Metastatic hepatocellular carcinoma is formed by metastases from various organs of the body to the liver. The liver is one of the most metastatic organs for malignant tumors because it receives both hepatic artery and portal vein blood supply. Studies have shown that about 25% to 50% of primary tumors can metastasize to the liver during the development of malignant tumors. Thus, early diagnosis of metastatic liver cancer is important for developing treatment plans and improving survival rate of cancer patients.
Like other diseases, the diagnosis of metastatic liver cancer needs to be established with the combination of medical history, clinical manifestations and auxiliary examination results. However, not all patients with metastatic liver cancer have a clear history of tumor and lack of specific clinical manifestations in the early stage, therefore, adjuvant examinations become the main means to improve the early diagnosis of metastatic liver cancer, and the current research status of this field will be described in this paper.
1. Imaging examination
Clinically, imaging examinations are often used to determine the presence of metastases in the liver.
1.1 Ultrasound
Conventional ultrasonography is currently recognized as the imaging method of choice for metastatic hepatocellular carcinoma. Metastatic hepatocellular carcinoma mostly appears as multiple nodules, and single lesions and diffuse type are rare. The nodules are often irregular in shape, appearing as peripheral hypoechoic or strongly echogenic or mixed echogenic type. Cluster sign can be seen, i.e. numerous small echogenic nodules clustering or fusing to form a large tumor or a central anechoic zone, i.e. a circular anechoic zone in the center of a strongly echogenic zone, which is caused by central liquefaction and necrosis of metastatic cancer.
Color Doppler provides a better method for the differential diagnosis of liver cancer by ultrasound because it can show the relationship between blood flow and the mass, and it can also show whether there is cancer thrombus formation in the portal system, understand the anatomical relationship between the mass and large blood vessels, whether there is cancer dissemination and intra-abdominal lymphatic metastasis. It is valuable for preoperative determination of treatment plan, estimation of resection possibility, selection of indications for hepatic artery embolization and postoperative monitoring of recurrence. However, color Doppler is not ideal for the blood flow display of liver tumors with deeper location, smaller size and lack of blood supply. The sonographic performance of such metastatic cancers varies, and they are often not easily distinguished from benign lesions, so conventional ultrasound has certain limitations for the qualitative diagnosis of intrahepatic lesions. However, with the advent of acoustic contrast agents and the development of low mechanical index ultrasonography, ultrasonography has gradually matured and greatly improved the accuracy of ultrasonography, and the diagnostic accuracy of focal lesions in the liver is comparable to or even surpasses that of enhanced CT and MRI [2].Hiraoka et al [3], through a study of 109 patients with gastrointestinal malignancies, pointed out that ultrasonography technique had a sensitivity, specificity and accuracy of 100%, 97.5% and 95.5%, respectively, in the detection of metastatic liver cancer, comparable to positron emission tomography/computed tomography, which was 100%, 98.7% and 93.6%, respectively.
The main shortcoming of ultrasonography is that lesions on the diaphragmatic surface of the right lobe of the liver and the hilar region are easily missed; the diagnostic accuracy and sensitivity depend largely on the experience and skill of the diagnosing physician and the sensitivity of the instrument.
1.2 CT
CT is one of the most commonly used methods to diagnose metastatic liver cancer. The accuracy of CT diagnosis mainly depends on the type of primary tumor and the scanning technique used. The accuracy of CT diagnosis depends mainly on the type of primary tumor and the scanning technique used. For lesions less than 2 cm or 1 cm in diameter, the sensitivity of delayed high-dose enhancement CT combined with CT angiography can reach 82% to 87%. The sensitivity of spiral CT scan for the detection of metastases less than 10 mm can reach 68%, and the detection rate of metastases above 10 mm can reach 98%, which is the most commonly used imaging examination for the diagnosis of metastatic liver cancer at present [4].
The CT manifestation of metastatic liver cancer varies depending on the primary cancer and the type of pathological tissue, most of them are substantial, a few are cystic, and are seen in multiple cases, and the “bull’s eye sign” and circumferential enhancement are its typical changes. In dynamic enhancement scans, depending on the metastatic carcinoma, it can be summarized as follows: (1) the tumor edge shows transient enhancement, which is more common; (2) the tumor edge shows continuous enhancement; (3) the density difference with the liver parenchyma is not large, and there is basically no enhancement effect; (4) the whole tumor shows transient enhancement, followed by low density, similar to hepatocellular carcinoma. According to statistics, calcified metastatic carcinoma accounts for about 17% of liver metastatic carcinoma, and high-density calcification in the form of dots, plaques and feathers can be seen on plain scan.
1.3 Magnetic resonance imaging (MRI)
MRI is a safe, non-invasive and important tool for liver imaging. MRI uses multiple sequences and parameters to display tumor lesions in liver tissue in multiple directions and angles, and diffusion-weighted imaging and MR spectroscopy can study metastatic liver cancer from functional and metabolic levels. In addition, the use of liver-specific contrast agents in MRI has further improved the detection rate of metastatic hepatocellular carcinoma [5].
