Renal cell cancer

Introduction

Kidney cancer, or renal cell carcinoma (RCC), is the most common malignancy seen in the practice of nephrology. It is one of the relatively few cancers whose incidence is increasing despite our growing knowledge of the associated risk factors, yet the study of this disease within nephrology pedagogy and continuing education is woefully lacking. Although there are many subtypes of RCC, the most common by far is clear cell RCC (ccRCC) and the vast majority of these are characterized by mutations in the von Hippel-Lindau ( VHL ) gene. Because this subtype is also the most studied, both in the clinic and in the laboratory, it will be the major subject of this chapter. Indeed, because of the various genetic and consequent metabolic abnormalities seen in all types of kidney cancer, this disease has been labeled the “ internist’s tumor ” and “ a metabolic disease .” Evaluating the various signs and symptoms of the disease in light of its genetics and biology (see later) allows a better understanding of its behavior and provides insight into new therapeutic approaches. After reading this chapter, it is hoped that practicing nephrologists are not only more aware of the biology of RCC, but also understand the profound effect of its presence in the setting of chronic kidney disease (CKD) and the consequence of its treatment on the incidence and progression of CKD.

Basic science considerations

The finding that ccRCC is, to a greater extent than other malignancies, characterized by metabolic reprogramming—in which “normal” metabolism is altered for the benefit of the cancer—has led to advances in therapeutic design, which are based on this finding. ^, Indeed, many of the paraneoplastic effects that are commonly seen with the clinical presentation ( Table 25.1 ) are a result of this altered metabolism. Another characteristic of the varieties of kidney cancer is that most are associated with genetic mutations, which in many cases contribute to the metabolic derangements. For these reasons, an understanding of the biologic underpinnings of kidney cancer is essential for anyone who deals with this disease, both in the clinical and research settings.

Clinical presentation

RCCs, which originate within the renal cortex, constitute 80% to 85% of primary renal neoplasms. Transitional cell carcinoma of the renal pelvis is the next most common (8%). Other parenchymal epithelial tumors, like oncocytomas, collecting duct tumors, and renal sarcomas are rare. Nephroblastoma or Wilms tumor is common in children.

Patients are frequently asymptomatic at presentation and the diagnosis is often made in the renal clinic during imaging for workup of CKD. Indeed, approximately one-third of patients have metastatic disease at diagnosis, at which point the prognosis is markedly poor. In symptomatic cases, the most common presenting symptoms are flank pain, hematuria, a palpable abdominal mass, and weight loss. ^, The fact that fewer patients are presenting with symptoms and more with radiologic incidental diagnosis may contribute to better outcomes in RCC, as the disease-specific 5-year survival is better in patients who are diagnosed incidentally, likely because the tumor is less advanced in these cases (76% incidental vs. 44% symptomatic). Several online (although unvalidated) “calculators” for renal survival are available, for example: http://www.lifemath.net/cancer/renalcell/outcome/index.php . There have also been published reports of nomograms and other such tools for calculating survival. ^,

Hematuria is generally observed with tumor invasion into the collecting system. When severe, such bleeding can cause clots and “colicky” abdominal discomfort. Scrotal varicoceles, mostly left-sided, are observed in as many as 11% of men with RCC. This finding occurs when the tumor obstructs the gonadal vein where it enters the renal vein. Inferior vena cava involvement can produce a variety of symptoms, such as lower extremity edema, ascites, hepatic dysfunction (Budd-Chiari syndrome), and pulmonary emboli. Metastasis occurs most commonly in lung, lymph nodes, bone, liver, and brain, and in many cases the initial diagnosis of RCC is made via biopsy of accessible metastasis or by finding a renal mass on abdominal imaging.

Paraneoplastic syndromes can develop in some patients in the form of systemic symptoms (see Table 25.1 ) and can arise from ectopic production of hormones like erythropoietin, parathyroid hormone-related protein (PTHrP), gonadotropins, human chorionic somatomammotropin, an adrenocorticotropic hormone (ACTH)-like substance, renin, glucagon, and insulin. Anemia, hepatic dysfunction, fever, cachexia, hypercalcemia, erythrocytosis, thrombocytosis, and AA amyloidosis can also be present. Erythrocytosis occurs because of overproduction of erythropoietin caused by impaired degradation of hypoxia-inducible transcription factors under normoxic conditions. Hypercalcemia occurs because of lytic bone lesions, overproduction of PTHrP, increased prostaglandins production, and bone resorption. Tumor nephrectomy will naturally correct many of these symptoms, but needs to be undertaken cautiously, especially in patients with CKD (see later).

Screening

Screening of asymptomatic individuals is not recommended because of the low prevalence of RCC in the general population. However, high risk individuals should undergo periodic screening with abdominal ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to detect early disease. Candidates for screening include patients with any of the following conditions:

• 1.

  Prior kidney irradiation

• 2.

