PATHOMidterms - 1. Renal Pathology

Kathryna Lesley T. Ayro, MD, FPSP | August 1, 2015 | ADVANCED PATHOLOGY

PATHOLOGY OF THE KIDNEY AND URINARY TRACT

    Introduction • Kidney has limited reactions to various injuries The kidney being the excretory organ is usually subjected to all various injuries affecting the body. Most systemic diseases usually involve the kidney in general and the most common cause of morbidity and mortality of all systemic and metabolic diseases include the kidney to be one of the causes • Factors: o Location of a particular type injury o Host response or stability of the immune system o Type of injury - presence or absence of other comorbid problems • Classification of renal diseases o Clinical They are classified if pre-renal, post-renal and renal causes o Etiologic o Immunologic They could be primary or secondary to systemic diseases o Morphologic They are classified based on what is observed under the microscope • Can also be classified into syndromes Most of the syndromes usually overlap in the later stages of the renal disease. It is difficult to identify the initial insult of that causes the renal disease. o Nephritic syndrome o Nephrotic syndrome o Non-nephrotic proteinuria o Microscopic hematuria o Acute and chronic renal injury o RPGN o Asymptomatic renal insufficiency Renal Biopsy • Evaluation of patients with renal diseases • Purposes: o Establish an accurate diagnosis

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Obtain critical information on the evolution and prognosis of a disease process o Develop a rational approach to the treatment of renal diseases • Disease recurrence in renal transplant • Presence of cellular or humoral rejection • Methods: o Percutaneous route – more common o Open biopsy • Handling: o Light microscopy (H&E Stain) o Immunofluorescence o Electron microscopy • 2 cores – ideally o Cold solution of 2% glutaraldehyde in phosphate for IF (Immunofluorescence) o Saline then fixative for LM (10% buffered formalin) but mercuric solution gives the best detail o Snap frozen in liquid nitrogen or isopentane cooled on dry ice for IF (Immunofluorescence) Percutaneous route of renal biopsy is also used in prostatic biopsy • Interpretation o Evaluate the four renal components The four renal components are: glomeruli, tubules, blood vessels, interstitial spaces o Hypercellularity In hypercellularity, there is increase in the number of cells. You should identify if there is increase in the (1) endothelial cells, (2) epithelial cells, (3) mesangial cells or (4) inflammatory cell infiltrates § Primary or secondary § WHO definition of normocellularity • No more than 3 cells in an individual glomerular mesangial region • 2-3 micrometer section o

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Glomeruli • Light microscopy (LM) o Size and cellularity o Mesangium o Presence of leucocytes o Capillary walls o Necrosis o Deposits: type and location o Crescents: type and percentage o Sclerosis: distribution and percentage o Adhesion to bowman’s capsule o Thrombi • Electron microscopy (EM) o Basement membrane § Thickness, contours, density o Cellular changes o Mesangium o Deposits: type and location o Inclusions • Immunofluoresence (IF) o Positive or negative reaction o Immunoglobulins, complements, fibrin o Pattern: linear or granular o Intensity EM: There is basement membrane thickening as seen in membranous glomerulonephritis Identify the deposits if they are in the glomerular basement membrane, endothelial cells or in the epithelial cells or if there is increase in mesangial cells IF: Identify the pattern of complements, if linear, it is similar to anti-GBM diseases, good pasture syndrome, or RPGN. If granular, it means that there are patchy deposits in the glomerular basement membrane as seen in post-strep glomerulonephritis. Tubules • LM o o o o o o o

Necrosis Reparative changes Dilation Casts: type Crystals Cellular inclusions Vascularization

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Basement membrane

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Cellular changes Inclusions Basement membrane Deposits: type and location

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Reactions and pattern Intensity

EM

IF

LM: We also evaluate the tubules for the presence of tubular necrosis. There are different stages of tubular injury from (1) simple swelling or cloudy swelling, (2) reduction of the cytoplasmic vacuoles and eventually (3) coagulative necrosis. This will determine if the stage of injury is reversible or not. Cloudy swelling indicates reversible damage and irreversible for necrosis. Blood Vessels • LM o Intimal thickening: type (sclerosis) o Elastic changes o Medial hypertrophy (decrease in vascular lumen) o Hyalinosis o Thrombosis and embolism o Necrosis o Inflammation o Juxtaglomerular apparatus • EM o Intimal and medial changes o Deposits • IF o Reaction and distribution Remember that kidneys are highly vascularized organ and they display evident increase in vascular pressure. They undergo hyalinization and sclerosis and they are usually consistent with chronic hypertension Benign hypertension – hyalinization, tunica medial hypertrophy, and sclerosis Malignant hypertension – hyperplastic arteriolitis Interstitium • LM o o

Edema Inflammation (acute or chronic)

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Fibrosis: type and percentage

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Cellular infiltration Deposits

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Reaction and distribution

EM

IF

Renal biopsy unlike any other biopsy does not directly conclude a diagnosis in one core biopsy but it needs to evaluate the four renal components before it can conclude a medically accurate renal disease.

