CHAPTER 29

Renal Tumors

Luiz M. Kolankiewicz, MD, MC, Maj USAFR

Renal cell carcinomas (RCCs), either as benign or malignant renal tumors, have obscure signs and symptoms, are clinically occult, and often are diagnosed by primary care providers (PCPs) in the initial workup of a classical triad of flank pain, palpable abdominal renal mass, and hematuria. In addition, renal masses are nowadays more frequently seen in the evaluation of nonurologic abnormalities on sonograms, CT scanning, and MRI. Hematuria, gross or microscopic, is usually observed only if the tumor has invaded the collecting system; this occurs in only a small fraction of patients, but when present strongly suggests advanced disease. The PCP should be familiar with the appropriate evaluation and treatment of common renal neoplasms. Consultation with a urologist is usually necessary for proper evaluation, diagnosis, and treatment options.

This chapter concentrates on the epidemiology, pathology, clinical and radiographic presentation, staging methods, and surgical and systemic treatment modalities of primary renal neoplasms.

OVERVIEW OF RENAL TUMORS

Diagnostic Criteria

Although incidental detection of renal masses is the primary diagnostic modality, many are still found in the workup of hematuria.

Hematuria is defined as abnormal excretion of red blood cells (RBCs) into the urine. Healthy individuals excrete about 1 million RBCs per day in their urine, or about one to three RBCs per high-power field (HPF). Therefore, excretion of more than three RBCs per HPF is abnormal and may warrant further evaluation. Asymptomatic “microscopic hematuria” is very common. Microscopic hematuria may be detected in up to 13% of adults. Hematuria can be a sign of advanced underlying disease and should not be ignored.

Gross hematuria occurs when there is enough blood present in the urine to turn it red or brown. Microscopic and gross hematuria are generally caused by the same conditions; however, they may manifest differently for specific pathological conditions. Therefore, the diagnostic approaches to these two conditions are different. Routine screening of healthy individuals for the presence of hematuria is not recommended by the U.S. Preventive Services Task Force (USPSTF). Despite official recommendations, urinalyses are nonetheless frequently obtained as a screening test. Whenever a urinalysis reveals hematuria, the person’s age, gender, race, medical history, and physical findings should be considered in deciding whether to proceed with further evaluation.

History and Physical Examination

A complete history and physical examination are part of any hematuria workup. Three major factors influence the workup: the patient’s gender, race, and age. The common causes of hematuria in children and young adults are different from those in older individuals. Hematuria in adults older than 40 years must be considered a sign of malignancy (of the bladder, upper urinary tract, or kidney origin) until proved otherwise. Although malignancy is much less frequent in patients with hematuria who are younger than 40 years, a nephroblastoma (Wilms’ tumor) should be considered and the precise nature of the hematuria should be elucidated.

Hematuria accompanied by pain, either in the flank or the pelvis, may be an indication of stone disease. Colicky pain suggests ureteral obstruction from a stone, blood clot, or sloughed renal papilla. This is especially the case if the pain radiates to the testicle or labia. Fever may be an indication of an infection, possibly pyelonephritis. Pyuria is significant in almost all cases, and hematuria without pyuria should not be attributed to infection. The passage of blood clots can sometimes help to localize the site of bleeding to the upper tracts—long and string-like versus more clumped (bladder). Recent trauma may be readily apparent in some patients, but hematuria secondary to apparently trivial trauma may indicate a condition such as aureteropelvic junction obstruction. Recent strenuous physical exercise is sometimes associated with hematuria as well. A past history of urologic conditions or procedures is obviously important. A family history of urologic disease may be crucial because some cases of RCC are familial, with and without von Hippel–Lindau (VHL) disease. Numerous environmental and occupational exposures have been implicated in the etiology of RCC. These include tobacco use, obesity, and NSAID (nonsteroidal anti-inflamatory drug) use, as well as occupational exposure to toxic compounds such as cadmium and asbestos. Specific exposure to rubber and dye elements are particularly relevant to transitional cell carcinoma (TCC). Polycystic kidney disease, either acquired or congenital, will rarely also confer a propensity to development of renal cell cancer.

The classification of “renal adenoma” remains controversial in the urologic literature Table 29.2 presents a synopsis of the following discussion about specific renal tumors. It may be possible to distinguish an RCC from a renal adenoma based on nuclear and cytoplasmic criteria, but there are no reliable gross, microscopic, or ultrastructural differences between the two lesions. Previously, size alone was the standard criterion. This was based on the autopsy study by Bell (1938), demonstrating that renal lesions smaller than 3 cm rarely metastasized, whereas almost 70% of lesions >3 cm had metastasized. There are, however, several reports of lesions as small as 5 mm with metastases. Small, solid renal masses that enhance with intravenous contrast are probably small RCCs.

