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M E T H O D S I N M O L E C U L A R M E D I C I N ETM RReennaall CCaanncceerr MMeetthhooddss aanndd PPrroottooccoollss EEddiitteedd bbyy JJaacckk HH.. MMyyddlloo,, MMDD HHuummaannaa PPrreessss RCC: Clinical Features and Management 3 1 Renal Cell Carcinoma Clinical Features and Management Paul Russo 1. Introduction In 1999 it was estimated that renal cell carcinoma (RCC) would account for 29,990 new cancer cases diagnosed in the United States (61% in men and 39% in women), and lead to 11,600 deaths. RCC accounts for 2–3% of all malignancies in adults and causes 2.3% of all cancer deaths in the United States annually(1). Approx 4% of all RCC cases are bilateral at some point in the life of the patient. Data from over 10,000 cases of renal cancer entered in the Connecticut Tumor Registry suggests an increase in the incidence of renal cancer from 1935–1989; in women the incidence increased from 0.7 to 4.2 in 100,000, and in men from 1.6 to 9.6 in 100,000 (2). Factors implicated in the development of RCC include cigarette smoking, exposure to petroleum prod- ucts, obesity, diuretic use, cadmium exposure, and ionizing radiation (3–9). In the last 20 yr, the surgical management of RCC has evolved. Radical nephrectomy is no longer considered the only approach to RCC and modifications in the radical nephrectomy—relating specifically to adrenalectomy and regional lymph- node dissection—are now widely accepted. In the last 10 yr, reports from major centers have shown the effective application of partial nephrectomy, or nephron- sparing surgery, in the treatment of small, incidentally discovered renal tumors. In the last 5 yr, advances in endosurgical instrumentation have allowed dedicated investigators to explore laparoscopic and laparoscopically assisted nephrectomy as alternatives to open surgical techniques. Finally, the limits of operative treatment for advanced cases of RCC are being explored, including the role of surgery in locally recurrent RCC, in renal tumors involving the inferior vena cava, and in the treatment of patients with metastatic disease. From: Methods in Molecular Medicine, vol. 53: Renal Cancer: Methods and Protocols Edited by: J. H. Mydlo © Humana Press Inc., Totowa, NJ 3 4 Russo 2. Clinical Presentation 2.1. Incidental Presentation and Differential Diagnosis The widespread use of abdominal computed tomography, ultrasonography, and MRI in the evaluation of nonspecific abdominal complaints has lead to the increased detection of the incidental renal mass or incidentaloma, from 10–15% to over 50% during the last 20 yr (10–12). Some urologists use office transabdominal ultrasound as part of the routine history and physical exam of every new patient visit, thus further increasing, the possibility of an incidental tumor discovery (13). Another source of incidentally detected renal tumors is with patients undergoing imaging in the follow-up care of other malignancies. Twenty-seven percent of patients with RCC will have a diagnosis of at least one other malignancy in their lifetime—the most common being breast cancer, pros- tate cancer, colorectal cancer, bladder cancer, and non-Hodgkin’s lymphoma (14). Incidentally discovered renal tumors are confined within the renal capsule (P2 or less) in 75% of cases, and are associated with a 5-yr survival rate of at least 75% following operative treatment (15–17). When compared to symptomatic RCC, incidentally discovered RCC tumors are significantly smaller in size (mean 5 cm), have a lower P stage, and are associated with a high likelihood of survival. Analysis of histological grade and DNA ploidy pattern reveals no differences between incidental RCC and symptomatic RCC (18). The resulting stage migration in RCC has resulted in a decrease in the incidence of metastatic disease to less than 20% and improved 5-yr survival (19). The incidental discovery of smaller renal carcinomas has also encouraged the more liberal application of partial nephrectomy (nephron-sparing surgery) (20). Today, over one-half of surgically resected cases of RCC are detected without clinical symptoms, and the likelihood of complete resection with partial or radical nephrectomy is great. The differential diagnosis of a renal mass includes benign cyst (simple, complex, hemorrhagic), pseudotumors (column of Bertin), angiomyolipoma, vascular malformation, lymphoma, sarcoma, adult Wilm's tumor, or metastatic tumor. When a clinician is faced with a solid renal mass, approx 90% of such masses will be RCCs or the benign-behaving variant of RCC (oncocytoma) (21). In general, preoperative percutaneous needle biopsy or aspiration of the clinically localized solid renal mass is not recommended because of the high rate of RCC or oncocytoma