RCC growth
Clinical manifestations
Local tumor growth
Hematuria, flank pain, abdominal mass, perirenal hematoma
Metastases
Persistent cough, bone pain, cervical lymphadenopathy, constitutional symptoms (weight loss/fever/malaise)
Obstruction of the inferior vena cava
Bilateral lower extremity edema, nonreducing or right-sided varicocele
Paraneoplastic syndromes [132]
Elevated ESR (56 %), hypertension (38 %), anemia (36 %), cachexia/weight loss (35 %), pyrexia (17 %), abnormal liver function (14 %), hypercalcemia (5 %), polycythemia (4 %), neuromyopathy (3 %), amyloidosis (2 %)
Table 17.2
Extrarenal manifestations of patients with familial RCC syndromes
Syndrome | Gene | Chromosome | Type of RCC | Extra-renal manifestations |
|---|---|---|---|---|
Von Hippel–Lindau | VHL | 3p25–26 | Clear cell RCC | Hemangioblastomas of the central nervous system, retinal angiomas, pheochromocytoma, epididymal cyst adenomas, pancreatic cysts |
Hereditary papillary RCC | c-Met | 7q31 | Type 1 papillary RCC | None |
Familial leiomyomatosis and RCC | Fumarate hydratase | 1q42 | Typ2 2 papillary RCC | Cutaneous leiomyomas, uterine leiomyomas |
Birt–Hogg–Dubé | BHD1 | 17p12q11 | Chromophobe RCC, oncocytoma, hybrid/oncocytic tumors, occasional clear cell RCC | Cutaneous fibrofolliculomas, lung cysts, spontaneous pneumothorax |
17.2.1 Diagnosis
Prior to computed tomography (CT), renal masses were diagnosed with intravenous pyelogram or renal arteriography. The majority of renal masses are now detected with routine imaging. Focused imaging with CT or magnetic resonance imaging (MRI) can be used for diagnosis and staging renal masses. It is important to consider that, depending on the size of the mass, up to 22 % of small renal masses (≤4 cm) treated surgically are found to be benign [5]. Imaging is generally used to clinically stage all patients (Table 17.3).
Stage | Tumor size | Localization | Description |
|---|---|---|---|
T1 | Diameter ≤7 cm | Localized | Tumor confined to the kidney |
T2 | Diameter >7 cm | Localized | Tumor confined to the kidney |
T3 | Any size | Regional | Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia |
T4 | Any size | Metastatic | Tumor invades beyond the Gerota fascia |
Renal mass biopsy has become an important tool for initial evaluation and management of incidentally found small renal masses. Renal mass biopsies are typically considered in patients with suspected infection, extrarenal metastases, lymphoma, and/or in poor operative candidates in preparation for minimally invasive treatments (radiofrequency ablation vs. cryotherapy) or active surveillance. Recent reports have demonstrated a false negative rate of less than 1 % for renal mass biopsies [6].
The most common histologic subtype of RCC is clear cell (70–80 %) followed by papillary RCC (10–15 %), chromophobe RCC (3–5 %), collecting duct carcinoma (<1 %), multilocular cystic ccRCC (uncommon), renal medullary carcinoma (rare), RCC associated with Xp11.2 translocations/TFE3 gene fusions (rare), mucinous tubular and spindle cell carcinoma (rare), and unclassified RCC (1–3 %) [7]. Additional details on the histology can be found in Chap. 18.
17.2.2 Screening
Due to the relatively low incidence of RCC in the general population, there is no indication for widespread implementation of screening. Screening patients with RCC for somatic mutations has been recommended in younger patients (45 years or younger) presenting with a family history of RCC, bilateral/multifocal renal masses, associated extrarenal clinical manifestations, and/or certain specific tumor histologies [8].
17.2.3 Treatment
The initial treatment provided to patients presenting with RCC depends on clinical stage and performance status at presentation. For localized kidney cancer (non-metastatic) the standard of care is radical or partial nephrectomy. Recent studies have focused on the long-term outcomes of patients receiving nephron-sparing surgery (NSS) due to the increased risk of chronic renal disease after radical nephrectomy. Alternatively, outcomes for partial nephrectomy for renal masses that are less than or equal to 7 cm but confined to the kidney (clinical stage T1) have been shown to have equivalent oncologic outcomes compared to radiofrequency ablation (RFA) [9]. Other option for management of small renal masses (≤4 cm) includes active surveillance where masses are followed with serial imaging to establish growth kinetics and intervention is performed if the mass demonstrates significant growth.
