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SURGICAL PATHOLOGY RENAL DISEASES ROBERTO D. PADUA JR., MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE Glomerular lesions associated with the nephrotic syndrome Disease Light Microscopy Minimal change glomerulopathy Minimal or no mesangial prominence Diffuse mesangial hypercellularity with nephrotic syndrome Mild mesangial hypercellularity Focal and segmental glomerulosclerosis Focal and segmental mesangial sclerosis Membranous glomerulonephritis Uniform capillary wall thickening, sometimes with spiked dome pattern Diabetic nephropathy Nodular and diffuse mesangial sclerosis, insudative lesions Amyloidosis Mesangial and vascular deposits of Congo redpositive material with green birefringence Light chain deposition disease Mesangial widening and deposition of PAS positive material Fibrillary glomerulonephritis Mesangial widening and ocassional hypercellularity, capillary wall thickening Glomerular lesions associated with the nephrotic syndrome Disease Light Microscopy Fibrillary glomerulonephritis Mesangial widening and occasional hypercellularity, Capillary wall thickening Immunotactoid glomerulopathy Mesangial widening and occasional hypercellularity, Capillary wall thickening Mesangial widening Congenital nephrotic syndrome 1. Finnish type 2. Diffuse Mesangial sclerosis Tubular ectasia, microcysts, glomerular sclerosis Diffuse mesangial sclerosis WHO Classification of Lupus nephritis and clinicopathologic classification Class Pathology findings Clinical renal manifestations 1. Normal or minimal abnormality Kidney is normal by light, electron, and immunofluorescence microscopy Usually asymptomatic 2. Pure mesangial alterations Mesangial expansion but mostly patent capillaries Mesangial immune deposits Low-grade proteinuria with or without hematuria Normal renal function 3. Focal proliferative GN Focal and segmental proliferative intra- and/or extracapillary necrotizing and/or sclerosing lesions in <50% of glomeruli Predominantly mesangial and subendothelial immune deposits Nephritic urinary sediment Variable but usually non-nephrotic proteinuria WHO classification of Lupus nephritis with clinicopathologic classification Class Pathology findings Clinical renal manifestations 4. Diffuse proliferative GN Predominantly global proliferative lesions, necrosis, crescents in >50% of glomeruli Variable sclerosis, prominent inflammatory interstitial infiltrate Predominantly mesangial and subendothelial immune deposits Nephritic and nephrotic syndromes, hypertension, variable degree of renal insufficiency 5. Membranous GN Diffuse thickening of capillary walls subepithelial (and mesangial) immune deposits Nephrotic syndrome or severe proteinuria 6. Advanced sclerosing GN Glomerular obsolescence and Chronic renal failure segemntal glomerulosclerosis, tubular atrophy, and interstitial fibrosis Few, if any, immune deposits Dysplastic lesions of the renal artery Diagnosis Age Sex Freq Lesion Intimal fibroplasia 1-50 M=F 1-2% Narrowing by intimal proliferation without lipid Medial fibroplasia 30-60 F>M 60-70% “String of beads”, alterating stenosis and mural thinning Medial hyperplasia 30-60 F>M 5-15% Smooth muscle hyperpalsia and thickening Perimedial fibroplasia 30-60 F>M 15-24% Fibrosis of outer media, occasionally aneurysms Medial dissection 30-60 F>M 5-15% Fibrosis of media with dissecting aneurysms Periarterial fibroplasia 15-50 F>M 1% Perivascular fibrosis and inflammation Cystic diseases of the kidney Multicystic renal dysplasia Anomalous differentiation of the mesonephros Most common form of cystic disease in children Most common cause of abdominal masses in newborns Dysplasia is usually unilateral Cystic diseases of the kidney Multicystic renal dysplasia Dysplastic kidney of an infant. Cystic diseases of the kidney Multicystic renal dysplasia Section of kidney showing embryonic-like connective tissue and tubules Cystic diseases of the