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Keywords:

  • active surveillance;
  • kidney cancer;
  • renal biopsy;
  • small renal mass

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

The incidence of small renal masses is increasing, as a result of the wide adoption of imaging exams. Their management, however, is complicated, especially in patients with decreased life expectancy or comorbidities. Approximately 20% of small renal masses are benign and, even if malignant, just 10% show aggressive pathological features. Furthermore, competing cause mortality seems to exceed the cancer-specific mortality in patients aged over 70 years. The role of percutaneous tumor biopsy is still not well defined. All these observations raise the concern as to whether surgery might represent an overtreatment for some cases of small renal masses, calling into question the role of active surveillance. The aim of this review was to evaluate the current evidence pertaining to several hot questions that need to be addressed when contemplating active surveillance for small renal masses. The most relevant publications on this subject available in the literature were selected. Five representative series of active surveillance along with the main related variables were identified. Some relevant items surrounding the field of active surveillance were identified and submitted to an evidence-based discussion. According to the recent evidence, small renal masses under active surveillance tend to show an indolent course with a low probability of disease progression, the latter being triggered most of the time by a tendency to grow faster. Unfortunately, we are currently unable to predict those few cases with aggressive behavior. According to the current evidence, active surveillance is feasible and safe in elderly and comorbid patients.


Abbreviations & Acronyms
AS

active surveillance

CT

computed tomography

MRI

magnetic resonance imaging

RCC

renal cell carcinoma

SRM

small renal masses

US

ultrasound

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

RCC is the most lethal among urological cancers, with a 25% chance of metastases at presentation and 38% total mortality.[1] Surgery, with the addition of systemic therapy in advanced disease, is currently the standard care of treatment.[2] The past decade has witnessed a continuous increase in the incidence of RCC. Most of the rise has been driven by localized disease,[3] likely reflecting an early diagnosis of incidental SRM. Mean tumor size has decreased from 4.1 cm in 1993 to 3.6 cm in 2004.[4] Despite a parallel increase of surgery in RCC, the mortality rate has continued to rise.[5] Notably, an increased trend for all causes mortality has been observed also for SRM. Along with others, this might be due to the fact that the largest increase in RCC incidence has occurred in patients in the seventh to ninth decades of life,[6] an age group with several comorbidities, and frequent use of imaging methods, such as US. Competing cause mortality has been shown to largely exceed the cancer-specific mortality in patients aged over 70 years with SRM (<4 cm).[7] In patients aged over 75 years, surgery for T1 RCC was not associated with improvement in overall survival, but cardiovascular disease and renal dysfunction were the leading causes of death.[8] All these observations taken together raise the concern of whether an increased surgical management of incidentally detected SRM and the parallel rising mortality rate reflect a lack of benefit of our current treatment strategies. In other words, we might overtreat cases of RCC that are likely to have an indolent clinical course.[9] These observations call into question the role of AS for SRM. The aim of the present review was to evaluate the current evidence pertaining to several hot questions that need to be addressed when contemplating AS for SRM.

Evidence acquisition

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

A thorough literature search was carried out using Pubmed and Embase databases in order to identify the most relevant publications addressing the role of AS for SRM or RCC. Appropriateness in addressing general end-points for any neoplasm, namely cancer-specific and overall survival, was used as selection criteria. Progression was defined as the occurrence of metastatic disease. For the purpose of the present study, any contrast enhancing renal mass up to 4 cm in size on CT or MRI is defined as SRM.[10] The categorization of indications for AS outlined by Crispen et al.,[11] that distinguish absolute indication for AS (for patients who are not surgical candidates in view of prohibitive medical comorbidities), relative indications (to avoid the potential need for replacement therapy) and elective indications (referred to patients who refuse surgery despite being at low surgical risk), was found the most useful for clinical purposes. A total of 37 studies was selected and reviewed; among these, we identified five representative series of AS whose main results are reported in Table 1. In the selected papers, several crucial questions were identified and we will discuss these issues hereinafter.

