Chapter 40 Renal Neoplasia Scott E. Delacroix Jr., Christopher G. Wood, and Eric Jonasch

Renal Cell Carcinoma, 1508 Chemotherapy, 1525 Other Kidney Tumors, 1528 Epidemiology, 1508 Immunotherapy, 1525 Renal Sarcomas, 1528 Pathology and Cytogenetics, 1509 Nonmyeloablative Allogeneic Wilms’ Tumor, 1528 Molecular Biology and Hereditary Transplantation, 1526 Disorders, 1511 Renal Pelvic Tumors, 1527 Clinical and Laboratory Features, 1513 Clinical Features and Diagnostic Radiologic Diagnosis, 1514 Evaluation, 1527 Staging and Prognosis, 1516 Staging and Grading of Renal Pelvic Surgical Treatment, 1518 Tumors, 1527 Radiation Therapy, 1520 Treatment, 1527 Systemic Therapy, 1520

Renal cell carcinomas arise within the renal cortex and 2% of all cancer deaths. Worldwide, the mortality from renal account for about 80% to 85% of all primary renal neoplasms. cell carcinoma is estimated to exceed 100,000 per year.6 Transitional carcinomas arising from the renal pelvis are the The incidence varies widely from country to country, next most common, accounting for 7% to 8% of primary with the highest rates seen in Northern Europe and North renal neoplasms. Other parenchymal epithelial tumors, such ­America.7 Although the incidence is reported to be lower as oncocytomas, collecting duct tumors, and renal sarcomas, in individuals living in African countries,7 the incidence is are uncommon but are becoming more frequently recognized equivalent among whites and African Americans living in the pathologically. Nephroblastoma (Wilms’ tumor) is common United States.8 Historically, renal cell carcinoma was twice as in children and accounts for 5% to 6% of all primary renal common in men as in women, but more recent data suggest tumors. that this gap is beginning to narrow. The incidence in Asian Metastatic lesions to the kidney (secondary neoplasms) Americans and Pacific Islanders is half that of their white and occur in 7% to 20% of patients with cancer at autopsy.1-3 African American counterparts.5 Renal cell carcinoma occurs These secondary lesions are very rare in the absence of pro- predominantly in the sixth to eighth decades; it is uncommon gression of the primary neoplasm.4 in patients younger than 40 years of age and rare in children.9-11 This chapter focuses on the epidemiology, pathology, The incidence of renal cell carcinoma has steadily increased genetics, clinical and radiographic presentation, staging meth- over time. Between 1975 and 1995 in the United States the ods, and surgical and systemic management of primary renal incidence rates per 100,000 person-years increased by 2.3%, neoplasms. A brief description of the biology and manage- 3.1%, 3.9%, and 4.3% annually for white men, white women, ment of the less common tumors as well as evaluation of sus- African American men, and African American women, respec- pected metastatic disease is also presented. tively.8 Mortality rates are equivalent for whites (6.2 males and 2.8 females per 100,000 persons) and African Ameri- cans (6.1 and 2.7, respectively), whereas Asian American Renal Cell Carcinoma and Pacific Islanders have the lowest mortality rates (2.4 and 1.2, respectively).5 American Indians and Alaskan Natives Epidemiology have an increased incidence of cancer of the kidney and an alarmingly high mortality rate (9.3 males and 4.3 females per In 2009, it was estimated that renal cell and renal pelvic can- 100,000 persons).5,12 cer would be newly diagnosed in 58,000 people in the United The overall incidence in the United States for all races has States and that almost 13,000 people would die of the disease.5 risen at a rate that is threefold higher than the mortality rate. Renal cell carcinoma represents 3.9% of all U.S. cancers and Since 1950, there has been a 126% increase in the incidence 1508 Chapter 40 Renal Neoplasia 1509 accompanied by a 37% increase in annual mortality.13,14 The in 10% and multifocal in 27.3%, and the histologic subtypes 5-year survival rate of patients with a diagnosis of kidney can- were divided between clear cell renal carcinomas (60%) and cer has improved from 34% for those receiving this diagnosis papillary renal cell carcinomas (40%). These cancers were all in 1954 to 67% for those receiving this diagnosis in 2004.5 staged as T1 disease, and none of the tumors was seen on The proportion of renal cell carcinomas discovered inciden- preoperative imaging. An increased incidence of sarcomatoid tally increased from approximately 10% in the 1970s to 60% features was not seen in this group, possibly because of the in 1998.14 In addition, at one major institution, the percentage benign indications for extirpation. of organ-confined tumors increased from 47% in 1989 to 78% Although most renal cell carcinomas are sporadic, factors in 1998.15 An examination of contemporary data shows that suggesting a hereditary cause include the occurrence of the the mortality rate decreased by approximately 5% between disease in first-degree relatives,30-33 onset before the age of 1990 and 2005.5 There is a continued stage migration, with 40, and bilateral or multifocal disease.34 Several kindreds with stage 1 disease increasing from 43% to 57% between 1993 and familial clear cell carcinoma have been identified that have con- 2004, whereas stage 2 and 3 disease showed a statistically sig- sistent abnormalities on the short arm of chromosome 3.35-38 nificant decline. The incidence of stage 4 disease has remained Other kindreds with papillary tumors have been identified stable over this time same period.16 with different genetic abnormalities,39 which suggests that Numerous environmental and clinical factors have been these tumors represent distinct disease entities. Although the implicated in the etiology of renal cell carcinoma.17 These true prevalence of hereditary renal cell carcinoma is unknown, include tobacco use; occupational exposure to toxic compounds it is estimated that hereditary carcinomas make up 3% to 5% such as cadmium, asbestos, and petroleum by-products; obe- of all renal cell carcinomas.40 A more detailed discussion of sity; acquired polycystic disease of the kidney (typically associ- the molecular biology of renal cell carcinoma is provided in a ated with dialysis); and analgesic abuse nephropathy. Cigarette later section. smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one third of all cases.18-20 The risk of developing kidney cancer in patients with acquired polycystic Pathology and Cytogenetics disease of the kidney has been estimated to be 30 times greater than in the general population.21 In particular, it is estimated Renal cell carcinoma was first reported by Konig in 1826. In that acquired cystic disease develops in 20% to 90% of patients 1883, Grawitz hypothesized on histologic grounds that renal receiving long-term dialysis, depending on the duration of cell carcinomas arose from rests of adrenal tissue within the dialysis,22 and that renal cell carcinoma develops in between kidney.41 Although immunohistologic and ultrastructural anal- 3.8% and 4.2% of these patients.23 Patients with large cysts yses currently point toward the proximal renal tubule as the appear to be an increased risk for malignant transformation. true cell of origin,42 the term hypernephroma continues to be The carcinomas are multiple and bilateral in approximately incorrectly applied to these cancers. one half the cases, a finding that is consistent with the diffuse Renal cell tumors occur with equal frequency in the right nature of the underlying disease.24 The prolonged ingestion and left kidney and are distributed equally throughout the of analgesic combinations, particularly compounds contain- kidney.43 The average diameter is about 7 cm, but tumors have ing phenacetin and aspirin, can lead to chronic renal failure. ranged from less than 2 cm to more than 25 cm in diameter. Such patients are at increased risk of renal pelvic tumors and Previously, renal lesions smaller than 2 to 3 cm were incor- possibly renal cancer, although the latter association remains rectly considered to be benign adenomas. Such distinctions controversial.25-27 Because of its carcinogenic properties, phen- between benign and malignant tumors are no longer made on acetin was removed from the U.S. marketplace by the U.S. the basis of size but rather according to fundamental histo- Food and Drug Administration (FDA) in 1983 and later from logic criteria. Therefore, from a practical standpoint, all solid European markets. renal masses require resection or biopsy for accurate histologic An enhanced risk of renal cell carcinoma has been observed diagnosis. Improved percutaneous biopsy techniques have a in patients with certain inherited disorders, which implicates role in the management of renal masses, but are definitively various genetic abnormalities in its etiology. These disorders less accurate than extirpation in providing pathologic and his- include von Hippel–Lindau syndrome, hereditary papillary tologic information. renal cancer, hereditary leiomyoma renal cancer syndrome, Renal cell carcinomas have historically been classified and Birt-Hogg-Dube syndrome. In addition patients with according to cell type (clear, granular, spindle, or oncocytic) tuberous sclerosis and hereditary polycystic kidney disease, and growth pattern (acinar, papillary, or sarcomatoid).43 This although they do not have a dramatically increased incidence classification has undergone a transformation to more accu- of renal cancer, can have cancers with unique features. rately reflect the morphologic, histochemical, and molecu- Hereditary polycystic kidney disease (autosomal dominant lar features of different types of adenocarcinomas (Table polycystic kidney disease, or ADPKD) has a long-debated 40-1).44-46 Based on research studies, five distinct subtypes association with renal cancer; however, when renal cancer have been identified. These include clear cell (conventional), does occur in patients with this disorder, it typically displays chromophilic (papillary), chromophobic, oncocytic, and col- a number of distinct clinical characteristics.28 The tumors are lecting duct (Bellini duct) tumors. Each of these tumors has a more often bilateral at presentation, multicentric, and with unique growth pattern, cell of origin, and cytogenetic charac- sarcomatoid features when symptomatic or advanced. A recent teristics. Table 40-1 summarizes this information, which more analysis of 89 nephrectomy specimens from ADPKD patients accurately reflects the increased knowledge of the molecular who underwent extirpation for nononcologic indications and genetic abnormalities of these lesions than did the ear- reported an increased risk of renal cancer.29 Specifically, over- lier classification.45 Sarcomatoid variants of almost all of the all incidence was increased to 8.3%. The tumors were bilateral aforementioned histologic subtypes have been described and 1510 Section V Disorders of Kidney Structure and Function

TABLE 40-1 Pathologic Classification of Renal Cell Carcinoma

Cytogenetic Characteristics

CARCINOMA TYPE GROWTH PATTERN ­(INCIDENCE) CELL OF ORIGIN MAJOR MINOR Clear cell Acinar or sarcomatoid (75%-85%) Proximal tubule −3p +5, +7, +12, −6p, −8p −9, −14q, −Y Chromophilic* Papillary or sarcomatoid (12%-14%) Proximal tubule +7, +17, −Y +12, +16, +20, −14 Chromophobic Solid, tubular, or sarcomatoid (4%-6%) Intercalated cell of cortical Hypodiploidy — ­collecting duct Oncocytic Typified by tumor nests (2%-4%) Intercalated cell of cortical Undetermined† — ­collecting duct Collecting duct Papillary or sarcomatoid (1%) Medullary collecting duct Undetermined† — *These tumors were previously classified as papillary tumors. †This classification is based on the work of Storkel and van den Berg.45 represent a dedifferentiation (poor differentiation) of the indi- oncocytomas nor collecting duct tumors have been associated vidual subtype.47 with a consistent pattern of genetic abnormalities. Clear cell or conventional renal cell carcinomas make up Medullary renal cell carcinoma is a rare aggressive variant 75% to 85% of tumors and are characterized by a deletion or usually seen in individuals with sickle cell trait.65 This entity functional inactivation in one or both copies of chromosome was designated by Davis and colleagues as the “seventh sickle arm 3p.48 A higher nuclear grade (Fuhrman classification) or cell nephropathy.”65 Histologically, a variety of growth pat- the presence of a sarcomatoid pattern correlates with a poorer terns have been described, including reticular, solid, tubular, prognosis.49,50 trabecular, cribriform, sarcomatoid, and micropapillary.66 Little Chromophilic or papillary carcinomas (synonymous) make is known about the cytogenetics of this tumor. Gene expres- up 10% to 15% of renal cancers. In hereditary disease papil- sion profiling has shown clustering more closely associated lary carcinomas are multifocal and bilateral, and commonly with urothelial carcinoma than with renal cell carcinoma.67,68 present as small tumors.51 These tumors also appear to arise Classification and further characterization of this rare but from the proximal tubule but are both morphologically and lethal entity will require further molecular and pathologic genetically distinct from clear cell carcinomas. Although these research with a larger collection of specimens. tumors often have a low stage at presentation and are thus The Xp11.2 translocation carcinoma was first described attributed a more favorable prognosis,51,52 in advanced stages, in 1991 by Tomlinson and colleagues.69 This translocation they can be as aggressive as clear cell lesions.53 In recent years, results in the fusion of a novel gene, designated RCC17, at the class of papillary renal cell carcinoma has been subdivided chromosome band 17q25 to the gene for transcription factor into papillary type 1 and type 2.54 This differentiation has for immunoglobulin heavy-chain enhancer 3 (TFE3) located been based on histologic appearance54 and has been validated on chromosome band Xp11.70 These tumors usually occur in through microarray analysis of molecular markers.55 Subtyp- children and young adults, appearing at a median age of 20 ing permits identification of an independent prognostic fac- years, and account for at least one third of carcinomas seen tor, because patients with type 2 papillary renal cell carcinoma in childhood and adolescence.67 Tumor cells are described as have a worse outcome even when stratified by TNM stage.54,55 having voluminous clear cytoplasm and bulging distinct cell Chromophobe carcinomas make up about 4% of all renal borders, reminiscent of soap bubbles. The architecture is pre- cell carcinomas. Histologically, they are composed of sheets dominantly solid, tubular, acinar, or alveolar, with areas with a of cells that are uniformly darker cells than those of the usual pseudopapillary appearance.71 Transcription factor 3 is a sen- clear cell carcinoma, with a peripheral eosinophilic granularity. sitive and specific marker for translocation carcinomas with a These cells lack the abundant lipid and glycogen characteris- sensitivity ranging from 82% to 97.5%.67 Although relatively tic of the clear cell renal cell carcinoma, and are believed to indolent, these tumors are refractory to systemic therapy and arise from the intercalated cells of the renal collecting ducts.56-58 respond only to aggressive surgical resection. They have a hypodiploid number of chromosomes, but also Renal oncocytomas are infrequent but increasingly recog- no 3p loss.59-61 These tumors are usually well circumscribed nized benign tumors.72-74 Oncocytomas are composed of a and generally have an excellent prognosis. As a group, chro- pure population of oncocytes—large, well-differentiated neo- mophobe renal cell carcinomas tend to present at lower stages plastic cells with intensely eosinophilic granular cytoplasm. and grades, yet once metastatic, chromophobe carcinomas are The cytoplasm of these cells is packed with mitochondria, highly refractory to therapy and have a prognosis equivalent or which leads to their histologic appearance. Immunohisto- worse than that of clear cell carcinomas.62 chemical studies suggest that oncocytomas probably also arise Collecting duct (Bellini duct) tumors are also very rare but from the intercalated cells of the distal collecting tubules.73 are frequently very aggressive in behavior.63 These tumors The pathologic differentiation of a typical renal oncocytoma are located in the renal medulla and pelvis and thus usually from an oncocytic renal cell carcinoma can be difficult. Some present with gross hematuria. In contrast to clear cell carci- series suggest that 3% to 7% of solid renocortical tumors pre- nomas, these tumors produce mucin and react with antibod- viously classified as renal cell carcinomas are in fact oncocyto- ies to both high-molecular-weight and low-molecular-weight mas.72 Grossly, oncocytomas are generally well encapsulated keratins.64 Sarcomatoid variants have also been noted. Neither and are only rarely invasive. Larger oncocytomas frequently Chapter 40 Renal Neoplasia 1511

Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma 75% 5% 10% 5% 5% Gene VHL Met FH BHD FIGURE 40-1 Human renal epithelial neoplasms. Histologic classification of renal tumors and incidence. The associated gene for inherited neoplasms is listed, although these genes can also be mutated in sporadic cases (especially the von Hippel–Lindau gene in clear cell carcinomas). (From Linehan WM, Walther MM, Zbar B: The genetic basis of cancer of the kidney, J Urol 170:2163, 2003.)

have a stellate central fibrous scar, which is often visible on their ability to form tumors in nude mice xenograft assays, preoperative radiologic studies. Renal oncocytomas almost which supports the role of the VHL gene as a renal cancer invariably have a benign clinical behavior and are rarely asso- tumor suppressor gene.79 ciated with metastases, even when the primary tumor is very Tumors associated with VHL mutations (including the large. Nephrectomy is usually the treatment of choice for large hereditary tumors in von Hippel–Lindau syndrome and a renal masses regardless of type, but the possibility of oncocy- majority of the sporadic cases of clear cell renal cell carci- toma should be considered with incidentally discovered small noma80) are typically hypervascular and occasionally lead to renal masses or tumors in a solitary kidney. the overproduction of red blood cells (polycythemia).81 This is due to overproduction of vascular endothelial growth fac- tor (VEGF) and erythropoietin, respectively. Working from Molecular Biology and Hereditary Disorders the knowledge that the two genes encoding these proteins are hypoxia inducible, several groups went on to show that Much of the recent success in developing therapies for renal cells lacking the protein encoded by VHL are unable to sup- cell carcinoma has arisen out of an improved understanding press the accumulation of hypoxia-inducible factors, including of the molecular biology of clear cell renal carcinoma and its VEGF, under well-oxygenated conditions.82-84 The hypoxia- highly prevalent mutation in VHL, the von Hippel–Lindau inducible factor (HIF) family of transcription factors is at gene. Only 4% of cases of renal cell carcinoma are familial, the center of maintaining oxygen homeostasis and regulates yet elucidation of the genetic mutations involved in hereditary a variety of hypoxia-inducible genes. HIF is a heterodimer renal cell carcinoma has led to targeted therapies that ben- composed of HIF-α and HIF-β subunits.85 Although the efit the majority of sporadic cases Figure( 40-1).75 Cloning of HIF-β subunit is constitutively expressed, HIF-α is normally the VHL gene in 1993,76 and the subsequent functional and degraded in the presence of oxygen and accumulates only structural characterization of the gene product,77 have con- under hypoxic conditions.86,87 A 200–amino acid oxygen- tributed greatly to our understanding of the genetics of this dependent degradation domain lies within the central region disease and of renal cell carcinoma in general. of HIF1-α.88,89 This region is sufficient to target HIF for Von Hippel–Lindau syndrome is transmitted in an auto- degradation by the ubiquitin-proteasome pathway in the pres- somal dominant fashion and is characterized by a predispo- ence of oxygen89-91 (Figure 40-2). At present, several dozen sition to various neoplasms, including renal cell carcinoma HIF target genes have been identified, including the genes (with clear cell histology), renal cysts, retinal angiomas, spi- for VEGF, platelet-derived growth factor (PDGF), and trans- nocerebellar hemangioblastomas, pheochromocytomas, and forming growth factor-α. Their protein products play critical pancreatic carcinomas and cysts.78 Renal cysts are frequently roles in cellular and systemic physiologic responses to hypoxia, multiple and bilateral. including glycolysis, erythropoiesis, angiogenesis, and vascular Renal cell carcinoma develops in about a third of all remodeling.85 patients and is a major cause of death in patients with von Papillary renal cell carcinoma possesses unique genetic Hippel–Lindau syndrome. Tumor development in this setting features. In hereditary cases, papillary renal cell carcinoma is is linked to somatic inactivation of the remaining wild-type characterized by the formation of multiple bilateral tumors allele. Moreover, biallelic VHL inactivation due to somatic with trisomy of chromosomes 7 and 17.92 The hereditary mutations and/or hypermethylation is observed in more than papillary renal cell carcinoma gene was identified on chro- 50% of sporadic clear cell carcinomas. Restoration of VHL mosome bands 7q31.1-34, and germline missense mutations function in VHL–/– renal cell carcinoma cell lines suppresses in the tyrosine kinase domain of the c-Met proto-oncogene 1512 Section V Disorders of Kidney Structure and Function

Normoxia Hypoxia Proline hydroxylase Asparagine hydroxylase No hydroxylation + + of HIF-α Oxygen Oxygen HIF- Cytoplasm OH OH α HIF-β HIF-α Normal VHL Mutated VHL protein protein Translocation Ub of HIF to HO Ub Ub nucleus HIF Ub Ub Elongin VHL HO -α HO C protein Rbx HIF-α Nucleus HO cul2 HIF-α HIF-β Elongin B HIF-α ubiquitination by VHL protein SCF Proteasome p300 complex

