Editor’s Choice
Tumour thrombus consistency: a new tool to stage patients with pT3 renal cell carcinoma (RCC) with venous tumour thrombus? Despite the further refinements included in the newly released seventh edition, the pT3 substages identified by the 2010 American Joint Committee on Cancer–Union Internationale Contre le Cancer TNM classification present overlapping prognoses and include patients with heterogeneous outcomes. Novara et al. [1] showed that 5-year cancer-specific survival (CSS) for the pT3a subcategory was 75% in patients with renal vein invasion only and 32.4% in patients with concomitant renal vein and perirenal fat invasion. Similarly, CSS probability for the pT3b subcategory was 65.9% in patients with infra-diaphragmatic vena caval thrombus only and 36.5% in patients with concomitant invasion of the perirenal fat. In addition, the Mayo Clinic validation of the 2010 TNM classification showed that pT3b and pT3c disease behaved similarly to each other [2] and patients with pT3a disease and concomitant perirenal fat invasion and renal vein thrombus had a markedly lower 10-year CSS than those with level 0 renal vein thrombus alone. These results confirm that staging tumour disease according to cephalic extension of venous tumour thrombus (VTT) is controversial, as previously shown by several studies [3,4]. Is it possible that other characteristics of VTT, rather than simply the thrombus level reached in the renal vein or inferior vena cava, could have an impact on patient survival? Could other features be involved? These are probably the main unanswered questions and it is now time to search for new approaches to VTT evaluation. Bertini et al. [5], reported VTT consistency as an independent predictor of CSS and overall survival (OS) for the first time, both in the overall population of RCC patients and in patients with non-metastatic disease. The authors aimed to standardize the pathological definition of VTT consistency. Briefly, in solid VTT, tumour growth was defined as compact and cohesive, with a rounded linear profile and sometimes a partial endothelial lining simulating a pseudocapsule. In friable VTT, tumour cells were defined as intermingled with abundant necrosis and fibrin, with a scalloped, irregular profile and fragmented aspect, sometimes with thin papillary features. Finally, VTT was classified as solid when at least 90% of the samples showed solid features. The findings of Bertini et al. [5] were confirmed by Weiss et al. [6] in the present well conducted study, who used that same
182
© 2014 The Authors BJU International © 2014 BJU International
classification of VTT consistency and showed that friable VTT was an independent predictor of OS in patients without evidence of distant and nodal metastases; however, the lack of significance of VTT consistency in the overall study population might be explained by the differing percentages of metastatic disease in the current study. In addition, neither study described the exact extent of nodal or metastatic disease, so tumour burden could have been a factor influencing patient outcomes. Nevertheless, the results of the two studies suggest that friable VTT might be associated with a higher potential for tumour haematogenous spread and, in patients with clinically non-metastatic disease, could predict a higher risk of systemic progression. The most interesting finding is that thrombus level was never found to be an independent predictor of OS. This means that patients with friable VTT of the renal vein could be at higher risk of micrometastatic disease that those with a solid VTT of the inferior vena cava, irrespective of its cranial extent. In this case, solid VTT could be considered as locally advanced disease, while friable VTT could be considered as true systemic disease. The authors also showed that friable VTT has a lower level of connective tissue and cell–cell adhesion (E-cadherin) than that of solid VTT. Thus, they demonstrated for the first time, the molecular bases of the different VTT consistencies that account for increased metastatic potential and the poor prognosis of patients with friable VTT. The enhanced understanding of the biological factors responsible for the friable vs solid phenotype will be crucial in identifying potential novel targeted therapies. A limitation of this VTT consistency classification can be found in the interobserver variability resulting from the potentially subjective interpretation of the definition of this new pathological feature. Further studies are certainly needed to validate not only the prognostic impact of VTT consistency on survival but also its widespread applicability to routine pathological reports. Weiss et al. reported that there was only discordance between the two investigators who reviewed pathological slides in 10% of cases, and concluded that VTT consistency can be comfortably assessed on standard haematoxylin and eosin-stained specimens. This is consistent with the previous report [5], where 60 (35%) specimens were submitted to pathological evaluation by a
Editor’s Choice
second, independent pathologist to assess interobserver variability. The study was found to have good concordance between the two pathologists (κ = 0.78), thus supporting the reproducibility of the proposed pathological definition of VTT consistency [5]. The above-mentioned preliminary reports seem to suggest that VTT consistency could be considered for routine pathological evaluation as it has the potential to become a new tool for prognosis, staging and decision-making in this sub-group of patients with high-risk disease.
