Chapter 22. Renal Parenchymal Neoplasms

With the liberal use of computed tomography (CT) scans and magnetic resonance imaging (MRI), benign renal masses are being detected more frequently. Benign renal tumors include, oncocytoma, angiomyolipoma, leiomyoma, lipoma, hemangioma, and juxtaglomerular tumors.

Renal Oncocytoma

Renal oncocytoma has a spectrum of behavior ranging from benign to malignant. Composed of large epithelial cells with finely granular eosinophilic cytoplasm (oncocytes), oncocytomas occur in various organs and organ systems including adrenal, salivary, thyroid, and parathyroid glands as well as the kidney. An estimated 3–5% of renal tumors are oncocytomas (Romis et al, 2004). Men are affected more often than women.

Renal oncocytomas generally occur and are contained within a well-defined fibrous capsule. Metastasis is extremely rare though invasion of the lymphovascular spaces has been observed. On cut section, the surface of the tumor is usually tan or light brown with a central stellate scar, but necrosis typical of renal adenocarcinoma is absent. The tumors are usually solitary and unilateral, although several bilateral cases and multiple oncocytomas occurring simultaneously (oncocytomatosis) have been reported (Tickoo et al, 1999).

Oncocytomas can also be associated with benign tumors of hair follicles (fibrofolliculomas), colon polyps/tumors, and pulmonary cysts as part of the Birt–Hogg–Dubé syndrome (Toro et al, 1999). The familial renal oncocytoma syndrome has also been described (Philips et al, 2001). These patients may have a characteristic genetic abnormality involving a gene located on 17p encoding a protein named folliculin (Nickerson et al, 2002) Histologically, well-differentiated oncocytomas are made up of large, uniform cells containing an intensely eosinophilic cytoplasm, which on ultrastructural studies is found to be packed with mitochondria. Mitotic activity is absent, and nuclear pleomorphism is uncommon (Figure 22–1). Consistent chromosomal alterations such as loss of chromosome 1 or Y and translocations in the short arm of chromosome 11 have been described in oncocytomas (Lindgren et al, 2004; Philips et al, 2001). The cellular origin of renal oncocytes has not been fully elucidated, although some early evidence suggested that oncocytes resemble proximal convoluted tubular cells (Merino and Librelsi, 1982). Other findings suggest that their origin may be a precursor stem cell (Cohen et al, 1988) or the intercalated cells of the collecting ducts (Storkel et al, 1989).

The diagnosis of oncocytoma is predominantly pathologic because there are no reliable distinguishing clinical characteristics. Gross hematuria and flank pain occur in <20% of patients. No characteristic features of the tumors appear on CT, ultrasound (US), intravenous urography (IVU), or MRI. Angiographic features of oncocytomas include the “spoke-wheel” appearance of tumor arterioles, the “lucent rim sign” of the capsule, and a homogeneous capillary nephrogram phase. Unfortunately, these findings are not invariable, and similar findings have been reported in patients with renal cell carcinoma (RCC).

High-grade oncocytomas may be intermixed with elements of RCC and can be found as coexisting lesions within the same or opposite kidney (Licht et al, 1993). The role of fine-needle aspiration in the preoperative diagnosis of oncocytomas remains controversial and limited due to a lack of characteristic features that distinguish oncocytoma from RCC.

Angiomyolipoma (Renal Hamartoma)

Angiomyolipoma is a rare benign tumor of the kidney seen in two distinct clinical populations. Angiomyolipomas are found in approximately 45–80% of patients with tuberous sclerosis and are typically bilateral and asymptomatic. Tuberous sclerosis is a familial inherited disorder comprising adenoma sebaceum, mental retardation, and epilepsy. In patients without tuberous sclerosis, renal angiomyolipomas can be unilateral and tend to be larger than those associated with tuberous sclerosis (Anderson and Hatcher, 1990). There is no known histologic difference between the lesions seen in these two populations. As many as 25% of cases can present with spontaneous rupture and subsequent hemorrhage into the retroperitoneum (Wong et al, 1981).

Angiomyolipomas are unencapsulated yellow to gray lesions, typically round to oval, that elevate the renal capsule, producing a bulging smooth or irregular mass. They are characterized by three major histologic components: mature fat cells, smooth muscle, and blood vessels. Renal hamartomas may extend to perirenal or renal sinus fat and involve regional lymphatics and other visceral organs (Ditonno et al, 1992). The presence of renal hamartomas in extrarenal sites is a manifestation of multicentricity rather than metastatic potential, because only one well-documented case of malignant transformation of angiomyolipoma has been reported (Lowe et al, 1992).

Female patients with a rare condition termed lymphangioleiomyomatosis may have multiple renal and hepatic angiomyolipomata, multiple pulmonary cysts, enlarged abdominal lymph nodes, and lymphangiomyomas (Avila et al, 2000; Urban et al, 1999). The diagnosis of renal angiomyolipoma has evolved with the widespread use of US and CT. Ultrasonography and CT are frequently diagnostic in lesions with high fat content. Fat visualized on US appears as very high intensity echoes. Fat imaged by CT has a negative density, −20 to −80 Hounsfield units, which is pathognomonic for angiomyolipomas when observed in the kidney (Figure 22–2) (Pitts et al, 1980). MRI can also be utilized to identify fat within the lesion and confirm a diagnosis of angiomyolipoma. MRI is particularly useful in distinguishing lipid poor angiomyolipoma which have much lower fat content compared to routine angiomyolipomas, from other solid renal lesions (Kim et al, 2006).

The management of angiomyolipomas historically has been correlated with symptoms. Steiner and colleagues (1993) reported a long-term follow-up study of 35 patients with angiomyolipomas. They proposed that patients with isolated lesions <4 cm be followed up with yearly CT or US. Patients with asymptomatic or mildly symptomatic lesions >4 cm should be followed up with semiannual US. Patients with lesions >4 cm with moderate or severe symptoms (bleeding or pain) should undergo renal-sparing surgery or renal arterial embolization. Recent data indicate that even larger angiomyolipoma's (AML's) upto 8 cm can be observed and treated as dictated by symptoms. Approximately 25–30% of patients who are observed will ultimately require treatment in the form of embolization, surgery or radio frequency ablation (Sooriakumaran, 2010). However the long-term efficacy of selective embolization remains suboptimal and the long-term efficacy of radiofrequency ablation is yet to be determined. More recent data also suggests that immunosuppressive agents such as sirolimus (an inhibitor of mammalian target of rapamycin or mTOR) may also be effective in treating AML arising in patients with tuberous sclerosis (Bissler et al, 2008).

Other Rare Benign Renal Tumors

Several other benign renal tumors are quite rare, including leiomyomas, hemangiomas, lipomas, and juxtaglomerular cell tumors. With the exception of juxtaglomerular tumors, there are no features that unequivocally establish the diagnosis before surgery; therefore, the pathologist most often provides the diagnosis after nephrectomy.

Leiomyomas are rare small tumors typically found in smooth-muscle-containing areas of the kidney including the renal capsule and renal pelvis. Two groups of renal leiomyomas have been described (Steiner et al, 1990). The more common group comprises cortical tumors that are <2 cm and may be multiple. These tumors are typically found at autopsy and are not clinically significant. A larger, commonly solitary leiomyoma has been described, which may cause symptoms and is confirmed pathologically after nephrectomy.

Hemangiomas are small vascular tumors occurring in the kidney with a frequency second only to that in the liver among visceral organs. Multiple lesions in one kidney occur in approximately 12% of cases; however, they are rarely bilateral. They can occasionally be the elusive source of hematuria in an otherwise well-evaluated patient. The diagnosis may be determined by CT angiography, MR angiography, or by direct visualization by endoscopy (Ekelund and Gothlin, 1975).

Renal lipomas are very uncommon deposits of mature adipose cells without evident mitosis that arise from the renal capsule or perirenal tissue. They are seen primarily in middle-aged females and, owing to the characteristic CT differentiation of fat, are best detected radiographically on CT scanning.