in such masses, the low rate of metastatic tumors (<5%) presenting as a solid renal mass, concerns regarding the high rate of false-negative results, and the possibility of causing bleeding or tumor-tract seeding (22). With these concerns in mind, percutaneous needle biopsy is reserved for patients with obvious metastatic disease for which tissue confir- mation of RCC will allow systemic treatment or access to a clinical trial (23). RCC: Clinical Features and Management 5 2.2. Bilateral Renal Tumors Bilateral RCC occurs in approx 4% of all RCC cases, and may be hereditary or sporadic in origin. Hereditary forms of RCC, such as von Hippel-Lindau (VHL) disease, hereditary papillary renal cell carcinoma (HPRC), and familial renal oncocytoma, differ in general from sporadic, unilateral forms of RCC because they tend to be multifocal and bilateral, and occur at a younger age (third to fifth decade). In von Hippel-Lindau disease, other potentially life- threatening neoplasms—such as CNS hemangioblastoma and pheochromocy- toma, as well as cystic changes in the kidney, pancreas, and epididymis—are commonly associated with the bilateral renal tumors. The VHL tumor- suppressor gene has been cloned and localized to the short arm of chromosome 3 (24–29). Hereditary papillary RCC has been described as a distinct form of inherited renal cancer that does not display a loss of heterozygosity at chromosome 3/VHL (30,31). In addition, the nearly benign variant of RCC—oncocytoma—can present as bilateral tumors with a familial distribution (32), has been found to exhibit an array of chromosomal abnormalities, including the loss of the Y chromosome and abnormalities in chromosome 1 and 22, and can have a hereditary pattern of inheritance (33). RCC can also present as a bilateral tumor without evidence of hereditary or familial involvement. Histologic patterns in these patients are predominantly clear-cell (59%), followed by papillary (17%) and oncocytoma (10%). In this cohort of patients, 66% presented synchronously (34). Bilateral RCC provides a surgical challenge that balances complete resection with attempts to maintain adequate renal function off dialysis. 2.3. Symptomatic Presentation RCC is associated with a wide array of systemic symptoms—including microscopic and gross hematuria, anemia, polycythemia, hypercalcemia, weight loss, malaise, acute varicocele, and fever—and has been referred to by some as the internist’s disease (35). Physical examination is performed with special attention to supraclavicular and cervical lymph nodes, the presence of a palpable abdominal mass, the presence of a bruit, lower-extremity edema, varicocele, SC nodules, and penile or vaginal metastases. Laboratory evaluation should include a CBC, serum calcium, liver function studies, and a serum creatinine. A reversible abnormality in liver function, called Stauffer’s syndrome, can also be observed. Today, less than 5% of patients present with the classic Virchow’s triad of hematuria, flank pain, and flank mass. Of all RCC cases, the rate of those presenting with metastatic or locally advanced disease is approx 30% (36). 6 Russo 2.4. Extent of Disease Evaluation The extent of disease evaluation should include a chest x-ray and abdominal CT scan to focus on the regional nodes and lung, the most common sites of early metastatic disease (37,38). An abdominal CT scan can correctly predict the T-stage in 80% of cases (38). If a nodule on the chest X-ray is observed, then a chest CT is indicated to rule out multiple pulmonary metastases. Chest CT has a greater yield of finding metastatic nodules in a patient with a large primary tumor (39). A bone scan is not routinely performed unless the patient has an elevated alkaline phosphatase or complains of bone pain (37). If the CT scan raises the possibility of renal vein or inferior vena-caval extension, then Doppler ultrasound or MRI is performed to define the uppermost level of the thrombus (40). CT of the brain is not routinely performed unless the patient complains of a headache, manifests a neurologic deficit, or experiences a seizure. As an aid to the operating surgeon, angiography, is utilized in selected cases if partial nephrectomy is planned and the tumor is centrally located. 