The most common encountered are focal segmental glomerulosclerosis/glomerulonephritis Review of Glomerular Diseases (Refer to table) Glomerular diseases are studied based on the clinical presentation of the patient. Classifying such diseases focus on the presentation of the initial stages because in the later stages, the syndromes usually overlap. NEPHROTIC SYNDROMES -the most common clinical presentation proteinuria (>3.5g/day)

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gross

Note that Diabetic Focal glomerulonephritis is a metabolic disease while SLE Secondary Glomerular disease is an autoimmune disease, both are systemic diseases but presents a wide range off renal involvement (nephropathy) presenting with nephrotic syndromes.

Review of Glomerular Diseases Classification of Glomerular Disease by Distribution A. Classification of disease distribution when many glomeruli are considered 1. FOCAL – disease affects only some of glomeruli 2. DIFFUSE – disease affects almost or all glomeruli B. Classification of disease distribution when single glomerulus is considered 1. SEGMENTAL - a lesion involving only a part of the glomerulus 2. GLOBAL - a lesion involving the entire glomerulus

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Primary Glomerulonephritis 1. Minimal change disease -minimal -normal LM findings -no deposits -negative immunofluorescence -elimination or flattening of podocytes in EM -very common in children (80%) -very responsive to corticosteroid therapy -also called lipoid nephrosis due to the luminal histiocytes containing lipids (foamy histiocytes) in the tubules -presents with selective albuminuria, very common in children -global fat bodies is sometimes seen in urine 2. Diffuse membranous glomerulonephritis -more common in adults -very distinct glomerular basement membrane specially in silver stain -sometimes associated with viral infections but can also be primary -also responsive to corticosteroid therapy but more resistant than minimal change disease Secondary Glomerulonephritis 1. Diabetic focal glomerulonephritis -KW lesion (microscopic finding)

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-usually present as nephrotic syndrome -pathogenesis: there is glycosylation of the glomerular basement membrane -> increasing the permeability of the protein -> presenting as nephrotic syndrome 2. Amyloidosis -secondary disease because of amyloid deposition -sometimes associated with multiple myeloma, having similar presentations 3. SLE secondary glomerular disease -pathogenesis: immune complex deposited in the glomerular basement membrane -there is also accompanied proliferation of cells in the glomeruli usually focal and segmental involvement -EM: presence of subendothelial and mesangial deposits but depends on the stage NEPHRITIC SYNDROMES -the most common clinical presentation hematuria with RBC casts -expected RBC casts in the urine

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1. Post-infectious/post-streptococcal glomerulonephritis -most common -formation of immune complex produced by the infection deposited in the glomerular basement membrane -IF: lumpy bumby appearance – granular IgG deposits -EM: subepithelial humps – prominence of the epithelial lining 2. IgA nephropathy (Berger’s disease) -pathogenesis: activation of the alternate complement pathway RPGN SYNDROMES -the clinical presentation is hematuria 1. Good pastures syndrome -linear IF pattern -LM: presence of crescents 2. Crescentic nephritis -linear IF pattern -LM: presence of crescents

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NEPHROTIC/NEPHRITIC SYNDROMES -presents both gross hematuria and proteinuria 1. Focal segmental glomerulosclerosis -seen for patients positive/reactive in HIV -seen in patients in chronic renal failure showing (1)sclerosis – more extensive to KW lesion and forms nodules and (2) hyalinization 2. MPGN Type 1 -present with lobular deposits in IF 3. MPGN Type 2 --present with linear deposits in IF - tram-tracking or reduplication of the basement membrane All will progress to chronic glomerulonephritis or end stage renal disease where most of the glomeruli have: -Hyalinization -Sclerosis -Extensive tubular atrophy -Extensive stromal fibrosis and inflammation PEDIATRIC RENAL TUMORS • WILM’S TUMOR • MESOBLASTIC NEPHROMA • NEPHROGENIC RESTS • NEPHROBLASTOMATOSIS • INTRARENAL NEUROBLASTOMA • RHABDOID TUMOR WILM’S TUMOR • Nephroblastoma • Most common renal malignancy of early childhood • 2-4 years of age • Originates from primitive metanephric tissue • Deletions of short arm of chromosome 11 o WT1 and WT2 • Genetics Risk is increased in the following: o WAGR- 33% § Wilm’s tumor, Aniridia, Genital anomalies, retardation § Deletions of 11p13 o Denys Drash Syndrome – 90%