The role of cytoreductive nephrectomy or “debulking nephrectomy” in patients with metastatic disease evidence of metastatic disease has also been established [10]. Studies demonstrated an improvement in progression-free survival in patients who underwent cytoreductive nephrectomy for metastatic RCC. Ongoing clinical trials are evaluating the role of cytoreductive nephrectomy in the era of targeted drug therapy. Furthermore, clinical trials are ongoing to evaluate the role of neoadjuvant targeted therapy to improve the chances of performing nephron-sparing surgery in patients who would otherwise only be candidates for a radical nephrectomy [11].
17.2.4 Prognosis
Pathologic stage, tumor size, nuclear grade, histologic subtype, and molecular subtypes have the greatest utility for prognosis. Pathologic stage is the most important prognostic factor [12]. Five-year relative survival among RCC patients diagnosed between 1992 and 2007 in the U.S. is 73 % among white patients and 68 % among black patients [13]. Among white patients, 5-year relative survival is 93 % for those diagnosed with localized disease, 66 % for regionally spread disease, and 10 % for distant metastasis [13].
17.3 Descriptive Epidemiology
Globally, there were an estimated 337,860 new cases of kidney cancer and 143,406 deaths due to kidney cancer in 2012 [14]. U.S. and international cancer statistics generally combine RCC and cancer of the renal pelvis, with RCC comprising approximately 90 % of total kidney cancer.
There is considerable variation in incidence of kidney cancer between geographical regions (Fig. 17.1). Age-standardized incidence rates vary from 1.2 per 100,000 in Africa to 11.7 per 100,000 in North America [14]. Variation in mortality rates is lower, with age-standardized mortality rates ranging from 1.0 per 100,000 in Africa to 3.1 per 100,000 in Europe [14].
Rates of kidney cancer are higher among men than women worldwide, with rates approximate two times higher in men (Fig. 17.1). Among men and women, and in countries with lower and higher incidence, incidence rates begin to increase around age 30 and continue to rise until after age 70. There is some suggestion of a plateau or decrease in incidence rates by age 80 (Figs. 17.2 and 17.3).
Incidence of kidney cancer has been increasing in recent decades worldwide. Age-standardized incidence rates of kidney cancer over time are shown for several countries in Fig. 17.4. In the U.S., the annual percent change in age-standardized incidence rates has been approximately 2 % per year throughout the period from 1975 to 2012 [15]. The increase in incidence is likely due in part to increased diagnosis related to use of imaging technologies including ultrasound and computer tomography (CT) scanning. Increased prevalence of risk factors for kidney cancer including diabetes, obesity, and hypertension may also play a role. The increased incidence of kidney cancer in the U.S. has been largely seen for localized cancers, suggesting that increased diagnosis due to increased use of imaging has played a key role in the increase in incidence; however, smaller increases in the diagnosis of more advanced cancers suggests that other factors have also played a role [2]. Mortality rates increased with incidence rates from the 1970s to the 2000s, but have plateaued in the past decade in the US and Europe, with suggestions of a decrease in some countries in Northern and Western Europe [3, 15, 16]. In the U.S., the annual percent change in age-standardized kidney cancer mortality rates was 1.3 % for 1980–1989 and 0.4 % for 1990–2012, and then decreased −0.9 % from 2003 to 2012 [15].
In the U.S., kidney cancer incidence and mortality rates are higher in blacks than in whites (Fig. 17.5). Incidence and mortality rates have also increased more since the 1970s for blacks than for whites, with an age-standardized annual percent change of 2.8 % for blacks and 2.1 % for whites from 1975 to 2012, and an increase in mortality rates of 0.8 % in blacks and 0.3 % in whites from 1969 to 2012 [15]. Median age at diagnosis is lower in blacks than whites [13, 17]. The reasons for these differences are not clear; however, the prevalence of obesity and hypertension are higher in blacks than in whites [18].
17.4 Risk Factors
Smoking and obesity-related traits including obesity, hypertension, and diabetes have been consistently identified as risk factors for RCC. Several reproductive factors among women also appear to be associated with RCC risk. There is also some evidence for associations with analgesic use, physical activity, alcohol intake, and other aspects of diet. The association between these factors and RCC incidence is discussed below; data on the associations with survival after diagnosis are also discussed when available.