3. Staging Prior to surgery a tumor stage is assigned. Two staging systems—the Robson system(41) and UICC TMN classification (42)—are utilized in RCC. Descrip- tive limitations in the Robson system include regional node involvement and renal vein or inferior vena-cava involvement. The TMN staging system more explicitly describes the extent of the local and regional disease and is thus preferred at our institution. The current AJCC staging system was recently modified in 1998 to include all tumors as T1 that are 7 cm or less (Table 1). This represents a change from the 1993 system that described T1 tumors as those less than 2.5 cm. Prospective validation of the 1998 AJCC system is anticipated. Neither staging system currently differentiates the metastatic potentials of the variants of RCC where tumor size may be less important than histopathology, ranging from the potentially aggressive conventional clear-cell carcinoma, to the intermediate papillary and chromophobe carcinoma, to the only rarely metastatic oncocytic tumors (43–45).When prognostic factors are viewed together, size has the greatest prognostic impact on conventional clear- cell RCC. In time, staging systems will probably also incorporate histologic subtypes into the prognosis of renal tumors. The most important prognostic determinants of 5-yr survival are the local extent of the tumor (organ-confined disease-TMN P1, Robson stage I, 70–80%; or extending into perinephric fat TMN P3a or Robson stage II, 60–70%), the presence of regional nodal metastases (single, multiple, contralateral, fixed, or juxtaregional-Robson IIIb or TMN N1, N2, 5–20%), and the presence of metastatic disease at presentation (Robson IVb or TMN M1, 0–5%). Other adverse prognostic indicators usually associated with locally advanced or metastatic RCC: Clinical Features and Management 7 Table 1 TNM Clinical Classification T-primary tumor Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 ≤7.0 cm; limited to kidney T2 >7.0 cm; limited to the kidney T3 Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia T3a Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia T3b Tumor grossly extends into renal vein(s) or vena cava below the diaphragm T3c Tumor grossly extends into vena cava above the diaphragm T4 Tumor invades beyond the Gerota fascia N-regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single regional lymph node N2 Metastasis in more than one regional lymph node M-distant metastasis Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T1 N1 M0 T2 N1 M0 T3 N0, N1 M0 Stage IV T4 N0, N1 M0 Any T N2 M0 Any T Any N M1 tumors include high pathologic grade, sarcomatoid histology, large tumor size (>10 cm), weight loss, hypercalcemia, and an elevated sedimentation rate (46). 3. Surgical Treatment of RCC Despite recent exciting breakthroughs in our understanding of the molecular biology of RCC and its histologic variants, surgical resection still remains the 8 Russo only effective treatment for clinically localized renal tumors. The historical approach to renal tumors focused on simple nephrectomy, which was supplanted by perifascial or radical nephrectomy that was presumed—but never proven—to be a more effective operation. As migration to an earlier stage during detection of renal tumors has occurred—resulting from the above described advances in abdominal imaging—partial nephrectomy in general, and nephron-sparing surgery in particular, have emerged as effective alternatives to radical nephrectomy in appropriately selected cases. Careful case selection has enabled the surgical resection of renal tumors with vena-caval tumor extension, limited metastatic disease, and isolated local recurrence. Although laparascopy must be considered investigational, advances in instrumentation may substantially enhance the appeal of this minimally invasive approach, which limits perioperative morbidity and hospital stay. 4.1. Radical Nephrectomy Using a thoracoabdominal incision, Mortensen (1948) reported the first radical nephrectomy—an operation that removed all of the contents of Gerota’s fascia in an attempt to address the 13% of patients with renal tumors that invaded the perinephric fat (47). The radical nephrectomy was popularized in the 1960s by Robson, who described this operation as the perifascial resection of the tumor-bearing kidney, along with perirenal fat, regional lymph nodes, and the ipsilateral adrenal gland (48). In 1969, Robson reported the results of radical nephrectomy and described a 65% survival rate for tumors confined within Gerota’s fascia (Robson stage 1 and 2), but the finding of regional nodal metastases led to less than a 30% 5-yr survival rate (49). Depending on the surgeon’s preference—relating mainly to patient’s body habitus, the tumor size, and tumor location—the radical nephrectomy can be performed through an eleventh-rib flank incision, a transperitoneal midline or subcostal incision, or a transthoracic incision. In retroperitoneal nephrectomy, the peritoneum and pleura are dissected off the perirenal soft tissues and Gerota’s fascia, exposing the kidney. In transabdominal approaches to the kidney, the colon, small intestine, liver, pancreas and spleen (for left-sided tumors) are mobilized, exposing the great vessels and the kidney within Gerota’s fascia. During