kidney Autosomal dominant (adult) polycystic kidney disease Hereditary condition char by expanding cysts that progressively destroy the renal parenchyma of both kidneys renal failure 1 or 2 per 1000 live births 10% of cases requires dialysis or renal transplantation Transmitted as autosomal dominant with complete penetrance Cystic diseases of the kidney Adult polycystic kidney diseases Mutation in PKD1 (16p13.3) – 85 to 90% Mutation in PKD2 (4q13-23) PKD3 – seen in ADPKD not linked to PKD1 & 2 Male=Females Symptomatic in 4th-5th decade of life with gradual onset of renal failure Clinical manifestations – flank pain, flank mass, hematuria, HPN, renal failure 20% develop nephrolithiasis Cystic diseases of the kidney Adult polycystic kidney diseases Diagnosis – UTZ, CT-scan Bilateral involvement of kidneys Markedly enlarged kidneys with bosselated outer cortical surface Cysts develop in all segments of the renal tubule and glomerular capsule Light microscopy – cysts are lined by cuboidal, flattened epithelium, and hyperplastic polypoid foci also seen Cystic diseases of the kidney Adult polycystic kidney diseases External and cut surface of a nephrectomy specimen from a patient with ADPKD. Cystic diseases of the kidney Autosomal recessive (infantile) polycystic kidney disease Rare disorder – 1 per 20,000 live births Genetic defect localized in the short arm of chromosome 6 Liver and both kidneys are affected Neonatal period – renal symptoms Later in life – hepatic disease Cystic diseases of the kidney Infantile polycystic kidney disease Present with large abdominal masses at birth “Potter” phenotype – char facies due to oligohydramios, joint deformities, pulmonary hypoplasia Death is due to respiratory failure Beyond perinatal period – renal failure, HPN, and portal HPN Estimated perinatal mortality is 30-50% 5-year survival rate after first month of life is 80-95% Cystic diseases of the kidney Infantile polycystic kidney disease Kidneys markedly enlarge bilaterally but retain their reniform configuration Cysts tend to be linear and radiate from the medulla to the outer cortex Microscopcally, cysts appear as dilated tubular structures lined by cuboidal or flattened epithelium, intervenning tissue may contain uninvolved nephron Cystic diseases of the kidney Medullary sponge kidney Char by dilated medullary and papillary collecting ducts which give the medulla a sponge-like appearance True incidence is unknown (1 per 5000 pop) Asymptomatic unless complicated by nephrolithiasis, hematuria, or infections Symptoms start in the 4th-5th decades of life Male=Female 25% of cases have associated hemihypertrophy of the body Cystic diseases of the kidney Nephronophthisis-medullary cystic kidney disease complex 2 major groups Nephrolithiasis – autosomal recessive mode of inheritance 3 forms Juvenile (NPH1) = 13 years ESRD Infantile (NPH2 = 1-3 years Adolescent (NPH3) = 19 years MCKD – autosomal dominant trait 2 variants MCKD1 = 62 years MCKD2 = 32 years Cystic diseases of the kidney Nephronophthisis-MCKD complex Juvenile Most NPH common genetic cause of ESRD in children Both sexes are equally affected Clinical presentation = polydipsia, polyuria, anuresis, dec. in urinary concentration, severe anemia, growth retardation 12% of cases assoc with retinitis pigmentosa (Senior-Loken syndrome) Other assoc conditions = hepatic fibrosis, skeletal malformations, defects in the CNS NPHP1 identified on chromosome 2q13 nephrocystin Cystic diseases of the kidney Nephronophthisis-MCKD complex MCKD Symptoms occur in the 3rd and 4th decades of life Similar to NPH1 minus the growth retardation and severe anemia + extrarenal disorders Associated with huperuricemia and gout MCKD1 = 1q21; MCKD2 = 16p13 Cystic diseases of the kidney Nephronophthisis-MCKD complex Kidneys are normal or slightly reduced in size with a granular surface Renal involvement is always bilateral Cut section – cortex and medulla both thinned Cysts arise