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Clinical Aspects of Renal Cell Carcinoma
EAU Update Series 1 (2003) 189–196
Clinical Aspects of Renal Cell Carcinoma ¨ bekb Ziya Kirkalia,*, Can O a
Department of Urology, Dokuz Eylul University, School of Medicine, Inciralti, Izmir 35340, Turkey University of Istanbul Cerrahpasa, School of Medicine, Istanbul, Turkey
b
Abstract Renal cell carcinoma (RCC) represents a heterogeneous group of tumors, the most common of which is clear cell adenocarcinoma. RCC accounts for 3% of adult tumors. The incidence has increased more than 30% over the past two decades. It is generally postulated that the increased incidence rates reflect earlier diagnosis at an earlier stage, largely due to more liberal use of radiological imaging techniques. However, advanced disease has also been diagnosed more frequently and the mortality rate has increased as well. Prevention of RCC should focus on smoking cessation and maintaining ideal body mass index. Familial forms of kidney cancer have been described on four distinct histological patterns: clear cell, papillary, chromophobe, and oncocytoma. Genetic forms afflict individuals at an earlier age with a multifocal and recurrent pattern; therefore, nephron-sparing procedures should be the treatment of choice for these patients. The yield of screening the general population for RCC is still relatively low and hence not cost-effective. Screening should be reserved for individuals who carry high risk for RCC. The classic triad of flank pain, macroscopic hematuria, and palpable abdominal mass is now detected in fewer than 10% of patients, and is a late sign. Today, most tumors are diagnosed incidentally. Paraneoplastic syndromes have been reported in 10–40% of patients and can be seen at any stage of disease. The indications and application of percutaneous biopsy for renal masses are limited and mainly used to make differential diagnosis with an infectious process, lymphoma and metastases to the kidney. # 2003 Elsevier B.V. All rights reserved. Keywords: Kidney; Cancer; Incidence; Epidemiology; Genetics; Screening; Symptom; Paraneoplastic syndrome; Diagnosis; Biopsy; Renal cell carcinoma
1. Incidence Renal cell carcinoma (RCC) represents a heterogeneous group of tumors, the most common of which is clear cell adenocarcinoma. RCC accounts for 3% of adult tumors. It is the third most common malignancy of the urinary tract with an overall 8.7 new diagnoses per 100,000/year. Nearly 30,000 new cases are detected in the USA and 20,000 in the European Union [1]. Annual mortality-to-incidence ratio with RCC is significantly higher compared to other urological malignancies; nearly12,000 patients die of the disease in the USA yearly [2]. The overall 5-year survival rate is 60%. There is a male predominance with a ratio of 3:2 [3]. *
Corresponding author. Tel. þ90-232-278-7477; Fax: þ90-232-464-6766. E-mail address: [email protected] (Z. Kirkali).
RCC is primarily a disease of the elderly with typical presentation in the sixth and seventh decades of life. The incidence rates are 10–20% higher in African Americans in both men and women [4]. As for geographical variation, the rates are low in Asian countries and high in the USA and Canada. The highest rates in the world have been reported from several central European countries [5,6]. The incidence of RCC has increased more than 30% over the past two decades. It is generally postulated that the increased incidence rates reflect earlier diagnosis at an earlier stage, largely due to more liberal use and better quality of modern radiological imaging techniques such as ultrasonography, computerized tomography (CT) and magnetic resonance imaging (MRI) [4,7–10]. An interesting observation is that a higher proportion of women and elderly are noted within the incidentally detected cohorts [4,11–13]. This can be
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explained, at least in part, by more frequent physician visits by females and the elderly [11]. Although the fact that increases in RCC were most prominent for the localized tumors is in favor of the hypothesis of diagnosis at an earlier stage and more effective treatment, upward trends were also apparent for more advanced tumors. Moreover, mortality rate of kidney cancer has also been increasing steadily throughout the world [4,14–16]. Therefore, incidental diagnosis of presymptomatic tumors alone falls short of fully explaining this rising incidence of RCC.
2. Epidemiologic factors Several potential risk factors have been implicated in the development of RCC. However, discrepancies among these studies and the weakness of associations between various types of exposure and RCC render drawing definite conclusions difficult. Cigarette smoking has been generally linked to increased risk of RCC. The relative risk ranges from 30–50%. A dose response relation has been observed in both men and women, whereas the risk declines after cessation of smoking. A systematic review of the literature showed that only consumption over 20 pack years led to a significant association [17]. When analyzed for gender, most studies failed to show an association between smoking and RCC in women [17]. An association with other tobacco products, i.e. cigars, pipes, chewing tobacco has not been consistently detected [5]. It is unlikely that smoking has contributed to the rising incidence of RCC, at least in the USA, since the prevalence of smoking in the USA has declined since 1960s [5]. Obesity was found to be related to RCC in nearly all studies. Weight is usually expressed as body mass index (BMI) and the association was only for severe obesity, defined as a BMI above the fourth quartile [17]. The association is stronger for women. Obesity may predispose to RCC by increasing the levels of endogenous estrogens, since it is well established that estrogens promote the development of kidney tumors in hamsters [18]. Obesity may also increase the bioavailability of free insulin-like growth factor, which may be involved in carcinogenesis [19]. Consequently, the apparent increase in the prevalence of obesity in the past few decades may have contributed to the uprising incidence of this cancer. Hypertension has been linked to RCC in a number of studies. Nevertheless, some found that the risk diminished to insignificant levels after adjusting for diuretics and other hypertensive medications [5]. In a systematic
