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

Abstract

Marginal survival benefit in the treatment of early hepatocellular carcinomaJournal of HepatologyVol. 58Issue 2PreviewEarly treatment has been recommended for hepatocellular carcinoma (HCC) due to its high cure rate. However, the reported survival benefits of treating early HCC may be affected by lead time. Full-Text PDF 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]Lederle F.A. Pocha C. Screening for liver cancer: the rush to judgment.Ann Intern Med. 2012; 156: 387-389Crossref PubMed Scopus (68) Google Scholar], it is now reasonably well accepted, and screening is now part of clinical practice [[2]Sherman M. Bruix J. Porayko M. Tran T. Screening for hepatocellular carcinoma: the rationale for the American association for the study of liver diseases recommendations.Hepatology. 2012; 56: 793-796Crossref PubMed Scopus (122) Google Scholar]. 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]Poustchi H. Farrell G.C. Strasser S.I. Lee A.U. McCaughan G.W. George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.Hepatology. 2011; 56: 1998-2004Crossref Scopus (108) Google Scholar]. 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 [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar, 6Omata M. Lesmana L. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific association for the study of the liver consensus recommendations of hepatocellular carcinoma.Hepatol Int. 2012; 4: 439-474Crossref Scopus (827) Google Scholar].However, it is well known that small HCCs can remain untreated and dormant for significant periods of time [7Barabara L. Benzi G. Gaini S. Fusconi F. Zironi G. Siringo S. et al.Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumour growth rate and patient survival.Hepatology. 1992; 16: 132-137Crossref PubMed Scopus (366) Google Scholar, 8Ebara M. Ohto M. Shinagawa T. Sugiura N. Kimura K. Matsutani S. et al.Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis.Gastroenterology. 1986; 90: 289-298PubMed Google Scholar]. Well differentiated HCCs with increased echogenicity on ultrasound have been described as having doubling times of >300 days [[7]Barabara L. Benzi G. Gaini S. Fusconi F. Zironi G. Siringo S. et al.Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumour growth rate and patient survival.Hepatology. 1992; 16: 132-137Crossref PubMed Scopus (366) Google Scholar], although small HCCs tended to have low echogenicity in a report from Japan where a number of HCCs between 1 and 2 cm in diameter did not change size over a 10–20 month period [[8]Ebara M. Ohto M. Shinagawa T. Sugiura N. Kimura K. Matsutani S. et al.Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis.Gastroenterology. 1986; 90: 289-298PubMed Google Scholar].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]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar].EASL and AASLD guidelines define the smallest HCC as simply very early stage HCC (<2 cm) [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar]. It is recommended that lesions <1 cm should be observed. If the lesion is between 1–2 cm 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 [6Omata M. Lesmana L. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific association for the study of the liver consensus recommendations of hepatocellular carcinoma.Hepatol Int. 2012; 4: 439-474Crossref Scopus (827) Google Scholar, 10Tan C.H. Low S.A. Thng C.H. APASL and AASLD consensus guidelines on imaging diagnosis of hepatocellular carcinoma: a review.Int J Hepatol. 2011; : 1-11Crossref Google Scholar]. 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 [9Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 11Kanai T. Hirohashi S. Upton M.P. Noguchi M. Kishi K. Makuuchi M. et al.Pathology of small hepatocellular carcinoma. a proposal for a new gross classification.Cancer. 1987; 60: 810-819Crossref PubMed Scopus (334) Google Scholar, 12Takayama T. Makuuchi M. Horohashi S. Sakamoto M. Mamamoto J. Shimada K. Early hepatocellular carcinoma as an entity with a high rate of surgical cure.Hepatology. 1998; 28: 1241-1246Crossref PubMed Scopus (354) Google Scholar]. There is also a recent international consensus report on the pathology of such lesions [[13]Pathological diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (608) Google Scholar]. 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 1.3 cm 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]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]). Such lesions are currently recognized in AASLD, EASL and Japanese guidelines [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar, 14Kudo M. Han K.H. Kodudo N. Cheng A.L. Choi B.I. Furuse J. et al.Liver cancer working group report.Jpn J Clin Oncol. 2010; 40: S19-S27Crossref Scopus (52) Google Scholar].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 (<2 cm 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 1.3 months (74.7 months vs. 73.4 months). 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]Tremosini S. Forner A. Boix L. Vilana R. Bianca L. Reig M. et al.Prospective validation of an immunohistochemical panel (glypican-3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma.Gut. 2012; 61: 1481-1487Crossref PubMed Scopus (121) Google Scholar]. The use of these markers is mentioned by the international pathology consensus group [[13]Pathological diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (608) Google Scholar]. 