Kidney tumor - Printer Friendly Page
Last revised 18 May 2007
Reviewed by Christiane Rakozy, M.D. (see Reviewers page)
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Table of Contents Kidney-tumor
Cystic non-neoplastic lesions: acquired (dialysis associated) cysts, adult polycystic kidney disease, childhood polycystic kidney disease, cystic renal dysplasia, glomerulocystic kidney of tubular sclerosis, medullary sponge kidney, mesothelial cysts. nephronophthisis, simple cysts
Neoplasms-pediatric: clear cell sarcoma, congenital mesoblastic nephroma, metanephric stromal tumor, nephroblastomatosis, nephrogenic rests, neuroblastoma, oncocytoid carcinoma after neuroblastoma, ossifying tumor, renal cell carcinoma, rhabdoid tumor, Wilms’ tumor of children
Renal cell carcinoma: classification, general, renal cell carcinoma, adenocarcinoma of renal pelvis, Xp11.2/TFE3 gene fusions, chromophobe, clear cell, collecting duct, lymphoepithelioma-like, medullary, metastases, mucinous tubular and spindle cell, papillary, rhabdoid features, sarcomatoid, small cell, squamous cell, tubulocystic, unclassified, urothelial
Other neoplasms-adult/both: adenoma, angiomyolipoma, angiosarcoma, carcinoid, clear cell sarcoma of soft parts, desmoplastic small round cell tumor, fibroepithelial polyp of renal pelvis, hemangioma, hemangiopericytoma, inflammatory myofibroblastic tumor, juxtaglomerular, leiomyoma, leiomyosarcoma, leukemia, lipoma, lymphangioma, lymphoma, medullary fibroma, metanephric adenofibroma, metanephric adenoma, metanephric adenosarcoma, mixed epithelial and stromal, multilocular renal cyst, myelolipoma, myxoma, oncocytoma, pelvic lipomatosis, perineurioma, PNET/Ewing’s, post-kidney transplant, sarcoma, schwannoma, sinus histiocytosis, solitary fibrous tumor, spiradenocylindroma, synovial sarcoma, teratoma, Wilms’-adult
Miscellaneous: features to report, grossing, staging, nuclear grading
Go to Kidney-nontumor
Cystic non-neoplastic lesions
Acquired (dialysis associated) cysts
May be related to uremia, not dialysis per se
Seen in 7-22% of uremic patients not on dialysis, 40% on dialysis for 3 years, 80% on dialysis for 10 years
Bilateral, affects all parts of kidney
Increased (7-50x) risk of renal cell carcinoma (7% @ 10 years, usually papillary), often multifocal, usually 3 cm or less, tumors usually not as aggressive as classic renal cell carcinoma with only rare metastases; papillary or clear cell tumors may have non-classic molecular mechanisms in these patients (Mod Path 1999;12:301, Archives 1986;110:592); tumors have lower proliferative activity (Mod Path 1998;11:339, Hum Path 2002;33:230)
Cysts may form due to obstruction by oxalate crystals, fibrosis or hyperplasia
Atypical epithelial proliferations are present in 1/3 of cases, and are associated with gains of #7, #12, #17, #20, Y, suggesting they represent early neoplasms (Hum Path 2002;33:761)
Case reports: associated renal cell carcinomas (clear cell and papillary subtypes) with abundant calcium oxalate crystals (Archives 2003;127:E89)
Gross: moderately enlarged bilateral kidneys with cysts up to 2 cm in cortex and medulla containing clear fluid, often with calcium oxalate crystals; papillary hyperplasia common
Micro: cysts lined by flattened to hyperplastic cuboidal or columnar epithelium; may have atypical papillary projections
Adult polycystic kidney disease
Also called autosomal dominant polycystic kidney disease
Autosomal dominant, almost complete penetrance
1-2/1000 live births, no gender preference; causes 10% of chronic renal failure requiring transplantation or dialysis
Multiple expanding cysts of both kidneys destroy renal parenchyma slowly, leading to renal failure in adulthood
Associated with von Meyenburg complexes in liver (97%), hepatic cysts (40-88%), berry aneurysms (10-30%, cause death in 4-10%), mitral valve prolapse (20%), cysts in pancreas, lung, spleen, pineal gland, seminal vesicles; also aortic aneurysms, hepatic fibrosis, intestinal diverticula
Associated with loss of ability to concentrate urine, hypertension by age 20, infection, hematuria, renal stones (20%)
Cysts compress and obstruct only part of normal nephron, so normal renal function until age 30-49 years
25% die from infection, 40% from hypertension and heart disease, 15% from berry aneurysms or stroke
Cause of cysts unknown: may be due to altered cell-cell and cell-matrix interactions
Poor prognostic factors: sickle cell trait (not disease), men, hypertension
Molecular:
PKD1 gene on 16p13.3 (altered in 85-90% of cases) produces polycystin 1; function unknown
PKD2 gene on 4q13-23 (altered in 10% of cases) produces polycystin 2; later onset and development of chronic renal failure than PKD1
PKD3 gene: minority of cases, gene unmapped
10% lack a family history and are considered new mutations
Case reports: with littoral cell angioma of spleen (Archives 2001;125:1505), with polycystic liver disease and hemorrhagic hereditary telangiectasia (AJSP 1998;22:368), 15 year old white girl with no family history but classic findings and oral-facial-digital syndrome type I (Archives 1991;115:519)
Gross: large kidneys (up to 4 kg), always bilateral (although degree of involvement may vary), bosselated outer surface composed of mass of cysts up to 4 cm; cysts contain clear to brown fluid
Micro: cysts are saccular expansions or diverticula of all portions of renal tubule and glomerular capsule that later become disconnected and filled with fluid; cysts are lined by cuboidal or flattened epithelium, may have papillary projections or polyps; functional nephrons exist between cysts; may have foci of interstitial scarring, tubular atrophy and pyelonephritis; 20% have associated renal adenomas
References: AJSP 2002;26:198 (TSC2/PDK1 continuous gene syndrome), Mod Path 1996;9:233 (hepatic cysts)
Childhood polycystic kidney disease
Autosomal recessive; bilaterally enlarged kidneys at birth; affects 1 per 6,000-20,000 live births
Mapped to chromosome #6p
Perinatal mortality 30-50%; 5 year survival is 80-95% if survive first month of life
Must remove kidneys so lungs can grow; children have Potter sequence with characteristic facies due to oligohydramnios, pulmonary hypoplasia and joint deformities
Possible pulmonary hypoplasia since kidneys restrict growth of lungs; later develop portal hypertension with splenomegaly; usually no cysts other than kidney and liver
Liver always affected (every portal triad, every case) with herring duct cysts, congenital hepatic fibrosis, variable bile duct ectasia and biliary dysgenesis