review, it was concluded that hypertension could only be classified as risk marker, not as a risk factor, because of a lack of dose dependent effect [17]. On the other hand, an association between hypertension and increased risk of mortality from RCC has been reported as well [20]. Antihypertensive medication, specifically diuretics, has also been held responsible for the development of RCC in various studies. Thiazide diuretics were reported to be risk markers. Surveys revealed that the prevalence of hypertension declined after 1980 [5]. Therefore, it would appear unlikely that the contribution of hypertension to the upward trends of renal tumors has been significant. Nutrition is one of the key factors causing large differences in cancer rates between populations. There is an approximately five–eightfold difference between the rates of RCC in Asian populations and Western countries [19]. Mortality rates for kidney and other cancers in the first-generation Asian migrants are intermediate between Asian countries and the host Western countries [21]. Fried, saute´ ed, well-done and charred meat were associated with increased RCC risk, and protective effects were observed with frequent fruit and vegetable consumption [22,23]. Protective effects were also observed for vitamins C, E, and carotenoids [24,25]. Epidemiologic evidence does not support a clear association between alcohol, coffee, and tea consumption and RCC [17]. Occupational exposure to iron, steel, petrol, asbestos and cadmium has been implicated in the development of renal cancer. Occupations involving exposure to these materials would appear to be risk markers for the disease [17]. Preexisting kidney disease: A higher rate of detection has been observed among patients with chronic renal failure undergoing hemodialysis, particularly among those with acquired renal cystic disease (ARCD) [26–28]. There is conflicting data on the association between kidney stones, urinary tract infection, kidney injury and RCC and data in general does not support a direct link. Oral contraceptive use was reported to be protective against RCC in non-smokers and after 10 years of use [29]. No correlation was established with estrogen replacement. Prevention of RCC should focus on smoking cessation. Excess weight is a risk factor and effort should be made to maintain ideal BMI for each individual. Diet would appear to be one of the most compelling reasons to explain the international differences in incidence. At present, there is insufficient information to make specific dietary recommendations. However, it would be reasonable to suggest a diet that reduces overall risk of
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mortality from arteriosclerosis and cancer. This would contain regular consumption of fruits, vegetables and grains along with minimizing fat and calorie intake [19].
3. Familial forms Significant advances have been made in our understanding of the molecular genetics of renal cancer within the last decade. Genetic syndromes have been described on four distinct histological patterns: clear cell, papillary, chromophobe, and oncocytoma. Genetic forms afflict individuals at an earlier age with a multifocal and recurrent pattern. Therefore, management of these patients involves life-long monitoring, and measures to curtail the frequency of invasive procedures and preserve renal parenchyma. Genetic anomalies that lead to the development of cancer can be a consequence of (1) inactivation of tumor suppressor genes, (2) activation of oncogenes, and (3) alterations in DNA repair process; the third mechanism has not been described for RCC thus far [30]. 3.1. Clear cell histology 3.1.1. Von Hippel–Lindau disease Von Hippel–Lindau Disease (VHL) is the familial form of the clear cell variant of RCC. VHL is an autosomal-dominant disorder with nearly complete penetrance, which occurs with a frequency of 1 in 40,000 live births. Genetic linkage studies have mapped the VHL defect to the short arm of chromosome 3 (3p25–26) and the VHL tumor suppressor gene has been completely sequenced [31]. It is associated with vascular tumors of multiple organs. Major manifestations include retinal angiomas, hemangioblastomas of the central nervous system, RCC, renal cysts, pheochromoyctoma, adenocarcinoma and cysts of the pancreas, epididymal cystadenoma and endolymphatic sac tumors of the ear [32]. The probability of developing RCC by the seventh decade of life is 70% [33]. There is a tendency for earlier occurrence of RCC with a mean age of diagnosis of 35 years, and for its bilateral and multifocal involvement. Metastatic RCC is the leading cause of death from VHL [34]. It is projected that a typical kidney of a 37-year-old patient with VHL may contain more than 600 independent solid tumors and 1100 cysts [35]. This potential for frequent new tumor occurrences warrants lifelong close surveillance for these patients. For the urologist, preservation of renal parenchyma is the main concern. The National Cancer Institute in the US introduced the ‘‘3-centimeter rule’’ for surgical intervention based on the
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observation of the lack of metastasis for tumors smaller than 3 cm [36]. Nephron-sparing surgery is the current gold standard in the management of these patients. Alternatively, new minimally invasive techniques such as percutaneous or laparoscopically guided cryotherapy or radiofrequency ablation are being assessed in the treatment of VHL induced tumors [37]. 3.1.2. Familial clear cell carcinoma Few cases of hereditary clear cell carcinoma without any detectable VHL mutation have been described. This form is characterized by two or more cases of clear cell RCC in first-degree relatives at an earlier age of onset when compared to sporadic cases. A balanced translocation involving 3p14 has been described [30]. 3.2. Papillary histology 3.2.1. Hereditary papillary renal cell carcinoma (HPRCC) Papillary RCC is the second most common histologic subtype of RCC [38]. Recently a familial form, namely hereditary papillary RCC (HPRC), has been described [38]. Genetic studies have identified germline mutations of the MET proto-oncogene on the long arm of chromosome 7 (7q31.3) [39]. It has an autosomal dominant inheritance pattern with incomplete penetrance [38]. Histologically it is a unique variant easily distinguished from sporadic papillary RCC [40]. These families are at risk for developing bilateral and multifocal papillary RCC with a median age at presentation of 45 years [38,41]. Patients with HPRC may have up to 3400 microscopic papillary renal carcinoma in each kidney [42]. 3.2.2. Hereditary leiomyomata and renal cell carcinoma (HLRCC) HLRCC was described in a number of families and is typified by predisposition to developing painful, cutaneous leiomyomata, uterine fibroids, and papillary RCC. Natural history of kidney tumors is distinct from those of HPRC with rapid tumor growth and early metastasis in HLRCC. The syndrome has an autosomal dominant transmission, and genetic studies have revealed the germline defect as loss or mutation of one copy of fumarate hydratase on chromosome 1q [43]. 3.3. Oncocytic/chromophobe histology A genetic predisposition to develop multiple, bilateral oncocytic tumors have been reported in five families [44]. These were reported to be slow growing and asymptomatic tumors with a male to female ratio of 4:1. The genetic defect unique to this syndrome remains unknown.