HRE VEGF Destruction of Cytoplasm HIF-mediated transcriptional activation HIF-α

FIGURE 40-2 Von Hippel–Lindau (VHL) gene and hypoxia-inducible factors (HIFs). The role of VHL and HIFs in normoxic and hypoxic conditions in the normal cell (VHL+/– or VHL+/+). Mutations in the VHL protein cause constitutive expression of HIFs and thus lead to unregulated expression of HIF-inducible pathways, which produces the effects on the left under all conditions. (From Cohen HT, McGovern FJ: Renal-cell carcinoma, N Engl J Med 353:2477, 2005.) were detected in several families with hereditary papillary pneumothorax in association with lung cysts, and a predisposi- renal cell carcinoma.93 In sporadic papillary renal cell car- tion to kidney neoplasms, which may be chromophobe renal cinoma, mutations of the c-Met proto-oncogene have been cancers, oncocytomas, or tumors with features of both (termed detected in 13% of papillary renal cell carcinoma patients mixed oncocytic).100-102 The characteristic skin lesions, fibrofol- with no family history of kidney cancers.94 These mutations liculomas (hamartomas of the hair follicle), consist of multiple are oncogenic and create a constitutively active, ligand- painless dome-shaped papules, 2 to 3 mm in diameter, that independent autophosphorylation of c-Met. These data develop on the skin of the head and neck after age 30. The may underestimate the significance of alterations in c-Met, affected gene, folliculin, was described in 2002.103 The iden- because other mutations, chromosomal duplications (e.g., tification of loss-of-function mutations in the folliculin gene trisomy 7), and epigenetic events likely increase the fre- (localized to chromosome arm 17p) suggests that it functions quency of c-Met activation. as a tumor suppressor gene.103 A high frequency of somatic The disorder that results from autosomal dominant muta- mutations has been detected in renal tumors from patients tions in the fumarate hydratase (FH) gene is known as mul- with germline mutations in the BHD gene, which suggests tiple cutaneous and uterine leiomyomas (MCUL). Overlapping that malignancy results from the inactivation of both cop- with this syndrome is another autosomal dominant condition, ies of the gene.104 Mutations in the folliculin gene do not hereditary leiomyomatosis and renal cell cancer syndrome appear to play a role in sporadic renal cell carcinoma.105,106 (HLRCC). This syndrome also results from mutations in Folliculin is thought to regulate the activity of mammalian the FH gene. Autosomal recessive FH gene mutations also target of rapamycin (mTOR) through complex mechanisms underlie the disorder fumarate deficiency. This condition is that are yet to be delineated.107,108 mTOR has an integral associated with progressive encephalopathy, cerebral atrophy, role in pathways relating to the response to hypoxia (HIF), seizures, hypotonia, and renal developmental delay. Heterozy- autophagy, and independent gene expression regulation gous carriers of FH deficiency occasionally (but only rarely) (Figure­ 40-3).109 exhibit leiomyomas.95 HLRCC is characterized by cutaneous Tuberous sclerosis is an autosomal dominant condition leiomyomas, uterine fibroids, and renal carcinomas, which are associated with mutations in the tuberous sclerosis complex predominantly single, although multiple and bilateral tumors genes (TSC1 and TSC2).110,111 The TSC1/TSC2 complex have been reported.96,97 The renal tumors are aggressive, and mediates multiple inputs (growth factor signals, amino they may metastasize and lead to death in patients in their acids, and adenosine triphosphate) that regulate mTOR thirties. Although originally classified as hereditary papillary activity and thus cell growth.107 Affected individuals typi- renal cell carcinoma type 2, the unique cytomorphologic fea- cally manifest facial angiofibromas, show cognitive impair- tures of the renal tumors, as well as the finding of mutations ment, and develop renal angiomyolipomas.112 Although the in the FH gene in affected families, suggest that this may be a incidence of renal cancer is only slightly increased, such distinct entity.98,99 cancers have been associated with biallelic loss of the TSC2 Birt-Hogg-Dube syndrome is characterized by prominent gene, which implicates this pathway in the pathogenesis of cutaneous manifestations, the development of spontaneous renal cancer. Chapter 40 Renal Neoplasia 1513

VHL PTEN

EGFR TGF-α

Temsirolimus TSC1 TSC2 Renal-cell HIF carcinoma Sirolimus

FKBP12 VEGF PDGFβ mTOR

Angiogenesis

VEGFR2 PDGFRβ

elF4E S6K Sorafenib

Protein translation Sunitinib

FIGURE 40-3 Mammalian target of rapamycin (mTOR) integration with hypoxia-inducible factors. (From Brugarolas J: Renal-cell carcinoma—molecular pathways and therapies, N Engl J Med 356:185, 2007.)

Clinical and Laboratory Features had high-grade tumors, 5.7% had nodal metastases, and 13% had distant metastases. Cancer-specific mortality in this group The propensity of renal cell carcinoma to present with diverse of patients with incidentally discovered renal cancers was and often obscure signs and symptoms has led to its being 14.4% (525 patients). This is the largest series of incidentally labeled the internist’s tumor. The clinical presentation of renal discovered renal tumors.114,116 cell carcinoma can be extremely variable. Many tumors are Currently, most patients diagnosed with renal cell carci- clinically occult, which leads to delayed diagnosis, when a more noma are asymptomatic. In early reports of patients under- advanced and symptomatic stage is common. Indeed, 25% of going nephrectomy for renal cell carcinoma,117,118 the most individuals have distant metastases or locally advanced disease common presenting symptom was hematuria (which occurred at the time of presentation.46 By contrast, other patients har- in up to 59% of patients), followed by abdominal mass, pain, boring renal cell carcinoma experience a wide array of symp- and weight loss. In contemporary series these symptoms are toms or have a variety of abnormalities on laboratory tests, less common at presentation and up to 60% of patients are even in the absence of metastatic disease. The current clinical asymptomatic. paradigm of renal cell carcinoma is the ever-increasing inci- The classic triad of flank pain, hematuria, and palpable dental detection of renal cancer through the use of abdominal abdominal renal mass occurs in fewer than 10% of patients and imaging. Incidentally discovered renal tumors are estimated when present it strongly suggests advanced disease.114,115,117 to represent from 40% to 60% of all pathologically diagnosed Hematuria, gross or microscopic, is usually observed only renal cell carcinomas. This has led to the recharacterization if the tumor has invaded the collecting system. Gibbons of the disease as the radiologist’s tumor. Based on an analysis and associates reported the absence of gross or microscopic of the Surveillance, Epidemiology, and End Results (SEER) hematuria in 63% of their patients with proven renal cell database for the period 1998 through 2002, renal tumor size carcinoma.118 Scrotal varicocele was reported in up to 11% decreased from 6.7 cm to 5.8 cm with a concordant increase in of patients.119 Most varicoceles due to an obstructing retro- the age-adjusted incidence in renal cell carcinoma.113 peritoneal mass are left-sided and typically fail to empty in The presence or absence of local or systemic symptoms of the recumbent position (grade 3 varicocele). Varicoceles typi- renal cell carcinoma has been shown to correlate with TNM cally result from obstruction of the gonadal vein at its entry stage and grade, and, most importantly, is an independent point into the left renal vein by tumor thrombus. Varicocele variable (on multivariate analysis) predicting overall progno- development in an adult should always raise the possibility of sis.114,115 Although the presence of symptoms strongly cor- an associated neoplasm within the kidney. In addition, infe- relates with prognosis, a significant portion of incidentally rior vena cava involvement by tumor thrombus can produce discovered (asymptomatic) tumors can lead to cancer-specific a variety of clinical manifestations, including ascites; hepatic mortality. In a recent study of 3912 patients who had been sur- dysfunction, possibly related to Budd-Chiari syndrome; pul- gically treated for incidentally discovered renal masses, 3650 monary emboli; and bilateral lower extremity edema. patients (90%) were diagnosed with a primary renal malig- Often, symptoms or signs related to metastases prompt nancy, of which 28.3% had locally advanced tumors, 27.6% medical evaluation.120 Most patients (75%) presenting with 1514 Section V Disorders of Kidney Structure and Function metastatic disease have lung involvement (most common site Radiologic Diagnosis of metastasis). Other common sites, from most to least com- mon, include lymph nodes, bone, liver, adrenal gland, contra- The prognosis for patients whose tumors were diagnosed inci- lateral kidney, and brain. Patients may present with pathologic dentally is more favorable than that for patients whose tumors fractures, cough, hemoptysis, dyspnea related to pleural effu- caused symptoms, partly because the former group consists of sions, or palpable nodal masses. Clear cell pathologic features patients with smaller tumors that tend to be confined to the in the metastatic lesion and/or the finding of a renal mass on kidney.116,138 For patients with symptoms suggestive of renal staging computed tomographic (CT) scan usually leads to the cell carcinoma, numerous radiologic approaches are available proper diagnosis. for the evaluation of the kidney. With the advent of CT, mag- A number of patients with renal cell carcinoma experience netic resonance imaging (MRI), and sophisticated ultraso- systemic symptoms or paraneoplastic syndromes.121-123 Fever nography, many of the more invasive procedures of the past is one of the more common manifestations of renal cell carci- are largely of historical interest and are rarely used in clinical noma, occurring in up to 20% of patients.124 It is usually inter- practice. Although intravenous pyelography remains useful in mittent and is often accompanied by night sweats, anorexia, the evaluation of hematuria, CT and ultrasonography are the weight loss, and fatigue. Secondary amyloidosis has been mainstays of evaluation of a suspected renal mass. As seen on reported in as many as 3% to 5% of patients.121 Anemia is also CT, the typical renal cell carcinoma has a heterogeneous den- common in patients with renal cell carcinoma and frequently sity and enhances with contrast (Figure 40-4).139,140 precedes the diagnosis by several months.119,123,125,126 Hepatic dysfunction in the absence of metastatic disease was noted and labeled Stauffer’s syndrome.127 This syndrome, manifested by abnormal results on liver function tests (particularly elevated levels of alkaline phosphatase, α2-globulin, and transaminases) and prolonged prothrombin time, has been reported to occur in up to 7% of patients with renal cell carcinoma. Hepatic dysfunction frequently occurs in association with fever, weight loss, and fatigue. The syndrome likely results from the over- production of cytokines, such as granulocyte-macrophage colony-stimulating factor or possibly interleukin-6, by the tumor.128,129 Even though the laboratory abnormalities and other symptoms often revert to normal after nephrectomy, this syndrome is associated with an elevated risk of recurrence and an overall poor 5-year survival. Hormones produced by renal cell carcinomas include parathyroid-like hormone, gonadotropins, placentolactogen, adrenocorticotropic hormone–like substance, renin, erythro- poietin, glucagon, and insulin.130 Several of these have been associated with specific paraneoplastic phenomena. Erythro- A cytosis, defined as a hematocrit value greater than 55 mL/dL, occurs in 1% to 5% of patients with renal cell carcinoma and appears to be due to constitutive erythropoietin production by renal cancer cells. Hypercalcemia occurs in up to 15% of all patients with renal cell carcinoma. The presence of hypercalcemia has been defined as an independent negative prognostic factor in patients with metastatic renal cell carcinoma and can be asso- ciated with lytic bone metastases.131 Hypercalcemia can occur in the absence of osseous metastases, and the ectopic pro- duction of parathyroid hormone–related peptide by the pri- mary tumor has been documented in these cases.132 In other patients, elevated prostaglandin levels have been implicated in the development of hypercalcemia, which may respond to indomethacin treatment.133 Long-acting bisphosphonates such as pamidronate or zoledronic acid are the treatment of choice in renal cell carcinoma patients with metastatic disease and hypercalcemia.134 These agents may be especially beneficial B in patients with lytic bone metastases, in whom such therapy might also reduce the incidence of pathologic fractures.134,135 FIGURE 40-4 A, Computed tomographic (CT) scan revealing massive The concurrent use of antiangiogenic therapies and bisphos- renal cell carcinoma arising from the right kidney (arrow) and pushing the phonates has been found to increase the risk for osteonecrosis kidney anteriorly. Note the distortion of the collecting system. B, CT scan 136,137 for the same patient demonstrates tumor thrombus (arrow) in the center of of the jaw compared with bisphosphonate therapy alone. the inferior vena cava. (From Richie JP, Garnick MB: Primary renal and ure- This finding will prompt further investigation into the risks of teral cancer, in Rieselbach RE, Garnick MB [editors]: Cancer and the kidney, concurrent usage. Philadelphia, 1982, Lea & Febiger, p 662.) Chapter 40 Renal Neoplasia 1515

Cystic renal masses are graded based on a long-standing benefits of imaging.146 Currently used gadolinium-based classification system first introduced by Bosniak in 1986 and MRI contrast agents have an FDA-required black box warn- since updated and validated in numerous studies with surgical ing due to the risk of inducing nephrogenic systemic fibrosis. pathologic assessment.141 The Bosniak renal cyst classifica- Renal arteriography is rarely employed in current practice, tion has been classically applied in evaluation of cystic masses having been supplanted by magnetic resonance angiography using contrast-enhanced CT. Ultrasonography, although less and CT with three-dimensional reconstruction (Figure 40-5) sensitive than CT in detecting renal masses,142 can be of use to delineate vascular anatomy and assist in surgical plan- (albeit limited) in characterizing simple or minimally com- ning.147 MRI with gadolinium is superior to CT for evaluat- plex renal cysts—those containing one or two hairline thin ing the inferior vena cava if tumor extension into this vessel septa.143 is suspected.148 MRI is also a useful adjunct to ultrasonogra- Cystic renal masses are characterized based on wall thick- phy in the evaluation of renal masses if radiographic contrast ness; presence or absence, number, and thickness of septa; cannot be administered because of allergy or inadequate renal enhancement of septa and/or thickened wall; and presence function. or absence of solid enhancing components (Table 40-2).144 Although most solid renal masses are renal cell carcino- Presence of malignancy correlates with the Bosniak classifi- mas, some benign lesions complicate the diagnosis. The most cation: in category I and II lesions, malignancy is very rare; common of these rare tumors are angiomyolipomas (renal in category IIF lesions the malignancy rate is approximately hamartomas). Unless very small, angiomyolipomas are readily 5% to 15%; in category III lesions it is 30% to 60%; and in distinguishable from renal cell carcinoma by the finding of a category IV lesions it is more than 90%. Use of MRI in con- distinctive fat density on CT.149 However, given that several junction with a modified Bosniak system for evaluating cystic reports have shown that macroscopic fat can be detected within masses has been studied and is an acceptable alterative when renal cell carcinomas, it may no longer be possible to dismiss the patient cannot undergo CT scanning with contrast.145 all fat-containing lesions identified on CT as benign.150 Fat- In some patients unable to undergo contrast-enhanced CT poor angiomyolipomas have also been described that are very due to moderate to severe chronic renal insufficiency, the risk difficult to distinguish from renal cell carcinomas on preop- of nephrogenic systemic fibrosis may outweigh the potential erative imaging and thus frequently must be resected to rule out a malignant neoplasm.151 As mentioned previously, renal oncocytomas have been described to present on CT as a cen- tral stellate scar within a homogeneous, well-circumscribed TABLE 40-2 Bosniak Classification of Renal Cysts CATEGORY DESCRIPTION I A benign simple cyst with a hairline thin wall that does not contain septa, calcifications, or solid compo- nents. It measures water density and does not enhance. II A benign cyst that may contain a few hairline thin septa in which “perceived” enhancement may be pres- ent. Fine calcification or a short segment of slightly thickened calcification may be present in the wall or septa. Uniformly high attenuation lesions <3 cm (so-called high-density cysts) that are well marginated and do not enhance are include in this group. Cysts in this category do not require further evaluation. IIF (F for Cysts that may contain multiple hairline thin septa follow-up) or minimal smooth thickening of their wall or septa. Perceived enhancement of their septa or wall may be present. Their wall or septa may contain calcification that may be thick and nodular, but no measurable con- trast enhancement is present. These lesions are gener- ally well marginated. Totally intrarenal nonenhancing high-attenuation renal lesions >3 cm are also included in this category. These lesions require follow-up ­studies to prove benignity. III “Indeterminate” cystic masses that have thickened irregular or smooth walls or septa in which measurable enhancement is present. These are surgical lesions, although some will prove to be benign (e.g., hemor- rhagic cysts, chronic infected cysts, multiloculated cystic nephroma), and some will be malignant, such as cystic renal cell carcinoma and multiloculated cystic renal cell carcinoma. IV These are clearly malignant cystic masses that can have all the criteria of category III, but also contain enhanc- FIGURE 40-5 Three-dimensional reconstruction of 2-mm computed ing soft tissue components adjacent to, but indepen- tomographic slices for a patient with a venous tumor thrombus from renal dent of, the wall of septum. These lesions include cell carcinoma. (From Hallscheidt PJ, Fink C, Haferkamp A, et al: Preopera- cystic carcinomas and require surgical removal. tive staging of renal cell carcinoma with inferior vena cava thrombus using From Israel GM, Bosniak MA: An update of the Bosniak renal cyst classification multidetector CT and MRI: prospective study with histopathological cor- system, Urology 66:484, 2005. relation, J Comput Assist Tomogr 29:64, 2005.) 1516 Section V Disorders of Kidney Structure and Function

72 solid mass. This finding is nonspecific, however, and can- TABLE 40-3 Sites and Frequencies of Metastases in Renal not be used to clinically exclude the diagnosis of clear cell Cell Carcinoma carcinoma. SITE INCIDENCE (%) The role of radionucleotide bone scanning in the initial diagnosis and preoperative staging of renal cell carcinoma is Lung 50-60 unclear. Although bone scanning demonstrates high sensitiv- Lymph node 30-40 ity in the detection of osteoblastic metastases, renal cell carci- Bone 30-40 noma usually produces osteolytic lesions that may be missed by bone scan. Atlas and colleagues suggested that a combination Liver 30-40 of bone pain on presentation plus an elevated serum alkaline Adrenal 20 phosphatase level were comparable to bone scan in evaluat- Opposite kidney 10 ing patients with renal cell carcinoma.152 Koga and colleagues demonstrated bone scan to have a sensitivity of 94% and spec- Brain 5 ificity of 86%, with a low yield in patients with earlier-stage From McDougal WS, Garnick M: Clinical signs and symptoms of kidney cancer, in Vogelzang NJ, Scardino PT, Shipley WU, et al (editors): Comprehensive textbook of primary tumors. They recommended omitting bone scanning genitourinary oncology, Baltimore, 1996, Williams & Wilkins. in patients with T1 to T3a tumors and no bone pain.153 A number of studies have been published evaluating the role of fluorine 18 2-fluoro-2-deoxy-D-glucose positron emis- Staging and Prognosis sion tomography (FDG-PET) for the detection and manage- ment of renal cell carcinoma primary and metastatic lesions. After the presumptive diagnosis of renal carcinoma has been Kang and colleagues studied 66 patients with primary renal made, attention must be turned to the delineation of the carcinoma and reported 60% sensitivity of FDG-PET for the extent of involvement of regional and distant metastatic sites. primary renal mass compared with 91.7% for CT, whereas the Renal carcinomas can grow locally into very large masses and specificity of both was 100%.154 Other studies have shown invade through surrounding fascia into adjacent organs. The sensitivity rates as low as 31%.155,156 FDG-PET is unlikely to most common sites of metastases are the regional lymphatics, be used as a stand-alone study in the evaluation of a patient lungs, bone, liver, brain, ipsilateral adrenal gland, and contra- with a solid renal mass. lateral kidney. The frequency of metastases to these sites is In the restaging and follow-up of renal cell carcinoma, listed in Table 40-3.160,161 Metastases to unusual sites, such as FDG-PET scanning provides information that is comple- the thyroid gland, pancreas, mucosal surfaces, skin, and soft mentary to that of conventional imaging and can alter manage- tissue, are not uncommon in this disease. CT of the abdo- ment decisions. The sensitivity and specificity of FDG-PET men is the principal radiologic tool for defining the local and in detecting recurrent or metastatic disease are better than the regional extent of a renal cell carcinoma. The accuracy of CT sensitivity and specificity when it is used for the evaluation in staging renal cell carcinoma is close to 90%.162 In clinically of primary lesions.155 In this disease process, the sensitivity is advanced disease, staging evaluation should also include CT significantly lower when metastatic lesions smaller than 1 cm of the chest and bone scanning. Approximately 2% of patients are evaluated. False-negative and false-positive readings are have bilateral tumors and 25% to 30% of patients have overt significant, and FDG-PET is not a substitute for contrast- metastases at initial presentation.160 If metastatic disease is enhanced CT in the detection and follow-up of metastatic suspected on the basis of staging studies, pathologic confirma- renal cell carcinoma. tion is required before therapy is contemplated. It is often more An additional application of PET involves the use of anti- useful to perform a biopsy of a metastatic site rather than the bodies such as the chimeric monoclonal antibody chimeric primary tumor due to the presence of necrosis in the primary G250 to carbonic anhydrase IX.156 Carbonic anhydrase IX is lesion. CT or ultrasound-guided percutaneous needle biopsy expressed in more than 90% of clear cell renal ­carcinomas.157,158 of a suspected lung, liver, lymph node, adrenal, or sometimes Iodine 124–labeled antibody chimeric G250 PET had a sen- even skeletal metastasis frequently yields diagnostic material. sitivity of 94% in correctly identifying clear cell renal carci- The TNM staging system for renal cell carcinoma (Table nomas. G250 PET also correctly predicted all non–clear cell 40-4) has largely supplanted the previously used system of Rob- histologic types. G250 PET is currently being evaluated in son. This system was modified in 2002 with the division of T1 a phase III clinical trial. Despite the encouraging result for tumors into T1a for tumors equal to or less than 4 cm in diameter G250 PET in assessing primary tumors, its performance in and T1b for tumors larger than 4 cm. It also included renal sinus evaluating metastatic lesions has been shown to be signifi- invasion in the T3a classification and renal vein invasion in the cantly inferior to that of FDG-PET.159 T3b subset.163 The seventh edition of the American Joint Com- Although morphologic or functional imaging modalities mittee on Cancer (AJCC) staging system was released in 2010 such as CT, MRI, and PET have been used to evaluate renal and includes relevant changes to the T3 and T4 definitions; it masses, Doppler ultrasonography with contrast agent injection also defines node-positive disease as N1 regardless of number of has been shown to provide both morphologic and functional positive nodes. This updated system accurately characterizes the information regarding renal lesions. The size of tumors can disease with respect to prognosis. Pathologic stage remains the be accurately measured and the percentage of contrast uptake most consistent single prognostic variable that influences sur- (which provides an approximation of tumor vascularity) can vival. Survival based on stage is shown in Tables 40-4 and 40-5. be evaluated using this technique. In the era of new antian- The Fuhrman grading system for renal cell carcinoma is giogenic treatment modalities, assessment of tumor neovascu- based on nuclear characteristics (size, contour, and nucleoli) larization is of major importance, and this parameter could be and uses a scale from 1 to 4, where 4 represents the high- a potential biomarker for treatment evaluation. est degree of nucleolar irregularity and indicates a poorer Chapter 40 Renal Neoplasia 1517