Gross: markedly enlarged kidneys with smooth surface; small cysts in cortex and medulla; dilated channels are perpendicular to cortical surface; cysts present in medulla (collecting duct)
Micro: dilation of all collecting tubules with fluid accumulation; cysts lined by cuboidal or flattened cells from collecting tubules
Also called multicystic renal dysplasia
Abnormal metanephric differentiation, occurring by week 20 in utero, results in persistence of abnormal structures
90% are associated with ureteropelvic obstruction, ureteral agenesis, atresia or reflux; 10% have unknown cause
May be due to hyperplastic smooth muscle in ureters
Causes the majority of neonatal abdominal masses; presents as flank mass or pyelonephritis
Also most common form of cystic renal disease in children
If blastema present, patient at risk for Wilms’ tumor
Rarely familial, but is associated with Dandy Walker syndrome
Also associated with cardiac malformations
2/3 unilateral
Segmental dysplasia seen only in children with duplex (duplicated) kidney (incomplete fusion of upper and lower poles)
Case reports: newborn with bilateral renal dysplasia, severe pancreatic fibrosis, intrahepatic biliary dysgenesis, total situs inversus with normal cytogenetics (Hum Path 1988;19:871)
Gross: large, irregular kidney, usually cystic, often multicystic with variably sized cysts, can’t distinguish cortex from medulla; cysts are variably sized
Micro: lobar disorganization present; cysts of various sizes lined by flattened to cuboidal epithelium, may contain nodular blastema (undifferentiated cells), islands of undifferentiated mesenchyme, cartilage (10-20%), immature collecting ducts with fibromuscular collar, primitive glomerular structures
Glomerulocystic kidney of tuberous sclerosis
Case report in newborn (Archives 2000;124:327)
Not a typical finding in tuberous sclerosis
Glomerulocystic kidneys (kidneys with glomerular cysts) also seen in non-tuberous sclerosis patients (maternal phenacetin use during pregnancy, Archives 1977;101:462; no known cause, Archives 1976;100:186)
Case reports: newborn with features of tuberous sclerosis (Path Res Pract 1992;188:367)
Gross: enlarged kidney with cortical cysts
Micro: Bowman’s epithelium and tubular epithelium show hyperplastic changes; cells have abundant granular cytoplasm and may fill tubular lumina; also vascular dysplasia (abnormal smooth muscle hyperplasia), metanephric hamartoma
Multiple cystic dilations of collecting ducts in medulla bilaterally with normal cortex
1 per 5000 births; no gender preference; not familial
Normal renal function; does not progress to end stage renal disease
Associated with hemihypertrophy of body (25% of cases), Marfan’s, Caroli’s, Ehlers-Danlos
Signs/symptoms: calcifications on Xray, hematuria, stones, infection at age 30+ years
Treatment: cranberry juice to keep urine acid (don’t remove these kidneys)
Gross: normal sized kidneys with dilated medullary ducts with multiple, small cysts in medullary pyramids and papillae, giving medulla a sponge-like appearance
Micro: medullary cysts lined by cuboidal epithelium or urothelium; may have concretions adherent to cyst wall; often severe inflammation and scarring in interstitium, often with tubular atrophy near papillary tips
Also called primary retroperitoneal cysts of mesothelial origin
Somewhat rare
May present as renal masses
Gross: may be hemorrhagic
Micro: cyst lined by single cell lining of non-pleomorphic cells with abundant eosinophilic cytoplasm, vesicular nuclei and small nucleoli; may have small gland-like spaces
Positive stains: keratin, vimentin, hyaluronic acid, HBME-1, WT1, thrombomodulin, calretinin
Negative stains: BerEP4, CEA, B72.3, LeuM1
DD: mucinous cystadenoma (ovarian-like stroma, mucin+, CEA+, negative for hyaluronic acid), lymphangioma (multicystic, has smooth muscle and lymphocytes in cyst wall and lumen, keratin negative), simple hemorrhagic cysts
References: Archives 2000;124:766
Nephronophthisis - uremic medullary cystic disease complex
Small medullary cysts at corticomedullary junction with cortical atrophy, interstitial fibrosis
Incidence: 1 per million
Cortical and tubulointerstitial damage initially causes polyuria and polydipsia, progressing to chronic renal failure in 5-10 years
Consider in children/teenagers with unexplained chronic renal failure, family history, chronic tubulointerstitial nephritis on biopsy
Nephronophthisis: autosomal recessive; median onset of end stage renal disease by type is infantile-1-3 years, juvenile-13 years, adolescent-19 years
Infantile/adolescent nephronophthisis: responsible genes are at 9q22-31 and 3q21-22; function unknown
Juvenile nephronophthisis: most common cause of end stage renal disease in children; no gender preference; symptoms at age 4 years with polydipsia, polyuria, enuresis, decrease in urinary concentration, severe anemia, growth retardation; 12% associated with retinitis pigmentosa; rarely associated with hepatic fibrosis, skeletal malformations, CNS defects; affected by NPHP1 gene at 2q13 encoding nephrocystin, function unclear
Medullary cystic kidney disease: autosomal dominant; no associated growth retardation or anemia; is associated with hyperuricemia and gout; median age of onset of end stage renal disease is MCKD1-62 years, MCKD2-32 years; responsible genes are at 1q21 and 16p13
Case reports: 4 year old girl who also had basal ganglia calcification and pancreatic lipomatosis (Archives 1988;112:630)
Gross: bilateral involvement of normal or moderately small kidneys with contracted granular surface, thin-walled medullary cysts up to 2 cm, particularly at corticomedullary junction, which is indistinct
Micro: cysts lined by flattened or cuboidal epithelium; also tubulointerstitial fibrosis and lymphocytic infiltrate, tubular atrophy with thickened tubular basement membrane (highlighted by PAS); glomeruli usually preserved
EM: homogenously thickened tubular basement membrane, split into thin lamellae, reticulated or disintegrated
Not a disease, but an occasional finding that increases with age (0.1% in children, 20% at age 50+ years)
May be confused with cystic renal cell carcinoma, but avascular with smooth contours
Hemorrhage may cause acute pain; may calcify
Gross: up to 10 cm, but translucent, with glistening membrane, filled with clear fluid, usually cortical
Micro: single layer of cuboidal, flattened or atrophic epithelium; may have thickened walls with hemosiderin-laden macrophages and atrophic epithelium