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.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. 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]Lederle F.A. Pocha C. Screening for liver cancer: the rush to judgment.Ann Intern Med. 2012; 156: 387-389Crossref PubMed Scopus (68) Google Scholar], it is now reasonably well accepted, and screening is now part of clinical practice [[2]Sherman M. Bruix J. Porayko M. Tran T. Screening for hepatocellular carcinoma: the rationale for the American association for the study of liver diseases recommendations.Hepatology. 2012; 56: 793-796Crossref PubMed Scopus (122) Google Scholar]. 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]Poustchi H. Farrell G.C. Strasser S.I. Lee A.U. McCaughan G.W. George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed?.Hepatology. 2011; 56: 1998-2004Crossref Scopus (108) Google Scholar]. 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 [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar, 6Omata M. Lesmana L. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific association for the study of the liver consensus recommendations of hepatocellular carcinoma.Hepatol Int. 2012; 4: 439-474Crossref Scopus (827) Google Scholar]. However, it is well known that small HCCs can remain untreated and dormant for significant periods of time [7Barabara L. Benzi G. Gaini S. Fusconi F. Zironi G. Siringo S. et al.Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumour growth rate and patient survival.Hepatology. 1992; 16: 132-137Crossref PubMed Scopus (366) Google Scholar, 8Ebara M. Ohto M. Shinagawa T. Sugiura N. Kimura K. Matsutani S. et al.Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis.Gastroenterology. 1986; 90: 289-298PubMed Google Scholar]. Well differentiated HCCs with increased echogenicity on ultrasound have been described as having doubling times of >300 days [[7]Barabara L. Benzi G. Gaini S. Fusconi F. Zironi G. Siringo S. et al.Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumour growth rate and patient survival.Hepatology. 1992; 16: 132-137Crossref PubMed Scopus (366) Google Scholar], although small HCCs tended to have low echogenicity in a report from Japan where a number of HCCs between 1 and 2 cm in diameter did not change size over a 10–20 month period [[8]Ebara M. Ohto M. Shinagawa T. Sugiura N. Kimura K. Matsutani S. et al.Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis.Gastroenterology. 1986; 90: 289-298PubMed Google Scholar]. 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]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. EASL and AASLD guidelines define the smallest HCC as simply very early stage HCC (<2 cm) [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar]. It is recommended that lesions <1 cm should be observed. If the lesion is between 1–2 cm 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 [6Omata M. Lesmana L. Tateishi R. Chen P.J. Lin S.M. Yoshida H. et al.Asian Pacific association for the study of the liver consensus recommendations of hepatocellular carcinoma.Hepatol Int. 2012; 4: 439-474Crossref Scopus (827) Google Scholar, 10Tan C.H. Low S.A. Thng C.H. APASL and AASLD consensus guidelines on imaging diagnosis of hepatocellular carcinoma: a review.Int J Hepatol. 2011; : 1-11Crossref Google Scholar]. 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 [9Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 11Kanai T. Hirohashi S. Upton M.P. Noguchi M. Kishi K. Makuuchi M. et al.Pathology of small hepatocellular carcinoma. a proposal for a new gross classification.Cancer. 1987; 60: 810-819Crossref PubMed Scopus (334) Google Scholar, 12Takayama T. Makuuchi M. Horohashi S. Sakamoto M. Mamamoto J. Shimada K. Early hepatocellular carcinoma as an entity with a high rate of surgical cure.Hepatology. 1998; 28: 1241-1246Crossref PubMed Scopus (354) Google Scholar]. There is also a recent international consensus report on the pathology of such lesions [[13]Pathological diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (608) Google Scholar]. 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 1.3 cm 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]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]). Such lesions are currently recognized in AASLD, EASL and Japanese guidelines [4EASL-EORTC Clinical practice guidelines; management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar, 5Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6512) Google Scholar, 14Kudo M. Han K.H. Kodudo N. Cheng A.L. Choi B.I. Furuse J. et al.Liver cancer working group report.Jpn J Clin Oncol. 2010; 40: S19-S27Crossref Scopus (52) Google Scholar]. 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 (<2 cm 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 1.3 months (74.7 months vs. 73.4 months). 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]Tremosini S. Forner A. Boix L. Vilana R. Bianca L. Reig M. et al.Prospective validation of an immunohistochemical panel (glypican-3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma.Gut. 2012; 61: 1481-1487Crossref PubMed Scopus (121) Google Scholar]. The use of these markers is mentioned by the international pathology consensus group [[13]Pathological diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.Hepatology. 2009; 49: 658-664Crossref PubMed Scopus (608) Google Scholar]. 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. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.