References 1
2
3
4
Conflict of Interest 5
None declared. Marco Roscigno and Luigi Filippo Da Pozzo AO Papa Giovanni XXIII, Piazza OMS 1, Bergamo, Italy e-mail: [email protected]
6
Novara G, Ficarra V, Antonelli A et al. Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? Eur Urol 2010; 58: 588–95 Kim SP, Alt AL, Weight CJ et al. Independent validation of the 2010 American Joint Committee on Cancer TNM classification for renal cell carcinoma: results from a large, single institution cohort. J Urol 2011; 185: 2035–9 Martinez-Salamanca JI, Huang WC, Millan I et al. Prognostic impact of the 2009 AICC/AJCC TNM staging system for renal cell carcinoma with venous extension. Eur Urol 2011; 59: 120–7 Bertini R, Roscigno M, Freschi M et al. The extent of tumour fat invasion affects survival in patients with renal cell carcinoma and venous tumour thrombosis. BJU Int 2010; 108: 820–4 Bertini R, Roscigno M, Freschi M et al. Impact of venous tumour thrombus consistency (solid vs friable) on cancer-specific survival in patients with renal cell carcinoma. Eur Urol 2011; 60: 358–65 Weiss VL, Braun M, Perner S et al. Prognostic significance of venous tumour thrombus consistency in patients with renal cell carcinoma (RCC). BJU Int 2014; 113: 209–17
© 2014 The Authors BJU International © 2014 BJU International
183
Tumour thrombus consistency: a new tool to stage patients with pT3 renal cell carcinoma (RCC) with venous tumour thrombus? Despite the further refinements included in the newly released seventh edition, the pT3 substages identified by the 2010 American Joint Committee on Cancer–Union Internationale Contre le Cancer TNM classification present overlapping prognoses and include patients with heterogeneous outcomes. Novara et al. [1] showed that 5-year cancer-specific survival (CSS) for the pT3a subcategory was 75% in patients with renal vein invasion only and 32.4% in patients with concomitant renal vein and perirenal fat invasion. Similarly, CSS probability for the pT3b subcategory was 65.9% in patients with infra-diaphragmatic vena caval thrombus only and 36.5% in patients with concomitant invasion of the perirenal fat. In addition, the Mayo Clinic validation of the 2010 TNM classification showed that pT3b and pT3c disease behaved similarly to each other [2] and patients with pT3a disease and concomitant perirenal fat invasion and renal vein thrombus had a markedly lower 10-year CSS than those with level 0 renal vein thrombus alone. These results confirm that staging tumour disease according to cephalic extension of venous tumour thrombus (VTT) is controversial, as previously shown by several studies [3,4]. Is it possible that other characteristics of VTT, rather than simply the thrombus level reached in the renal vein or inferior vena cava, could have an impact on patient survival? Could other features be involved? These are probably the main unanswered questions and it is now time to search for new approaches to VTT evaluation. Bertini et al. [5], reported VTT consistency as an independent predictor of CSS and overall survival (OS) for the first time, both in the overall population of RCC patients and in patients with non-metastatic disease. The authors aimed to standardize the pathological definition of VTT consistency. Briefly, in solid VTT, tumour growth was defined as compact and cohesive, with a rounded linear profile and sometimes a partial endothelial lining simulating a pseudocapsule. In friable VTT, tumour cells were defined as intermingled with abundant necrosis and fibrin, with a scalloped, irregular profile and fragmented aspect, sometimes with thin papillary features. Finally, VTT was classified as solid when at least 90% of the samples showed solid features. The findings of Bertini et al. [5] were confirmed by Weiss et al. [6] in the present well conducted study, who used that same
182
© 2014 The Authors BJU International © 2014 BJU International