Kidney Neoplasms
Pediatric tumors
Also called bone metastasizing renal tumor
Mean age 36 months, range 2 months-14 years, peaks at ages 2-3 years; 2/3 male
4% of childhood renal tumors; 20 new cases per year in US; rarely in adults
Frequent relapse, bone and skull metastases common; also metastases to regional lymph nodes (29% at presentation), brain, lung, liver; metastases often 5 years or more after removal of primary tumor
Overall survival 69%, 98% for stage 1
Good prognostic factors are treatment with doxorubicin and low stage; death more common after combination chemotherapy other than doxorubicin
Gross: large (mean 11 cm), well circumscribed, centered in central kidney or medulla; homogenous tan/gray or myxoid appearance; firm with occasional cysts
Micro: classic - nests or cords of small cells with indistinct cell margins; light staining cytoplasm, round nuclei containing fine chromatin and grooves, no nucleoli, rare mitoses; only 20% have clear cells (due to vacuoles); vascularized stroma is alveolar and arborizing, scattered preexisting tubules or glomeruli are trapped in periphery of tumor; vascular invasion common; other patterns are myxoid (50%), sclerosing (35%, includes hyalinizing which has osteoid-like pattern resembling osteosarcoma), cellular (26%), epithelioid (13%, tumor cells align along vessels), palisading (11%), spindle (7%), storiform (4%) and anaplastic (3%)
Positive stains: vimentin
Negative stains: keratin, CD99, WT1, p53
EM: rare organelles, sparse cytoplasmic filaments, primitive cell junctions, complex cytoplasmic processes
DD: Wilms’ tumor (pushing border, more aggressively invasive, epithelioid areas are keratin+)
References: AJSP 2000;24:4, AJSP 1999;23:1455 (teenager/young adult tumors), Hum Path 1985;16:1219
Congenital mesoblastic nephroma
Also called fetal, mesenchymal or leiomyomatous hamartoma
Most common renal tumor of infancy, first described in 1967 (Pediatrics 1967;40:272)
A congenital tumor; age at presentation varies by type (classic: 16 days, cellular: 5 months, mixed: 2 months); may present in utero causing nonimmune fetal hydrops and polyhydramnios
Diagnosis should be questioned if applied to patients over 2 years old
Frequency: classic (24%), cellular (66%), mixed (10%)
5-10% recur or metastasize (usually cellular type), usually by age 1, to lung, brain or rarely bone
Some consider similar tumor in adults to be a mixed epithelial and stromal tumor
Report: involvement or not of medial kidney margin by tumor
Treatment: nephrectomy with wide margins; chemotherapy if resection is incomplete in infants 3 months or older or if tumor ruptures during surgery
Case reports: Case of Week #57, 3 week old infant with flank mass and mixed type (Archives 2004;128:929), tumor in newborn (Archives 2002;126:103)
Gross: classic - variably circumscribed, white/yellow, whorled mass, mean 5 cm, near hilum, involving over half of kidney with indistinct tumor-kidney interface; resembles leiomyoma with whorled cut surface; may be cystic; may involve renal sinus; hemorrhage and necrosis are uncommon
cellular - necrosis, large cystic areas and hemorrhage, mean 9 cm
mixed - mean 10 cm; cysts, hemorrhage and necrosis in cellular areas
Micro: classic, cellular and mixed types; usually no necrosis or hemorrhage, not well circumscribed
Classic – resembles infantile fibromatosis or leiomyoma with fascicles and whorls of bland spindled myofibroblasts and thin collagen fibers; tumor surrounds tubules and glomeruli, has irregular borders; metaplastic and dysplastic elements common, usually cartilage, also extramedullary hematopoiesis and cuboidal metaplasia; usually few mitotic figures; no desmoplasia
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
Positive stains: smooth muscle actin, desmin, vimentin, renin (within tumor vessels or vessels in trapped cortex)
Negative stains: keratin (except for entrapped epithelium), laminin
Molecular: cellular subtype has t(12;15)(p13;q25) translocation, results in ETV6-NTRK3 fusion gene, also present in infantile fibrosarcoma (Mod Path 2000;13:29; Mod Path 2001;14:1246); mixed and classic subtypes lack this translocation (Histopathology 2006;48:748)
DD: Wilms’ tumor (also has skeletal muscle and blastema, older age and nephrogenic rests; previously treated tumors may have well differentiated spindle cell stroma), clear cell sarcoma (similar age but clear cells and chicken-wire vasculature; fine nuclear chromatin and low mitotic rate; negative smooth muscle markers, tumor cells isolate single nephrons), rhabdoid tumor (more invasive margins, usually epithelioid cells with cytoplasmic inclusions and prominent nucleoli, usually presents with metastases), metanephric stromal tumor (nodular low power pattern, onion-skin cuffing around entrapped renal tubules, heterologous differentiation and vascular changes, CD34+, older patients), adult mixed epithelial and stromal tumor (look and stain similar but mean age in 50’s, usually women, positive for estrogen and progesterone receptors)
References: Hum Path 1989;20:682, Hum Path 1988;19:1347 (renin)
Benign abdominal mass in infants (mean age 2 years)
Often misdiagnosed as congenital mesoblastic nephroma
Treatment: excision is curative
Gross: fibrous lesion centered in renal medulla containing smooth walled cysts; mean 5.5 cm
Micro: identical to stromal component of metanephric adenofibroma; unencapsulated bland spindle cells that entrap native kidney; usually undermine calyceal or pelvic urothelium, may entrap nerves, often has scalloped border with renal cortex; nodular appearance of hypo- and hypercellular areas with onion-skin cuffing around entrapped renal tubules; spindle cells have thin, tapered, hyperchromatic nuclei with thin or indistinct cytoplasmic extensions; occasional epithelioid cellular stroma; stroma may show glial, cartilaginous or neuroblastic differentiation, angiodysplasia of entrapped arterioles and juxtaglomerular cell hyperplasia in entrapped glomeruli; no vascular invasion
Positive stains: vimentin, CD34 (often patchy), S100 (variable)
Negative stains: smooth muscle actin, muscle specific actin, desmin, keratin, EMA, CD117/c-kit
DD: congenital mesoblastic nephroma (deeply invasive, sharply defined linear transitions in cellularity, no perivascular or peritubular collarettes, no heterologous differentiation, CD34-, desmin+, older patients), clear cell sarcoma (regular branching capillary vascular pattern, no heterologous differentiation, CD34-), metanephric adenofibroma (neoplastic epithelium, not entrapped tubules)
