Discussion
Among undifferentiated cancers with abundant lymphocyte infiltration, those derived from the head and neck region are called lymphoepithelioma3. Undifferentiated cancers with abundant lymphocyte infiltration in organs other than the head and neck are called lymphoepithelioma-like carcinomas (LELC), and in the WHO classification 4th edition, LELC in the liver were classified as lymphoepithelioma-like hepatocellular carcinomas (LEL-HCC)1. However, in the 2019 revision of the WHO classification, HCC with abundant lymphocyte infiltration was included in the classification of ”hepatocellular carcinoma, lymphocyte-rich” regardless of the degree of differentiation2. The frequency of lymphocyte-rich HCC among all HCC cases is less than 1%, and it is reported that its prognosis is better than that of classical HCC2,4. Most cases of LELC in other organs are associated with Epstein-Barr virus (EBV)5 Infection, but most cases of HCC, lymphocyte-rich are negative for EBV6. We searched PubMed for articles from 1995 to 2019 using the keywords ”lymphoepithelioma-like hepatocellular carcinoma” or ”hepatocellular carcinoma lymphocyte rich”. As a result, there were 58 cases corresponding to poorly differentiated HCC, lymphocyte-rich (Table 27-24). We examined a total of 59 cases including the current case. The median age was 60 years; 27 cases were hepatitis B virus (HBV) positive and 18 were hepatitis C virus (HCV) positive. EBV was negative in all but 1 case. Although there are few reports on the proportion of infiltrating lymphocyte types, there are many cases in which both CD4-positive cells, including regulatory T cells, and CD8-positive cells, considered to be cytotoxic T lymphocytes (CTLs), were present to the same extent. In this case as well, CD4 and CD8 were equally positive. FoxP3 was positive in some of the CD4-positive cells, indicating the presence of regulatory T cells.
In the IMbrave150 trial, the combination of the immune checkpoint inhibitor (ICI) atezolizumab and the angiogenesis inhibitor bevacizumab for unresectable HCC significantly prolonged overall survival compared with sorafenib. As a result, this combination therapy has come to be used clinically for unresectable HCC. The response rate for this treatment in unresectable HCC is 27.3%25, which is a good result, but it is still necessary to identify biomarkers for predicting the effect of ICIs in terms of pharmacoeconomics and personalized medicine. In addition, Chan et al. reported that there are many mutations in the Wnt pathway, including CTNNB1, in normal HCC, as well many mutations in CCND1 in LEL-HCC. These findings suggest that LEL-HCC may have different tumor properties compared with normal HCC26. Therefore, we decided to histopathologically assess the ICI treatment strategy for poorly differentiated HCC, lymphocyte-rich. So far, there have been no reports of the use of ICIs in poorly differentiated HCC, lymphocyte-rich, but there have been multiple reports of cases in which ICIs were effective for LELC in other organs27, 28. In a study of 217 cases of HCC by Calderaro et al., the PD-L1 positive rate (> 1% of tumor cell-positive cases were defined as PD-L1 positive) of LEL-HCC tumor cells was 3 of 13 cases, which was not different from the positive rate of 17% for all HCC. However, the PD-L1 positive rate of surrounding inflammatory cells was significantly high (PD-L1 expression by inflammatory cells was classified as high if the number of PD-L1 positive clusters around the tumor was equal or superior to 6 [median of the full series]) in 12 of 13 cases (92%)29. In this case as well, multiple PD-L1-positive immune cell clumps were found around the tumor (Fig. 8). It is known that ICIs induces an immune response by inhibiting PD-L1 on tumor-related macrophages30, and ICIs may be effective in poorly differentiated HCC, lymphocyte-rich. In the study by Calderaro et al., the analysis of the PD-L1 positive rate of LEL-HCC and tumor cells was limited to only 13 cases. In the present case, 40% of the tumor cells were also PD-L1 positive. There are other reports7that have shown PD-L1 positivity in tumor cells and infiltrating lymphocytes of poorly differentiated HCC, lymphocyte-rich, which is consistent with our case. To better understand the tendency for PD-L1 expression in tumor cells in poorly differentiated HCC, lymphocyte-rich cases, it is necessary to accumulate more cases. Considering the aforementioned details, it is likely that poorly differentiated HCC lymphocyte-rich, which was once designated as LEL-HCC, can be expected to have a good therapeutic response to ICIs, and these findings may contribute to the stratification of HCC treatment in the future.