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.