the radical nephrectomy, the surgeon gains early control of the renal hilum and ligates and divides the renal artery and the renal vein. Approx 20% of people have multiple renal arteries, leading the surgeon to carefully identify, ligate, and divide any aberrant renal, lumbar, or tumor vessels that may supply the kidney. The classic radical nephrectomy is completed with an ipsilateral adrenalectomy and regional lymph-node dissection, typically skeletonizing the ipsilateral great vessel (vena cava or aorta). A more complete retroperitoneal lymph-node dissection is performed if metastatic lymph nodes are discovered at the time of radical nephrectomy. RCC: Clinical Features and Management 9 Despite the wide acceptance of radical nephrectomy by urologic surgeons over the last 25 yr (49–51), no data have convincingly confirmed the need for the component parts of the operation (i.e., the need for adrenalectomy (52), or the need for and extent of lymph-node dissection) (53,54). Randomized comparisons with and without the component parts comparing radical nephrectomy to simple nephrectomy have not yet been described. At the same time, the evolution of nephron-sparing operations during the era of the incidental renal tumor detection has now been fully established as a legitimate alternative to radical nephrectomy (20,55–60). 4.2. Lymph Node Dissection Lymphatic drainage from the kidneys is a complex process, and differs depending on the side. The right kidney drains into precaval, retrocaval, and interaortocaval nodes (not paracaval), whereas the left kidney drains to the para-aortic, preaortic, and retroaortic nodes. In renal cancer, regional lymph nodes can be enlarged because of a benign inflammatory response or from metastatic involvement (61). In a series of 163 patients with operable RCC, preoperative CT scanning was falsely negative in five patients, two with grossly enlarged hilar nodes (>2.5 cm), and three with micrometastatic disease in nodes <1 cm. Of 43 patients with preoperative CT scans demonstrating enlarged regional nodes (1–2.2 cm, median 1.4 cm), 18 patients (42%) had metastatic RCC, and in 25 patients (58%) the enlarged nodes were inflammatory. The cause of the reactive regional nodes may be related to an immune response secondary to necrosis within the primary tumor. Given the current limitations of CT scanning, no patient should be denied a potentially curative resection based on regional lymph-node enlargement alone. Although the original description of the radical nephrectomy described a concomitant and complete retroperitoneal lymph-node dissection with skeletonization of both the inferior vena cava and aorta, most urological surgeons rarely perform an operation of this extent today. A node dissection clearing the ipsilateral great vessel and the renal hilum is generally done. Clini- cal data compiled over the last 25 yr leaves little doubt that the finding of even a single positive lymph node represents an ominous prognostic sign, with most series reporting less than 20% 5-yr survivors. It is unknown whether complete lymph-node dissection at the time of radical nephrectomy provides a therapeutic advantage to the patient. The accepted rationale for lymph-node dissection in RCC is: to improve staging accuracy, to resect micrometastatic disease, and to determine if enlarged regional nodes are inflammatory or metastatic (61). Improvement in staging accuracy would better identify patients at high risk for systemic disease and would provide a rational basis for entry of such patients into poor risk- 10 Russo adjuvant trials. Lymph-node metastasis, in the absence of other metastatic disease, occurs in approx 10–15% of cases. (53,54,62–64). Guiliani and colleagues correlated tumor stage with degree of lymph-node metastases and found that tumors confined to Gerota’s fascia had a 13% rate of positive nodes, whereas for tumors beyond Gerota’s fascia the rate was 37% (62). This issue is further complicated today by our enhanced understanding of the different histologic subtypes and the impact of histology on prognosis. Currently there is no available data on the risk of nodal metastases as correlated to histologic subtype. Proponents of extended lymph-node dissection argue that the resection of microscopically involved nodes (palpably normal) can add a therapeutic benefit as well as reduce the possibility of local tumor recurrence in more potentially aggressive primary tumors. Golimbu and colleagues described 52 patients who underwent radical nephrectomy and regional lymph-node dissection, and compared the outcome to 141 patients with palpably normal nodes undergoing radical nephrectomy alone. Lymph-node dissection added no apparent survival benefit for patients with stage I tumors, but a 