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The pathology of renal tumors
The Pathology of Renal Tumors By John E. Tomaszewski
ENAL CELL carcinoma (RCCa) is the most frequent tumor of the kidney in adults. RCCa comprises about 3% of all adult malignancies with 27,000 new cases and 10,000 deaths per year in the USA. 1There is a predominance in men. Peak incidence is in the sixth decade of life. The diagnosis of RCCa is suggested by the classic triad of flank pain, hematuria, and a flank mass. This constellation of findings is often found late in the course when metastatic disease is common. Specific laboratory findings in RCCa are related to hormone production. Polycythemia is secondary to erythropoietin production by the tumor. Hypercalcemia is secondary to ectopic production of a parathormone-like substance. Renal cell carcinomas are thought to arise from tubular epithelial cells. Much discussion has occurred regarding the exact site of origin within the nephron, but current thinking is that RCCa may arise from any segment. Genetically, most clear and granular RCCas will show deletions in the short arm of chromosome 3 beginning at 3p13. 2 A tumor suppressor gene in this region is hypothesized.
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HISTOPATHOLOGY
The significance of the histopathologic classification in RCCa has been debated. Any histopathologic classification should impart some prognostic information and provide a frame-
ABBREVIATIONS RCCa, renal cell carcinoma; ACD, acquired cystic disease; ATP, adenosine triphosphate; WAGR, Wilms' aniridia genital anomaly-retardation syndrome; WT, Wilms' tumor; NWTS, National Wilms' Tumor Study; TCCa, transitional cell carcinoma; WHO, World Health Organization; AML, angiomyolipoma.
work with which to separate metastatic RCCa from other neoplasms. Several schemes have been proposed. None are particularly robust in their predictive value in large part because of the extensive heterogeneity to be found in RCCa. The following classification is an adaptation of that recently used by Murphy et al. 3 These categories represent the basic patterns that may be admixed in varying combinations and proportions in RCCa. Clear Cell Carcinoma
This is the classical histopathology in RCCa. The tumor cells have water-clear cytoplasm reflecting the high content of glycogen and lipids that are removed from the tissue sections during processing (Fig 1). Because of the histopathologic similarity to ceils of adrenal cortex, the term "hypernephroid" carcinoma was originally used to describe this tumor. In clear cell carcinoma neutral lipids can be highlighted with Oil Red O stain in unprocessed materials; phospholipids are more resistant to processing and can be decorated with the Sudan Black B reaction; glycogen can be stained with the periodic acid-Schiff reaction. Because of the high lipid content, these tumors tend to have a yellow color on gross examination. Lipid vacuoles and glycogen can also be found on ultrastructural examination. The nuclei of clear cell carcinoma are usually of low grade. The tumor cells grow in sheets or small islands, or form tubules that are supported by a delicate fibrovascular stroma. Tumor ceils may show partial brush border preservation by ultrastructural examination suggesting proximal tubular differentiation, but lectin studies suggest heterogeneity with markers of both proximal and distal tubule. 4 Granular Cell Carcinoma
From the University of Pennsylvania Medical Center, Philadelphia. Address reprint requests to John E. Tomaszewski, MD, Associate Professor of Pathology and Laboratory Med&ine, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4283. Copyright © 1995 by W.B. Saunders Company 0037-198X/95 / 3002-000355.O0/ 0 116
The phenotype is that of tumor ceils with variable granular eosinophilia of the cytoplasm. The granular cytoplasm is secondary to a high content of cytoplasmic organelles including mitochondria, rough endoplasmic reticulum, and Golgi. The lipid content is less than that in clear cell carcinomas. On gross examination these Seminars in Roentgenology, Vol XXX, No 2 (April), 1995: pp 116-127
PATHOLOGY OF RENAL TUMORS
Fig 1. Clear cell type of renal carcinoma. The tumor shows prominent cytoplasmic clearing, a delicate fibrovascular stroma, and low-grade nuclear cytology (Hematoxylin-eosin, original magnification x 100).
tumors have a variable brown color secondary to a high content of lipochrome pigment. Cell borders are partially defined. The degree of nuclear pleomorphism tends to be more than that in clear cell carcinoma.
Chromophobe Cell Carcinoma This type is the most recently described. In rats exposed to N-nitrosomorpholine, chromophobe cell tumors arise from the proximal tubule. 5 Thoenes et al6 were first to describe in detail the human counterpart for the rat chromophobe carcinoma. This tumor has no doubt been confused with clear and granular cell carcinomas in the past. Chromophobe cell carcinomas comprise about 5% of all RCCas. These tumors range from 2 to 22 cm. They are well circumscribed, solitary, and brown to gray in color. On microscopic examination the ceils have extremely well defined cell borders (Fig 2), giving the tumor a superficial resemblance to the cell walls of vegetable material. The cytoplasm distends the cell and varies from pale and transparent to brightly eosinophilic. Pale cells tend to have a ground glass appearance to the cytoplasm and are oriented toward the fine fibrovascular septa. The cytoplasm of chromophobe carcinoma can be highlighted with Hale's colloidal iron stain 7 indicating a high content of mucopolysaccharides. Ultrastructurally, the cytoplasm has a dense perinuclear arrangement of microvesicles that range from 150 to 300 nm. These vesicles have a high content of carbonic anhydrase C suggesting a relationship to the
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Fig 2, Chromophobe cell renal carcinoma showing distinct cell borders and pale cytoplasm (Hematoxylin-eosin, original magnification x 100),
intercalated cells of the collecting duct. 8 Unlike other RCCas, chromophobe carcinomas are negative for vimentin.
Papillary Carcinoma Papillary RCCas are said to compose 10% to 15% of renal neoplasms. On gross examination they have a light gray to yellow color depending on the amount of lipid. Hemorrhage and necrosis are frequent and these tumors often have reduced vascularity.9 Papillary neoplasms are frequently the subtype found in the wall of cortical cysts. Histopathologically, papillary RCCa is formed from fine vascular stalks with varying numbers of foamy macrophages covered by a single layer of epithelium (Fig 3). The epithelium varies from low cuboidal to colum-
Fig 3. Papillary RCCa. The tumor is composed of papillary fronds supported by a delicate fibrovascular stroma, admixed with foamy macrophages, and covered by a low cuboidal epithelium showing low-grade nuclei (Hematoxylin-eosin, original magnification x 100}.
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nat and the nuclear cytology of these cells is usually bland. The cytoplasm is usually acidophilic or weakly basophilic. Clear cell cytoplasm is not common. Tumors with large numbers of foam cells may show cholesterol clefts in areas of necrosis. Psammoma bodies are common in some tumors. Tumor cells may have abundant hemosiderin granules indicating tumor breakdown and pigment uptake by the neoplastic epithelium. The cytogenetic profile of papillary RCCa includes abnormalities of chromosomes 7 and 17 including frequent trisomies. ~°
Collecting Duct Carcinoma The category of collecting duct carcinoma is also a relatively new one that has created controversy. This tumor is rare and constitutes about 1% of renal cancers. H44 Collecting duct carcinoma (also termed Bellini duct carcinoma) is thought to arise from the terminal collecting ducts that empty into the renal pelvis. In keeping with this postulated origin, this tumor offers an interesting set of features that may be considered as intermediate between RCCa and transitional carcinoma. Grossly, the tumor may be localized to the medulla or it may involve both medulla and cortex. Because of this medullary orientation, collecting duct carcinoma produces distortion of the pelvis. Hemorrhage and necrosis is common. Microscopically, this tumor has a mixed tubular and papillary architecture. Tubules and papillae are lined by a single layer of cuboidal epithelium. When the tubules dominate, the tumor may have a spongy appearance. The tubules can anastomose in a complicated fashion. Desmoplastic stoma is common. Nuclear pleomorphism varies from mild to marked. Adjacent collecting ducts may have atypical hyperplasia. In keeping with origin from a cell at the junction of the nephron and the collecting system, collecting duct carcinomas produce both high and low molecular weight cytokeratins. They are positive for epithelial membrane antigen and peanut agglutinin. The prognosis of collecting duct carcinoma is difficult to know because of the small numbers of reported cases; however the emerging impression is that of an aggressive tumor.
JOHN E. TOMASZEWSKI
Sarcomatoid Carcinoma Sarcomatoid RCCa is a high-grade cancer of renal tubular origin that can be confused with true renal sarcoma because of the dominant spindle cell morphology. These tumors are usually quite large and tend to be aggressively invasive. Many cases present with metastasis. Sarcomatoid carcinomas have a tan to gray color and can show gross heterogeneity with firm fibrous areas alternating with more typical RCCa. The histopathology also shows a variegated pattern with interlacing fascicles of spindle cells admixed with epithelioid carcinomatous components that are usually of high grade (Fig 4). Carcinomatous and spindled components may be intimately intermingled or they may be geographically separated within the same tumor. Similar heterogeneity is found in ultrastructural and antigenic studies of sarcomatoid carcinoma. Epithelioid elements are generally positive for low-molecular-weight cytokeratin and epithelial membrane antigen, whereas the spindled ceils are much more variable in their cytokeratin content. Spindled elements can have desmosomes on ultrastructural examination. 15 If heterologous elements are found in a spindled cell renal neoplasm, the possibility of a true carcinosarcoma should be considered. C Y S T I C RCCA
Renal cell carcinoma is associated with cystic disease of some sort in 2.3% to 7.0% of cases. 16 Gibson 17has outlined four ways in which cancer may be associated with cysts. These include (1)
Fig 4. Sarcomatoid RCCa showing epithelioid and spindled cells with enlarged nuclei, macronucleoli, and nuclear pleomorphism (Hematoxylin-eosin, original magnification x 100).