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§ Gonadal dysgenesis (male pseudohermaphroditism) and early onset nephropathy § P13 of chromosome 11 • Dominant genetic missense mutation affecting DNA binding properties o Beckwith-Wiedmann Syndrome § Organomegaly: macroglossia, hemihypertrophy, renal medullary cysts, omphalocoele and adrenal cytomegaly § P15.5 of chromosome 11, WT2 • Cells with attempts to recapitulate the different stages of nephrogenesis • Classic tri-phasic combination o Blastema (dark, undifferentiated cells) o Stroma o Epithelial (some are differentiated cells) • Clinical features: o Commonly presents as large abdominal mass Sometimes patients are asymptomatic until you palpate an abdominal mass at the age of 2. o Hematuria, abdominal pain after a traumatic incident Slight injury in the abdomen will cause hemorrhage that will initiate the symptoms o Prognosis is good with surgery, radiotherapy and chemotherapy –diagnosis before age 2

MESOBLASTIC NEPHROMA • Also called: o Fetal hamartoma o Mesenchymal hamartoma o Leiomyomatous hamartoma • Most common renal tumor of infancy • Congenital tumor • May present in utero causing non-immune fetal hydrops and polyhydramnios •

Gross: o Classic § variably circumscribed § white/yellow, whorled mass § mean 5 cm, near hilum o Cellular § necrosis § large cystic areas and hemorrhage § mean 9 cm. in diameter

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Microscopic o Classic, cellular and mixed types; usually no necrosis or hemorrhage, not well circumscribed o Classic § resembles infantile fibromatosis or leiomyoma with fascicles and whorls of bland spindled myofibroblasts and thin collagen fibers § tumor surrounds tubules and glomeruli § metaplastic and dysplastic elements common, usually cartilage, also extramedullary hematopoiesis and cuboidal metaplasia § usually few mitotic figures (resemble sarcomatous lesion) § no desmoplasia o Cellular § resembles infantile fibrosarcoma with densely packed plump atypical spindle cells with abundant cytoplasm, vesicular nuclei and nucleoli § frequent mitotic figures (25-30/10 HPF) and necrosis

Note: It is important to identify if the tumor is of renal origin or a tumor from the adrenal gland

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NEPHROGENIC RESTS • congenital, not neoplastic • may originate from persistent nephrogenic blastema • single or multiple, unilateral or bilateral; rarely occur in ectopic sites • considered precursor lesion of Wilms’ tumor, found in 30-44% of kidneys resected for Wilms’ tumor o Intralobar rests (compared to perilobar rests): • may progress to Wilms’ tumor at higher rate § more commonly associated with WT1 mutations, Denys-Drash syndrome and WAGR syndrome o Perilobar rests: § rarely progress to malignancy § may be associated with loss of imprinting at 11p, are associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome • Microscopic: o aggregates of primitive metanephric tissue, either perilobar or intralobar • Perilobar: o Peripheral with sharply demarcated margins,composed of blastema and tubules with scanty or sclerotic stroma, often solitary • Intralobar: o randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules, usually multifocal

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DD: Wilms’ tumor (particularly for extrarenal rests)

NEUROBLASTOMA • Primary renal tumors or secondary spread from adrenal or other retroperitoneal site • Metastases to bone and orbit • Poor prognosis if N-myc amplification (30%) or 1p• Laboratory: catecholamines in serum and urine • Microscopic: small blue cell tumor with HomerWright rosettes • Positive stains: catecholamines (90%), NSE (neuron specific enolase), S100 • DD: Wilms’ tumor (rosettes resemble Wilms’ tubules) ADULT RENAL TUMORS • Renal Cell Carcinoma • Adenomas • Oncocytoma • Angiomyolipoma • Metastatic Tumors RENAL CELL CARCINOMA TRIAD: hematuria, flank pain, abdominal mass • General Features: o Adult – 5th to 6th decade o Male to female ratio is 2:1 o Increased risk – cigarette smoking and HPN o Associated with the following: § Von Hippel Lindau – 50% § Acquired cystic disease § Tuberous sclerosis § Neuroblastoma o Peculiarities § Occasional regression § Common recipient of metastasis of a cancer into another cancer It can also have another primaries with renal cell carcinoma. And like your melanoma, it has the greatest mimic in medicine. It can mimic any other tumor even mesangial tumor when it is not classic, and can metastasize widely even with a small tumor. • Clinical Features o Triad § Hematuria