The signal changes of liver metastases on T1WI and T2WI sequences are varied, with most T1WI showing moderately low signal and enhancing scans showing mild enhancement. It is moderately high signal on T2WI, and MRI signal intensity is heterogeneous due to changes such as necrosis, cystic changes, hemorrhage, fatty infiltration, atrophy, and calcification that often occur within the tumor. The accumulation of fatty tissue in the abdominal cavity and abdominal wall and fatty deposits in the liver in obese individuals can compromise MRI for the examination of liver disease. The application of fat suppression sequence STIR can suppress the fat component in the surrounding tissues and organs and the liver, resulting in a clearer display of the lesion, thus improving the diagnostic rate.
DWI is a new functional MRI technique sensitive to the motion of water molecules, which can indirectly reflect the important information of cellular level tissue alteration and tumor cell composition and cell membrane integrity by detecting the irregular diffusion motion of water molecules inside living tissues, which can provide important information for the early diagnosis of metastatic liver cancer and is mostly applied in combination with conventional MRI [7]. Apparent diffusion coefficient is commonly used to express the diffusion ability of in vivo water molecules detected by DWI, and the ADC values within metastatic liver cancer lesions are significantly lower than those of surrounding normal liver tissue [8]. Studies have shown that DWI can achieve 97.5%, 82% and 98% detection rate, accuracy and sensitivity, respectively, for malignant focal lesions in the liver, and 92% sensitivity for the detection of lesions below 1 cm [9]. Currently, the biggest problem with DWI assessment of liver lesions is the lack of imaging and measurement standards.
The availability of contrast agents has made MRI more widely available. liver-specific contrast agents for MRI include Gd-BOPTA, Gd-EOB-DTPA and MnDPDP. motosugi et al [10] found that the sensitivity of Gd-BOPTA-MRI examination was higher than that of enhanced CT examination in the diagnosis of patients with liver metastases from pancreatic cancer (85% vs 69%) . in a comparative study by Chung et al [6] through the application of EOB-MRI and DWI, it was pointed out that EOB-MRI examination is a more effective examination for patients with liver metastases from colorectal cancer, while DWI can provide further differential information, and the combined application of both can significantly improve the accuracy and sensitivity of metastatic liver cancer diagnosis.
1,4 PET
PET/CT is a new imaging technology combining PET and CT, which plays an increasingly important role in the diagnosis and treatment of liver cancer. Currently, the most commonly used imaging agent in PET is 18F-FDG (18F-fluorodeoxyglucose), which is used to perform metabolic imaging by using the molecular structural similarity between 18F-FDG and glucose. Tumor tissues may show high uptake of 18F-FDG due to active glucose metabolism. 18F-FDGPET has high sensitivity for liver metastases, especially for lesions that cannot be identified by CT. Studies have shown that the standardized uptake values (SUVs) of metastatic tumors in the liver are significantly higher than 2.0, whereas only some (59%) patients with primary liver cancer have SUVs greater than 2.0 and benign lesions have SUVs less than 2.0 [11].Mainenti et al [12] showed in a comparative study that PET diagnoses metastatic liver cancer patients was superior to ultrasonography, spiral CT, and MRI examinations. Kinkel et al [13] showed that the sensitivity of ultrasound, CT, MRI and PET in the diagnosis of metastatic liver cancer was 55%, 72%, 76% and 90%, respectively, and therefore PET was considered the most sensitive imaging method for the diagnosis of metastatic liver cancer. However, it should be noted that recent studies [14] have shown that adjuvant chemotherapy can significantly reduce the sensitivity of PET in detecting metastatic liver cancer by affecting the metabolic status of tumor cells, while the sensitivity of CT, MRI and ultrasound is less affected.
2. Histopathological biopsy
In recent years, pathological diagnosis, as the gold standard of tissue characterization, occupies an indispensable and important position in the diagnosis of tumor. Clinically, biopsy can be performed by percutaneous liver aspiration under ultrasound guidance. The diagnosis can be clarified by obtaining liver tissues through liver aspiration for pathological cytological testing or flow cytological testing, which is of great value for the diagnosis of liver occupying lesions with a substantial liver mass detected by imaging and negative serum AFP test, which can reduce unnecessary exploratory surgery and provide a pathological basis for clinical treatment planning. Therefore, it is an effective method with easy operation, high safety, high specimen acquisition rate, high diagnostic rate and small trauma with few complications, and it is worth promoting its application. In addition, diagnostic laparoscopy with biopsy can also be used as an effective diagnosis method for metastatic hepatocellular carcinoma, and it can be effective for small lesions as well as for treatment.
3.Other
Currently, other scholars have applied the methods of routine liver function index test [15], peripheral blood micrometastasis detection [16] and peripheral blood tumor-related gene content determination to the diagnosis of metastatic liver cancer, and preliminary research results have been achieved, but they have not been promoted to clinical application.
4. Conclusion
In conclusion, there are many auxiliary examinations for metastatic liver cancer, and each examination has its own advantages and defects. In the process of clinical application, surgeons need to weigh them with patients’ own characteristics and the treatment characteristics of their units, and selective combined application is expected to further improve the early diagnosis rate of metastatic hepatocellular carcinoma.