References: AJSP 2000;24:917
Congenital, not neoplastic
Single or multiple, unilateral or bilateral
Massive aggregates of primitive metanephric tissue, present in 1% of neonatal kidneys and 30% with Wilms’ tumor
Florid cases are associated with congenital anomalies and hypertension
Case histories: male newborn died at age 1 hour of respiratory failure with bilateral, pancortical nephroblastomatosis (Archives 1989;113:729)
Treatment: conservative
Gross: diffuse involvement of entire subcapsular region
Micro: tightly packed nephrogenic cells with primitive appearance, but not anaplastic; scanty stroma; no cartilage or primitive mesenchyme
References: Adv Anat Path 2001;8:276
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
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
Perilobar rests rarely progress to malignancy, may be associated with loss of imprinting at 11p, are associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome
Case reports: midline lumbosacral ectopic nephrogenic rest in healthy newborn male (AJSP 2004;28:1389)
Micro: microscopic aggregates of primitive metanephric tissue, either perilobar or intralobar
Perilobar: peripheral with sharply demarcated margins, composed of blastema and tubules with scanty or sclerotic stroma, often solitary
Intralobar: randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules, usually multifocal
DD: Wilms’ tumor (particularly for extrarenal rests)
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
Micro: small blue cell tumor with Homer-Wright rosettes
Positive stains: catecholamines (90%), NSE, S100
DD: Wilms’ tumor (rosettes resemble Wilms’ tubules)
Oncocytoid renal cell carcinoma after neuroblastoma
Mean age 9 years, range 5-13 years; with mean interval between neuroblastoma and carcinoma of 7 years (range 3-12 years)
Micro: expansile masses composed of solid and papillary patterns of large cells with well defined cell membranes, abundant eosinophilic, oncocytic or reticular cytoplasm; enlarged nuclei with mildly irregular contours, distinct nucleoli; occasional lipid-laden histiocytes, psammoma bodies, mitotic figures; often resembles high grade papillary renal cell carcinoma, but predominantly solid and without necrosis
Positive stains: EMA, vimentin; variable CK 20
Negative stains: HMB45, S100, CK 7
Molecular: loss of 20q13; also others not typical for other renal cell carcinomas
EM: microvilli and cell junctions, less mitochondria than oncocytoma; no microvesicles
References: AJSP 1999;23:772
Ossifying renal tumor of infancy
Calcified mass in renal pelvis composed of spindle cells in partially calcified osteoid matrix
References: Pediatr Pathol Lab Med 1995;15:745
Renal cell carcinoma in children
<1% of all renal cell carcinomas occur in children
22%% are papillary, 15% clear cell, 5% collecting duct, 24% unclassified; ASPL-TFE3 and PRCC-TFE3 carcinomas are common
Usually no loss of heterozygosity for VHL gene, even for clear cell carcinomas
References: AJSP 2004;28:1117; AJSP 1999;23:795
1-2% of childhood renal tumors
60% are < 1 year old, 30% 1-3 years old, rare > 5 years
Associated with hypercalcemia and calcifications in tubules
Usually stage 2 or higher; 9% are bilateral
Very aggressive; 82% present with metastases; 90% die in 2 years
15% are associated with primary embryonal tumors in the midline posterior fossa, often medulloblastoma
Case reports: tumor in 38 year old woman (Archives 2003;127:e371); 10 year old girl with extrarenal pelvic rhabdoid tumor (Archives 2003;127:633), presentation as skin metastasis (Archives 1998;122:1099)
Gross: solid, soft, well circumscribed, involves medullary region
Micro: diffuse, trabecular or alveolar patterns of large monomorphic cells with well defined cell borders; cells have pink cytoplasm; cleared chromatin, macronucleoli and eccentric nuclei due to large eosinophilic hyaline globule (perinuclear inclusions); tumor has aggressive invasive pattern; occasionally cells are spindled; variable necrosis and mitoses
Fine needle aspirates: usually single cells
Positive stains: keratin (particularly CK8), vimentin, EMA
Negative stains: muscle markers, neural markers, WT1
EM: hyaline globules composed of tangled intermediate filaments
Molecular: deletions or mutations of hSNF5/INI1 gene at 22q11.2 (use FISH)
DD (rhabdoid features): Wilms’ tumor with myogenic cells (usually foci of typical Wilms’ blastema or definitive nephrogenic differentiation is present), congenital mesoblastic nephroma, renal cell carcinoma, urothelial carcinoma, PNET/Ewing’s, collecting duct carcinoma
References: AJSP 1989;13:439
Also called nephroblastoma
Most common kidney tumor of childhood, affecting 1 per 8-10,000 children, no gender preference
90% occur before age 6 years, only rarely a congenital lesion; occasionally in teenagers or adults
Presents as large abdominal mass felt by mother holding child; occasionally extrarenal (retroperitoneum, sacrococcygeal region, testis, uterus, inguinal canal, mediastinum); may present with lung metastases or traumatic rupture
Spreads into perirenal soft tissue; may invade renal vein; metastasizes to regional lymph nodes (15%), lung, liver, peritoneum; rarely bone (1%)
Apparently derives from nephrogenic blastema cells
Bilateral tumor or tumor early in life is associated with urogenital congenital abnormalities
Tissue diagnosis important as clinical diagnosis is wrong in 5%; FNA and frozen section are unreliable
90% long term survival
Risk factors: WAGR syndrome, Denys-Drash and Beckwith-Wiedemann syndromes (although most are sporadic); nephroblastomatosis
WAGR syndrome (OMIM #194072): Wilms’ tumor (1/3), Aniridia, Genitourinary anomalies, mental Retardation; due to 11p13 deletion (WT-1); also intralobar nephrogenic rests
Denys-Drash syndrome: gonadal dysgenesis (male pseudohermaphroditism), glomerulosclerosis and Wilms’ tumor; also intralobar nephrogenic rests; most develop Wilms’; have WT-1 dominant negative missense mutation, NOT a deletion (AJSP 1983;7:387, Hum Path 1987;18:80)
Beckwith-Wiedemann syndrome (OMIM #130650): exophthalmos, macroglossia, and gigantism; also hemihypertrophy, renal medullary cysts, adrenal cytomegaly, hypoglycemia; have WT-2 (11p15.5) abnormality, may be due to genomic imprinting; higher risk for hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas, pancreatic tumors, perilobar nephrogenic rests
