obstruction Hydroureter Dilation of ureter Hydronephrosis Obstructive uropathy Enlargement of renal pelvis and calyces Compensatory hypertrophy and hyperfunction – When blockage is unilateral – Obligatory growth Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014 – Compensatory growth Postobstructive diuresis nephrogenic diabetes insipidus  Lower Urinary Tract Obstruction Obstruction – Urethal stricture, prostate enlargement, pelvic organ prolapse – Partial obstruction of bladder outlet or urethra Low bladder wall compliance (high press. at low volumes). Neurogenic bladder (neurological origin) – Dyssynergia (loss of coordinated muscular contration) Detrusor hyperreflexia-overactive (upper NS) Detrusor areflexia-underactive (below S1) Overactive bladder syndrome (OBS) – Frequency, urgency, nocturia.  3.1% in autopsy series No gender differences until 20 years – Females more common 20-60 – Males more common older than 60. 2-2.5% of children at autopsy PNG Population unknown. Ref: Jamie Bartley Teaching Slides, Detroit, 2009  Effects variable and depend on whether the obstruction is unilateral or bilateral. Mechanical obstruction of urine outflow results in: – Increase backflow pressure into kidneys – Stagnation of urine – Increased risk of infection – Increased risk of formation of stones – Induce non-infective inflammation in interstitial tissue of kidneys Progressive dilation of renal pelvis and calyces Progressive atrophy of renal parenchyma Ref: Robins Pathological Basis of Diseases, 6th Ed. Dilation of perlvis & calyces depends on whether obstruction is sudden & complete or incomplete and chronic Sudden & complete – reduced GFR leads to mild dilation and atrophy of renal parenchyma Subtotal or intermittent - normal GFR leads to progressive Ref: Anjali Shinde Teaching Slides dilation Ref: Robins Pathological Basis of Diseases, 8th Ed.  Chronic cases – cortical atrophy and diffuse institial fibrosis. Advanced stages – kidneys become a thin wall cystic structure, significant parenchymal atrophy and obliteration of renal pyramids and thin cortex.  Acute obstruction – pain (renal colic) if calculi lodged in ureters. Prostatic enlargement cause urinary symptoms. Unilateral complete or partial hydronephrosis - asymptomatic for long periods of time. Present late. Bilateral partial obstruction – polyuria and nocturia (unable to concentrate urine). Hypertension common in chronic cases Acute complete bilateral obstruction – oliguria, anuria and azotemia. Surgical Emergency.  Depends on site, partial or complete, acute or chronic and duration of obstruction. Generally, if diagnosed early and obstruction relieved, recovery is good with return to normal kidney function. Late diagnosis – chronic renal failure.  Prof. Nazik Elmalaika Husain, MBBS, MSc, MD, MHPE, PhD. Professor, Pathology Dep., FMHS, OIU, Sudan.  Definition Types Pathogenesis Risk factors Sites Laboratory Diagnosis.  Masses of crystals, protein, or other substances that form within, and may obstruct the urinary tract. Renal stones are classified according to the minerals that make up the stone into 4 types: 1. Calcium oxalate (phosphate) – 75% 2. Struvite (Magnesium Ammonium Phosphate) – 10-15% 3. Uric Acid – 6% 4. Cystine – 1-2% 5. Unknown - ?10%.  Calcium oxalate stones – hypercalcemia and hypercalciuria from various causes. Magnesium ammonium phosphate stones – infections from urea splitting bacteria (e.g. Proteus and some staphylococci). Uric acid stones – hyperuricemia (e.g. gout, leukemias). However, >50% of patients with urate stones do not have hypeuricemia nor increased urine uric acid excretion. Cystine stones – caused by genetic defects in renal reabsorption of amino acids & cystine. Cystine stones form at low urinary Ph.  Increased concentration of stone constituents (saturated and thus precipitate) – Changes in urinary Ph (low Ph, higher risk). – Decreased urine volume – Urinary tract infection However, many calculi occur in the absence of these factors. ? Deficiency of inhibitors of crystal formation. Long list. Read up.  Conditions encourage stone formation – Stasis, obstruction, infection. – Salt in a higher concentration than the volume able to dissolve the salt. – Dehydration/decreased urine volume. – pH alteration (alkaline pH favors formation). Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014  Unilateral in 80% Renal calyces and pelves common sites small (2-3 mm) smooth or irregular spiked edges Bladder Staghorn calculi - large stone at pelvis forming a cast of the pelvic and calyceal system.  