Clinical aspects of renal tumors

Clinical Aspects of Renal Tumors By S, Bruce Malkowicz

R malignancy, accounting for approximately 3% of newly diagnosed cancers. In 1994 27,600

impact on our understanding and treatment of these tumors.

new renal tumors were diagnosed, and 11,300 cancer related deaths occurred. The disease therefore is not uncommon, accounting for 11 cases per 100,000 individuals. ~ The majority of tumors (85% to 90%) are renal parenchyma lesions, which are generally renal adenocarcinoma. Renal cell carcinoma (RCC) is primarily a surgical disease. Patients with organ-confined lesions show excellent disease-specific survival. Individuals with more extensive lesions present greater technical challenges, yet often benefit from surgical extirpation. Treatment for advanced disease remains limited because these lesions are essentially resistant to radiation therapy or cytoreductive chemotherapy. Biological response modifiers have been studied intensively in this disease given the very rare but albeit real occurance of spontaneous regression of renal tumors. Immunotherapy remains an active area of clinical research, although major improvements in patient long-term outcomes have yet to be realized. However, notable advances in the molecular genetics of these lesions have recently been described that may have a significant future

EPIDEMIOLOGY

ENAL tumors are the eighth most common

ABBREVIATIONS RCC, renal cell carcinoma; LOH, loss of beterozygosity; VHL; yon Hippel-Lindau; CT, computed tomography; UICC, Union Internationale Contre le Cancer; MRI, magnetic resonance imaging; CR, complete response; PR, partial response; FUDR, floxuridine; MDR, multiple drug resistance; IL 2, interleukin 2; LAK, lymphokine activated killer; TCC, transitional cell carcinoma.

From the School of Medicine, University of Pennsylvania, Philadelphia. Supported by the American Cancer Society CDA 92-51. Address reprint requests to S. Bruce Malkowicz, MD, Assistant Professor of Urology, Co-Director; Urologic Oncotogy, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104. Copyright © 1995 by W..B. Saunders Company 003 7-19832/95/3002-000255.O0/0 102

The male-to-female ratio of disease incidence is roughly 2:1. The majority of patients present in the fifth to seventh decades of life, and the racial distribution of this disease is equal. Disease incidence is highest in Scandinavia, whereas the lowest incidence levels occur in east Asia. Renal tumors are more commonly detected in urban settings. 2 Although most cases are sporadic, familiaI groups have been identified. A high incidence is noted among patients with Von Hippel-Lindau disease (25% clinically, 60% at autopsy). The strongest etiologic correlation is with tobacco product use (two-fold increased relative risk). 3 It is believed that 20% to 30% of renal tumors can be attributed to this practice. Additional associations with renal tumors have been observed with cadmium exposure, employment in the leather industry, and exposure to the longabandoned contrast media, thorotrastY A recent association has been noted with the development of acquired renal cysts and renal tumors in patients undergoing hemodialysis. This condition was first reported in 1977.6 The condition has a wide reported range of incidence (30% to 95%), 7 and the cysts appear cortical as well as medullary in location. The extent of the disease seems to be associated with the length of time on dialysis, but there is no association between the severity of the disease, the degree of azotemia, or the original cause of the renal failure,s These patients are younger than most renal tumor patients, with a mean age of 40 years. The pathogenesis of this condition is incompletely understood, but may be caused to some extent by intratubular obstruction. Oxalate crystaIs as well as proliferative tubular epithelium have been noted in tissue specimens) Alterations in proliferative activity may play a major role in tumor formation. Reversal of the cystic disease has been noted in patients undergoing transplantation. 1° Of significant importance is the associated higher incidence of renal tumors in patients Seminars in Roentgenology, Vol XXX, No 2 (April), 1995: pp 102-115

CLINICAL ASPECTS OF RENAL TUMORS

with end-stage renal disease (with or without cystic disease). Neoplasia is seen in 0% to 45% of kidneys with acquired cystic disease. In the majority of acquired cystic disease series, renal tumors are noted in 10% to 25% of cases. These ranges occur in part because of different size definitions for tumors and whether the diagnosis is made radiologically or pathologically.11 In addition to localized lesions, several cases of metastatic disease have been described. This suggests that patients on hemodialysis should undergo periodic surveillance of their native renal units. PATHOLOGY OF RENAL TUMORS

A representative list of renal lesions is given in Table 1. The most common renal neoplasm clinically encountered is RCC. These lesions are generally grossly tan to yellow, often with areas of hemorrhage. Their growth pattern is expansile, and they often have a pseudocapsule. There is no significant difference between the right or left kidney with regard to the development of these tumors. Renal tumors may also be multicentric, a significant characteristic when considering partial nephrectomy as a therapeutic modality. Lesions smaller than 3 cm have often been referred to as adenomas, yet this definition is highly controversial. Metastases have been associated with primary lesions of this size; therefore, such tumors are now generally considered small RCCs. The majority of RCCs are comprised of clear cells that are lipid- and glycogen-rich. A small percentage of RCCs are of the granular cell or spindle cell variety. Spindle cell carcinomas can be confused with sarcomas, but can be distinguished from sarcomas by their expression of keratin. The proximal convoluted tubule is thought to be the cell of origin for RCC. This Table 1. Renal Tumors