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3.3.1. Birt–Hogg–Dube´ Familial chromophobe RCC is associated with Birt–Hogg–Dube´ syndrome, an autosomal dominant syndrome characterized by dermatologic disorders, i.e. benign fibrofolliculomas and trischodiscomas of the hair follicle. Polyps of the colon and medullary carcinoma of the thyroid, and multifocal pulmonary cysts are other manifestations of this syndrome [45,46]. Although histologically renal tumor is chromophobe in the majority of cases, oncocytoma, papillary or clear cell carcinoma have been reported as well [47].
4. Screening There are arguments for and against screening for RCC. Retroperitoneal localization of the kidneys usually does not allow for early diagnosis, thus RCC often remains asymptomatic until locally advanced or metastatic disease develops. It is a disease with high mortality rate, which can only be cured by surgical removal, if diagnosed while still organ confined. Nephron-sparing surgery can be offered to patients with an early diagnosis while the lesion is less than 4 cm. Despite recent advances in the management of advanced disease, our capability to salvage these patients is very limited. Some studies have shown a survival advantage in patients with early or incidental diagnosed RCC. These investigators have demonstrated that RCC is localized in more than 85% in incidentally discovered tumors, compared to 40–45% in symptomatic cases [8,48–52]. The major drawback for widespread implementation of screening for RCC is its low incidence (8.9/100,000/ year) in the general population [3]. Even the ideal test with 100% sensitivity and specificity would not be cost-effective with such a low incidence in the current health care systems where cost is a major concern. Another limitation to generalized screening is the relatively high prevalence of clinically insignificant and/or benign lesions, such as renal adenomas [53,54]. Thus, widespread screening would impose a risk for unnecessary patient anxiety, diagnosis, treatment, and expense [55]. In a recent study conducted in two German cities, the proportion of higher stage and larger tumors was higher in the screened than in the incidentally detected group [56]. While 6 patients with RCC benefited from screening, 4 did not since they either had incurable disease or were unfit for surgery. It would be fair to conclude that the overall consensus in the literature is that the yield of screening the general population for RCC is still relatively low and hence not
Table 1 Screening for RCC: target populations Patients with end stage renal failure (preferably male, on hemodialysis, long life expectancy) Patients with von Hippel–Lindau syndrome (VHL) Relatives of patients with VHL who have specific gene defects Relatives of patients with other familial forms of RCC Patients with tuberous sclerosis
cost-effective [55,57]. Screening for RCC is limited to target populations (Table 1). The relative risk of RCC is 5 to 100-fold higher in patients with end stage renal failure [58–60]. ARCD develops in up to 80% of patients with end stage renal failure. RCC arises in 1–2% in patients with ARCD [58–60]. Screening should be carried out with ultrasonography or CT and beginning on the third year on dialysis in younger and healthier men [55,57]. Molecular screening should be considered for anyone suspected of having VHL and for the close relatives of patients with VHL. Those with specific VHL gene defects should be vigorously followed, whereas individuals with wild type for both alleles can be spared from life-long surveillance. The screening consists of: (1) annual physical examination, blood pressure measurement, and ophthalmologic evaluation beginning in infancy, (2) measurement of urinary cathecolamine levels at age 2 years, and repeated every 1–2 years, (3) MRI of the central nervous system biannually beginning at age 11 years, (4) abdominal and pelvic ultrasonography annually beginning at age 11 years; CT scanning biannually should cysts or tumors develop, (5) periodic audiometric evaluation [61,62]. Molecular screening for HPRCC is available and should be considered for appropriate family members [39]. The presence of mutations of the MET protooncogene or a family history would pose a risk and an indication for periodic ultrasound or CT examinations. Tuberous sclerosis is an autosomal dominant disorder characterized by the development of adenoma sebaceum, epilepsy, mental retardation, renal cysts and angiomyolipomas. An increased incidence of RCC has been reported, but remains controversial [63,64]. Most authors recommend screening for renal lesions in tuberous sclerosis; both for RCC and angiomyolipomas.
5. Clinical presentation The majority of renal tumors remain asymptomatic until advanced disease develops due to the retroperitoneal location of the kidneys. Local symptoms arise only after it achieves adequate size to displace or
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invade other organs. RCC was once an elusive disease because of its protean manifestations. The signs and symptoms were often latent and difficult to diagnose. Therefore, RCC used to be referred to as ‘‘internist’s tumor’’. Fortunately, with the improvements in and more frequent use of imaging modalities, more than 50% of RCCs are now detected incidentally and in earlier stages. Novick and Campbell have thus suggested to re-name it as ‘‘radiologists tumor’’ [57]. The classic triad of flank pain, macroscopic hematuria, and palpable abdominal mass is now detected in fewer than 10% of patients, and is a late sign [52,65,66]. Mode of presentation may be an independent predictor of disease-free and disease-specific survival [11]. Nearly half of the patients presenting with all three symptoms already suffer from metastatic disease; yet, the individual symptoms are observed more frequently [67]. Hematuria is the most frequent and may occur in 40–60% of cases [65,68]. Flank pain may be seen in up to 40% of patients, and is caused by either bleeding within the tumor or invasion of contiguous tissues. Palpable mass has been reported to occur in one third of cases [67,69]. Constitutional symptoms such as fatigue, malaise, weight loss, nausea, fever, or night sweats denote advanced disease. Symptoms directly related to metastatic disease, such as bone pain or persistent cough could lead to initial presentation in a minority of patients. Non-reducing varicocele or lower extremity edema may signify venous involvement. Renal medullary carcinoma (RMC) is a very rare form of RCC, which predominantly affects AfricanAmerican children and young adults with sickle cell trait or sickle cell disease [70,71]. Patients present clinically with high stage tumor and succumb to disease within a few weeks to months. Paraneoplastic syndromes have been reported in 10– 40% of patients with RCC [72] (Table 2). Paraneoplastic syndromes do not connote to metastatic disease and may represent the initial presenting symptoms or signs of RCC while the disease is still localized and curable. Paraneoplastic syndromes may stem from the production of biologically active substances from the tumor, or by normal tissue as an immune response to the tumor. Several hormones reported to be excreted by RCC include parathyroid-like hormone, gonadotropins, renin, erythropoietin, glucagons, human chorionic gonadotropin, insulin, placentolactogen, and adrenocorticotropic hormone-like substance [72–74]. Increased production of various cytokines, including interleukin-6, have been held responsible as well [75]. Hypercalcemia has been reported in 10–20%, with an increased incidence in higher stages of disease