The juxtaglomerular cell tumor is the most clinically significant member of this subgroup of rare benign tumors because it causes significant hypertension that can be cured by surgical treatment. It is a very rare lesion, with <100 reported cases and may have characteristic chromosomal alterations (Brandal et al, 2005). The tumors occur more commonly in young adults, more often females in their 20s and 30s and are rarely malignant. The tumors originate from the pericytes of afferent arterioles in the juxtaglomerular apparatus and can be shown to contain renin secretory granules. They are typically encapsulated and located in the cortical area. Symptoms of the “typical” tumors include hypertension, hypokalemia, hyperaldosteronism, and high renin (Dong et al, 2010). Some atypical cases may demonstrate just hypertension with normal potassium levels or may even be non functional. The diagnosis is confirmed by selected renal vein sampling for renin. Although complete nephrectomy was advocated in the past, several recent reports indicate that partial nephrectomy can be equally effective (Haab et al, 1995).

In the United States in 2010, an estimated 58,240 new cases of adenocarcinoma of the kidney were expected to be diagnosed, and 13,040 deaths were expected to occur from this disease (Jemal et al, 2010). RCC accounts for roughly 2.8% of adult cancers and constitutes approximately 85% of all primary malignant renal tumors. There appears to be an increase in the incidence of all stages of RCC over the past few decades (Hock et al, 2002; Mindrup et al, 2005). RCC occurs most commonly in the fifth to sixth decade and has a male–female ratio of 2:1. The incidence of renal cancer may vary based on race, with black men demonstrating a higher incidence than in men of all other races. Black men may also have a higher likelihood of a subsequent RCC in the contralateral kidney (Rabbani et al, 2002). Asians appear to have the lowest incidence of RCC (Miller, 1996).

Etiology

The cause of renal adenocarcinoma is unknown. Occupational exposures, chromosomal aberrations, and tumor suppressor genes have been implicated. Cigarette smoking is the only risk factor consistently linked to RCC by both epidemiologic case-control and cohort studies (La Vecchia et al, 1990), with most investigations demonstrating at least a twofold increase in risk for the development of RCC in smokers (Yu et al, 1986). Exposure to asbestos, solvents, and cadmium has also been associated with an increased incidence of RCC (Mandel et al, 1995).

RCC occurs in two forms, inherited and sporadic. In 1979, Cohen and colleagues described a pedigree with hereditary RCC in which the pattern of inheritance was consistent with an autosomal dominant gene with a balanced reciprocal translocation between the short arm of chromosome 3 and the long arm of chromosome 8. Subsequent work has documented that both the hereditary and sporadic forms of RCC are associated with structural changes in chromosome 3p (Erlandsson, 1998; Kovacs et al, 1988; Noordzij and Mickisch, 2004).

Other hereditary forms of RCC have been described. Von Hippel-Lindau disease is a familial cancer syndrome in which affected individuals have a mutation of chromosome 3p predisposition to develop tumors in multiple organs, including cerebellar hemangioblastoma, retinal angiomata, and bilateral clear cell RCC. In 1993, Latif and colleagues identified the von Hippel–Lindau gene, leading to the detection of a germ line mutation in approximately 75% of families affected by von Hippel–Lindau disease (Chen et al, 1995). It has also been recognized that at least 50% of cases of sporadic clear cell RCC has mutations in the Von Hippel–Lindau (VHL) gene (Gnarra et al, 1994).

Hereditary papillary renal carcinoma was described in 1994 and is characterized by a predisposition to develop multiple bilateral renal tumors with a papillary histologic appearance (Zbar et al, 1994). In contrast to von Hippel–Lindau patients, the major neoplastic manifestations appear to be confined to the kidney.

Acquired cystic disease of the kidneys is a well-recognized entity of multiple bilateral cysts in the native kidneys of uremic patients (Reichard et al, 1998). The risk of developing RCC has been estimated to be >30 times higher in patients receiving dialysis who have cystic changes in their kidney than in the general population (Brennan et al, 1991). Several series reported in the literature suggest that RCC occurs in 3–9% of patients with acquired cystic disease of the kidneys (Gulanikar et al, 1998). Most RCC cases have been described in patients undergoing hemodialysis, but RCC has been reported in association with peritoneal dialysis (Smith et al, 1987) and successful renal transplants (Vaziri et al, 1984) and in patients with long-term renal insufficiency not requiring dialysis (Bretan et al, 1986; Fallon and Williams, 1989).

Pathology

RCC originates from the proximal renal tubular epithelium, as evidenced by electron microscopy (Makay et al, 1987) and immunohistochemical analysis (Holthöfer, 1990). These tumors occur with equal frequency in either kidney and are randomly distributed in the upper and lower poles. RCCs originate in the cortex and tend to grow out into perinephric tissue, causing the characteristic bulge or mass effect that aids in their detection by diagnostic imaging studies. Grossly, the tumor is characteristically yellow to orange because of the abundance of lipids, particularly in the clear cell type. RCCs do not have true capsules but may have a pseudocapsule of compressed renal parenchyma, fibrous tissue, and inflammatory cells.

Histologically, RCC is most often a mixed adenocarcinoma containing clear cells, granular cells, and, occasionally, sarcomatoid-appearing cells. The classifications of the subtypes of RCC are based on morphology and cytogenetic characteristics. Most RCCs are classified into one of the following histologic subtypes: conventional clear cell, papillary (chromophilic), chromophobe, collecting duct, neuroendocrine, and unclassified (Mostofi and Davis, 1998). Benign renal tumors are papillary adenoma, renal oncocytoma, and metanephric adenoma. Clear cells are rounded or polygonal with abundant cytoplasm, which contains cholesterol, triglycerides, glycogen, and lipids (Figure 22–3).

The cells present in the papillary (chromophilic) type contain less glycogen and lipids, and electron microscopy reveals that the granular cytoplasm contains many mitochondria and cytosomes. Chromophobe-type carcinomas contain large polygonal cells with distinct cell borders and reticulated cytoplasm, which can stain diffusely with Hale's colloidal iron (Theones et al, 1988). Oncocytic RCC or oncocytomas tend to have cytoplasm packed with mitochondria, giving it a granular appearance. Collecting duct tumors tend to have irregular borders and a basophilic cytoplasm with extensive anaplasia and are likely to invade blood vessels and cause infarction of tissue. Sarcomatoid cells are spindle shaped and form sheets or bundles. This later cell type rarely occurs as a pure form and is most commonly a small component of either the clear cell or papillary cell type (or both).

Pathogenesis

RCCs are vascular tumors that tend to spread either by direct invasion through the renal capsule into perinephric fat and adjacent visceral structures or by direct extension into the renal vein. Approximately 25–30% of patients have evidence of metastatic disease at presentation. The most common site of distant metastases is the lung. However, liver, bone (osteolytic), ipsilateral adjacent lymph nodes and adrenal gland, brain, the opposite kidney, and subcutaneous tissue are frequent sites of disease spread.

Tumor Staging and Grading

Tumor Staging

The ultimate goal of staging is to select appropriate therapy and obtain prognostic information. Appropriate studies for a complete clinical staging evaluation include history and physical examination, complete blood count, serum chemistries (renal and hepatic function), urinalysis, chest x-ray (chest CT scan for an equivocal exam), CT scan of abdomen and pelvis, and a radionuclide bone scan (with x-rays of abnormal areas).

The original staging system described by Robson (1963) is easy to use, but it does not relate directly to prognosis and hence it is no longer commonly used. The tumor-node-metastasis (TNM) system more accurately classifies the extent of tumor involvement and is currently most often used. The TNM classification system for RCC has undergone multiple revisions with the most recent edition being the 2010 version (Table 22–1). In the most recent American Joint Committee on Cancer TNM staging, stage T1 disease is further divided into T1a (tumor size <4 cm) and T1b (size 4–7 cm) as there is a difference in long-term survival between stage T1a and T1b (Ficarra et al, 2005).

Tumor Grading

Fuhrman grading has become commonly used by pathologists in North America (Fuhrman et al, 1982; Goldstein, 1997). The system uses four grades based on nuclear size and irregularity and nucleolar prominence. The system is most effective in predicting metastasis (50% of high-grade tumors within 5 years). When high-grade, predominantly granular tumors are corrected for grade and stage, there is no apparent difference between clear cell and granular cell tumor prognosis (McNichols et al, 1981). However, patients presenting with advanced disease do poorly irrespective of tumor grade.