PATHOLOGY OF RENAL TUMORS
RCCa may become necrotic and cystic; (2) carcinoma may originate within a cyst wall; (3) carcinoma and cysts may be located in close proximity and possibly be pathogenetically related; or (4) carcinoma and cysts may be widely separated and only coincidentally associated. Renal cell carcinoma will often have areas of cystic change. At times this may be extensive (Fig 5). Levine et aP s classified 24/545 (4%) of RCCas as "cystic hypernephromas." Such cystic changes are most probably degenerative phenomena as the tumor outstrips its blood supply. In cystic RCCa, tumor cells line the cavity and often have a clear cell cytology. Hemorrhage, necrosis, and sclerosis may be prominent. Solid nodules of tumor are often seen. Carcinoma arising in the wall of a simple cyst is a rare event. There are three situations in which RCCa and simple cysts may coexist. First, a simple cyst and tumor may be present in the same kidney, but be geographically and pathogenetically unrelated. Second, tumor may be found adjacent to a simple cyst, and induce the formation of that cyst through tubular and vascular obstruction. Thirdly, carcinoma may arise in the wall of a simple cyst. This last scenario is extremely rare, there being only a few reported cases in the literature, a9In such cases the simple cyst is partially or completely intact with a single layer of flat, cytologically bland epithelium, and the carcinoma is found in an intramural location. Approximately 34% of patients maintained on hemodialysis for more than 3 years will
Fig 5. Cystic RCCa. This gross photo shows a tumor which is predominantly cystic with only a small nodule of solid carcinoma at the inferior aspect of the mass,
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develop cysts in their end-stage kidneys. 2° The pathogenesis of the cysts in acquired cystic disease (ACD) is unknown, but theories have included tubular obstruction or increased compliance of the tubular basement membranes under the stress of some cystogenic influence such as a uremic toxin. The frequency of cyst formation increases with time. Grossly, kidneys with ACD are moderately enlarged, generally weighing less than 300 g. Cysts are numerous, bilateral, and mostly small, ranging in size from microscopic cysts that are 2 to 3 times the diameter of a collecting tubule to cysts that are macroscopic and up to 2 cm in diameter. The cysts are variably lined. Some cysts have a lining of cuboidal epithelium that is low and unremarkable. In other cysts the epithelium is prominently nucleolated; still other areas show papillary hyperplasia of the lining. Renal cell neoplasms are a frequent complication of ACD, and are found in about 17% of cases. Affected kidneys show a spectrum of change including cysts, atypical cysts, small neoplasms ("adenomas"), and flank carcinomas. The frequency of RCCa in patients with ACD is about seven times the expected yearly incidence in the age-matched general population. 21 ONCOCYTOMA
Renal oncocytomas had been recognized by German pathologists as a separate entity for many years. In the English literature, however, their designation as a special diagnostic category has been relatively recent. Klein and Valensi's 22 report of 13 cases from one institution in 1976 spurred interest in the lesion. Since that time several hundred cases have been described in the world literature. Oncocytomas represent approximately 4% to 5% of renal cell neoplasms. The male to female patient ratio is about 2:1. The age at presentation is wide (15 to 84 years old) with the peak incidence in the seventh decade. These tumors tend to be clinically silent, with the majority being discovered incidentally. Thirty-six percent are symptomatic: flank pain 71%; hematuria 33%; weight loss 7%; fever 8%. Oncocytomas are well-circumscribed tumors. They tend to be quite large, with an average diameter of 7 cm. Classic oncocytomas are
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described as having a mahogany brown color, most probably secondary to the large amount of cytochrome pigment associated with the many mitochondria. Focal hemorrhage is uncommon. Necrosis should not be found. The presence of a central stellate scar (Fig 6) is characteristic, but by no means constant, and is seen in only a minority of cases. About 3% of oncocytomas are bilateral, and 5% are multicentric in the same kidney. One extraordinary report documented over 200 oncocytomas in a single kidney. 23 Calcification in oncocytomas is unusual. Cystic change can occur. The histologic hallmark of this tumor is the presence of the oncocytic cell. An oncocyte is an eosinophilic cell with abundant granular cytoplasm and a round uniform nucleus (Fig 7). The cytoplasm of these ceils is packed with mitochondria, and histochemically, oncocytes contain an abundance of oxidative enzymes and Adenosine Triphosphate (ATP). Oncocytes can, of course, be found in a variety of other sites including salivary gland (Warthin's tumor), thyroid (H~rthle cell), and parathyroid. Oncocytomas often show a diffuse or organoid histology; however tubular and trabecular patterns can also be found. Only minimal nuclear atypia is found in most oncocytomas, but bizarre nuclei, ascribed to degenerative changes, have been described. Clear cell loci, mitoses, necrosis, high-grade atypia, macronucleoli, ballooning distention of the cytoplasm, or a predominate papillary pattern are not part of the classic histology of oncocytoma. The prognostic significance of these atypical features is unclear. 24 Because the diagnosis of oncocytoma is only clinically useful if it carries with it a distinctly
Fig 6. Oncocytoma. The tumor is well circumscribed and has a dense central scar.
JOHN E. TOMASZEWSKI
Fig 7. Oncocytoma, This neoplasm is composed of a uniform population of cells with abundant eosinophilic cytoplasm and small, round, and regular nuclei that are centrally located in each cell (Hematoxylin-eosin, original magnification × 100).
favorable prognosis, and it is unclear at this point in time whether cases with atypical features will have a good long-term outcome, it is our opinion that the diagnosis of oncocytoma should be restricted to only those cases with classic histology. Oncocytic renal neoplasms with atypical features should be flagged as tumors of uncertain malignant potential. Renal Cortical Carcinoma Versus Adenoma
The concept of a completely benign renal neoplasm that can be accurately predicted in life to be nonrecurring and nonmetastatic is most closely approximated by the oncocytoma as discussed above. Clear cell, granular cell, and papillary renal neoplasms of small size, ie, < 2.5 cm, have been termed by some as "renal cortical adenomas." Bell's 25 classic work found a good correlation between tumor size and frequency of metastases. However, even this data showed that large tumors do not always metastasize and that occasional tumors of less than 3.0 cm do metastasize. Thus, the predictive value of tumor size for metastatic potential is good but not 100%. In a surgical specimen, even small renal neoplasms should be considered as having some limited potential for progression. The term "renal adenoma" may be misleading because it conveys a certainty about good outcome that may not be entirely documented. For small renal tumors of low grade we prefer the phrase "renal neoplasm of low malignant potential."
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PROGNOSTIC FACTORS IN RCCA
Pathological Staging of RCCa The pathological staging of RCCa is probably the single most important statement as to the prognosis. Staging may be performed under the scheme of Robson et al, 26 o r according to the TMN classification. 27The Robson system, which is somewhat simpler and commonly used, is outlined in Table 1. Average 5-year survival rates according to Robson stages are as follows2S: stage I, 65%; stage II, 48%; stage III, 39%; stage IV, 7%. Renal vein extension (Fig 8) does not by itself impart a worsened short-term prognosis, although long-term survival may be impacted by this feature. 29
Grading of RCCa There have been several attempts at constructing a meaningful grading system for RCCa. At this writing there seems to be general acceptance in the current literature that a nuclear grading system is most effective. The Fuhrman 3° grading system (Table 2) is a commonly referenced system for nuclear grading in RCCa. The 5-year survival for patients with nuclear grade 1 tumors is 86%; grade 2, 72%; grade 3, 44%; grade 4, 24%.
Histopathology The value of histopathology as an independent prognostic parameter separate from grade and stage is disputed. Medeiros et al, 31 when controlling for nuclear grade, was unable to find a significant difference between different cell types in the low nuclear grades. In general the prognosis for papillary and chromophobe carcinomas is good; the outlook for clear cell carcinoma is intermediate; the outcomes for granular cell and collecting duct carcinomas are poor; sarcomatoid carcinoma is almost always lethal.
Fig 8. vein,
The differences among these different categories may be heavily influenced by the nuclear grades that are dominant in each category.
Flow Cytometry This technique must be considered as adjunctive. Ploidy analysis generally correlates with nuclear grade. It is unclear whether or not flow cytometry adds additional information beyond that supplied by nuclear grading. 32 NEPHROBLASTOMA AND OTHER PEDIATRIC RENAL TUMORS
Nephroblastoma or Wilms' Tumor Nephroblastoma or Wilms' tumor is the most common pediatric renal neoplasm. The mean age of diagnosis for boys is 37 months and for girls is 43 months. There are a number of conditions that are associated with nephroblastoma including the Wilms'-aniridia genital anomaly-retardation syndrome (WAGR), Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome (glomerulonephritis, pseudohermaphroditism, nephroblastoma), and familial nephroblastoma. WAGR patients were
Table 1. Staging of Renal Cell Carcinoma According to Robson w Stage 1 Stage 2 Stage 3
Stage 4
Confined to kidney Extends into perirenal fat but confined by Gerota's fascia Gross extension into renal vein or vena cava; lymphatic involvement; vascular and lymphatic spread Extension into adjacent organs (other than adrenal), or distant metastases
RCCa with tumor thrombus extending into renal
Table 2. Fuhrman Nuclear Grading System for RCCa Nuclear Size Grade { F m ) I il Ill IV
10 15 20 >20
NuclearContour Round Slightly irregular Very irregular Bizarre and multilobated
Nucleoli Absent Present, small Large, prominent Large, prominent
Chromatin Fine Fine Fine Clumped
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Fig 9. Wilms' tumor. This mass is well circumscribed, solid, and has a vaguely Iobulated appearance.