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Table 2 Paraneoplastic syndromes associated with renal cell carcinoma Hypercalcemia Polycythemia/increased erythropoietin Hypertension Stauffer’s syndrome (non-metastatic hepatic dysfunction) Cachexia, weight loss Fever Nuromyopathy Amyloidosis Increased gonadotropins Increased prolactin Increased enteroglucagon Impaired glucose metabolism
[74,76,77]. The production of parathyroid hormonelike peptides is usually held responsible [73,74,78,79]. The most common clinical features are nausea, anorexia, fatigue, constipation and decreased deep tendon reflexes. The most effective management is to treat the underlying tumor. Medical management includes hydration and subsequent use of loop diuretics [74]. Recently, bisphosphonates have proven to be very effective in the treatment of hypercalcemia [80]. Polycythemia may be either due to increased production of erythropoietin by either the cancerous tissue or by the adjacent normal parenchyma in response to hypoxia induced by tumor expansion [81]. About 25–40% of patients with RCC may have hypertension [73,74]. Various causes have been reported among which renin production by the tumor, compression of the renal artery or its branches by the tumor, or arteriovenous fistula within the tumor are most commonly accepted as the etiology [73,82]. A unique paraneoplastic syndrome associated with RCC is non-metastatic hepatic dysfunction, or Stauffer’s syndrome. Various laboratory abnormalities include elevated serum alkaline phosphatase, prolonged prothrombine time, increased a-globulins, hypoalbunemia, elevated serum bilirubin and transaminases, and IL-6 [83,84]. Fever, weight loss and fatigue have been considered part of the syndrome [74,83]. The syndrome resolves in 60–70% of cases following nephrectomy. Persistence or recurrence is a strong indicator of viable tumor and is a poor prognosticator [73].
6. Differential diagnosis Imaging in RCC is covered as a separate topic of this series; therefore, our discussion on differential diagnosis herein will be very brief. Benign lesions such as renal infarct, pseudotumor caused by a hypertrophied column of Bertin, abscess, or a vascular lesion such as arteriovenous fistula need to be distinguished from
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RCC on the basis of clinical findings and appropriate radiological imaging. The presence of fat on CT or ultrasonography is pathognomonic of angiomyolipoma, a benign lesion that consists of fat, vasculature and smooth muscle [85]. Association with tuberous sclerosis would aid in confirming the diagnosis. Metastatic tumors to the kidney are often multiple, ordinarily hypovascular and particularly common with lung carcinoma and melanoma [86]. In patients with a centrally located tumor, urothelial carcinoma of the renal collecting system should be considered in differential diagnosis. History of previous urothelial carcinoma, urine cytology, retrograde pyelograms and ureteroscopy are alternatives helpful in decision-making. Lymphoma may present in various clinical forms. The majority of patients have bilateral renal involve-
ment; nonetheless, diffuse infiltration of the kidney(s) or a solitary nodule may be other ways of presentation [87,88]. A history of lymphoma, or radiological signs of lymphoma such as splenomegaly and lymphadenopathy imply that the renal mass may be lymphoma. Biopsy: The indications and application of percutaneous biopsy for renal masses are rather limited. It is mainly used to differentiate RCC from other renal masses and disease treated surgically from non-surgical disease such as renal abscess, lymphoma and metastatic disease [89,90]. The major shortcomings are the risk of a false negative biopsy, hemorrhage, and although low, the risk of seeding of the biopsy tract [91,92]. Biopsy can be performed in cases of suspected metastatic disease, or in the elderly to obtain a diagnosis and avoiding radical nephrectomy.
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[77] Fahn H, Lee Y, Chen M, Huang JK, Chen KK, Chang LS. The incidence and prognostic significance of humoral hypercalcemia. J Urol 1991;145:248–50. [78] Goldberg MF, Tahijan AH, Order SE, Dammin GJ. Renal adenocarcinoma containing a parathyroid hormone-like substance and associated with marked hypercalcemia. Am J Med 1964;36:805. [79] Walther MM, Patel B, Choyke P, Lubensky IA, Vocke CD, Harris C, et al. Hypercalcemia in patients with metastatic renal cell carcinoma: effect of nephrectomy and metabolic evaluation. J Urol 1997;158: 733–9. [80] Body J. Bisphosphonates. Eur J Cancer 1998;34:263–9. [81] Gross AJ, Wolff M, Fandrey J, Miersch WD, Dieckmann KP, Jelkmann W. Prevalence of paraneoplastic erythropoietin production by renal cell carcinoma. Clin Invest 1994;72:337–40. [82] Robertson PW, Klidjian A, Harding LK, Walters G, Lee MR, RobbSmith AH. Hypertension due to a renin-secreting renal tumor. Am J Med 1967;43:963–76. [83] Stauffer M. Nephrogenic hepatosplenomegaly. Gastroenterology 1961;40:694. [84] Blay JY, Rossi JF, Wijdenes J, Menetrier-Caux C, Schemann S, Negrier S, et al. Role of interleukin-6 in the paraneoplastic inflammatory
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CME questions Please visit htttp://www.uroweb.org/updateseries to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. Which has not been proven to be a risk factor for the development of renal cell carcinoma? A. Stone disease. B. Cigarette smoking. C. Obesity. D. Hypertension. 2. The most common histology of the renal tumor in Birt–Hogg–Dube´ syndrome is: A. clear cell, B. papillary, C. chromophobe, D. oncocytoma. 3. Screening for renal cell carcinoma is suggested for all except:
A. close relatives of patients with Von Hippel– Lindau disease, B. heavy smokers, C. patients with acquired renal cystic disease, D. the presence of mutations of the MET protooncogene. 4. Which of the following statements is correct? A. Flank pain, hematuria and palpable mass are detected in 40% of the patients with RCC. B. Paraneoplastic syndrome is a sign of metastatic disease. C. Hypercalcemia can be observed in 40% of the patients with RCC. D. Paraneoplastic syndromes may be used as a prognosticator in RCC.