from the loop of Henle, DCT, and CD Tubulointerstitial fibrosis with lymphocytic inflammatory infiltrate, tubular atrophy and cysts formation seen histologically Cystic diseases of the kidney Acquired renal cystic disease 7-22% of patients with renal failure who are not on dialysis 40% of patients on dialysis for 3 years 80-90% of patients on dialysis for 10 years Theory – cysts results from obstruction of the renal tubules, by local fibrosis, oxalate deposition, or epithelial hyperplasia Usually asymptomatic but the cysts may bleed, rupture or become infected Most serious complication is development of renal adenocarcinoma (50X in patients on dialysis) Cystic diseases of the kidney Simple cysts Most common cystic abnormality seen in the kidneys Incidence increases with age Usually asymptomatic and found incidentally on autopsy May cause pain as a result of hemorrhage or infection Occur more commonly in the renal cortex derived from pre-existing tubules Usually unilocular less than 5cm in diameter Pediatric tumors and tumor-like conditions Wilm’s tumor Also known as nephroblastoma, embryoma, carcinosarcoma, adenosarcoma, adenomyosarcoma Primarily seen in infants – 50% occurring before 3 y/o; 90% before the age of 6 years Both kidneys are equally affected Incidence of synchronous or metachronous bilateral involvement is 5-10% Extrarenal sites have been reported Pediatric tumors and tumor-like conditions Wilm’s tumor Expression of WT1 gene Conditions associated with definite increased risk : WAGR syndrome, omphalocoele-macroglossia (Beckwith-Wiedemann syndrome), hemihypertrophy, Denys-Drash syndrome Conditions associated with possible increased risk : renal and genital malformations, cutaneous nevi and angiomas, trisomy 18, Klippel-Trenaunay syndrome, neurofibromatosis, Bloom syndrome, and cerebral gigantism Pediatric tumors and tumor-like conditions Wilm’s tumor Clinical presentation – abdominal mass, HPN, proteinuria Diagnosis IVP – shows intrarenal mass that displaces and distorts the pelvis UTZ CT-scan MRI Potential tumor markers – inc hyaluronic acid, acquired Von Willebrand’s factor, inactive renin, inc eryhtropoietin Pediatric tumors and tumor-like conditions Wilm’s tumor Gross Solitary, well-circumscribed, rounded, and soft Cut section is solid, pale gray or tan often exhibits areas of cystic change, necrosis, and hemorrhage A lobular pattern results from fibrous septation Wilm’s tumor - Gross Tumors show a variegated appearance Tumor is homogenous and nodular Tumor has extensive areas of infarct-like necrosis Wilm’s tumor Microscopic = has 3 major components Undifferentiated blastema – cellular, composed of small round-to-oval primitive cells Mesenchymal (stromal) tissue – spindle cell fibroblast-like configuration; exhibit differentiation toward various cell types particularly smooth muscle and skeletal muscle Epithelial tissue – characterized by the formation of embryonic tubular (sometimes glomerular) structures that closely recapitulate the appearance of normal developing metanephric tubules (and glomeruli) Wilm’s tumor Histochemical features Blastematous and Immunohistochemical elements – (+) for vimentin, keratin, EMA Mesenchymal – (+) for myogenin and desmin, NSE, S-100, glial fibrillary acidic protein Type I insulin-growth factor receptors – responsible for increased proliferation and inhibition of differentiation Electron Closely microscopic features resembles developing metanephros Wilm’s tumor Spread and metastasis Local spread in perirenal soft tissues adrenal glands, bowel, liver, vertebrae, paraspinal region Renal vein invasion is common 15% of cases involves regional LN Distant metastasis – lungs, liver, and peritoneum Therapy Stage I and II – nephrectomy and 2 agent chemo Wilm’s tumor Prognosis Overall cure rate for unilateral Wilm’s tumor is 8090% Age – less than 2y/o – good Stage – most important prognostic determinator; increased rate of relapse: presence of