Renal cell carcinoma Papillary cystadenocarcinoma Oncocytoma Angiomyolipoma Collecting duct tumor Fibrosarcoma Transitional cell carcinoma of the collecting system Squamous cell carcinoma of the collecting system Nephroblastoma Hemangiopericytoma

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supposition is supported by meticulous histological studies, and more recently through immunohistochemical confirmation. 12 Less common variants of RCC such as papillary cystadenocarcinoma, collecting duct tumor, or chromophobecell carcinoma probably originate from more distal aspects of the nephron. 13 Significant advances have been made in the molecular genetics of renal tumors. Early loss of heterozygosity (LOH) studies implicated an area on the short arm of chromosome 3 as the site of a potential tumor suppressor gene in renal tumors. 14 Through linkage analysis of family members with yon Hippel-Lindau (VHL) disease, a more restricted site was identified on 3p25-26. With positional cloning strategies, a unique gene has been identified as the suppressor gene responsible for VHL. At present, it appears that the gene encodes for a protein with no similarities to other tumor suppressors. It is a well-conserved gene that encodes for two transcripts of 6 and 6.5 kilobases, yet its primary function is unknown. 15 The complete sequence of the gene has not been identified. Recent studies of mutations of the VHL gene in familial and sporadic RCC strongly suggest that mutations in this gene are primarily responsible for the genesis of RCC. 16 VHL mutations were shown in 57% of clear cell RCC specimens, and in 98% of RCC specimens the VHL gene was reduced to homozygosity. Nearly half of sporadic renal cell tumors have mutations in exon 2, something seen rarely in germ line lesions. This suggests that environmental factors may lead to these mutations and promote renal tumors. Complete sequencing of this gene and further structural and functional understanding of the gene product will have a significant impact on the diagnosis and management of RCC. Papillary RCC is often noted for its distinct histology and less aggressive clinical presentation. It is interesting to note that familial presentations of the disease are not linked to polymorphic markers on chromosome 3p, and that these and sporadic papillary tumors show no LOH at 3p loci. 17 Renal oncocytomas are well-circumscribed parenchymal masses composed of densely acidophilic cells that on electron microscopy show multiple mitochondria. They comprise approxi-

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mately 3% to 7% of renal lesions and have the same sex and slightly younger age distribution as compared with RCC. As opposed to RCC, the principle genetic alteration appears to involve changes in mitochondrial DNA; the mitochondrial cytochrome c oxidase subunit I. L8 Oncocytomas can be difficult to distinguish from granular cell carcinoma. Grossly they are usually tan in color, encapsulated, and contain a central dense fibrous band or scar extending in a stellate pattern. Angiographically there is often a spoke-wheel appearance to the vessels. These lesions are benign and merit conservative treatment, yet their preoperative diagnosis is unreliable. A clear diagnosis cannot be made on frozen section. Radical nephrectomy is the safest method of treatment unless other factors argue for a conservative approach. 13,19 Angiomyolipomas consist of fat, muscle, and blood vessels, and can usually be definitively diagnosed by computed tomography. Isolated angiomyolipomas usually occur in middle-aged women, and are noted as an incidental image finding or present more dramatically as an acute spontaneous perirenal hemorrhage. 2° Approximately 20% of presenting lesions are associated with tuberous sclerosis. Patients with tuberous sclerosis show angiomyolipomas in approximately 40% to 60% of cases. In this patient group the lesions are multiple, often bilateral, and associated with other findings such as seizure disorders, mental retardation, and adenoma sebaceum. 21 Treatment may include surgery (total or partial nephrectomy), selective infarction, and in the case of multiple bilateral or small asymptomatic lesions, observation. Decisions regarding therapy have been aided by more recent data on tumor size at initial presentation and outcomes of observed patients. 22 Generally, lesions in patients without tuberous sclerosis that present as _<4 cm tend to remain asymptomatic and are not in need of intervention, whereas over half of lesions > 4 cm become symptomatic and require therapy in approximately 2 yearsY Tuberous sclerosis patients generally present with larger lesions that are at increased risk for becoming symptomatic and requiring intervention. In a recent study of 42 renal units followed for a mean period of 3.8 years, approximately half of the lesions were observed. None under 4 cm and only one

S. BRUCE MALKOWICZ

between 4 and 10 cm progressed in size, albeit asymptomatically.24 Patients treated with selective embolization or partial nephrectomy all retained good renal function, and none of the patients with unilateral disease have experienced a contralateral recurrence. Significant tumor growth over time, minimal functioning renal parenchyma, and pronounced symptoms may direct one toward surgery, whereas the presence of functioning renal tissue, bilateralty, and minimal symptoms suggests a nonsurgical approach in patients with larger lesions. The most common tumors that metastasize to the kidneys are carcinomas of the lung, breast, and uterus. Metastatic melanoma is noted often on autopsy. Metastatic lesions appear poorly vascularized and have irregular borders on imaging studies. CLINICAL PRESENTATION