found to have a constant deletion of chromosome 11p13 in their somatic cells. Similar deletions were found in the tumor cells of some patients with nephroblastoma. These findings led to the discovery of a tumor-associated gene in Wilms' tumor (WT). WT1 was identified by two groups. 33,34 WT1 is a transcription factor that is found in the early developing kidney. Abnormalities of WT1 are found in some case of sporadic Wilms' tumor and in many cases of the nephroblastoma associated conditions. WT2 is another candidate gene located at 11p15.5. 35 There is a high frequency of abnormalities of chromosome 16q, suggesting a possible third gene at this site. 36 On gross examination, Wilms' tumor is usually a solitary mass (Fig 9) that is separated from the adjacent renal parenchyma by a pseudocapsule. The average size is about 500 g. The tumors are often soft. Septa may divide the tumor and give a lobulated appearance. Tumors may project into the pelvis in a polypoid fashion. Some Wilms' tumors have prominent cystic
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change. Occasional tumors are pedunculated projections from the cortex. The histopathology of Wilms' tumor is variegated. There are three microscopic components: blastema, epithelium, and stroma (Fig 10). Most elements represent some aspect in normal or abnormal kidney development; however, heterologous elements show the multipotential nature of nephritogenic precursors. Blastema is the condensed mesenchyme from which the kidney develops. The nuclei are small and compact, and the blastemal cells have little cytoplasm. Blastemal cells may be arranged in diffuse, nodular, serpentine or basaloid patterns. The epithelial component in nephroblastoma usually recapitulates some normal kidney structure. Tubules, collecting ducts, and abortive glomeruli in varying degrees of maturation can all be seen. Heterologous epithelial elements may include mucinous, squamous, and rarely, ciliated epithelium. The stromal portions commonly seen in Wilms' tumors are cells resembling embryonic mesenchyme, fibroblasts, and smooth muscle. Less common heterologous elements may include skeletal muscle, cartilage, bone, and neural tissue. Cases with dominant heterologous elements may be termed "teratoid nephroblastoma." The clinical relevance of recognizing histopathologic diversity is to ensure accurate recognition of Wilms' tumor cases. Histopathologic examination can also provide information about prognosis based on recognition of favorable and unfavorable categories. Unfavorable histology
Fig 10. Wilms" tumor. This photomicrograph shows blastema (right lower corner) composed of dense spindle cells, admixed with primitive tubules (upper and left side} (Hematoxylin.eosin, original magnification x60).
PATHOLOGY OF RENAL TUMORS
refers to cases with anaplasia and includes cases with (1) atypical multipolar mitoses and/or (2) marked nuclear enlargement with the longest nuclear axis being at least three times larger than nonanaplastic nuclei. 37 In the National Wilms' Tumor Study (NWTS) only about 5% of cases show anaplasia. Cases with only focal anaplasia may have a good prognosis. 38Anaplasia has no effect on outcome for stage I tumors. The staging of nephroblastoma is outlined in Table 3. Survivals by stage and histopathology across all therapies in the Third NVVTS39 are listed in Table 4. There are a few gray areas in pathological staging. Microscopic loci of invasion of the renal sinus that do not escape the hilar plane should be categorized as stage I. Extensive infiltration of the renal sinus is stage II. An inflammatory pseudocapsule does not necessarily mean stage II disease, although an increased rate of relapse in stage I cases may be seen with an inflammatorypseudocapsule. Other features that may portend an increased relapse rate in cases that are otherwise stage I include invasion of the renal sinus, extensive infiltration of the renal capsule without complete transcapsular penetration, and invasion of intrarenal vessels. 40 Other pediatric renal neoplasms which constitute about 10% of all cases include mesoblastic nephroma, clear cell sarcoma, and rhabdoid tumor.
Mesoblastic Nephroma
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Table 4. Results of the Third National Wilm's Tumor Study: Survival by Stage and Histology27 Stage
Histology
% Relapse-Free at 4 yr
% Alive at 4 yr
I II III IV I-Ill IV
Favorable Favorable Favorable Favorable Unfavorable Unfavorable
90.4 88,1 79.0 74.9 64.8 55,6
96.5 92.3 87.0 68.4 68.4 55.3
Bolande et al. 41 In the cellular variant the nuclei are more numerous, larger, and vesicular.
Clear Cell Sarcoma Clear cell sarcoma is also called bonemetastasizing renal tumor of childhood. The peak incidence is in the second year of life. Very rare cases occur during adolescence. There is a predominance in boys. The tumors average about 500 g and often involve the medullary region. By light microscopy the classic clear cell sarcoma is composed of cords of uniform cells separated by delicate capillary septa. The cytoplasm contains numerous microvesicles with a high content of mucopolysaccharides accounting for the "clear cell" appearance. Cells with more eosinophilic cytoplasm are also found. The nuclei are usually bland with fine chromatin and variable nuclear grooves. There are many histologic variants that can cause confusion with nephroblastoma. Metastases are common. The death rate is 30% to 4 0 % . 42
Mesoblastic nephroma, also known as congenital mesoblastic nephroma or leiomyomatous hamartoma, is a neoplasm of the first few months of life. The tumors vary in size and average about 6 cm. They are often oriented toward the renal hilus. On microscopic examination mesoblastic nephromas are monotonous and composed of spindled cells (Fig 11) with a fibroblastic or myofibroblastic morphotype. Spindled cells can be arranged in interlacing fascicles in the classic subtype as described by Table 3. Staging of Wilm's Tumor According to the NWTS I. Limited to the kidney and completely resected IL Tumor infiltrates beyond the kidney but completely resected Ill. Residual nonhematogenous tumor confined to abdomen IV. Hematogenous metastasis
Fig 11, Mesoblastic nephroma. This low-power photomicrograph shows a cellular tumor composed of spindle cells with low-grade nuclear cytology infiltrating around benign medullary kidney (right lower corner) (Hematoxylin-eosin, original magnification x25).
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Fig 12. "Rhabdoid cells" with eccentric cytoplasmic inclusions in renal cell carcinoma (Hematoxylin-eosin, original magnification × 125),
Rhabdoid Tumor
Rhabdoid tumor is an unusual tumor of childhood comprising 2.5% of cases. 43 Most rhabdoid tumors occur before age 3, and there is a slight predominance in boys. Grossly, the tumors are well circumscribed, soft, and usually weigh less than 500 g. On microscopic examination the cells are only loosely cohesive. Rhabdoid tumor cells characteristically have abundant eosinophilic cytoplasm with distinct cell borders, vesicular nuclei, and prominent nucleoli. The classical "rhabdoid cell" has a cytoplasmic inclusion that is eccentric, pale, and slightly fibrillar. On ultrastructural examination these cytoplasmic inclusions are composed of whorls of intermediate filaments, and by immunohistochemical examination they are positive for vimentin and cytokeratin. A wide variety of tumors (nephroblastoma, RCCa (Fig 12), transitional cell carcinoma, rhabdomyosarcoma, and many others) may have rhabdoid cells, and thus this feature is not specific for the diagnosis of rhabdoid tumor. 44 Rhabdoid tumors are aggressive, with most patients dead within 1 year.
exposure, smoking, analgesic abuse especially with phenacetin, a history of urinary tract infection or stones (15% to 20%), obstruction, and rare conditions such as Balkan nephropathy. The principle of field effect applies. Renal pelvic and ureteral tumors occur simultaneously in 6% to 38% of cases. Ten percent to 50% of patients with upper tract lesions will have previous, coincident, or subsequent bladder tumors. About 3 % of renal pelvic cancers are bilateral. 45 On gross examination the majority of renal TCCas have an exophytic papillary appearance (Fig 13). Some are both endophytic and exophytic. A minority are purely endophytic. This later group is usually high grade. The histopathology of TCCa in the renal pelvis is exactly the same as that of the urinary bladder. Papillary tumors are graded according to the World Health Organization (WHO) classification as grade 1, 2, or 3 depending on the degree of epithelial stratification, the extent of nuclear pleomorphism, and the mitotic activity (Fig 14). Flat carcinoma in situ may also be seen, but it is less common than in the bladder. The assignment of stage is a critical aspect of pathological reporting in TCCa of the renal pelvis. Stage O tumors are confined to the mucosa; stage A neoplasms have invasion of the lamina propria of the extrarenal pelvis or focal superficial invasion of the renal pyramids; in stage B there is invasion of the muscularis of the extrarenal pelvis or diffuse microscopic invasion of the renal pyramids; stage C tumors show gross invasion of the kidney or microscopic invasion of the perirenal fat; stage D1 tumors
TRANSITIONAL CELL CARCINOMA OF RENAL PELVIS
Transitional cell carcinoma (TCCa) of the kidney may arise from any portion of the renal pelvis, but the extrarenal pelvis is most frequently affected. TCCa in the kidney has the same age and sex distributions as bladder tumors. Risk factors for the development of TCCa of the renal pelvis include organic chemical
Fig 13. Gross photograph of papillary TCCa of renal pelvis, stage A.
PATHOLOGY OF RENAL TUMORS
Fig 14. Photomicrograph of grade II papillary transitional cell carcinoma of renal pelvis (Hematoxylin-eosin, original magnification x25}.
have regional nodal metastases, whereas stage D2 malignancies have distant spread. RARE RENAL NEOPLASMS
There are a number of neoplasms that are found in the kidney as clinical masses with low frequency. Space does not permit a recitation of the pathological features of these lesions. The reader is referred to the recently published excellent atlas by Murphy, Beckwith, and Farrow. 46 These neoplasms are listed in Table 5.