inflammatory pseudocapsule, invasion of the renal sinus, extensive infiltration of the renal capsule, and tumor infiltration of intrarenal vessels Size – bigger tumor – poor Anaplasia - poor Wilm’s tumor Prognosis Extensive tubular differentiation – good prognosis Skeletal muscle differentiation – good prognosis Mucin production – poor prognosis P53 mutation – poor prognosis Pediatric tumors and tumor-like lesions Mesoblastic nephroma Also known as fetal, mesenchymal, or leiomyomatous hamartoma A congenital renal neoplasm that is usually discovered before the patient reaches 6 months of age Gross Solid, yellowish gray to tan, with a whorledconfiguration Most are centered near the hilus of the kidney Well-circumscribed but may infiltrate the renal parenchyma and perirenal fat Areas of necrosis and hemorrhage are usually absent Gross appearance. The tumor is well-circumscribed with a fibrous cut surface. Mesoblastic nephroma Microscopic Cellular growth of spindle cells Proliferating cells have features of fibroblast, myofibroblasts, and smooth muscle cells Tubules and glomeruli may be seen surrounded by spindle cells with some exhibiting hyperplastic and metaplastic changes Small islands of hyaline cartilage and foci of extramedullary hematopoiesis may be present There is no capsule separating the tumor from rhe uninvolved parenchyma Areas of necrosis and hemorrhage may be seen Microscopic appearance showing a monotonous proliferation of spindle cells with bland nuclei and abundant fibrillary acidophilic cytoplasm. Mesoblastic nephroma Contain the t(12;15)(p13;q25) translocation, which results to gene fusion Definitive treatment is nephrectomy Pediatric tumors and tumor-like lesions Multicystic nephroma Also called multilocular cystic nephroma; multilocular cyst Arises in early infancy but may present clinically at any age Clinical presentations result from the presence of a mass or ureteral obstruction by one of the daughter locules Multicystic nephroma Gross Lesion is usually solitary, unilateral and sharply delineated from the uninvolved renal parenchyma Cut surface shows a multilocular appearance, individual cyst measures 1 mm to 3 cm or more The cysts do not communicate with each other or with the pelvis Extension of the lesion beyond the renal capsule may occur Gross appearance of muticystic nephroma involving most of the kidney. Multicystic nephroma Microscopic Cysts are lined by tubular epithelium ranges in height from columnar to flat resembling endothelium and simulating the appearance of lymphangioma A “hobnail” pattern is common LPO. Shows multiple cysts lined by flattened epithelium and separated by a cellular spindle cell stroma. The epithelial lining of the cyst shows a “hobnail” pattern. The cyst lining is flat, simulating endothelium. Pediatric tumors and tumor-like lesions Nephroblastomatosis and nephrogenic rests Congenital dysontogenetic rather than neoplastic disorders Can be associated with Wilm’s tumor They share the same mutation of WT1 Single or multifocal, unilateral or bilateral subcapsular aggregates of primitive metanephric tissue Microscopic in size – called nephrogenic rests Massive – called nephroblastomatosis Pediatric tumors and tumor-like lesions Clear cell sarcoma Also known as bone-metastasizing renal tumor Comprises 4% of childhood renal tumors, peaks in the 2nd year of life Gross Large, sharply outlined and centered in the medullary or central region of the kidney Homogenous cut surface of light brownish gray color and myxoid appearance Consistency is hard and cystic formations are common The tumor is well circumscribed and whitish, and it bulges on the cut surface. Clear cell sarcoma Microscopic Diffuse growth of relatively small cells with round normochromatic nuclei, inconspicous nucleoli, vacuolated cytoplasm, and indistinct cell margins Nuclear grooves are common, mitosis infrequent Trabecular pattern of growth. Clear cell sarcoma Origin of neoplasm is