Symptoms appear if causing obstruction, or produce ulceration and cause bleeding. Can be asymptomatic. Smaller stones pass into ureters producing intense pain (renal colic). Hematuria Recurrent UTI.  UEC BUN Urinalysis – hematuria, crystals, pyuria Other modes of investigation – USS, X-ray, CT.  Generally good. Depends on underlying cause of kidney stone formation. Any question? Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Pathology Department, FMHS, Omdurman Islamic University, Sudan. 1 Outlines The World Health Organization (WHO) 2022 classification of urinary and male genital tumors (5th edition). Diagnostic criteria, molecular correlates and nomenclature have been updated. Selected tumors. The WHO (2022) of Kidney tumors A. Renal cell tumors 1. Clear cell renal tumors 2. Papillary renal tumors 3. Oncocytic and chromophobe renal tumors. 4. Collecting duct tumors 5. Other renal tumors 6. Molecularly defined renal carcinomas. B. Metanephric tumors C. Mixed epithelial and stromal renal tumors D. Renal mesenchymal tumors E. Embryonal neoplasms of the kidney F. Miscellaneous renal tumors. * Classification of Renal tumors: Oncocytoma. Clear cell renal cell carcinoma. Nephroblastoma (Wilms tumor). 4  General information With the exception of oncocytoma, benign tumors rarely cause clinical problems. Malignant tumors, on the other hand, are of great importance clinically and deserve considerable emphasis. By far the most common of these malignant tumors is renal cell carcinoma that affects adults, followed by Nephroblastoma (Wilms tumor), which is found in children.  Renal oncocytoma * Clinical Features: 5 - 9% of renal tumors M:F = 2:1 Most cases are asymptomatic, although flank pain may be a presenting complaint; hematuria may be seen. CT or MRI may identify a central scar. 6  Renal oncocytoma: Pathophysiology Benign neoplasms are believed to arise from renal intercalated cells and are packed with respiration-defective mitochondria. Often possess pathogenic mitochondrial mutations; it is suggested that the defective mitochondria activates a metabolic checkpoint leading to autophagy impairment and mitochondrial accumulation. Some cases have hybrid morphologies and Multiple tumors can be associated with syndromic conditions.  Renal oncocytoma: Pathophysiology 2 main molecular variant events associated with oncocytomas: rearrangements of CCDN1 (11q13 translocations) or aneuploidy manifested mostly in losses of chromosome Y and 1. Also suggested that in some oncocytomas (the ones that harbor aneuploidy losses of chromosome 1 and Y), additional p53 mutations may allow for progression to eosinophilic chromophobe renal cell carcinoma. Renal oncocytoma * Gross Pathology: Well-circumscribed, homogeneous cortical tumor. Mahogany-brown cut surface. Often shows a central, irregular fibrous scar. Bilateral or multicentric in 2% to 3% of cases. 9 10  Renal oncocytoma On microscopic examination: Well circumscribed lesion; usually no pseudocapsule. Composed of large round eosinophilic cells (oncocytes) with dense granular cytoplasm; nuclei are round and regular with even chromatin; small but conspicuous nucleoli are present. The cells are arranged in nests separated by edematous and hyalinized fibrous stroma. 11 Renal oncocytoma Positive stains: CD117 / KIT, E-cadherin, S100A1, PAX8 Low molecular weight keratin (CAM 5.2) and pancytokeratin. Negative stains: CK7 negative or scattered rare positive cells, AMACR, CAIX, Vimentin, HMB45, melanA, CK20, Hale colloidal iron. 14 15 * Epidemiology: Renal cell carcinomas represent about 1% to 3% of all visceral cancers and account for 85% of renal malignancy in adults. The tumors occur most often in older individuals, usually in the sixth and seventh decades of life, showing a male preponderance in the ratio of 2:1. Most renal cancer is sporadic, but unusual forms are a familial. 16  * Risk factors 1. Cigarette smoking is the most significant risk factor. 2. Obesity (particularly in women). 3. Hypertension. 4. Unopposed estrogen therapy. 5. Exposure to asbestos, petroleum products, and heavy metals. 6. Acquired polycystic kidney disease secondary to dialysis. 17  * Clinical presentation Silent 1. Hematuria. 