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§ Flank pain § Abdominal mass Weight loss, anemia, fever, metastatic foci Hepatomegaly due to hepatic dysfunction and renal cell carcinoma = Stauffer syndrome Hypercalcemia, hypertension, polycythemia (presented as a paraneoplastic syndrome)

Morphology o Gross § Well delineated § Usually in the cortex § Solid golden yellow on cut sections § With hemorrhages, necrosis, calcifications and cystic change o Microscopic: “clear cells” o EM § Abundant glycogen, some fat, numerous cell junction, scanty organelles, long microvilli It usually have benign features but it is also infiltrative and one important feature of RCC is that it invades your renal vein and inferior vena cava. •

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IM and HIS § Keratin § EMA § CEA Co-expression of keratins and vimentins is the rule- not found in renal tubular cells To determine whether renal cell ca or not - keratin, vimentin and CD10 Cytogenetics - terminal deletion of the short arm of chromosome 3 (beginning at 3p13); absent in oncocytic and papillary types Other histologic types

Papillary renal cell carcinoma § Chronic dialysis § Hereditary – c-met oncogene § Multicentric and bilateral § No loss of 3p13 § Consistent expression of keratin 7 § Trisomy of chromosome 3q, 7, 8, 12, 16, 17, 20

Collecting duct carcinoma § Arise from or differentiate towards collecting duct (Bellini) - more common in the medullary area than in the cortical region

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§ More common in males and centered in the medulla, with tubulopapillary architecture with desmoplastic stroma § Aggressive behavior § Monosomies of chromosome 1, 6, 15, 22

Renal medullary carcinoma § Rare § Young black patients with sickle cell disease § Also called the seventh sickle cell nephropathy § Arises from collecting duct system; may be due to regenerating renal papillary epithelium § All patients have been black; average age 21-24 years, 75% male; 75% right kidney § Aggressive, death in 4-6 months, resistant to chemotherapy § May be related to collective duct carcinoma since similar histologic and immunoreactive features § Clinical: • gross hematuria • flank pain • weight loss • usually advanced disease at presentation with metastases to lymph nodes, adrenal gland, peritoneum, perinodal retroperitoneal tissue, liver, lungs or inferior vena cava § Cytogenetics: • sickle cell trait or hemoglobin SC disease in almost all cases; associated with monosomy 11 (beta globin gene is at end of 11p) § Gross: • ill-defined firm, rubbery, tan-gray tumor in renal medulla and adjacent soft tissues

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• mean 7 cm; satellite nodules in cortex; hemorrhage and necrosis common § Microscopic: • tubular, solid, reticular, adenoid cystic, yolk sac like patterns • not tubulopapillary; infiltrative • contains mucin; tumor cells have hyperchromatic nuclei, prominent nucleoli, rhabdoid features • vascular invasion common • desmoplastic stroma • neutrophils common within tumor, lymphocytes at rim; angiolymphatic invasion, hemorrhagic and geographic necrosis common; frequent mitotic figures § Positive stains: high molecular weight cytokeratin, variable vimentin and mucicarmine, occasional EMA (epithelial membrane antigen) and CEA (carcinoma epmbryonic antigen) It is difficult to differentiate it with collecting duct of Bellini so it is evaluated with immunostaining to consider it if it is epithelial in origin § Negative stains: colloidal iron, PAS, desmin (used for sarcomatous lesion) § DD: collecting duct carcinoma (irregular glands within desmoplastic stroma with neutrophils), high grade urothelial carcinoma, rhabdoid tumor

Chromophobe renal cell carcinoma Just like clear cell carcinoma but the cytoplasmic membrane is very distinct morphologically

