Lymphoepithelioma-like carcinoma in liver not associated with Epstein-Barr virus: a report of 3 cases and literature review

The first patient was a 62-year-old Chinese man who was hospitalized on September 5, 2018, due to the a high AFP level was found during a routine physical examination and a liver tumor indicated by abdominal ultrasound. Laboratory examination showed the following: AFP 19.5 ng/ml (0–7 ng/ml); CEA 5.31 ng/ml (0–5 ng/ml); CA199 17.26 U/ml (0–37 U/ml). Hepatitis B examination showed that HBsAb(+), HBeAb(+), and HBcAb(+). There were no abnormality in routine blood test. Blood biochemical tests showed DBIL of 5.9 μmol/L (0–5.1 μmol/L) and IBIL of 13.70 μmol/L (0–11.97 μmol/L). A coagulation test showed a plasma D-dimer level of 0.61 mg/L FEU (0–0.55 mg/L FEU). Abdominal MRI suggested a liver left lateral lobe space-occupying lesion, about 3.2 × 2.5 cm (Fig. 2a, b). According to PET-CT, there was a slightly low-density nodular shadow under the capsule of the left outer lobe of the liver, of approximately 2.8 × 2.4 cm, and the boundary was unclear. Radiation uptake was increased, and the maximum SUV was 4.0. It was regarded as a malignant lesions, and the radiation uptake of the remaining liver parenchyma was no clearly different. Multiple lymph nodes were found in the abdomen, with some increase in radioactivity uptake. The maximum SUV is 4.6; the large lymph node diameter was approximately 0.9 cm. No other extrahepatic tumor was found by imaging.

After discussion by a multidisciplinary team (MDT), we decided to perform surgery for the patient using laparoscopic left lateral lobectomy of the liver. Intraoperative findings were as follows: no ascites; no nodules in the abdominal and pelvic peritoneum; no abnormalities in the spleen, stomach, small intestine or large intestine; and no obvious expansion of the gallbladder or common bile duct. The appearance of the gallbladder was normal, and no stones or masses were found. Enlarged lymph nodes were not detected around the hepatoduodenal ligament. The liver was soft without obvious cirrhosis. The tumor was located in the left lateral lobe. It was tough and protruded from the surface of the liver. The rest of the liver was normal. Macroscopically, a 16 × 8 × 4 cm segment of the liver was resected, and a 2.8 × 2.5 × 2.5 cm gray-white hard tumor mass was present in the section. The pathologic diagnosis was lymphoepithelioma-like carcinoma (LELC); it was mainly hepatocellular carcinoma with differentiation of scattered cholangiocarcinoma, largely solid nest-like (Fig. 2c, d). The Edmondson-Steiner stage was III (poorly differentiated). The tumor was a small cancer involving the liver capsule without clear necrosis or microvascular invasion (MVI:0). There was no satellite nodule in the surrounding liver tissue and no cancer at the cutting edge of the liver. The TNM stage was T1N0M0, and the BCLC stage was A. Immunochemistry analysis showed AFP(−), Arg-1(−), CA199(−), CK18(3+), CK19(1+), CK7(1+), GPC3(3+), hepatocyte(+) and EBER ISH(−) (Fig. 2e, f, g, h). This case can be diagnosed as LELC. The operation was successful, and the patient was discharged on the 4th day after the operation. After MDT discussion, we decided to perform regular observation rather than postoperative adjuvant treatment according to the pathological diagnosis. The patient has been alive for 15 months since the surgery, and the patient’s quality of life is good.

The second patient was a 63-year-old Chinese woman who was hospitalized on January 22, 2015 due to paroxysmal right upper abdominal pain for 1 year. Hepatitis B examination showed HBsAb(+), HBeAb(+), and HBcAb(+). Laboratory examination showed the following: AFP, 1.49 ng/mL (0–7 ng/mL); CEA, 0.545 ng/mL (0–5 ng/mL); and CA199, 9.02 U/mL (0–37 U/mL). The patient was treated with aspirin after coronary stent implantation for coronary heart disease 3 years prior. The patient’s previous history of hypertension was under good control. The patient underwent hysterectomy 15 years previously for endometriosis. Abdominal MRI suggested an S7 space-occupying lesion, considering the possibility of a malignant tumor, cholangiocarcinoma or metastatic cancer, with liver lymph node metastasis and a slightly larger spleen. Due to the imaging examination of patients was from other hospitals, it is not provided here. On January 27, 2015, the patient underwent irregular resection of the right liver plus hilar lymphadenectomy. Macroscopically, a 7 × 7 × 3.5 cm segment of the liver was resected; a 3.2 × 2 × 2.2 cm gray-white hard tumor mass was found in the section. The tumor boundary was not clear, involving the hepatic capsule, and the closest distance from the base margin was 1.1 cm. There was no obvious nodular change in the surrounding liver. The pathological diagnosis was LELC, mainly hepatocellular carcinoma (Fig. 3a, b). The tumor involved the hepatic capsule, and no cancer was found at the cutting edge of the liver base. Lymphocytes had infiltrated the peripheral hepatic portal area, and no metastatic cancer was found in the lymph nodes removed. The Edmondson-Steiner stage was III (poorly differentiated). The TNM stage was T1N0M0. The BCLC stage was A. Immunochemistry analysis showed CK18(2+), CK7(−), CK19(−), Arg-1(−), CD10(−), CEA(−), hepatocyte(−), AFP(−), EBER(−), CD20(−), CD4(1+) and CD8(−) (Fig. 3c, d, e, f). This case can be diagnosed as LELC.