uncertain Histogenetically related to Wilm’s tumor High tendency for relapse and propensity for skeletal metastasis – skull Overall 5-year survival rate is 69% Pediatric tumors and tumor-like lesions Rhabdoid tumor Most cases occur in young infants Median age at diagnosis is 18 months Associated in about 15% of the cases with primary embryonal tumors in the midline posterior fossa particularly medulloblastoma Gross Solid, soft, and relatively well circumscribed Pediatric tumors and tumor-like lesions Rhabdoid tumor Microscopic Monomorphic neoplasm involving the medullary region Most characteristic feature is the presence of a large cytoplasmic eosinophilic hyaline globule that displaces the nucleus laterally An eosinophilic amorphous (“hyaline”) material fills the scanty cytoplasm and pushes the nucleus aside. Pediatric tumors and tumor-like lesions Metanephric stromal tumor Presents grossly as a fibrous lesion centered in the renal medulla that contains smoothwalled cysts. Neoplastic cells are spindle shaped, with onionskin cuffing around entrapped tubules Reactive to CD34 Surgical excision is curative Adult tumors and tumor-like conditions Renal cell Carcinoma Average age of diagnosis is 55 – 60 years Male:Female is 2:1; bilaterality is 1% Cigarette smoking and HPN increases the risk Conditions that may be complicated by RCC von Hippel-Lindau disease Acquired cystic disease ADPKD and multicystic nephroma Tuberous sclerosis Neuroblastoma Familial cutaneous leiomyomatosis Malignant lymphoma Renal cell carcinoma Clinical features Presents with hematuria (59%), flank pain (41%), or abdominal mass (45%) – diagnostic triad (9%) Other manifestations Weight loss – 28% Anemia – 21% Fever – 7% Due to metastatic deposits – 10% Renal cell carcinoma Clinical features Systemic/Paraneoplastic manifestations Leukemoid reaction Systemic amyloidosis Polyneuropathy Gastrointestinal disturbances Hepatomegaly/hepatic dysfunction (Stauffer syndrome) Hypercalcemia HPN Polycythemia Gynecomastia Cushing’s syndrome Renal cell carcinoma Diagnosis IVP, UTZ, CT-scan, MRI Morphologic features Gross Well delineated and centered on the cortex Cut surface – solid golden yellolw tumor sharply separated from the surrounding tissues by fibrous pseudocapsule Hemorrhage, necrosis, calcification, and cystic change can occur RCC developing in ADPKD Well circumscribed with light yellow color Variegated with a combination of cystic, solid, and hemorrhagic areas Well circumscribed and homogenous The tumor involves almost the entire kidney and extends into the renal vein Renal cell carcinoma Microscopic Tumor cells are large, the appearance of the cytoplasm ranging from optically clear, with sharply outlined boundaries (“vegetable cells”) to deeply granular with many transitional forms RCC, diffuse pattern of growth with entrapment of glomeruli HPO, optically clear cytoplasm and sharply outlined cell membrane Renal cell carcinoma Cytology Examination of voided urine or bladder washing are inefficient - <25% Retrograde brushing cytology is better Percutaneous FNA is a safe and accurate technique Renal cell carcinoma Spread and metastases 1/3 of RCC are found to invade perinephric fat and/or regional LN at the time of diagnosis Common finding is invasion of the main renal vein Extend into the inferior vena cava, the right atrium, and the renal sinus Distant metastasis to the lungs and skeleton (pelvis and femur) Renal cell carcinoma Therapy Primary treatment – surgical excision Transabdominal or thoracoabdominal radical nephrectomy – removal of the entire kidney, surrounding fat, Gerota’s fascia, and adrenal gland Some authors advocate node dissection in continuity with nephrectomy or after the renal mass has been removed (minimum distance of 4 – 6 cm above and below the renal vessel No benefits have yet been demonstrated for administration of adjunctive radiation therapy or chemotherapy Renal cell carcinoma Prognosis The overall 