One study of several thousand autopsy and surgical specimens described two distinct histologic types of adenomas (Faria, Reis, & Trigueiros, 1994). Adenomas with a papillary or tubulopapillary pattern are more common, are smaller, are frequently multiple, and probably are not precursors of RCC. They are usually composed of basophilic, eosinophilic, or oncocytic cells. Adenomas with a solid or papillary pattern are frequently solitary, are larger, and may be a morphologic precursor of RCC. They are often composed of clear cells and characterized by either deletion or functional inactivation of chromosome arm 3p. In recent studies where immunohistochemical analyses were used to further characterize renal adenomas, it was suggested that these lesions may be associated with the development of papillary RCC and thought to be a premalignant precursor (Cairns, 2010).

Renal adenomas appear as solid masses on imaging. They cannot be distinguished from RCC by imaging techniques, and most urologists think these potentially malignant tumors should undergo treatment as if they were RCCs. How should these small RCCs or renal adenomas be managed? Although the standard therapeutic approach for RCC remains radical nephrectomy, there is growing interest in the use of partial nephrectomy, especially for incidentally discovered lesions. In select cases, it may even be reasonable to observe small tumors. In general, Bosniak class I, II, and IIF cysts are likely to represent benign lesions, thus requiring either no therapy or just continued radiographic follow-up, in the case of class IIF lesions. These recommendations are based on a number of series published in the literature by Bosniak (2005). These series included both radiographic and pathologic follow-up. Bosniak showed that, for lesions <3 cm at diagnosis, and followed for at least 2 years, no metastases were clinically detectable. The majority of patients eventually went on to have surgery, and none developed metastases. This “watchful waiting” approach may be acceptable for an elderly patient with other significant medical problems, but it should be undertaken in consultation with a urologist. It is certainly not to be suggested for the young and otherwise healthy patient, because small renal tumors do grow and do have the capacity to metastasize. Table 29.1 lists the Bosniak classification of different renal cysts. Figure 29.1 shows radiographic examples of Bosniak cysts.

RENAL ONCOCYTOMA

Anatomy, Physiology, and Pathology

Renal oncocytoma is the most common benign tumor that appears as an enhancing renal mass on cross-sectional imaging; it is presumed to be RCC until surgical excision, representing challenges in preoperative diagnosis for the urologist. Grossly, oncocytomas are well circumscribed with pseudocapsule tumors and a characteristic mahogany color. A large stellate central scar is often seen. Hemorrhage and necrosis are typically absent. Microscopically, the tumor is composed of large well-differentiated cells with intensely eosinophilic cytoplasm containing abundant mitochondria. These oncocytes rarely exhibit mitoses.

Plain radiographs occasionally show lucent areas within large angiomyolipomas, suggesting the diagnosis, but typically the IVU demonstrates an expansile mass that cannot be distinguished from RCC. On USG, they are usually more echogenic than surrounding parenchyma. They share this feature with about one third of RCCs. However, with the development of high-quality CT scanning, it was realized that the detection of fat within a renal lesion allows confident preoperative diagnosis and the potential to avoid surgery in most cases that are not symptomatic. Table 29.2 illustrates this information.

In fat-poor suspected angiomyolipoma, a percutaneous biopsy can provide a diagnosis with the advent of HMB-45 (monoclonal antibody against melanoma-associated antigen; Catalano, Samir, Sahani, & Hahn, 2008; He et al., 2011).

The most common presentation is incidental discovery during imaging for other medical conditions. Patients may present with acute flank pain with or without spontaneous hemorrhage. Occasionally, the onset of symptoms is preceded by seemingly trivial trauma. The blood vessels of angiomyolipoma lack a complete elastic layer, predisposing these lesions to aneurysm formation and bleeding. Steiner et al. demonstrated that lesions <4 cm rarely become symptomatic, whereas lesions >4 cm require surgical intervention in about half the cases for bleeding (Steiner, Goldman, Fishman, & Marshall, 1993). Treatment must be individualized, based on presentation, pregnancy, tumor size, and renal function. In case of acute hemorrhage, renal angioembolization is the treatment of choice.

When the CT scan is unequivocal and the patient is asymptomatic, no intervention is required for small angiomyolipomas. In cases where the diagnosis is in question, exploration and partial or radical nephrectomy may be necessary. Symptomatic patients with angiomyolipomas can often be treated successfully with percutaneous angioembolization.

Malignant Renal Neoplasms

RENAL CELL CARCINOMA

Anatomy, Physiology, and Pathology • The origin of RCC is the renal cortex, and these tumors occur with equal frequency in the right and left kidneys. Grossly, the tumors are often yellow or orange because of the abundance of fat seen in the clear-cell variant. The clear cytoplasm observed by light microscopy of the clear-cell variety is caused by removal of glycogen and lipids during histologic processing. The granular type is usually more white to gray. The sarcomatoid cell type is less frequently seen. Usually, there is a mixed picture. As RCC grows, it compresses the normal parenchyma, forming a pseudocapsule. RCC has a propensity for invasion into vascular spaces, including the renal vein, inferior vena cava, and occasionally even the right atrium.

