Wednesday, January 16, 2013

Early hepatocellular carcinoma – Is there such a thing as too early?

Early hepatocellular carcinoma – Is there such a thing as too early?

Journal of Hepatology
Volume 58, Issue 2 , Pages 210-211, February 2013

Australian National Liver Transplant Unit, A.W. Morrow Gastroenterology and Liver Center, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Newtown, New South Wales, Australia
 
Received 28 October 2012; accepted 8 November 2012. published online 15 November 2012.
See Article, pages 306–311
 
Small hepatocellular carcinoma (HCC) is usually detected in the setting of screening in cirrhotic patients. Although the role of screening continues to be challenged [1], it is now reasonably well accepted, and screening is now part of clinical practice [2]. Indeed, it seems now impossible to do a randomized control trial to test this. We attempted this, but with proper informed consent, we found that patients do not accept randomization into a non-screened arm [3]. The aim of screening is, of course, to detect small HCC that can be treated by local resection/ablation or liver transplantation. It is generally accepted that these therapies provide the best chance of long-term survival, although recurrence and emergence of new HCCs may impact on tumor free survival [4], [5], [6].

However, it is well known that small HCCs can remain untreated and dormant for significant periods of time [7], [8]. Well differentiated HCCs with increased echogenicity on ultrasound have been described as having doubling times of >300days [7], although small HCCs tended to have low echogenicity in a report from Japan where a number of HCCs between 1 and 2cm in diameter did not change size over a 10–20month period [8].

Thus questions have always existed – how small is small? How small can you go with just observation without intervention? The manuscript by Midorikawa et al., attempts to answer these questions with interesting results and challenging conclusions [9].

EASL and AASLD guidelines define the smallest HCC as simply very early stage HCC (<2cm) [4], [5]. It is recommended that lesions <1cm should be observed. If the lesion is between 1–2cm without the characteristic findings of arterial hyper vascularity and venous or delayed phase washout on 4 phase CT scan or contrast enhanced MRI, then biopsy is recommended. APASL guidelines do not recommend biopsy but recommend a series of additional imaging techniques aimed at detection of Kupffer cell uptake [6], [10]. Once HCC is diagnosed, all 3 guidelines recommend local therapies (ablation, resection or transplantation).

Japanese investigators have studied small or early HCC for some time [9], [11], [12]. There is also a recent international consensus report on the pathology of such lesions [13]. Midorikawa et al., defined a lesion that can be called early HCC or carcinoma in situ. These lesions were non-enhancing on arterial phase imaging but hypovascular on the portal phase. Such lesions were 1.3cm in diameter on average. Biopsy features included well-differentiated HCC, hyper cellularity and the presence of portal tracts (Gilson’s triad). The abnormal cells showed stromal invasion into the intra-tumoral portal tracts and structural atypia (Supplementary Fig. 1 in [9]). Such lesions are currently recognized in AASLD, EASL and Japanese guidelines [4], [5], [14].

In the study published in this issue of the Journal, only some patients were treated (n=12) whilst 46 underwent resection. Follow-up was compared to 201 patients with “overt” HCC (<2cm lesion with characteristic imaging findings) that underwent resection. Sixteen patients with overt HCC were observed. The authors attempted to establish the difference between the benefit of resection over observation of “early” HCC and the benefit of resection over observation in patients with overt HCC. This analysis showed that the survival difference was only 1.3months (74.7months vs. 73.4months). Consequently the authors concluded that “early” HCC under their definition does not require treatment. Patients can be observed and monitored: when overt HCC is diagnosed then local treatment would be indicated.

What are we to make of all this? There are several issues with this paper. Firstly, it is not exactly clear why early HCC patients were not treated (choice and co-morbidities) and it is also not clear what they died of (although advanced HCC it is implied as the cause). Secondly, there is emerging data that the use of immunohistochemical markers (such as glypican-3, glutamine synthetase, and heat shock proteins 70) can be used to define true HCC. A combination of these markers may have a sensitivity of up to 40% and a specificity of 100%, although a recent analysis of biopsy material found little advantage compared to expert pathology review [15]. The use of these markers is mentioned by the international pathology consensus group [13]. Unfortunately the usefulness of these markers in early but not overt HCC was not investigated in the Midorikawa et al., study. Thirdly, the pathological analysis is mostly based on resected specimens. Fine needle aspiration biopsy (FNAB) was used in the non-treated patients but the findings between the FNAB specimens and the resected specimens were not analyzed nor discussed. Lastly, although all early HCC patients had well differentiated lesions −2/46 (4%) had vascular invasion – hardly early HCC/carcinoma in situ.

Additional concerns include the lack of data on patients with radiological findings of no arterial enhancement but a portal phase defect in which the biopsy could not diagnose HCC at all. The authors have not reported on this group of patients. Presumably such patients exist and had dysplastic nodules. It also appears that in this group no patients actually had histological findings of HCC not fitting the pathological definition of early HCC. Both these issues are very important in judging the clinical usefulness and utility of biopsy combined with a watch and wait approach.

Although the findings in this paper have significant caveats, they do remind us that HCC at its early or very early stages (carcinoma in situ) can growth very slowly. The concept that it can be observed until progression occurs seems provocative. It would seem that it is not unreasonable to undertake “safe” treatments (e.g., ablation) for such lesions, but more “invasive” therapies such as resection or liver transplantation appear to be best reserved for overt HCC. Such approaches are not currently standard of practice according to EASL, AASLD and APASL guidelines, but the lesions reported in the paper are in fact recognized in these guidelines. The data in this paper needs consideration and discussion when the guidelines are next revised. Personally, I think that the clinical usefulness and utility of the approach suggested by Midorikawa et al., (Fig. 1) will be limited, but discussion of this issue needs to take place.

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Conflict of interest The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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