17.4.1 Smoking
The International Agency for Research on Cancer (IARC) considers there to be “sufficient” evidence that cigarette smoking causes RCC [19]. A 2005 meta-analysis [20] of 19 case-control and 5 cohort studies found the relative risk of RCC for ever smokers versus never smokers was 1.38 (95 % CI 1.27–1.50), with a dose-dependent increase in risk for number of cigarettes per day (Table 17.4). Associations of cigarette smoking were stronger in cohort and population-based case-control studies compared to hospital-based case-control studies. The IARC review from 2004 found adjustment for hypertension or body mass index (BMI) did not appear to have a large impact on the smoking associations in studies that reported relative risks with and without adjustment for these other risk factors [20].
Smoking category | Men | Women |
|---|---|---|
Never smokers | 1.00 (reference) | 1.00 (reference) |
Ever smoker, 1–9 cigs/day | 1.60 (1.21–2.12) | 0.98 (0.71–1.35) |
Ever smoker, 10–19 cigs/day | 1.83 (1.30–2.57) | 1.38 (0.90–2.11) |
Ever smoker, 20+ cigs/day | 2.03 (1.51–2.74) | 1.58 (1.14–2.20) |
The relative risk for ever smoking was slightly higher in men than in women among the five cohort studies included in the 2005 meta-analysis (Men: Relative Risk (RR) 1.54, 95 % Confidence Interval (CI) 1.42–1.68; Women: RR 1.22, 95 % CI 1.09–1.36). Three cohort studies have been published since the meta-analysis. One in the Nurses’ Health Study (women) and the Health Professionals Follow-up Study (men) found a significant trend for increased risk of RCC with increasing pack-years of smoking among men (p = 0.003) and a borderline significant trend among women (p = 0.09) [21]. Another found significant trends in both men and women (p < 0.001 for men, p = 0.02 for women) [22]. A third found significantly increased risk for 22.5 or more pack-years of smoking among men and women combined [23].
The 2005 meta-analysis found some suggestion that increased years since quitting smoking was associated with a lower risk of RCC; however, this was seen only among men, and there was significant heterogeneity between studies. Five [24–28] of six [29] studies included in the 2004 IARC review found significant negative trends with increasing number of years since quitting. The time required for the relative risk to return to that of never smokers varied across studies and ranged from 10 years to greater than 20. A study published after the IARC review found that years since quitting was associated with a linear decrease in risk of RCC, but that 30 years were required for risk to return to that of never smokers [30].
Two studies have examined smoking and risk of specific histological subtypes of RCC. One study based on data from two large case-control studies, one in the US with population-based controls and one in Europe with hospital-based controls, found no association overall between smoking and any subtype of RCC; however, the US study found an increased risk of clear cell and papillary subtypes, but not of chromophobe [31]. Consistent with this, a study comparing 705 consecutive RCC cases with 111 cancer-free nephrectomy patients found that smoking was associated with clear cell and papillary, but not with chromophobe RCC [32].
An IARC review of involuntary smoking in 2004 found no evidence on environmental tobacco smoke (ETS) and RCC risk. At that time only one study had examined the issue and found nonsignificant increased risks for both men and women reporting more than 8 h per day of ETS exposure [29]. Two more recent population-based case-control studies found significantly increased risks of RCC with both home and occupational ETS exposure [33, 34].
Survival. A meta-analysis of 5 studies examining smoking and disease-specific mortality in RCC patients found that current smoking was significantly associated with poorer survival, with a hazard ratio of 1.5 (95 % CI 1.1–2.1) compared to never smokers [35]. Current smoking was also associated with increased overall mortality, poorer overall survival, poorer cancer-specific survival, and worse progression-free survival across 14 studies of smoking in RCC patients.
Current smokers tend to be diagnosed with more advanced (higher stage) disease, and it is not clear whether smoking is associated with poorer prognosis independent of stage at diagnosis. A study of 2242 surgically treated clear cell RCC patients from the Mayo Clinic found no association between current smoking and risk of RCC-specific death after adjustment for stage, with a hazard ratio of 1.03 (95 % CI 0.85–1.23) [36]. However, a clinical study of 1809 patients found that smoking was independently associated with survival among patients diagnosed with non-metastatic cancer, but not among those with metastasis at diagnosis. Among patients with non-metastatic disease, each pack-year of smoking was associated with a 1 % increased risk of cancer-specific death (p = 0.008), with adjustment for stage, grade, and other clinical prognostic factors [37]. As in the Mayo Clinic study, smoking was associated with higher stage and grade at diagnosis in this study population. The role of smoking in RCC survival warrants further investigation, perhaps with incorporation of tumor biomarkers that could shed light on whether smoking plays an independent role in cancer progression after diagnosis and treatment.