TABLE 40-4 TNM Staging for Renal Cell Carcinoma TABLE 40-5 Correlation of Stage Grouping with Survival in Patients with Renal Cell Cancer Primary Tumor (T) TX Primary tumor cannot be assessed 5-YEAR T0 No evidence of primary tumor STAGE GROUPING ­SURVIVAL (%) T1a Tumor 4 cm in greatest dimension, limited to the kidney I T1 N0 M0 90-95 T1b Tumor >4 cm, but ≤7 cm in greatest dimension, limited to the kidney II T2 N0 M0 70-85 T2a Tumor >7 cm but 10 cm in greatest dimension, limited ≤ III T3a N0 M0 50-65 to the kidney T2b Tumor >10 cm, limited to the kidney T3b N0 M0 50-65 T3a Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumor invades perirenal T3c N0 M0 45-50 and/or renal sinus fat, but not beyond Gerota’s fascia T1 N1 M0 25-30 T3b Tumor grossly extends into the vena cava below the diaphragm T2 N1 M0 25-30 T3c Tumor grossly extends into the vena cava above the T3 N1 M0 15-20 ­diaphragm or invades the wall of the vena cava T4 Tumor invades beyond Gerota’s fascia (including IV T4 Any N M0 10 ­contiguous extension into the ipsilateral adrenal gland Any T N2 M0 10 Regional Lymph Nodes (N) Any T Any N M1 <5 NX Regional lymph nodes cannot be assessed M, Distant metastasis; N, nodes; T, tumor. N0 No regional lymph node metastases N1 Regional lymph node metastases Distant Metastasis (M) 1.0

M0 No distant metastases 0.9 Risk factors are prior nephrectomy M1 Distant metastases KPS < 80 0.8 low HGB Adapted from Edge SB, American Joint Committee on Cancer: AJCC cancer staging high corrected calcium manual, 7th ed. New York: Springer, xiv. 0.7 high LDH

0.6 0 risk factors (164 patients, 30 alive) 54 1 or 2 risk factors (348 patients, 23 alive) prognosis. Mitotic activity is not considered in the grad- 0.5 3, 4, or 5 risk factors (144 patients, 1 alive) ing system. Although use of the Fuhrman grading system as 0.4 a prognostic tool has been validated for clear cell renal car- cinoma, its use for the other histologic subtypes (especially Proportion surviving 0.3 54,164 papillary and chromophobe) is a topic of debate. 0.2 Recent identification of novel clinicopathologic prognos- ticators in renal cell carcinoma have resulted in a gradual 0.1 transition from classifications that use clinical factors, such 0.0 as the TNM staging system and Fuhrman grade, to systems 0 1 2 3 4 5 6 7 8 11109 12 141315 16 17 that integrate multiple validated prognostic factors. Motzer Years following systemic therapy FIGURE 40-6 Survival and prognostic stratification for renal cell carci- and colleagues examined features predictive of survival in noma. Survival rates in a series of 86 patients with metastatic renal cell 670 patients with stage IV disease enrolled in clinical trials carcinoma treated by various modalities are compared with the survival of at Memorial Sloan-Kettering Cancer Center (MSKCC).131 patients treated with adjunctive nephrectomy. (From Motzer RJ, Mazum- Significant factors predictive of poor outcome in a multivari- dar M, Bacik J, et al: Survival and prognostic stratification of 670 patients ate analysis included Karnofsky performance status score of with advanced renal cell carcinoma, J Clin Oncol 17:2530, 1999.) less than 80%, hemoglobin level of less than 10 mg/dL, serum lactate dehydrogenase level of more than 1.5 times the upper limit of normal, corrected serum calcium level of more than Investigators at the University of California at Los 10 mg/dL, and lack of prior nephrectomy. A risk model was Angeles (UCLA) have developed the UCLA Integrated created using these five factors to assign patients to one of Staging System (UISS), a system based on TNM stage, three groups: those with zero risk factors (favorable risk), grade, and Eastern Cooperative Oncology Group (ECOG) those with one or two risk factors (intermediate risk), and performance status.169 Patients are stratified into three risk those with three or more risk factors (poor risk). Median sur- groups according to the probability of tumor recurrence vival for the group as a whole was 10 months, but ranged from and survival, and risk group–specific surveillance guidelines 15 months for patients in the favorable-risk group down to 4 are offered. Based on data from a large sample of patients, months for patients in the poor-risk group (Figure 40-6).131 investigators at the Mayo Clinic devised the stage, size, These prognostic factors have been validated in cohorts heav- grade, and necrosis (SSIGN) scoring system, in which ily treated with multiple nonantiangiogenic and noncytokine patients with clear cell renal carcinoma were assigned a therapies.165 The MSKCC criteria have been validated across score based on tumor stage, tumor size, nuclear grade, and multiple institutions, and adding the number of metastatic the presence of necrosis.170 Using the SSIGN score, cancer- sites to this model even better defines outcomes for patients specific survival at 1 to 10 years after treatment can be esti- with favorable, intermediate and poor risk.166-168 Currently, mated for an individual patient. Investigators at MSKCC this is the most commonly used nomogram for prognostica- combined tumor stage, tumor size, histologic subtype, and tion in clinical and experimental settings. symptoms at presentation into a nomogram that predicted 1518 Section V Disorders of Kidney Structure and Function the probability of freedom from recurrence at 5 years after TABLE 40-6 Indications for Partial Nephrectomy treatment.169 This nomogram has been updated for the Absolute clear cell variant of renal cell carcinoma and includes tumor stage, tumor size, nuclear grade, necrosis, vascular invasion, All renal masses <4 cm amenable to partial nephrectomy (clinical T1a) 171 Bilateral tumors and symptoms at presentation as prognostic factors. For Tumor in solitary kidney clear cell carcinomas, clinical factors that influence sur- Tumor in functionally solitary kidney vival include performance status grade and the presence of Compromised renal function paraneoplastic signs or symptoms such as anemia, hyper- Multiple recurrent tumors (von Hippel–Lindau syndrome) calcemia, hepatopathy, fever, and weight loss.172-174 Vari- Relative ous microscopic features, such as Fuhrman nuclear grade, Localized tumor with progressive disorder that may impair renal sarcomatoid histologic features, as well as biologic features ­function like interleukin-6 or VEGF production may be useful in History of familial renal cell carcinoma predicting survival.32,173,175-177 Oncocytoma (preoperative pathologic diagnosis) Elective Surgical Treatment Tumors 4-7 cm (clinical T1b) amenable to partial nephrectomy Controversial Nephrectomy Large (>5 cm) tumors in patients with normal contralateral kidney The mainstay of treatment of primary renal cell carcinoma is Centrally located tumors in patients with normal contralateral kidney surgical excision or nephrectomy. Nephrectomy represents the only proven curative modality. Radical nephrectomy, which involves the early ligation of the renal artery and renal vein and excision en bloc of the kidney with surrounding Gerota’s fascia the findings of several series.185-187 A therapeutic benefit and ipsilateral adrenal gland, became the procedure of choice in of extended lymphadenectomy in patients with clinically the 1960s. Robson reported a 5-year survival rate of 66% with evident lymphadenopathy but with no evidence of distant this procedure, which compared favorably with the previously metastasis has been suggested.188 The overall morbidity of reported surgical survival rate of 48% for simple nephrectomy. lymph node dissection is very low. The possible therapeutic Various surgical approaches (open and minimally invasive) are benefits in selected patients as well as the benefit to staging, available for the effective performance of this procedure. Min- especially in patients being enrolled in adjuvant clinical tri- imally invasive approaches have been shown to have equiva- als, has not been negated by the current literature. In locally lent oncologic outcomes to open approaches. advanced disease, regional lymph node dissection should be With better understanding of tumor biology and chang- performed when technically feasible.181 ing patterns of presentation, the value of radical nephrectomy is being reassessed. Involvement of the ipsilateral adrenal Nephron-Sparing Surgery gland occurs only 4% of the time, and in most instances, it is associated with direct extension from a large upper-pole The American Urological Association recently published lesion or the presence of nodal or distant metastases.178-180 guidelines for nephron-sparing surgery or partial nephrec- As a consequence, adrenalectomy is often reserved for tomy.189 This has expanded the role of nephron-sparing patients with large upper-pole lesions or those with soli- surgery from elective to standard of care for patients with tary ipsilateral adrenal metastases identified on preoperative cT1a tumors (tumors less than 4 cm) amenable to partial staging studies. nephrectomy, and as an option in patients with tumors from 4 to 7 cm in whom preservation of renal function is a pri- Lymph Node Dissection ority. The generally accepted criteria for consideration of nephron-sparing or partial nephrectomy are listed in Table The benefit of performing a regional lymph node dissec- 40-6. These include bilateral tumors, tumor in a solitary kid- tion in conjunction with the radical nephrectomy is con- ney, and compromised renal function.190,191 Overall survival troversial.181 With improved preoperative CT staging, of patients undergoing partial nephrectomy is equivalent the incidence of unsuspected nodal metastases in patients to that of patients with disease of a comparable stage who with low-stage tumors is less than 1%. Multiple preopera- underwent radical nephrectomy.192-194 A recent retrospective tive and intraoperative evaluative nomograms exist and can review of the data for 648 patients who underwent either aid the surgeon in determining the benefit of lymph node radical or partial nephrectomy for cT1a renal masses sug- dissection in conjunction with nephrectomy.182,183 The gested a survival advantage for partial nephrectomy.195 This only randomized trial to evaluate lymph node dissection may be explained by the increased rate of future develop- in patients with renal cell carcinoma showed no improve- ment of renal insufficiency in patients who undergo radical ment in survival with such dissection.184 The results of this nephrectomy.196,197 study are tempered by the fact that the majority of patients In patients with small, solitary tumors, the rate of local enrolled had low-stage (T1 and T2) tumors, and thus the recurrences is 0% to 7%,198 with a number of series reporting higher-risk patients most likely to derive a therapeutic no local recurrences. Several retrospective series15,199-202 and benefit from lymph node dissection were not adequately one prospective study203 have demonstrated equivalent sur- studied. A therapeutic benefit of lymph node dissection vival for patients who undergo partial nephrectomy and those in patients with metastatic disease undergoing cytoreduc- who undergo radical nephrectomy. Many urologists recom- tive nephrectomy has been supported (level 2 data) by mend complete nephrectomy in patients documented to have Chapter 40 Renal Neoplasia 1519 tumors with sarcomatoid histologic features on frozen section radiofrequency ablation) and local tumor progression (5.2% for or evidence of renal vein invasion. cryoablation vs. 12.9% for radiofrequency ablation), but a com- parison trial needs to be performed because of the many inher- 218,221 Minimally Invasive Techniques (Radical and Partial ent flaws in a comparative analysis of this type. Nephrectomy) Surveillance In 1991, Clayman and colleagues published the first case report of a laparoscopic nephrectomy, performed in an 85-year-old woman Surveillance has been considered for patients with multiple and/ with renal cell carcinoma.204 Since then, a number of groups have or bilateral tumors, for example, patients with von Hippel–Lindau reported on increasingly larger series of patients who underwesnt syndrome. Some have advocated waiting until the largest lesion this procedure.205-208 Overall survival and disease-free survival is greater than 3 cm before performing a partial nephrectomy.222 were no different in the groups undergoing laparoscopic surgery In the past, others have suggested bilateral nephrectomies with and in those undergoing open surgery. With increased experience transplantation for this population.193 For tumors smaller than 4 in the technique, the total intraoperative and postoperative costs cm, progression to metastatic disease has been very low (<2%) in became less for patients undergoing minimally invasive proce- all retrospective series. Active surveillance is a reasonable option dures due to the shorter postoperative hospital stay.209 Lapa- for patients with limited life expectancy or for those unfit for roscopic radical nephrectomy is a viable alternative to an open intervention.189 Patients should be counseled about the risk, procedure, with equivalent surgical efficacy and safety, and sub- albeit small, of progression to metastatic disease. As improve- stantially reduced postoperative recovery time.210 ments occur in nephron-sparing surgery and in minimally inva- Minimally invasive techniques (including laparoscopic sive ablation, surveillance may become less common, and more and robotic partial nephrectomies) are being used in the set- drastic approaches such as transplantation less necessary. ting of nephron-sparing surgery.211-213 Unfortunately, adop- tion of partial nephrectomy overall in the United States has Vena Caval Involvement been slow. Due to the technical expertise required to perform minimally invasive partial nephrectomy, performance rates are Inferior vena caval involvement with tumor thrombus is found even lower than for open partial nephrectomy, but they are in about 5% of patients undergoing radical nephrectomy.223 It steadily increasing. Laparoscopic techniques have been associ- occurs more frequently with right-sided tumors and is com- ated with a higher complication rate (from 1.5 to 2.0 times monly associated with metastases. Venal caval obstruction greater) than their open counterparts and with a warm isch- may produce various clinical manifestations. These include emia time that is approximately 1.5 times longer. Postoperative abdominal distension with ascites; hepatic dysfunction, pos- nadir creatinine levels have not been significantly different in sibly related to Budd-Chiari syndrome; nephrotic syndrome; multiple series comparing open partial nephrectomy with lapa- caput medusa; varicocele; malabsorption; and pulmonary roscopic partial nephrectomy.214 Oncologic outcomes for the emboli. The anatomic location of the tumor thrombus is prog- laparoscopic procedure have been equivalent to those for open nostically relevant. Although 5-year survival in patients with partial nephrectomy at large experienced centers.215 Robotic subdiaphragmatic lesions approaches 50%, patients with supra- partial nephrectomy is currently being evaluated at multiple diaphragmatic thrombi do considerably less well.224,225 A team sites, and after short follow-up, outcomes seem to duplicate of specialists is usually required for the surgical management of those of laparoscopic partial nephrectomy.216 In several retro- these patients, particularly if tumor thrombectomy of an intra- spective series, robotic partial nephrectomy has been associated cardiac tumor is contemplated. Even at experienced centers, with decreased overall blood loss and shorter warm ischemia the operative mortality may be as high as 5% to 10%.226,227 time compared with laparoscopic partial nephrectomy.217,218 Five-year survival in patients with coexisting nodal or systemic The proposed benefit over laparoscopic partial nephrectomy is metastases is extremely low,223 yet a distinct subset of patients in reconstruction of the renal unit after extirpation (especially may benefit from resection and subsequent systemic therapy.228 of more complex masses), but this claim awaits validation in larger series with adequate follow-up. Cytoreductive Nephrectomy Energy-Based Tissue Ablation In 2001, results of two randomized studies were published demonstrating a significant survival advantage in patients Over the past decade, cryoablation and radiofrequency abla- with metastatic disease who underwent nephrectomy prior to tion have emerged as treatment alternatives for a select group embarking on a course of cytokine therapy.229,230 Important of patients with localized renal tumors. Although long-term caveats to these reports are the following: nephrectomy did follow-up has not been achieved, oncologic effectiveness in not improve response to immunotherapy per se, and the mar- the intermediate term is comparable to that of the current gold gin of survival improvement was substantial only in patients standard treatment modalities.219,220 Ablative techniques are with a performance status of grade 0. UCLA investigators hindered by their association with a substantially increased risk reported a median survival of 16.7 months and a 19.6% 5-year of local tumor recurrence compared with extirpative procedures survival rate in patients treated with interleukin-2–contain- and the need for retreatment. Identification of residual disease ing therapy after debulking nephrectomy.231 In addition, the also seems to be more problematic with radiofrequency ablation Cytokine Working Group reported a 21% to 24% response than with cryoablation. There are no randomized trials compar- rate in patients who received cytokine therapy following recent ing radiofrequency ablation with cryoablation. A meta-analysis nephrectomy.232 These two analyses suggested that interleu- comparing the two modalities favored cryoablation with regard kin-2–based therapy should be considered after nephrectomy to need for repeat ablation (1.3% for cryoablation vs. 8.5% for in patients who have metastatic renal cancer. 1520 Section V Disorders of Kidney Structure and Function

TABLE 40-7 Criteria for Nephrectomy before Interleukin- stents and hydration, and hypercalcemia, fatigue, fever, and 2–Based Immunotherapy other systemic symptoms can often be controlled with non- steroidal antiinflammatory drugs, bisphosphonates, hydration, Greater than 75% debulking of total tumor burden technically feasible 245 No central nervous system, bone, or liver metastases and appetite stimulants such as medroxyprogesterone. Adequate pulmonary and cardiac function No active infection or significant comorbid condition Eastern Cooperative Oncology Group performance status of 0 or 1 Resection of Metastatic Disease Predominantly clear cell histologic type* Surgical resection of metastatic disease has been actively pursued *Not required prior to surgery; however, patients in whom pretreatment biopsy speci- mens reveal a predominant non–clear cell histology were not considered for surgery. in certain clinical situations. Patients who have a synchronous From Fallick ML, McDermott DF, LaRock D, et al: Nephrectomy before interleu- solitary metastasis at presentation have decreased survival com- kin-2 therapy for patients with metastatic renal cell carcinoma, J Urol 158:1691, 1997. pared with patients who develop metastasis after the primary tumor is removed (metachronous metastasis).246 Nonetheless, Several other reports indicated that anywhere from 13% to it is common to resect solitary or oligometastastic disease, often 77% of patients treated in this way never progressed to immu- in the ipsilateral lung or adrenal gland, in conjunction with notherapy because of complications of treatment or rapid, symp- nephrectomy, and occasionally patients remain disease free long tomatic disease progression. This further emphasizes the need for term.247-249 On the other hand, 5-year survival rates as high as proper patient selection if debulking nephrectomy is to be enter- 50% have been reported for patients undergoing resection of tained.233-236 Recognizing this, Fallick and associates developed isolated metachronous metastases.250-252 Time to presentation strict criteria for determining which patients should undergo of metastatic disease (after initial nephrectomy) is a significant debulking nephrectomy before receiving systemic interleukin-2 prognostic indicator for those undergoing metastasectomy. therapy.237 The criteria they used are displayed in Table 40-7. Cytoreductive nephrectomy in the era of molecular tar- geted agents has not been prospectively evaluated but is gener- Radiation Therapy ally accepted based on the earlier studies with cytokine-based Adjuvant Therapy to Nephrectomy therapy.238,239 A recent abstract reported a lack of survival ben- efit for nephrectomy in a subset analysis of poor-risk patients Studies looking at the possible benefit of adjuvant radiation treated with temsirolimus for metastatic renal cell carcinoma.240 therapy are few, and their results are inconclusive. There has This group represented patients with poor prognostic factors, been no well-designed clinical trial of either preoperative or many of whom would not qualify for cytoreductive nephrec- postoperative radiation therapy in patients with renal cell car- tomy under current guidelines. However, except in the studies of cinoma. In the absence of such data, adjuvant radiation ther- temsirolimus, more than 90% of the patients included in all ran- apy should be considered unproven and should be used only in domized clinical trials of the newer target agents had undergone an investigational setting. removal of the primary tumor. Newer targeted therapies are bet- ter at downsizing the primary tumor than is immunotherapy, Radiation Therapy for Metastatic Disease but reductions are generally less than 20% by volume. Several centers have reported on small series of patients with neoadju- The major sites of systemic metastases include lung, bone, and vant (presurgical) treatment with molecularly targeted agents. brain. Radiation treatment of disease in these areas can pro- A phase II study evaluating neoadjuvant treatment with bevaci- vide palliation of bone pain, prevention of cord compression zumab or bevacizumab plus erlotinib in patients with metastatic or fracture, regression of central nervous system metastases, renal cell carcinoma was recently reported. Clinical outcomes and control of hemoptysis or airway obstruction. Objective were comparable to those when the targeted agents were used responses occur in about 50% of patients with symptomatic in the postsurgical setting, but delayed wound healing resulted skeletal metastases.253,254 Symptomatic improvement is often in a prolonged time to resumption of systemic therapy in 10% achieved even in the absence of radiologically determined of patients of these patients with metastatic disease.241 The tumor regression. Radiation therapy is also highly effective largest series of metastatic patients undergoing cytoreductive in controlling hemorrhage from bronchial mucosal lesions. nephrectomy after pretreatment with targeted agents con- Palliation of large renal bed recurrences by external beam firmed an increased risk for specific wound related complica- irradiation has been unsatisfactory. Some relief of pain has tions, but overall and severe complications (Clavien >3) were been achieved in about 50% of patients, but it is usually of not significantly different than in those patients undergoing short duration. In patients with brain metastases, whole-brain upfront cytoreductive surgery.241a These data, combined with radiation therapy alone has not demonstrated significant effi- those from small case series, have generated hypotheses that cacy.255 Stereotactic radiation surgery has been reported to should be further evaluated in larger prospective trials.242,243 be effective therapy in selected patients with small (<3 cm) central nervous system metastases from renal cell carcino- 256-258 Palliative Nephrectomy mas. Whole-brain radiation treatment may be omitted, even in patients who undergo stereotactic radiosurgery.256 Although severe local symptoms such as bleeding and pain, systemic symptoms such as fatigue or fever, and abnormal laboratory test results such as hypercalcemia have been fre- Systemic Therapy quent justification for nephrectomy in the past, such “pal- liative nephrectomies” are rarely necessary now.244 Pain and Although surgical resection of localized disease can be cura- bleeding can often be controlled with systemic pain medicines tive, 25% to 30% of patients have metastatic disease at presen- or angioinfarction, clot colic can be minimized with ureteral tation, and as many as 30% to 40% of patients with a surgical Chapter 40 Renal Neoplasia 1521