Clinical Findings

Symptoms and Signs

The classically described triad of gross hematuria, flank pain, and a palpable mass occurs in only 7–10% of patients and is frequently a manifestation of advanced disease. Patients may also present with hematuria, dyspnea, cough, and bone pain that are typically symptoms secondary to metastases. With the routine use of CT scanning for evaluation of nonspecific findings, asymptomatic renal tumors are increasingly detected incidentally (>50%).

Paraneoplastic Syndromes

RCC is associated with a wide spectrum of paraneoplastic syndromes including erythrocytosis, hypercalcemia, hypertension, and nonmetastatic hepatic dysfunction. Overall, these manifestations can occur in 10–40% of patients with RCC.

RCC is the most common cause of paraneoplastic erythrocytosis, which is reported to occur in 3–10% of patients with this tumor (Sufrin et al, 1989). In patients with RCC, the elevated erythrocyte mass is physiologically inappropriate and may result either from enhanced production of erythropoietin from the tumor or as a consequence of regional renal hypoxia promoting erythropoietin production from nonneoplastic renal tissue (Hocking, 1987).

Hypercalcemia has been reported to occur in up to 20% of patients with RCC (Muggia, 1990). Hypercalcemia may be due to production of a parathyroid hormone-related peptide that mimics the function of parathyroid hormone (Strewler et al, 1987) or other humoral factors such as osteoclast-activating factor, tumor necrosis factor, and transforming growth factor-alpha (Muggia, 1990).

Hypertension associated with RCC has been reported in up to 40% of patients (Sufrin et al, 1989), and renin production by the neoplasm has been documented in 37%. The excess renin and hypertension associated with RCC are typically refractory to antihypertensive therapy but may respond after nephrectomy (Gold et al, 1996).

In 1961, Stauffer described a reversible syndrome of hepatic dysfunction in the absence of hepatic metastases associated with RCC. Hepatic function abnormalities include elevation of alkaline phosphatase and bilirubin, hypoalbuminemia, prolonged prothrombin time, and hypergammaglobulinemia. Stauffer's syndrome tends to occur in association with fever, fatigue, and weight loss and typically resolves after nephrectomy. The reported incidence of Stauffer's syndrome varies from 3% to 20% (Gold et al, 1996). It may be due to overproduction of granulocyte-macrophage colony stimulating factor by the tumor (Chang et al, 1992).

RCC is known to produce a multitude of other biologically active products that result in clinically significant syndromes, including adrenocorticotropic hormone (Cushing's syndrome), enteroglucagon (protein enteropathy), prolactin (galactorrhea), insulin (hypoglycemia), and gonadotropins (gynecomastia and decreased libido; or hirsutism, amenorrhea, and male pattern balding) (Sufrin et al, 1986).

A paraneoplastic syndrome present at the time of disease diagnosis does not, in and of itself, confer a poor prognosis. However, patients whose paraneoplastic metabolic disturbances fail to normalize after nephrectomy (suggesting the presence of clinically undetectable metastatic disease) have very poor prognoses (Hanash, 1982).

Laboratory Findings

In addition to the laboratory abnormalities associated with the various RCC paraneoplastic syndromes, anemia, hematuria, and an elevated sedimentation rate are frequently observed.

Anemia occurs in about 30% of RCC patients. The anemia typically is not secondary to blood loss or hemolysis and is commonly normochromic. The serum iron and total iron-binding capacity are usually low, as in the anemia of chronic disease. Iron therapy is usually ineffective; however, surgical removal of early-stage tumors usually leads to physiologic correction of the anemia. The potential role of recombinant erythropoietin for patients with unresectable disease represents a potential, but untested, option.

Gross or microscopic hematuria can be seen in up to 60% of patients presenting with RCC. An elevated erythrocyte sedimentation rate is also commonly seen, with a reported incidence as high as 75%. These findings are nonspecific, and normal findings do not rule out a diagnosis of RCC.

X-Ray Findings

Although many radiologic techniques are available to aid in the detection and diagnosis of renal masses, CT scanning remains the primary technique with which others must be compared. Other radiologic techniques used include US and MRI.

Ultrasonography

US examination is a noninvasive, relatively inexpensive technique able to further delineate a renal mass. It is approximately 98% accurate in distinguishing simple cysts from solid lesions. Strict ultrasonographic criteria for a simple cyst include through transmission, a well-circumscribed mass without internal echoes, and adequate visualization of a strong posterior wall (Figure 22–4).

CT Scanning

CT scanning is more sensitive than US for detection of renal masses. A typical finding of RCC on CT is a mass that becomes enhanced with the use of intravenous contrast media. In general, RCC exhibits an overall decreased density in Hounsfield units compared with normal renal parenchyma but shows either a homogeneous or heterogeneous pattern of enhancement (increase in density of >10 Hounsfield units) following contrast administration (Figure 22–5). In addition to defining the primary lesion, CT scanning is also the method of choice in staging the patient by visualizing the renal hilum, perinephric space, renal vein and vena cava, adrenals, regional lymphatics, and adjacent organs. In patients with equivocal chest x-ray findings, a CT scan of the chest is indicated. Patients who present with symptoms consistent with brain metastases should be evaluated with either head CT or MRI. Spiral CT with 3-dimensional reconstruction has become useful for evaluating tumors before nephron-sparing surgery to delineate the 3-dimensional extent of the tumor and precisely outline the vasculature, which can aid the surgeon in preventing positive surgical margins (Holmes et al, 1997). Intraoperative ultrasonography is also often used to confirm the extent and number of masses in the kidney at the time of performing a partial nephrectomy.

Renal Angiography

With the widespread availability of CT scanners, the role of renal angiography in the diagnostic evaluation of RCC has markedly diminished and is now very limited. There remain a very few specific clinical situations in which angiography may be useful; for example, guiding the operative approach in a patient with an RCC in a solitary kidney when attempting to perform a partial nephrectomy may be indicated (Figure 22–6). However, CT angiography or MR angiography can give better information with less risk to the patient.

Radionuclide Imaging

Determination of metastases to bones is most accurate by radionuclide bone scan, although the study is nonspecific and requires confirmation with bone x-rays of identified abnormalities to verify the presence of the typical osteolytic lesions. There is evidence that patients without bone pain and with a normal alkaline phosphatase level have a very low incidence of bone metastases (Henriksson et al, 1992), and thus a routine bone scan is not necessary in such patients.

Magnetic Resonance Imaging

MRI is equivalent to CT for staging of RCC (Hricak et al, 1988). Its primary advantage is in the evaluation of patients with suspected vascular extension (Figure 22–7). Prospective trials have demonstrated that MRI is superior to CT in assessing inferior vena caval involvement (Kabala et al, 1991) and is at least as accurate as venacavography (Horan et al, 1989). In contrast to both CT and cavography, MRI evaluation does not require either iodinated contrast material or ionizing radiation. Recent studies using MRI angiography with gadolinium or CT angiography have improved vascular evaluation of renal neoplasms (Bluemke and Chambers, 1995). MR angiography can also be used to delineate the vascular supply before planned nephron-sparing surgery.

Positron Emission Tomography (PET) and Targeted Imaging

This technique allows the measurement of systemically administered biochemical agents such as 18-fluoro-2-deoxyglucose (FDG), which can accumulate in the kidney. Although FDG-PET scanning can yield false-positive results in some patients with RCC (Bachor et al, 1996), it may be useful in monitoring response to systemic therapy in those with metastatic disease (Hoh et al, 1998). FDG-PET may also be more accurate than routine CT scanning in detecting disease recurrence or progression, which may alter treatment decisions in up to 50% of cases (Ramdave et al, 2001). However, most recent studies suggest that FDG-PET is of insufficient sensitivity to be useful for staging RCC.