Table 1. Most representative series of AS for SRM
AuthorBaseline parametersGrowth rateProgression and deathDelayed intervention
nAgeIndications for ASMean size, cm (range)Biopsy at study entry (%)Pathology (%)Mean follow up (months)Growth cm/yearOther growth parametersProgression to M+Growth rate of progressed (cm/year)Overall death rateCSSn (%)ReasonsPathology
Chawla et al.[12]234 patientsNANA2.6131/234 (46%)

RCC 92%

Benign 8%

340.28 (0.09–0.86)

3/286

−1%

1 case: 1.3

1 case: 0.2

NA100%NANA

8% benign

10% Furhman 3

Abouassaly et al.[13]110 patients81

All patients >75 years, mean Charlson score: 2

38% CRF

2.5 (0.9–11.2)5/110 (5%)

Benign 80%

RCC 20%

240.26 (0–3.26)

No growth 43%

No correlation size/growth

0/106

0%

NA34/106 (32%)100%4/106 (4%)

2/4 rapid growth

2/4 Patients' choice

1 Oncocytoma

1 pT3

2 had cryoablation

Crispen et al.[11]

173 tumors

154 patients

71

75% elective

13% relative

12% absolute

2.4NANA310.28

Growth: 74% (no correlation with size)

No growth: 26%

2/154 (1.3%)1 case: 1.3 (1 case: 8 cm at baseline)NA100%68/173 (39%)

● Patients' choice 62%

● Tumor growth 29%

13% benign

25% Furhman 3–4

pT3–4%

Rosales et al.[14]

223 tumors

212 patients

71Mean Charlson score: 32.8 (0.5–13.7)40/212 (19%)

RCC 92.5%

Benign 5%

Non diagnostic 2.5%

350.344/212 (1.9%)

1 case: 2.1 cm/year

3 cases: 1.1 cm/year

15/212 (7%)99.50%11 (5%)

● Tumor growth 8/15 (53%)

● Patients' choice 2/15

100% RCC
Jewett et al.[15]

209 SRM

178 patients prospective

73 (41–96)Clinical T1aN0M0, patients unfit for surgery (due to age, comorbidity or refusal of surgery)2.1 (0.4–4)99/178 (56%)

RCC 55%

Benign 12%

non diagnostic 33%

280.13 cm/yearNA2/178 (1.1%)

1 case: 2.3

1 case: no growth

11/178 (6%)99.40%42/178 (23%)

● Patients' choice: 18%

● Progression*: 5%

All progressions treated with surgery had RCC

What is the nature of a SRM?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Overall, up to 80% of SRM are malignant and the vast majority of these are RCC. Variations in the rate of benign lesions across series depend on the size cut-off (30% in ≤2 cm masses,[16] 11–15% when >4 cm masses are included[17, 18]). The incidence of benign lesions among SRM between 2 and 4 cm was recently found to be just 4.8%, much lower than previously reported.[19] However, there is no proof that the smaller the lesion the higher the chance of being benign. In one series, up to 85% of SRM below 1 cm were malignant.[18] On the contrary, a recent study reported a 42.8% incidence of benign lesions in nodules <1 cm.[19] Elderly patients seem to have a higher propensity (3.5-fold) to harbor a benign lesion than younger patients.[9] Multidetector computed tomography,[20] currently the best diagnostic imaging technique for SRM, remains unable to accurately identify benign lesions such as oncocytomas and even a small proportion of angiomyolipomas that do not contain fat.[21]

If malignant, should SRM be viewed as harmless?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

The majority of malignant SRM would fall in the T1a category of the TNM.[21] CT carries a significant risk of understaging. Nearly 10% of clinical T1a RCC below 3 cm and 35% of those between 3 and 4 cm will prove to be pathological T3a because of the inability of contrast CT to detect microscopic perirenal or sinus fat invasion. A parallel raise in the rate of high (3–4) Fuhrman grade with increasing volume has also been documented (5% for less than 3 cm SRM vs 25% between 3 and 4 cm).[22] The proportion of SRM carrying pathological aggressive features has been estimated to be approximately 10%.