Only 11% of RCCs present with the classic triad of hematuria, flank pain, and a palpable mass, and such patients generally have advanced disease. Most patients will present with one or two components of the triad. Hematuria is present in 40% to 60%, flank pain in 40% to 50%, and flank mass in 20% to 35%. Only 1% to 3% of renal tumors are bilateral. 2 General symptoms include weight loss (33%), fever (15%), hypochromic anemia (33%), and night sweats. Renal tumors may present as a manifestation of metastasis such as bone pain. Growth along the left renal vein can block the testicular vein, producing a varicocele. The appearance of a sudden varicocele in a man older than 40 years, especially one that does not disappear on recumbency, warrants an investigation. 25 Renal tumors can often be associated with paraneoplastic syndromes. Hypercalcemia secondary to parathormone-like production is not uncommon (5%). Stauffer's syndrome (nonmetastatic reversible hepatic dysfunction [7% to 14%]) refers to reversible abnormal liver studies, often with weight loss and fever. Abnormal liver function tests alone may occur in a greater percentage of patients. These laboratory values will revert to normal in the majority of patients. Stauffer's syndrome is associated with poor long-term outcome?6 Recurrent or persistent hepatic dysfunction, on the other

CLINICAL ASPECTS OF RENAL TUMORS

hand, is indicative of tumor recurrence or undetected metastases. Less common syndromes include protein wasting enteropathy, erythrocytosis, neuromyopathy, and gonadotropin production. Amyloidosis is present in approximately 2% of patients with renal tumors. 25 Approximately 25% to 40% of patients present with metastatic disease. Between 20% and 30% of patients initially show locally advanced disease, whereas the remainder of patients have localized tumors. 27 Fairly recent analyses suggest that the general distribution of presenting tumor stages have not changed significantly over the past several decades, but advances in imaging have contributed to a dramatic increase in the proportion of incidentally found lesions. It has been reported that 25% of all renal tumors and two thirds of locally confined renal tumors are detected serendipitously. Furthermore, the overall 5-year survival rate for these patients with incidentally discovered lesions is much higher (90% versus 30%). 28,29 EVALUATION OF THE RENAL MASS

The multiple issues regarding the imaging of renal masses are discussed later in this monography. From the surgeon's perspective, there has been a dramatic change in the nature of the initial diagnosis, which would classically be made by a combination of intravenous urography and angiography, to contemporary diagnosis related to findings noted incidentally on ultrasonography and computed tomography (CT). In general, a CT scan with and without contrast provides the most significant amount of information. The size and location of the lesion as well as possible venous involvement are issues of primary concern. The degree of adenopathy, if any, is also of major importance, as is an evaluation for any possible visceral metastases. Often, there is mention on reports of possible hepatic involvement by direct tumor extension. This is rarely noted at the time of surgery because of the intervening renal capsule, Gerotas fascia, and visceral peritoneum of the liver. If on imaging studies the tumor is ressectable but quite bulky, one may elect to selectively infarct that kidney as a preoperative aid to the dissection. When tumor involvement of the renal vein or vena cava is suggested on a prior study, the addition of magnetic resonance

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imaging is invaluable. It can provide vivid and precise images that delineate the cephalad margin of a caval thrombus, and also differentiates vessel compression from tumor extension. Furthermore it can provide valuable information that can delineate distal clot thrombus from tumor thrombus and distinguish persistent caval blood flow from complete obstruction. 3° Nuclear scintography is less often used in the contemporary preoperative evaluation of renal masses. The role of positron emission tomography is presently investigational. STAGING

The most commonly used staging system is the Robson modification of the Flocks and Kadesky system (Table 2). The system is conceptually straightforward but does not account for nodal involvement across stages. Although patients with localized nodal involvement arc classified as stage III B, their 5-year survival rate is approximately 18%. The general good performance of patients with renal vein tumor thrombus in the absence of true vein wall invasion or associated metastases (IIIA) is masked by lumping them with the aforementioned node-positive group. 31 The Union Internationale Contre le Cancer (UICC) TNM classification is quite complete yet can be somewhat cumbersome (Table 3). The disease-specific 5-year survival rates for different stages of RCC are illustrated in Table 4. The discriminant value of the different T sizes in this system has been questioned for some time. A recent analysis of a large series of patients suggests that the 2.5-cm cutoff for T1 and T2 lesions is ineffective in providing any predictive survival information. Table 2. Robson Staging System for RCC Stage I

Stage [I

Stage III

Stage IV

Tumor is confined to the kidney; perinephric fat, renal vein, and regional nodes show no evidence of malignancy. Tumor involves the perinephric fat but is confined within Gerota's fascia; renal vein and regional nodes show no evidence of malignancy. Tumor involves the renal vein or regional nodes with or without involvement of the vena cava or perinephric fat. Distant metastases secondary to RCC are evident on presentation or there is histologic involvement of contiguous visceral structures by tumor.