classification of VTT consistency and showed that friable VTT was an independent predictor of OS in patients without evidence of distant and nodal metastases; however, the lack of significance of VTT consistency in the overall study population might be explained by the differing percentages of metastatic disease in the current study. In addition, neither study described the exact extent of nodal or metastatic disease, so tumour burden could have been a factor influencing patient outcomes. Nevertheless, the results of the two studies suggest that friable VTT might be associated with a higher potential for tumour haematogenous spread and, in patients with clinically non-metastatic disease, could predict a higher risk of systemic progression. The most interesting finding is that thrombus level was never found to be an independent predictor of OS. This means that patients with friable VTT of the renal vein could be at higher risk of micrometastatic disease that those with a solid VTT of the inferior vena cava, irrespective of its cranial extent. In this case, solid VTT could be considered as locally advanced disease, while friable VTT could be considered as true systemic disease. The authors also showed that friable VTT has a lower level of connective tissue and cell–cell adhesion (E-cadherin) than that of solid VTT. Thus, they demonstrated for the first time, the molecular bases of the different VTT consistencies that account for increased metastatic potential and the poor prognosis of patients with friable VTT. The enhanced understanding of the biological factors responsible for the friable vs solid phenotype will be crucial in identifying potential novel targeted therapies. A limitation of this VTT consistency classification can be found in the interobserver variability resulting from the potentially subjective interpretation of the definition of this new pathological feature. Further studies are certainly needed to validate not only the prognostic impact of VTT consistency on survival but also its widespread applicability to routine pathological reports. Weiss et al. reported that there was only discordance between the two investigators who reviewed pathological slides in 10% of cases, and concluded that VTT consistency can be comfortably assessed on standard haematoxylin and eosin-stained specimens. This is consistent with the previous report [5], where 60 (35%) specimens were submitted to pathological evaluation by a
Editor’s Choice
second, independent pathologist to assess interobserver variability. The study was found to have good concordance between the two pathologists (κ = 0.78), thus supporting the reproducibility of the proposed pathological definition of VTT consistency [5]. The above-mentioned preliminary reports seem to suggest that VTT consistency could be considered for routine pathological evaluation as it has the potential to become a new tool for prognosis, staging and decision-making in this sub-group of patients with high-risk disease.
References 1
2
3
4
Conflict of Interest 5
None declared. Marco Roscigno and Luigi Filippo Da Pozzo AO Papa Giovanni XXIII, Piazza OMS 1, Bergamo, Italy e-mail: [email protected]
6
Novara G, Ficarra V, Antonelli A et al. Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? Eur Urol 2010; 58: 588–95 Kim SP, Alt AL, Weight CJ et al. Independent validation of the 2010 American Joint Committee on Cancer TNM classification for renal cell carcinoma: results from a large, single institution cohort. J Urol 2011; 185: 2035–9 Martinez-Salamanca JI, Huang WC, Millan I et al. Prognostic impact of the 2009 AICC/AJCC TNM staging system for renal cell carcinoma with venous extension. Eur Urol 2011; 59: 120–7 Bertini R, Roscigno M, Freschi M et al. The extent of tumour fat invasion affects survival in patients with renal cell carcinoma and venous tumour thrombosis. BJU Int 2010; 108: 820–4 Bertini R, Roscigno M, Freschi M et al. Impact of venous tumour thrombus consistency (solid vs friable) on cancer-specific survival in patients with renal cell carcinoma. Eur Urol 2011; 60: 358–65 Weiss VL, Braun M, Perner S et al. Prognostic significance of venous tumour thrombus consistency in patients with renal cell carcinoma (RCC). BJU Int 2014; 113: 209–17
© 2014 The Authors BJU International © 2014 BJU International
183