Clinical Aspects of Renal Cell Carcinoma ¨ bekb Ziya Kirkalia,*, Can O a
Department of Urology, Dokuz Eylul University, School of Medicine, Inciralti, Izmir 35340, Turkey University of Istanbul Cerrahpasa, School of Medicine, Istanbul, Turkey
b
Abstract Renal cell carcinoma (RCC) represents a heterogeneous group of tumors, the most common of which is clear cell adenocarcinoma. RCC accounts for 3% of adult tumors. The incidence has increased more than 30% over the past two decades. It is generally postulated that the increased incidence rates reflect earlier diagnosis at an earlier stage, largely due to more liberal use of radiological imaging techniques. However, advanced disease has also been diagnosed more frequently and the mortality rate has increased as well. Prevention of RCC should focus on smoking cessation and maintaining ideal body mass index. Familial forms of kidney cancer have been described on four distinct histological patterns: clear cell, papillary, chromophobe, and oncocytoma. Genetic forms afflict individuals at an earlier age with a multifocal and recurrent pattern; therefore, nephron-sparing procedures should be the treatment of choice for these patients. The yield of screening the general population for RCC is still relatively low and hence not cost-effective. Screening should be reserved for individuals who carry high risk for RCC. The classic triad of flank pain, macroscopic hematuria, and palpable abdominal mass is now detected in fewer than 10% of patients, and is a late sign. Today, most tumors are diagnosed incidentally. Paraneoplastic syndromes have been reported in 10–40% of patients and can be seen at any stage of disease. The indications and application of percutaneous biopsy for renal masses are limited and mainly used to make differential diagnosis with an infectious process, lymphoma and metastases to the kidney. # 2003 Elsevier B.V. All rights reserved. Keywords: Kidney; Cancer; Incidence; Epidemiology; Genetics; Screening; Symptom; Paraneoplastic syndrome; Diagnosis; Biopsy; Renal cell carcinoma
1. Incidence Renal cell carcinoma (RCC) represents a heterogeneous group of tumors, the most common of which is clear cell adenocarcinoma. RCC accounts for 3% of adult tumors. It is the third most common malignancy of the urinary tract with an overall 8.7 new diagnoses per 100,000/year. Nearly 30,000 new cases are detected in the USA and 20,000 in the European Union [1]. Annual mortality-to-incidence ratio with RCC is significantly higher compared to other urological malignancies; nearly12,000 patients die of the disease in the USA yearly [2]. The overall 5-year survival rate is 60%. There is a male predominance with a ratio of 3:2 [3]. *
Corresponding author. Tel. þ90-232-278-7477; Fax: þ90-232-464-6766. E-mail address: [email protected] (Z. Kirkali).
RCC is primarily a disease of the elderly with typical presentation in the sixth and seventh decades of life. The incidence rates are 10–20% higher in African Americans in both men and women [4]. As for geographical variation, the rates are low in Asian countries and high in the USA and Canada. The highest rates in the world have been reported from several central European countries [5,6]. The incidence of RCC has increased more than 30% over the past two decades. It is generally postulated that the increased incidence rates reflect earlier diagnosis at an earlier stage, largely due to more liberal use and better quality of modern radiological imaging techniques such as ultrasonography, computerized tomography (CT) and magnetic resonance imaging (MRI) [4,7–10]. An interesting observation is that a higher proportion of women and elderly are noted within the incidentally detected cohorts [4,11–13]. This can be
1570-9124/$ – see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/S1570-9124(03)00056-4
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explained, at least in part, by more frequent physician visits by females and the elderly [11]. Although the fact that increases in RCC were most prominent for the localized tumors is in favor of the hypothesis of diagnosis at an earlier stage and more effective treatment, upward trends were also apparent for more advanced tumors. Moreover, mortality rate of kidney cancer has also been increasing steadily throughout the world [4,14–16]. Therefore, incidental diagnosis of presymptomatic tumors alone falls short of fully explaining this rising incidence of RCC.