2. Flank pain. 3. Flank lump. This triad is seen in only 10% of cases. The most reliable of the three is hematuria, but it is usually intermittent and may be microscopic; thus, the tumor may remain silent until it attains a large size. 18  Renal cell carcinoma tends to produce a diversity of systemic symptoms not related to the kidney termed paraneoplastic syndromes, ascribed to abnormal hormone production including; Polycythemia (erythropoietin):: Hct > 60%. Hypercalcemia (PTH like hormone). Hypertension. 19  Hepatic dysfunction. Feminization or masculinization (↑ gonadotrophin). Cushing syndrome. Leukemoid reactions. Amyloidosis. 20  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 patients with renal cell carcinoma, there is radiologic evidence of metastases at the time of presentation. The most common locations of metastasis are the lungs (more than 50%) and bones (33%), followed in order by the regional lymph nodes, liver and adrenals, and brain. 21 * Classification 22  This is the most common type, accounting for 70% to 80% of RCT. * Gross Pathology: Solitary renal cortical mass. Bilaterality and multifocality more common in familial cases. Well-circumscribed, lobulated with golden-yellow cut surface. Cystic change, hemorrhage, necrosis, and calcification often present. 23 24  * Histopathology: Nests of clear cells interspersed by delicate vascular network. 25  Cancer cells with clear cytoplasm. It contain glycogen. PAS +ve. 26 Positive stains: PAX8 and PAX2. CAIX: diffuse, membranous in 75 - 100% of clear cell RCC. Generally, CD10 (proximal tubular marker), RCC, vimentin and epithelial markers including AE1 / AE3, CAM 5.2, EMA. Negative stains: CK20, inhibin, MelanA / MART1, calretinin, TTF1, CEA.  Metastasis: Lung and bone Bone: produce osteolytic lesion and cause pathological fracture. Marker of bone mets.: ↑alkaline phosphatase. 28 Nephroblastoma (Wilms tumor) 29 Nephroblastoma (Wilms tumor) Nephroblastoma (or Wilms tumor) is a malignant embryonal tumor originating from nephrogenic blastema, which imitates the histology of developing kidney. Primarily occurs in children. Named after the German surgeon Max Wilms (who is often wrongly attributed to be the first one describing this entity). Nephroblastoma: Epidemiology Most common: 3 - 4 years of age. European and North American rates are about the same (8 per million). More common in Africans; least common in East Asian population. Congenital Wilms tumors very rare. Rare adult cases. Slight female preponderance. Majority of patients with Wilms tumor are nonsyndromic. 10 - 15% associated with syndromes and congenital anomalies. 1 - 2% familial. Relapses occur in ~15% of children, the majority within 2 years of diagnosis. Nephroblastoma: Etiology Thought to develop from persistent metanephric tissue or nephrogenic rests. Believed to be due genetic alterations of embryological development of the genitourinary tract. WT1 gene at chromosome 11p13 implicated in tumorigenesis. WT2 gene at chromosome 11p15 is a second locus.  Nephroblastoma: Clinical features Usually presents as abdominal mass with no associated symptoms. Other signs or symptoms (present in 20 - 30% of cases): Abdominal pain Hematuria Hypertension Anemia. Most common predisposition syndromes and conditions with different risk (high, moderate, low).  Nephroblastoma associated syndromes WAGR syndrome A = aniridia, G = genital abnormality, R = mental retardation Denys-Drash Syndrome Gonadal Dysgenesis and renal abnormality. Beckwith-widemann Enlargement of Individual organ Syndrome (macroglossia). Enlargement of entire body segment (hemihypertrophy). Enlargement of adrenal cortical gland. 34 Nephroblastoma Gross: lobulated, tan mass Micro: Tumor consists of blastemal, epithelial and stromal elements (triphasic) which can be present in variable amounts, and may show different lines and degrees of differentiation (from poor to well differentiated). Excellent, long-term survival 90%. Nephroblastoma (Wilms tumor): Morphology Small blue blastemal cells 36 Blastemal component composed of undifferentiated cells, arranged in small nodules.  Classification of Renal tumors (WHO 2022). I. Oncocytic and chromophobe renal tumors: Oncocytoma. II. Clear cell renal tumors: Clear cell renal cell carcinoma. III. Embryonal neoplasms of the kidney: Nephroblastoma (Wilms tumor). THANKS  Tumors of Urinary Bladder and urothelial tract Prof. Nazik Elmalaika O.S. Husain, MBBS, MD, MSc, MHPE, PhD. Pathology Department, FMHS, Omdurman Islamic University, Sudan. The WHO 2022 classification of urinary and male genital tumors (5th edition) Is organized based on tumor lineage: 1. Urothelial tumors, 2. Squamous cell neoplasm, and 3. Glandular neoplasms. 