The enzyme carbonic anhydrase IX (CA IX) is expressed at high levels in clear cell RCC. CA IX is regulated by the VHL gene through HIF1α and with loss of the VHL tumor suppressor gene being very common in clear cell RCC, there is loss of regulation of CA IX expression which is significantly increased. It is expressed at low levels in the gastrointestinal, mucosa, and biliary tract but not in other normal tissues. This characteristic can be exploited to detect clear cell RCC using a radiolabeled monoclonal antibody scan using the antibody G250 which targets carbonic anhydrase IX (Stillebroer et al, 2010). Up to 80% of clear cell RCC are found to express G250 antigen and in nearly imaging studies (Oosterwijnk et al, 1993). Other renal tumors such as chromophobe and papillary RCC demonstrate very little CA IX expression. More recently an immuno-PET approach has been used combining the monoclonal antibody to CA IX and a PET scan to better visualize renal lesions. In early studies, 94% of renal tumors were correctly identified using this approach (Divgi et al, 2007).

Fine-Needle Aspiration

Fine-needle aspiration of renal lesions is the diagnostic approach of choice in those patients with clinically apparent metastatic disease who may be candidates for nonsurgical therapy. Other settings in which fine-needle aspiration may be appropriate include establishing a diagnosis in patients who are not surgical candidates, differentiating a primary RCC from a renal metastasis in patients with known primary cancers of nonrenal origin, and evaluating some radiographically indeterminate lesions. Fine needle aspiration is being increasingly used to confirm the diagnosis of a neoplasm particularly in patients who may undergo observation or percutaneous ablative therapy (Shah et al, 2005). While core needle biopsies may be able to accurately diagnose malignancy in up to 100% of cases >4 cm and 95% of cases <4 cm, this may require multiple cores for accuracy (Wunderlich et al, 2005). Rare reports of seeding of the needle tract have been reported but the risk of seeding is reported to be <0.01% (Volpe et al, 2007). Recently, core biopsies of the primary renal mass have been more commonly utilized in patients with metastatic disease (when biopsying a metastatic site is not feasible), in order to guide appropriate targeted systemic therapy (prior to or instead of cytoreductive nephrectomy), since the choice of systemic therapy can be influenced by the specific RCC histology. The accuracy of needle core biopsies is reported to be >90% with sensitivity ranging between 70–100% and specificity of 100% (Volpe et al, 2007). The accuracy of fine needle aspiration cytology of renal masses is reported to be slightly lower mainly because of lower sensitivity. Specificity can still be high and close to 100%.

Instrumental and Cytologic Examination

Patients presenting with hematuria should also be evaluated with cystoscopy. Blood effluxing from the ureteral orifice identifies the origin of bleeding from the upper tract. Most renal pelvis tumors can be distinguished radiographically from RCC; however, endoscopic evaluation of the bladder, ureters, and renal pelvis is occasionally helpful in making a diagnosis. In addition, although urine cytologic study is rarely helpful in the diagnosis of RCC, cytologic study of urine with renal pelvis washing is frequently diagnostic in renal pelvis tumors.

Differential Diagnosis

When a patient presents with clinical findings consistent with metastatic disease and is found to have a renal mass, a diagnosis of RCC can be straightforward. Most patients present with a renal mass discovered after an evaluation of hematuria or pain or as an incidental finding during an imaging workup of an unrelated problem. The differential diagnosis of RCC includes other solid renal lesions. The great majority of renal masses are simple cysts. Once the diagnosis of a cyst is confirmed by US, no additional evaluation is required if the patient is asymptomatic. Equivocal findings or the presence of calcification within the mass warrant further evaluation by CT. A wide variety of pathologic entities appear as solid masses on CT scans, and differentiation of benign from malignant lesions is frequently difficult. Findings on CT scan that suggest malignancy include amputation of a portion of the collecting system, presence of calcification, a poorly defined interface between the renal parenchyma and the lesion, invasion into perinephric fat or adjacent structures, and the presence of abnormal periaortic adenopathy or distant metastatic disease. The frequency of benign lesions among renal masses <7 cm in size is as high as 16–20% (Duchene et al, 2003; Snyder et al, 2006). Masses >7 cm are rarely benign.

Some characteristic lesions can be defined using CT criteria in combination with clinical findings. Angiomyolipomas (with large fat components) can easily be identified by the low-attenuation areas classically produced by substantial fat content. A renal abscess may be strongly suspected in a patient presenting with fever, flank pain, pyuria, and leukocytosis, and an early needle aspiration and culture should be performed. Other benign renal masses (in addition to those previously described) include granulomas and arteriovenous malformations. Renal lymphoma (both Hodgkin's disease and non-Hodgkin's disease), transitional cell carcinoma of the renal pelvis, adrenal cancer, and metastatic disease (most commonly from a lung or breast cancer primary) are additional diagnostic possibilities that may be suspected based on CT and clinical findings.

Treatment

Specific Measures

Localized Disease

Surgical removal of the early-stage lesion remains the only potentially curative therapy available for RCC patients. Appropriate therapy depends almost entirely on the stage of tumor at presentation and therefore requires a thorough staging evaluation. The prognoses of patients with stages T1–T3a disease are similar following radical nephrectomy.

Radical or partial nephrectomies are the primary treatments for localized RCC. The goal is to achieve the removal of tumor and to take a wide margin of normal tissue. Radical nephrectomy entails en bloc removal of the kidney and its enveloping fascia (Gerota's) including the ipsilateral adrenal, proximal one-half of the ureter, and lymph nodes up to the area of transection of the renal vessels (Figure 22–8).

Various open incisions provide optimal access for the radical nephrectomy, including an anterior subcostal (unilateral chevron) or thoracoabdominal incision, and, occasionally, a midline incision or the classic flank incision.

The likelihood of local recurrence after radical nephrectomy is 2–3% (Itano et al, 2000). Repeat resection of isolated local recurrence can be curative and yield a survival benefit (Itano et al, 2000; Tanguay et al, 1996). The role of regional lymphadenectomy in RCC remains controversial. Between 18% and 33% of patients undergoing radical nephrectomy with lymph node dissection for RCC have metastatic disease identified (Skinner et al, 1988). Although several retrospective studies (Thrasher and Paulson, 1993) and a prospective, nonrandomized study (Herrlinger et al, 1991) suggest that regional lymphadenectomy can improve survival in patients with T1–T2 RCC. More recent studies including a randomized prospective study as well as a population-based study failed to show any survival benefit that could be obtained by routinely performing regional lymphadenectomy especially in patients with organ-confined disease (Blom et al, 1999; Joslyn et al, 2005). Removal of the adrenal is unnecessary if the tumor is not in the upper pole, because adrenal involvement is uncommon in this instance.

Preoperative renal artery embolization (angioinfarction) has been used in the past as a surgical adjunct to facilitate radical nephrectomy, but because there is no conclusive evidence that preoperative embolization actually decreases blood loss or facilitates surgery, its use should be limited to patients with very large tumors in which the renal artery may be difficult to reach early in the procedure. In addition, this technique may be useful to palliate patients with nonresectable tumors and significant symptoms such as hemorrhage, flank pain, or paraneoplastic syndromes.

Radiation therapy has been advocated as a neoadjuvant (preoperative) or adjuvant method to radical nephrectomy, but there is no evidence that postsurgical radiation therapy to the renal bed, whether or not residual tumor is present, contributes to prolonged survival.

RCC may invade renal vascular spaces and produce tumor thrombi extending into renal veins, inferior vena cava, hepatic veins, and, occasionally, the right atrium. Between 5% and 10% of patients presenting with RCC have some degree of vena caval involvement (Figure 22–9) (Skinner et al, 1988). Patients presenting with involvement of the vena cava below the hepatic veins (T3bN0M0) but without evidence of regional or distant metastases have a prognosis similar to patients with stage T2 disease when treated by radical excision. The surgical approach to the removal of caval thrombi depends entirely on the level of cephalad extension. In general, these thrombi do not invade the wall of the cava and therefore can be removed without resection of the caval wall. For tumor thrombi that have reached the level of the right atrium, the use of cardiopulmonary bypass is typically required.

Laparoscopic or robotic radical nephrectomy and partial nephrectomy can also be accomplished successfully and safely. Laparoscopic/robotic radical nephrectomy is being used increasingly for patients with localized renal tumors. This approach results in quicker recovery with efficacy comparable to that of open radical nephrectomy and is now the approach of choice in appropriate patients with <10 cm tumors and without local extension or a renal vein or caval thrombus (Gill et al, 2001; Portis et al, 2002).