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and fat in varying proportions. AML may be sporadic or it may occur in association with hereditary disorders such as tuberous sclerosis, von Recklinghausen's disease, von HippelLindau syndrome, and adult polycystic disease. Eighty percent of patients with tuberous sclerosis will have AML. AML shows a curious immunoreactivity for the nevomelanocytic marker HMB45. 47 Typical AML is an intrarenal tumor, although extrarenal locations may include capsular, perirenal soft tissue, retroperitoneal, abdominal, and pelvic organs, and lymph nodes. AML varies widely in size with multiple small tumors being more common in tuberous sclerosis. AML tends to be large when isolated. AML is usually well circumscribed (Fig 15), although it does not have a true capsule and can have some local infiltration of the adjacent kidney. AML may show hemorrhage. Histologically AML is defined by the presence of thick-walled vessels, smooth muscle,
ANGIOMYOLIPOMA
Angiomyolipoma (AML) is a benign renal neoplasm composed of blood vessels, muscle Table 5. Rare Renal Neoplasms
Epithelial Carcinoid Small cell carcinoma Juxtaglomerular cell tumor Teratoma Cystic nephroma Mesenchymal Medullary fibroma Leiomyoma Lipoma Hemangioma Lymphangioma Mesoblastic nephroma Leiomyosarcoma Liposarcoma Hemangiopericytoma Malignant fibrous histiocytoma Fibrosarcoma Rhabdomyosarcoma Angiosarcoma Osteosarcoma
Fig 15. Gross photograph of angiomyolipoma. The tumor has admixed solid and fatty areas and superficially mimics RCCa.
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nancy. The vessel walls are usually thick with fibrosis and fragmentation of the internal elastica. Aneurysmal dilatations may be seen. AML may invade regional lymph nodes without being considered malignant. Documentation of true metastatic behavior is exceedingly rare. 48 METASTATIC DISEASE INVOLVING KIDNEY
Fig 16. Low-power photomicrograph of angiomyolipoma with an admixture of mature adipose tissue, thick-walled vessels and smooth muscle (Hematoxylin-eosin, original magnification x25}.
and mature adipose tissue in varying proportions (Fig 16). Smooth muscle tends to spin off of the outer tables of the thick-walled vessels, and this component may Show moderate nuclear pleomorphism and mitotic activity. These features should not be construed as signs of malig-
The kidney is a common landing site for a variety of metastases. Lung cancer, melanoma, adenocarcinomas of the gastrointestinal tract, and cancers of the ovary and testis are common primary sites that metastasize to the kidney. Lymphomas and leukemias frequently involve the kidney in late-stage disease, although renal failure from this involvement is unusual. NONNEOPLASTIC RENAL MASSES
Finally, not all kidney masses are malignant. Malakoplakia and xanthogranulomatous pyelonephritis are two examples of inflammatory conditions that can produce mass lesions in the kidney.
REFERENCES 1. Boring CC, Squires TS, Tong T: Cancer statistics, 1993. CA Cancer J Clin 43:7-26, 1993 2. Zbar B, Brauch H, Talmadge C, et al: Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 327:721-724, 1987 3. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, p 92 4. Ulrich W, Horvat R, Krisch K: Lectin histochemistry of kidney tumors and its pathomorphological relevance. Histopathology 9:1037-1050, 1985 5. Bannasch P, Zerban H: Animal models and renal carcinogenesis, in Eble JN (ed): Tumors and Tumor-Like Conditions of the Kidneys and Ureters. New York, Churchill Livingstone, 1990, pp 1-34 6. Thoenes W, Storkel S, Rumpelt HJ: Human chromophobe cell renal carcinoma. Virchow's Arch (Cell Pathol) 48:207-217, 1985 7. Thoenes W, Storkel S, Rumpelt HJ, et al: Chromophobe cell renal carcinoma and it's variants--A report on 32 cases. J Pathol 155:277-287, 1988 8. Storkel S, Steart PV, Drenckhahn D, et al: The human chromophobe cell renal carcinoma: its probable relation to intercalated ceils of the collecting duct. Virchow's Arch (Cell Pathol) 56:237-245, 1989 9. Bard RH, Lord B, Fromowitz F: Papillary adenocarcinoma of the kidney. II. Radiographic and biologic characteristics. Urology 19:16-20, 1982 10. Kovacs G: Papillary renal cell carcinoma. A morpho-
logic and cytogenetic study of 11 cases. Am J Pathol 134:27-34, 1989 11. Cromie WJ, Davis Cj, DeTure FA: Atypical carcinoma of kidney, possibly originating from collecting duct epithelium. Urology 13:315-317, 1979 12. Fleming S, Lewi H J: Collecting duct carcinoma of the kidney. Histopathology 10:1131-1141, 1986 13. Hal MA, Diaz-Perez R: Atypical carcinoma of kidney originating from collecting duct epithelium. Urology 19:8992, 1982 14. Kennedy S, Merino M, Linehan WM, et al: Collecting duct carcinoma of the kidney. Hum Pathol 21:449-456, 1990 15. Deitchman B, Sidhu GS: Ultrastructural study of a sarcomatoid variant of renal cell carcinoma. Cancer 46:11521157, 1980 16. Marshall FF: The role of selective exploration in ambiguous renal cystic lesions. Urol Clin North Am 7:689695, 1980 17. Gibson TE: Inter-relationship of renal cysts and tumors: Report of three cases. J Urol 71:241, 1954 18. Levine SR, Emmett JL, Woolner LB: Cyst and tumor occurring in the same kidney. J Urol 91:8, 1964 19. Weitzner S: Clear cell carcinoma of the free wall of a simple renal cyst. J Urol 106:515-517, 1971 20. Hughson MD: Cancer in acquired cystic disease, in Grantham J J, Gardner KD (eds): Problems in diagnosis and management of polycystie kidney disease. Kansas City, MO, Polycystic Kidney Research Foundation, 1985, pp 224-234 21. Matas AJ, Simmons RL, Kjellstrand CM, et ah
PATHOLOGY OF RENAL TUMORS
Increased incidence of malignancy during chronic renal failure. Lancet 2:883-886, 1975 22. Klein MJ, Valensi QJ: Proximal tubular adenomas of kidney with so-called oncocytic features. Cancer 38:906-914, 1976 23. Warfel KA, Eble JN: Renal oncocytomatosis. J Urol 127:1179-1180, 1982 24. Barnes CA, Beckman EN: Renal oncocytoma and its congeners. Am J Clin Patho179:312-318, 1983 25. Bell ET: A classification of renal tumors with observations on the frequencies of various types. J Uro139:238-243, 1938 26. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. J Urol 101:297-301, 1969 27. American Joint Committee on Cancer (AJCC), Beahrs OH, Henson DE, et al: Manual for Staging of Cancer, 4th ed. Philadelphia, Lippincott, 1992, pp 201-204 28. Petersen RO, ed: Urologic Pathology, 2nd ed. Philadelphia, Lippincott, 1992, p 99 29. Golimbu M, Joshi P, Sperber A, et al: Renal carcinoma: Survival and prognostic factors. Urology 27:291-301, 1986 30. Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655-663, 1982 31. Medeiros LJ, Gelb AB, Weiss LM: Renal cell carcinoma. Prognostic significance of morphologic parameters in 121 cases. Cancer 61:1639-1651, 1988 32. Petersen RO, ed: Urologic Pathology, 2nd ed. Philadelphia, Lippincott, 1992, p 97 33. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilm's tumor locus. Cell 60:509520, 1990 34. Gessler M, Poustka A, Cavenee W, et al: Homozygous deletion in Wilm's tumors of a zinc-finger gene identified by chomosome jumping. Nature 343:774-778, 1990 35. Koufos A, Grundy P, Morgan K, et al: Familial Weidemann-Beckwith syndrome and a second Wilm's tumor locus both map to 11p15.5. Am J Hum Genet 44:711719, 1989 36. Maw MA, Grundy PE, Millow LJ, et al: A third Wilm's tumor locus on chromosome 16q. Cancer Res 52:3094-3098, 1992
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37. Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilm's tumor. A report from the National Wilm's Tumor Study pathology center. Hum Pathol 19:1199-1209, 1988 38. Faria P, Beckwith JB: A new definition of focal anaplasia identifies cases with good outcome. A report from the National Wilm's Tumor Study. Mod Pathol 6:3P, 1993 39. D'Angio GJ, Breslow N, Beckwith JB, et al: Treatment of Wilm's tumor: Results of the Third National Wilm's Tumor Study. Cancer 64:349-360, 1989 40. Weeks DA, Beckwith JB, Luckey DW: Relapseassociated variables in stage I favorable histology Wilm's tumor. A report of the National Wilm's Tumor Study. Cancer 60:1204-1212, 1987 41. Bolande RP, Brough AJ, Izant RJ: Congenital mesoblastic nephroma of infancy. A report of eight cases and the relationship to Wilm's tumor. Pediatrics 40:272-278, 1967 42. Sotelo-Avila C, Gonzalez-Crussi F, Sadowinski S, et al: Clear cell sarcoma of the kidney: A clinicopathologic study of 21 patients with long-term follow-up evaluation. Hum Pathol 16:1219-1230, 1986 43. Weeks DA, Beckwith JB, Mierau GW, et al: Rhabdoid tumors of the kidney: a report of 111 cases from the National Wilms' Tumor Study pathology center. Am J Surg Pathol 13:439-458, 1989 44. Weeks DA, Beckwith JB, Mierau GW, et al: Renal neoplasms mimicking rhabdoid tumor of the kidney. A report from the National Wilms' Tumor Study pathology center. Am J Surg Pathol 15:1042-1054, 1991 45. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, p 313 46. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, pp 145-178 47. Hoon V, Thung SN, Kaneko M, et al: HMB-45 reactivity in renal angiomyolipomas and lymphangioleimyomatosis. Arch Pathol Lab Med 118:732-734, 1994 48. Ferry JA, Malt RA, Young RH: Renal angiomyolipoma with sarcomatous transformation and pulmonary metastases. Am J Surg Pathol 15:1083-1088, 1991
ENAL CELL carcinoma (RCCa) is the most frequent tumor of the kidney in adults. RCCa comprises about 3% of all adult malignancies with 27,000 new cases and 10,000 deaths per year in the USA. 1There is a predominance in men. Peak incidence is in the sixth decade of life. The diagnosis of RCCa is suggested by the classic triad of flank pain, hematuria, and a flank mass. This constellation of findings is often found late in the course when metastatic disease is common. Specific laboratory findings in RCCa are related to hormone production. Polycythemia is secondary to erythropoietin production by the tumor. Hypercalcemia is secondary to ectopic production of a parathormone-like substance. Renal cell carcinomas are thought to arise from tubular epithelial cells. Much discussion has occurred regarding the exact site of origin within the nephron, but current thinking is that RCCa may arise from any segment. Genetically, most clear and granular RCCas will show deletions in the short arm of chromosome 3 beginning at 3p13. 2 A tumor suppressor gene in this region is hypothesized.