2. Epidemiologic factors Several potential risk factors have been implicated in the development of RCC. However, discrepancies among these studies and the weakness of associations between various types of exposure and RCC render drawing definite conclusions difficult. Cigarette smoking has been generally linked to increased risk of RCC. The relative risk ranges from 30–50%. A dose response relation has been observed in both men and women, whereas the risk declines after cessation of smoking. A systematic review of the literature showed that only consumption over 20 pack years led to a significant association [17]. When analyzed for gender, most studies failed to show an association between smoking and RCC in women [17]. An association with other tobacco products, i.e. cigars, pipes, chewing tobacco has not been consistently detected [5]. It is unlikely that smoking has contributed to the rising incidence of RCC, at least in the USA, since the prevalence of smoking in the USA has declined since 1960s [5]. Obesity was found to be related to RCC in nearly all studies. Weight is usually expressed as body mass index (BMI) and the association was only for severe obesity, defined as a BMI above the fourth quartile [17]. The association is stronger for women. Obesity may predispose to RCC by increasing the levels of endogenous estrogens, since it is well established that estrogens promote the development of kidney tumors in hamsters [18]. Obesity may also increase the bioavailability of free insulin-like growth factor, which may be involved in carcinogenesis [19]. Consequently, the apparent increase in the prevalence of obesity in the past few decades may have contributed to the uprising incidence of this cancer. Hypertension has been linked to RCC in a number of studies. Nevertheless, some found that the risk diminished to insignificant levels after adjusting for diuretics and other hypertensive medications [5]. In a systematic
review, it was concluded that hypertension could only be classified as risk marker, not as a risk factor, because of a lack of dose dependent effect [17]. On the other hand, an association between hypertension and increased risk of mortality from RCC has been reported as well [20]. Antihypertensive medication, specifically diuretics, has also been held responsible for the development of RCC in various studies. Thiazide diuretics were reported to be risk markers. Surveys revealed that the prevalence of hypertension declined after 1980 [5]. Therefore, it would appear unlikely that the contribution of hypertension to the upward trends of renal tumors has been significant. Nutrition is one of the key factors causing large differences in cancer rates between populations. There is an approximately five–eightfold difference between the rates of RCC in Asian populations and Western countries [19]. Mortality rates for kidney and other cancers in the first-generation Asian migrants are intermediate between Asian countries and the host Western countries [21]. Fried, saute´ ed, well-done and charred meat were associated with increased RCC risk, and protective effects were observed with frequent fruit and vegetable consumption [22,23]. Protective effects were also observed for vitamins C, E, and carotenoids [24,25]. Epidemiologic evidence does not support a clear association between alcohol, coffee, and tea consumption and RCC [17]. Occupational exposure to iron, steel, petrol, asbestos and cadmium has been implicated in the development of renal cancer. Occupations involving exposure to these materials would appear to be risk markers for the disease [17]. Preexisting kidney disease: A higher rate of detection has been observed among patients with chronic renal failure undergoing hemodialysis, particularly among those with acquired renal cystic disease (ARCD) [26–28]. There is conflicting data on the association between kidney stones, urinary tract infection, kidney injury and RCC and data in general does not support a direct link. Oral contraceptive use was reported to be protective against RCC in non-smokers and after 10 years of use [29]. No correlation was established with estrogen replacement. Prevention of RCC should focus on smoking cessation. Excess weight is a risk factor and effort should be made to maintain ideal BMI for each individual. Diet would appear to be one of the most compelling reasons to explain the international differences in incidence. At present, there is insufficient information to make specific dietary recommendations. However, it would be reasonable to suggest a diet that reduces overall risk of
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mortality from arteriosclerosis and cancer. This would contain regular consumption of fruits, vegetables and grains along with minimizing fat and calorie intake [19].
3. Familial forms Significant advances have been made in our understanding of the molecular genetics of renal cancer within the last decade. Genetic syndromes have been described on four distinct histological patterns: clear cell, papillary, chromophobe, and oncocytoma. Genetic forms afflict individuals at an earlier age with a multifocal and recurrent pattern. Therefore, management of these patients involves life-long monitoring, and measures to curtail the frequency of invasive procedures and preserve renal parenchyma. Genetic anomalies that lead to the development of cancer can be a consequence of (1) inactivation of tumor suppressor genes, (2) activation of oncogenes, and (3) alterations in DNA repair process; the third mechanism has not been described for RCC thus far [30]. 3.1. Clear cell histology 3.1.1. Von Hippel–Lindau disease Von Hippel–Lindau Disease (VHL) is the familial form of the clear cell variant of RCC. VHL is an autosomal-dominant disorder with nearly complete penetrance, which occurs with a frequency of 1 in 40,000 live births. Genetic linkage studies have mapped the VHL defect to the short arm of chromosome 3 (3p25–26) and the VHL tumor suppressor gene has been completely sequenced [31]. It is associated with vascular tumors of multiple organs. Major manifestations include retinal angiomas, hemangioblastomas of the central nervous system, RCC, renal cysts, pheochromoyctoma, adenocarcinoma and cysts of the pancreas, epididymal cystadenoma and endolymphatic sac tumors of the ear [32]. The probability of developing RCC by the seventh decade of life is 70% [33]. There is a tendency for earlier occurrence of RCC with a mean age of diagnosis of 35 years, and for its bilateral and multifocal involvement. Metastatic RCC is the leading cause of death from VHL [34]. It is projected that a typical kidney of a 37-year-old patient with VHL may contain more than 600 independent solid tumors and 1100 cysts [35]. This potential for frequent new tumor occurrences warrants lifelong close surveillance for these patients. For the urologist, preservation of renal parenchyma is the main concern. The National Cancer Institute in the US introduced the ‘‘3-centimeter rule’’ for surgical intervention based on the
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observation of the lack of metastasis for tumors smaller than 3 cm [36]. Nephron-sparing surgery is the current gold standard in the management of these patients. Alternatively, new minimally invasive techniques such as percutaneous or laparoscopically guided cryotherapy or radiofrequency ablation are being assessed in the treatment of VHL induced tumors [37]. 3.1.2. Familial clear cell carcinoma Few cases of hereditary clear cell carcinoma without any detectable VHL mutation have been described. This form is characterized by two or more cases of clear cell RCC in first-degree relatives at an earlier age of onset when compared to sporadic cases. A balanced translocation involving 3p14 has been described [30]. 3.2. Papillary histology 3.2.1. Hereditary papillary renal cell carcinoma (HPRCC) Papillary RCC is the second most common histologic subtype of RCC [38]. Recently a familial form, namely hereditary papillary RCC (HPRC), has been described [38]. Genetic studies have identified germline mutations of the MET proto-oncogene on the long arm of chromosome 7 (7q31.3) [39]. It has an autosomal dominant inheritance pattern with incomplete penetrance [38]. Histologically it is a unique variant easily distinguished from sporadic papillary RCC [40]. These families are at risk for developing bilateral and multifocal papillary RCC with a median age at presentation of 45 years [38,41]. Patients with HPRC may have up to 3400 microscopic papillary renal carcinoma in each kidney [42]. 3.2.2. Hereditary leiomyomata and renal cell carcinoma (HLRCC) HLRCC was described in a number of families and is typified by predisposition to developing painful, cutaneous leiomyomata, uterine fibroids, and papillary RCC. Natural history of kidney tumors is distinct from those of HPRC with rapid tumor growth and early metastasis in HLRCC. The syndrome has an autosomal dominant transmission, and genetic studies have revealed the germline defect as loss or mutation of one copy of fumarate hydratase on chromosome 1q [43]. 3.3. Oncocytic/chromophobe histology A genetic predisposition to develop multiple, bilateral oncocytic tumors have been reported in five families [44]. These were reported to be slow growing and asymptomatic tumors with a male to female ratio of 4:1. The genetic defect unique to this syndrome remains unknown.