Nephroblastomatosis: premalignant lesion; immature nephrogenic elements within otherwise normal kidney; called nephrogenic rests when microscopic in size; found in 1% of neonatal kidneys vs. 30% of kidneys with Wilms’ tumor; more diffuse than Wilms’, no anaplasia, have only scanty stroma; treat conservatively
Anaplasia: hyperchromatic, pleomorphic nuclei that are 3x larger than adjacent cells plus abnormal (polypoid) mitotic figures; seen in 5%
Focal anaplasia: tumors with anaplasia confined to one or a few discrete loci within primary tumor, with no anaplasia or marked nuclear atypia elsewhere
Case reports: 7 year old boy with teratoid tumor arising within supernumerary ectopic ureteropelvic structure (Archives 1998;122:925), presentation as sudden death due to tumor emboli (Archives 1990;114:605), immature glomeruli and aberrant glomerulogenesis (Archives 1988;112:536), botyroid tumor of renal pelvis (Archives 1984;108:147), associated with membranoproliferative glomerulonephritis and focal and segmental glomerulosclerosis (Archives 1984;108:141), hemihypertrophy and bilateral, sequential tumors (Archives 1978;102:639), infant also with neuroblastoma and Fanconi’s anemia (Hum Path 2002;33:1047), extrarenal tumors thought due to displaced mesonephric / metanephric rests (Hum Path 1989;20:691), bilateral cystic nephroblastomas, Dandy-Walker syndrome, microcephaly, cataracts, cerebellar heterotopia; also in sister, both with trisomy 8 mosaicism (Hum Path 1985;16:754)
Poor prognostic factors:
(a) anaplasia in stage II-IV tumors only; diffuse anaplasia worse than focal anaplasia but even small foci are associated with poor prognosis due to chemotherapy resistance
(b) high stage (most epithelial-predominant tumors are stage I; most blastema-predominant tumors are stage III/IV)
(c) in tumors with rhabdomyomatous features, serum creatine kinase and CK-MB levels may reflect clinical course (AJCP 2001;116:354)
(d) age >2 years
(e) P-glycoprotein expression in endothelial cells (AJCP 2002;117:484)
(f) inflammatory pseudocapsule, invasion of renal sinus, tumor invasion of intrarenal vessels
(g) large size
Staging (National Wilms Tumor Study Group)
Stage I: tumor limited to kidney and completely resected, renal capsule intact, tumor not ruptured or biopsied prior to removal, no residual tumor beyond margins of resection, no tumor within renal vein (tumor within intrarenal vessels is OK), no nodal involvement or distant metastases
Stage II: tumor extends beyond kidney but is completely resected, regional extension of tumor (vascular invasion outside of renal parenchyma or within the renal sinus, or capsular penetration but with negative surgical margin), operative tumor spill confined to flank (no peritoneal contamination), tumor biopsy (except FNA) prior to surgery
Stage III: nonhematogenous metastases to abdomen only (such as regional lymph nodes), including tumor implants in or penetrating peritoneum; gross or microscopic tumor present postoperatively (i.e. positive resection margins), tumor spill before or during surgery not confined to flank, removal of tumor in > 1 piece
Stage IV: hematogenous metastases or nodal metastases outside of abdominopelvic region (e.g. lung, liver or elsewhere beyond renal drainage system)
Stage V: bilateral renal involvement at diagnosis (but each side should be staged separately as I-IV above)
Note: epithelial cell complexes from damaged nephrons, metaplastic calyceal urothelium, mesothelial inclusions and Tamm-Horsfall protein within nodal sinuses may be mistaken for metastases (Hum Path 1990;21:1239)
Treatment of Wilms’ tumor:
80-90% overall are cured; a small percentage develop second neoplasms
Stage I and (II without anaplastic features): nephrectomy, actinomycin D, vincristine for 6 months or less
Stage II with anaplastic features, III or IV: other chemotherapeutic agents or radiation therapy
Bilateral tumors: biopsy plus chemotherapy plus post-chemotherapy tumor excision
Gross: large, solitary, well-circumscribed mass (10% bilateral or multicentric), soft, homogenous, tan-gray; hemorrhage, necrosis, cysts and lobular pattern are common
Grossing notes: take sections through the renal pelvis/sinus and include medial sinus margin (medial end of soft tissues surrounding renal artery and vein), junction between normal kidney and tumor, tumor capsule and uninvolved kidney; document where sections are taken on a diagram, snap freeze tumor and normal tissue for molecular studies (Archives 2003;127:1280)
Micro: triphasic with undifferentiated blastema (cellular with small blue primitive cells with scanty cytoplasm, nuclei are overlapping with finely dispersed chromatin; patterns are diffuse, nodular, cordlike or basaloid), fibroblast-like stroma, epithelium (abortive tubules, glomeruli with elongate/ovoid nuclei having molded/wedged shapes); may have smooth muscle, cartilage, adipose tissue, squamous /mucinous epithelium, bone, neural tissue
Prominent skeletal muscle component is associated with bilateral tumors in young children in 50% of cases
Rarely arises within a teratoma; teratoid Wilms’ tumor has large variety of tissues resembling teratoma
Anaplasia: hyperchromatic, pleomorphic nuclei that are 3x larger than adjacent cells plus abnormal (polypoid) mitotic figures
Severe nuclear unrest: nuclear pleomorphism or atypia approaching, but insufficient for anaplasia
Focal anaplasia: all conditions must be met - (a) no anaplasia in tumor within renal vessels or outside kidney; (b) random biopsies are free of anaplasia; (c) anaplasia confined to sharply localized regions within primary intrarenal tumor site and (d) each focus of anaplasia must be surrounded on all sides by nonanaplastic tissue which does not show severe nuclear unrest
Diffuse anaplasia: any conditions met - (a) anaplasia in tumor in any extrarenal site, including vessels of renal sinus, extracapsular infiltrates, metastases or intrarenal vessels; (b) anaplasia in random biopsy; or (c) anaplasia unequivocally present in 1 region of tumor, with extreme nuclear unrest elsewhere in the lesion
Renal sinus vascular invasion: tumor fills lumen or invades vessel wall; also free floating rounded tumor fragments not associated with other displacement artifact
Positive stains: blastema: WT-1, desmin but not other muscle markers, focal vimentin; epithelium: WT-1, keratin, EMA, CK57+ tubules; stroma: weak WT-1; other stains consistent with morphologic appearance (myogenin if rhabdomyoblastomatous, S100 if neural, etc.)
