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Keywords:

  • small renal cell carcinoma (RCC);
  • microvascular invasion;
  • long-term follow-up;
  • pT1a;
  • recurrence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

What's known on the subject? and What does the study add?

  • Small, organ-confined renal cell carcinoma (RCC) generally has favourable pathological characteristics and a good prognosis. However, late recurrence is a known characteristic of the biological behaviour of RCC and no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy.
  • In the present study with long-term follow-up of patients with small RCCs, 18 of 172 patients (10.5%) with pT1a RCC developed recurrence and eight of these (4.7%) died from cancer. Patients with microvascular invasion had a higher risk for cancer death than those without (P < 0.001, Log-rank test). Therefore long-term follow-up is required after surgery, particularly when the disease has microvascular invasion.

Objectives

  • To identify the long-term clinical course of small, organ-confined renal cell carcinoma (RCC).
  • To detect the risk factors of recurrence and of cancer death in small RCC.

Patients and Methods

  • Retrospectively reviewed 172 patients who were pathologically diagnosed as having pT1a RCC without metastasis at our institution from 1980 to 2005.
  • All pathology slides were re-reviewed by a single experienced pathologist.
  • Associations of microvascular invasion (MVI), development of metastasis, and cancer death were evaluated using Cox proportional hazards analysis.

Results

  • During a median (range) follow-up of 104.5 (8–308) months, 18 patients (10.5%) developed progression and eight patients (4.7%) died from cancer.
  • Kaplan–Meier curves showed higher cancer-specific survival (CSS) in patients without MVI (P < 0.001).
  • In multivariate analysis, MVI was the only factor that reached statistical significance (P = 0.006).
  • The 10-year CSS rates were 85.1% and 96.5% in patients with and without MVI, respectively.

Conclusions

  • Patients with MVI have worse survival than those without MVI.
  • This suggests that long-term follow-up of patients with small RCCs is needed because of the risk of recurrence and cancer death even 10 years after surgery, particularly when the disease has apparent MVI.

Abbreviations
CSS

cancer-specific survival

MVI

microvascular invasion

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

The widespread use of routine abdominal imaging enables detection of small, organ-confined RCC [1]. The disease generally has favourable pathological characteristics and a good prognosis [2-4]. On the other hand, tumour size alone is not sensitive enough to precisely predict the long-term clinical behaviour of RCC [5, 6].

A recent study reported a new nomogram to assess the competing risks of death in patients with RCC [7]. In that study, increased tumour size was directly related to death from RCC and inversely related to death from other causes. Although the study reported the 5-year probabilities of death, the long-term prognosis of RCC was not clarified; nor was the outcome of incidentally detected small renal masses in long-term follow-up. However, late recurrence is known as a characteristic biological behaviour of RCC [8]. In addition, no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy [9]. In this context, we evaluated the outcomes of small, organ-confined RCC during long-term follow-up.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

We retrospectively reviewed the clinical and pathological features of 651 patients diagnosed as having RCC at our institution from 1980 to 2005. The study included only patients who were followed-up for ≥5 years when they were alive at the final visit. We analysed the parameters and outcomes of patients who were diagnosed as having small (pT1a), organ-confined RCC. All patients received routine blood tests, a chest X-ray and CT preoperatively. Bone scintigraphy was done if the clinical symptoms suggested bone metastasis. We routinely perform chest CT and abdominal ultrasonography or CT at least annually for detecting metastatic disease postoperatively.

Pathological staging was determined according to the 2009 TNM staging system: a ≤4 cm carcinoma confined to the renal parenchyma is classified as pT1a. According to previous reports [10], the histological type and nuclear grade were assigned. Microvascular invasion (MVI) was assessed routinely at pathological diagnosis. All pathology slides were re-reviewed by a single experienced pathologist. Elastica van Gieson staining was used depending on the pathologist's decision.

