Intrahepatic cholangiocarcinoma is an aggressive malignancy with a poor prognosis. While the incidence and prevalence of intrahepatic cholangiocarcinoma are on the rise with each passing decade, more attention has paid to it. Radiologic examinations are an integral part of diagnosis and prognosis assessment of intrahepatic cholangiocarcinoma. In this article, we focus on the evaluation of CT and MRI in the diagnosis and prognosis of intrahepatic cholangiocarcinoma, highlighting the role of radiology in the prognosis.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer after hepatocellular carcinoma (HCC), with a prevalence of approximately 1.2–1.5:1 in men and women . The incidence of ICC is increasing globally [2,3,4,5]. According to recent studies, it is believed that ICC may have multiple cellular origins, including intrahepatic cholangiocarcinoma cells, differentiated hepatocytes, pluripotent stem cells, bile duct trunk/progenitor cells, and peribiliary glands (PBG), particularly the intrahepatic bile duct glands [6, 7]. The occurrence of ICC was associated with multiple factors . ICC and HCC had similar risk factors that include cirrhosis, chronic hepatitis B and C, obesity, diabetes, and alcohol consumption, which suggested that the primary liver cancers had a common pathobiological pathway [8, 9]. Other risk factors associated with ICC include liver fluke, primary sclerosing cholangitis (PSC), biliary cyst, and intrahepatic cholelithiasis .
The clinical manifestations of ICC are not specific, and patients are usually asymptomatic during the early stages of the disease. However, as the disease progresses, patients might experience weight loss, abdominal discomfort, jaundice, hepatomegaly, and abdominal masses. The biliary obstruction was rarely observed in ICC . Studies have suggested that radical surgical resection was considered the best treatment option for ICC, because it improved long-term survival . However, the incidence of ICC is concealed, and the degree of malignancy is high. Thus, most patients have lost the opportunity of early operation due to most ICC patients generally present at a late stage, and this has resulted in a low surgical resection rate . Also, the postoperative recurrence of tumors requires attention. It has been reported that the postoperative recurrence of ICC was as high as 50–60% [12, 13]. Although radical surgery can achieve long-term survival of ICC patients, the 5-year overall survival (OS) rate rarely exceeded 30–35% after radical surgery, and the median overall survival was only about 28 months, according to a systematic review . Another study noted that when cases were inoperable due to the advanced stage, and the prognosis of such patients was poor as well as the median overall survival time was 11 months . Of note, the prognosis of untreated patients was abysmal, with a median survival of only 3 months . At present, when surgery was not a suitable option, radiotherapy, chemotherapy, radiofrequency ablation, and individualize treatment, had great potential to improve patient prognosis [17, 18].
ICC with poor prognosis is attracting attention. We evaluate the prognosis staging system of ICC. The TNM staging of a tumor has essential reference value for prognosis. Currently, it mainly referred to as the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition). However, most of the staging systems were obtained by data from surveying postoperation. CT and MRI have apparent advantages in evaluating tumor vascular invasion, intra- and extrahepatic metastasis . Early diagnosis and treatment are essential in improving the prognosis of patients with ICC. Thus, this review focuses on the role of CT and MRI in the evaluation of ICC prognosis and presents the underlying pathology.
Pathologic characteristics of ICC
The morphological features of ICC include nodular or agglomerate masses in the liver parenchyma, with irregular shapes, hard mass, and clear boundary within surrounding hepatic tissue, and was often accompanied by adjacent bile duct dilatation, but not all of the emergence [19, 20]. As in pathology, ICC tended to enrich fibrous hyperplasia, especially in the center of the tumor, so that the tumor could be seen as a gray-white lesion . Histopathologically, ICC was an adenocarcinoma that occurred in the bile duct and hypovascular with central fibrous stroma and coagulative necrosis, and occasionally mucus degeneration [21, 22]. Mass-forming ICC contains many tumor cells around the tumor, and the center of the tumor is mostly coagulated and necrotic tissue and different degrees of fibrous matrix, which is accompanied by sparse tumor cells [5, 23]. Apart from this, for some small ICC, the fibrous matrix differentiated well and enriched the tumor blood vessels , according to the pathological study of Kajiyama et al. , based on the degree of fibrous stromal hyperplasia, the scirrhous type with fibrous stromal content of more than 70% in ICC had a worse prognosis and higher incidence of lymphatic infiltration and nerve invasion than nonscirrhous-type ICC. The biological behavior of intrahepatic cholangiocarcinoma was highly invasive, and it was easy to form portal vein tumor thrombus and directly invade the surrounding liver parenchyma, thus forming multiple foci in the liver . Intrahepatic cholangiocarcinoma is a highly invasive form of cancer. It quickly forms portal vein tumor thrombus, which directly invades the surrounding liver parenchyma to form multiple foci in the liver. As the tumor advances, ICC invades the Gillson sheath and spreads along the portal vein and lymphatic vessels. The World Health Organization (WHO) described the diffusion along the Glisson sheath as a unique form of ICC metastasis . By understanding these pathological features, we can better understand the imaging characteristics of CT and MRI.