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§ Well circumscribed, solitary (it can grossly mimic a benign tumor) § Usually with absent necrosis and hemorrhage § Sharply defined borders and abundant cytoplasm often with PERI-NUCLEAR REGION § Positive Hale’s colloidal iron – acidic mucins § Positive for EMA, keratin, CD9, E-cahedrin § Negative for vimentin § Loss of chromosome 1, 2, 6, 10, 13, 17, 21 § Can undergo sarcomatoid transformation § Close relationship to oncocytoma § More favorable prognosis Spread and metastasis o Peri-nephric fat and regional LN o Renal sinus o Distant metastases (same as prostatic carcinoma metastasizing in the lungs and bones) § Lung § Bones – pelvis, femur o Notorious to unusual places • Prognosis o Staging § I – kidney § II – peri-renal fat but within Gerota’s fascia § III – renal vein, IVF, or regional LN § IV – other than adrenal metastasis o Distant metastasis: single most important prognostic parameter o Tumor size: 5.0 – 5.5 cm o Renal vein invasion § Gross invasion: important for high grade tumors § Microscopic invasion: important predictor of relapse o Microscopic grade: important predictor of survival (strongly correlated with staging) o P53 overexpression: metastatic disease and poor survival in early stage disease Staging is important before doing a radical nephrectomy. •

Characterisitically yellow and cells with prominent cytoplasmic membrane showing a cobblestone appearance. The nucleus is pleomorphic and hyperchromatic compared to RCC. Sarcomatoid renal cell carcinoma Hardest type of RCC to find and usually asked for immunostaining to rule out sarcoma or markers of mesenchymal tumors like vimentin, two tracts were always used, those that will identify it as mesenchymal and those that identify it as epithelial § Spindle cell carcinoma, anaplastic carcinoma, carcinosarcoma § High nuclear grade § Strong reactivity to vimentin § Extremely aggressive

ADENOMAS • Tubulo-papillary adenoma o Papillary and tubular pattern

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Cortical in location Rarely exceed 1 cm. Cytoplasm is acidophilic Common in end stage disease and long term dialysis Metanephric adenoma o Young to middle aged females o Larger than tubule-papillary adenomas o Tubules and papillary structures with scanty stroma o o o o

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ONCOCYTOMA It is usually made up of oncytes, similar to the thyroid namely oncytoma of the thyroid or Hurthle cell adenoma of the thyroid. A prominent feature of oncocyte is the extensively eosinophilic cytoplasm due to the abundance of mitochondria. So when subjected to formalin, the red feature (eosinophilic cytoplasm) turns into brown creating a grossly mahogany brown color. • Solid and mahogany brown tumor • Often with stellate scar centrally • Can be multicentric and bilateral • Cells with abundant acidophilic cytoplasm in tubular or alveolar patterns • Small nuclei and regular • Express mitochondrial markers • Cytogenetics: allelic deletions at 10q • No 3p abnormalities They are benign lesion but they become malignant once they invade the renal parenchyma and usually encapsulated. ANGIOMYOLIPOMA • Less than 1% of renal tumors • Usually adults • Benign (almost always) neoplasm composed of thick walled blood vessels, smooth muscle and fat; includes spindle and epitheloid cells • Usually one large mass; multiple masses suggests tuberous sclerosis • Risk factors: o Tuberous sclerosis (50% of AMLs occur in these patients) o Tuberous sclerosis: § Autosomal dominant neurocutaneous disorder

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§ With hamartomas/tumors of brain (subependymal giant cell cell tumor), retina, skin (cutaneous angiofibroma), heart (rhabdomyomas), bone, lung (lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia), kidney (angiomyolipoma in 40-80%, renal cell carcinoma, some epitheloid tumors may be misclassified), cysts § Clinically mental retardation and infantile/childhood seizures Blood vessels have thick walls appearing as blood vessels supporting a polyp. Risk factors: – TSC2/PKD1 contiguous gene syndrome: both kidneys enlarged and cystic with classic angiomyolipomas and rare intraglomerular microlesions • Member of perivascular epithelioid cell (PEC) tumor family; related to lymphangioleiomyomatosis (in lung); "sugar" tumor of lung, clear cell tumors of pancreas and uterus • Neoplastic, not a hamartoma; many cases have loss of heterozygosity of TSC2 gene • Adipose tissue and smooth muscle cells are monoclonal, but may arise independently • Also occurs in liver, where epithelioid smooth muscle cell component predominates • May coexist with renal cell carcinomas in non tuberous sclerosis patients, particularly clear cell, which is HMB45 negative • Gross: – red, gray-white, yellow (for vascular, smooth muscle and adipose components) – resembles clear cell carcinoma – may invade local lymph nodes and renal vein even though benign • Microscopic: – triphasic with myoid spindle cells, islands of mature lipid-distended cells, dysmorphic thick walled blood vessels without elastic lamina