The approach to the patient with either bilateral RCC or disease in a solitary kidney differs from the standard approach of radical nephrectomy. Bilateral RCC occurs with a frequency as high as 3% (Smith, 1986). Radical nephrectomy in these patients or in those with solitary kidneys obviously commits patients to long-term dialysis or renal transplantation and the morbidities of these conditions. Staging these patients is essentially the same as previously outlined, with the notable exception that either MR or CT angiography is often used to assess the extent of tumor within the kidney and the renal artery anatomy. Surgical alternatives to radical nephrectomy include open or laparoscopic/robotic partial nephrectomy, ex vivo partial nephrectomy (bench surgery followed by autotransplantation) (Novick et al, 1980), and enucleation of multiple lesions (Marshall et al, 1986). Given the lack of curative adjuvant therapy, the risk of inadequate excision, and subsequent recurrence from various renal-sparing approaches, partial nephrectomy with an adequate parenchymal margin remains the preferred treatment.

Partial nephrectomy and wedge resection with an adequate margin of normal parenchyma is considered standard primary surgical therapy for patients with tumors <4 cm in size, even in the presence of a normal contralateral kidney. Local recurrence of tumor in the same kidney ranges from 0% to 10%, and it is between 0% and 3% for tumors <4 cm in size (Hafez et al, 1997; Morgan and Zincke, 1990; Uzzo and Novick, 2001). In patients with multiple small tumors, such as those with von Hippel–Lindau disease, enucleation of the tumor(s) is also an acceptable approach. Long-term follow-up demonstrates that partial nephrectomy has a similar outcome as radical nephrectomy (Herr, 1999). Laparoscopic or robotic partial nephrectomy for these small tumors is recently gaining in use. The main advantages of the laparoscopic/robotic approach to partial nephrectomy are lower blood loss, less pain, and faster recovery.

Additional therapeutic approaches being increasingly applied for the treatment of small, incidentally discovered renal lesions include the use of cryoablation, high-intensity focused US, and radiofrequency ablation (Murphy and Gill, 2001). Cryoablation with liquid nitrogen or argon gas, either percutaneously using MRI guidance or via laparoscopic probes, has proved to be feasible and effective in selected patients (Gill et al, 2000; Shingleton and Sewell, 2002). Radiofrequency ablation has also been accomplished via the percutaneous approach with minimal morbidity in small groups of patients (Pavlovich et al, 2002). These approaches are particularly attractive in patients with single or multiple small lesions or older individuals with many comorbidities. The long-term effectiveness of both radiofrequency ablation as well as cryoablation appears to be acceptable (Kimura et al, 2010). It appears that cryoablation is superior to radiofrequency ablation in terms of long-term cancer control. Bleeding, scarring of renal pelvis, and urine leak are among the commonly reported complications with the ablative therapies.

Observation as treatment can also be considered an acceptable management approach for small (<3.0 cm) lesions, particularly in elderly patients. One recent study noted a growth rate of 0–1.3 cm/year in 40 patients followed up for a mean of 3.5 years (Bosniak, 1995), indicating that with careful follow-up, watchful waiting may be appropriate in selected patients. Only one-third of small (<4 cm) renal masses are observed to increase in size over 2 years with none experiencing disease progression (Volpe et al, 2004). This further suggests that at least initially observation is a reasonable option particularly for older patients with comorbidities who may not be amenable to surgery.

Disseminated Disease

Approximately 30% of patients with RCC will present with advanced disease. Metastatic RCC has a variable natural history, with 5-year survival rates typically <10% (Motzer et al, 1996). Infrequently, the disease may have a more protracted course. The biological diversity of RCC is illustrated by the 6.6% response rate (including 3% complete responders) in the placebo arm of a phase III trial of interferon-gamma (IFN-γ) in advanced RCC (Gleave et al, 1998).

Role of stratification factors: The experience with IFN has led to the understanding that patients can be grouped into three different risk categories, which predicts their overall survival from metastatic RCC. The so-called Motzer criteria, or Memorial Sloan-Kettering Cancer Center risk group, stratify patients into good, intermediate and poor risk based on performance status, prior nephrectomy, hemoglobin, lactate dehydrogenase (LDH), and calcium level (Motzer et al, 1999). Importantly, even though IFN is currently no longer used in the treatment of RCC, these risk groups were utilized to select different patient populations in the development of currently available targeted therapies (below).

Surgery

The role of radical nephrectomy in the management of patients with advanced disease has been reevaluated based on the results of randomized clinical trials. Historically, radical nephrectomy was primarily used as a palliative procedure in the setting of metastatic disease for managing patients with severe hemorrhage or unremitting pain. Over the past 20 years, retrospective observations of the potential for nephrectomy to improve the outcome of patients receiving biologic response modifier therapy prompted a prospective evaluation of this effect. The Southwest Oncology Group performed a randomized phase III trial, randomizing patients with advanced RCC to nephrectomy followed by interferon-alpha (IFN-α) 2b versus interferon alone. The median survival of patients undergoing nephrectomy followed by interferon was 3 months longer compared to those receiving only interferon (Flanigan et al, 2001). A similar, smaller, randomized trial conducted in Europe demonstrated similar findings (Mickisch et al, 2001). These two studies have prompted a shift in the standard of care for patients with metastatic RCC and good performance status who desire systemic therapy to include a nephrectomy prior to systemic therapy. Nephrectomy in the presence of metastatic disease (cytoreductive nephrectomy) can be performed via the open approach or laparoscopically. Patients who undergo the nephrectomy laparoscopically may have shorter hospital stay, less blood loss, and obtain adjuvant therapy earlier (Rabets et al, 2004)

The continued role of cytoreductive nephrectomy prior to systemic therapy has undergone considerable scrutiny after 2004, with the availability of new targeted systemic therapy (anti-vascular endothelial growth factor (anti-VEGF) tyrosine kinase inhibitors (TKIs) and mTOR inhibitors). While a majority of patients who received these drugs in clinical trials (and in current medical practice in 2010) have had prior cytoreductive nephrectomy, no randomized comparison regarding the role of cytoreductive nephrectomy in prolonging survival in the targeted therapy era is yet available. An ongoing clinical trial in Europe is examining this question. Trials are also examining the role of neoadjuvant-targeted therapy prior to cytoreductive nephrectomy.

Patients presenting with a solitary metastatic site particularly in the lung that is amenable to surgical resection may be candidates for combined nephrectomy and removal of the metastatic foci (Hoffman et al, 2005). This approach can result in 5-year survival rates of 30–40% with patients developing metachronous solitary lung metastases having a better prognosis (Hoffman et al, 2005). In patients who are destined to receive adjuvant therapy, even limited resection of metastases can yield improved survival further emphasizing the potential benefit of tumor debulking (Vogl et al, 2006).

The important role of surgical resection of solitary brain metastases has been highlighted by several randomized trials demonstrating an improvement in survival in patients with solitary brain metastases who undergo both surgical resection and whole-brain radiotherapy compared with patients who receive only radiation therapy (Patchell et al, 1990; Vecht et al, 1993).

Radiation Therapy

Radiation therapy is an important method in the palliation of patients with metastatic RCC. Despite the belief that RCC is a relatively radioresistant tumor, effective palliation of metastatic disease to the brain, bone, and lungs is reported in up to two-thirds of patients (Fossa et al, 1982; Onufrey and Mohiuddin, 1985).

Biologic Response Modifiers

The use of metastatic RCC as a model for the investigation of various biologic response modifiers was a consequence of both the lack of effective chemotherapy and the long-recognized biologic “eccentricities” of this tumor. Spontaneous regression of metastatic RCC is a well-recognized, albeit rare, event (Kavoussi et al, 1986; Vogelzang et al, 1992). Although no specific evidence exists, many believe this phenomenon to be immunologically mediated.