Should all SRM be biopsied?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Ideally, a biopsy of a SRM represents a step forward in the prognostic understanding of a SRM by identifying those with a benign histology, defining the histological subtype and Fuhrman grade of those that are found to be malignant, and potentially providing tissue for genomic markers. The current understanding on renal biopsy is that it is a safe procedure from the oncological point of view (no cases of tumor seeding reported in recent series), with a trend in increasing accuracy and a decreasing rate of non-diagnostic biopsies.[23] Renal biopsy for SRM yielded a diagnostic accuracy varying between 90 and 100%, with a rate of diagnostic sufficiency between 78 and 96% in recent series where a core biopsy technique was used.[24-28] Subtype determination is possible in up to 93% of malignant SRM, with high concordance between biopsy and surgical specimens.[26] Limitation exists in the correct attribution of nuclear grade, which did not go beyond 43% in a recent series,[29] and in the ability to differentiate an oncocytoma from the eosinophilic variant of chromophobe RCC.[30] Besides, renal biopsy is considered unsafe and inaccurate (33% of sensitivity) in cystic masses.[31] Currently, there is no standardized methodology to optimize the results of renal biopsy in order to reduce the percentage of non-diagnostic sampling that remained as high as 33% in a recently released series.[15] In conclusion, bearing in mind the aforementioned limitations, renal biopsy should be pursued as an essential part of the clinical work-up of a SRM any time AS is contemplated.

What is the probability of dying from SRM AS compared with unrelated diseases?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

The observation that many patients with a malignant SRM might have a much higher chance of dying of unrelated diseases rather than the tumor itself has represented a major input for pursuing AS in SRM, particularly in elderly and comorbid patients. Nearly 30% of patients older than 70 years and a ≤4 cm SRM die from causes unrelated to RCC.[7] Patients with a Charlson Comorbidity Index of more than 2 and a localized RCC do not seem to gain any advantage form renal surgery.[32] A load of prognostic models has been proposed for estimating the cancer-specific survival of RCC patients with little use for the purpose of AS. Postoperative nomograms rely on variables that are by definition unknown in AS patients.[33] All the available preoperative nomograms are biased in that they report cancer-specific outcomes of surgically treated series.[34-36] Based on a large Surveillance, Epidemiology and End Results (US National Cancer Institute) cohort of localized (<20 cm) RCC and using easily accessible preoperative variables, a nomogram was constructed to calculate the probability of a given patient to die of kidney cancer, of other cancers and of non-cancer causes, respectively.[37] According to this nomogram (where Charlson score was not accounted), a 75-year-old patient with a <4 cm RCC will have approximately a 2–3% chance of dying of kidney cancer, a 10% chance of dying of other cancers and a 25% of non cancer-related death. For the purpose of AS, the current nomogram is still biased by taking into account a cohort of patients that received active treatment for kidney cancer. Notably, in a retrospective series of elderly (≥75 years) patients with clinical T1 RCC undergoing either surgery or AS, age and comorbidity index, but not the treatment choice (radical nephrectomy vs partial nephrectomy vs active surveillance) were significant predictors of overall survival. Cardiovascular events, mostly driven by chronic renal failure (a non-unusual adverse event of renal surgery in elderly patients), were the leading cause of death.[8]

What is the risk of progression and cancer-specific death under AS?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Currently, the natural history of kidney cancer is mostly unknown. In this respect, the few published series on AS for solid renal masses represent a unique source to assess the safety of this treatment strategy for SRM. The most feared risk of AS is the progression to metastatic disease. Table 1 reports the most representative series where more than 1000 patients with localized SRM have engaged AS, including a meta analysis of nine previous studies on AS for SRM.[12] Surprisingly, in all but one of the series, the rate of SRM developing metastatic progression did not go beyond 1–2%. These data need to be interpreted cautiously because of a number of drawbacks in the mentioned studies. The mean follow up is relatively short, usually not exceeding 2 years. Notably, the progression rate was 5% in the only series with the longest follow up (47 months).[38] It is plausible that more patients will progress at a longer follow up. As the pathology of the SRM is largely missing because of underuse of biopsy, favorable results might be partly biased by the rate of benign lesions. Additionally, AS was terminated in a significant proportion of patients, either by patients' choice or by physician's decision based on clinical criteria for progression that presently lack validation.

When AS can be considered?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Nowadays, AS can be considered as an appropriate strategy for elderly patients or in the case of significant comorbidities.[2] According to Gill et al., AS could also be optional for masses ≤1 cm in diameter, regardless of patients' life expectancy, in line with the high chance of benign histology within this size.[10] A recent observational study called into question other factors that could influence the decision to pursue AS, such as tumor size <3 cm and surgeons' approach. It would seem that “open” surgeons propose AS more eagerly compared with those who prefer a laparoscopic or robotic approach.[39] Presently, AS cannot be recommended for SRM in young and healthy patients.

