Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated carcinoma infiltrated by many lymphocytes and can appear in multiple tissues in the body. LEL-HCC is a rare tumor compared with LELC. In 2010, WHO (World Health Organization) confirmed the tumor as a "variant" of HCC, called lymphoepithelial-like hepatocellular carcinoma or inflammatory hepatocellular carcinoma.[10] In the past, an article reported that a patient had LEL-HCC and HCC at different locations simultaneously.[11] We reported the first patient with LEL-HCC and hepatic cyst. Due to the low invasiveness of LEL-HCC tissue, its imaging features were not as typical as traditional HCC.
To understand the characteristics of this rare disease, we reviewed 17 studies involving 57 cases of LEL-HCC patients.[11–27] The clinical characteristics of the cases in these articles are summarized in Table 1. All patients included 34 males and 23 females; the average age was 59.5 years, ranging from 37 to 81 years. Most of the cases in the reviewed sample were single lesions, with tumor diameters ranging from 10-72 mm, with an average of 37 mm. Among 57 patients, 27 patients were diagnosed with cirrhosis (43.8%). Chronic hepatitis is closely related to liver cancer, 25 cases were hepatitis B, and 8 cases were hepatitis C in the retrospective cases. The AFP of HCC patients is often higher than 400ng/ml, but the AFP of LEL-HCC patients is usually negative. The rise of AFP levels is caused by the increase in AFP release from liver cells into the blood during tumor progression. The increase in AFP is not obvious due to the suppression of carcinogenesis and the immune response of tumors in patients with LEL-HCC. In addition, most patients with LEL-HCC have no specific symptoms and are diagnosed mainly by clinical examination. There was no significant difference in the incidence of tumors between the right and the left lobe of the liver. Six patients were diagnosed with LEL-HCC after liver transplantation, and 51 patients were diagnosed with partial hepatectomy. Only 4 patients with vascular invasion showed that the LEL-HCC is not as invasive as traditional hepatocellular carcinoma. The reason may be that infiltrating lymphocytes have an inhibitory effect on the malignant behavior of cancer cells.[12]
Table 1
Clinicopathological characteristics of lymphoepithelioma-like HCC reported in the literature
Case (ref.)
|
Year
|
Age
|
Sex
|
No.of lesions
|
Site
|
Size(mm)
|
Cirrhosis
|
EBV
|
HBV
|
HCV
|
AFP (ng/ml)
|
Symptom
|
Treatment
|
Venous Invasion
|
Outcome (mo)
|
1 [12]
|
1998
|
62*
|
10M/1F
|
NR
|
NR
|
22*
|
6/11
|
-
|
-
|
+
|
194.5
|
NR
|
LR
|
1/11
|
OS:100%;
RFS:90.8% (60)
|
2 [13]
|
2000
|
54*
|
5M
|
2*
|
NR
|
34*
|
4/5
|
-
|
2/5
|
3/5
|
-
|
NR
|
LT
|
1/5
|
RFS:100% (36)
|
3 [14]
|
2004
|
39
|
F
|
1
|
NR
|
10
|
+
|
+
|
-
|
+
|
-
|
+
|
LT
|
-
|
DOD (4)
|
4 [15]
|
2007
|
56
|
M
|
1
|
R
|
30
|
+
|
-
|
-
|
+
|
-
|
-
|
LR
|
-
|
DOD (21)
|
5 [16]
|
2008
|
47
|
F
|
1
|
R
|
22
|
-
|
-
|
-
|
-
|
NR
|
+
|
LR
|
-
|
AWOD (15)
|
6 [17]
|
2009
|
57
|
M
|
2
|
R
|
27
|
+
|
-
|
+
|
-
|
17.5
|
+
|
LR
|
-
|
AWOD (60)
|
7 [18]
|
2013
|
79
|
M
|
1
|
L
|
50
|
-
|
-
|
-
|
-
|
43
|
+
|
LR
|
-
|
AWOD (20)
|
8 [19]
|
2014
|
68*
|
2M/6F
|
2:NR/6:1
|
NR
|
68*
|
-
|
-
|
-
|
-
|
6-/2+
|
NR
|
LR
|
NR
|
NR
|
9 [20]
|
2015
|
50
|
M
|
1
|
R
|
30
|
+
|
-
|
+
|
-
|
31.9
|
-
|
LR
|
-
|
AWD (6)
|
10 [21]
|
2015
|
81
|
F
|
1
|
L
|
72
|
-
|
-
|
-
|
+
|
80.5
|
-
|
LR
|
-
|
AWOD (15)
|
11 [22]
|
2015
|
57*
|
13M/7F
|
NR
|
NR
|
38*
|
8/20
|
-
|
17/20
|
-
|
7-/13+
|
NR
|
LR
|
2/20
|
OS:94.1%;
RFS:87.8% (60)
|
12 [23]
|
2015
|
42
|
F
|
1
|
L
|