R
HISTOPATHOLOGY
The significance of the histopathologic classification in RCCa has been debated. Any histopathologic classification should impart some prognostic information and provide a frame-
ABBREVIATIONS RCCa, renal cell carcinoma; ACD, acquired cystic disease; ATP, adenosine triphosphate; WAGR, Wilms' aniridia genital anomaly-retardation syndrome; WT, Wilms' tumor; NWTS, National Wilms' Tumor Study; TCCa, transitional cell carcinoma; WHO, World Health Organization; AML, angiomyolipoma.
work with which to separate metastatic RCCa from other neoplasms. Several schemes have been proposed. None are particularly robust in their predictive value in large part because of the extensive heterogeneity to be found in RCCa. The following classification is an adaptation of that recently used by Murphy et al. 3 These categories represent the basic patterns that may be admixed in varying combinations and proportions in RCCa. Clear Cell Carcinoma
This is the classical histopathology in RCCa. The tumor cells have water-clear cytoplasm reflecting the high content of glycogen and lipids that are removed from the tissue sections during processing (Fig 1). Because of the histopathologic similarity to ceils of adrenal cortex, the term "hypernephroid" carcinoma was originally used to describe this tumor. In clear cell carcinoma neutral lipids can be highlighted with Oil Red O stain in unprocessed materials; phospholipids are more resistant to processing and can be decorated with the Sudan Black B reaction; glycogen can be stained with the periodic acid-Schiff reaction. Because of the high lipid content, these tumors tend to have a yellow color on gross examination. Lipid vacuoles and glycogen can also be found on ultrastructural examination. The nuclei of clear cell carcinoma are usually of low grade. The tumor cells grow in sheets or small islands, or form tubules that are supported by a delicate fibrovascular stroma. Tumor ceils may show partial brush border preservation by ultrastructural examination suggesting proximal tubular differentiation, but lectin studies suggest heterogeneity with markers of both proximal and distal tubule. 4 Granular Cell Carcinoma
From the University of Pennsylvania Medical Center, Philadelphia. Address reprint requests to John E. Tomaszewski, MD, Associate Professor of Pathology and Laboratory Med&ine, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4283. Copyright © 1995 by W.B. Saunders Company 0037-198X/95 / 3002-000355.O0/ 0 116
The phenotype is that of tumor ceils with variable granular eosinophilia of the cytoplasm. The granular cytoplasm is secondary to a high content of cytoplasmic organelles including mitochondria, rough endoplasmic reticulum, and Golgi. The lipid content is less than that in clear cell carcinomas. On gross examination these Seminars in Roentgenology, Vol XXX, No 2 (April), 1995: pp 116-127
PATHOLOGY OF RENAL TUMORS
Fig 1. Clear cell type of renal carcinoma. The tumor shows prominent cytoplasmic clearing, a delicate fibrovascular stroma, and low-grade nuclear cytology (Hematoxylin-eosin, original magnification x 100).
tumors have a variable brown color secondary to a high content of lipochrome pigment. Cell borders are partially defined. The degree of nuclear pleomorphism tends to be more than that in clear cell carcinoma.
Chromophobe Cell Carcinoma This type is the most recently described. In rats exposed to N-nitrosomorpholine, chromophobe cell tumors arise from the proximal tubule. 5 Thoenes et al6 were first to describe in detail the human counterpart for the rat chromophobe carcinoma. This tumor has no doubt been confused with clear and granular cell carcinomas in the past. Chromophobe cell carcinomas comprise about 5% of all RCCas. These tumors range from 2 to 22 cm. They are well circumscribed, solitary, and brown to gray in color. On microscopic examination the ceils have extremely well defined cell borders (Fig 2), giving the tumor a superficial resemblance to the cell walls of vegetable material. The cytoplasm distends the cell and varies from pale and transparent to brightly eosinophilic. Pale cells tend to have a ground glass appearance to the cytoplasm and are oriented toward the fine fibrovascular septa. The cytoplasm of chromophobe carcinoma can be highlighted with Hale's colloidal iron stain 7 indicating a high content of mucopolysaccharides. Ultrastructurally, the cytoplasm has a dense perinuclear arrangement of microvesicles that range from 150 to 300 nm. These vesicles have a high content of carbonic anhydrase C suggesting a relationship to the
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Fig 2, Chromophobe cell renal carcinoma showing distinct cell borders and pale cytoplasm (Hematoxylin-eosin, original magnification x 100),
intercalated cells of the collecting duct. 8 Unlike other RCCas, chromophobe carcinomas are negative for vimentin.
Papillary Carcinoma Papillary RCCas are said to compose 10% to 15% of renal neoplasms. On gross examination they have a light gray to yellow color depending on the amount of lipid. Hemorrhage and necrosis are frequent and these tumors often have reduced vascularity.9 Papillary neoplasms are frequently the subtype found in the wall of cortical cysts. Histopathologically, papillary RCCa is formed from fine vascular stalks with varying numbers of foamy macrophages covered by a single layer of epithelium (Fig 3). The epithelium varies from low cuboidal to colum-
Fig 3. Papillary RCCa. The tumor is composed of papillary fronds supported by a delicate fibrovascular stroma, admixed with foamy macrophages, and covered by a low cuboidal epithelium showing low-grade nuclei (Hematoxylin-eosin, original magnification x 100}.
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nat and the nuclear cytology of these cells is usually bland. The cytoplasm is usually acidophilic or weakly basophilic. Clear cell cytoplasm is not common. Tumors with large numbers of foam cells may show cholesterol clefts in areas of necrosis. Psammoma bodies are common in some tumors. Tumor cells may have abundant hemosiderin granules indicating tumor breakdown and pigment uptake by the neoplastic epithelium. The cytogenetic profile of papillary RCCa includes abnormalities of chromosomes 7 and 17 including frequent trisomies. ~°
Collecting Duct Carcinoma The category of collecting duct carcinoma is also a relatively new one that has created controversy. This tumor is rare and constitutes about 1% of renal cancers. H44 Collecting duct carcinoma (also termed Bellini duct carcinoma) is thought to arise from the terminal collecting ducts that empty into the renal pelvis. In keeping with this postulated origin, this tumor offers an interesting set of features that may be considered as intermediate between RCCa and transitional carcinoma. Grossly, the tumor may be localized to the medulla or it may involve both medulla and cortex. Because of this medullary orientation, collecting duct carcinoma produces distortion of the pelvis. Hemorrhage and necrosis is common. Microscopically, this tumor has a mixed tubular and papillary architecture. Tubules and papillae are lined by a single layer of cuboidal epithelium. When the tubules dominate, the tumor may have a spongy appearance. The tubules can anastomose in a complicated fashion. Desmoplastic stoma is common. Nuclear pleomorphism varies from mild to marked. Adjacent collecting ducts may have atypical hyperplasia. In keeping with origin from a cell at the junction of the nephron and the collecting system, collecting duct carcinomas produce both high and low molecular weight cytokeratins. They are positive for epithelial membrane antigen and peanut agglutinin. The prognosis of collecting duct carcinoma is difficult to know because of the small numbers of reported cases; however the emerging impression is that of an aggressive tumor.
JOHN E. TOMASZEWSKI
Sarcomatoid Carcinoma Sarcomatoid RCCa is a high-grade cancer of renal tubular origin that can be confused with true renal sarcoma because of the dominant spindle cell morphology. These tumors are usually quite large and tend to be aggressively invasive. Many cases present with metastasis. Sarcomatoid carcinomas have a tan to gray color and can show gross heterogeneity with firm fibrous areas alternating with more typical RCCa. The histopathology also shows a variegated pattern with interlacing fascicles of spindle cells admixed with epithelioid carcinomatous components that are usually of high grade (Fig 4). Carcinomatous and spindled components may be intimately intermingled or they may be geographically separated within the same tumor. Similar heterogeneity is found in ultrastructural and antigenic studies of sarcomatoid carcinoma. Epithelioid elements are generally positive for low-molecular-weight cytokeratin and epithelial membrane antigen, whereas the spindled ceils are much more variable in their cytokeratin content. Spindled elements can have desmosomes on ultrastructural examination. 15 If heterologous elements are found in a spindled cell renal neoplasm, the possibility of a true carcinosarcoma should be considered. C Y S T I C RCCA
Renal cell carcinoma is associated with cystic disease of some sort in 2.3% to 7.0% of cases. 16 Gibson 17has outlined four ways in which cancer may be associated with cysts. These include (1)
Fig 4. Sarcomatoid RCCa showing epithelioid and spindled cells with enlarged nuclei, macronucleoli, and nuclear pleomorphism (Hematoxylin-eosin, original magnification x 100).