17.4.2 Hypertension and Renal Cell Carcinoma
Hypertension has been consistently associated with risk of RCC, independent of obesity, smoking, and diabetes. Because RCC may increase the risk of hypertension through tumor secretion of renin, renal artery stenosis, renal failure, or other means, the direction of observed associations in epidemiological studies has not always been clear. However, a sufficient number of studies have found that a long-term history of hypertension is associated with RCC risk and that there is a dose–response relationship between higher blood pressure and RCC risk to conclude that hypertension is a risk factor for the development of RCC [21, 22, 38–42]. In addition, a Swedish cohort study of men [38] with multiple measures of blood pressure over time found that increases over time were associated with increased risk and decreases were associated with decreased risk, suggesting that effectively controlling hypertension may reduce risk of RCC. A study of risk factors according to histological subtypes of RCC found no differences in the hypertension–RCC relationship between subtypes [31].
The relative risk of RCC for those with a history of hypertension diagnosis compared to those without is approximately 1.5–2.0 across studies [21, 22, 41, 42]. The relative risk associated with high systolic blood pressure (with definitions ranging from >130 to >160 mm Hg) compared to normal (typically <120 mm Hg) ranges from 1.5 to 2.5 across studies. For high diastolic blood pressure (>90 or >100 mm Hg, compared to <80 mm Hg), the relative risk ranges from 1.5 to 2.3 [38–40, 42]. These risks associated with hypertension are independent of obesity and smoking.
Some studies reported an increased risk of RCC with use of antihypertensive medications; however, the EPIC study, which prospectively measured blood pressure in nearly 300,000 people, found that medication use was only associated with RCC when hypertension was poorly controlled, suggesting that hypertension itself drives the observed associations with antihypertensive medications [40].
A population-based case-control study in Detroit and Chicago found that hypertension diagnosis was associated with RCC risk in both whites and blacks, and that risk increased with increasing time since diagnosis, reaching a 4.1-fold (95 % CI 2.3–7.4) for blacks and 2.6-fold (95 % CI 1.7–4.1) for whites higher risk after 25 years [43]. Another study based in the Kaiser Permanente Northern California health care network also found similar associations between hypertension and RCC risk across races [42]. This suggests that the increased incidence of RCC among African-Americans may be due, in part, to the increased prevalence of hypertension in this group. Interestingly, the angiotensin receptor inhibitors, a class of antihypertensives, has been shown to improve overall and progression-free survival in patients with metastatic RCC [44].
17.4.3 Obesity
A meta-analysis of cohort studies with 15,144 cases and 9,080,052 participants found increased risks of RCC with increased BMI [45]. The pooled relative risk for overweight (BMI 25–<30 kg/m2) was 1.28 (95 % CI 1.24–1.33), and for obese (BMI ≥30 kg/m2) was 1.77 (95 % CI 1.68–1.87) compared to BMI of 18.5–<25 kg/m2). There was no evidence of heterogeneity across studies. Relative risks were somewhat stronger for women than for men (RR for obesity of 1.63, 95 % CI 1.50–1.77 for men; 1.95, 95 % CI 1.81–2.10 for women).
An analysis of two case-control studies of RCC examining risk factors by histological subtype found that BMI was associated with risk of clear cell (odds ratio (OR) 1.2, 95 % CI 1.1–1.3 per 5 kg/m2 increase) and chromophobe (OR 1.2, 95 % CI 1.1–1.4) but not papillary RCC (OR 1.1, 95 % CI 1.0–1.2, p-value for difference from clear cell = 0.006) [31]. An Italian hospital-based case-control study also found a suggestion that higher BMI at age 30 was more strongly associated with clear cell than with non-clear cell histology (p-value for interaction = 0.08) [46].
Survival. Multiple clinical cohorts of patients treated for RCC, usually with surgery, have found that obesity is associated with improved survival [47, 48]. This has given rise to an “obesity paradox” which stipulates that while obese people are more likely to be diagnosed with RCC, they appear less likely to die of the disease.