“cure” later experience a recurrence. The current median sur- trials are currently accruing patients for adjuvant therapy: vival for patients with metastatic renal cell carcinoma can Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) vary greatly depending on multiple prognostic factors.165 and SORCE, which is evaluating sorafenib therapy in the MSKCC-defined risk categories of “favorable,” “intermedi- adjuvant setting. ate,” and “poor” are associated with median overall survival rates of 26 months, 14.4 months, and 7.3 months, respec- Neoadjuvant Therapy tively.165,167 Patient selection greatly influences response rate and survival, and this factor must be kept in mind in evaluat- The use of targeted agents as neoadjuvant therapy is on the ing the results of any phase II or III study. Treatment options verge of being explored in a large prospective trial. Use could over the years have included hormonal therapy, chemotherapy, be initiated through a clinical trial in two subsets of patients: and immunotherapy; however, more recently, attention has (1) patients with metastatic disease, to provide a test of the been given to targeted therapy approaches. benefits of cytoreductive nephrectomy; and (2) patients with locally advanced or marginally resectable disease, in hopes of Adjuvant Therapy downstaging disease or at least maintaining stability of dis- ease and determining which patients have early presentation Because a substantial number of patients with high-risk fea- of nonresponsive metastases. These and other questions will tures experience recurrence after primary nephrectomy, an not be answered until the appropriately sized clinical trials are adjuvant therapy could be useful in the treatment of these conducted. patients. The risk of recurrence after nephrectomy for an individual patient can be calculated using one of the validated Targeted Agents models discussed in the staging and prognosis section of this chapter.259 The ECOG completed a trial comparing adjuvant Given the frequency of biallelic loss of the VHL gene and interferon alfa therapy with observation after resection of associated dysregulation of hypoxia-inducible genes, includ- high-risk renal cell carcinoma. Eligible patients had tumors ing those for the proangiogenic growth factors VEGF and staged as T3b or T3c, T4, and/or N1 to N3. Patients were PDGF, renal cell carcinoma has been a particularly prom- randomly assigned to receive either a year of interferon alfa ising target for antiangiogenic therapy. The use of the term therapy or routine observation. At a minimum follow-up of targeted agents is a misnomer, because most of these drugs 36 months and a mean of 68 months overall, no statistically act on multiple systems within the cell and are multitargeted significant difference in disease-free survival was observed (Figure­ 40-7).267,268 The monoclonal antibodies are an excep- between the two study arms.260 tion to this. There are currently six drugs that have shown A smaller study performed by the European Organization an improvement in progression-free survival or overall sur- for Research and Treatment of Cancer (EORTC) also showed vival in large phase III randomized trials, with several more no benefit for the adjuvant administration of interferon alfa. awaiting data maturity. Response rates and tolerability of Although the results were disappointing, the study was useful these agents are better than those of cytokines, but there are in providing information on the natural history of stage III only sporadic cases of durable complete responses. Despite renal cell carcinoma. Specifically, it identified a high-risk group, the advances brought by targeted agents, there is still a role those with T3c, T4, and/or N2 or N3 disease, who had only for cytokine therapy in selected patients. With the influx a 20% to 25% chance of remaining disease free at 2 years.260 of so many new targeted agents and a second generation of This population was believed to be at sufficient risk of relapse agents currently being tested, the questions that remain to be to justify exploration of more aggressive therapy, such as high- answered include the following: (1) What is the appropriate dose interleukin-2, in an effort to prevent or delay relapse. sequencing of the agents? (2) Is combination therapy safe and Consequently, the Cytokine Working Group performed a trial more effective than single-agent therapy? The development randomly assigning patients who met these high-risk staging of novel clinical trial designs with multi-institutional and criteria to either a single cycle of high-dose interleukin-2 or multinational cooperation will be crucial in answering these observation (with interleukin-2–based therapy at the time of questions. recurrence). Unfortunately, this trial showed no survival ben- efit for the patients receiving high-dose interleukin-2 in the Sunitinib adjuvant setting.261 There is no evidence to support the use of Sunitinib is a small-molecule multitargeted kinase inhibitor interferon or interleukin-2 in the adjuvant setting in patients of VEGF receptor (VEGFR), PDGF receptor (PDGFR), with high-risk renal cancer. A small randomized trial using c-Kit, and FLT3 (FMS-like tyrosine kinase 3). Two phase thalidomide for adjuvant treatment also showed no survival II studies were performed in patients with metastatic renal benefit.262 Two trials that have investigated vaccine-based cell carcinoma refractory to cytokine therapy. The first trial treatment in the adjuvant setting are discussed later in this enrolled 63 patients, the majority of whom had tumors with chapter; one has shown promising results.263-265 clear cell histologic features and had undergone nephrec- Several adjuvant studies are currently enrolling patients. tomy. The response rate was 40% with no patients showing ECOG trial No. 2805, the Adjuvant Sorafenib or Sunitinib a complete response, and the progression-free survival was for Unfavorable Renal Carcinoma (ASSURE) study, is a dou- 8.1 months.269 A subsequent 106-patient study, in which all ble-blinded phase III trial randomly assigning 1923 patients individuals had clear cell carcinoma, had undergone nephrec- to receive no treatment, 1 year of sunitinib treatment, or 1 year tomy, and had shown no response to cytokine therapy, dem- of sorafenib treatment. Accrual at the time of submission of onstrated a 25% response rate after independent review. this chapter was over 1400 patients.266 The major endpoint Based on these phase II data, sunitinib was approved by the being assessed is disease-free survival. Two other phase III FDA in January 2006. 1522 Section V Disorders of Kidney Structure and Function

Cell stimuli (eg, growth factors)

TUMOR CELL FKBP Temsirolimus Inactivated PI3K Everolimus VHL tumor PTEN suppressor gene Bevacizumab Pro VHL VEGFR Akt Sunitinib HIFα HIFα Normoxia Sorafenib Axitinib Hypoxia and normal Pro OH VHL gene VEGF Pazopanib Pro mTORC1 HIFα PDGFR Raptor GβL OH HIFα HIF mLST8 4E-BP1 α VHL eIF-4E HIFα Ub E3 Ligase Pro Pro Ub p70S6K Ub P P Pro Ub eIF-4E 4E-BP1 HIFα PDGF Pro OH mRNA translation Proteasome-mediated ENDOTHLIAL degradation of HIF CELL Cyclin D1 Transcriptional c-Myc HIFα activation of HIF target genes Pro Cell growth and survival

FIGURE 40-7 Therapeutically relevant biologic pathways in renal cell carcinoma. In conditions of normoxia and normal von Hippel–Lindau (VHL) gene function, VHL protein is the substrate recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor-α (HIF-α) for prote- olysis. In cellular hypoxia or with an inactivated VHL gene, the VHL protein–HIF interaction is disrupted, which leads to stabilization or accumulation of HIF transcription factors. HIF accumulation can also result from activation of mammalian target of rapamycin (mTOR) downstream of cellular stimuli and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. mTOR phosphorylates and activates p70S6 kinase (p70S6K), which leads to enhanced translation of certain proteins, including HIF. Activated mTOR also phosphorylates 4E binding protein 1 (4E-BP1), which promotes dissociation of this complex and allow a eukaryotic translation initiation factor 4E (eIF-4E) to stimulate an increase in the translation of messenger RNAs (mRNAs) that encode cell cycle regulators, such as c-myc and cyclin D1. Activated HIF translocates into the nucleus and leads to transcription of a large repertoire of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). These ligands bind to their cognate receptors pres- ent on the surface of endothelial cells, which leads to cell migration, proliferation, and permeability. Sites of action of targeted therapies are illustrated. Temsirolimus and everolimus bind to FK506-binding protein (FKBP), and the resultant protein-drug complex inhibits the kinase activity of mTOR complex 1 (mTORC1). Bevacizumab is a VEGF ligand–binding antibody. Sunitinib, sorafenib, axitinib, and pazopanib are small-molecule inhibitors of multiple tyrosine kinase receptors, including the receptors for VEGF (VEGFR) and PDGF (PDGFR). (From Rini BI: Metastatic renal cell carcinoma: many treatment options, one patient, J Clin Oncol 27:3225, 2009; Rini BI, Campbell SC, Escudier B: Renal cell carcinoma, Lancet 373:1119, 2009.)

A phase III trial randomly assigning 750 patients to receive inhibitory activity against VEGFR, PDGFR, c-KIT, and either sunitinib or interferon alfa was completed in July FLT-3. A phase II randomized discontinuation study accrued 2005.270 The primary endpoint, progression-free survival, was 502 patients with renal cell carcinoma.273 All patients in this 11 months in the sunitinib arm versus 5 months in the inter- study received sorafenib therapy for 12 weeks. Those who had feron arm (P = 0.001), and overall survival was longer in the more than 25% shrinkage or 25% growth of disease continued sunitinib group, 26.4 months versus 21.8 months (P = 0.049). or discontinued therapy, respectively. Individuals in between Objective response rate as measured by Response Evaluation were randomly assigned to continue sorafenib or to receive a Criteria in Solid Tumors (RECIST) was 47% for sunitinib placebo. In this randomized group, progression-free survival compared with 12% for interferon alfa. The most commonly of patients receiving sorafenib was 24 weeks versus 6 weeks for reported sunitinib-related grade 3 adverse events were hyper- patients receiving the placebo (P = 0.0087). tension (12%), fatigue (11%), diarrhea (9%), and hand-foot A phase III trial (Treatment Approaches in Renal Can- syndrome (9%). Thyroid abnormalities can be found in more cer Global Evaluation Trial [TARGET]) was completed in than 80% of patients and warrant serial monitoring.271 The early 2005.274 Patients with metastatic renal cell carcinoma for development of grade 3 systemic hypertension during receipt whom one prior therapy had failed were randomly assigned to of treatment may be predictive of efficacy.272 receive either sorafenib or placebo. Median ­progression-free This oral medication is dosed on a 6-week cycle: 4 weeks at survival was 5.5 months in the treatment arm and 2.8 months 50 mg/day, followed by 2 weeks off therapy. in the placebo arm, and these results were highly statistically significant P( = 0.000001). Sorafenib was FDA approved in Sorafenib December 2005 for use in the treatment of advanced renal Sorafenib is a bis-aryl urea originally developed as a potent cell carcinoma. A later survival analysis, now with substan- inhibitor of both wild-type and mutant (V599E) B-Raf tial patient crossover, showed survival of 17.8 months in and c-Raf kinase isoforms. It was also found to possess the sorafenib arm versus 15.2 months in the placebo arm Chapter 40 Renal Neoplasia 1523

(P = 0.146). When the postcrossover placebo data were cen- with metastatic renal cell carcinoma that did not response to sored, the differences in survival became significant: 17.8 a prior first-line therapy. months versus 14.3 (P = 0.029).275 Results of a frontline study comparing sorafenib with interferon were published in 2009.276 Bevacizumab Progression-free survival was 5.7 months for sorafenib-treated Bevacizumab is an intravenously administered human mono- patients, and 5.6 months for interferon-treated patients. clonal antibody directed against VEGF. All circulating VEGF Crossover was permitted in the upfront interferon arm, and isoforms are bound and neutralized, which thus prohibits patients who subsequently received sorafenib demonstrated a ligand binding to the VEGF receptor and consequently inhib- median progression-free survival of 3.6 months. Due to the its signal transduction in the endothelial cell. Bevacizumab in relatively disappointing progression-free survival data in this combination with interferon alfa was FDA approved in July study, sorafenib has fallen out of favor as a frontline agent of 2009 as a first-line therapy for treatment-naive patients with choice. metastatic renal cell carcinoma. A large (n = 649) phase III This oral medication is dosed at 400 mg/day continuously, randomized trial compared bevacizumab plus interferon alfa with restaging performed every 2 months. to interferon alfa plus placebo. The median progression-free survival was 10.4 months versus 5.5 months (P < 0.0001) in Pazopanib favor of the group receiving the bevacizumab combination.280 Pazopanib is an oral second-generation multitargeted Another recently completed phase III trial enrolling 723 kinase inhibitor of VEGFR types 1, 2, and 3, PDGFR-α, treatment-naive patients showed a median progression-free PDGFR-β, and c-Kit.277 In a phase II clinical trial, the toler- survival of 8.5 months in patients receiving bevacizumab ability profile was different from that of other multitargeted plus interferon alfa versus 5.2 months in patients receiving kinase inhibitors, with hypertension in 8%, grade 4 myelo- interferon alfa monotherapy (P < 0.001). Overall toxicity was suppression in 7%, fatigue in 4%, and diarrhea in 3%. Therapy greater in the bevacizumab plus interferon group, includ- was discontinued in 11% of patients due to toxicity. An inter- ing significantly more grade 3 hypertension (95% vs. 0%), national phase III trial in patients with renal cell carcinoma anorexia (17% vs. 8%), fatigue (35% vs. 28%), and proteinuria was reported in 2009.278 Patients were randomly assigned (13% vs. 0%). No overall survival difference was reported in in a 2:1 ratio to receive 800 mg pazopanib orally per day or either study for the bevacizumab-treated arms.281,282 placebo. The primary endpoint was progression-free survival. Studies examining the role of erlotinib (a tyrosine kinase Crossover was permitted on the placebo arm at the time of inhibitor of the epidermal growth factor receptor) in combina- progression. Patients were either treatment naive (n = 233) tion with bevacizumab have been completed.283 A 63-patient or had received prior cytokine therapy (n = 202). Median phase II study, which included 43 patients who were previ- progression-free survival was 9.2 months in the pazopanib- ously untreated, demonstrated an 11-month progression-free treated group versus 4.2 months in the placebo arm (hazard survival.283 The role of erlotinib was subsequently dis- ratio [HR] = 0.42, 95% confidence interval [CI] = 0.34 to counted in a 100-patient study randomly assigning patients 0.62, P < 0.0000001). In the treatment-naive subset, the to receive either bevacizumab monotherapy or bevacizumab pazopanib-treated group had a progression-free survival of plus erlotinib.284 The progression-free survival for the beva- 11.1 months versus 2.8 months in the placebo group (HR = cizumab-only arm was 8.5 months, versus 9.9 months for the 0.42, 95% CI = 0.27 to 0.60, P < 0.0000001). An ongoing trial combination-therapy arm (P = 0.58). There was no survival is comparing upfront pazopanib to sunitinib therapy, using a difference. noninferiority design. Temsirolimus Axitinib Temsirolimus is a rapamycin analog that inhibits mTOR Axitinib is a oral second-generation multitargeted kinase downstream of the serine-threonine protein kinase AKT. It is inhibitor against VEGFR types 1, 2, and 3. A phase II clinical administered intravenously. A randomized phase III three-arm trial involving 52 patients in whom cytokines had been inef- study in which one group received 25 mg of intravenous tem- fective recorded an overall response rate (complete plus par- sirolimus weekly, one group received 9 million U of interferon tial responses by RECIST criteria) of 44.2%.279 At a median alfa three times weekly, and one group received 15 mg of intra- follow-up of 20 months, median progression-free survival was venous temsirolimus weekly plus 6 million U units of inter- 15.7 months and median overall survival was 31.1 months. feron alfa three times weekly showed significant ­differences Dosage reduction was required in 29% of patients because of between treatment groups.285 Patient inclusion criteria showed serious adverse events. Unlike with pazopanib, there were no significant differences from criteria in contemporary phase grade 3 or 4 cases of myelosuppression. III trials: 35% of patients had not undergone cytoreductive Another phase II study enrolled 62 patients who showed nephrectomy; 80% of patients had a Karnofsky performance no response to sorafenib. All patients had received prior status score of less than 80; and 20% of patients had tumors sorafenib therapy and 72% had received prior systemic with non–clear cell histologic features. The median survival therapy. Axitinib dosages were titrated up and down from of patients in the temsirolimus-only arm was significantly 5 mg/day. Overall response rate was 22.6%. Median pro- longer than that in patients receiving interferon monotherapy gression-free and overall survival were 7.4 and 13.6 months, (10.9 months vs. 7.1 months, P = 0.0069). The objective respectively. Serious adverse events (grade 3 or 4) were response rates as measured by RECIST criteria did not differ hand-foot syndrome (16.1%), fatigue (16.1%), hypertension among the three arms. The median survival of patients receiving (16.1%), dyspnea (14.5%), diarrhea (14.5%), and hypoten- the combination therapy was 8.4 months and was not signifi- sion (6.5%).279 A prospective randomized phase III trial of cantly different from that in the ­temsirolimus-only arm. The sorafenib versus axitinib is currently under way in patients most frequent serious adverse events in the temsirolimus-only 1524 Section V Disorders of Kidney Structure and Function arm were anemia (20%), asthenia (11%), and hyperglycemia replicating the same data for each new drug. Sequencing may (11%). Patients in the combination arm had a significantly hold promise in extending responses and adequately treating greater proportion of serious adverse events resulting in treat- tumors that become resistant. This can only be accomplished ment delays and dosage reductions. Temsirolimus is currently through integration of preclinical data (alternative escape first-line monotherapy for treatment-naive patients with pathways) into large clinical trials. poor-risk metastatic renal cell carcinoma (including tumors with non–clear cell histologic characteristics). Vaccines Everolimus Vaccines used for the treatment of metastatic renal cell car- Everolimus is an oral bioavailable mTOR inhibitor. A phase cinoma or used in the adjuvant setting fall into four classes: III clinical trial evaluating everolimus randomly assigned 1. Autologous tumor cell based patients who had earlier experienced disease progression while 2. Genetically modified tumor cell based being treated with at least one targeted agent to receive either 3. Dendritic cell based everolimus or placebo in a 2:1 ratio.286 Patients receiving 4. Peptide based everolimus demonstrated both a decreased risk of progression Only two randomized phase III studies have investigated the (HR = 0.30; 95% CI = 0.22 to 0.40) and increased median use of vaccines in the treatment of renal cell carcinoma. Both progression-free survival (4.0 months vs. 1.9 months) com- of these used vaccines in the adjuvant setting.263-265 In a phase pared with those receiving placebo. There were no significant III multinational open-label clinical trial, over 800 patients differences in overall survival, likely because most patients in with high-risk tumors were randomly assigned to receive a the placebo arm crossed over and received everolimus once heat shock protein complex (vitespen) derived from autologous disease progression was documented. Serious adverse events tumors or to observation alone. No difference in recurrence- (grade 3 or 4) in the everolimus and placebo groups were free survival was seen between the groups. Longer follow-up stomatitis (3% and 0%, respectively), fatigue (3% and 1%, is need to determine if there is a benefit for patients at lower respectively), and pneumonitis (3% and 0%, respectively). The risk.265 An autologous tumor vaccine (Reniale) was evaluated FDA approved everolimus for the treatment of patients with in a phase III trial, and improved progression-free survival in metastatic renal cell carcinoma after failure of treatment with patients with high-risk nonmetastatic renal cell carcinoma sunitinib or sorafenib. (P = 0.0476).263,264 In the subgroup with T3 tumors (staged according to AJCC edition 4), the 5-year progression-free sur- Epidermal Growth Factor Receptor–Blocking Agents vival was 67.5% versus 49.7% in the untreated control group. The epidermal growth factor receptor (EGFR) antagonists, There was also a trend toward increasing overall survival, with despite the presence of compelling preclinical data, have not the vaccine cohort having an overall survival of 68.9% at 10 years yet lived up to their promise. A high rate of EGFR expression compared with 62.1% in the control group (P = 0.066). A subset on renal cell carcinoma tumors, coupled with loss of VHL analysis of patients with T3 disease also showed a benefit in resulting in increased expression of transforming growth fac- overall survival (P = 0.024). The vaccine is not commercially tor alfa, supports the presence of an autocrine loop in renal available in Europe or the United States at this time. A multi- cell carcinoma. Inhibition of this autocrine loop by blocking national clinical trial that integrates the current staging system either the cell surface receptor (EGFR) or the ligand would be could provide more insight into patient selection and the role of expected to result in growth inhibition and clinical response. this vaccine in adjuvant treatment of high-risk disease. However, several phase II studies demonstrated little response Multiple phase I and phase II studies have shown mixed to single-agent therapy targeted against EGFR.62 In another results for vaccine use in patients with metastatic renal cell phase II trial, the combination of erlotinib with bevacizumab carcinoma.287-289 Ongoing studies are evaluating the effective- failed to show any clinical advantage over bevacizumab ther- ness of combining vaccine therapy with cytokine therapy, but apy alone.284 again results have been mixed, as shown by the lack of progres- sion to phase III trials in the population metastatic disease. Sequencing of Therapies Thalidomide Evidence-based guidelines are lacking with regard to the sequencing of systemic agents. There is evidence from a retro- Thalidomide has a somewhat unclear mechanism of action spective study that administration of salvage cytokine therapy but is believed to alter to some degree the expression of after treatment with targeted agents (sunitinib, sorafenib, angiogenic growth factors, including VEGF and fibroblast bevacizumab) is associated with a substantially higher rate growth factor in tissues. Although early anecdotal reports of severe cardiac toxicity. In this study, only 1 of 23 patients suggested possible objective responses in renal cell carcinoma, was able to tolerate a second cycle of interleukin-2, and the most reports of therapy with even high dosages of thalido- incidence of severe cardiac toxicity was extraordinarily high mide (800+ mg/day) suggest that the agent, at best, results in at 40%. Although there are case reports of a small number of disease stabilization.290-293 Toxic effects include somnolence, complete responses, the durability of which has yet to be deter- constipation, fatigue, and, with prolonged exposure, periph- mined, all patients receiving targeted therapy can expect to eral neuropathy.291 Several small phase II studies of lenalido- progress through multiple agents. The best optimal sequence mide (a thalidomide analog) have shown partial response rates of chemotherapy is unknown. One problem with current for this agent of 0% to 10%.294,295 No survival advantage has trial design is lack of flexibility to accept newer drugs into been detected. At this point, thalidomide therapy is generally the sequencing. Novel multi-institutional and multinational not recommended for the treatment of patients with renal cell trial design should be a priority if we are to progress beyond carcinoma. Chapter 40 Renal Neoplasia 1525