Histologic grading of RCC cells has been used with variable success to predict the clinical behavior of these tumors. Compared to pathologic stage, no additional prognostic information has been consistently obtained.

Epidemiology • RCC accounts for 85% of all renal parenchymal cancers and represents 2% to 3% of all adult malignancies. RCC has been known by many different terms: historically, hypernephroma, Grawitz’s tumor in 1883, and later nephrocarcinoma. There were approximately 58,000 new cases in 2009, resulting in 13,000 deaths (Jemal et al., 2009). It occurs most commonly in the fifth to sixth decade, although it has been reported in children and young adults. The male/female ratio is 2:1. Recent advances in imaging have led to increased incidental detection of RCC and improved prognosis of patients with such tumors.

The most common test to evaluate extent of disease is the CT scan (Figure 29.2). RCC is seen as a solid lesion that enhances after intravenous contrast administration. An increase in Hounsfield units of at least 20 is considered positive enhancement. Ten to 20 units of enhancement are considered intermediate and inconclusive. Approximately 10% of RCCs are hypovascular, however, and will not enhance with intravenous contrast (Gillenwater, Grayhack, Howards, & Duckett, 1996).

When involvement of the vena cava by tumor thrombus is in question, an MRI is often helpful and superior to CT with contrast. Caution should be exercised if MRI-gadolinium is needed, especially in patients with existing CKD, regarding the development of a rare but often serious syndrome known as NSF or nephrogenic fibrosing dermopathy that involves fibrosis of skin, joints, eyes, and internal organs. This syndrome was first identified in 1997 and to date is not fully understood (Thomsen, 2009). Occasionally, a cavogram or transesophageal USG is necessary to determine the exact location of a tumor thrombus in the vena cava. Knowledge of the superior extent of the thrombus is crucial for planning the surgical approach. Even patients with tumor in the right atrium can be cured of RCC with a radical nephrectomy and thrombectomy, although the potential morbidity and mortality rates of the procedure are certainly higher in this setting.

Tumor stage is recognized as the most important prognostic factor in RCC (Table 29.3). The TNM classification has supplanted the previously used Robson system. The TNM system was modified in 2002 with the reclassification of T1 tumors into T1a tumor <4 cm and T1b tumor >4 cm. It also included renal sinus invasion in the T3a classification and renal vein invasion. The seventh edition of the American Joint Cancer Classification (AJCC), released in 2010, contains additional relevant changes to T3 and T4 definitions as well as to node positive disease (N1) regardless of number of positive nodes (Edge et al., 2010).

Nuclear grade (Fuhrman classification) has recently become a more accepted prognostic factor for clear-cell renal carcinoma. The transition from Robson, TNM staging, and Fuhrman grade to integrate multiple validated prognostic factors from Memorial Sloan-Kettering Cancer Center or “MSKCC criteria” has been validated across different institutions. These criteria are currently the most commonly used nomogram that combine tumor stage, tumor size, histological subtype, Fuhrman nuclear grade, necrosis, vascular invasion, and symptoms predicting the probability of freedom from recurrence at 5 years after treatment (Table 29.4).

Table 29.3 provides the stage group classification of RCC. Table 29.4 compares information pertinent to tumor size and staging between previous classifications.

Surgical excision remains the standard therapy for clinically organ-confined RCC. Radical nephrectomy, which involves the early ligation of the renal artery and renal vein, entails en bloc removal of the kidney and its enveloping fascia. The classic radical nephrectomy includes the ipsilateral removal of adrenal gland as well. However, recent studies have shown a very low, <5% involvement of the adrenal gland (Robey & Schellhammer, 1986). Thus, adrenalectomy has fallen out of favor for all but large upper pole lesions, which may be more likely to involve the adrenal by direct extension. Regional lymphadenectomy is often performed, but there are no controlled studies that demonstrate improved survival with this additional procedure (Hellenthal et al., 2009).

The main value of removing the lymph nodes may be in more accurate staging, and nowadays multiple preoperative and intraoperative evaluative nomograms exist to assist the surgeon in deciding the benefit of lymph node dissection. Partial nephrectomy or nephron-sparing surgery implies removal of the tumor while leaving enough functional renal parenchyma to support life without the need for dialysis in the event that the other kidney is already absent or lost in the future. For this reason, the role of nephron-sparing surgery was expanded from elective to more standard of care. A partial nephrectomy is also often performed in a patient with impaired renal function or a patient with bilateral renal tumors. The size and location of the tumor are crucial determinants of whether a partial nephrectomy can be attempted. Because of the increase in the number of smaller, incidentally discovered renal masses, interest has grown in the use of partial nephrectomy even in patients with normal renal function and a normal contralateral kidney. Results using this approach in a series by Herr (1994) were excellent, with survival of about 95% and acceptable local recurrence rates of about 2%.

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