Radiological features of ICC
Imaging findings of ICC at unenhanced CT is non-specific, presenting the visible hypoattenuation with unclear boundaries, but the contrast-enhanced CT scan provides more valuable information for ICC. The typical manifestation of ICC in an enhanced CT scan image was usually enhancing in the form of tumor edge of the arterial phase, which exhibited centripetal enhancement over time [5, 9]. Having these typical imaging characteristics was more frequently diagnosed with ICC. A study showed that only 70% of cases had these typical characteristics of ICC . However, a small subset of ICC cases appeared similar to the enhanced form of HCC, indicating an enhancement in the arterial phase .
The features of ICC, as indicated by MRI, are like those of CT [28, 29]. The typical manifestations of tumors are axial T2-weighted images (T2WI) hyperintense and axial T1-weighted images (T1WI) hypointense. For areas with more fibrous components in the center of the mass, T2WI often exhibited low signal, which was manifested by marginal enhancement and centripetal or asymptotic enhancement on conventional MRI extracellular gadolinium contrast-enhanced scan . With the liver-specific contrast agent (Gd-EOB-DTPA) widely used in the diagnosis of liver disease, several studies have demonstrated the performance of ICC on gadoxetic acid disodium MRI. The characteristics of the extracellular contrast agent are almost the same as those of the common contrast agent. Compared to conventional MRI contrast agents, ICC may have a pseudowashout pattern in enhancement because of the uptake of hepatobiliary contrast agents by hepatocytes . Therefore, we need to be careful of the pitfalls of this enhancement pattern. Because ICC originates from intrahepatic biliary epithelial cells and the surface of the cell membrane lacks an organic anion-transport peptide carrier, most ICC cells do not take up hepatobiliary contrast agents thus show hypointense in the hepatobiliary phase [31, 32]. As the hepatobiliary contrast agent accumulates in the interstitial space of the liver, it becomes equivalent to the formation of ample extracellular space. Therefore, in the hepatobiliary phase, a mass was observed to be mixed with a low signal, which was not a uniform low signal . It may be related to the central fibrous interstitial of the tumor, which was closely associated with poor prognosis . Other significant findings include multiple tumors, capsule shrinkage, satellite nodules, and macrovascular invasions as a substantial risk factor for the poor outcome with ICC [34, 35].
Correlation between DWI and the prognosis of ICC
Diffusion-weighted imaging (DWI) can identify tissues based on cell density, and structural changes and is increasingly used in liver imaging [36,37,38]. The target sign on DWI was thought to be related to the histological components of ICC. Peripheral DWI diffusion restriction represented tumor cells and high-density blood vessels, whereas central dark areas represented tumor fibrosis and necrosis [30, 39, 40]. According to studies, 52–75% of ICCs can be characterized as specific targets sign on DWI, and diffusion was limited in high b values [30, 39, 40]. A study has shown that DWI targets can be used as an essential marker for distinguishing between ICC and HCC. In a study that was able to distinguish between small (≤ 3 cm) HCC and ICC, target signs were observed in ICC (75%) and HCC (3.1%) . In a separate study of MRI features that distinguished HCC from ICC, DWI targets were more common in ICC (52%) than HCC (3%) . The results of another study showed that the proportion of DWI targets was low, and only 15/51 (29%) showed DWI signature targets . One of the limitations was the lack of a target sign to differentiate between ICC and HCC. Therefore, the DWI target as a sign of ICC and HCC may not be applicable. Also, like in the case of ICC, small sclerosing liver cancer (≤ 3 cm) was often characterized by a liver fibrosis matrix (sclerosing liver cancer 71.4% vs. ICC 66.7%) . At present, it is unclear whether the target sign correlates with prognosis.