Studies using partially purified human leukocyte interferon in renal cancer were first reported in 1983, with subsequent studies using human lymphoblastoid interferon and, subsequently, recombinant interferon-alpha (r-IFN-α). Various doses and schedules of r-IFN-α have demonstrated reproducible overall response rates of 10–15% in advanced renal cancer (Pastore et al, 2001). A modest impact on survival has been demonstrated in some randomized trials of IFN-α. The Medical Research Council compared IFN-α to medroxyprogesterone acetate and demonstrated a 2.5-month median survival improvement favoring the IFN-α arm (Medical Research Council Renal Cancer Collaborators, 1999). Other large randomized studies have failed to demonstrate a survival advantage of IFN-α compared to other biologic response modifiers (Motzer et al, 2000; Negrier et al, 1998). IFN-α is commonly administered 3–5 days/week as a subcutaneous injection. Patients most likely to have a clinical benefit from interferon therapy are those who have minimal tumor burden (ie, primary kidney tumor removed), lung or nodal metastases only, and an excellent performance status. Given the modest activity of interferon in patients with advanced disease, trials of interferon administered in the adjuvant setting to patients at high risk of recurrence have been conducted but have not demonstrated clinical benefit (Pizzocaro et al, 2001; Trump et al, 1996). The experience with beta and gamma interferons has been less extensive. In 1989, Aulitzky and colleagues reported a 30% response rate in a trial of low-dose IFN-γ (Aulitzky et al, 1989). Unfortunately, subsequent trials, including a phase III trial, have demonstrated response rates of <10% (Gleave et al, 1998).

Interleukin-2 (IL-2), a T-cell growth factor, was first identified in 1976. Recombinant IL-2 was for a long time the only agent approved by the US Food and Drug Administration for patients with advanced renal carcinoma. The approval was based on several nonrandomized trials showing overall response rates for high-dose IL-2 in the 15% range and a complete response rate of 5%, resulting in some long-term survivors being seen with this treatment. The wide variability in response rates to IL-2 is likely a function of patient selection. Fyfe and colleagues (1995) reported a retrospective evaluation of 255 patients treated with high-dose IL-2 and found that an Eastern Cooperative Oncology Group performance score of 0 was a significant predictor of clinical response. More recently, the Cytokine Working Group presented the results of the SELECT trial, which was designed to prospectively evaluate predictive factors for response to high-dose IL-2. This trial showed that in optimally selected patients, response rates could be as high as 30%, with optimal criteria being clear cell histology and good or intermediate UCLA SANI score (which takes into account number of metastatic sites, thyroid function, lymph node status, constitutional symptoms, and histology). (McDermott et al, 2001).

Randomized trials comparing IFN-α, IL-2, and IL-2 plus INF-α have demonstrated higher objective response rates to the combination therapy, with no difference in survival and significantly higher toxicity associated with the combination (Negrier et al, 1998). Biochemotherapy regimens have been evaluated with a phase III trial demonstrating no advantage to the combination of IL-2, IFN-α, and fluorouracil versus IL-2 and IFN (Negrier et al, 2000).

With the advent of the targeted therapy era for RCC (forthcoming section), and given the low response rates to IFN, and the significant toxicities of high-dose IL-2 (despite it being the only treatment to date with potential for durable responses), immunotherapy treatments are currently offered to a minority of carefully selected patients and in centers with expertise.

Targeted Therapy

There has been significant progress in the development of several antiangiogenic agents and inhibitors of tyrosine kinase and other cell cycle activators in RCC, with currently six drugs having FDA approval for treatment of metastatic RCC in different settings and routinely used in clinical practice. Both inherited and sporadic RCCs appear to have mutations of the VHL gene resulting in loss of the gene product. This causes increased levels of hypoxia-inducible factor-alpha that in turn promotes increased expression of VEGF and promotes angiogenesis.

Bevacizumab is a monoclonal antibody that binds and inactivates VEGF A. It has shown the ability to yield partial responses, delay disease progression, and improve survival in patients with advanced renal cancer (Yang et al, 2003). Randomized trials comparing IFN with the IFN and bevacizumab combination have shown the superiority of the combination in terms of progression-free survival (Escudier et al, 2010; Rini et al, 2010).

Anti-VEGF TKIs are small molecules that are orally bioavailable. Currently FDA approved are sorafenib, sunitinib, and pazopanib. Sunitinib and pazopanib were shown to have significant activity in the first-line setting with higher response rates and longer progression-free survival compared to IFN or placebo (Motzer et al, 2007; Sternberg et al, 2010). Sorafenib was shown to have activity in patients who had previously received cytokine immunotherapy. (Escudier et al, 2009). Anti-VEGF TKI administration requires significant expertise in managing toxicities, which for instance include hypertension, diarrhea, rash, hand-foot skin reactions, cardiac abnormalities, and many others. Not all drugs in this class exhibit the same toxicities or frequency thereof. Most patients who entered clinical trials with TKIs had clear cell histology and prior cytoreductive nephrectomy.

mTOR inhibitors are another important class of agents with activity against RCC. The mTOR pathway interacts with the VEGF pathway at the molecular level and is another contributor of angiogenesis in RCC. Temsirolimus was the first mTOR inhibitor to be FDA approved and has been demonstrated to prolong survival in patients with advanced renal cancer who present with poor risk or multiple sites of metastases (Hudes et al, 2007). The phase III trial that demonstrated the efficacy of temsirolimus also notably included several patients with nonclear cell histology, a rare finding in the trials of TKIs. Everolimus was subsequently FDA-approved based on its ability to prolong progression-free survival as second-line therapy for patients with metastatic clear-cell RCC (Motzer et al, 2010). mTOR inhibitors can cause mouth sores, fatigue, pneumonitis, and hypertriglyceridemia among other side effects.

Given all the drugs available for metastatic RCC in 2010, there are many challenges ahead of us in understanding what is the best sequence of therapies to treat patients suffering from advanced RCC today. The sequential nature of the treatments also makes it difficult to prove overall survival benefits with each individually used drug in a clinical trial. The current belief is that the overall survival of patients with metastatic RCC has increased over time, approaching a median overall survival of 2 years (as opposed to 1 year in the interferon era). It is also to be highlighted that much of the clinical benefit seen with the targeted agents is not evidenced by tumor shrinkage (response rates, which are generally modest), but instead from increased duration of tumor control (progression-free survival and projected overall survival) benefits. Finally, in making decisions about which systemic therapy to use for a specific patient, many factors are taken into consideration including performance status, histology, sites and number of metastases, mode of administration, anticipated tolerance to each individual drug, line of therapy, and socioeconomic and clinical trial considerations.

Follow-Up Care

There is no universal agreement on the frequency or studies required in the follow-up care of patients with RCC. A stage-specific follow-up schedule is recommended for patients who have undergone radical or partial nephrectomy (Levy et al, 1998; Hafez et al, 1997). Patients with stage T1 disease need less stringent follow-up with yearly chest x-rays and liver and renal function tests. Those with stage T2 or T3 disease require more frequent follow-up of at least 3-month or 6-month intervals in the early postoperative period. Repeat CT scans of the abdomen should also be obtained, especially in those who have undergone partial nephrectomy, to rule out local recurrence. Patients with metastatic disease who are not undergoing therapy need continued follow-up to provide appropriate supportive care.

Prognosis

The prognosis of patients is most clearly related to the stage of disease at presentation. Recent studies report 5-year survival rates for patients with stage T1–T2 disease in the 80–100% range, with stage T3 in the 50–60% range. Patients presenting with metastatic disease have a poorer prognosis, with only a 16–32% 5-year survival rate.

Nephroblastoma, also known as Wilms tumor, is the most common solid renal tumor of childhood, accounting for roughly 5% of childhood cancers. Approximately 650 new cases are reported annually. The peak age for presentation is during the third year of life, and there is no sex predilection. The disease is seen worldwide with a similar age of onset and sex distribution. Tumors are commonly unicentric, but they occur in either kidney with equal frequency. In 5% of cases the tumors are bilateral.

