The main goals of a staging system for a neoplastic disease are: 1) to give patients a clear prognostic information; 2) to enable the comparison of the results of different treatments and 3) to suggest a specific treatment for a given stage of the disease.
Since the literature contains sound evidence of the validity of both the CLIP and the BCLC staging system, now revised in the AASLD guidelines, the claimed superiority of the BCLC over other similarly-validated systems, such as the CLIP, would be mostly based on the last of the above points. Whether or not either of these two systems is clearly superior, supporters of the BCLC maintain indeed that this system is the only one to link the patient's stage with a clear-cut treatment indication.
Generally speaking, the characteristics of patients recruited at a given center have an influence on the efficiency of a given staging system. Different staging systems will be more suitable, depending on where and why they are used . For instance, it is now generally accepted that the CLIP system works better for advanced HCC and the BCLC for early disease undergoing surgery and in non cirrhotics [19, 20]. Therefore, some authors go as far as to suggest that it might be useful to establish different staging systems, for patients undergoing resection or other ablative therapies, and for those undergoing palliative treatment .
For the BCLC staging system, however, the bottom line is: can we be fully confident that the proposed stage-related treatment indications are so helpful that adhering to them will give patients the best possible chances of survival?
Regarding the revised "very early"
HCC stage, our results suggest the following:
The proportion of patients with "very early" HCC is only 3% in a large series collected by primary referral centers involved in recruiting patients with non advanced disease. As this figure would probably decrease at less experienced centers, our information makes rather feeble the epidemiological relevance of this stage in clinical practice. It is doubtful whether the trend toward an earlier diagnosis of HCC observed in centers where surveillance of cirrhotics is performed would significantly modify the overall figure , given that this did not happen in our series, at least until 2004.
Survival rates in patients with "very early" HCC are satisfactory irrespective of the type of treatment. In the univariate analysis, the choice of treatment, overall, shows a borderline impact on survival. However, when patients who underwent OLTx, that should not be indicated in this stage of the disease with very few exceptions, and those who underwent BSC are disregarded, any difference disappears. In the multivariate analyses the choice of treatment has no impact on survival, even when including BSC. However, being low the number of patients with " very early " HCC we might have missed the expected difference in survival among treatment groups and prospective validation analysis is needed to define the best treatment in this subgroup of patients.
Finally, the percentage of patients treated according to the AASLD recommendations was rather small. Since this result was common to "early" HCCs, it will be commented later.
The picture is slightly different for patients with "early" disease, who account for a substantial share of HCCs. Here the survival was highest after OLTx, therapeutic procedure performed only in 2% of the patients, possibly as a result of reduced organ availability, comorbidity or advanced age. Same considerations apply also to the group of "very early " HCC. RESECTION followed in terms of efficacy, then percutaneous treatments, while survival was lowest in patients treated with TACE or BSC. Actually, patients treated with TACE were more likely to have larger tumors and Child B status, with no difference in the number of nodules, but the difference between TACE, RESECTION and percutaneous treatments remained even after correction for these two factors, in patients in Child A disease and small tumors. Nonetheless, TACE offered a prognostic advantage with respect to BSC, suggesting that it still is of some therapeutic value.
Another point much debated in the literature concerns the comparison between RESECTION and locoregional treatments. This point was not addressed directly in our study but, by comparing the results of RESECTION, RFTA and PEI, we found that the first two treatments performed better than PEI. This would be, at least in part, in line with data recently provided by prospective randomized studies, showing that RESECTION was as effective as percutaneous treatments and RFTA superior to PEI [22–25]. Our retrospective observations just confirm what above and it is worth bearing in mind, however, that RESECTION has hitherto been the treatment of choice for patients with limited disease, though these findings insinuate that recommending RESECTION in the current practice as the front-line treatment for patients with "early" (and even more for those with "very early") HCC is not so confidently supported by the literature .
The above considerations are confirmed by the result of multivariate Cox's analysis, where the type of treatment did not emerge as independent predictor of survival, implying that, in the relatively homogeneous group of patients with "early " HCC, its prognostic impact is overcome by that of other more powerful factors, e.g. age, gender, Child-Pugh class and tumor burden.
In a recent work, Wang et al analyzed a large cohort of patients to assess the impact on survival of treatment choice in the different BCLC stages . A clear-cut difference in survival with respect of the therapeutic option was found for "early" HCC patients, as well as in our study; for "very early" HCC patients the Authors reported a borderline significance for the decreasing linear trend in survival, with a distinct difference between surgery and TACE, but not between surgery and percutaneous treatments. Furthermore, as the Authors state, the analysis presents some limitations, both in the stage assignation of patients and in the choice of treatment (for instance, no patients were transplanted, and very few underwent percutaneous ablation), so that the results can not be considered as conclusive. In any case, also in their experience, the percentage of patients with "very early" HCC was negligible (3%), as in our series.
An additional point to make is that the percentage of patients with "early" disease treated according to the AASLD guidelines, albeit higher than in "very early" HCC, remained relatively small. While for " very early " HCC no survival benefit was found for patients treated according to the guidelines, in "early" HCC the difference between the two subgroups was statistically significant, but again, without being identified in the multivariate analysis as an independent predictor of survival.
Our study presents some limitations, due to the wide time interval of patients recruitment: it is well-known that in recent years diagnostic and therapeutic techniques have significantly developed, leading to a wider identification of early HCC stages and allowing more frequently the application of radical treatments. Furthermore, our data collection began before the publication of BCLC staging system, and this may have influenced our results.
Being aware of this and in order to minimize any bias, an internal validation analysis was carried out in a series of 100 consecutive "early" HCC patients, diagnosed in a more recent period: even in this case the principal data obtained in the whole patients group were basically confirmed.
Why do so few centres follow the AASLD recommendations? We can suggest three explanations:
Our series was recruited before the emanation of AASLD guidelines and, although its therapeutic algorithm had been proposed before by the Barcelona group, it was still under debate and revision. Indeed, most ITA.LI.CA clinicians followed the Italian guidelines  which had been available earlier. We tried to limit this bias selecting a more appropriate series of patients, but further validation analysis on recent years may be useful to understand how much the application of the guidelines is different from our results.
The experience matured in clinical practice could have suggested that "very early" HCC occurring in well compensated patients can be efficiently treated with different approaches. In line with our result, a recent randomized controlled trial has shown that RESECTION and PEI ensure the same survival to cirrhotic patients with one or two nodules ≤2 cm each .
Finally, the therapeutic choice concerning "early" tumors stems from the day-to-day experience gained by operators who evaluate the position and boundaries of the HCC node(s), the extent of vascularization and portal hypertension, concomitant diseases, the patient's age or will, local expertise and resources.
This may have produced the gap between theoretically ideal and real-life treatment decisions. Even though, generally speaking, guidelines should not be considered as mandatory advices, should we try harder to stick to the AASLD recommendations? Based on the outcome of this study, it is hard to say.