Chemotherapy Two phase III studies using single-agent interferon therapy showed a modest impact on survival in patients with advanced Many studies of single-agent chemotherapy for renal cell renal cancer. For example, one phase III trial comparing inter- carcinoma have been performed, with most agents show- feron alfa-2a plus vinblastine chemotherapy with vinblas- ing minimal or no activity.296 In a review of the chemo- tine alone reported a median survival of 67.6 weeks for the therapy literature, Yagoda and colleagues297 reported a 4% interferon-plus-vinblastine arm compared with 37.8 weeks overall response rate in 3635 patients with renal cell carci- for patients receiving vinblastine alone (P = 0.0049).310 In noma treated with various chemotherapy approaches. More another trial that randomly assigned patients with advanced recently, gemcitabine chemotherapy has been studied in renal disease to receive either interferon or medroxyprogesterone cell carcinoma. When gemcitabine is used as a single agent, acetate, there was a 28% reduction in the risk of death in the response rates between 6% and 30% are reported.298-300 A interferon group (P = 0.017) and an improvement in median combination of gemcitabine and 5-fluorouracil demonstrated survival of 2.5 months.311 a response rate of 17% in 41 patients with metastatic renal More recent studies have suggested that the antitumor cell carcinoma.301 Median progression-free survival in this effects of interferon are quite limited. For example, a French pretreated group of patients was 28.7 weeks. Follow-up stud- Immunotherapy Group phase III trial comparing interferon ies using gemcitabine and capecitabine, the oral prodrug form with both interleukin-2 and interleukin-2 plus interferon of 5-fluorouracil, demonstrated response rates of 11% and reported a response rate of only 7.5% for the interferon arm overall survival of 14 months.302 A more recent study demon- with a 1-year event-free survival rate of only 12%.312 In the strated a median progression-free survival and overall survival Programme Etude Rein Cytokines (PERCY) Quattro trial, of 4.6 and 17.9 months, respectively.303 There were six partial untreated patients with more than one metastatic site and a responses and one complete response (objective response rate Karnofsky performance score of 80 or higher were randomly = 8.4%; 95% CI = 3.5 to 16.6). In addition, major responses assigned to receive either medroxyprogesterone, interferon have been reported with cisplatin- and taxane-based ther- alfa, subcutaneous interleukin-2, or interferon plus subcuta- apy in patients with collecting duct tumors.304 A case series neous interleukin-2 in a 2 × 2 factorial design.313 The primary of patients with sarcomatoid renal cell carcinoma and other endpoint was overall survival, which did not differ among aggressive renal cell carcinomas treated with doxorubicin the groups (median overall survival = 15 months, all P values (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) every >0.5). This study casts doubt on the utility of outpatient cyto- 2 to 3 weeks along with granulocyte colony-stimulating fac- kine therapy in the treatment of patients with metastatic renal tor support was reported in 2004. Two patients had a com- cell carcinoma of intermediate prognosis. plete response, five had a partial response, three had a mixed Efforts to improve upon the clinical activity of interferon response, and one had stable disease. The median duration of alfa have included combining it with 5-fluorouracil, 13-cis- response was 5 months (range = 2 to 21+ months).305 Prospec- retinoic acid, interferon gamma, thalidomide, and interleu- tive studies need to be performed to validate this observation. kin-2. For the most part these efforts have met with limited success, with occasionally promising phase II findings failing to be confirmed in phase III trials.314,315 Immunotherapy Interleukin-2 Immunotherapeutic strategies for treatment of renal cell car- cinoma have included therapy with nonspecific stimulators of Clinical investigation of interleukin-2 as treatment for renal the immune system, specific antitumor immunotherapy, and cell carcinoma began in the mid-1980s. Initial studies were adoptive immunotherapy. The most consistent results have performed with high-dose bolus interleukin-2 and lympho- been reported with interferon alfa and interleukin-2. Although kine-activated killer cells, because animal studies had shown the mechanism of action of these cytokines is incompletely a steep dose-response curve for interleukin-2 and benefit for understood, the induction of antitumor responses in mice by the addition of lymphokine-activated killer cells.316 Dra- interferon alfa and interleukin-2 has been linked to the direct matic and durable responses were reported in a small subset killing of tumor cells by activated T and natural killer cells as of patients.317,318 Subsequent clinical studies have shown that well as to the antiangiogenic effects of these agents. high-dose bolus interleukin-2 alone possesses antitumor activ- ity that is essentially equivalent to that of the combination of 319,320 Interferon interleukin-2 and lymphokine-activated killer cells. In 1992, high-dose bolus interleukin-2 received FDA Interferon alfa has undergone extensive clinical evaluation approval for treatment of metastatic renal cell carcinoma over the past 2 decades as treatment for metastatic renal cell based on data from 255 patients treated in seven clinical trials carcinoma. Results of these investigations are thoroughly at 21 institutions. In these studies, recombinant interleukin-2 described in several reviews.306-308 Although no clear dose- (Proleukin, Chiron Corporation, Emeryville, Calif.) at a dose response relationship exists, daily doses in the 5 million to of 600,000 to 720,000 IU/kg was administered by 15-minute 10 million U range appear to have the highest therapeutic intravenous infusion every 8 hours on days 1 to 5 and 15 to index.309 Toxic effects of interferon include flulike symptoms 19 (maximum, 28 doses). Treatment was repeated at approxi- such as fever, chills, myalgias, and fatigue, as well as weight mately 12-week intervals for a maximum of three cycles in loss, altered taste, depression, anemia, leukopenia, and ele- patients showing a tumor response. There were 12 complete vated values on liver function tests. Most adverse effects, espe- responses (5% of patients) and 24 partial responses (9% of cially the flulike symptoms, tend to diminish with time during patients). Follow-up data on the study patients were accu- long-term therapy. mulated through late 1998 (median follow-up = 8 years). 1526 Section V Disorders of Kidney Structure and Function

The clinical results appear to have steadily improved over high-dose interleukin-2 in patients with bone or liver metas- time. At last report 17 patients (7%) were classified as com- tases (P = 0.001) or a primary tumor in place (P = 0.040), a plete responders and 20 (8%) as partial responders. The surprising finding since liver and bone lesions were generally median survival for the group as a whole was 16.3 months, considered to be relatively refractory to immunotherapy. with 10% to 15% of patients estimated to remain alive 5 to The National Cancer Institute published results of a study 10 years after treatment with high-dose interleukin-2. A large comparing high-dose interleukin-2, low-dose inpatient bolus percentage of patients showing a response, particularly those interleukin-2, and outpatient subcutaneous interleukin-2.334 remaining free from progression for longer than 2 years and Patients with measurable metastatic renal cell carcinoma and those resected to disease-free status after responding to high- a good performance status were randomly assigned to receive dose interleukin-2, appear unlikely to experience progression either 720,000 U/kg (high-dose) or 72,000 U/kg (low-dose) and may actually be “cured.”321 interleukin-2, both given by intravenous bolus every 8 hours. Several investigators have evaluated regimens involving After 117 patients were randomly assigned to these treatments, interleukin-2 administered by alternative routes or in lower a third arm of low-dose daily subcutaneous interleukin-2 was dosages in an attempt to reduce toxicity. Continuous intra- added. A total of 156 patients were randomly assigned to venous infusion regimens of interleukin-2 and lymphokine- receive high-dose intravenous interleukin-2, and 150 patients activated killer cells appeared to produce tumor response received low-dose intravenous interleukin-2. There were no rates similar to those seen with high-dose bolus intravenous interleukin-2–related deaths in any arm. There was a higher interleukin-2.321-323 Although more convenient to administer, proportion of responses with high-dose intravenous interleu- continuous-infusion regimens, on a milligram per milligram kin-2 (21%) than with low-dose intravenous interleukin-2 basis, were actually more toxic than high-dose bolus interleu- (13%; P = 0.048), but no overall survival difference was seen. kin-2.323 Furthermore, omitting the lymphokine-activated The response rate for subcutaneous interleukin-2 was 10%. In killer cells324 and/or reducing the dose of interleukin-2 fur- patients showing a complete response, response durability and ther to allow prolonged administration, although it produced survival were better with high-dose intravenous therapy than enhanced immune activation, appeared to limit antitumor with low-dose intravenous therapy (P = 0.04). activity.325 Attempts to improve efficacy have included the addition of interferon alfa and 5-fluorouracil to interleukin-2. Stud- Nonmyeloablative Allogeneic Transplantation ies can be differentiated according to route of interleukin-2 administration—high-dose intravenous bolus injection, con- Since its inception as a therapy, allogeneic bone marrow trans- tinuous intravenous infusion, or subcutaneous injection— plantation has evolved from a means to achieve chemother- and whether or not the drug was given in combination with apy dose escalation to a form of adoptive immunotherapy.335 5-­fluorouracil.326-329 Despite publication of promising data There is extensive evidence supporting the presence of a graft- by several groups, follow-up trials conducted by the Cyto- versus-malignancy effect in hematologic malignancies,336,337 kine Working Group failed to confirm the promise of cyto- and preclinical data demonstrate the presence of a graft-ver- kine combination therapy.330,331 Interleukin-2 and interferon sus-tumor effect in solid tumors as well.338-340 In patients with alfa administered subcutaneously with or without weekly breast cancer, several reports have demonstrated the presence 5-­fluorouracil produced response rates and median survival of a graft-versus-tumor effect in the setting of conventional similar to those observed with high-dose interleukin-2 alone ablative allogeneic transplantation for metastatic disease.341 or high-dose interleukin-2 and interferon; however, the qual- Due to the high level of morbidity and mortality experienced ity and durability of the responses appeared to be consider- in standard high-dose allogeneic transplantation, and the evi- ably less than those observed with high-dose interleukin-2 dence supporting the therapeutic importance of the immune- alone.328 mediated effect of the donor graft, different groups began Investigators in France reported the results of a large-scale developing nonmyeloablative allogeneic bone marrow and phase III randomized trial comparing intermediate-dose peripheral blood stem cell transplantation regimens for use interleukin-2 administered by continuous intravenous infu- in the treatment of both hematologic and solid tumors.342-346 sion plus subcutaneous interferon alfa with either interleu- The goal of these regimens is to create a conditioning regimen kin-2 or interferon alfa administered alone.332 The response sufficient for proper donor engraftment with the least recipi- rate and 1-year event-free survival were significantly greater ent graft ablation possible. for the combined interleukin-2 and interferon alfa arm than Preliminary experiences with nonmyeloablative allogeneic for either of the single-agent arms, although there was no sig- transplantation in patients with renal cell carcinoma have nificant difference in overall survival among the three groups. been reported by a number of centers.347-350 In all studies, The Cytokine Working Group conducted a random- the provision existed for posttransplantation donor lympho- ized phase III trial to determine the value of outpatient cyte infusion if complete donor chimerism was not achieved. ­interleukin-2 plus interferon alfa-2b therapy compared with The largest series, reported by Childs and colleagues, dem- high-dose intravenous interleukin-2 therapy in patients with onstrated response in 10 of 19 patients after a conditioning metastatic renal cell carcinoma.333 One hundred ninety- regimen of cyclophosphamide and fludarabine.348 Complete two patients were enrolled. One death was reported in donor chimerism appeared to be a prerequisite for response, as each arm. The response rate was 23.2% (22 of 95 patients) was some degree of graft-versus-host disease. More recently, in the high-dose interleukin-2 group versus 9.9% (9 of 91 Bregni and colleagues reported partial or complete responses patients) in the interleukin-2 plus interferon group (P = in 5 out of 24 patients with metastatic renal cell carcinoma 0.018). Median survivals were 17.5 and 13 months (P = 0.24), after allogeneic nonmyeloablative transplantation with thio- respectively, in the two groups. Survival was superior with tepa, cyclophosphamide, and fludarabine conditioning.350a Chapter 40 Renal Neoplasia 1527

Pedrazzoli and colleagues reported on 17 patients with treat- analysis commonly yields positive findings, as in bladder cancers. ment-refractory solid tumors, of whom 7 had renal cell car- A positive cytologic result in the presence of a filling defect cinoma, who underwent conditioning with fludarabine and of the renal pelvis or ureter confirms the diagnosis. Results of cyclophosphamide.349 Four of the patients had a performance retrograde pyelography with brush biopsy of suspicious lesions status of 2 or poorer, and the remaining three had a perfor- may also yield the diagnosis of cancer. If there is still uncer- mance status of 1. In the study reported by Pedrazzoli and tainty in the diagnosis after pyelography, including a retro- colleagues, all renal cell carcinoma patients died of progres- grade evaluation, ureteroscopy may be performed to further sive disease before day 100. All studies reported substantial evaluate the filling defect or obstruction. hematologic toxicities as well as graft-versus-host disease. Bad outcome was also consistently associated with poorer pretransplantation performance status. Staging and Grading of Renal Pelvic Tumors Nonmyeloablative transplantation requires substantial further development before it can be considered for a larger Upper tract urothelial carcinomas (UTUCs) are graded on a number of patients. The conditioning regimens need to be scale from grade I, representing a well-differentiated lesion, rendered less toxic. Posttransplantation immunosuppression to grade IV, representing an anaplastic and undifferentiated needs to be refined to decrease graft failure and graft-­versus- lesion. Because of the difficult access to some tumors of the host disease, and to permit bone marrow from unrelated upper tract, clinical staging is difficult. Histologic grade of donors to be used. Ideally, as our understanding of the anti- biopsy specimens can be used to predict pathologic stage of gens that elicit a graft–versus–renal cell carcinoma response is disease.351 In a staging system similar to that used for urinary improved, modification of the donor graft or the donor lym- bladder cancer, stage O is disease limited to the mucosa; stage phocyte infusion to enrich for renal cell carcinoma–specific A is invasion into the lamina propria without muscularis inva- T cell clones may enhance response. With appropriate tumor sion; stage B is invasion into the muscularis; stage C is invasion antigens in hand, it will also be possible to combine transplan- into the serosa; and stage D is metastatic disease. Lymphatic tation with vaccination. metastases usually indicate that more widespread metastatic disease is or will be present. The AJCC TNM classification is also similar to the staging for bladder carcinoma.352 Renal Pelvic Tumors

The cellular lining of the urinary collecting system, originating Treatment in the proximal renal pelvis, traversing the ureter and urinary bladder, and ending in the distal urethra, is composed of tran- For low-grade, low-stage transitional cancers, the general sitional epithelium or urothelium. This entire surface may be approach to treatment is conservative, consisting of local affected by carcinogenic influences, and this may help explain excision and preservation of the kidney parenchyma. For the multiplicity in time and place of “urothelial” tumors, which high-stage and high-grade lesions that have infiltrated into some have termed polychronotropism.Renal pelvic tumors the renal parenchyma, the surgical treatment of choice is account for approximately 10% of all primary renal cancers. nephroureterectomy and removal of a cuff of bladder that Tumors of the upper tract are twice as common in men, encompasses the ipsilateral ureteral orifice. This approach generally occur in patients older than 65 years of age, and are is generally required because of the high likelihood of local usually unilateral. The disease is more common in the Balkan recurrence in the bladder at the ureterovesical junction or in region (Bulgaria, Greece, Romania, Yugoslavia), where it is the distal ureter. Five-year recurrence-free and cancer-specific often bilateral. As with urothelial tumors of the urinary blad- survival rates for patients with UTUC who undergo radi- der, exposure to cigarette smoke, certain chemicals, plastics, cal nephroureterectomy are 69% and 73%, respectively.353 In coal, tar, and asphalt may increase the incidence of the dis- patients with regionally advanced or metastatic renal pelvic ease. Long-term exposure to the analgesic phenacetin, usually tumors, systemic chemotherapy, identical to that administered ingested over years by women for headache relief, has been for bladder cancer, is often employed. associated with the development of renal pelvic tumors. Adjuvant therapy has not been adequately assessed, but one Although most tumors of the upper tract are transitional study identified 415 patients with T3N0 and T4N0 UTUCs cell carcinomas, which account for over 90% of lesions, squa- of whom 16% and 25%, respectively, received adjuvant che- mous carcinomas also occur, usually in the setting of chronic motherapy. Chemotherapy status was not associated with any infections with kidney stones. significant cancer-specific or overall survival differences.354 Adenocarcinomas and other miscellaneous subtypes are Another problem when reviewing the literature on adjuvant rare. chemotherapy for high-risk disease is the paucity of descrip- tions of lymph node dissection in the initial surgery. Despite this, definitions of regional templates for lymphadenectomy in Clinical Features and Diagnostic Evaluation this disease have been developed.77 For patients with patho- logically determined T3 disease the extent of lymph node dis- The most common presenting feature is gross hematuria, section is a significant prognostic indicator and correlates with which occurs in 75% of patients, followed by flank pain, which cancer-specific survival.77 Standard first-line regimens for is seen in 30%. Evaluation may reveal either a nonfunction- patients with locally advanced or metastatic transitional cell ing kidney and nonvisualization of the collecting system, carcinoma mirror those used in bladder cancer and include or, more commonly, a filling defect of the calyceal system, methotrexate, vinblastine, doxorubicin (Adriamycin), and cis- renal pelvis, or ureter on CT urogram. Exfoliative cytologic platin (MVAC) as well as gemcitabine and cisplatin (GC). 1528 Section V Disorders of Kidney Structure and Function