Wilms tumor occurs in familial and nonfamilial forms. The National Wilms Tumor Study (NWTS) group documented the occurrence of a familial Wilms tumor in approximately 1% of cases (Breslow and Beckwith, 1982). Although a relatively rare neoplasm, Wilms tumor has become a very important model for the study of tumorigenesis and has become a prototypical neoplasm for collaborative clinical trials, with approximately 85% of all new cases diagnosed in North America enrolled in NWTS group protocols (Beckwith, 1997). Approximately 10% of patients with Wilms tumors have recognized congenital malformations. Among the more common disorders associated with Wilms tumor are the WAGR syndrome (Wilms, aniridia, genitourinary malformation, mental retardation), overgrowth syndromes, such as Beckwith–Wiedemann syndrome and isolated hemihypertrophy, and nonovergrowth disorders, such as isolated aniridia and trisomy 18 (Weiner et al, 1998). Genitourinary abnormalities such as hypospadias, cryptorchidism, and renal fusion are found in 4.5–7.5% of patients with unilateral Wilms tumor and in up to 13.4% of those with bilateral disease (Breslow et al, 1993). Some of these genetic syndromes are associated with alterations in the WT1 gene but other genes such as the IGF1, H19, and p57 genes can also be implicated (Beckwith–Wiedemann).

Etiology

In 1972 Knudson and Strong proposed a two-hit hypothesis to explain the earlier age of onset and bilateral presentation in children with a familial history of Wilms tumor. In this hypothesis, the pathogenesis of the sporadic form of Wilms tumor results from two postzygotic mutations in a single cell. In contrast, the familial form of the disease arises after one prezygotic mutation and a subsequent postzygotic event. Karyotypic analyses of Wilms tumor patients with various congenital malformations and loss of heterozygosity studies helped identify a region on the short arm of chromosome 11 (11p13) (Huff, 1994; Riccardi et al, 1978). This work ultimately led to the identification of a gene associated with Wilms tumor development (WT1), which maps to chromosome 11p13 (Coppes et al, 1994). Although alterations in this gene have been associated with Wilms tumor and genitourinary abnormalities, only 5–10% of sporadic Wilms tumors have been demonstrated to have WT1 mutations (Varanasi et al, 1994). Genetic linkage studies of families with an inherited susceptibility to Wilms tumors suggest that other Wilms tumor genes exist (Weiner et al, 1998).

Pathogenesis and Pathology

In 1990 Beckwith and colleagues proposed a simplified nomenclature and classification of Wilms tumor precursor lesions known as nephrogenic rests (NR). Two distinct categories of NR were identified and designated as perilobar NR and intralobar NR. One concept of Wilms tumor development proposed that some NR remain dormant for many years, with some undergoing involution and sclerosis and others giving rise to Wilms tumors (Beckwith, 1997; Beckwith et al, 1990). The typical Wilms tumor consists of blastemal, epithelial, and stromal elements in varying proportions (Figure 22–10). Tumors composed of blastema and stroma or blastema alone have been described. Pure tubular and papillary forms that are very similar to papillary RCC have also been described.

The NWTS correlated pathologic specimens with clinical outcome and divided various histologic features into favorable and unfavorable prognostic groups. The unfavorable subgroup includes tumors that contain focal or diffuse elements of anaplastic cells or two other neoplastic entities considered not to be Wilms tumor variants, clear cell sarcoma of the kidney, and rhabdoid tumor of the kidney (Beckwith, 1997; Beckwith and Palmer, 1978). Favorable histology tumors comprise all Wilms tumors without anaplasia. Anaplastic tumors are characterized by extreme nuclear atypia, hyperdiploidy, and numerous complex translocations. Anaplasia occurs in 5% of Wilms tumors and incidence increases with age. It is more common in African-American children and is linked to p53 mutations (Bardesey et al, 1994). Presence of diffuse anaplasia indicates a worse prognosis compared to focal anaplasia.

Grossly, Wilms tumors are generally large, multilobulated, and gray or tan in color with focal areas of hemorrhage and necrosis. A fibrous pseudocapsule is occasionally seen. Tumor dissemination can occur by direct extension through the renal capsule, hematogenously via the renal vein and vena cava, or via lymphatic spread. Metastatic disease is present at diagnosis in 10–15% of patients, with the lungs (85–95%) and liver (10–15%) the most common sites of involvement. Regional lymphatics are involved in as many as 25% of patients. Metastases to liver, bone, and brain are uncommon.

Tumor Staging

The NWTS staging system is most widely used and is based on surgical and pathologic findings. The original classification was used in the first and second NWTS trials and was modified for NWTS III (D'Angio et al, 1989). Further modifications have been introduced to the staging in the NWTS V study.

Stage I—Tumor limited to kidney and completely excised. No penetration of renal capsule or involvement of renal sinus vessels. Tumor was not ruptured before or during removal. There is no residual tumor apparent beyond the margins of resection.

Stage II—Tumor extends beyond the kidney but is completely removed. There is either penetration through the outer surface of the renal capsule, invasion of renal sinus vessels, biopsy of tumor before removal, or spillage of tumor locally during removal. There is no residual tumor apparent at or beyond the margins of excision and no lymph node involvement.

Stage III—Residual nonhematogenous tumor confined to abdomen. Any one or more of the following occur: (a) regional lymph node involvement; (b) diffuse peritoneal contamination by tumor, such as spillage of tumor beyond the flank before or during surgery, or by tumor growth that has penetrated through the peritoneal surface; (c) implants are found on the peritoneal surfaces; (d) the tumor extends beyond the surgical margins either microscopically or grossly; (e) the tumor is not completely resectable because of local infiltration into vital structures; (f) tumor spill not confined to the flank occurred either before or during surgery; (g) transected tumor thrombus.

Stage IV—Hematogenous metastases to lung, liver, bone, and brain.

Stage V—Bilateral renal involvement at diagnosis. An attempt should be made to stage each side according to the previously given criteria on the basis of extent of disease before biopsy.

Clinical Findings

Symptoms and Signs

The diagnosis of Wilms tumor is most commonly made after the discovery of an asymptomatic mass by a family member or a physician during a routine physical examination. Common symptoms at presentation include abdominal pain and distention, anorexia, nausea and vomiting, fever, and hematuria. The most common sign is an abdominal mass. Hypertension is seen in 25–60% of cases and is caused by elevated renin levels (D'Angio et al, 1982; Pizzo et al, 1989). Up to 30% of patients demonstrate hematuria and coagulopathy can occur in 10%.

Laboratory Analysis

Urinalysis may show evidence of hematuria, and anemia may be present, particularly in patients with evidence of subcapsular hemorrhage. Patients with liver metastases may have abnormal serum chemistries.

X-Ray Imaging

Abdominal US and CT scanning are performed initially to evaluate the mass. CT of the abdomen is performed with suspected Wilms tumor and can be useful in providing information regarding tumor extension, the status of the contralateral kidney, and the presence of regional adenopathy. CT scanning remains an imperfect technique with a relatively high false-positive rate for hepatic invasion in right-sided tumors, and 7% of cases of surgically confirmed synchronous bilateral Wilms tumors were missed by preoperative CT imaging in the NWTS IV (Ritchey et al, 1995).

Abdominal MRI can sometimes be useful to distinguish between NR and Wilms tumor but is otherwise not routinely indicated. MRI can also provide important information in defining the extent of tumor into the inferior vena cava, including those with intracardiac extension. MRI is limited in that there is no bowel contrast agent, and its use in children requires sedation (Babyn et al, 1995).

Chest x-ray remains the initial examination of choice to evaluate for the presence of lung metastases. The role of a chest CT scan is controversial, and it is probably not indicated for routine use in low-risk patients; however, when done concomitantly with an abdominal CT, chest CT may provide clinically useful information in high-risk patients. If pulmonary metastases are seen on chest x-ray, CT of the chest will not alter current therapy. However, the need for chest CT imaging in patients with negative results of chest x-ray remains controversial, because it is not clear whether those lesions detected by CT alone require more aggressive treatment (Weiner et al, 1998).

Needle Biopsy

Preoperative biopsy is indicated routinely only in tumors deemed too large for safe primary surgical resection and for which preoperative chemotherapy or radiation therapy is planned.

Differential Diagnosis

The differential diagnosis of a flank mass in a child includes hydronephrosis, cystic kidneys, intrarenal neuroblastoma, mesoblastic nephroma, and various very rare sarcomas.

