Evaluation of a renal cyst/mass

Epidemiology and risk factors

Renal cell carcinoma (RCC) is the eighth most common malignancy in the world. According to the National Cancer Institute, in 2017 approximately 64,000 diagnoses were made in the United States and more than 330,000 worldwide. The incidence of RCC has been steadily increasing in the United States, but this may be caused by incidental detection from imaging studies. In the 1980s, approximately 40% of renal neoplasms were stage 1 (≤ 7 cm and confined to kidney), but now represent greater than 60% of RCC at presentation. ^, If the benign renal masses are included, an estimated 80,000 patients in the United States undergo renal mass evaluation on an annual basis.

Clear cell RCC (ccRCC) comprises greater than 75% of all RCC and papillary RCC is the next most common (predominantly seen in the end-stage renal disease [ESRD] population). The most common hereditary syndrome for RCC (specifically ccRCC) is the von Hippel-Lindau (VHL) disease, which accounts for a small proportion (2%–3%) of patients with RCC. Although only 1.6% of patients with ccRCC have VHL disease, the majority of those with VHL disease will develop ccRCC. The molecular biology and pathogenesis involves loss of VHL tumor suppressor function and persistent hypoxia-inducible factor activity, leading to apparent tissue “hypoxia” and resulting in activation of tumor pathways and promoting tumor growth. This gene mutation is also the most prevalent gene mutation (40%–80%) found in the general (including the sporadic) RCC population. ^,

The incidence of RCC is greatest in the sixth to seventh decade with higher risk of RCC among men (1.6:1 male:female ratio) and those of African descent. Potentially modifiable risk factors include tobacco use, obesity, hypertension (HTN), diabetes mellitus (DM), cystic disease, and ESRD. Paradoxically, obese patients with RCC have lower mortality. In addition, unlike tobacco exposure, alcohol use is associated with lower risk of RCC, even though it is linked to other cancers. ^, Chronic kidney disease (stages 3–4 CKD and ESRD) also appears to increase risk for RCC to some degree and, reciprocally, RCC is associated with increased risk of CKD decline. ^, Those with small renal masses and CKD share the same risk factors (tobacco use, obesity, DM, and HTN) partially caused by the high burden of comorbid diseases and may explain this bidirectional relationship.

Chronic kidney disease and renal cell carcinoma risk

RCC risk among CKD patients is high. For the dialysis-dependent ESRD population, the risk of RCC escalates to 100-fold greater than the general population and incidence of RCC among ESRD patients range 1% to 7%. ^, RCC risk rises with longer duration of dialysis, potentially from dialysis-related inflammatory processes and the link to acquired cystic kidney disease (ACKD). Incidence of ACKD is particularly high among ESRD patients and when progression to RCC occurs, the histologic subtype of papillary RCC is more prominent than in the general population. One Japanese cohort examining the relationship between histologic subtype and dialysis duration found that those with dialysis duration less than 10 years were more likely to have ccRCC, and those on dialysis for longer than 10 years had ACKD-associated RCC (more papillary RCC). The proportion of ESRD patients (22%–37%) with papillary RCC is 4 to 5 times greater than that of the general population (5%–7%). ^, Incidence of ccRCC and papillary RCC varies according to population and confers some degree of prognosis, as shown in Table 28.1 . ^,

Among pre-ESRD CKD patients, risk of RCC is also high and appears to increase with worsening estimated glomerular filtration rate (eGFR). When a cohort of 1 million cancer-free subjects were stratified by CKD stage, RCC risk was 39%, 81% greater for stage 3a and 3b CKD, respectively, than the reference group, then approached twofold greater for those with stage 4 CKD. The potential relationship between RCC and kidney function was further explored among 202,195 transplant recipients. Incidence of RCC rose during periods of graft failure and fell during periods of kidney function. Furthermore, early signs of kidney dysfunction, such as albuminuria, have also been associated with RCC, further supporting the relationship of kidney pathology with RCC.