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– smooth muscle component appears to spin off from vessel walls and may be hypercellular, atypical, pleomorphic or epithelioid – may resemble a high grade sarcoma if it metastasizes

The ureter unlike the pelvis is not expandable, so any tumor growing in this region will present as obstruction and can lead to hydronephrosis of the kidney. Also, due to its very thin vascular layer, invasion on the outside of the ureter can occur early

UROTHELIAL CARCINOMAS OF THE RENAL PELVIS AND LOWER URINARY TRACT • 5-10% of renal tumors • Benign papillomas to invasive TCCA • Manifests as hematuria • Never clinically palpable • Block urinary flow causing hydronephrosis and flank pain • Sometimes multiple

The urinary bladder has big space so the clinical manifestation if a tumor will arise would be painless hematuria. There is a continuous erosion of the tumor. Obstruction is not a major clinical symptom unless the tumor is located where the ureters are inserted or near the urethra.

URINARY BLADDER TUMORS Urothelial tumors are graded based on their (1) morphology if it is flat/ diffuse or papillay and then based on the (2) polarity of the cells from the basement membrane to the superficial layer (usually transitional epithelium has 4-5 layers of cells) and (3) presence of nuclear atypia. These features classifies the tumor if they are high or low grade. •

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Urothelial tumors o Inverted papilloma o Exophytic papilloma o Low malignant potential o Carcinoma-in-situ o Carcinoma Squamous cell carcinoma Adenocarcinoma Small cell carcinoma Sarcoma Clinical course: o Painless hematuria o Frequency, urgency, dysuria o Depends on the location of the tumor o Pyelonephritis and hydronephrosis o Prognosis: § Histologic grade § Tumor stage at the time of diagnosis § Histologic type

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In the urothelial tumor of the urinary bladder, they get a section of the tumor and get a section of the thick muscle layer to identify the presence or absence of invasion in deep vascular layer. Flat lesions usually do not present as an obstructive lesion. UROTHELIAL TUMORS • Morphology o Papilloma § 1% younger patients § Finger-like papillae § Histologically identical to normal urothelium o Grade I § Low malignant potential § Grossly similar to papilloma § Mild cytologic and architectural atypia § Increase in the number of layers of cells (6-8) o Grade II: greater loss of polarity, more layers of cells, mitoses, atypia, papillary architecture o Grade III: papillary, flat or both, greater pleomorphism, atypia and mitoses, larger in size, more disorganized • Grading WHO Grading Papilloma TCC Grade I

ISUP consensus Urothelial papilloma Urothelial neoplasm of low malignant potential

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TCC Grade II TCC Grade III

Urothelial carcinoma, low grade Urotelial carcinoma, high grade

• Carcinoma-in-situ – High grade, flat lesion confined to the bladder mucosa – Grossly appears as mucosal hyperemia, granularity or thickening – May be multifocal • Tumor Staging – Extent of tumor spread affects the prognosis – AJCC/UICC (American Joint Commission on Cancer/Union Internationale Contre le Cancer) PATHOLOGIC STAGING OF BLADDER CA Depth of Invasion AJCC/UICC Non invasive, papillary Ta Noninvasive, flat T1S Tis Lamina propria T1 Superficial muscularis T2 propria Deep muscularis propria T3a Perivesical fat T3b Adjacent structures T4 Lymph node metastases N1-3 Distant metastases M1 *N1, regional LN 5 cm. or other LN

Mesenchymal tumors o Most common is LEIOMYOMA o Sarcomas are not common § Inflammatory conditions may mimic sarcomas § Sarcomas are fleshy with necrosis and hemorrhages • Secondary tumors o More common than primary tumors o Direct extension from cervix, uterus, ovaries, prostate or rectum Uremia is the most common cause of death in patients with cervical carcinoma •

TUMORS OF URETHRA • Urethral caruncle o Inflammatory lesion, small painful red nodule o Highly vascularized fibroblastic tissue with inflammation • Papilloma (transitional or squamous depending on the location) • Carcinoma – uncommon o Papillary growth – transitional cell ca o Squamous cell ca – most common o More aggressive and invasive

OTHER TUMORS • Squamous cell carcinoma o 3-7% o Chronic bladder irritation and infection Schistosomiasis o Mixed with TCC is more common o More invasive and ulcerative, rare papillary forms • Adenocarcinoma - rare • Arise from urachal remnants • Small cell carcinoma and signet ring carcinomas o Very rare, highly malignant (rule out rectum, cervix, and uterus because they are more common in that area than in the urinary bladder)

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Review of Glomerular Diseases

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