How should patients under AS be followed up?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

The time interval and the most appropriate imaging technique for follow up of SRM under AS is yet to be defined. CT and MRI are thought to be more accurate in determining size variations, although no comparative study has been carried out to show their superiority over US.[40] Expert opinion advises a 6–12-month interval as the optimal compromise between oncological safety, and the risk of radiation exposure and kidney function morbidity as a result of contrast media.[10] Other authors recommend close imaging follow up (every 3 months) for the first year followed by a decreasing frequency to annual intervals by 3 years and thereafter.[15]

What does the growth rate of SRM under AS tell us?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Growth under AS is currently reported as the change in the maximal cross-sectional diameter at serial imaging techniques and expressed in cm per year. SRM tends to show a slow growth, not exceeding 2–3 mm per year (Table 1). Faster growth of 0.66 cm/year was reported in the only series where mean tumor size exceeded 4 cm. Of note, the <4 cm SRM subgroup showed a growth of 0.27 cm/year.[41] Some authors have found a significant correlation between size and growth rate, with larger masses growing faster,[41, 42] some others did not.[11, 13] As linear growth is not reflective of overall change in tumor volume, it has been suggested that calculating the tumor volume would provide a better representation of changes in total tumor cell number.[11]

The logical speculation that fast growth might correlate with an aggressive behavior is partly hampered by some evidence. In the prospective study by Jewett et al.,[15] benign lesions grew as fast as malignant lesions (0.17 cm/year vs 0.14 cm/year). By contrast, 27% of SRM that were histologically confirmed RCC decreased in size and an additional 15% remained unchanged. In another series, up to 43% of SRM did not grow at all.[13] This percentage far exceeds the expected rate of benign disease among SRM. Overall, 16 patients of the series listed in Table 1 progressed to metastatic disease, and 11 out of 16 showed a “fast growth”, approaching or even surpassing 1 cm per year in the nine out of 11 patients where the data is available. Rapid growth kinetics can thus be assumed as a good, albeit not absolute, predictor of progression of a SRM.

When should AS be terminated?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

Ideally, patients with SRM under AS should be switched to active treatment before developing metastatic disease, a disease stage where a window of opportunity for effective treatment is lost. Others argue that size progression during AS might prevent the possibility for nephron-sparing surgery. Currently, there is no definition of progression for SRM under AS that has been shown to be predictive of aggressive behavior. Both the reach of tumor size cut-off and growth kinetics has been used as arbitrary criteria to terminate AS of SRM. Table 1 shows the rate, the reason for terminating AS and the pathology of the surgical sample where available. At the available follow up, the majority of patients remained under AS. Out of patients' preference, “rapid growth” of the mass was the leading reason prompting termination of AS. As expected, a small but significant proportion of patients receiving treatment had a benign lesion. It has been advised that AS be terminated in any case of local progression, defined as any growth up to 4 cm or a doubling of calculated SRM volume in ≤12 months.[15] A total of 25 patients from that series (14%) met these criteria: 15 continued AS because of comorbidities, whereas one was lost to follow up. Notably, nephron-sparing surgery was still possible for six out of nine who received surgery. Two out of 15 for whom histology was available were benign lesions, whereas the remaining were RCC.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References

SRM under AS tend to show an indolent course with a low probability of disease progression, the latter being triggered most of the time by a tendency to grow faster. Unfortunately, we are currently unable to predict those few cases with aggressive behavior. According to the current evidence, AS is feasible and safe in elderly and comorbid patients. Prospective studies using standardized pathological criteria derived by biopsy of the mass and longer follow up will tell whether AS can also be extended to young and fit patients with SRM, for whom AS remains at their choice.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence acquisition
  5. What is the nature of a SRM?
  6. If malignant, should SRM be viewed as harmless?
  7. Should all SRM be biopsied?
  8. What is the probability of dying from SRM AS compared with unrelated diseases?
  9. What is the risk of progression and cancer-specific death under AS?
  10. When AS can be considered?
  11. How should patients under AS be followed up?
  12. What does the growth rate of SRM under AS tell us?
  13. When should AS be terminated?
  14. Conclusions
  15. Conflict of interest
  16. References