10–15% survival benefit in stage II tumors suggested some therapeutic benefit (65). This study and others like it are subject to selection biases that can only be clarified in a prospective and randomized trial. Because of differences in operative lymphadenectomy templates, it is difficult to compare lymph-node data from one institution to the next. The ultimate impact of lymphadenectomy can only be assessed by a prospective and randomized trial where the surgical templates for operation are uniformly agreed upon and carefully adhered to, and the data is controlled for tumor stage and histologic subtype. At the present time, the therapeutic impact of regional lymphadenectomy in RCC remains controversial, yet it is reasonable to perform complete retroperitoneal lymphadenectomy for large tumors (>T1) when metastatic lymph nodes are documented at the time of radical nephrectomy. A regional node dissection (ipsilateral great vessel and hilar nodes) should at the very least be done in other cases. Node dissection is unnecessary in the case of small renal tumors treated by partial nephrectomy or laparoscopic techniques, since the expected yield approaches zero. This approach will provide prognostic information valuable for patient counseling as well as entry into appropriate adjuvant clinical trials (66). 4.3. Adrenalectomy Adrenalectomy has traditionally been included as a component of the radical nephrectomy (47–49), yetthe therapeutic impact has not been fully defined. With stage migration to an earlier-stage renal tumor, clarification of the therapeutic value of adrenalectomy is now required, particularly because the approach to small renal tumors by partial nephrectomy and laparoscopy is underway. The mechanisms by which metastatic disease can gain access to the RCC: Clinical Features and Management 11 adrenals could be as follows: direct extension through perinephric soft tissues; hematogenous spread through ipsilateral adrenal veins, or the systemic circu- lation; and lymphatic spread. Sagalowsky and colleagues reported an incidence of adrenal metastases of 4.3% in 695 nephrectomies (52). Adrenal metastases were more likely to occur in patients with tumors that occupied the entire kidney or the upper pole, and were most common in tumors with advanced T-stage. Thirty percent of patients also had evidence of metastatic disease to regional nodes or distant sites. Despite resection of the affected adrenal gland, in 21 of the 30 cases of metastatic disease in the adrenals, 17 patients (81%) died of their disease—most within 26 mo of resection. There is little doubt that metastatic disease in the adrenals is an ominous prognostic sign similar to that of nodal metastases. This experience closely parallels that of surgical oncologists resecting isolated adrenal metastases from other primary cancer sites, such as lung and breast, where 5-yr survival rates of 24% can be achieved with resection—particularly if the patients had a disease-free interval greater than 6 mo (67). In addition, improvements in preoperative imaging with CT and MRI have allowed highly accurate assessment of the status of the adrenals prior to operation. Gill and colleagues correctly cleared the adrenals in 119 patients who had their adrenals preoperatively confirmed as uninvolved at the time of radical nephrectomy. Conversely, when the adrenal gland appeared abnormal on preoperative imaging, 24% of patients were found to have metastatic involvement (68). Although its potential therapeutic advantage is probably very small, ipsilateral adrenalectomy is still performed for large renal tumors—particularly those involving the upper pole of the kidney, or for those patients with preoperative imaging suggesting an adrenal abnormality. For small renal tumors treated by partial nephrectomy or laparoscopic nephrectomy, adrenalectomy is unnecessary. 4.4. Laparoscopic Renal Cancer Surgery Reports from several centers have described a preliminary experience with laparoscopic radical and partial nephrectomy for the resection of small renal tumors. As described, the techniques offer the patient a shorter postoperative recovery and hospital stay, but lead to long operations even in the hands of the few expert laparoscopic surgeons in the United States committed to the development of this approach. Thanks to the efforts of these committed investigators, laparoscopic techniques have evolved, allowing for 5-port transperitoneal resection of kidneys for both benign and malignant disease as well as for donor nephrectomy(69–72). As with many laparoscopic procedures, the benefits of reduced hospital stay, reduced analgesic requirements in the postoperative period, and a more rapid return to normal activities and work for the patient were offset by the increases