A meta-analysis [47] of 15 studies of BMI and cancer-specific mortality found a pooled relative risk of 0.66 (95 % CI 0.53–0.81) for a 5 kg/m2 increase in BMI, with evidence of significant heterogeneity across studies. The heterogeneity may be partially explained by geographical differences, with a stronger association in Asian compared to European and American studies, and to adjustment for presence of symptoms at diagnosis, with a stronger association in studies that adjusted for symptom presence. Sex does not appear to have been examined as a source of heterogeneity in the meta-analysis. However, a Japanese study of 435 patients surgically treated for RCC found that obesity was associated with better prognosis in men, but not in women [49]. A study of 2769 patients surgically treated for non-metastatic RCC in Korea found that higher BMI was associated with significantly improved cancer-specific survival in clear cell RCC, with significantly worse cancer-specific survival in chromophobe RCC, and was not associated with survival in papillary RCC [50]. The lack of association with papillary RCC is consistent with the observations for incidence as well.
It has been hypothesized that obese patients develop a biologically less aggressive disease. Supporting this, a study in a subset of 126 patients from a clinical cohort surgically treated at Memorial Sloan-Kettering Cancer Center who had data available from The Cancer Genome Atlas Project found significantly lower gene expression of fatty acid synthase (FASN) in obese patients [48]. FASN expression, in turn is associated with increased cancer-specific mortality in clear cell RCC.
However, the “obesity paradox” may also be explained by methodological problems with the study designs, rather than by any underlying biology. Reverse causation is a major concern, given that the evidence comes from clinical cohorts with measures of obesity at the time of diagnosis or treatment. At that point, there may have been weight loss due to undiagnosed disease, which likely correlates with disease severity. In addition, these clinical cohorts likely suffer from selection bias, as they tend to be based among surgically treated RCC patients, rather than among all patients diagnosed with RCC, regardless of treatment strategy. Finally, another form of selection bias is a methodological problem in studies of disease survival when the exposure of interest is also a risk factor for disease incidence [51]. Given these potential limitations, more study is needed to understand the role of obesity in RCC survival.
17.4.4 Height
A recent review and meta-analysis for the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Continuous Update Project found a significant positive association between adult attained height and kidney cancer risk. Across 10 studies included in the dose–response meta-analysis, with 9874 cases, a 5 cm increase in height was associated with a 10 % increased risk of kidney cancer (95 % CI 1.08–1.12) [52]. The association was similar for men and for women. In two studies of kidney cancer mortality, height was nonsignificantly inversely associated with mortality in one study [53] and nonsignificantly inversely associated with mortality in the other [54].
17.4.5 Diabetes and Diabetes Medications
Diabetes mellitus (DM) has been associated with an increased risk of various cancers [55]. There is particular interest in studying this association in renal cell carcinoma (RCC) due to advances in genetic sequencing that have allowed the identification of metabolic alterations that are key drivers of disease [1]. Furthermore, the most well-established risk factors for RCC are hypertension and obesity, which are components of the metabolic syndrome. The proposed mechanisms through which diabetes may exert an effect on RCC risk include insulin resistance, hyperinsulinemia, increased growth factors, and inflammation [56].
Studies evaluating the association of DM on incident and fatal RCC have yielded conflicting results. A recent meta-analysis of 18 case-control and cohort studies found an increased risk of RCC in patients with DM (RR 1.40, 95 % CI 1.16–1.69). The risk for women was somewhat higher than for men (RR for women 1.47, 95 % CI 1.18–1.83; RR for men 1.28, 95 % CI 1.10–1.48) [57]. Results were very similar in the 5 studies that adjusted for BMI, smoking, and alcohol intake (Only 3 of 18 studies adjusted for hypertension, and the effect of this adjustment was not examined in the meta-analysis). Among 8 cohort studies that evaluated the association between DM and RCC mortality, the pooled RR was 1.12 and not statistically significant (95 % CI 0.99–1.20) [57].
Studies varied in their ascertainment of diabetic status (physician confirmed vs. self-reported) and exclusion of type 1 diabetes. Most studies were not able to assess the association between severity of DM (i.e., HgA1c or diabetic complications) and incident or fatal RCC.
Survival. A common challenge faced in published series analyzing differences in outcomes between diabetic and nondiabetic cases is the potential for confounding introduced by a substantial imbalance in clinical demographic features between the two groups. Most studies have not found a difference in RCC histologic subtype, grade, or stage at presentation in patients with DM compared to those without diabetes [58–60]. However, two studies found that patients with DM presented with higher grade disease [61, 62].