4. Urachal and diverticular neoplasms 5. Urethral neoplasms 6. Tumors of the Müllerian type.  Objectives UROTHELIAL TUMORS Urothelial Papilloma Inverted Urothelial Papilloma Papillary Urothelial Neoplasm of Low Malignant Potential. Non-invasive Papillary Urothelial Carcinoma, Low-grade. Non-invasive Papillary Urothelial Carcinoma, High-grade. Urothelial Carcinoma In-situ. Invasive Urothelial Carcinoma, Conventional Type. PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER. ADENOCARCINOMA, NOS OF URINARY BLADDER. Tumors of Urinary Bladder and urothelial tract Clinical: – Painless hematuria – 50-70 year, men 3x>women – Risk factors Smoking Industrial solvents, hydrocarbons, dyes Cystitis Schistosomiasis Drugs: Cyclophosphamide. Tumors of Urinary Bladder and urothelial tract Clinical: – High recurrence rate – Fatal by ureteric obstruction – Overall survival 5y: 57% – Ureteric carcinoma 5y survival: 10%.  UROTHELIAL PAPILLOMA MORPHOLOGY Solitary, exophytic, thin fibrovascular cores lined by normal urothelium (4-7 layers, normal thickness) without cytologic atypia. Non-branching, non-fused papillae; +/- ballooning of umbrella cells.  OTHER HIGH YIELD POINTS Benign, age range: 8-87 years, majority 5th decade, M>F Locations: Trigone, other; Size: 2-3 cm Pathogenesis: HRAS, KRAS mutations Gross: Polypoid/papillary DD: Polypoid/papillary cystitis (broad edematous core, inflammation) IHC: Positive: CD44 (basal cells), Ck20 (umbrella cells) like normal urothelium. UROTHELIAL PAPILLOMA  INVERTED UROTHELIAL PAPILLOMA MORPHOLOGY Inverted/endophytic pattern, anastomosing and proliferating cords of urothelial cells with maintained polarity, palisaded basal cells at the periphery of cords surrounding central streaming urothelial cells, and normal thickness. No atypia.  OTHER HIGH YIELD POINTS Benign, age group: any age Locations: Bladder neck, trigone, followed by renal pelvis, ureter, urethra; Gross: Polypoid Pathogenesis: HRAS, KRAS mutations Differential diagnosis: Other inverted papillary tumors like LGPUC, HGPUC, invasive urothelial ca. IHC: Positive: CD44 (basal cells); Negative: CK20, p53.  INVERTED UROTHELIAL PAPILLOMA Inverted/endophytic pattern, Palisaded basal cells at the periphery anastomosing and of cords. proliferating cords of urothelial cells.  PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL MORPHOLOGY Papillary architecture, fibrovascular cores lined by thickened urothelium with mild cytologic atypia (monotonous appearing cells with mild nuclear enlargement); not appreciable at low magnification. No marked cytologic atypia (easily appreciated at low  OTHER HIGH YIELD POINTS Age group: 6th to 7th decade, M>F, Without a history of urothelial carcinoma Pathogenesis: Not known, some cases with TERT promoter and FGFR3 mutations. Cystoscopy: Papillary lesion, small, single. Gross: Papillary lesion; IHC: Not useful. PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL: Fibrovascular cores lined by thickened urothelium with mild cytologic atypia.  NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMA, LOW-GRADE MORPHOLOGY Papillary architecture, fibrovascular cores lined by urothelial cells of variably increased thickness with or without mild cytologic atypia (mild nuclear enlargement, hyperchromasia, and size variation), mild loss of polarity, not appreciable at low magnification. No marked cytologic atypia (easily appreciated at low magnification) Mitosis mostly basal. Inverted variant with an inverted growth pattern.  OTHER HIGH YIELD POINTS Age group: >60 years, M>F; Risk factors: Smoking, chemical exposure. Pathogenesis: FGFR3 alterations, TERT promoter mutations. Cystoscopy/gross: Exophytic papillary tumor, single or multiple, variable size. Prognosis: Frequent recurrence (50%), rare progression to invasive urothelial carcinoma. IHC: Not useful. NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMA, LOW- GRADE: Papillary architecture, fibrovascular cores lined by urothelial cells of variably increased thickness with or without mild cytologic atypia.  NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMA, HIGH-GRADE MORPHOLOGY Papillary architecture, fibrovascular cores lined by urothelial cells of variably increased thickness with marked cytologic atypia (marked nuclear enlargement, hyperchromasia, prominent nucleoli, irregular contours, and size variation), loss of polarity/disordered architecture, easily appreciable at low magnification Frequent mitosis, including atypical forms. More complex and fused papillae compared to LGPUC. High grade features present in at least 5% of total tumor. Inverted variant with an inverted growth pattern.  