46
|
-
|
-
|
-
|
-
|
56.3
|
-
|
LR
|
-
|
AWOD (8)
|
13 [24]
|
2017
|
73
|
F
|
1
|
S7
|
12
|
+
|
NR
|
+
|
NR
|
2.4
|
-
|
LR
|
-
|
AWD (60)
|
14 [25]
|
2017
|
58
|
F
|
1
|
S6
|
40
|
-
|
-
|
-
|
-
|
6852.0
|
NR
|
LR
|
-
|
AWOD (2)
|
15 [26]
|
2017
|
37
|
F
|
1
|
R
|
32
|
+
|
-
|
+
|
+
|
105.8
|
+
|
LR
|
-
|
AWOD (52)
|
16 [27]
|
2018
|
62
|
F
|
1
|
S6
|
50
|
+
|
NR
|
+
|
NR
|
394.9
|
+
|
LR
|
-
|
NR
|
17 [11]
|
2018
|
77
|
F
|
2
|
S4.S5
|
22
|
-
|
-
|
+
|
-
|
9.3
|
-
|
LR
|
-
|
AWD (28)
|
18
|
2020
|
47
|
F
|
1
|
L
|
23
|
-
|
-
|
+
|
-
|
2.8
|
-
|
LR
|
-
|
AWOD (1)
|
F, female; M, male; L, left liver; R, right liver; LR, liver resection; LT, liver transplantation; AWD, alive with disease; AWOD, alive without disease; DOD, died of disease; NR, not report; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein-Barr virus; AFP, Alpha-fetoprotein; ∗ Indicated as mean value.
Epstein-Barr virus (EBV) is a member of the genus Lymphotropic Virus of the Herpesviridae family, and most adults have viral antibodies. Previous studies have shown that the EBV virus is closely related to nasopharyngeal carcinoma and Burkitt's lymphoma. In addition, lymphoid epithelioid carcinoma in most hollow organs is also associated with the EBV virus. However, there is no direct evidence of lymphoid epithelial cancer in the liver and breast related to EBV.[28] Only one case of EBV-positive patients has been diagnosed with LEL-HCC.[14] EBV is not limited to lymphoid epithelioma-like carcinoma [29]. It plays a carcinogenic role in common epithelial carcinomas and may also play a carcinogenic role in precancerous hyperplasia and dysplasias. Almost all tissues and organs of LELC have a better prognosis than other subtypes of tumors at the same location.
The pathological features of LEL-HCC are poorly differentiated or undifferentiated, large, and atypical tumor cells; mitotic division is common. The tumor stroma is full of abundant inflammatory cells dominated by lymphocytes, similar to lymphoepithelial lesions.[30] Lymphocytes can produce specific antibodies and then combine with immunoreactive substances, such as alexin to destroy cancer cells. Our immunohistochemical analysis showed that CD3(+), CD20(+), Ki-67(+), CK(+), and CK19(+) in tumor cells. Some articles have shown that T cells are more predominant than B cells in LEL-HCC, mainly composed of CD4 and CD8.[16, 17, 26, 27] CD20+ (a B lymphocyte marker expressed on mature B cells but not on plasma cells) lymphocytes promote favorable outcomes in several human cancers, and the underlying mechanisms might include producing tumor-specific antibodies and secreting cytokines that enhance anti-tumor immunity in the local tumor environment.[31] The expression of CK and CK19 is related to the poor differentiation of HCC. Intact CKs inhibit cell aggregation and promote cell movement by anchoring specific cell membrane receptors, closely related to tumor cells' invasion and metastasis mechanism.[32] Ki67 is a nuclear antigen associated with proliferating cells. Its function is to participate in karyokinesis and is indispensable in cell proliferation. As an antigen that marks the cell proliferation state, Ki67 positive indicates that cancer cells are proliferating more actively, and the mechanism needs to be further researched. The first-line treatment of LEL-HCC is liver resection, which has been proven to achieve satisfactory results. Due to the massive infiltration of inflammatory cells in LEL-HCC, related to the body's supernormal immune response to tumors, PD1/PD-L1 targeted immunotherapy for LEL-HCC may have good prospects.[24]