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S. BRUCE MALKOWICZ

Table 3. TNM Staging for RCC Primary tumor iT) TX Primary tumor cannot be assessed TO No evidence of primary tumor T1 Tumor _<2.5 cm in greatest dimension limited to the kidney T2 Tumor > 2.5 cm in greatest dimension limited to the kidney T3 Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota's fascia T3a Tumor invades adrenal gland or perinephric tissues but not beyond Gerota's fascia T3b Tumor grossly extends into renal vein(s) or vena cava T4 Tumor invades beyond Gerota's fascia Regional lymph nodes iN) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N1 Metastasis in a single lymph node, <_2 cm in greatest dimension N2 Metastasis in a single lymph node, >2 cm but not > 5 cm in greatest dimension, or multiple lymph nodes, none > 5 cm in greatest dimension N3 Metastasis in a lymph node > 5 cm in greatest dimension Distant metastasis (M) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

In patients with NO M0 disease, size cutoffs for localized lesions (2.5 to 10.0 cm) were uninformative. In a multivariate regression model analysis, studying T1 Nail Mall and T2 Nail Mall patients, a 5-cm cutoff maximized the value of tumor size in predicting survival. This observation will require further validation in other large series. 32 Grading systems based on nuclear characteristics of renal tumors have been developed but are somewhat hampered by subjective biases and the lack of discrimination between class 2 and 3 patients in the 1 to 4 grading systems. Most studies do, however, suggest that they provide independent information with regard to patient survival when used. 33,34 Nil attempt to Table 4. Five-Year Disease-Specific Survival Rate for RCC Robson Stage I

II III IV

Survival Rate

85%-100% 45%-65% 20%-40% 0-10%

refine pathological information gathered renal tumor nuclei analysis has been made through flow cytometry and nuclear morphometry. In several studies, tumor ploidy is associated with patient survival and tumor progression. A significant survival rate advantage (80% versus 60% five-year rate) and a decreased probability of progression (20% versus 40%) is noted in patients with diploid tumors. 35Nuclear morphometry studies are conflicting. It has been suggested that parameters such as nuclear roundness and mean nuclear area are strongly associated with survival, whereas other investigations contend that these parameters are less reliable and that more sophisticated geometric indices are required to accurately predict outcome.36, 37

More accessible predictors of outcome include the presence or absence of renal pelvis involvement, as well as invasion into the perirenal fat. Several studies suggest that renal pelvis invasion is usually associated with other factors associated with poor outcome, yet it is difficult to associate renal pelvic involvement as an isolated finding with increased adverse outcomes. 38 Extension of tumor into the perinephric fat is clearly associated with poorer outcome when compared with organ-confined disease. 39 Similarly, any degree of lymph node involvement is associated with poorer outcomes (5% to 30% at 5 years). 34,39,40 The impact of renal vein involvement was initially addressed by Skinner et aP 4 and has been thoroughly analyzed by others. Multivariant analysis in several series suggests that renal vein involvement alone does not account for an adverse outcome in patients with organ-confined lesions. Vena caval tumor involvement represents the extreme end of tumor vascular involvement. Lesions are characterized as located at the renal vein or subhepatic (level I), infrahepatic but sub-atrial (level II) or intracardiac (level III) (Fig 1). Five-year survival rates of patients successfully treated for such lesions ranges from 11% to 60%, with most contemporary series showing 30% to 60% 5-year survival rates. Although earlier series suggested that the extent of the tumor thrombus affected survival, recent series indicated that in the absence of other poor prognosticators (perirenal fat involvement, positive lymph nodes or metastases) vena

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EXTENT OF TUMOR THROMBUS

Fig 1. Anatomic classification of renal tumors with vena caval extention.

GROUP I

caval involvement alone at any level does not have a significant impact on postsurgical survival. 41-43 The extent of vena caval involvement can affect the technical complexity of surgery and perioperative morbidity/mortality, which are addressed below. Furthermore, a distinction can be made between mobile, nonobstructing lesions and vena caval tumor thrombi with direct venous wall invasion. In one series, patients with mobile tumors experience a 69% 5-year survival rate, whereas those with unresectable venous wall involvement have a 5-year survival rate of 25%. Median survival was 9.9 years for those patients with noninvasive tumors, but only 1.2 years in patients with venous wall invasion of their tumors. 42 Metastasis is a very strong predictor of poor patient survival. Common sites of metastases include the lungs, liver, bones, central nervous system, and adrenal glands. In general, patients with distant metastatic disease have a 5-year survival rate of 5% to 10%, and a 10-year survival rate of less than 5%. 44-45In patients who present with advanced metastatic disease, nephrectomy does not greatly improve patient outcome. 31 Multivariate analysis in several studies suggests that performance status, the number of metastatic sites, the site of metastases (pulmonary versus other), and weight loss can provide prognostic information. 46-48Time interval between initial disease and metastatic recurrence may also be a factor, especially if this period is more than 2 years. It is not significant in all analyses, and this may be caused by the variable frequency of follow-up and workup regimen at the time of assessment. Weight loss is frequently mentioned as a predictive factor in

iROUP III

GROUP I1

univariate and multivariate analysis, and in one study the combination of weight loss and the erythrocyte sedimentation rate was noted as a particularly strong factor in predicting a negative outcome. 48 Patients with solitary metastases that can be completely excised can experience a reasonable five-year survival of 25% to 35%. The majority of these patients have pulmonary metastases only. Additional research also suggests that complete resection of more than one pulmonary metastasis can provide a significant disease-free interval. However, in patients with a high burden of metastatic disease, the outcome is very poor and nephrectomy is not recommended unless it is part of an approved protocol. THERAPY

Total surgical extirpation is the only effective method of treatment of primary renal carcinoma. Renal surgery was documented as early as 1861, with the first successful deliberate nephrectomy for kidney cancer performed in 1883. 51 In the 1960s, the radical nephrectomy supplanted the simple nephrectomy as the treatment of choice, s2 Because these original studies on the effectiveness of radical nephrectomy employed historical controls, it has been presumed but never proven that such an approach would improve the surgical cure rate in this disease. The technical modifications involved in performing the surgery are in accordance with general oncological principles and do not unnecessarily complicate the procedure. Therefore, this approach was generally accepted as the standard of care. A renal tumor may be approached by several