Despite the adverse relationship between CKD and RCC risk, prognosis of RCC among those with ESRD appears to be better than in the general population, ^{, , –} with a 5-year cancer-specific survival of 90.1% for the ESRD population and 69% for the general population. The lower mortality among those with ESRD may be explained by more favorable demographic and tumor characteristics and potentially earlier diagnosis. ^{, ,} A French cohort of ESRD patients was more functional and was diagnosed with RCC at a younger age (fifth vs. sixth decade) than in the general population. Detection appears to be earlier and asymptomatic potentially because of higher frequency of imaging among ESRD patients. The ESRD group had smaller tumor size, lower stage, lower grade, and was less likely to have nodal invasion or metastases. Furthermore, the predominant tumor subtype of papillary RCC tends to have a milder clinical course.

Cystic disease

The close association of RCC and ESRD has often been explained by the predominance of ACKD among ESRD patients, with an annual incidence among dialysis patients (0.15%–0.34%) of up to 40 times that of the general population (0.008%). In ESRD, ACKD prevalence ranges 10% to 44% soon after dialysis initiation but exceeds 90% as dialysis vintage reaches 5 to 10 years. In addition to long dialysis duration, male sex and younger age appear to be associated with ACKD. ESRD and male sex are risk factors common to RCC. ACKD is also reported in pre-ESRD CKD (7%–22%) and transplant (23%) populations. Although ACKD prevalence for these groups also far exceeds that of the general population, ACKD remains less common among these groups compared with dialysis patients. ^{, , ,}

Cysts appear to accumulate because of chronic hypoxia and acid-base dysregulation and possibly in response to growth factors. ^{, ,} The acquired cysts open into the tubules and retain functional capacity to some degree, which is suggested by higher cyst fluid creatinine concentration than serum content and the regression of these cysts after renal transplantation. ^,

The cystic lesions of ACKD are thought to be precursors of RCC that progress in the setting of prolonged lack of kidney function. The cystic lesions share common pathologic characteristics with RCC. The most prominent subtype of RCC among ESRD patients is papillary RCC, not the clear cell carcinoma usually seen in the general population. The RCC associated with ESRD has similar immunohistochemical patterns as with ACKD. ^,

Cystic diseases other than ACKD have not been closely associated with RCC. The incidence of RCC in polycystic kidney disease is no different from that of the general population.

Screening for renal cell carcinoma

Even with the higher incidence of RCC among ESRD patients, routine screening for RCC is not recommended. Decision analysis performed of ACKD screening did not demonstrate a clear benefit to survival in the ESRD population. However, young individuals who are healthy with longer expected lifespan are suggested to be reasonable candidates for screening. ^, Debate continues regarding screening among potential transplant recipients who have an equally high rate of RCC as the ESRD population (3.5%). ^, However, transplant recipients diagnosed with RCC have good prognosis with tumor detection at a younger age, earlier stage, smaller tumor size, and favorable RCC subtype of papillary RCC. Presence of RCC does not adversely affect graft survival. Ten-year cancer-specific survival (∼90%) in transplant recipients is higher than for both the general (75%) and ESRD populations (77%). ^,

Physical examination

Physical examination has a limited role in the diagnosis of clinically localized disease and is most useful in distinguishing the signs and symptoms of advanced disease. For many years, RCC was known as the internists’ tumor , reflecting the variety of systemic symptoms and more common presentation at advanced stage. For instance, paraneoplastic syndromes (i.e., hypertension, polycythemia, hypercalcemia, abnormal liver function) are present in approximately 10% to 20% of patients with metastatic RCC. ^, In the contemporary era where most patients are diagnosed with clinically localized, early stage disease, physical examination may reveal medical conditions that influence management decisions, including body habitus, prior abdominal scars, stigmata of CKD, and so on.

Laboratory evaluation

There are no biomarkers or routine laboratory tests used to routinely diagnose renal malignancies. As such, laboratory tests are useful in assessment of renal function (glomerular filtration rate) and metastatic evaluation. Routine laboratory tests for renal mass evaluation include complete blood count, basic or complete metabolic panel, and urinalysis. Serum creatinine and urinalysis for protein are recommended before any intervention and, if abnormal, used to classify CKD stage.