Negative stains: blastema negative for CK7, CD57; usually p53; epithelium negative for vimentin
Molecular: abnormal expression of WT1 (11p13, encodes zinc finger transcription factor expressed early in urogenital system development) and WT2 (11p15.5); also #1, 7q, 8, 12 and 16; p53 abnormalities in anaplastic foci; no t(12;15) of cellular mesoblastic nephroma; no t(11;22) of PNET/Ewing’s; no 22q11.2 of rhabdoid tumor; no N-myc of neuroblastoma
EM: resembles developing metanephros, with well developed cell junctions, microvilli, layer of thick flocculent coating around cell surface
DD: small blue cell tumors (if blastema predominates), neuroblastoma (immature tubules may simulate rosettes, but tubules have a lumen, single cell layer, distinct basal lamina and surrounding fibromyxoid stroma), multilocular renal cyst or renal cell carcinoma (rounded nuclei) for epithelial predominant Wilms’; perilobar nephrogenic rest (no fibrous capsule)
References: AJSP 1996;20:909 (focal vs. diffuse anaplasia), AJSP 2001;25:1290 (vs. metanephric adenoma and nephrogenic rests), Mod Path 1997;10:895 (desmin), Pediatr Dev Pathol 1998;1:79
Cystic partially differentiated nephroblastoma
WHO definition: multilocular cystic neoplasm of very young children, has epithelial and stromal elements and nephroblastomatous tissue
Usually hyperdiploid with trisomy 12
Case reports: 51 XY, +7, +8, +12, +13, +17 tumor (Hum Path 1996;27:980)
Renal cell carcinoma
Based on cytology, tissue characteristics (Thoenes, Storkel & Rumpelt) and cytogenetics (Kovacs)
The 2004 World Health Organization (WHO) and AFIP fascicles (4th series) classify epithelial tumors as follows:
Benign: papillary adenoma, metanephric adenoma, metanephric adenofibroma, (metanephric stromal tumors), oncocytoma
Malignant (renal cell carcinoma): clear cell renal cell carcinoma with subtype multilocular cystic renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, X:1 translocation carcinomas, carcinoma associated with neuroblastoma, unclassified carcinoma
References: Path Res Pract 1986;181:125, Cancer 1997;80:987, J Path 1997;183:131, Histopathology 2002;41:283; J Path 1997;183:131 (Heidelberg classification)
Kidney morcellation: fragmentation of kidney and associated tumors due to laparoscopic nephrectomy
Suggested sampling is influenced by radiologic features, probably should sample 5% of specimen including grossly visible tumor; staging is severely limited (AJSP 2001;25:1158)
DD of “pink cell tumor” of kidney:
Various tumors may have pink cytoplasm, but this is not used for classification
Includes clear cell carcinoma, eosinophilic variant; papillary carcinoma, eosinophilic variant; oncocytoma; chromophobe carcinoma, eosinophilic variant; rhabdoid tumor; alveolar soft parts sarcoma; paraganglioma; collecting duct carcinoma; granular cell tumor; apocrine breast carcinoma
A common problem is differentiating oncocytoma from chromophobe carcinoma
30,000 new renal cancers/year in US, 12,000 deaths; 85% are renal cell carcinomas
Usually > 50 years old, 2/3 male, only 1% bilateral
Risk factors: tuberous sclerosis (although tumors may actually be epithelioid angiomyolipomas), von Hippel-Lindau disease (see under clear cell), other familial syndromes, renal transplantation, dialysis and acquired renal cystic disease, cigarette smoking, high blood pressure, treated neuroblastoma
Dialysis: associated with small, multiple, bilateral tumors with cysts; usually papillary; metastases in 5-7%
Stauffer syndrome: hepatomegaly with hepatic dysfunction and renal cell carcinoma
Clinical: "great mimic" due to associated paraneoplastic syndromes (hypercalcemia, hypertension, gynecomastia, Cushing’s syndrome, leukemoid reaction, polycythemia, systemic amyloidosis, polyneuromyopathy)
"Classic" clinical features of costoverterbral pain, palpable mass and hematuria are present in only 10%
Tumors now usually detected incidentally; historically were often large (10 cm) when discovered
Presents 25% of time as metastases (lung, bones, lymph nodes, adrenals, liver, brain), at unusual locations (also melanoma and choriocarcinoma) such as contralateral adrenal gland, anus (Archives 2002;126:856); metastases often solitary and detected years or decades after removal of primary; rarely metastases to bladder (Mod Path 1999;12:351), phalanges (Mod Path 1991;4:66)
Occasionally regresses without treatment (also choriocarcinoma, melanoma, neuroblastoma)
Most common recipient of metastases from another tumor (usually lung)
Cytology: 25% sensitive for bladder washings/urine, higher for retrograde brushing; FNA helpful to differentiate cyst vs. carcinoma or to confirm recurrence; high false positive rate for FNAs in one study (Archives 2002;126:670)
In cytology, must distinguish carcinoma from renal tubular cells; tumor cells have abundant cytoplasm that is vacuolated, fluffy, or granular, usually with indistinct cell borders (but chromophobe renal cell carcinoma has distinct borders); tumor nuclei have variable atypia, irregular contours, haphazard orientation with abnormal chromatin, variably prominent nucleoli; renal tubular cells have well defined cell borders, homogenous cytoplasm, round, regular and orderly nuclei
Prognostic factors: stage and nuclear grade most important (AJSP 2002;26:281); Fuhrman nuclear grade strongly associated with insulin like growth factor-1 receptor staining (Hum Path 2004;35:1132)
Possibly necrosis, Ki-67 labeling index and CD44 labeling index (Hum Path 2001;32:1209)
MUC1 staining in 70% of cells associated with lower metastasis-free survival (AJCP 2002;118:47)
Increased XIAP (apoptosis inhibitor) staining is associated with poorer disease free survival (Hum Path 2004;35:1022)
Histologic classification may be significant, although less so after TNM classification (AJSP 2003;27:612)
Treatment: radical nephrectomy, partial nephrectomy for small peripheral tumors; cure possible even with extension into renal vein, inferior vena cava and right atrium; chemotherapy ineffective, interferon may be helpful
Excision of solitary metastases is often effective
5 year survival: 70% (all histologic types and stages), varies from 60-80% in stage I vs. 5% in stage IV
Gross: well circumscribed, centered on cortex, often extends into renal vein or vena cava, may have satellite nodules, often hemorrhage, necrosis, calcification and cystic change causing variegated appearance
Micro: subtypes are described separately below; precursor lesion is intratubular epithelial dysplasia (present in 1/3, crowded tubular epithelium with large, vesicular nuclei 2-3x normal, eosinophilic macronuclei, resembles carcinoma in situ; p53+, Mod Path 1996;9:690, AJSP 1994;18:1117)