The patient recovered well and was discharged 1 week later. There was no obvious abnormality upon regular re-examination for more than 1 year. The patient received whole-body PET-CT f on December 26, 2016, which revealed high uptake by multiple lymph nodes in the portal space. The largest SUV was 11.0. The short diameter was approximately 2.5 cm, which was considered to be lymph node recurrence after the operation for liver cancer. After discussion by the MDT, it was considered that surgery would be difficult because of the close proximity of the tumor to blood vessels and the duodenum. It was suggested that local radiotherapy should be performed, and IMRT was performed in our hospital from February 6, 2017, to March 10, 2017. The prescription dose of the first course was 95% pGTV 6.72 Gy/3.36 Gy/2f, 95% PTV 3.6 Gy/1.8 Gy/2f; the prescription dose of the second course was pGTV 55.2 Gy/2.4 Gy/23f, 95% PTV 41.4 Gy/1.8 Gy/23f; 25 doses were completed. Simultaneous Xeloda chemotherapy taken orally twice was used on the day of radiotherapy at a dose of 1650 mg/m2/d. The patient carried out auxiliary acid suppression, mucosal protection, liver protection treatment and was discharged without incident after treatment. After 60 months of follow-up, the patient was in good condition. Disease-free survival (DFS) was 23 months.

The third patient was a 50-year-old Chinese man who was hospitalized on April 29, 2014, due to a liver tumor found during a routine physical examination. We reported this case in 2015 [9]; here, we briefly introduce the course of the disease, focusing on its postoperative treatment and follow-up. Laboratory examination showed HBsAg(+), HBeAb(+), HBcAb(+), HCV-Ab(−), HBV-DNA(−), AFP 31.93 ng/ml (0–7 ng/ml), and CA199 10.51 U/ml (0–37 U/ml). The patient had type II diabetes mellitus, and his blood sugar was well controlled at presentation. Abdominal MRI showed a 2.7 × 2.2 cm right anterior segment tumor with cirrhosis. (Fig. 4a). Multiple enlarged lymph nodes were found in the retroperitoneum, with a maximum of approximately 5.2 × 3.4 cm (Fig. 4b). An enlarged lymph node was also observed behind the duodenal ligament and beside the portal vein (Fig. 4c). Abdominal ultrasound showed a hypoechoic nodule at the liver dome, of approximately 1.9 × 2 cm. A hypoechoic lymph node, of approximately 4.2 × 2.9 cm, was present 5 cm behind the peritoneum, without an obvious blood flow signal. After MDT discussion, percutaneous ultrasound-guided biopsy was recommended for the lesion and lymph node. Based on the pathology results, no cancer cells were found in the liver tumor but were present in the lymph node. PET-CT was also performed, which indicated increasing radioactive uptake, which was considered to be primary liver cancer. The patient underwent hepatectomy of the VIII segment and two enlarged lymph node resections on May 23, 2014. Microscopically, the tumor consisted of poorly differentiated hepatocellular carcinoma with lymphoid infiltration (Fig. 4d, e, f). The Edmondson-Steiner stage was III (poorly differentiated). The lymph nodes removed were infiltrated by hepatocellular cancer cells. Immunochemistry results showed AFP (1+), AE1/AE3 (2+), CK18 (2+), Arg-1(−), hepatocyte(−), CK19 (2+), CK20 (1+), CK7 (−), and EBER (−) (Fig. 4g, h, i). The pathological diagnosis was LELC. The TNM stage was T1N1M0, with BCLC stage C.