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different incisions. Transabdominal, subcostal, thoracoabdominal, and extrapleural intersperse flank incisions have all been used for performing radical nephrectomy. A decision regarding approach is affected by the patient's body habitus and the size of the lesion. Large lesions and upper-pole lesions are readily handled by a ninth rib thoracoabdominal incision that provides excellent exposure to the kidney and major blood vessels. Reapproximation of the costochondral junction and the diaphragm can be accomplished easily with little attendant morbidity. 53 An extrapleural transabdominal flank incision is very useful for smaller lesions. 54 In general, a "radical" nephrectomy includes exposure and early ligation of the renal artery and vein. The kidney is removed en bloc within the surrounding Gerota's fascia, and the ipsilateral adrenal and upper ureter are incorporated in the specimen. Occasionally very large vascular tumors may be angiographically embolized preoperatively if early access to the renal artery would be very difficult. This procedure may ease the technical difficulty of the procedure, but it is unproven that angiography significantly lessens blood loss. 55 One must also consider the potential morbidity from angiography, such as damage to the contralateral renal unit or bowel ischemia. Furthermore, patients may suffer from postinfarction syndrome, which includes severe flank pain and fever. There is no data to support the concept of improved survival secondary to enhanced "autoantigenicity" after embolization in any stage of the disease. 56 The automatic need for an ipsilateral adrenalectomy has also been reanalyzed. In early classic series the incidence of metastasis to the adrenal gland was reported at 10% to 15%. Recent analysis suggests that this figure is lower, especially when one is considering operable candidates. A contemporary review of almost 700 patients showed a 4.3% incidence of adrenal metastases. The risk for metastases was higher in tumors replacing the entire kidney or in the upper pole. Left-sided tumors were more often involved, and the mean size as well as the T stage of the primary lesion was greater in patients with involvement of the adrenal gland. One third of the patients with adrenal metastasis had other evidence of widespread disease.

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The mean postoperative survival of patients with adrenal involvement was 27 months. 57 Preoperative assessment of the adrenal gland was recently studied in a retrospective review of 157 patients. Ipsilateral adrenal abnormalities were noted in 38 patients, 10 of whom had histopathologic findings of cancer. None of the adrenal glands described as normal were falsely negative. Adrenal gland enlargement, displacement, and nonidentification were considered criteria for performing adrenalectomy as part of the radical nephrectomy. 58 A rationale for a regional retroperitoneal lymphadenectomy (ipsilateral and intra-aortocaval nodes) exists although a definite survival benefit has not been shown. An argument against a regional lymphadenectomy can be made because of the variable lymphatic drainage of the kidneys and the equal likelihood for hematogenous tumor dissemination. Hilar nodes are generally removed with the specimen, and many surgeons do remove the ipsilateral retroperitoneal nodes as a general practice. It is assumed that any early micrometastases would be treated in this manner. 59 Vena caval extension occurs in 5% to 10% of patients with RCC. Involvement of the renal vein alone may occur in up to 20% of patients. The presentation of vena caval involvement is subclassified according to the extent of tumor thrombus (Fig 1). Aggressive therapy is warranted in the absence of metastases, but survival is rarely improved in the presence of extensive nodal or metastatic spread. The technical approach to surgery is determined by the cephalad extent of the tumor, thus meticulous preoperative imaging is imperative. As mentioned previously, this is most often accomplished by the use of retroperitoneal magnetic resonance image (MRI) that can provide multiplanar images and distinguish thrombosis versus patency. In the case of level III lesions the use of adjunctive intraoperative transesophogeal ultrasonography has been described. A thoracoabdominal, midline, or subcostal approach has been advocated for the treatment of these tumors. 41"43 Level I lesions (50% of cases), especially those at the level of the renal vein, can be controlled with minimal vascular manipulation by partially clamping and oversewing the vena cava. Care must be taken not to narrow the caval lumen by

CLINICAL ASPECTS OF RENAL TUMORS

more than 50%. Level I lesions just below the hepatic portion of the renal vein require the surgeon to obtain vascular control of all venous outflow before opening the cava, yet can be accomplished with minimal morbidity in experienced hands. Level II thrombi account for 40% of cases and provide a technical challenge. These tumors require often-more-difficult-toobtain cephalad control, which may be performed suprahepatically or subatrially through a thoracic incision. Additionally portal outflow must be managed and may require a Pringle maneuver for a short period of time. Between 5% and 10% of renal tumors with caval extension will progress to the right atrium. Such lesions may be handled without cardiopulmonary bypass if atrial involvement is minimal and can be digitally reduced into the vena cava. Cardiopulmonary bypass must be used in larger lesions, and this may be augmented with hypothermia and total body exsanguination to provide a bloodless field.6° In general clinical follow-up after nephrectomy is performed on a 6-month basis over the first I to 3 years and then yearly thereafter. This usually consists of physical examination, chest radiograph, and chemistry panel including alkaline phosphatase. The role for CT in follow-up is less well defined, but it is generally used. It is probably of greater value in higher stage lesions. Postoperative Serial abdominal imaging is clearly more important in patients undergoing partial nephrectomy for renal cancer. Lesions in solitary kidneys or bilateral simultaneous lesions present a significant challenge to the surgeon. In general a patient can avoid dialysis with one sixth of their renal mass. If a procedure to spare renal tissue is technically feasible and affords a better quality of life with equal risks of mortality, an attempt at partial nephrectomy is reasonable in such patients. Standard indications for performing parenchyma-sparing surgery are listed in Table 5. They include cases in which a renal tumor exists in one renal unit, yet the other is threatened by another condition such as vascular disease or calculus. Similarly, systemic diseases such as diabetes or glomerulosclerosis may render a patient intolerant of the loss of a renal unit. A tumor in a solitary kidney or bilateral presenta-