Positive stains: keratin, EMA, RCC-Ma (80% sensitive, most sensitive for papillary, then clear cell, chromophobe, 25% in sarcomatoid, 0% in collecting duct, AJSP 2001;25:1485); 67% of metastatic renal tumors are RCC-Ma+ (also some breast carcinomas); CD10 (81%), N-cadherin (75%), CD15 (63%), vimentin (25%), S100 (5%)
Negative stains: CK7, CK20, inhibin, MelanA (A103), calretinin, TTF1, CEA
DD: clear cell hepatocellular carcinoma (positive for HepA, polyclonal CEA, ubiquitin for Mallory bodies, usually negative for EMA, LeuM1, pancytokeratin); in brain, metastatic renal cell carcinoma (inhibin negative) may resemble hemangioblastoma (inhibin+, AJSP 2003;27:1152), epithelioid angiomyolipoma
References for marker studies: Mod Path 1998;11:1160 (inhibin and A103), Mod Path 1998;11:516 (inhibin), AJSP 2003;27:199 (beta defensin1, parvalbumin, vimentin)
Adenocarcinoma of renal pelvis
Rare, should form unquestionable glandular structures, not just secrete mucin
Derived from pyelitis glandularis and pyelitis cystica (similar to lesions in bladder and ureter, secondary to chronic inflammation or renal stones)
Tumors from renal pelvis are either tubulovillous (72%), mucinous (22%) or papillary, non-mucinous and non-intestinal (6%); tubulovillous have worst prognosis (Archives 1993;117:1156)
Case reports: 65 year man with mucin secreting tumor (Archives 1988;112:847)
Associated with Xp11.2 translocations / TFE3 gene fusion
Most common are ASPL-TFE3 and PRCC-TFE3
Usually children and young adults
Usually nodal involvement
Gross: tan yellow, frequently hemorrhagic and necrotic
Micro: fibrous pseudocapsule, often calcified; nested and pseudo-papillary growth patterns of polygonal tumor cells with sharp cell borders, voluminous clear to eosinophilic cytoplasm, irregular nuclei containing vesicular chromatin and small nucleoli; surrounded by thin walled vessels; also minor solid, acinar, alveolar and tubular patterns; resemble clear cell and papillary renal cell carcinoma; no/rare mitotic figures
Positive stains: RCC, TFE3 (nuclear stain, not routinely used), 50% for cytokeratin and EMA (frequently only focal), CD10
Molecular: t(X;17)(p11.2;q25) - balanced translocation of TFE3 and ASPL gene; also found in alveolar soft part sarcoma, but unbalanced; t(X;1)(p11.2;q21) - TFE3 transcription factor gene on Xp11.2 and PRCC gene at 1q21.2
EM: features of clear cell carcinoma, including cell junctions, numerous mitochondria, microvilli, basement membrane, abundant glycogen
DD: clear cell carcinoma (no papillary patterns, older patients, vimentin+, keratin+, TFE3-, 3p-, no intracisternal microtubules on EM), papillary carcinoma (predominantly papillary, no nested alveolar patterns, no extensive areas of clear cells, keratin+, TFE3-, trisomy 7 and 17), clear cell sarcoma of kidney
References: AJSP 2004;28:1117 (children and young adults), AJSP 2002;26:1553
Chromophobe type, renal cell carcinoma
Origin from intercalated cell of cortical collecting duct
5% of adult renal epithelial tumors; ages 45+, no gender preference
Most are T2 N0 M0 (i.e. confined within the renal capsule) and have good behavior (5 year survival 78-92%, 3-6% die of disease); same behavior as clear cell when stratified by grade/stage
Poor prognosis if sarcomatoid appearance
Multiple tumors (mean 5.3) are associated with Birt-Hogg-Dube’ syndrome (autosomal dominant, small dome-shaped papular fibrofolliculomas of face, neck and upper trunk, renal tumors, lung cysts, spontaneous pneumothorax), mean age 51 years at first renal tumor diagnosis, usually bilateral chromophobe carcinomas, oncocytomas or hybrids, also oncocytosis (AJSP 2002;26:1542)
Cytogenetics: multiple monosomies; usually hypodiploid; 80% show loss of 1, 2, 6, 10, 13, 17, 21 or Y; also mitochondrial (mt) DNA rearrangements; loss of 3p in 25% of cases
Case reports: osteosarcoma-like differentiation (AJSP 2002;26:1358), with sarcomatoid and collecting duct carcinoma components (Archives 2003;127:e38)
Gross: well circumscribed, tan brown (same color as cortex), geographic necrosis, small cysts, no central scar
Micro: compact architecture of nests or broad alveoli/trabeculae, composed of large polygonal cells with "hard" or distinct cell border ("vegetable cells", due to cytoplasmic retraction); abundant cytoplasm with reticular pattern (light/pale, flocculent, not clear), also called type 3 cells, some have perinuclear halo or translucent zone (type 2 cells); also type 1 cells that are small with solid, slightly granular, eosinophilic cytoplasm; usually lower grade nuclei, bunching of nuclear material at nuclear membrane; 50% have calcification; usually no chicken wire vasculature (more fibrovascular than vascular); mitotic figures present but may be scant
Note: in some cases, formalin obscures cytoplasmic features (Archives 2000;124:904)
Positive stains: Hales colloidal iron (stains acid mucopolysaccharides in microvesicles, diffuse and strong, reticular), low molecular weight keratin (CK 8/18, weak CK17), CK7 (diffuse and strong, 82%), EMA/MUC1 (diffuse cytoplasmic), parvalbumin (calcium binding protein, also in normal collecting ducts and oncocytomas, Mod Path 2001;14:760), RON proto-oncogene (also oncocytomas, AJSP 2004;28:1045), CD117/c-kit (membranous, Mod Path 2004;17:611, AJSP 2004;28:676), coexpress CD44s and CD44v6; Ulex europaeus lectin, E-cadherin, RCC-Ma (variable)
Panels of markers: beta defensin1+, parvalbumin+, vimentin- in 100% (8/8) (AJSP 2003;27:199)
Negative stains: vimentin (or weak), N-cadherin, low Ki-67 labeling index (Mod Path 1999;12:310, Mod Path 1998;11:1115), CD10 (usually)
EM: 150-350 nm membrane bound microvesicles (possibly from mitochondrial outpouchings), abnormal but few mitochondria with tubulovesicular cristae, rare short and stubby microvilli; eosinophilic variant is similar but with more mitochondria
DD: oncocytoma, eosinophilic papillary or clear cell carcinomas (all Hales colloidal iron negative)
References: AJSP 2002:26:281, Mod Path 2004;17:180, Mod Path 2004;17:1455 (CD10 expression), AJSP 1998;22:419 (colloidal iron staining); Hum Path 1998;29:1181 (hypodiploid by flow cytometry). AJSP 2000;24:1248 (EM findings)
Eosinophilic variant of chromophobe renal cell carcinoma
Micro: fine eosinophilic granularity, peripheral accentuation of cytoplasm, perinuclear halo, wrinkled nuclear membrane and coarse chromatin (resembles koilocytes), still some classic chromophobe cells