Ultrasonography can confirm the presence of hydronephrosis and evaluate for the presence of cystic kidneys. Neuroblastoma, while pathologically distinct from Wilms tumor, frequently presents in the abdomen as a mass arising from the adrenal glands or paraspinal ganglion. Neuroblastomas are radiographically indistinguishable from Wilms tumors, but there are several features that may aid in the differentiation. In contrast to Wilms tumors, which are typically confined to one side of the abdomen, neuroblastomas usually cross the midline. Wilms tumors are intrarenal masses and rarely cause a change in the axis of the kidney, while neuroblastomas may cause an outward and downward displacement of the kidney (drooping lily). Children with neuroblastomas are more likely to present with metastatic disease, and these tumors have a higher frequency of calcification observed radiographically. In addition, neuroblastomas may produce various tumor markers including vanillylmandelic acid and other catecholamines that are not seen in patients with Wilms tumor (Pizzo et al, 1989).

Mesoblastic nephromas are benign hamartomas and cannot be preoperatively distinguished from Wilms tumors. They are most commonly seen in the neonatal period and are typically identified by surgical pathology after nephrectomy. The tumor can occur in adults (Truong et al, 1998).

Treatment

The goal of therapy is to provide the highest possible cure rate with the lowest treatment-related morbidity. Significant improvements in survival rates for children with Wilms tumor have been achieved by an improved understanding of the disease and a multimodality approach to therapy, advocated by the National Wilms Tumor Registry (NWTS), which incorporates surgery, radiation therapy, and chemotherapy.

Surgical Measures

For patients with unilateral kidney involvement whose tumors are deemed surgically resectable (tumors not crossing the midline or involving adjacent visceral organs), radical nephrectomy via a transabdominal incision is the procedure of choice.

Retroperitoneal lymph node dissection is not of proven value and is not recommended. However, biopsy of regional lymphatics (renal hilum and para-aortic nodes) and careful examination of the opposite kidney and the remainder of the abdomen provide crucial data for staging and prognosis. Tumor extending into the vena cava should be removed unless there is evidence of total obstruction. Excision of tumor extending into adjacent organs can be attempted if feasible. Complete excision of all tumors would allow downstaging and decrease the amount of additional chemotherapy. A major point of emphasis during surgical extirpation is to avoid spillage because there is evidence that this increases abdominal recurrence of disease (Ross and Kay, 1999; Shamberger et al, 1999).

A child with bilateral Wilms tumor, like an adult with bilateral RCC, requires an individualized approach. Patients with favorable histology tumors can frequently be managed with preoperative chemotherapy followed by renal-sparing surgery (Kumar et al, 1998). In patients for whom preoperative chemotherapy is planned, a biopsy for diagnosis and staging is indicated (Blute et al, 1987). In some centers, needle aspiration biopsy has proved to be a reliable diagnostic tool when evaluated by experienced pathologists (Hanash, 1989). In patients with unfavorable histology tumors, the therapeutic approach consists of aggressive surgery followed by chemotherapy and radiation therapy.

Chemotherapy

Wilms tumor has been long recognized as a chemosensitive neoplasm. Consecutive multicenter randomized trials conducted by the National Wilms' Tumor Study Group (NWTSG), starting in the 1960s, have carefully explored various treatment strategies to determine the role of various antineoplastics and the integration of surgery and radiotherapy, with the goal of optimizing response rates and cure while minimizing the toxicity of therapy. Current studies are focused on continued efforts to minimize toxicity (primarily by decreasing chemotherapy treatment duration and removing radiotherapy) in those favorable subgroups with impressive cure rates, and modifying efforts in poor-risk subgroups to improve response and survival.

Patients with stage I favorable or anaplastic histology and stage II favorable histology tumors undergo surgical resection and have adjuvant chemotherapy with vincristine and dactinomycin combinations without radiotherapy. Patients with stage III and IV favorable histology tumors undergo surgical resection and have adjuvant therapy with vincristine, dactinomycin, and doxorubicin, with adjuvant radiotherapy. Patients with stage II–IV focally anaplastic histology tumors receive therapy similar to that for advanced-stage favorable histology tumors. In the NWTS V, patients with stage II–IV anaplastic tumors are receiving vincristine, doxorubicin, cyclophosphamide, and etoposide (Kalapurakal et al, 2004). Salvage chemotherapy regimens include agents such as cyclophosphamide, ifosfamide, carboplatin, and etoposide. For stage V or bilateral Wilms tumors, diagnosis is established by bilateral biopsies followed by chemotherapy. Second-look surgery may be necessary to reassess response 6–8 weeks after chemotherapy. Renal sparing procedures can be attempted but the rate of renal failure is high.

Radiation Therapy

Wilms tumor has long been recognized as a radiosensitive tumor. Despite the proven efficacy of radiation therapy in children, its use is complicated by its potential for growth disturbances and recognized cardiac, pulmonary, and hepatic toxicities. The development of effective chemotherapy combinations has practically replaced radiation therapy in the preoperative setting. The first and second NWTS trials demonstrated that postoperative radiotherapy was not required for patients with favorable histology stage I disease. NWTS III failed to show an advantage for postoperative radiotherapy in patients with favorable stage II disease and demonstrated that the relapse rate of patients with stage III disease was no different for patients receiving 1000 cGy compared with the traditional 2000 cGy (D'Angio et al, 1989). Postoperative radiation is recommended for patients with stage III or IV disease with favorable histology, stages II–IV with focal anaplasia and clear cell sarcoma, and all stages of rhabdoid tumor of the kidney (Weiner et al, 1998).

Prognosis

The multimodality approach to the treatment of children with Wilms tumors has significantly improved outcomes. The 4-year survival of patients with favorable histology Wilms tumor now approaches 90% (Weiner et al, 1998). The most important negative prognostic factors remain the unfavorable histologic subtypes (clear cell sarcoma, rhabdoid, and anaplastic tumors). Although the addition of doxorubicin in NWTS III significantly improved the 2-year survival rate for patients with clear cell sarcomas (61.5–90.3%), it did not affect the survival of children with rhabdoid tumors. Analysis of patients with bilateral Wilms tumors registered with NWTS II and III revealed a 3-year survival rate of 82% (Blute et al, 1987).

Future challenges include improvements in therapy for patients with anaplastic tumors (stages II–IV), clear cell sarcoma, and rhabdoid tumors, and efforts to improve outcomes in favorable histology tumors while decreasing both short-term and late toxicities. Long-term toxicity in these patients include renal failure, cardiac toxicity with congestive heart failure due to chemotherapy, and lung radiation as well as a higher risk for secondary malignancies.

The kidney is a frequent site for metastatic spread of both solid and hematologic tumors. Wagle et al (1975) surveyed 4413 autopsies at a major cancer center and found 81 (18%) cases of secondary carcinoma of the kidney (hematologic tumors were excluded). The most frequent primary site of cancer was lung (20%), followed by breast (12%), stomach (11%), and renal (9%). The authors noted that metastases to the renal parenchyma typically demonstrated capsular and stromal invasion with sparing of the renal pelvis and that bilateral secondary renal involvement was found in approximately 50% of cases.

Albuminuria and hematuria are relatively common findings in patients with secondary renal metastases; however, pain and renal insufficiency are rare (Olsson et al, 1971; Wagle et al, 1975). Secondary metastatic disease to the kidneys tends to be a late event, frequently in the setting of widely disseminated disease, which typically portends a poor prognosis. Therapy is dictated by the responsiveness of the primary neoplasm; that is, patients with breast and ovarian cancers for which there is effective therapy are more likely to respond than patients with primary lung or gastric cancers.

Autopsy series have reported clinically evident renal invasion by lymphoma to be 0.5–7%, with the rates of Hodgkin's and non-Hodgkin's lymphoma distributed equally (Goffinet et al, 1977; Weimar et al, 1981). Renal involvement is usually in the form of bilateral, multiple, discrete tumor nodules. Renal involvement by non-Hodgkin's lymphoma is typically characterized by diffuse, aggressive histologic findings (ie, diffuse large cell) in the setting of extensive disease. Therapy typically consists of combination chemotherapy, with the prognosis of patients similar to that of patients without renal involvement but with widely disseminated, aggressive lymphomas (Geffen et al, 1985).