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Table 5. Indications for Renal Sparing Surgery Solitary renal unit Diseased contralateral renal unit (reflux nephropathy or calculous) Bilateral benign renal paranchymal disease Bilateral renal vascular disease Bilateral renal tumors

tion of tumors are an obvious consideration for partial nephrectomy. When such surgery is considered, thorough preoperative imaging is imperative. Renal arteriography and selective venography may be useful in delineating the nature of these lesions. The exact extent of a tumor is often aided by a thin-cut CT scan with and without contrast. A careful preoperative assessment for metastases is also mandatory. At the time of surgery regional hypothermia with ice slush can be very useful and can allow for safe renal ischemia for up to 3 hours. 61The use of intravenous mannitol is also helpful in protecting renal function. During surgery intraoperative ultrasound may provide further help in delineating the margins of a tumor. 62 The role for ex vivo "bench surgery" is very limited, and it is rarely performed. Although attractive, simple enucleation of renal tumors is not a satisfactory method for treating such patients. Several studies have shown that renal tumors express a pseudocapsule and that the chance for microscopic margins in the face of grossly negative margins is as high as 40%. 63 In one study it was noted that lesions greater than 6 cm recurred in virtually all patients treated in this fashion. For bilateral lesions in which one tumor will not be amenable to a partial nephrectomy, it is prudent to first perform the partial nephrectomy and proceed at a later date with a radical nephrectomy after showing function in the renal remnant. 64,65 Patients with VHL disease represent a special case of bilateral renal tumors. This condition is associated with central nervous system and retinal hemangioblastomas, cysts of multiple organs, and RCC that is often multicentric and bilateral. Renal cell carcinoma occurs in 45% of these patients. The classic approach to such patients has been conservative surgery to preserve as much renal parenchyma as possible. In long-term follow-up, however, a significant num-

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ber of these patients (25% to 77%) have shown recurrence and mortality (0% to 33%). Thus, close postoperative surveillance is mandatory. It has been suggested that patients with highgrade bilateral disease may otherwise benefit from initial bilateral nephrectomy, dialysis, and subsequent transplantation if they are suitable candidates.66-68 The results of partial nephrectomy for treatment of select patients with sporadic renal tumors has been very good. In multiple studies involving over 700 patients, disease-specific 5-year survival is in the range of 57% to 100%, with a large number of studies presenting survival rates in the 90% range. 69 Local and distant recurrence rates have ranged from 4% to 10% percent. These results must also be considered against the morbidity figures for middle-aged dialysis patients who have a 50.5% 2-year and 16.2% 5-year actuarial survival rate. 7° Through meticulous attention to technical details, the rate of significant complications from renal nephron-sparing surgery can be quite low. In a recent review of 259 procedures performed over 36 years, local or renal-related complications occurred in 30% of patients. 7~ The majority of them were urinary fistulas or acute renal failure. Only one fistula required open surgical repair, and two thirds resolved spontaneously. Predisposing factors included central location, tumor size greater than 4 cm, and the need for major reconstruction of the collecting system. Acute renal failure was more common in patients when greater than 50% of parenchyma was excised, tumor size was greater than 7 cm, and ischemia time greater than 60 minutes. Complications were also greater in cases of ex vivo surgery, which is now rarely performed. Of the 33 patients with acute renal failure, 9 required temporary dialysis and 5 required permanent dialysis. Three percent of patients overall required repeat surgery, and only 2.9% of patients experienced an adverse clinical outcome attributed to surgical complications. The success with nephron-sparing surgery in specialized cases has led to a re-evaluation of radical nephrectomy on renal tumor patients with a normal contralateral kidney. The standard of therapy in this case still is a complete radical nephrectomy. Reasons for this include

S. BRUCE MALKOWICZ

the small risk for metachronous disease, the lack of documented contralateral renal dysfunction after nephrectomy, and the 10% to 13% presence of multifocal lesions in renal tumors mirrored by the 10% recurrence rate noted after nephron-sparing surgery.69 Several studies suggest, however, that selected patients may perform as well with nephron-sparing surgery as with a standard radical nephrectomy. With a mean follow-up of approximately 3 years, a disease-specific survival rate of 90% to 100% was noted. The majority of these patients had smaller tumors, which may account for these good results. This was recently supported by a subset analysis of patients undergoing nephronsparing surgery. In a comparative analysis of over 200 patients undergoing nephron-sparing surgery for renal tumors, it was noted that in patients with incidentally found unilateral, singular lesions less than 4 cm in diameter, no postoperative recurrences were noted and the cancer-specific survival rate was 100%. This suggests a set of criteria that may make patients with a normal contralateral unit eligible for nephron-sparing surgeryd2 METASTATIC RCC