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3.3.1. Birt–Hogg–Dube´ Familial chromophobe RCC is associated with Birt–Hogg–Dube´ syndrome, an autosomal dominant syndrome characterized by dermatologic disorders, i.e. benign fibrofolliculomas and trischodiscomas of the hair follicle. Polyps of the colon and medullary carcinoma of the thyroid, and multifocal pulmonary cysts are other manifestations of this syndrome [45,46]. Although histologically renal tumor is chromophobe in the majority of cases, oncocytoma, papillary or clear cell carcinoma have been reported as well [47].
4. Screening There are arguments for and against screening for RCC. Retroperitoneal localization of the kidneys usually does not allow for early diagnosis, thus RCC often remains asymptomatic until locally advanced or metastatic disease develops. It is a disease with high mortality rate, which can only be cured by surgical removal, if diagnosed while still organ confined. Nephron-sparing surgery can be offered to patients with an early diagnosis while the lesion is less than 4 cm. Despite recent advances in the management of advanced disease, our capability to salvage these patients is very limited. Some studies have shown a survival advantage in patients with early or incidental diagnosed RCC. These investigators have demonstrated that RCC is localized in more than 85% in incidentally discovered tumors, compared to 40–45% in symptomatic cases [8,48–52]. The major drawback for widespread implementation of screening for RCC is its low incidence (8.9/100,000/ year) in the general population [3]. Even the ideal test with 100% sensitivity and specificity would not be cost-effective with such a low incidence in the current health care systems where cost is a major concern. Another limitation to generalized screening is the relatively high prevalence of clinically insignificant and/or benign lesions, such as renal adenomas [53,54]. Thus, widespread screening would impose a risk for unnecessary patient anxiety, diagnosis, treatment, and expense [55]. In a recent study conducted in two German cities, the proportion of higher stage and larger tumors was higher in the screened than in the incidentally detected group [56]. While 6 patients with RCC benefited from screening, 4 did not since they either had incurable disease or were unfit for surgery. It would be fair to conclude that the overall consensus in the literature is that the yield of screening the general population for RCC is still relatively low and hence not
Table 1 Screening for RCC: target populations Patients with end stage renal failure (preferably male, on hemodialysis, long life expectancy) Patients with von Hippel–Lindau syndrome (VHL) Relatives of patients with VHL who have specific gene defects Relatives of patients with other familial forms of RCC Patients with tuberous sclerosis
cost-effective [55,57]. Screening for RCC is limited to target populations (Table 1). The relative risk of RCC is 5 to 100-fold higher in patients with end stage renal failure [58–60]. ARCD develops in up to 80% of patients with end stage renal failure. RCC arises in 1–2% in patients with ARCD [58–60]. Screening should be carried out with ultrasonography or CT and beginning on the third year on dialysis in younger and healthier men [55,57]. Molecular screening should be considered for anyone suspected of having VHL and for the close relatives of patients with VHL. Those with specific VHL gene defects should be vigorously followed, whereas individuals with wild type for both alleles can be spared from life-long surveillance. The screening consists of: (1) annual physical examination, blood pressure measurement, and ophthalmologic evaluation beginning in infancy, (2) measurement of urinary cathecolamine levels at age 2 years, and repeated every 1–2 years, (3) MRI of the central nervous system biannually beginning at age 11 years, (4) abdominal and pelvic ultrasonography annually beginning at age 11 years; CT scanning biannually should cysts or tumors develop, (5) periodic audiometric evaluation [61,62]. Molecular screening for HPRCC is available and should be considered for appropriate family members [39]. The presence of mutations of the MET protooncogene or a family history would pose a risk and an indication for periodic ultrasound or CT examinations. Tuberous sclerosis is an autosomal dominant disorder characterized by the development of adenoma sebaceum, epilepsy, mental retardation, renal cysts and angiomyolipomas. An increased incidence of RCC has been reported, but remains controversial [63,64]. Most authors recommend screening for renal lesions in tuberous sclerosis; both for RCC and angiomyolipomas.