Several studies suggest a positive association between DM at time of surgery and survival outcomes. The largest study comes from a multi-institution retrospective cohort of 2597 patients (14 % with DM) with localized RCC (pT1–2). Patients with DM had a worse recurrence free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) [63]. However, this study was limited by short follow-up, with a median of 3 years. Studies with longer follow-up have reported conflicting results. A study from the Mayo clinic of 257 patients with diabetes and matched nondiabetic patients treated surgically for RCC found that those patients with DM had worse DSS and OS over a median 8.7 years of follow-up [64]. However, other studies have reported similar outcomes between patients with and without DM [60, 62]. Further studies with longer follow-up and competing risks analyses are needed to assess the effect of DM on survival outcomes in patients with DM.
17.4.6 Analgesic Use
Both acetaminophen (Tylenol) and nonaspirin NSAIDs (ibuprofen, naproxen) have been associated with risk of RCC. A 2013 meta-analysis of 11 case-control studies and 3 cohort studies found a pooled relative risk for acetaminophen use (any use or regular use, depending on the study, compared to no use) of 1.28 (95 % CI 1.15–1.44) [65]. There were no significant differences by study design, country, or outcome (5 of the 14 studies used combined “kidney cancer” as the outcome rather than RCC). Nine of the studies also examined high intake of acetaminophen and found a pooled RR of 1.68 (95 % CI 1.22–2.30). In five studies that assessed duration of use there was no association between longer duration and risk of kidney cancer. Results were similar among 10 studies that adjusted for (at least) BMI and smoking.
Use of nonaspirin NSAIDs was also associated with significantly increased risk, with a pooled RR of 1.25 (95 % CI 1.06–1.46) for any or regular use compared to no use across five studies, 3 case-control and 2 cohort. Two of these studies [66] looked at higher intakes, with a significantly increased risk, and one [67] looked at duration of use, with an increased risk for 10 more years of use. Among 3 studies that adjusted for (at least) BMI and smoking, results were somewhat stronger (pooled RR 1.38, 95 % CI 1.16–1.65). However, an additional large cohort study, the NIH-AARP cohort, with 1084 cases of RCC, was published after this meta-analysis and found no association between nonaspirin NSAID use and RCC [68].
The 2013 meta-analysis found no association between aspirin use and kidney cancer across 14 studies [65]. Since then, the NIH-AARP cohort also found no association between aspirin use and RCC risk [68].
The biological mechanisms for the observed associations for acetaminophen and nonaspirin NSAIDs are not clear. Acetaminophen is a metabolite of phenacetin, an analgesic banned in the US since 1983, which causes renal failure and cancers of the renal pelvis [69]. However, the association for acetaminophen was seen in studies focusing on RCC in the meta-analysis [65], and it has been shown to induce kidney tumors in mice [70, 71]. NSAIDs inhibit renal synthesis of prostaglandins, which can result in chronic subacute renal injuries [72–74]; this could theoretically lead to carcinogenesis.
17.4.7 Reproductive Factors and Hormones
Sex differences in renal cell carcinoma (RCC) incidence suggest the possible role of hormonal factors. As a result of this observed difference, hormonal therapy for advanced RCC was the subject of clinical trials in the 1970s and 1980s, preceding the advent of cytokines; however, response rates were low and there is currently no established role for hormonal agents in the management of RCC [75].
The androgen receptor has consistently been found to be expressed in RCC [76, 77]. Furthermore, androgen receptor mRNA expression has been associated with prognosis [78]. Recent studies have also linked androgen receptor function to RCC progression through its influence on HIF2α[alpha]/VEGF signaling [79].
Polymorphisms in the estrogen receptor have been associated with RCC [80]. Recently, studies have evaluated the role of estrogen as a possible inhibitor of carcinogenesis in RCC. Estrogen receptor-β[beta] may have a role in decreasing cell proliferation and inducing apoptosis [81]. Estrogen receptor-α[alpha] expression has also been implicated in RCC risk [82]. Animal and in vitro models have demonstrated a potential role of estrogen and progesterone in the development of RCC [83].
Parity has been associated with risk of RCC, with a 10–15 % higher risk of RCC per childbirth, and an increased risk for earlier age at first birth [84–88]. However, other studies have found no such associations [89]. Associations with oral contraceptive use and postmenopausal hormone use have been inconsistent [84–86, 90–92].
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