After the operation, abdominal CT showed enlarged retroperitoneal lymph nodes, which was considered recurrence. From August 4, 2014, to September 2, 2014, the patient received 3 cycles of oxaliplatin and tegio chemotherapy; from October 5, 2014, the patient received 1 cycle of paclitaxel/cisplatin chemotherapy; from October 21, 2014, to November 14, 2014, the patient received 2 cycles of paclitaxel chemotherapy; from November 28, 2014, to December 28, 2014, the patient received 3 cycles of cisplatin chemotherapy. CT re-examination after nine cycles of chemotherapy indicated that the multiple enlarged retroperitoneal lymph nodes had changed little compared with the anterior lymph nodes. Later, patient was treated with radiotherapy. The following was found for the target area: GTV - retroperitoneal lymph nodes were seen on imaging; PGTV - GTV expanded outward by 0.5 cm; CTV - GTV, hilar and retroperitoneal lymphatic drainage area; PTV - CTV plus 0.5 cm (front, back, left and right) plus 1 cm (up and down). The patient was treated with a dose of 95% of PGTV, 60.2 Gy/2.15 Gy/28F, and 95% of PTV. The radiotherapy was completed on March 5, 2015, and the patient was discharged.

However, the patient was deceased at the 24-month follow-up. The DFS for this case was 1 month, with overall survival (OS) of 24 months. This patient was previously reported by us, and we updated and integrated the information. The detailed clinical data and pathological features of the above three patients are shown in Table 1 and Table 2.

All of the above three patients were satisfied with the surgical treatment and no adverse reactions occurred.

LEL-HCC is one of the pathological classifications of LELC. To date, 67 cases of LEL-HCC have been reported, as detailed in Table 3. The available demographics of the patients and features of the tumors are displayed in Table 4. Calderaro et al [25] reported 13 cases of LEL-HCC treated with liver resection for hepatocellular carcinoma, but no relevant information was provided. According to the current literature analysis, the majority of patients with LEL-HCC are male (63%) and White, with a median age of 58 years old (37–81). Twenty-two cases were complicated with HBV infection, accounting for 41%; 19 with HCV infection, accounting for 35%; and 24 with cirrhosis, accounting for 45%. In total, 21 patients exhibited increased AFP, higher than 20 μg/l, accounting for 51%. Most cases were BCLC stage 0/A; 25% of patients showed vascular invasion but only one patient EBV infection. Most of the patients received surgical treatment, accounting for 91%, and 6 patients received liver transplantation.

Macroscopically, the tumor has good boundaries and encapsulation and is gray-white and soft to touch [9]. The median size of the tumor is 38 mm (10–130). Histologically, the cancer cells are poorly differentiated, composed of atypical cells, with prominent nuclei and nucleoli. A large number of lymphocytic infiltrates are characteristic and common in LEL-HCC, which can be used to distinguish it from typical HCC [11, 18]. Most infiltrating lymphocytes are T cells, mainly CD8+ T cells, and local CD20+ B cells are also found [18].

The diagnosis of LEL-HCC mainly depends on pathological methods. There is no specificity in the clinical manifestations and imaging examination of patients. Most patients are confirmed by pathological diagnosis and immunohistochemistry after surgical treatment.

In terms of survival and prognosis, the prognosis of LELC is better than that of typical liver cancer. According to Chan et al [24], LEL-HCC has better overall survival (5-year survival 94.1%: 63.9%; P <0.05) and progression-free survival (5-year survival 87.8%: 46.6%, P<0.05) than HCC. This research suggested that LEL-HCC is an independent prognostic factor for overall survival.

LEL-CC is one of the pathological classifications of LELC. To date, 34 cases of LEL-CC have been reported (see Table 5). The available demographics of the patients and features of the tumors are displayed in Table 4. Overall, there are fewer cases than for LEL-HCC. According to the current literature analysis, patients with LEL-CC are mainly Asian women, with 92% of patients being Asian, with a median age of 57 years (46–64). Thirteen patients had HBV infection, accounting for 39%, and 2 patients had HCV infection, accounting for 6%; 5 patients had cirrhosis, accounting for 15%. AFP was normal, and 24 patients had EBV infection, accounting for 76%. Twenty-eight patients received surgical treatment, accounting for 93%.

Macroscopically, the tumor tissue is white-brown, firm and without capsule and similar to typical ICC [10]. The median size of the tumor is 35 mm (15–120). Histologically, there are two different components in LEL-CC; LEL-CC and typical cholangiocarcinoma exist at the same time, or only LEL-CC is present, and the histological differences are in sharp contrast with LEL-HCC [40, 42]. The infiltrating lymphocytes are mainly CD3+ T cells, local CD20+ B cells and CD138+ plasma cells [10, 49].

Similar to LEL-HCC, the diagnosis of LEL-CC mainly depends on pathological methods. The clinical manifestations and imaging examination of patients are not specific. For the vast majority of patients, surgical treatment and later pathological diagnosis are performed.

In terms of prognosis and survival, LEL-CC-related data are limited. A retrospective study [46] compared 7 cases of LEL-CC with 11 cases of stage matched ICC, indicating no significant difference in DFS (5-year survival was 57.1%; 11.7%; P = 0.1) and that total survival was significantly higher than that of ICC (5-year survival was 100%; 13.2%; P = 0.003).