The survival intervals were defined as the time elapsed from surgery to the last clinical evaluation or the patient's death. The survival curves were estimated using the Kaplan–Meier method. Patients who were alive or who died from other causes than RCC were censored. The log-rank test was used for comparison of the survival curves. Prognostic factors were assessed using the Cox proportional hazards models. All values were considered to be statistically significant at P < 0.05. The study was approved by the Institutional Review Board in our university (No 23-89, 20-October-2011).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Pathological T1aN0M0 RCCs were found in 172 of the 651 patients. The median (range) tumour size was 2.8 (1.2–4.0) cm. All patients treated with partial or radical nephrectomy had negative surgical margins. Table 1 shows the characteristics of pT1aN0M0 patients. One patient with sarcomatoid component with clear cell carcinoma was found in surgical specimens of the 172 patients. During a median (range) follow-up of 104.5 (8–308) months, 18 patients (10.5%) developed progression and eight patients (4.7%) died from cancer. The chances of subsequent progressive disease at 10 and 15 years were 10.5% and 17.2%, respectively (Fig. 1). However, Kaplan–Meier curves showed high cancer-specific survival (CSS) rates of 95.5% and 93.1% at 10 and 15 years, respectively (Fig. 2). Table 2 shows the details of cases with recurrence. Pathological evaluation revealed that 14 of the 172 patients had MVI. Among those with MVI, four subsequently had progression and died from the disease. Of the 158 patients without MVI, only 12 (7.6%) subsequently developed recurrence. Among them, four (2.5%) died from the disease. Kaplan–Meier curves revealed higher CSS in patients without MVI (P < 0.001, log-rank test). The 10-year CSS rates were 85.1% and 96.5% in patients with and without MVI, respectively (Fig. 3). Multivariate analysis suggested that MVI was the only statistically significant prognostic factor for CSS (Table 3, P = 0.006, Cox proportional hazards analysis).

figure

Figure 1. Kaplan–Meier analysis of recurrence-free survival.

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figure

Figure 2. Kaplan–Meier analysis of CSS.

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figure

Figure 3. Kaplan–Meier CSS curves in patients with or without MVI.

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Table 1. Characteristics of patients with pT1aN0M0 disease.
CharacteristicVlaue
Number of patients172
Median (range) follow-up, months104.5 (8–308)
Gender: n (%) 
Male133 (77.3
Female39 (22.7)
Median (range) age, years60 (23–82)
Side, n (%): 
Right90 (52.3)
Left82 (47.7)
Surgery, n (%): 
Partial nephrectomy65 (37.8)
Radical nephrectomy107 (62.2)
Median (range) tumour size, cm2.8 (1.2–4.0)
Histological type, n (%): 
Clear cell151 (87.8)
Non clear cell21 (12.2)
Papillary10
Chromophobe8
Xp11.2 translocation2
Multilocular1
Nuclear grade, n (%): 
G151 (29.7)
G2107 (62.2)
G314 (8.1)
MVI, n (%): 
Negative158 (91.9)
Positive14 (8.1)
Patients with recurrence, n (%)18 (10.5)
Patients with RCC death, n (%)8 (4.7)
Median (range) time to recurrence, months59 (5–199)
Table 2. Clinical and pathological background of patients having recurrence.
Pts.Age, yearsHistological type/MVIGradeRecurrence sitesYears to recurrenceTreatment for recurrenceYears after recurrenceOutcome
  1. Clear, Clear cell type; Pap., papillary type; Sarc., sarcomatoid component; neg., negative; pos., positive; Grade, nuclear grade; Perito., peritoneum; IFN, interferon; IVR, interventional radiology; NED, no evidence of disease.

 #144Clear/neg.G1Lung7.0IFN+surgery5.9Alive, NED
 #274Clear/neg.G2Lung7.0Surgery6.5Alive, NED
 #353Clear/neg.G2Lung16.6Surgery9.1Alive, NED
 #445Clear/neg.G2Kidney12.1Surgery3.0Alive, NED
 #559Clear/pos.G2Skin3.9IFN+surgery12.7Alive, NED
 #650Clear/neg.G1Kidney4.0Surgery1.8Alive, NED
 #771Clear/neg.G1Lung13.8Surgery4.9Alive with cancer
 #853Clear/pos.G2Lung0.4IFN7.5Alive with cancer
 #944Clear/neg.G2Liver3.5None3.8Alive with cancer
#1059Clear/neg.G2Lung12.6IFN+surgery2.4Alive with cancer
#1174Clear/neg.G2Adrenal5.8Surgery2.3Cancer death
#1247Clear/pos.G2Kidney10.0None6.3Cancer death
#1365Clear/pos.G2Perito.8.3None5.0Cancer death
#1466Pap./neg.G2Liver1.3IVR5.3Cancer death
#1558Pap./neg.G2Lung1.4Surgery1.0Cancer death
#1658Clear/neg.G2Brain3.8IFN1.1Cancer death
#1760Clear/pos.G1Lung1.3None2.9Cancer death
#1861Clear (Sarc.)/posG3Local0.6IFN1.8Cancer death
Table 3. Association between clinical or pathological factors and CSS determined by multivariate Cox proportional hazard regression analysis.
FactorsHazard ratio (95%CI)P
MVI (negative vs positive)8.191 (1.808–37.098)0.006
Interferon (α vs β, and γ)1.855 (0.425–8.102)0.411
Histology clear cell vs non clear cell carcinoma)1.558 (0.244–9.932)0.639
Grade (1 vs 2 and 3)1.454 (0.148–14.316)0.748
Tumour size (<2.8 vs ≥2.8 cm)0.985 (0.214–4.543)0.984