PATHOLOGY OF RENAL TUMORS
RCCa may become necrotic and cystic; (2) carcinoma may originate within a cyst wall; (3) carcinoma and cysts may be located in close proximity and possibly be pathogenetically related; or (4) carcinoma and cysts may be widely separated and only coincidentally associated. Renal cell carcinoma will often have areas of cystic change. At times this may be extensive (Fig 5). Levine et aP s classified 24/545 (4%) of RCCas as "cystic hypernephromas." Such cystic changes are most probably degenerative phenomena as the tumor outstrips its blood supply. In cystic RCCa, tumor cells line the cavity and often have a clear cell cytology. Hemorrhage, necrosis, and sclerosis may be prominent. Solid nodules of tumor are often seen. Carcinoma arising in the wall of a simple cyst is a rare event. There are three situations in which RCCa and simple cysts may coexist. First, a simple cyst and tumor may be present in the same kidney, but be geographically and pathogenetically unrelated. Second, tumor may be found adjacent to a simple cyst, and induce the formation of that cyst through tubular and vascular obstruction. Thirdly, carcinoma may arise in the wall of a simple cyst. This last scenario is extremely rare, there being only a few reported cases in the literature, a9In such cases the simple cyst is partially or completely intact with a single layer of flat, cytologically bland epithelium, and the carcinoma is found in an intramural location. Approximately 34% of patients maintained on hemodialysis for more than 3 years will
Fig 5. Cystic RCCa. This gross photo shows a tumor which is predominantly cystic with only a small nodule of solid carcinoma at the inferior aspect of the mass,
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develop cysts in their end-stage kidneys. 2° The pathogenesis of the cysts in acquired cystic disease (ACD) is unknown, but theories have included tubular obstruction or increased compliance of the tubular basement membranes under the stress of some cystogenic influence such as a uremic toxin. The frequency of cyst formation increases with time. Grossly, kidneys with ACD are moderately enlarged, generally weighing less than 300 g. Cysts are numerous, bilateral, and mostly small, ranging in size from microscopic cysts that are 2 to 3 times the diameter of a collecting tubule to cysts that are macroscopic and up to 2 cm in diameter. The cysts are variably lined. Some cysts have a lining of cuboidal epithelium that is low and unremarkable. In other cysts the epithelium is prominently nucleolated; still other areas show papillary hyperplasia of the lining. Renal cell neoplasms are a frequent complication of ACD, and are found in about 17% of cases. Affected kidneys show a spectrum of change including cysts, atypical cysts, small neoplasms ("adenomas"), and flank carcinomas. The frequency of RCCa in patients with ACD is about seven times the expected yearly incidence in the age-matched general population. 21 ONCOCYTOMA
Renal oncocytomas had been recognized by German pathologists as a separate entity for many years. In the English literature, however, their designation as a special diagnostic category has been relatively recent. Klein and Valensi's 22 report of 13 cases from one institution in 1976 spurred interest in the lesion. Since that time several hundred cases have been described in the world literature. Oncocytomas represent approximately 4% to 5% of renal cell neoplasms. The male to female patient ratio is about 2:1. The age at presentation is wide (15 to 84 years old) with the peak incidence in the seventh decade. These tumors tend to be clinically silent, with the majority being discovered incidentally. Thirty-six percent are symptomatic: flank pain 71%; hematuria 33%; weight loss 7%; fever 8%. Oncocytomas are well-circumscribed tumors. They tend to be quite large, with an average diameter of 7 cm. Classic oncocytomas are
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described as having a mahogany brown color, most probably secondary to the large amount of cytochrome pigment associated with the many mitochondria. Focal hemorrhage is uncommon. Necrosis should not be found. The presence of a central stellate scar (Fig 6) is characteristic, but by no means constant, and is seen in only a minority of cases. About 3% of oncocytomas are bilateral, and 5% are multicentric in the same kidney. One extraordinary report documented over 200 oncocytomas in a single kidney. 23 Calcification in oncocytomas is unusual. Cystic change can occur. The histologic hallmark of this tumor is the presence of the oncocytic cell. An oncocyte is an eosinophilic cell with abundant granular cytoplasm and a round uniform nucleus (Fig 7). The cytoplasm of these ceils is packed with mitochondria, and histochemically, oncocytes contain an abundance of oxidative enzymes and Adenosine Triphosphate (ATP). Oncocytes can, of course, be found in a variety of other sites including salivary gland (Warthin's tumor), thyroid (H~rthle cell), and parathyroid. Oncocytomas often show a diffuse or organoid histology; however tubular and trabecular patterns can also be found. Only minimal nuclear atypia is found in most oncocytomas, but bizarre nuclei, ascribed to degenerative changes, have been described. Clear cell loci, mitoses, necrosis, high-grade atypia, macronucleoli, ballooning distention of the cytoplasm, or a predominate papillary pattern are not part of the classic histology of oncocytoma. The prognostic significance of these atypical features is unclear. 24 Because the diagnosis of oncocytoma is only clinically useful if it carries with it a distinctly
Fig 6. Oncocytoma. The tumor is well circumscribed and has a dense central scar.
JOHN E. TOMASZEWSKI
Fig 7. Oncocytoma, This neoplasm is composed of a uniform population of cells with abundant eosinophilic cytoplasm and small, round, and regular nuclei that are centrally located in each cell (Hematoxylin-eosin, original magnification × 100).
favorable prognosis, and it is unclear at this point in time whether cases with atypical features will have a good long-term outcome, it is our opinion that the diagnosis of oncocytoma should be restricted to only those cases with classic histology. Oncocytic renal neoplasms with atypical features should be flagged as tumors of uncertain malignant potential. Renal Cortical Carcinoma Versus Adenoma
The concept of a completely benign renal neoplasm that can be accurately predicted in life to be nonrecurring and nonmetastatic is most closely approximated by the oncocytoma as discussed above. Clear cell, granular cell, and papillary renal neoplasms of small size, ie, < 2.5 cm, have been termed by some as "renal cortical adenomas." Bell's 25 classic work found a good correlation between tumor size and frequency of metastases. However, even this data showed that large tumors do not always metastasize and that occasional tumors of less than 3.0 cm do metastasize. Thus, the predictive value of tumor size for metastatic potential is good but not 100%. In a surgical specimen, even small renal neoplasms should be considered as having some limited potential for progression. The term "renal adenoma" may be misleading because it conveys a certainty about good outcome that may not be entirely documented. For small renal tumors of low grade we prefer the phrase "renal neoplasm of low malignant potential."
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PROGNOSTIC FACTORS IN RCCA
Pathological Staging of RCCa The pathological staging of RCCa is probably the single most important statement as to the prognosis. Staging may be performed under the scheme of Robson et al, 26 o r according to the TMN classification. 27The Robson system, which is somewhat simpler and commonly used, is outlined in Table 1. Average 5-year survival rates according to Robson stages are as follows2S: stage I, 65%; stage II, 48%; stage III, 39%; stage IV, 7%. Renal vein extension (Fig 8) does not by itself impart a worsened short-term prognosis, although long-term survival may be impacted by this feature. 29
Grading of RCCa There have been several attempts at constructing a meaningful grading system for RCCa. At this writing there seems to be general acceptance in the current literature that a nuclear grading system is most effective. The Fuhrman 3° grading system (Table 2) is a commonly referenced system for nuclear grading in RCCa. The 5-year survival for patients with nuclear grade 1 tumors is 86%; grade 2, 72%; grade 3, 44%; grade 4, 24%.
Histopathology The value of histopathology as an independent prognostic parameter separate from grade and stage is disputed. Medeiros et al, 31 when controlling for nuclear grade, was unable to find a significant difference between different cell types in the low nuclear grades. In general the prognosis for papillary and chromophobe carcinomas is good; the outlook for clear cell carcinoma is intermediate; the outcomes for granular cell and collecting duct carcinomas are poor; sarcomatoid carcinoma is almost always lethal.
Fig 8. vein,
The differences among these different categories may be heavily influenced by the nuclear grades that are dominant in each category.
Flow Cytometry This technique must be considered as adjunctive. Ploidy analysis generally correlates with nuclear grade. It is unclear whether or not flow cytometry adds additional information beyond that supplied by nuclear grading. 32 NEPHROBLASTOMA AND OTHER PEDIATRIC RENAL TUMORS
Nephroblastoma or Wilms' Tumor Nephroblastoma or Wilms' tumor is the most common pediatric renal neoplasm. The mean age of diagnosis for boys is 37 months and for girls is 43 months. There are a number of conditions that are associated with nephroblastoma including the Wilms'-aniridia genital anomaly-retardation syndrome (WAGR), Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome (glomerulonephritis, pseudohermaphroditism, nephroblastoma), and familial nephroblastoma. WAGR patients were
Table 1. Staging of Renal Cell Carcinoma According to Robson w Stage 1 Stage 2 Stage 3
Stage 4
Confined to kidney Extends into perirenal fat but confined by Gerota's fascia Gross extension into renal vein or vena cava; lymphatic involvement; vascular and lymphatic spread Extension into adjacent organs (other than adrenal), or distant metastases
RCCa with tumor thrombus extending into renal
Table 2. Fuhrman Nuclear Grading System for RCCa Nuclear Size Grade { F m ) I il Ill IV
10 15 20 >20
NuclearContour Round Slightly irregular Very irregular Bizarre and multilobated
Nucleoli Absent Present, small Large, prominent Large, prominent
Chromatin Fine Fine Fine Clumped
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Fig 9. Wilms' tumor. This mass is well circumscribed, solid, and has a vaguely Iobulated appearance.