OTHER HIGH YIELD POINTS Mean age: 70 years, 3M:1F Risk factors: Smoking, chemical exposure Pathogenesis: TERT promoter mutations, FGFR3 alterations, p53 mutations, p16 loss (chromosome 9p). Cystoscopy: Exophytic papillary tumor, single or multiple, variable size, less translucent than LG. Prognosis: Frequent recurrence (60%), progression to invasive urothelial carcinoma (25%). IHC: Positive: CK20 (full thickness), increased Ki67; Negative: CD44. Non-invasive papillary urothelial carcinoma, high-grade Non-invasive papillary urothelial carcinoma, high-grade  UROTHELIAL CARCINOMA IN-SITU MORPHOLOGY Flat lesion of variable thickness, markedly atypical urothelial cells, disordered architecture/loss of polarity. No papillary architecture. Variants: Pagetoid (single cells growing in a pagetoid manner), clinging (mostly denuded with few attached malignant cells), glandular. UROTHELIAL CARCINOMA IN-SITU: Flat lesion of variable thickness, markedly atypical urothelial cells. UROTHELIAL CARCINOMA IN-SITU: Flat lesion of variable thickness, markedly atypical urothelial cells.  OTHER HIGH YIELD POINTS Affects elderly patients Pathogenesis: TERT promoter alterations, p53, DNA damage repair genes, PI3K and MAPK pathways Cystoscopy: Erythematous mucosal patches, difficult to identify, can be multifocal Prognosis: Frequent recurrence and progression to invasive urothelial carcinoma.  OTHER HIGH YIELD POINTS Differential diagnosis: Urothelial dysplasia (cytologic atypia of a neoplastic process but falls short of a diagnosis of CIS) FISH: UroVision chromosomes 3,7,17, 9p21 IHC: Not necessary in classic cases Positive: CK20 (full thickness), p53, increased Ki67 Negative: CD44 (or decreased). UROTHELIAL CARCINOMA IN-SITU: Positive: CK20 (full thickness), p53, increased Ki67. INVASIVE UROTHELIAL CARCINOMA, CONVENTIONAL TYPE MORPHOLOGY Nests, sheets, cords, or single cells invading lamina propria and beyond. Mixed architectural patterns.  OTHER HIGH YIELD POINTS Seventh decade or later, 4M:1F Locations: urinary bladder, 10% upper tract (renal pelvis, ureter). Risk factors: Smoking, radiation, chemicals-benzidine dyes, opiates, high socioeconomic status. Pathogenesis: TERT promoter mutations, TP53 mutations, others. Gross: Sessile, ulcerated, polypoid, or papillary. IHC: Positive: GATA3, HMWCK, CK7, CK20, P63, uroplakin, Negative: PAX8.  INVASIVE UROTHELIAL CARCINOMA, CONVENTIONAL TYPE: Nests, sheets, cords, or single cells invading lamina propria and beyond.  PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER MORPHOLOGY Pure (100%) squamous morphology with the presence of intercellular bridges, keratin pearls, and keratinized cells. Should not contain conventional UC.  OTHER HIGH YIELD POINTS Risk factors: Indwelling catheter >10 years, bladder stones, smoking, Schistosoma haematobium infection (Egypt, Sudan). Pathogenesis: Chronic inflammation, loss of chromosome 17q and18p in Schistosoma associated cases. Gross: Large tumors, solid, polypoid, nodular, or ulcerated. Prognosis: Worse than conventional. IHC: Positive: CK5, CK6, p63, desmoglein3; Negative: Uroplakins. PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER  ADENOCARCINOMA, NOS OF URINARY BLADDER MORPHOLOGY Pure (100%) adenocarcinoma morphology. Various patterns: enteric/colonic type, mucinous, signet ring cell, or mixed. Should not contain conventional UC.  OTHER HIGH YIELD POINTS Rare, 2%, Peak age: 7th decade. Locations: urinary bladder, renal pelvis urethra. Pathogenesis: Unknown, chronic irritation. Gross: Single, sessile, nodular, ulcerated. IHC: Positive: CK20, CDX2, Villin, +/- CK7, Nuclear beta- catenin. Negative: GATA3 (can be + in some cases). ADENOCARCINOMA, NOS OF URINARY BLADDER Enteric/colonic type Signet ring cell type Urothelial carcinoma of the ureter Urothelial carcinoma of the renal pelvis.  Conclusion UROTHELIAL TUMORS Urothelial Papilloma Inverted Urothelial Papilloma Papillary Urothelial Neoplasm of Low Malignant Potential. Non-invasive Papillary Urothelial Carcinoma, Low-grade. Non-invasive Papillary Urothelial Carcinoma, High-grade. Urothelial Carcinoma In-situ. Invasive Urothelial Carcinoma, Conventional Type. PURE SQUAMOUS CELL CARCINOMA OF URINARY BLADDER. ADENOCARCINOMA, NOS OF URINARY BLADDER. THANKS