The role for radical nephrectomy in patients with metastatic RCC is limited. The outcomes in patients with a solitary metastasis or two pulmonary metastases were previously discussed, and it is in this population that surgery is of greatest benefit. Additionally, there is a role for the treatment of renal fossa recurrence in the absence of other distant disease when it is technically feasible in patients with a good performance status. 73As previously stated, however, patients with multiple metastases have at best a 5% to 10% long-term survival. Outcome is adversely affected by findings such as weight loss and multiple metastases at different sites. Size of the primary tumor has been considered a factor in survival in some studies but not in others. 74 The phenomenon of spontaneous regression is exceedingly rare and at best is documented in less than one-h alf percent of patients. Improved survival in patients with metastases after nephrectomy is negligible in those few series in which it has been compared. Postoperative mortality is as high as 10 percent in these

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patients, as compared with 0.5% to 1% for nonmetastatic disease. Additionally, when nephrectomy is planned before investigational treatment protocols, anywhere from 20% to 30% of patients may never be treated because of delays incurred from postoperative complications and recovery from surgery. 75'76 An often cited reason for nephrectomy in the face of significant metastatic disease is palliative benefit. The primary tumor can occasionally be the source of significant hematuria. Blood loss and the difficulties with blood clot urinary retention could be reduced with a nephrectomy but may also be alleviated by angioinfarction of that renal unit. Paraneoplastic syndromes are unlikely to be improved by removal of only the primary lesion. Occasionally nephrectomy is considered for pain management of these patients. Such cases need to be individualized. If the primary tumor is very large yet not locally invasivc, such a procedure may be useful. In most patients with a high volume of metastatic disease, however, there is a significant amount of local tumor extension and pain secondary to musculoskelatal or nervous system involvement. The pain is unlikely to be improved with nephrectomy.77 Nephrectomy may or may not be included in an advanced disease treatment protocol. ADJUVANT THERAPY AND THERAPY FOR ADVANCED DISEASE

Radiation therapy usually plays a palliative role in the treatment of advanced RCC. It can be effective in solitary osseous metastases but is less effective in treating recurrances in the renal fossa. The role of radiation as an adjunct to surgery for local or regional disease is somewhat difficult to define. True advantages are hard to show, yet in the CT era, it has been shown that radiation can be delivered with much less morbidity.78,79 Metastatic RCC is generally unresponsive to attempts at treatment. That lack of success in applying classic cytoreductive chemotherapy to this lesion has prompted thoughtful investigation using newer modalities such as biological response modifiers, immunotherapy, and more recently, gene therapy. Vinblastine and CCNU (a nitrosourea) are approved for use in advanced RCC but the

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response rate to such therapy is at best 15%, with very few documented complete responses (CR).2 A recent review of 72 agents used for the treatment of advanced RCC was quite sobering in that the percentage of patients with CR + partial response (PR) was 5.6% (confidence interval of 4.8% to 6.4%). s° The majority of these studies are limited phase-two trials. Of these agents floxuridine (FUDR) was of interest. In some trials response rates of up to 57% were noted. When these investigations were pooled, however, circadian and constant-rate continuous-infusion studies showed a 16% response rate with a 95% CI of 11% to 20%. 71 In general, trials with multiple cytoreductive agents display little improvement in the face of increased morbidity. These data suggest the highly refractory nature of RCC to chemotherapy. Much of this may be attributed to the overexpression of plasma membrane p-glycoprotein 170 (pg-170) 82in these tumors. This product of the multiple drug resistance gene (MDR) acts as a cell membrane pump that can remove chemotherapeutic agents from a cell, thus making it resistant to that drug. In vitro, several agents can inactivate this pump, making tumor cells more susceptible to chemotherapeutic agents. Calcium channel blockers and other substances such a dipyridimole have been less successful MDR blockers in the clinical setting. One reason for this may be the several forms of MDR besides pg-170, including the glutathione S-transferase system, which is also expressed in many renal tumors, s3 The use of hormone therapy, primarily progesterone, for treatment of renal tumors is based on an estrogen-inducible renal tumor system in certain rodents. 2 In the clinical setting the antitumor effect of progestational agents is very limited and is beneficial in at best 5% of patients. Antiandrogens and antiestrogens have been studied and show modest activity. IMMUNOTHERAPY

The use of immunological agents in the treatment of advanced RCC has great appeal because a constitutive immunologic response can be elicited in some renal tumors. Autologous tumor vaccines have been attempted in the past with mixed results and recent efforts have been directed more towards the use of cytokines.