  Inherited conditions associated with increased incidence of RCC or other renal tumors, including von Hippel-Lindau syndrome and tuberous sclerosis

• 3.

  End-stage renal disease (ESRD), especially younger subjects without serious comorbidities, who have been on dialysis for 3 to 5 years, because they can develop acquired cystic disease of the kidney

• 4.

  A strong family history of RCC

Diagnosis

Patients with signs or symptoms suggestive of RCC should get imaging evaluation for the presence of a renal mass. Historically, patients were diagnosed with RCC after presenting with flank pain, gross hematuria, and a palpable abdominal mass, but this triad is noted only in the minority of patients with disease. Incidental diagnosis of RCC is becoming more common because of frequent use of radiologic investigations done for unrelated problems, most notably for acute kidney injury (AKI) or hematuria workup in the renal clinic. As previously mentioned, unexplained paraneoplastic syndromes can prompt an RCC investigation; this is the origin of the moniker the internist’s tumor . Most paraneoplastic symptoms disappear after tumor resection.

Typical radiologic features of ccRCC include exophytic growth, intratumoral necrosis or hemorrhage, and high uptake of contrast agents ( Fig. 25.1 ). CT is more sensitive in detecting a renal mass, but renal ultrasound is useful in distinguishing a simple benign renal cyst from a more complex cyst or a solid tumor. Criteria for a simple renal cyst include: round shape, sharply demarcated lesion with smooth walls, no echogenicity within the cyst, and hyperechoic posterior wall, indicating good transmission through a cyst. By contrast, if the cyst has thickened irregular walls or septa and enhances after intravenous contrast, this suggests further investigation for malignancy. MRI can be helpful if ultrasonography and CT are nondiagnostic or contrast cannot be given. CT or MR angiography is preferable to renal arteriography for preoperative mapping of the vasculature, in preparation for possible nephron-sparing surgery. Fluorodeoxyglucose positron emission tomography ( FDG-PET) scanning, although useful for screening and staging other malignancies, has been problematic for RCC, although newer PET techniques evaluating evidence of metabolic reprogramming such as F-glutamine-PET, although currently experimental, might ultimately prove more clinically useful.

Tissue diagnosis can be obtained from total or partial nephrectomy or by biopsy of a metastatic lesion before treatment (see later). Adjacent noncancerous tissue should also be evaluated by the pathologist because concurrent renal disease and even CKD is frequently present in patients with RCC (because of shared risk factors, Fig. 25.2 ) and in many cases, is undiagnosed. A phone call to the pathologist before total or partial nephrectomy should be done to ensure that the pathologist evaluates the noncancerous kidney tissue for other unsuspected renal diseases (e.g., diabetes, immunoglobulin A nephropathy, thin basement membrane disease), which would allow for optimal long-term management and follow-up of CKD by the nephrologist. Percutaneous biopsy of a small renal mass can be considered if there is a high index of suspicion of metastatic lesion to the kidney, lymphoma, or a focal kidney infection. Biopsy can also be considered if the patient is not a surgical candidate and before initiating medical treatment. The risk of tumor seeding with RCC biopsy has been largely debunked and as such, this technique should be used without hesitation if there is any doubt about the histology, to avoid unnecessary surgery.

In staging RCC, the extent of local and regional involvement is best determined by abdominal CT, which can also detect renal vein invasion, nodal metastasis, perinephric invasion, and adjacent organ invasion. Distant metastases can be detected by bone scan, CT of the chest, MRI, and PET/CT. In addition to radiologic diagnosis, tissue diagnosis provides information about the histopathologic type of RCC and adjacent noncancerous kidney tissue, which has important implications for prognosis and treatment. Biopsy of the metastatic site is often easier and thus may be preferable. If the patient is diagnosed with metastatic disease and therefore requires systemic therapy, most modern drugs for the disease are associated with renal-relevant adverse effects, which are best managed by the nephrologist in concert with the oncologist and/or urologist (see later).

Clinical issues with renal cell carcinoma subtypes

Clear cell renal cell carcinoma

The ccRCC histologic subtype is most common (see Fig. 25.3 ) and is one of the most lethal subtypes. It arises from the proximal tubular epithelium and, in its metastatic form, is associated with a high mortality. The large majority of cases of ccRCC are sporadic and only 2% to 3% of ccRCC are linked to hereditary disease, most commonly von Hippel-Lindau syndrome.

Papillary renal cell carcinoma

The second most common subtype, papillary RCC (pRCC), ( Fig. 25.4 ) is also of proximal tubule origin but has been studied less extensively. There are two subtypes, type 1 pRCC and type 2 pRCC, the latter with a worse prognosis.

Chromophobe renal cell carcinoma

This rare (5%) kidney cancer ( Fig. 25.4 ) originates from the collecting duct and is similar to the benign oncocytoma. ^, It is more common in young females and is the least aggressive of all the RCC types, unless characterized by sarcomatous transformation.