The apparent diffusion coefficient (ADC) was generally regarded as a marker of tumor aggressiveness, especially for HCC, ADC value can reflect the degree of tumor load [41, 42]. Higher ADC values in ICC are attributed to low tumor cellularity, necrosis, or cysts, and lower values are attributed to high tumor cellularity. However, the different contributions of tumor cellularity and fibrosis to the signal intensity of lesion DWI may further interfere with the use of ADC to characterize for ICC . Nevertheless, in a study by Lewis et al. , it was found that ADC value was negatively correlated with histopathologic tumor grade, and lower ADC value predicted poor prognosis. However, the ADC value did not reflect the degrees of histopathological fibrosis content. In another study investigating qualitative and quantitative DWI for ICCs (n = 91), the findings revealed that the percentage of intratumoral diffusion restriction might be a prognostic factor for overall survival . It could be attributed to those in whom less than one-third of the tumor showed that diffusion restriction had a more fibrous matrix in the tumor. Additionally, a previous study pointed out that patients who had 45% or more and 60% or more of the tumor volume increase in ADC above a predetermined threshold level had better survival and prognosis compared with patients who had less than 45% and less than 60% of the tumor volume increase in ADC after therapy . Similarly, the other study also concluded the same findings with this article, where the authors pointed out that patients with ICC who cannot be inoperable who underwent transarterial chemoembolization (TACE), the increase in ADC value was associated with a better prognosis . Whereas in a study of intrahepatic and hilar cholangiocarcinoma, pointed out that there was no significant difference in ADC values between intrahepatic and hilar cholangiocarcinomas. ADC values could not distinguish the biological behavior of the two tumors . ADC value measurement is susceptible to the influence of technical factors and reference organs, and its prognostic effect in ICC needs to be further verified.
Correlation between enhancement pattern and prognosis
Contrast-enhanced CT or MRI has become widely used in diagnostic as well as staging for patients with ICC. It not only contributes to finding the tumor manifestation and biliary tract dilatation but also helps to identify prognostic features of ICC.
The enhancement mode might have been associated with tumor characteristics or malignant potential . In primary liver cancer, most HCC lesions exhibit early arterial phase enhancement and fast washout, while ICC typically show slow enhancement. A few ICC lesions were demonstrated as an early enhancement on the arterial phase, and recently, more attention has been paid to study on its prognosis. Nanashima et al.  pointed out, according to the type of ICC enhancement, which was divided into hypovascular or delayed enhancement, and early enhancement in the arterial phase. The results of this study showed that early arterial enhancement indicated a low malignancy potential and a better prognosis. At the same time, further research showed that the size of ICC could be related to the enhancement mode of the arterial stage, and it was easier to observe the obvious enhancement of the arterial phase in small ICC [47, 48]. The microvessel count (MVC) of ICC, as assessed by CD34 staining has been reported to be associated with an enhancement pattern in the hepatic arterial phase (HAP), and lower vessel density indicated a worse prognosis for the tumor . Tumor MVC may provide a useful prognostic index for the survival of ICC patients after hepatectomy. Apart from that, another study also showed that tumor arterial vessel density (AVD) was an independent prognostic factor for ICC. AVD was inversely correlated with vascular invasion and lymph node metastasis . Intrahepatic cholangiocarcinoma in the background of cirrhosis may have significant enhancement of the arterial phase, and the high density of intratumoral artery and microvessel might explain the visible enhancement of ICC in cirrhosis . Two other studies also supported this idea that arterial phase enhancement was related to intravascular tumor density and better prognosis [47, 51].