Initial response rates may vary depending on prognostic fac- TABLE 40-8 Staging of Wilms’ Tumor tors, but long-term survival is poor. Another consideration is neoadjuvant chemotheraphy in Stage 1 Tumor limited to the kidney and completely excised high-risk/locally advanced disease because of the risk to the Stage 2 Tumor beyond the kidney but completely resected, or patient of renal insufficiency after nephroureterectomy and localized tumor spill at surgery the resultant inability to receive optimal adjuvant chemother- Stage 3 Residual tumor in the local regional area (e.g., peritoneal apy.355,356 This is a difficult argument to make considering the implants, lymph nodal involvement, tumor spillage clear lack of data regarding the overall effectiveness of adju- beyond flank) vant treatment in UTUC, but management practice has been Stage 4 Hematogenous involvement to metastatic sites, diffuse extrapolated from the literature on bladder transitional cell car- spill at surgery cinoma. Data reported for a large cohort of patients who under- Stage 5 Bilateral involvement at presentation went nephroureterectomy for UTUC provided some insight into operative decisions.356 Based on the criterion of a glomer- ular filtration rate of 60 mL/min or above, only 48% of patients heterozygosity in WT1 and at 16q occur in 20% of patients; were eligible for chemotherapy preoperatively, and that number inactivation of WT2 has also been described. Other genetic decreased to 22% postoperatively. After nephroureterectomy abnormalities have suggested the presence of other abnormal the opportunity for treatment with optimal chemotherapy was chromosomal locations. Patients with trisomy357 and XX/XY lost in 61% of patients able to receive it preoperatively. In a mosaicisms have been reported to have an increased incidence patient at risk for postoperative renal insufficiency and a signifi- of Wilms’ tumor. cant risk for advanced UTUC, strong consideration should be given to the neoadjuvant administration of chemotherapy. Pathology and Staging Microscopically, Wilms’ tumors consist of blastemic, epithe- Other Kidney Tumors lial, and stromal cells, often arranged in patterns that resemble tubular or glomeruloid features. The multipotential aspects Renal Sarcomas of Wilms’ tumors may be characterized by the presence of teratomatous or teratoid features, including components of Renal sarcomas account for approximately 1% to 2% of pri- mesenchymal structures such as muscle, cartilage, and lipoid mary renal cancers. Fibrosarcomas are the most common and tissues. In contrast to these differentiated structures, undif- have a poor prognosis as a result of their typically late presen- ferentiated or sarcomatoid lesions can also occur and are asso- tation and the presence of locally advanced involvement into ciated with a worse prognosis. The presence of nephrogenic the renal vein or metastatic disease at presentation. Five-year rests in the setting of Wilms’ tumors is common; they are survival rates are less than 20%. Other, rarer sarcoma variants thought to be precursor lesions. According to Wilimas and may occur and include leiomyosarcoma, rhabdomyosarcoma, associates,358 these rests are “defined as a focus of persistent osteogenic sarcoma, and liposarcoma. nephrogenic cells, some of which can be induced to form a Wilms tumor.” The most common staging system divides Wilms’ tumors into five categories (Table 40-8). Wilms’ Tumor Clinical Features In children, Wilms’ tumor (nephroblastoma) is the most com- mon cancer of the kidney, accounting for approximately 400 new The most common presentation of Wilms’ tumor is as an cases per year in the United States. The development of a suc- asymptomatic abdominal mass in a young patient (median age cessful treatment regimen for the disease in the 1990s was due of 3.5 years). Other physical abnormalities, including aniridia, to the coordinated efforts of a multidisciplinary team of oncolo- genitourinary abnormalities, and hemihypertrophy, may occa- gists, radiation therapists, and surgeons. The disease tends to sionally be detected. Hematuria, anemia, hypertension, and/or occur more frequently in African American children. A variety acute severe abdominal pain may also be present. Abdominal of etiologic factors have been suggested to increase the risk of ultrasonography is an important diagnostic test to further eval- Wilms’ tumor, but for none has a definitive link been established. uate the mass and its anatomic extension, which may include inferior or superior extension into the vena cava. Intravenous Genetics pyelography and CT are also warranted. Assessment for metas- tases to liver, chest, and bone complement the evaluation. The Several well-described genetic abnormalities are associated lungs are the most common site of metastasis. The diagnosis is with Wilms’ tumor. Patients with Wilms’ tumor may also usually established by surgery. If the diagnostic tests and clini- manifest other abnormalities, which include aniridia, WAGR cal features suggest the presence of a Wilms’ tumor, preopera- syndrome (Wilms’ tumor, aniridia, other genitourinary tive needle biopsy should be avoided because of the attendant abnormalities, mental retardation), Denys-Drash syndrome risks of tumor spillage and subsequent upstaging. (Wilms’ tumor, glomerulitis, pseudohermaphrodism), hemi- hypertrophy, trisomy, other rare physical abnormalities such as Multimodality Treatment macroglossia, and developmental sexual disorders. Abnormalities of the genes WT1 (chromosome arm High cure rates have been achieved with the concerted effort 11p13) and WT2 (11p15), and mutations at 16q have all been of multimodality teams performing surgery, radiation therapy, implicated in the molecular genetics of Wilms’ tumor. Loss of and chemotherapy. Surgical removal of the affected kidney, Chapter 40 Renal Neoplasia 1529 along with examination of the regional lymph nodes, and 16. Kane CJ, Mallin K, Ritchey J, et al. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer. 2008;113:78. detailed abdominal exploration are the goal. Removal of all 17. Mandel JS, McLaughlin JK, Schlehofer B, et al. International renal-cell gross tumor should be attempted and justifies the radical cancer study. IV. Occupation. Int J Cancer. 1995;61:601. resection that is often required. Tumors are classified as favor- 18. La Vecchia C, Negri E, D’Avanzo B, et al. Smoking and renal cell able and unfavorable in histologic features. All patients receive carcinoma. Cancer Res. 1990;50:5231. 19. Yu MC, Mack TM, Hanisch R, et al. Cigarette smoking, obesity, diuretic at least two-drug chemotherapy with dactinomycin and vin- use, and coffee consumption as risk factors for renal cell carcinoma. J Natl cristine; those with more advanced disease receive additional Cancer Inst. 1986;77:351. doxorubicin, cyclophosphamide, and etoposide with abdomi- 20. Hunt JD, van der Hel OL, McMillan GP, et al. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. Int J Cancer. nal radiation (1080 Gy) and possibly radiation to the chest 2005;114:101. (1200 Gy). Specific recommendations regarding the exact 21. Brennan JF, Stilmant MM, Babayan RK, et al. Acquired renal cystic disease: protocols to be used are determined by the operative findings, implications for the urologist. Br J Urol. 1991;67:342. the histologic subtype of the tumor, and whether there was 22. Matson MA, Cohen EP. Acquired cystic kidney disease: occurrence, prevalence, and renal cancers. Medicine (Baltimore). 1990;69:217. evidence of tumor spillage during the resection. 23. Denton MD, Magee CC, Ovuworie C, et al. Prevalence of renal cell Chemotherapy is an important component of treatment carcinoma in patients with ESRD pre-transplantation: a pathologic analysis. for Wilms’ tumors. Not only is chemotherapy administered Kidney Int. 2002;61:2201. 24. Grantham JJ. Acquired cystic kidney disease. Kidney Int. 1991;40:143. after surgery, but neoadjuvant chemotherapy can diminish the 25. Chow WH, McLaughlin JK, Linet MS, et al. Use of analgesics and risk of size of the primary tumor and cause regression of metastatic renal cell cancer. Int J Cancer. 1994;59:467. lesions as well as downsize tumors in patients with stage 5 dis- 26. Lornoy W, Becaus S, de Vleeschouwer M, et al. Renal cell carcinoma, a new complication of analgesic nephropathy. Lancet. 1986;1:1271. ease (bilateral disease). Before the extensive use of chemother- 27. McCredie M, Pommer W, McLaughlin JK, et al. International renal-cell apy, the survival rate for patients with stage 2 or 3 tumors was cancer study. II. Analgesics. Int J Cancer. 1995;60:345. less than 45%. Now, cure rates approaching 80% to 90% are 28. Keith DS, Torres VE, King BF, et al. Renal cell carcinoma in autosomal routinely achieved; survival rates of 92% to 97% are obtainable dominant polycystic kidney disease. J Am Soc Nephrol. 1994;4:1661. 29. Hajj P, Ferlicot S, Massoud W, et al. Prevalence of renal cell carcinoma in in earlier stages of disease. Chemotherapy administration in patients with autosomal dominant polycystic kidney disease and chronic the adjuvant and neoadjuvant settings varies greatly between renal failure. Urology. 2009;74(3):631. Europe (studies of the International Society of Paediatric 30. Gago-Dominguez M, Yuan JM, Castelao JE, et al. Family history and risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2001;10:1001. Oncology [SIOP]) and the United States (Wilms’ Tumor 31. Schlehofer B, Pommer W, Mellemgaard A, et al. International renal- Study Group [WTSG]). cell-cancer study. VI. The role of medical and family history. Int J Cancer. As these excellent results continue to accumulate, treatment 1996;66:723. programs aimed at lessening treatment duration and mini- 32. McLaughlin JK, Mandel JS, Blot WJ, et al. A population-based case- control study of renal cell carcinoma. J Natl Cancer Inst. 1984;72:275. mizing long-term consequences, such as induction of second 33. Mellemgaard A, Engholm G, McLaughlin JK, et al. Occupational risk tumors, continue to be evaluated. Such programs include the factors for renal-cell carcinoma in Denmark. Scand J Work Environ Health. more selective use of radiation therapy and a decrease in the 1994;20:160. 34. Gnarra JR, Glenn GM, Latif F, et al. Molecular genetic studies of sporadic duration of chemotherapy. and familial renal cell carcinoma. Urol Clin North Am. 1993;20:207. 35. Cohen AJ, Li FP, Berg S, et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med. 1979;301:592. 36. Pathak S, Strong LC, Ferrell RE, et al. Familial renal cell carcinoma References with a 3;11 chromosome translocation limited to tumor cells. Science. 1982;217:939. 1. Bracken RB, Chica G, Johnson DE, et al. Secondary renal neoplasms: an 37. Carroll PR, Murty VV, Reuter V, et al. Abnormalities at chromosome autopsy study. South Med J. 1979;72:806. region 3p12-14 characterize clear cell renal carcinoma. Cancer Genet 2. Pollack HM, Banner MP, Amendola MA. Other malignant neoplasms of Cytogenet. 1987;26:253. the renal parenchyma. Semin Roentgenol. 1987;22:260. 38. Zbar B, Brauch H, Talmadge C, et al. Loss of alleles of loci on the short 3. Klinger ME. Secondary tumors of the genito-urinary tract. J Urol. arm of chromosome 3 in renal cell carcinoma. Nature. 1987;327:721. 1951;65:144. 39. Zbar B, Tory K, Merino M, et al. Hereditary papillary renal cell carcinoma. 4. Sánchez-Ortiz RF, Madsen LT, Bermejo CE, et al. A renal mass in the J Urol. 1994;151:561. setting of a nonrenal malignancy: when is a renal tumor biopsy appropriate? 40. Coleman JA, Russo P. Hereditary and familial kidney cancer. Current Opin Cancer. 2004;101:2195. Urol. 2009;19:478. 5. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 41. Grawitz P. Die sogennanten Lipoma der Niere. Virchows Arch Pathol Anat. 2009;59(4):225-249. 1883;93:39. 6. GLOBOCAN [online database]. 2009. Available at http://www-dep.iarc.fr/ 42. Tannenbaum M. Ultrastructural pathology of human renal cell tumors. Accessed November 1, 2009. Pathol Annu. 1971;6:249. 7. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: 43. Richie J, Skinner D. Renal neoplasia. Philadelphia: Saunders; 1981:p 2109. Globocan 2000. Int J Cancer. 2001;94:153. 44. Thoenes W, Storkel S, Rumpelt H. Histopathology and classification of 8. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cancer in the United States. JAMA. 1999;281:1628. cytological and histopathological elements and their use for diagnostics. 9. Siemer S, Hack M, Lehmann J, et al. Outcome of renal tumors in young Pathol Res Pract. 1986;181:125. adults. J Urol. 2006;175:1240. 45. Storkel S, van den Berg E. Morphological classification of renal cancer. 10. Cook A, Lorenzo AJ, Salle JL, et al. Pediatric renal cell carcinoma: World J Urol. 1995;13:153. single institution 25-year case series and initial experience with partial 46. Garnick M. Primary neoplasms of the kidney. In: Brady H, Wilcox C, eds. nephrectomy. J Urol. 2006;175:1456. Therapy in nephrology and hypertension: a companion to Brenner and Rector’s 11. Estrada CR, Suthar AM, Eaton SH, et al. Renal cell carcinoma: Children’s the kidney. Philadelphia: Saunders; 1999. Hospital Boston experience. Urology. 2005;66:1296. 47. Delahunt B. Sarcomatoid renal carcinoma: the final common 12. Watson RA. Kidney cancer in American Indian and native Alaskan men dedifferentiation pathway of renal epithelial malignancies. Pathology. and women—time to notice, time to care. Urology. 2008;72:726. 1999;31:185. 13. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 48. Presti Jr JC, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and 2006;56:106. molecular characterization of renal cortical tumors. Cancer Res. 1991;51:1544. 14. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of 49. Weiss L, Gelb A, Medeiros L. Adult renal epithelial neoplasms. Am J Clin renal cell carcinoma. J Urol. 2001;166:1611. Pathol. 1995;103:624. 15. Lee CT, Katz J, Shi W, et al. Surgical management of renal tumors 4 cm. or 50. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic less in a contemporary cohort. J Urol. 2000;163:730. parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655. 1530 Section V Disorders of Kidney Structure and Function

51. Mancilla-Jimenez R, Stanley RJ, Blath RA. Papillary renal cell carcinoma: a 82. Nakamura N, Ramaswamy S, Vazquez F, et al. Forkhead transcription clinical, radiologic, and pathologic study of 34 cases. Cancer. 1976;38:2469. factors are critical effectors of cell death and cell cycle arrest downstream of 52. Sene AP, Hunt L, McMahon RF, et al. Renal carcinoma in patients PTEN. Mol Cell Biol. 2000;20:8969. undergoing nephrectomy: analysis of survival and prognostic factors. Br J 83. Tanimoto K, Makino Y, Pereira T, et al. Mechanism of regulation of Urol. 1992;70:125. the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor 53. Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival suppressor protein. EMBO J. 2000;19:4298. associated with metastatic renal cell carcinoma of non–clear-cell histology. 84. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-alpha J Clin Oncol. 2002;20:2376. binding and ubiquitylation by the von Hippel-Lindau tumor suppressor 54. Delahunt B. Advances and controversies in grading and staging of renal cell protein. J Biol Chem. 2000;275:25733. carcinoma. Mod Pathol. 2009;22(suppl 2):S24. 85. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes 55. Pignot G, Elie C, Conquy S, et al. Survival analysis of 130 patients with Dev. 1983;14:2000. papillary renal cell carcinoma: prognostic utility of type 1 and type 2 86. Masson N, William C, Maxwell PH, et al. Independent function of two subclassification.Urology . 2007;69:230. destruction domains in hypoxia-inducible factor-alpha chains activated by 56. Thoenes W, Storkel S, Rumpelt HJ, et al. Chromophobe cell renal prolyl hydroxylation. EMBO J. 2001;20:5197. carcinoma and its variants—a report on 32 cases. J Pathol. 1988;155:277. 87. Lonergan KM, Iliopoulos O, Ohh M, et al. Regulation of hypoxia-inducible 57. Storkel S, Steart PV, Drenckhahn D, et al. The human chromophobe cell mRNAs by the von Hippel-Lindau tumor suppressor protein requires renal carcinoma: its probable relation to intercalated cells of the collecting binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. duct. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;56:237. 1998;18:732. 58. Ortmann M, Vierbuchen M, Fischer R. Sialylated glycoconjugates in 88. Jaakkola P, Mole DR, Tian Y-M, et al. Targeting of HIF-α to the chromophobe cell renal carcinoma compared with other renal cell tumors. von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl Indication of its development from the collecting duct epithelium. Virchows hydroxylation. Science. 2001;292:468. Arch B Cell Pathol Incl Mol Pathol. 1991;61:123. 89. Yu F, White SB, Zhao Q, et al. HIF-1α binding to VHL is regulated 59. Akhtar M, Kardar H, Linjawi T, et al. Chromophobe cell carcinoma by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A. of the kidney. A clinicopathologic study of 21 cases. Am J Surg Pathol. 2001;98:9630. 1995;19:1245. 90. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases 60. Speicher MR, Schoell B, du Manoir S, et al. Specific loss of chromosomes that modify HIF. Science. 2001;294:1337. 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by 91. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. comparative genomic hybridization. Am J Pathol. 1994;145:356. 2005;353:2477. 61. Kovacs A, Kovacs G. Low chromosome number in chromophobe renal cell 92. Bentz M, Bergerheim U, Li C, et al. Chromosome imbalances in papillary carcinomas. Genes Chromosomes Cancer. 1992;4:267. renal cell carcinoma and first cytogenetic data of familial cases analyzed by 62. Druker BJ, Schwartz L, Marion S, et al. Phase II trial of ZD 1839 (Iressa), comparative genomic hybridization. Cytogenet Cell Genet. 1996;75:17. and EGF receptor inhibitor, in patients with renal cell carcinoma. Proc Am 93. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in Soc Clin Oncol. 2002;21:720. the tyrosine kinase domain of the MET proto-oncogene in papillary renal 63. Kennedy SM, Merino MJ, Linehan WM, et al. Collecting duct carcinoma carcinomas. Nat Genet. 1997;16:68. of the kidney. Hum Pathol. 1990;21:449. 94. Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET 64. Rumpelt HJ, Storkel S, Moll R, et al. Bellini duct carcinoma: further proto-oncogene in papillary renal carcinomas. Oncogene. 1999;18:2343. evidence for this rare variant of renal cell carcinoma. Histopathology. 95. McGrath JA. Biologic lessons from mutations in the Kreb’s cycle enzyme, 1991;18:115. fumarate hydratase. J Invest Dermatol. 2003;121:vii. 65. Davis Jr CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The 96. Kiuru M, Launonen V, Hietala M, et al. Familial cutaneous leiomyomatosis seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1. is a two-hit condition associated with renal cell cancer of characteristic 66. Assad L, Resetkova E, Oliveira VL, et al. Cytologic features of renal histopathology. Am J Pathol. 2001;159:825. medullary carcinoma. Cancer. 2005;105:28. 97. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine 67. Srigley JR, Delahunt B. Uncommon and recently described renal leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A. 2001;98:3387. carcinomas. Mod Pathol. 2009;22(suppl 2):S2. 98. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH 68. Yang XJ, Sugimura J, Tretiakova MS, et al. Gene expression profiling predispose to dominantly inherited uterine fibroids, skin leiomyomata and of renal medullary carcinoma: potential clinical relevance. Cancer. papillary renal cell cancer. Nat Genet. 2002;30:406. 2004;100:976. 99. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate 69. Tomlinson GE, Nisen PD, Timmons CF, et al. Cytogenetics of a renal cell hydratase gene cause hereditary leiomyomatosis and renal cell cancer in carcinoma in a 17-month-old child. Evidence for Xp11.2 as a recurring families in North America. Am J Hum Genet. 2003;73:95. breakpoint. Cancer Genet Cytogenet. 1991;57:11. 100. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt- 70. Heimann P, El Housni H, Ogur G, et al. Fusion of a novel gene, RCC17, Hogg-Dube syndrome. Am J Surg Pathol. 2002;26:1542. to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell 101. Pavlovich CP, Grubb 3rd RL, Hurley K, et al. Evaluation and management carcinomas. Cancer Res. 2001;61:4130. of renal tumors in the Birt-Hogg-Dube syndrome. J Urol. 2005;173:1482. 71. Bruder E, Passera O, Harms D, et al. Morphologic and molecular 102. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms characterization of renal cell carcinoma in children and young adults. Am J and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Surg Pathol. 2004;28:1117. Epidemiol Biomarkers Prev. 2002;11:393. 72. Lieber MM. Renal oncocytoma: prognosis and treatment. Eur Urol. 103. Nickerson M, Warren M, Toro J, et al. Mutations in a novel gene lead to 1990;18(suppl 2):17. kidney tumors, lung wall defects, and benign tumors of the hair follicle in 73. Zerban H, Nogueira E, Riedasch G, et al. Renal oncocytoma: origin from patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002;2:157. the collecting duct. Virchows Arch B Cell Pathol Incl Mol Pathol. 1987;52:375. 104. Vocke CD, Yang Y, Pavlovich CP, et al. High frequency of somatic 74. Morra MN, Das S. Renal oncocytoma: a review of histogenesis, frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal histopathology, diagnosis and treatment. J Urol. 1993;150:295. tumors. J Natl Cancer Inst. 2005;97:931. 75. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the 105. Khoo SK, Kahnoski K, Sugimura J, et al. Inactivation of BHD in sporadic kidney. J Urol. 2003;170:2163. renal tumors. Cancer Res. 2003;63:4583. 76. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau 106. Nagy A, Zoubakov D, Stupar Z, et al. Lack of mutation of the folliculin disease tumor suppressor gene. Science. 1993;260:1317. gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma. 77. Kondo T, Nakazawa H, Ito F, et al. Impact of the extent of regional Int J Cancer. 2004;109:472. lymphadenectomy on the survival of patients with urothelial carcinoma of 107. Inoki K, Corradetti MN, Guan K-L. Dysregulation of the TSC-mTOR the upper urinary tract. J Urol. 2007;178:1212. pathway in human disease. Nat Genet. 2005;37:19. 78. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history 108. Hartman TR, Nicolas E, Klein-Szanto A, et al. The role of the Birt-Hogg- of von Hippel-Lindau disease. Q J Med. 1990;77:1151. Dubé protein in mTOR activation and renal tumorigenesis. Oncogene. 79. Pause A, Lee S, Worrell RA, et al. The von Hippel-Lindau tumor- 2009;28:1594. suppressor gene product forms a stable complex with human CUL-2, 109. Brugarolas J. Renal-cell carcinoma—molecular pathways and therapies. a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A. N Engl J Med. 2007;356:185. 1997;94:2156. 110. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the 80. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805. Oncol. 2004;22:4991. 111. Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort 81. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible of 224 tuberous sclerosis patients indicates increased severity of TSC2, factor requires direct binding to the beta-domain of the von Hippel-Lindau compared with TSC1, disease in multiple organs. Am J Hum Genet. protein. Nat Cell Biol. 2000;2:423. 2001;68:64. Chapter 40 Renal Neoplasia 1531

112. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus 144. Israel GM, Bosniak MA. An update of the Bosniak renal cyst classification conference: revised clinical diagnostic criteria. J Child Neurol. 1998;13:624. system. Urology. 2005;66:484. 113. Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal 145. Israel GM, Hindman N, Bosniak MA. Evaluation of cystic renal masses: carcinoma in the United States: trends from the Surveillance, Epidemiology, comparison of CT and MR imaging by using the Bosniak classification and End Results program. J Urol. 2006;176:2397. system. Radiology. 2004;231:365. 114. Patard J-J, Leray E, Cindolo L, et al. Multi-institutional validation of a 146. Bhave G, Lewis JB, Chang SS. Association of gadolinium based magnetic symptom based classification for renal cell carcinoma.J Urol. 2004;172:858. resonance imaging contrast agents and nephrogenic systemic fibrosis.J Urol. 115. Patard J-J, Leray E, Rodriguez A, et al. Correlation between symptom 2008;180:830. graduation, tumor characteristics and survival in renal cell carcinoma. Eur 147. Hallscheidt PJ, Fink C, Haferkamp A, et al. Preoperative staging of renal Urol. 2003;44:226. cell carcinoma with inferior vena cava thrombus using multidetector CT 116. Bensalah K, Pantuck AJ, Crepel M, et al. Prognostic variables to predict and MRI: prospective study with histopathological correlation. J Comput cancer-related death in incidental renal tumours. BJU Int. 2008;102:1376. Assist Tomogr. 2005;29:64. 117. Skinner DG, Colvin RB, Vermillion CD, et al. Diagnosis and management 148. Semelka RC, Shoenut JP, Magro CM, et al. Renal cancer staging: of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer. comparison of contrast-enhanced CT and gadolinium-enhanced fat- 1971;28:1165. suppressed spin-echo and gradient-echo MR imaging. J Magn Reson 118. Gibbons RP, Monte JE, Correa Jr RJ, et al. Manifestations of renal cell Imaging. 1993;3:597. carcinoma. Urology. 1976;8:201. 149. Daponte D, Zungri E, Algaba F, et al. [Isolated renal angiomyolipoma. 119. Pinals RS, Krane SM. Medical aspects of renal carcinoma. Postgrad Med J. Study of 10 cases]. J Urol (Paris). 1983;89:267. 1962;38:507. 150. Yamashita Y, Ueno S, Makita O, et al. Hyperechoic renal tumors: anechoic 120. Linehan W, Shipley W, Parkinson D. Cancer of the kidney and ureter. In: rim and intratumoral cysts in US differentiation of renal cell carcinoma DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of from angiomyolipoma. Radiology. 1993;188:179. oncology. Philadelphia: Lippincott; 1993:1023-1051. 151. Milner J, McNeil B, Alioto J, et al. Fat poor renal angiomyolipoma: patient, 121. Chisholm GD, Roy RR. The systemic effects of malignant renal tumours. computerized tomography and histological findings.J Urol. 2006; Br J Urol. 1971;43:687. 176:905. 122. Laski ME, Vugrin D. Paraneoplastic syndromes in hypernephroma. Semin 152. Atlas I, Kwan D, Stone N. Value of serum alkaline phosphatase and Nephrol. 1987;7:123. radionuclide bone scans in patients with renal cell carcinoma. Urology. 123. Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell 1991;38:220. carcinoma. Semin Urol Oncol. 1996;14:216. 153. Koga S, Tsuda S, Nishikido M, et al. The diagnostic value of bone scan in 124. Cranston WI, Luff RH, Owen D, et al. Studies on the pathogenesis of fever patients with renal cell carcinoma. J Urol. 2001;166:2126. in renal carcinoma. Clin Sci Mol Med. 1973;45:459. 154. Kang DE, White Jr RL, Zuger JH, et al. Clinical use of fluorodeoxyglucose 125. Sufrin G, Murphy GP. Humoral syndromes of renal adenocarcinoma in F 18 positron emission tomography for detection of renal cell carcinoma. man. Rev Surg. 1977;34:149. J Urol. 1806;171:2004. 126. Sufrin G, Mirand EA, Moore RH, et al. Hormones in renal cancer. J Urol. 155. Nieh P. PET scans in urology. AUA Update Series. 2009;28:121. 1977;117:433. 156. Divgi CR, Pandit-Taskar N, Jungbluth AA, et al. Preoperative 127. Walsh PN, Kissane JM. Nonmetastatic hypernephroma with reversible characterisation of clear-cell renal carcinoma using iodine-124-labelled hepatic dysfunction. Arch Intern Med. 1968;122:214. antibody chimeric G250 (124I-cG250) and PET in patients with renal 128. Chuang YC, Lin AT, Chen KK, et al. Paraneoplastic elevation of serum masses: a phase I trial. Lancet Oncol. 2007;8:304. alkaline phosphatase in renal cell carcinoma: incidence and implication on 157. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an prognosis. J Urol. 1997;158:1684. independent predictor of survival in advanced renal clear cell carcinoma: 129. Stadler WM, Richards JM, Vogelzang NJ. Serum interleukin-6 levels in implications for prognosis and therapy. Clin Cancer Res. 2003;9:802. metastatic renal cell cancer: correlation with survival but not an independent 158. Bui MH, Visapaa H, Seligson D, et al. Prognostic value of carbonic prognostic indicator. J Natl Cancer Inst. 1835;84:1992. anhydrase IX and KI67 as predictors of survival for renal clear cell 130. Gotoh A, Kitazawa S, Mizuno Y, et al. Common expression of parathyroid carcinoma. J Urol. 2004;171:2461. hormone–related protein and no correlation of calcium level in renal cell 159. Brouwers AH, Dorr U, Lang O, et al. 131 I-cG250 monoclonal antibody carcinomas. Cancer. 1993;71:2803. immunoscintigraphy versus [18 F]FDG-PET imaging in patients with 131. Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic metastatic renal cell carcinoma: a comparative study. Nucl Med Commun. stratification of 670 patients with advanced renal cell carcinoma.J Clin 2002;23:229. Oncol. 1999;17:2530. 160. Ritchie AW, Chisholm GD. The natural history of renal carcinoma. Semin 132. O’Grady AS, Morse LJ, Lee JB. Parathyroid hormone–secreting renal Oncol. 1983;10:390. carcinoma associated with hypercalcemia and metabolic alkalosis. Ann 161. McDougal WS, Garnick M. Clinical signs and symptoms of kidney cancer. Intern Med. 1965;63:858. In: Vogelzang NJ, Scardino PT, Shipley WU, et al. eds. Comprehensive 133. Brereton HD, Halushka PV, Alexander RW, et al. Indomethacin-responsive textbook of genitourinary oncology. Baltimore: Williams & Wilkins; 1996. hypercalcemia in a patient with renal-cell adenocarcinoma. N Engl J Med. 162. Johnson CD, Dunnick NR, Cohan RH, et al. Renal adenocarcinoma: CT 1974;291:83. staging of 100 tumors. AJR Am J Roentgenol. 1987;148:59. 134. Lipton A, Colombo-Berra A, Bukowski RM, et al. Skeletal complications 163. Greene FL, Page DL, Morrow M. AJCC cancer staging manual. 6th ed. New in patients with bone metastases from renal cell carcinoma and therapeutic York: Springer; 2002. benefits of zoledronic acid.Clin Cancer Res. 2004;10:6397S. 164. Sika-Paotonu D, Bethwaite PB, McCredie MR, et al. Nucleolar grade but 135. Weber K, Doucet M, Kominsky S. Renal cell carcinoma bone metastasis— not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg elucidating the molecular targets. Cancer Metastasis Rev. 2007;26:691. Pathol. 2006;30:1091. 136. Aragon-Ching JB, Ning YM, Chen CC, et al. Higher incidence of 165. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in osteonecrosis of the jaw (ONJ) in patients with metastatic castration previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. resistant prostate cancer treated with anti-angiogenic agents. Cancer Invest. 2004;22:454. 2009;27:221. 166. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative 137. Christodoulou C, Pervena A, Klouvas G, et al. Combination of treatment for clinical trials of new therapies against advanced renal cell bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw carcinoma. J Clin Oncol. 2002;20:289. more frequently than bisphosphonates alone. Oncology. 2009;76:209. 167. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and 138. Patard J-J. Incidental renal tumours. Current Opin Urol. 2009;19:454. extension of the Memorial Sloan-Kettering prognostic factors model 139. Jaschke W, van Kaick G, Peter S, et al. Accuracy of computed tomography for survival in patients with previously untreated metastatic renal cell in staging of kidney tumors. Acta Radiol Diagn (Stockh). 1982;23:593. carcinoma. J Clin Oncol. 2005;23:832. 140. Richie JP, Garnick MB. Primary renal and ureteral cancer. In: Rieselbach 168. Eggener SE, Yossepowitch O, Pettus JA, et al. Renal cell carcinoma RE, Garnick MB, eds. Cancer and the kidney. Philadelphia: Lea & Febiger; recurrence after nephrectomy for localized disease: predicting survival from 1982:p 662. time of recurrence. J Clin Oncol. 2006;24:3101. 141. Bosniak MA. The current radiological approach to renal cysts. Radiology. 169. Zisman A, Pantuck AJ, Figlin RA, et al. Validation of the UCLA integrated 1986;158:1. staging system for patients with renal cell carcinoma. J Clin Oncol. 142. Amendola MA, Bree RL, Pollack HM, et al. Small renal cell carcinomas: 2001;19:3792. resolving a diagnostic dilemma. Radiology. 1988;166:637. 170. Frank I, Blute ML, Cheville JC, et al. An outcome prediction model 143. D’Orsi CJ, Kaplan WD. The radiologic and radionucleotide evaluation of for patients with clear cell renal cell carcinoma treated with radical the kidney. In: Rieselbach RE, Garnick MB, eds. Cancer and the kidney. nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN Philadelphia: Lea & Febiger; 1982:56-102. score. J Urol. 2002;168:2395. 1532 Section V Disorders of Kidney Structure and Function

171. Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic 199. Belldegrun A, Tsui KH, de Kernion JB, et al. Efficacy of nephron-sparing nomogram predicting recurrence for patients with conventional clear cell surgery for renal cell carcinoma: analysis based on the new 1997 tumor- renal cell carcinoma. J Urol. 2005;173:48. node-metastasis staging system. J Clin Oncol. 1999;17:2868. 172. Fahn HJ, Lee YH, Chen MT, et al. The incidence and prognostic 200. Barbalias GA, Liatsikos EN, Tsintavis A, et al. Adenocarcinoma of the significance of humoral hypercalcemia in renal cell carcinoma.J Urol. kidney: nephron-sparing surgical approach vs. radical nephrectomy. J Surg 1991;145:248. Oncol. 1999;72:156. 173. Ljungberg B, Joanssen H, Stenling R. Prognostic factors in renal cell 201. Indudhara R, Bueschen AJ, Urban DA, et al. Nephron-sparing surgery carcinoma. Int Urol Nephrol. 1988;20:115. compared with radical nephrectomy for renal tumors: current indications 174. Grignon DJ, Ayala AG, el-Naggar A, et al. Renal cell carcinoma. A and results. South Med J. 1997;90:982. clinicopathologic and DNA flow cytometric analysis of 103 cases.Cancer . 202. Lerner SE, Hawkins CA, Blute ML, et al. Disease outcome in patients 1989;64:2133. with low stage renal cell carcinoma treated with nephron sparing or radical 175. Uhlman DL, Nguygen PL, Manivel JC, et al. Association of surgery. J Urol. 1868;155:1996. immunohistochemical staining for p53 with metastatic progression and 203. D’Armiento M, Damiano R, Feleppa B, et al. Elective conservative surgery poor survival in patients with renal cell carcinoma. J Natl Cancer Inst. for renal carcinoma versus radical nephrectomy: a prospective study. Br J 1994;86:1470. Urol. 1997;79:15. 176. Santhanam U, Ray A, Sehgal PB. Repression of the interleukin 6 gene 204. Clayman RV, Kavoussi LR, Soper NJ, et al. Laparoscopic nephrectomy: promoter by p53 and the retinoblastoma susceptibility gene product. Proc initial case report. J Urol. 1991;146:278. Natl Acad Sci U S A. 1991;88:7605. 205. Rassweiler J, Fornara P, Weber M, et al. Laparoscopic nephrectomy: the 177. Oda H, Nakatsuru Y, Ishikawa T. Mutations of the p53 gene and p53 experience of the laparoscopy working group of the German Urologic protein overexpression are associated with sacromatoid transformation in Association. J Urol. 1998;160:18. renal cell carcinomas. Cancer Res. 1995;55:658. 206. Rassweiler JJ, Henkel TO, Potempa DM, et al. The technique 178. Sagalowsky AI, Kadesky KT, Ewalt DM, et al. Factors influencing adrenal of transperitoneal laparoscopic nephrectomy, adrenalectomy and metastasis in renal cell carcinoma. J Urol. 1994;151:1181. nephroureterectomy. Eur Urol. 1993;23:425. 179. Shalev M, Cipolla B, Guille F, et al. Is ipsilateral adrenalectomy a necessary 207. McDougall E, Clayman RV, Elashry OM. Laparoscopic radical component of radical nephrectomy? J Urol. 1995;153:1415. nephrectomy for renal tumor: the Washington University experience. J Urol. 180. Gill IS, McClennan BL, Kerbl K, et al. Adrenal involvement from renal 1996;155:1180. cell carcinoma: predictive value of computerized tomography. J Urol. 208. Weight CJ, Fergany AF, Gunn PW, et al. The impact of minimally invasive 1994;152:1082. techniques on open partial nephrectomy: a 10-year single institutional 181. Delacroix Jr SE, Wood CG. The role of lymphadenectomy in renal cell experience. J Urol. 2008;180:84. carcinoma. Curr Opin Urol. 2009;19:465. 209. Meraney AM, Gill IS. Financial analysis of open versus laparoscopic radical 182. Blute ML, Leibovich BC, Cheville JC, et al. A protocol for performing nephrectomy and nephroureterectomy. J Urol. 2002;167:1757. extended lymph node dissection using primary tumor pathological features 210. Lane BR, Gill IS. 5-Year outcomes of laparoscopic partial nephrectomy. for patients treated with radical nephrectomy for clear cell renal cell J Urol. 2007;177:70. carcinoma. J Urol. 2004;172:465. 211. Jeschke K, Peschel R, Wakonig J, et al. Laparoscopic nephron-sparing 183. Hutterer GC, Patard JJ, Perrotte P, et al. Patients with renal cell carcinoma surgery for renal tumors. Urology. 2001;58:688. nodal metastases can be accurately identified: external validation of a new 212. Gettman MT, Bishoff JT, Su LM, et al. Hemostatic laparoscopic partial nomogram. Int J Cancer. 2007;121:2556. nephrectomy: initial experience with the radiofrequency coagulation- 184. Blom J, van Poppel H, Marechal J, et al. Radical nephrectomy with and assisted technique. Urology. 2001;58:8. without lymph-node dissection: final results of the European Organization 213. Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for for Research and Treatment of Cancer (EORTC) randomized phase 3 trial renal tumor: duplicating open surgical techniques. J Urol. 2002; 30881. Eur Urol. 2009;55:6. 167:469. 185. Vasselli JR, Yang JC, Linehan WM, et al. Lack of retroperitoneal 214. Riggs SB, Larochelle JC, Belldegrun AS. Partial nephrectomy: a lymphadenopathy predicts survival of patients with metastatic renal cell contemporary review regarding outcomes and different techniques. Cancer J. carcinoma. J Urol. 2001;166:68. 2008;14:302. 186. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with 215. Canes D. Long-term oncological outcomes of laparoscopic partial retroperitoneal lymph nodes. Impact on survival and benefits of nephrectomy. Curr Opin Urol. 2008;18:145. immunotherapy. Cancer. 2003;97:2995. 216. Shapiro E, Benway BM, Wang AJ, et al. The role of nephron-sparing 187. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with robotic surgery in the management of renal malignancy. Curr Opin Urol. retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2009;19:76. 2003;169:2076. 217. Kural AR, Atug F, Tufek I, et al. Robot-assisted partial nephrectomy versus 188. Canfield SE, Kamat AM, Sanchez-Ortiz RF, et al. Renal cell carcinoma laparoscopic partial nephrectomy: comparison of outcomes. J Endourol. with nodal metastases in the absence of distant metastatic disease (clinical 2009;23:1491. stage TxN1-2M0): the impact of aggressive surgical resection on patient 218. Benway BM, Bhayani SB, Rogers CG, et al. Robot assisted partial outcome. J Urol. 2006;175:864. nephrectomy versus laparoscopic partial nephrectomy for renal tumors: a 189. Guideline for management of the clinical stage 1 renal mass. Linthicum Md: multi-institutional analysis of perioperative outcomes. J Urol. 2009;182:866. American Urological Association Education and Research; 2009. 219. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation: outcome at 3 190. Moll V, Becht E, Ziegler M. Kidney preserving surgery in renal cell years. J Urol. 1903;173:2005. tumors: indications, techniques and results in 152 patients. J Urol. 220. Anderson JK, Matsumoto E, Cadeddu JA. Renal radiofrequency ablation: 1993;150:319. technique and results. Urol Oncol. 2005;23:355. 191. Thrasher JB, Robertson JE, Paulson DF. Expanding indications for 221. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small conservative renal surgery in renal cell carcinoma. Urology. 1994;43:160. renal mass: a meta-analysis. Cancer. 2008;113:2671. 192. Steinbach F, Stockle M, Hohenfellner R. Current controversies in nephron- 222. Bazeed MA, Scharfe T, Becht E, et al. Conservative surgery of renal cell sparing surgery for renal-cell carcinoma. World J Urol. 1995;13:163. carcinoma. Eur Urol. 1986;12:238. 193. Provet J, Tessler A, Brown J, et al. Partial nephrectomy for renal cell 223. Libertino JA, Swierzewski DJ, Swierzewski MJ. Renal cell carcinoma with carcinoma: indications, results and implications. J Urol. 1991;145:472. extension into the vena cava. In: Libertino J, ed. Reconstructive urologic 194. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. surgery. St. Louis: Mosby–Year Book; 1998:47-54. 1996;335:865. 224. Cherrie RJ, Goldman DG, Lindner A, et al. Prognostic implications of vena 195. Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy caval extension of renal cell carcinoma. J Urol. 1982;128:910. for pT1a renal masses may be associated with decreased overall survival 225. Hatcher PA, Anderson EE, Paulson DF, et al. Surgical management compared with partial nephrectomy. J Urol. 2008;179:468. and prognosis of renal cell carcinoma invading the vena cava. J Urol. 196. Lau WK, Blute ML, Weaver AL, et al. Matched comparison of radical 1991;145:20. nephrectomy vs nephron-sparing surgery in patients with unilateral 226. Marshall FF, Dietrick DD, Baumgartner WA, et al. Surgical management renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc. of renal cell carcinoma with intracaval neoplastic extension above the 2000;75:1236. hepatic veins. J Urol. 1988;139:1166. 197. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after 227. Novick AC. Current surgical approaches, nephron-sparing surgery, and nephrectomy in patients with renal cortical tumours: a retrospective cohort the role of surgery in the integrated immunologic approach to renal-cell study. Lancet Oncol. 2006;7:735. carcinoma. Semin Oncol. 1995;22:29. 198. Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: 228. Boorjian SA, Blute ML. Surgery for vena caval tumor extension in renal indications, techniques and outcomes. J Urol. 2001;166:6. cancer. Curr Opin Urol. 2009;19:473. Chapter 40 Renal Neoplasia 1533

229. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus 258. Ikushima H, Tokuuye K, Sumi M, et al. Fractionated stereotactic interferon-alfa–based immunotherapy compared with interferon alfa radiotherapy of brain metastases from renal cell carcinoma. Int J Radiat alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. Oncol Biol Phys. 2000;48:1389. 2001;358:966. 259. Lane BR, Kattan M. W.: Prognostic models and algorithms in renal cell 230. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed carcinoma. Urol Clin North Am. 2008;35:613. by interferon alfa-2b compared with interferon alfa-2b alone for metastatic 260. Messing EM, Manola J, Wilding G, et al. Phase III study of interferon renal-cell cancer. N Engl J Med. 2001;345:1655. alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern 231. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003;21:1214. metastatic renal-cell carcinoma. N Engl J Med. 2001;345:1711. 261. Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus 232. McDermott D, Flaherty L, Clark J, et al. A randomized phase III trial interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine of high-dose interleukin-2 (HD IL2) versus subcutaneous (SC) 112/ working group randomized trial. J Clin Oncol. 2003;21:3133. interfereon (IFN) in patients with metastatic renal cell carcinoma (RCC). 262. Margulis V, Matin SF, Tannir N, et al. Randomized trial of adjuvant Proc Am Soc Clin Oncol. 2001;20:685:abstract. thalidomide versus observation in patients with completely resected high- 233. Bennett RT, Lerner SE, Taub HC, et al. Cytoreductive surgery for stage IV risk renal cell carcinoma. Urology. 2009;73:337. renal cell carcinoma. J Urol. 1995;154:32. 263. Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal 234. Rackley R, Novick A, Klein E, et al. The impact of adjuvant nephrectomy tumour cell vaccine and risk of tumour progression in patients with renal- on multimodality treatment of metastatic renal cell carcinoma. J Urol. cell carcinoma after radical nephrectomy: phase III, randomised controlled 1994;152:1399. trial. Lancet. 2004;363:594. 235. Taneja SS, Pierce W, Figlin R, et al. Immunotherapy for renal 264. May M, Kendel F, Hoschke B, et al. [Adjuvant autologous tumour cell cell carcinoma: the era of interleukin-2–based treatment. Urology. vaccination in patients with renal cell carcinoma. Overall survival analysis 1995;45:911. with a follow-up period in excess of more than 10 years]. Urologe A. 236. Walther MM, Yang JC, Pass HI, et al. Cytoreductive surgery before high 2009;48:1075. dose interleukin-2 based therapy in patients with metastatic renal cell 265. Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous carcinoma. J Urol. 1997;158:1675. therapeutic vaccine (HSPPC-96; vitespen) versus observation alone 237. Fallick ML, McDermott DF, LaRock D, et al. Nephrectomy before for patients at high risk of recurrence after nephrectomy for renal cell interleukin-2 therapy for patients with metastatic renal cell carcinoma. carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. J Urol. 1997;158:1691. 2008;372:145. 238. Polcari AJ, Gorbonos A, Milner JE, et al. The role of cytoreductive 266. Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma nephrectomy in the era of molecular targeted therapy. Int J Urol. [NCT00326898/ECOG 2805]. 2009. Available at http://www.clinicaltrials. 2009;16:227. gov. Accessed November 1, 2009. 239. Margulis V, Wood CG, Jonasch E, et al. Current status of debulking 267. Rini BI. Metastatic renal cell carcinoma: many treatment options, one nephrectomy in the era of tyrosine kinase inhibitors. Curr Oncol Rep. patient. J Clin Oncol. 2009;27:3225. 2008;10:253. 268. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 240. Logan T, McDermott D, Dutcher J. Exploratory analysis of the influence 2009;373:1119. of nephrectomy status on temsirolimus efficacy in patients with advanced 269. Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of renal cell carcinoma with poor risk features. J Clin Oncol. 2008;26(May 20 sunitinib malate (SU11248) versus interferon-alfa (IFN-α) as first-line suppl):5050:abstract. systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J 241. Jonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility study Clin Oncol. 2006;24(18S):LBA3:[ASCO Annual Meeting Proceedings Part I]. of bevacizumab in untreated patients with metastatic renal cell carcinoma. 270. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated J Clin Oncol. 2009;27:4076. results for sunitinib compared with interferon alfa in patients with 241a.  Chapin BF, Delacroix SE, Culp SH, et al. Safety of presurgical targeted metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584. therapy in the setting of metastatic renal cell carcinoma. Eur Urol. 2011;1-8. 271. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with Epub May 25, 2011. metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 242. Chiong E, Wood CG, Margulis V. Role of cytoreductive nephrectomy in 2007;99:81. renal cell carcinoma. Future Oncol. 2009;5:859. 272. Rixe O, Billemont B, Izzedine H. Hypertension as a predictive factor of 243. Wood CG, Margulis V. Neoadjuvant (presurgical) therapy for renal cell sunitinib activity. Ann Oncol. 2007;18:1117. carcinoma: a new treatment paradigm for locally advanced and metastatic 273. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled disease. Cancer. 2009;115:2355. randomized discontinuation trial of sorafenib in patients with metastatic 244. Kaufman JJ. Cancer of the urogenital tract: kidney. Reasons for renal cell carcinoma. J Clin Oncol. 2006;24:2505. nephrectomy: palliative and curative. JAMA. 1968;204:607. 274. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell 245. De Conno F, Martini C, Zecca E, et al. Megestrol acetate for anorexia in renal-cell carcinoma. N Engl J Med. 2007;356:125. patients with far-advanced cancer: a double-blind controlled clinical trial. 275. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of Eur J Cancer. 1998;34:1705. renal cell carcinoma: Final efficacy and safety results of the phase III 246. Dekernion JB, Ramming KP, Smith RB. The natural history of metastatic treatment approaches in renal cancer global evaluation trial. J Clin Oncol. renal cell carcinoma: a computer analysis. J Urol. 1978;120:148. 2009;27:3312. 247. Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic 276. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of renal cell carcinoma. J Clin Oncol. 1998;16:2261. first-line treatment with sorafenib versus interferon alfa-2a in patients with 248. Dineen MK, Pastore RD, Emrich LJ, et al. Results of surgical treatment of metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280. renal cell carcinoma with solitary metastasis. J Urol. 1988;140:277. 277. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally 249. Swanson D. A.: Surgery for metastases of renal cell carcinoma. Scand J Surg. administered small-molecule multitargeted tyrosine kinase inhibitor for 2004;93:150. renal cell carcinoma. Expert Opin Investig Drugs. 2008;17:253. 250. Belldegrun A, Abi-Aad AS, Figlin RA, et al. Renal cell carcinoma: basic 278. Sternber CN, Szczylik C, Lee E, et al. A randomized, double-blind biology and current approaches to therapy. Semin Oncol. 1991;18:96. phase III study of pazopanib in treatment-naive and cytokine-pretreated 251. O’Dea MJ, Zincke H, Utz DC, et al. The treatment of renal cell carcinoma patients with advanced renal cell carcinoma (RCC). J Clin Oncol. with solitary metastasis. J Urol. 1978;120:540. 2009;27(suppl):15s:[abstract 5021^]. 252. Tolia BM, Whitmore Jr WF. Solitary metastasis from renal cell carcinoma. 279. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in J Urol. 1975;114:836. patients with cytokine-refractory metastatic renal-cell cancer: a phase II 253. Fossa SD, Kjolseth I, Lund G. Radiotherapy of metastases from renal study. Lancet Oncol. 2007;8:975. cancer. Eur Urol. 1982;8:340. 280. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon 254. Halperin EC, Harisiadis L. The role of radiation therapy in the alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, management of metastatic renal cell carcinoma. Cancer. 1983;51:614. double-blind phase III trial. Lancet. 2007;370:2103. 255. Wronski M, Maor MH, Davis BJ, et al. External radiation of brain 281. Rini B, Halabi S, Rosenberg J, et al. Bevacizumab plus interferon-alpha metastases from renal carcinoma: a retrospective study of 119 patients versus interferon-alpha monotherapy in patients with metastatic renal from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys. cell carcinoma: results of overall survival for CALGB 90206. J Clin Oncol. 1997;37:753. 2009;27(suppl):18s:[abstract LBA5019]. 256. Mori Y, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for 282. Escudier BJ, Ravaud A, Bracarda S, et al. Efficacy and safety of first-line brain metastasis from renal cell carcinoma. Cancer. 1998;83:344. bevacizumab (BEV) plus interferon-α2a (IFN) in subgroups of patients (pts) 257. Goyal LK, Suh JH, Reddy CA, et al. The role of whole brain radiotherapy with metastatic renal cell carcinoma (mRCC). San Francisco: Paper and stereotactic radiosurgery on brain metastases from renal cell carcinoma. presented at the Genitourinary Cancers Symposium; February 14-16, Int J Radiat Oncol Biol Phys. 2000;47:1007. 2008. 1534 Section V Disorders of Kidney Structure and Function

283. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal 313. Negrier S, Perol D, Ravaud A, et al. Medroxyprogesterone, interferon cell carcinoma with a combination of bevacizumab and erlotinib. J Clin alfa-2a, interleukin 2, or combination of both cytokines in patients Oncol. 2005;23:7889. with metastatic renal carcinoma of intermediate prognosis: results of a 284. Bukowski RM, Kabbinavar FF, Figlin RA, et al. Randomized phase II study randomized controlled trial. Cancer. 2007;110:2468. of erlotinib combined with bevacizumab compared with bevacizumab alone 314. Motzer RJ, Schwartz L, Law TM, et al. Interferon alfa-2a and 13-cis- in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536. retinoic acid in renal cell carcinoma: antitumor activity in a phase II trial 285. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or and interactions in vitro. J Clin Oncol. 1950;13:1995. both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271. 315. Neidhart JA, Anderson SA, Harris JE, et al. Vinblastine fails to improve 286. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced response of renal cancer to interferon alfa-n1: high response rate in patients renal cell carcinoma: a double-blind, randomised, placebo-controlled phase with pulmonary metastases. J Clin Oncol. 1991;9:832. III trial. Lancet. 2008;372:449. 316. Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer– 287. Amato RJ, Shingler W, Naylor S, et al. Vaccination of renal cell cancer resistant established pulmonary melanoma metastases by the intravenous patients with modified vaccinia Ankara delivering tumor antigen 5T4 adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin (TroVax) administered with interleukin 2: a phase II trial. Clin Cancer Res. 2. J Exp Med. 1984;159:495. 2008;14:7504. 317. Fisher RI, Coltman Jr CA, Doroshow JH, et al. Metastatic renal cancer 288. Bleumer I, Tiemessen DM, Oosterwijk-Wakka JC, et al. Preliminary treated with interleukin-2 and lymphokine-activated killer cells. A phase II analysis of patients with progressive renal cell carcinoma vaccinated with clinical trial. Ann Intern Med. 1988;108:518. CA9-peptide-pulsed mature dendritic cells. J Immunother. 2007;30:116. 318. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the 289. Kaufman HL, Taback B, Sherman W, et al. Phase II trial of modified vaccinia treatment of 157 patients with advanced cancer using lymphokine-activated Ankara (MVA) virus expressing 5T4 and high dose interleukin-2 (IL-2) in killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J patients with metastatic renal cell carcinoma. J Transl Med. 2009;7:2. Med. 1987;316:889. 290. Minor DR, Monroe D, Damico LA, et al. A phase II study of thalidomide 319. Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients in advanced metastatic renal cell carcinoma. Invest New Drugs. 2002;20:389. with metastatic renal cell carcinoma who received high-dose recombinant 291. Daliani DD, Papandreou CN, Thall PF, et al. A pilot study of thalidomide in interleukin-2 therapy. J Clin Oncol. 1995;13:688. patients with progressive metastatic renal cell carcinoma. Cancer. 2002;95:758. 320. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of 292. Escudier B, Lassau N, Couanet D, et al. Phase II trial of thalidomide in high-dose interleukin-2 alone or in conjunction with lymphokine-activated renal-cell carcinoma. Ann Oncol. 2002;13:1029. killer cells for the treatment of patients with advanced cancer. J Natl Cancer 293. Motzer RJ, Berg W, Ginsberg M, et al. Phase II trial of thalidomide for Inst. 1993;85:622. patients with advanced renal cell carcinoma. J Clin Oncol. 2002;20:302. 321. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose 294. Choueiri TK, Dreicer R, Rini BI, et al. Phase II study of lenalidomide in recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci patients with metastatic renal cell carcinoma. Cancer. 2006;107:2609. Am. 2000;6(suppl 1):S55-57. 295. Patel PH, Kondagunta GV, Schwartz L, et al. Phase II trial of lenalidomide 322. Dillman RO, Oldham RK, Tauer KW, et al. Continuous interleukin-2 and in patients with metastatic renal cell carcinoma. Invest New Drugs. lymphokine-activated killer cells for advanced cancer: a National Biotherapy 2008;26:273. Study Group trial. J Clin Oncol. 1991;9:1233. 296. Harris DT. Hormonal therapy and chemotherapy of renal-cell carcinoma. 323. Weiss GR, Margolin KA, Aronson FR, et al. A randomized phase II trial Semin Oncol. 1983;10:422. of continuous infusion interleukin-2 or bolus injection interleukin-2 plus 297. Yagoda A, Petrylak D, Thompson S. Cytotoxic chemotherapy for advanced lymphokine-activated killer cells for advanced renal cell carcinoma. J Clin renal cell carcinoma. Urol Clin North Am. 1993;20:303. Oncol. 1992;10:275. 298. Casali M, Marcellini M, Casali A, et al. Gemcitabine in pre-treated advanced 324. Gold PJ, Thompson JA, Markowitz DR, et al. Metastatic renal cell renal carcinoma: a feasibility study. J Exp Clin Cancer Res. 2001;20:195. carcinoma: long-term survival after therapy with high-dose continuous- 299. De Mulder PH, Weissbach L, Jakse G, et al. Gemcitabine: a phase II infusion interleukin-2. Cancer J Sci Am. 1997;3(suppl 1):S85. study in patients with advanced renal cancer. Cancer Chemother Pharmacol. 325. Sosman JA, Kohler PC, Hank JA, et al. Repetitive weekly cycles of 1996;37:491. interleukin-2. II. Clinical and immunologic effects of dose, schedule, and 300. Mertens WC, Eisenhauer EA, Moore M, et al. Gemcitabine in advanced addition of indomethacin. J Natl Cancer Inst. 1988;80:1451. renal cell carcinoma. A phase II study of the National Cancer Institute of 326. Atkins MB, Sparano J, Fisher RI, et al. Randomized phase II trial of high- Canada Clinical Trials Group. Ann Oncol. 1993;4:331. dose interleukin-2 either alone or in combination with interferon alfa-2b in 301. Rini BI, Vogelzang NJ, Dumas MC, et al. Phase II trial of weekly advanced renal cell carcinoma. J Clin Oncol. 1993;11:661. intravenous gemcitabine with continuous infusion fluorouracil in patients 327. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for with metastatic renal cell cancer. J Clin Oncol. 2000;18:2419. metastatic renal cell cancer: the Cytokine Working Group experience, 1989- 302. Stadler WM, Halabi S, Rini B, et al. A phase II study of gemcitabine and 1997. Cancer J Sci Am. 1997;3(suppl 1):S73. capecitabine in metastatic renal cancer: a report of Cancer and Leukemia 328. Dutcher JP, Fisher RI, Weiss G, et al. Outpatient subcutaneous Group B protocol 90008. Cancer. 2006;107(6):1273. interleukin-2 and interferon-alpha for metastatic renal cell cancer: five- 303. Tannir NM, Thall PF, Ng CS, et al. A phase II trial of gemcitabine year follow-up of the Cytokine Working Group Study. Cancer J Sci Am. plus capecitabine for metastatic renal cell cancer previously treated with 1997;3:157. immunotherapy and targeted agents. J Urol. 2008;180:867. 329. Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with 304. Gollob JA, Upton MP, DeWolf WC, et al. Long-term remission in a interleukin-2 and alpha-interferon for the treatment of patients with patient with metastatic collecting duct carcinoma treated with Taxol/ advanced cancer. J Clin Oncol. 1863;7:1989. carboplatin and surgery. Urology. 2001;58:1058. 330. Figlin RA, Belldegrun A, Moldawer N, et al. Concomitant administration 305. Nanus DM, Garino A, Milowsky MI, et al. Active chemotherapy of recombinant human interleukin-2 and recombinant interferon alfa-2A: for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer. an active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol. 2004;101:1545. 1992;10:414. 306. Muss HB. Interferon therapy for renal cell carcinoma. Semin Oncol. 1987;14:36. 331. Atzpodien J, Lopez Hanninen E, Kirchner H, et al. Multiinstitutional 307. Muss HB. The role of biological response modifiers in metastatic renal cell home-therapy trial of recombinant human interleukin-2 and interferon carcinoma. Semin Oncol. 1988;15:30. alfa-2 in progressive metastatic renal cell carcinoma. J Clin Oncol. 308. Neidhart JA. Interferon therapy for the treatment of renal cancer. Cancer. 1995;13:497. 1986;57:1696. 332. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, 309. Muss HB, Costanzi JJ, Leavitt R, et al. Recombinant alfa interferon in renal recombinant human interferon alfa-2a, or both in metastatic renal- cell carcinoma: a randomized trial of two routes of administration. J Clin cell carcinoma. Groupe Français d’Immunothérapie. N Engl J Med. Oncol. 1987;5:286. 1998;338:1272. 310. Pyrhonen S, Salminen E, Ruutu M, et al. Prospective randomized trial of 333. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in advanced renal cell cancer. J Clin Oncol. 1999;17:2859. patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133. 311. Interferon-alpha and survival in metastatic renal carcinoma: early results 334. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose of a randomised controlled trial. Medical Research Council Renal Cancer and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Collaborators. Lancet. 1999;353:14. Oncol. 2003;21:3127. 312. Negrier S, Caty A, Lesimple T, et al. Treatment of patients with metastatic 335. Gale RP, Champlin RE. How does bone-marrow transplantation cure renal carcinoma with a combination of subcutaneous interleukin-2 leukaemia? Lancet. 1984;2:28. and interferon alfa with or without fluorouracil. Groupe Français 336. Weiden PL, Flournoy N, Sanders JE, et al. Antileukemic effect of graft- d’Immunothérapie, Fédération Nationale des Centres de Lutte Contre le versus-host disease contributes to improved survival after allogeneic marrow Cancer. J Clin Oncol. 2000;18:4009. transplantation. Transplant Proc. 1981;13:248. Chapter 40 Renal Neoplasia 1535

337. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft- 348. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal- versus-host disease in human recipients of allogeneic-marrow grafts. N Engl cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell J Med. 1979;300:1068. transplantation. N Engl J Med. 2000;343:750. 338. Morecki S, Moshel Y, Gelfend Y, et al. Induction of graft vs. tumor effect in 349. Pedrazzoli P, Da Prada GA, Giorgiani G, et al. Allogeneic blood stem cell a murine model of mammary adenocarcinoma. Int J Cancer. 1997;71:59. transplantation after a reduced-intensity, preparative regimen: a pilot study in 339. Morecki S, Yacovlev E, Diab A, et al. Allogeneic cell therapy for a murine patients with refractory malignancies. Cancer. 2002;94:2409. mammary carcinoma. Cancer Res. 1998;58:3891. 350. Rini BI, Zimmerman TM, Gajewski TF, et al. Allogeneic peripheral 340. Moscovitch M, Slavin S. Anti-tumor effects of allogeneic bone marrow blood stem cell transplantation for metastatic renal cell carcinoma. J Urol. transplantation in (NZB X NZW)F1 hybrids with spontaneous 2001;165:1208. lymphosarcoma. J Immunol. 1984;132:997. 350a.  Bregni M, Bernardi M, Servida P, et al. Long-term follow-up of metastatic 341. Eibl B, Schwaighofer H, Nachbaur D, et al. Evidence for a graft-versus- renal cancer patients undergoing reduced-intensity allografting. Bone tumor effect in a patient treated with marrow ablative chemotherapy Marrow Transplant. 2009;44(4):237-242. and allogeneic bone marrow transplantation for breast cancer. Blood. 351. Brown GA, Matin SF, Busby JE, et al. Ability of clinical grade to predict 1996;88:1501. final pathologic stage in upper urinary tract transitional cell carcinoma: 342. Childs R, Clave E, Contentin N, et al. Engraftment kinetics after implications for therapy. Urology. 2007;70:252. nonmyeloablative allogeneic peripheral blood stem cell transplantation: 352. Greene FL. The American Joint Committee on Cancer: updating the full donor T-cell chimerism precedes alloimmune responses. Blood. strategies in cancer staging. Bull Am Coll Surg. 2002;87:13. 1999;94:3234. 353. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical 343. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma graft-versus-malignancy using fludarabine-based nonablative chemotherapy Collaboration. Cancer. 2009;115:1224. and allogeneic blood progenitor-cell transplantation as treatment for 354. Hellenthal NJ, Shariat SF, Margulis V, et al. Adjuvant chemotherapy for lymphoid malignancies. J Clin Oncol. 1998;16:2817. high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial 344. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell Carcinoma Collaboration. J Urol. 2009;182:900. transplantation and cell therapy as an alternative to conventional bone 355. Igawa M, Urakami S, Shiina H, et al. Neoadjuvant chemotherapy for locally marrow transplantation with lethal cytoreduction for the treatment of advanced urothelial cancer of the upper urinary tract. Urol Int. 1995;55:74. malignant and nonmalignant hematologic diseases. Blood. 1998;91:756. 356. Lane BSA, Larson B. Development of chronic kidney disease after 345. Spitzer TR, McAfee S, Sackstein R, et al. Intentional induction of mixed nephroureterectomy for upper tract urothelial carcinoma and implications for the chimerism and achievement of antitumor responses after nonmyeloablative administration of cisplatin based chemotherapy. Chicago. Paper presented at conditioning therapy and HLA-matched donor bone marrow the American Urological Association Annual Meeting, April 25-30, 2009. transplantation for refractory hematologic malignancies. Biol Blood Marrow 357. Wolk A, Gridley G, Niwa S, et al. International renal cell cancer study. VII. Transplant. 2000;6:309. Role of diet. Int J Cancer. 1996;65:67. 346. Sykes M, Preffer F, McAfee S, et al. Mixed lymphohaemopoietic chimerism 358. Wilimas JA, Magill L, Parham DM, et al. Is renal salvage feasible in and graft-versus-lymphoma effects after non-myeloablative therapy and unilateral Wilms’ tumor? Proposed computed tomographic criteria and HLA-mismatched bone-marrow transplantation. Lancet. 1999; their relation to surgicopathologic findings.Am J Pediatr Hematol Oncol. 353:1755. 1990;12:164. 347. Bregni M, Dodero A, Peccatori J, et al. Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood. 2002;99:4234.