found to have a constant deletion of chromosome 11p13 in their somatic cells. Similar deletions were found in the tumor cells of some patients with nephroblastoma. These findings led to the discovery of a tumor-associated gene in Wilms' tumor (WT). WT1 was identified by two groups. 33,34 WT1 is a transcription factor that is found in the early developing kidney. Abnormalities of WT1 are found in some case of sporadic Wilms' tumor and in many cases of the nephroblastoma associated conditions. WT2 is another candidate gene located at 11p15.5. 35 There is a high frequency of abnormalities of chromosome 16q, suggesting a possible third gene at this site. 36 On gross examination, Wilms' tumor is usually a solitary mass (Fig 9) that is separated from the adjacent renal parenchyma by a pseudocapsule. The average size is about 500 g. The tumors are often soft. Septa may divide the tumor and give a lobulated appearance. Tumors may project into the pelvis in a polypoid fashion. Some Wilms' tumors have prominent cystic
JOHN E. TOMASZEWSKI
change. Occasional tumors are pedunculated projections from the cortex. The histopathology of Wilms' tumor is variegated. There are three microscopic components: blastema, epithelium, and stroma (Fig 10). Most elements represent some aspect in normal or abnormal kidney development; however, heterologous elements show the multipotential nature of nephritogenic precursors. Blastema is the condensed mesenchyme from which the kidney develops. The nuclei are small and compact, and the blastemal cells have little cytoplasm. Blastemal cells may be arranged in diffuse, nodular, serpentine or basaloid patterns. The epithelial component in nephroblastoma usually recapitulates some normal kidney structure. Tubules, collecting ducts, and abortive glomeruli in varying degrees of maturation can all be seen. Heterologous epithelial elements may include mucinous, squamous, and rarely, ciliated epithelium. The stromal portions commonly seen in Wilms' tumors are cells resembling embryonic mesenchyme, fibroblasts, and smooth muscle. Less common heterologous elements may include skeletal muscle, cartilage, bone, and neural tissue. Cases with dominant heterologous elements may be termed "teratoid nephroblastoma." The clinical relevance of recognizing histopathologic diversity is to ensure accurate recognition of Wilms' tumor cases. Histopathologic examination can also provide information about prognosis based on recognition of favorable and unfavorable categories. Unfavorable histology
Fig 10. Wilms" tumor. This photomicrograph shows blastema (right lower corner) composed of dense spindle cells, admixed with primitive tubules (upper and left side} (Hematoxylin.eosin, original magnification x60).
PATHOLOGY OF RENAL TUMORS
refers to cases with anaplasia and includes cases with (1) atypical multipolar mitoses and/or (2) marked nuclear enlargement with the longest nuclear axis being at least three times larger than nonanaplastic nuclei. 37 In the National Wilms' Tumor Study (NWTS) only about 5% of cases show anaplasia. Cases with only focal anaplasia may have a good prognosis. 38Anaplasia has no effect on outcome for stage I tumors. The staging of nephroblastoma is outlined in Table 3. Survivals by stage and histopathology across all therapies in the Third NVVTS39 are listed in Table 4. There are a few gray areas in pathological staging. Microscopic loci of invasion of the renal sinus that do not escape the hilar plane should be categorized as stage I. Extensive infiltration of the renal sinus is stage II. An inflammatory pseudocapsule does not necessarily mean stage II disease, although an increased rate of relapse in stage I cases may be seen with an inflammatorypseudocapsule. Other features that may portend an increased relapse rate in cases that are otherwise stage I include invasion of the renal sinus, extensive infiltration of the renal capsule without complete transcapsular penetration, and invasion of intrarenal vessels. 40 Other pediatric renal neoplasms which constitute about 10% of all cases include mesoblastic nephroma, clear cell sarcoma, and rhabdoid tumor.
Mesoblastic Nephroma
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Table 4. Results of the Third National Wilm's Tumor Study: Survival by Stage and Histology27 Stage
Histology
% Relapse-Free at 4 yr
% Alive at 4 yr
I II III IV I-Ill IV
Favorable Favorable Favorable Favorable Unfavorable Unfavorable
90.4 88,1 79.0 74.9 64.8 55,6
96.5 92.3 87.0 68.4 68.4 55.3
Bolande et al. 41 In the cellular variant the nuclei are more numerous, larger, and vesicular.
Clear Cell Sarcoma Clear cell sarcoma is also called bonemetastasizing renal tumor of childhood. The peak incidence is in the second year of life. Very rare cases occur during adolescence. There is a predominance in boys. The tumors average about 500 g and often involve the medullary region. By light microscopy the classic clear cell sarcoma is composed of cords of uniform cells separated by delicate capillary septa. The cytoplasm contains numerous microvesicles with a high content of mucopolysaccharides accounting for the "clear cell" appearance. Cells with more eosinophilic cytoplasm are also found. The nuclei are usually bland with fine chromatin and variable nuclear grooves. There are many histologic variants that can cause confusion with nephroblastoma. Metastases are common. The death rate is 30% to 4 0 % . 42
Mesoblastic nephroma, also known as congenital mesoblastic nephroma or leiomyomatous hamartoma, is a neoplasm of the first few months of life. The tumors vary in size and average about 6 cm. They are often oriented toward the renal hilus. On microscopic examination mesoblastic nephromas are monotonous and composed of spindled cells (Fig 11) with a fibroblastic or myofibroblastic morphotype. Spindled cells can be arranged in interlacing fascicles in the classic subtype as described by Table 3. Staging of Wilm's Tumor According to the NWTS I. Limited to the kidney and completely resected IL Tumor infiltrates beyond the kidney but completely resected Ill. Residual nonhematogenous tumor confined to abdomen IV. Hematogenous metastasis
Fig 11, Mesoblastic nephroma. This low-power photomicrograph shows a cellular tumor composed of spindle cells with low-grade nuclear cytology infiltrating around benign medullary kidney (right lower corner) (Hematoxylin-eosin, original magnification x25).
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JOHN E. TOMASZEWSKI
Fig 12. "Rhabdoid cells" with eccentric cytoplasmic inclusions in renal cell carcinoma (Hematoxylin-eosin, original magnification × 125),
Rhabdoid Tumor
Rhabdoid tumor is an unusual tumor of childhood comprising 2.5% of cases. 43 Most rhabdoid tumors occur before age 3, and there is a slight predominance in boys. Grossly, the tumors are well circumscribed, soft, and usually weigh less than 500 g. On microscopic examination the cells are only loosely cohesive. Rhabdoid tumor cells characteristically have abundant eosinophilic cytoplasm with distinct cell borders, vesicular nuclei, and prominent nucleoli. The classical "rhabdoid cell" has a cytoplasmic inclusion that is eccentric, pale, and slightly fibrillar. On ultrastructural examination these cytoplasmic inclusions are composed of whorls of intermediate filaments, and by immunohistochemical examination they are positive for vimentin and cytokeratin. A wide variety of tumors (nephroblastoma, RCCa (Fig 12), transitional cell carcinoma, rhabdomyosarcoma, and many others) may have rhabdoid cells, and thus this feature is not specific for the diagnosis of rhabdoid tumor. 44 Rhabdoid tumors are aggressive, with most patients dead within 1 year.
exposure, smoking, analgesic abuse especially with phenacetin, a history of urinary tract infection or stones (15% to 20%), obstruction, and rare conditions such as Balkan nephropathy. The principle of field effect applies. Renal pelvic and ureteral tumors occur simultaneously in 6% to 38% of cases. Ten percent to 50% of patients with upper tract lesions will have previous, coincident, or subsequent bladder tumors. About 3 % of renal pelvic cancers are bilateral. 45 On gross examination the majority of renal TCCas have an exophytic papillary appearance (Fig 13). Some are both endophytic and exophytic. A minority are purely endophytic. This later group is usually high grade. The histopathology of TCCa in the renal pelvis is exactly the same as that of the urinary bladder. Papillary tumors are graded according to the World Health Organization (WHO) classification as grade 1, 2, or 3 depending on the degree of epithelial stratification, the extent of nuclear pleomorphism, and the mitotic activity (Fig 14). Flat carcinoma in situ may also be seen, but it is less common than in the bladder. The assignment of stage is a critical aspect of pathological reporting in TCCa of the renal pelvis. Stage O tumors are confined to the mucosa; stage A neoplasms have invasion of the lamina propria of the extrarenal pelvis or focal superficial invasion of the renal pyramids; in stage B there is invasion of the muscularis of the extrarenal pelvis or diffuse microscopic invasion of the renal pyramids; stage C tumors show gross invasion of the kidney or microscopic invasion of the perirenal fat; stage D1 tumors
TRANSITIONAL CELL CARCINOMA OF RENAL PELVIS
Transitional cell carcinoma (TCCa) of the kidney may arise from any portion of the renal pelvis, but the extrarenal pelvis is most frequently affected. TCCa in the kidney has the same age and sex distributions as bladder tumors. Risk factors for the development of TCCa of the renal pelvis include organic chemical
Fig 13. Gross photograph of papillary TCCa of renal pelvis, stage A.
PATHOLOGY OF RENAL TUMORS
Fig 14. Photomicrograph of grade II papillary transitional cell carcinoma of renal pelvis (Hematoxylin-eosin, original magnification x25}.
have regional nodal metastases, whereas stage D2 malignancies have distant spread. RARE RENAL NEOPLASMS
There are a number of neoplasms that are found in the kidney as clinical masses with low frequency. Space does not permit a recitation of the pathological features of these lesions. The reader is referred to the recently published excellent atlas by Murphy, Beckwith, and Farrow. 46 These neoplasms are listed in Table 5.