5-year survival rate is approximately 70% Stage Stage I – confined to the kidney Stage II – extension to perirenal fat but within Gerota’s fascia Stage III – renal vein or vena caval involvement Stage IV – extension to other organs other than adrenal or distant metastases Renal cell carcinoma Prognosis Distant metastases – the single most important parameter Tumor size Tumor size of 5.0 or 5.5 cm is more predictive of the survival of Stage I patients after radical nephrectomy Microscopic Low-grade grade = good High-grade = poor Renal cell carcinoma Prognosis Good prognosis Clear cell tumors Lymphocytic infiltration Renal cell carcinoma Prognosis Poor prognosis Granular cell tumors Renal vein invasion Increase cell proliferation p53 overexpression CD44S expression MUC1 expression Insulin-like growth factor I receptor Neural cell adhesion molecule Adult tumors and tumor-like conditions Adenomas Tubulo-papillary Minute adenomas cortical foci of tubular or papillary epithelium (measures 1-3mm in diameter) Present in approximately 20% or more of adult kidneys Cytoplasm is acidophilic rather than clear and not abundant Psammoma bodies may be present Adult tumors and tumor-like conditions Adenomas Metanephric Occur adenoma in young, or middle-aged female patients Larger than tubulo-papillary adenoma Composed mostly of tiny tubules and papillae accompanied by very scanty stroma Metanephric adenoma showing papillary growth pattern. Adult tumors and tumor-like conditions Adenomas Metanephric adenofibroma Previously termed nephrogenic adenofibroma A biphasic tumor An epithelial component similar to that of metanephric adenoma admixed with a bland spindle cell stroma Adult tumors and tumor-like conditions Oncocytoma Approximately 7% of all primary nonurothelial epithelial renal neoplasms Gross Solid and mahogany brown often have a central stellate scar, and can reach huge sizes Can be multicentric and bilateral Invasion of renal capsule or renal vein can occur The tumor is well circumscribed, mahogany brown and has a central fibrous scar. Oncocytoma Microscopic Composed of cells with abundant acidophilic granular cytoplasm, growing in nesting or tubular fashion Psammoma bodies can be present Typical nesting pattern of renal oncocytoma Adult tumors and tumor-like conditions Neuroendocrine tumors Small cell neuroendocrine carcinoma Carcinoid tumor Adult tumors and tumor-like conditions Angiomyolipoma Composed of admixture of vessel, smooth muscle, and fat Tumor found incidentally or result in retroperitoneal hemorrhage 1/3 of patients are associated with tuberous sclerosis TSC2/PKD1, contigous gene syndrome, increases the risk Adult tumors and tumor-like conditions Angiomyolipoma Gross Depends on the relative amounts of the various components and may simulate RCC Capsular invasion is present in 25% of cases, including perirenal soft tissue extension 1/3 of cases are multiple; 15% are bilateral Gross appearance of Angiomyolipoma. Adult tumors and tumor-like conditions Angiomyolipoma Microscopic Shows adipose tissue, tortous thick-walled blood vessels lacking elastic tissue lamina, and bundles of smooth muscle that seem to emanate from vessel walls Typical renal angiomyolipoma. The tumor is composed of adipose tissue, smooth muscle and vessel. Adult tumors and tumor-like conditions Juxtaglomerular cell tumor Present clinically with HPN because of extensive renin production Grossly, unilateral and solitary, less than 3cm in diameter and located in the cortex. Solid and well circumscribed, with a grayish-white to light yellow cut surface Microscopically, reminiscent of hemangiopericytoma and glomus tumor. Cells are uniform and round to polyhedral with a granular acidophilic cytoplasm The lesion has distinct vascular background Other benign tumors and tumor-like conditions Teratoma Medullary fibroma Leiomyoma Lipoma Myxoma Hemangioma Lymphangioma Benign peripheral nerve tumor Solitary fibrous tumor Hydatid cyst