5. Clinical presentation The majority of renal tumors remain asymptomatic until advanced disease develops due to the retroperitoneal location of the kidneys. Local symptoms arise only after it achieves adequate size to displace or
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invade other organs. RCC was once an elusive disease because of its protean manifestations. The signs and symptoms were often latent and difficult to diagnose. Therefore, RCC used to be referred to as ‘‘internist’s tumor’’. Fortunately, with the improvements in and more frequent use of imaging modalities, more than 50% of RCCs are now detected incidentally and in earlier stages. Novick and Campbell have thus suggested to re-name it as ‘‘radiologists tumor’’ [57]. The classic triad of flank pain, macroscopic hematuria, and palpable abdominal mass is now detected in fewer than 10% of patients, and is a late sign [52,65,66]. Mode of presentation may be an independent predictor of disease-free and disease-specific survival [11]. Nearly half of the patients presenting with all three symptoms already suffer from metastatic disease; yet, the individual symptoms are observed more frequently [67]. Hematuria is the most frequent and may occur in 40–60% of cases [65,68]. Flank pain may be seen in up to 40% of patients, and is caused by either bleeding within the tumor or invasion of contiguous tissues. Palpable mass has been reported to occur in one third of cases [67,69]. Constitutional symptoms such as fatigue, malaise, weight loss, nausea, fever, or night sweats denote advanced disease. Symptoms directly related to metastatic disease, such as bone pain or persistent cough could lead to initial presentation in a minority of patients. Non-reducing varicocele or lower extremity edema may signify venous involvement. Renal medullary carcinoma (RMC) is a very rare form of RCC, which predominantly affects AfricanAmerican children and young adults with sickle cell trait or sickle cell disease [70,71]. Patients present clinically with high stage tumor and succumb to disease within a few weeks to months. Paraneoplastic syndromes have been reported in 10– 40% of patients with RCC [72] (Table 2). Paraneoplastic syndromes do not connote to metastatic disease and may represent the initial presenting symptoms or signs of RCC while the disease is still localized and curable. Paraneoplastic syndromes may stem from the production of biologically active substances from the tumor, or by normal tissue as an immune response to the tumor. Several hormones reported to be excreted by RCC include parathyroid-like hormone, gonadotropins, renin, erythropoietin, glucagons, human chorionic gonadotropin, insulin, placentolactogen, and adrenocorticotropic hormone-like substance [72–74]. Increased production of various cytokines, including interleukin-6, have been held responsible as well [75]. Hypercalcemia has been reported in 10–20%, with an increased incidence in higher stages of disease
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Table 2 Paraneoplastic syndromes associated with renal cell carcinoma Hypercalcemia Polycythemia/increased erythropoietin Hypertension Stauffer’s syndrome (non-metastatic hepatic dysfunction) Cachexia, weight loss Fever Nuromyopathy Amyloidosis Increased gonadotropins Increased prolactin Increased enteroglucagon Impaired glucose metabolism
[74,76,77]. The production of parathyroid hormonelike peptides is usually held responsible [73,74,78,79]. The most common clinical features are nausea, anorexia, fatigue, constipation and decreased deep tendon reflexes. The most effective management is to treat the underlying tumor. Medical management includes hydration and subsequent use of loop diuretics [74]. Recently, bisphosphonates have proven to be very effective in the treatment of hypercalcemia [80]. Polycythemia may be either due to increased production of erythropoietin by either the cancerous tissue or by the adjacent normal parenchyma in response to hypoxia induced by tumor expansion [81]. About 25–40% of patients with RCC may have hypertension [73,74]. Various causes have been reported among which renin production by the tumor, compression of the renal artery or its branches by the tumor, or arteriovenous fistula within the tumor are most commonly accepted as the etiology [73,82]. A unique paraneoplastic syndrome associated with RCC is non-metastatic hepatic dysfunction, or Stauffer’s syndrome. Various laboratory abnormalities include elevated serum alkaline phosphatase, prolonged prothrombine time, increased a-globulins, hypoalbunemia, elevated serum bilirubin and transaminases, and IL-6 [83,84]. Fever, weight loss and fatigue have been considered part of the syndrome [74,83]. The syndrome resolves in 60–70% of cases following nephrectomy. Persistence or recurrence is a strong indicator of viable tumor and is a poor prognosticator [73].
6. Differential diagnosis Imaging in RCC is covered as a separate topic of this series; therefore, our discussion on differential diagnosis herein will be very brief. Benign lesions such as renal infarct, pseudotumor caused by a hypertrophied column of Bertin, abscess, or a vascular lesion such as arteriovenous fistula need to be distinguished from
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RCC on the basis of clinical findings and appropriate radiological imaging. The presence of fat on CT or ultrasonography is pathognomonic of angiomyolipoma, a benign lesion that consists of fat, vasculature and smooth muscle [85]. Association with tuberous sclerosis would aid in confirming the diagnosis. Metastatic tumors to the kidney are often multiple, ordinarily hypovascular and particularly common with lung carcinoma and melanoma [86]. In patients with a centrally located tumor, urothelial carcinoma of the renal collecting system should be considered in differential diagnosis. History of previous urothelial carcinoma, urine cytology, retrograde pyelograms and ureteroscopy are alternatives helpful in decision-making. Lymphoma may present in various clinical forms. The majority of patients have bilateral renal involve-
ment; nonetheless, diffuse infiltration of the kidney(s) or a solitary nodule may be other ways of presentation [87,88]. A history of lymphoma, or radiological signs of lymphoma such as splenomegaly and lymphadenopathy imply that the renal mass may be lymphoma. Biopsy: The indications and application of percutaneous biopsy for renal masses are rather limited. It is mainly used to differentiate RCC from other renal masses and disease treated surgically from non-surgical disease such as renal abscess, lymphoma and metastatic disease [89,90]. The major shortcomings are the risk of a false negative biopsy, hemorrhage, and although low, the risk of seeding of the biopsy tract [91,92]. Biopsy can be performed in cases of suspected metastatic disease, or in the elderly to obtain a diagnosis and avoiding radical nephrectomy.
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CME questions Please visit htttp://www.uroweb.org/updateseries to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. Which has not been proven to be a risk factor for the development of renal cell carcinoma? A. Stone disease. B. Cigarette smoking. C. Obesity. D. Hypertension. 2. The most common histology of the renal tumor in Birt–Hogg–Dube´ syndrome is: A. clear cell, B. papillary, C. chromophobe, D. oncocytoma. 3. Screening for renal cell carcinoma is suggested for all except:
A. close relatives of patients with Von Hippel– Lindau disease, B. heavy smokers, C. patients with acquired renal cystic disease, D. the presence of mutations of the MET protooncogene. 4. Which of the following statements is correct? A. Flank pain, hematuria and palpable mass are detected in 40% of the patients with RCC. B. Paraneoplastic syndrome is a sign of metastatic disease. C. Hypercalcemia can be observed in 40% of the patients with RCC. D. Paraneoplastic syndromes may be used as a prognosticator in RCC.