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

The recent widespread use of routine abdominal imaging often leads to the detection of incidental, small solid renal tumours. Most of these tumours are subsequently identified as RCC by histological examination. Indeed, they have favourable pathological characteristics and prognoses [11, 12]. However, even small, organ-confined RCC has heterogeneous biology. It is possible for this type of RCC to recur during follow-up, and it is well known that late recurrence is a characteristic biological behaviour of RCC [8]. Therefore, long-term follow up data are necessary to clarify the natural history of small, organ-confined RCC. In this context, the present study provides very valuable data with a median (range) follow-up of 104.5 (8–308) months.

It would be clinically relevant if specific clinical or pathological parameters could predict the long-term prognosis of small, organ-confined RCC. A recent study [7] reported a nomogram that estimated risk within 5 years from diagnosis of RCC. However, the study was not intended for estimation of the long-term risk of death. In the present study, we found that cancer recurrence and death occurred even in patients with small, organ-confined RCC after 10 years of follow-up.

Many factors have been reported to have close associations with overall and progression-free survivals of patients with RCC with metastatic disease and in those of all stages [13]. Some reports suggested that MVI was one of the relevant prognostic factors for RCC [14-18]. Kroeger et al. [17] investigated 475 patients with RCC with MVI and proved it to be an independent risk factor for metastatic disease. On the other hand, they were not able to show the independent predictive value of MVI for CSS. In their report, the median follow-up period was 22.4 months. Thus, the short-term follow-up may have been partly related to the negative relationship between MVI and CSS. Lang et al. [18] reported a positive correlation between MVI and CSS in long-term follow-up (median 183 months). Although their follow-up period was long and the number of patients large (255 patients), they included all patients with pT1 to pT3bN0M0, and the results for pT1a was not indicated. The present study suggested higher CSS in patients with pT1a RCC without MVI in long-term follow-up. This result clearly indicated that MVI was a significant predictor for CSS in patients with pT1a disease that was surgically resected. However, even in patients with pT1a RCC without MVI, late recurrence can occur in long-term follow-up, suggesting that other factors involved in recurrence have to be identified (Table 2).

Haematogenous spread of RCC is the pivotal mechanism for development of distant metastasis. In all, 10 of the 18 patients with recurrence remain alive. Of these 10, six underwent metastasectomy and are currently cancer free (Table 2). Early detection of recurrent disease may provide a chance for disease control with surgical treatment. Therefore, careful follow-up is necessary for patients with RCC with MVI even though the disease is small and organ-confined. Although there is no consensus on surveillance for small and organ-confined RCC later than 5 years postoperatively, the present data suggest that long-term follow-up may be needed for possible cancer recurrence and death. Indeed, late recurrence of RCC after the initial treatment is not rare, which indicates that lifelong follow-up may be mandatory [19].

The development of molecular-targeted therapy has changed the therapeutic approaches for treatment of metastatic RCC [20, 21]. The present study included data from before the development of targeted therapy. Therefore, we have no information on patients with small, organ-confined RCC who received molecular-targeted therapy. In the future, we need to evaluate the therapeutic outcome of recurrent disease treated with targeted agents.

The present study has some limitations. The study contained retrospective data and was a single institution experience. To fully clarify the natural history and biological characteristics of small, organ-confined RCC, we need a large-scale multicentre prospective study with long-term follow up.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References