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The interferons are inducible glycoproteins that have direct cell antiproliferative effects and that inhibit viral replication. The major subtypes are alpha, beta, and gamma, with alpha interferon the most intensely studied in RCC. 24 Several hundred patients have been treated with this substance in dosing ranges of 1 to 20 million units per administration. A CR + PR is noted in 15% to 20% of patients, but they are usually of short duration (8 to 10 months). 85,86 Some data exists to suggest a relationship between clinical relapse and the formation of antibodies to interferon. No significant improvements are noted with the use of other interferon species. Furthermore, there has not been a significant advantage in the use of interferon in combination with vinblastine. Recent studies of alpha interferon combined with 13-cis-retinotic acid have been interesting in that a 29% response rate was obtained lasting at least 10 months. Another report on interferon combined with 5-FU and interleukin 2 (IL 2) show a 47% response rate, 16% of which were CR. In general, interferon as a single agent displays activity in the treatment of advanced RCC, but the majority of responses are not sustained. Its most effective role in the treatment of this disease remains to be determined. Interleukin 2 was first isolated in the 1970s and recognized as a T cell growth factor. Since that time the gene has been cloned, allowing for multiple clinical trials to evaluate its efficacy in cancer therapy. These studies have been performed with IL 2 as a single agent, in combination with autologous lymphocytes (lymphokine activated killer cells (LAK) or tumor infiltrating lymphocytes), and in combination with other cytokines. Initial efforts at the National Cancer Institute showed a CR + PR of over 30% when patients were treated with IL 2 and LAK cells. 82 The treatment process was somewhat cumbersome because of the need to expand clones of T lymphocytes and the toxicity was significant. Since that time multiple studies using IL 2 alone have been conducted. The pooled data from over 200 patients showed a 15% response rate including 4% CR. The median duration of CR was 23 months and that for PR 19 months. Side effects were significant, however, with a drugrelated mortality rate of 4%. 88 Side effects generally include fever, fatigue, and anemia. The more serious side effects such as dyspnea,

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hypotension, congestive heart failure, or myocardial infarction are probably caused by changes in vascular permeability, and are the reasons for using intensive care monitoring in the appropriate circumstances. With this data IL 2 was approved in 1992 for the treatment of advanced RCC. Several different dosing schedules have been tested, ranging from outpatient subcutaneous administration to high-dose bolus administration. In a recent study on 149 patients receiving this high-dose regimen (720,000 IU/kg intravenously every 8 hours to a maximum of 15 doses per cycle) a 7% complete response and 20% CR + PR was noted. 89 Treatment deaths occurred in 1% of patients but occurred early in the series. None were seen after careful monitoring for cardiovascular status was instituted. Again, the intriguing aspect of this study was the durability of complete responses, which have ranged from 7 to 76 months. These findings do not suggest a tremendous clinical advantage but do establish the proof of principle of immunotherapy in renal cancer. Subsequent work in this area and advance in the modulation of MDR may yet provide better answers to the treatment of advanced renal cancer. Another approach to the treatment of advanced renal tumors has been through tumor vaccine therapy. 9° In general, most of these approaches have not been successful because the mechanisms used have focused on eliciting an endogenous antibody response to these lesions. Contemporary efforts have been redirected toward eliciting a significant T cell response against the tumor, which for the most part is protected by self-tolerance. In immune tolerance models it has been observed that low levels of cytokine production by T helper cells contribute to the tolerance state. Efforts to elicit a greater T cell response in renal tumors are underway through the gene transfer of GM-CSF to short-term cultured renal tumor cells that are later transplanted to the host and by the presentation of controlled release cytokines to re-implanted tumor cells. Gene transfer studies have entered early clinical trials. 91,92 TUMORS OF THE RENAL PELVIS

Transitional cell carcinoma (TCC) tumors of the renal pelvis are rare and comprise from 5% to 7% of renal tumors. Exact incidence is often difficult to discern because most coding systems

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tend to lump these lesions with RCC diagnoses. They are associated with the usual risk factors for TCC including tobacco usage, prior cyclophosphomide chemotherapy, and aniline dye exposure. Heavy phenacetin usage and a rare condition, Balkan nephropathy, is also associated with an increase in renal pelvic tumors. 93 The overwhelming majority of these lesions are TCCs with approximately 5% due to squamous cell carcinoma. These latter lesions are almost always associated with the irritation from chronic staghorn calculi. Like bladder cancer, these lesions are either superficial papillary lesions or irregular muscle invasive lesions. The orthodox approach to the treatment of renal pelvis tumors has been nephroureterectomy because of the high incidence of recurrent tumors in the ureteral stump or near the uret e r a l orifice. 94,95

This philosophy has been re-examined due to the development of sophisticated endoscopy equipment and the high survival rate of patients with low grade tumors. High-grade and moderate-grade lesions are still best treated with a nephroureterectomy that includes a nephrectomy (radical or simple) and removal of the

entire ureter with a cuff of bladder tissue. Low-grade lesions may be endoscopically excised and fulgurated. Low-grade lesions of the lower ureter can be treated with partial ureterectomy and reimplantation. These more conservative techniques are constrained by the anatomic difficulty in monitoring the endothelium and the functional intolerance of the upper urinary tract as opposed to the bladder wall to any fibrosis that may result from endoscopic resection of tumor and reinstrumentation during follow-up. Furthermore, there is always the possibility of understaging these lesions. Nephron-sparing surgery can be successful in upperand lower-pole low-grade tumors but is usually suboptimal in high-grade lesions. 96 Topical chemotherapy similar to that administered intravesically for superficial bladder cancer may be used to treat the upper tract urothelium, small heterogeneous series have shown feasibility but preclude meaningful analysis at this time. 97 Advanced disease is treated by the standard chemotherapeutic regimen for advanced TCC, a combination regimen of methotrexate, vinblastine, adriamycin, and ciplatinum. 98

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