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and fat in varying proportions. AML may be sporadic or it may occur in association with hereditary disorders such as tuberous sclerosis, von Recklinghausen's disease, von HippelLindau syndrome, and adult polycystic disease. Eighty percent of patients with tuberous sclerosis will have AML. AML shows a curious immunoreactivity for the nevomelanocytic marker HMB45. 47 Typical AML is an intrarenal tumor, although extrarenal locations may include capsular, perirenal soft tissue, retroperitoneal, abdominal, and pelvic organs, and lymph nodes. AML varies widely in size with multiple small tumors being more common in tuberous sclerosis. AML tends to be large when isolated. AML is usually well circumscribed (Fig 15), although it does not have a true capsule and can have some local infiltration of the adjacent kidney. AML may show hemorrhage. Histologically AML is defined by the presence of thick-walled vessels, smooth muscle,
ANGIOMYOLIPOMA
Angiomyolipoma (AML) is a benign renal neoplasm composed of blood vessels, muscle Table 5. Rare Renal Neoplasms
Epithelial Carcinoid Small cell carcinoma Juxtaglomerular cell tumor Teratoma Cystic nephroma Mesenchymal Medullary fibroma Leiomyoma Lipoma Hemangioma Lymphangioma Mesoblastic nephroma Leiomyosarcoma Liposarcoma Hemangiopericytoma Malignant fibrous histiocytoma Fibrosarcoma Rhabdomyosarcoma Angiosarcoma Osteosarcoma
Fig 15. Gross photograph of angiomyolipoma. The tumor has admixed solid and fatty areas and superficially mimics RCCa.
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JOHN E. TOMASZEWSKI
nancy. The vessel walls are usually thick with fibrosis and fragmentation of the internal elastica. Aneurysmal dilatations may be seen. AML may invade regional lymph nodes without being considered malignant. Documentation of true metastatic behavior is exceedingly rare. 48 METASTATIC DISEASE INVOLVING KIDNEY
Fig 16. Low-power photomicrograph of angiomyolipoma with an admixture of mature adipose tissue, thick-walled vessels and smooth muscle (Hematoxylin-eosin, original magnification x25}.
and mature adipose tissue in varying proportions (Fig 16). Smooth muscle tends to spin off of the outer tables of the thick-walled vessels, and this component may Show moderate nuclear pleomorphism and mitotic activity. These features should not be construed as signs of malig-
The kidney is a common landing site for a variety of metastases. Lung cancer, melanoma, adenocarcinomas of the gastrointestinal tract, and cancers of the ovary and testis are common primary sites that metastasize to the kidney. Lymphomas and leukemias frequently involve the kidney in late-stage disease, although renal failure from this involvement is unusual. NONNEOPLASTIC RENAL MASSES
Finally, not all kidney masses are malignant. Malakoplakia and xanthogranulomatous pyelonephritis are two examples of inflammatory conditions that can produce mass lesions in the kidney.
REFERENCES 1. Boring CC, Squires TS, Tong T: Cancer statistics, 1993. CA Cancer J Clin 43:7-26, 1993 2. Zbar B, Brauch H, Talmadge C, et al: Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 327:721-724, 1987 3. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, p 92 4. Ulrich W, Horvat R, Krisch K: Lectin histochemistry of kidney tumors and its pathomorphological relevance. Histopathology 9:1037-1050, 1985 5. Bannasch P, Zerban H: Animal models and renal carcinogenesis, in Eble JN (ed): Tumors and Tumor-Like Conditions of the Kidneys and Ureters. New York, Churchill Livingstone, 1990, pp 1-34 6. Thoenes W, Storkel S, Rumpelt HJ: Human chromophobe cell renal carcinoma. Virchow's Arch (Cell Pathol) 48:207-217, 1985 7. Thoenes W, Storkel S, Rumpelt HJ, et al: Chromophobe cell renal carcinoma and it's variants--A report on 32 cases. J Pathol 155:277-287, 1988 8. Storkel S, Steart PV, Drenckhahn D, et al: The human chromophobe cell renal carcinoma: its probable relation to intercalated ceils of the collecting duct. Virchow's Arch (Cell Pathol) 56:237-245, 1989 9. Bard RH, Lord B, Fromowitz F: Papillary adenocarcinoma of the kidney. II. Radiographic and biologic characteristics. Urology 19:16-20, 1982 10. Kovacs G: Papillary renal cell carcinoma. A morpho-
logic and cytogenetic study of 11 cases. Am J Pathol 134:27-34, 1989 11. Cromie WJ, Davis Cj, DeTure FA: Atypical carcinoma of kidney, possibly originating from collecting duct epithelium. Urology 13:315-317, 1979 12. Fleming S, Lewi H J: Collecting duct carcinoma of the kidney. Histopathology 10:1131-1141, 1986 13. Hal MA, Diaz-Perez R: Atypical carcinoma of kidney originating from collecting duct epithelium. Urology 19:8992, 1982 14. Kennedy S, Merino M, Linehan WM, et al: Collecting duct carcinoma of the kidney. Hum Pathol 21:449-456, 1990 15. Deitchman B, Sidhu GS: Ultrastructural study of a sarcomatoid variant of renal cell carcinoma. Cancer 46:11521157, 1980 16. Marshall FF: The role of selective exploration in ambiguous renal cystic lesions. Urol Clin North Am 7:689695, 1980 17. Gibson TE: Inter-relationship of renal cysts and tumors: Report of three cases. J Urol 71:241, 1954 18. Levine SR, Emmett JL, Woolner LB: Cyst and tumor occurring in the same kidney. J Urol 91:8, 1964 19. Weitzner S: Clear cell carcinoma of the free wall of a simple renal cyst. J Urol 106:515-517, 1971 20. Hughson MD: Cancer in acquired cystic disease, in Grantham J J, Gardner KD (eds): Problems in diagnosis and management of polycystie kidney disease. Kansas City, MO, Polycystic Kidney Research Foundation, 1985, pp 224-234 21. Matas AJ, Simmons RL, Kjellstrand CM, et ah
PATHOLOGY OF RENAL TUMORS
Increased incidence of malignancy during chronic renal failure. Lancet 2:883-886, 1975 22. Klein MJ, Valensi QJ: Proximal tubular adenomas of kidney with so-called oncocytic features. Cancer 38:906-914, 1976 23. Warfel KA, Eble JN: Renal oncocytomatosis. J Urol 127:1179-1180, 1982 24. Barnes CA, Beckman EN: Renal oncocytoma and its congeners. Am J Clin Patho179:312-318, 1983 25. Bell ET: A classification of renal tumors with observations on the frequencies of various types. J Uro139:238-243, 1938 26. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. J Urol 101:297-301, 1969 27. American Joint Committee on Cancer (AJCC), Beahrs OH, Henson DE, et al: Manual for Staging of Cancer, 4th ed. Philadelphia, Lippincott, 1992, pp 201-204 28. Petersen RO, ed: Urologic Pathology, 2nd ed. Philadelphia, Lippincott, 1992, p 99 29. Golimbu M, Joshi P, Sperber A, et al: Renal carcinoma: Survival and prognostic factors. Urology 27:291-301, 1986 30. Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655-663, 1982 31. Medeiros LJ, Gelb AB, Weiss LM: Renal cell carcinoma. Prognostic significance of morphologic parameters in 121 cases. Cancer 61:1639-1651, 1988 32. Petersen RO, ed: Urologic Pathology, 2nd ed. Philadelphia, Lippincott, 1992, p 97 33. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilm's tumor locus. Cell 60:509520, 1990 34. Gessler M, Poustka A, Cavenee W, et al: Homozygous deletion in Wilm's tumors of a zinc-finger gene identified by chomosome jumping. Nature 343:774-778, 1990 35. Koufos A, Grundy P, Morgan K, et al: Familial Weidemann-Beckwith syndrome and a second Wilm's tumor locus both map to 11p15.5. Am J Hum Genet 44:711719, 1989 36. Maw MA, Grundy PE, Millow LJ, et al: A third Wilm's tumor locus on chromosome 16q. Cancer Res 52:3094-3098, 1992
127
37. Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilm's tumor. A report from the National Wilm's Tumor Study pathology center. Hum Pathol 19:1199-1209, 1988 38. Faria P, Beckwith JB: A new definition of focal anaplasia identifies cases with good outcome. A report from the National Wilm's Tumor Study. Mod Pathol 6:3P, 1993 39. D'Angio GJ, Breslow N, Beckwith JB, et al: Treatment of Wilm's tumor: Results of the Third National Wilm's Tumor Study. Cancer 64:349-360, 1989 40. Weeks DA, Beckwith JB, Luckey DW: Relapseassociated variables in stage I favorable histology Wilm's tumor. A report of the National Wilm's Tumor Study. Cancer 60:1204-1212, 1987 41. Bolande RP, Brough AJ, Izant RJ: Congenital mesoblastic nephroma of infancy. A report of eight cases and the relationship to Wilm's tumor. Pediatrics 40:272-278, 1967 42. Sotelo-Avila C, Gonzalez-Crussi F, Sadowinski S, et al: Clear cell sarcoma of the kidney: A clinicopathologic study of 21 patients with long-term follow-up evaluation. Hum Pathol 16:1219-1230, 1986 43. Weeks DA, Beckwith JB, Mierau GW, et al: Rhabdoid tumors of the kidney: a report of 111 cases from the National Wilms' Tumor Study pathology center. Am J Surg Pathol 13:439-458, 1989 44. Weeks DA, Beckwith JB, Mierau GW, et al: Renal neoplasms mimicking rhabdoid tumor of the kidney. A report from the National Wilms' Tumor Study pathology center. Am J Surg Pathol 15:1042-1054, 1991 45. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, p 313 46. Murphy WM, Beckwith JB, Farrow GM: Atlas of Tumor Pathology: Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, DC: Armed Forces Institute of Pathology, 1994, pp 145-178 47. Hoon V, Thung SN, Kaneko M, et al: HMB-45 reactivity in renal angiomyolipomas and lymphangioleimyomatosis. Arch Pathol Lab Med 118:732-734, 1994 48. Ferry JA, Malt RA, Young RH: Renal angiomyolipoma with sarcomatous transformation and pulmonary metastases. Am J Surg Pathol 15:1083-1088, 1991