EM: abundant mitochondria with variable size and shape and predominantly tubulocystic cristae, also outpouchings of outer mitochondrial membranes resembling cytoplasmic microvesicles, abundant microvesicles, some containing homogenous, electron-dense, finely granular matrix, similar to mitochondrial matrix
DD: eosinophilic variant of clear cell carcinoma, oncocytoma
References: J Pathol 1988;155:277
Clear cell type, renal cell carcinoma
Also called conventional / classic type
Previously known as hypernephroma since tumor grossly resembles adrenal gland
Tumor cells are derived from proximal convoluted tubule
70% of adult renal epithelial tumors
Risk factors: adult polycystic disease, acquired kidney cystic disease, smoking (RR = 2.0), obesity in women, hypertension, von Hippel Lindau disease (develops in 50%); hereditary renal cell carcinoma without VHL, tuberous sclerosis (not via VHL mutations (Mod Path 2002;15:205)
von Hippel Lindau disease: autosomal dominant syndrome with hemangioblastomas of retina and cerebellum, cysts of pancreas, liver and kidney, clear cell tumors of other sites, papillary cystadenoma of epididymis, pheochromocytoma; bilateral or multiple renal cell carcinomas
Molecular: 3p- in 98% of cases (3p25 is von Hippel Lindau gene, also 3p12-14.2) is considered the initial mutation; also 5q21+ (70%), 14q- (41%)
Nondeleted allele of the VHL gene shows somatic mutations or hypermethylated induced inactivation in 80% of cases; VHL is a tumor suppressor gene that encodes elongin, which inhibits the generation of a transcriptional elongation complex of vascular endothelial growth factor; loss of VHL causes an increase in VEGF, may cause the increased vascularity of these tumors
Prognostic factors: stage, renal sinus invasion (AJSP 2000;24:451)
Metastases (declining order of frequency): lung, lymph nodes, liver, bone, adrenal glands, kidney, brain, heart, spleen, intestine, skin
Survival: 38% die of disease overall; metastases in 27-37% of patients; relatively unfavorable prognosis compared with papillary and chromophobe carcinoma
Case reports: anal metastasis presenting as hemorrhoid (Archives 2002;126:856), laryngeal metastasis (Archives 2000;124:1833), metastasis to follicular variant of papillary thyroid carcinoma (Archives 1999;123:703), metastases to parotid gland (Hum Path 1989;20:195), patient with malignant ascites and multiple tumors, origin from kidney determined by comparative microsatellite analysis (Hum Path 1999;30:1111), with intravascular diffuse large B cell lymphoma (Archives 2001;125:1239), neuromelanin pigmentation (AJSP 1995;19:350, Hum Path 2001;32:233), Gamna-Gandy nodules (Archives 2003;127:372)
Gross: orange/yellow (from lipid), usually upper pole, well circumscribed, hemorrhage, necrosis and calcification are common; frequent renal vein involvement; soft fleshy areas may indicate sarcomatous component; may undergo cystic degeneration, may be multifocal, bilateral in 1% (usually with von Hippel Lindau or tuberous sclerosis)
Micro: compact, tubulocystic, alveolar or rarely papillary architecture of cells with clear cytoplasm (from glycogen/lipid), distinct but delicate cell boundaries; cell size is 2x normal epithelial tubule cell; often glassy hyaline globules and myospherulosis; usually nuclear grade 2 or higher; chicken wire / delicate vasculature is common (sinusoids near each packet of cells); occasionally is an irregular central area of edematous stroma (basement membrane of renal cell carcinoma islets and tumor blood vessel endothelia may merge)
Renal cell carcinomas with predominantly papillary architectural and clear cells (other features not described) have molecular features of clear cell carcinoma (Archives 2003;127:1176)
Positive stains: PAS without diastase, oil red O (frozen tissue only), low molecular weight cytokeratin (CK 8/18, CK19, CK7), EMA/MUC1 (membranous), LeuM1, vimentin (note: coexpression of keratin and vimentin is somewhat specific for clear cell carcinomas), also brush border antigens (villin, CD10 [94%], CD13), RCC-Ma (85%), also S100, alpha-1-antitrypsin, alpha-1-antichymotrypsin, CD15; variable N-cadherin
Negative stains: CEA (Hum Path 2004;35:697), Hales colloidal iron (iron pigment stains), mucin, high molecular weight cytokeratin, inhibin, MelanA, CA125, thyroglobulin, TTF1, c-kit, parvalbumin, HepPar1, E-cadherin
EM: abundant glycogen, variable fat, scant organelles, well defined long microvilli similar to brush border of normal proximal tubules, numerous cell junctions; eosinophilic variant is similar but with more mitochondria; may have scant microvesicles
DD: FNA in von Hippel Lindau patients of pancreatic endocrine tumors resemble clear cell carcinomas, but also have cords, festoons and gyriform architecture suggestive of an endocrine tumor; also chromogranin and synaptophysin positive (AJSP 2001;25:602)
References: Mod Path 2000;13:874 (distinguishing from clear cell carcinoma of liver), Archives 2000;124:1476 (myospherulosis), AJSP 2003;27:199 (beta defensin-1, parvalbumin, vimentin)
Cystic
Up to 15% are cystic; 4 subtypes:
(a) intrinsic multilocular growth pattern (multilocular cystic renal cell carcinoma-WHO): variably sized cysts, separated by fibrous / hyalinized septa, cysts lined by tumor cells, usually low grade, excellent prognosis
Less than 1% of all clear cell carcinomas, usually T1, usually lower nuclear grade and stage than other renal cell carcinomas, usually cured by resection regardless of stage
Appear to have similar origin as classic clear cell carcinoma, despite better prognosis
Gross: fibrous pseudocapsule surrounds expansile mass composed of variably sized, noncommunicating cysts separated by irregular, thick fibrous septa
Micro: septa are hyalinized with calcification or ossification, often contain clear cells; cysts usually lined by clear cells; low nuclear grade
(b) intrinsic unilocular growth pattern: thick irregular wall lined by tumor cells, may be papillary
(c) cystic degeneration of solid tumor: hemorrhage, necrosis, thick irregular cyst wall, may be papillary, may be few tumor cells, but may still exhibit aggressive behavior (AJSP 2000;24:988)
(d) originating in a benign cyst
Eosinophilic
Often extensive (>50%) necrosis; higher grade and stage than other renal cell carcinomas, higher risk of progression
Micro: perinuclear eosinophilia, cytoplasmic eosinophilic globules; are clear cell areas elsewhere
EM: similar to classic type but with more mitochondria that are swollen and pleomorphic, with rarefied matrix and attenuated cristae; may have scant microvesicles
References: AJSP 2000;24:1247 (EM findings)
Rhabdoid
Typically children, rarely adults (5%), usually in transition with conventional clear cell renal cell carcinoma
Me