Nevertheless, the studies, as mentioned above, do not reflect well available enhancement during the hepatic arterial phase. Kim et al.  proposed that patients were divided into typical (hypoattenuation) or atypical (hyperattenuation and isoattenuation) enhancement according to the presence of enhancement in the largest volume (> 50%) of the tumors during the HAP. Arterial enhancement of ICC is an independent prognostic factor for disease-free survival. Based on this, another research presented that tumors were further divided into three types: hypovascular, rim enhancement, hypervascular based on the enhancement of HAP, and the better prognosis of ICC was related to enhancement in the arterial phase . The results of Min et al.  showed that the 5-year survival rate of the diffuse hyperenhancement was significantly higher than that of the diffuse hypoenhancement or peripheral rim enhancement, and the probability of tumor necrosis and vascular invasion was less than lower. A recent study has also drawn a similar conclusion, ICC in the group showed the diffuse arterial enhancement, portal vein invasion and intrahepatic metastasis that was lower than that in the group of low arterial enhancement, and 5-year survival rate was significantly higher than the strengthening group (86% vs. 27%) . A recent study by Teraoku et al. shed light on central hypoenhancement in the HAP in patients with ICC might be associated with hypoxia-inducible factor 1 (HIF-1) upregulation .
Besides this, arterial enhancement also plays an essential role in evaluating the prognosis of unresectable tumors. Lastly, two studies have recently demonstrated that hepatic intra-arterial chemotherapy would be useful in patients with arterial enhancement and was associated with a better prognosis [56, 57]. Therefore, the arterial phase enhancement is closely associated with the prognosis. Furthermore, it is also affected by factors such as liver background and tumor size.
Among these patterns, delayed enhancement of the ICC was most common. This enhancement feature was not only different from HCC but also was conducive to assess the prognosis of the tumor [58, 59]. Previous studies have indicated that patients with a delay enhancement area larger than 2/3 had a worse prognosis than those with a smaller delay enhancement area, and preoperative examination of the delay enhancement area of the tumor was a reliable method of evaluating prognosis . Some studies have confirmed that for part of cases of ICC, the survival rate was usually lower, and was indicated by delayed enhancement, and more fibrous matrix on the central mass. The enhancement effect of hepatobiliary contrast agent may be different from that of traditional MRI contrast agent . Liver-specific MRI contrast agent can also obtain hepatobiliary phase images. In Gd-EOB-DTPA-enhanced MRI, the degree of hepatobiliary enhancement also reflected the number of fibrous stroma and may, therefore, be a prognostic factor for ICC patients [32, 33]. The ICC manifested as an intermediate or hypointense signal in the hepatobiliary phase, reflecting the unemptied contrast agent in the fibrous matrix . Therefore, the signal intensity of hepatobiliary tumors reflects the number of fibrous matrices. However, some studies suggested that the incidence of necrosis could be higher in the hepatobiliary phase because of tumor necrosis, and not intratumoral fibrosis . However, this study did not analyze the association between signal intensity in the hepatobiliary stage and prognosis of ICC. Koh et al. study resonated with the same findings as Asayama et al.  Additionally, necrosis was not included in the study to further investigate the prognosis of ICC.
The predictive role of radiomics in ICC
Radiomic was first reported by Lambin  (a Dutch scholar) in 2012. Recently, research interest in radiomics has been growing, as radiomics has shown promise in improving models for predicting patient outcomes [63,64,65]. The heterogeneity of tumors makes particularly challenging in cancer staging. Radiomics can be used to identify patients with high recurrence risk, and this could help in the administration of personalized treatment. A recent study demonstrated that a large number of malignant radiomic features could be reproducible compared to liver parenchyma features. Still, the proportion of repeatable features decreased with the increase of contrast agent injection rates and pixel resolution . It is essential for radiomics feature extraction.
Liang et al.  developed a nomogram model to predict ER of ICC by extracting MRI enhanced arterial phase image features and radiomics features of ICC patients, and combined radiology features and clinical stages to predict ICC early recurrence before surgery after partial hepatectomy. The model, which was validated by a relatively small independent validation cohort, provided a reliable predictive model for ICC patient personalization and could be used for stratification of adjuvant chemotherapy in patients at high risk of ICC recurrence. Another study of 55 patients with ICC was retrospectively analyzed CT texture feature, and it can quantify vascularisation and homogeneity of the ICC architecture for transarterial radioembolization (TARE) to provide more suitable treatment strategies .
Lymph node metastasis (LNM) is an important prognostic factor in ICC patients. In a recent study , the investigators developed a nomogram model for preoperative prediction of intrahepatic cholangiocarcinoma LNM, including eight stable radiomics features, which improved the predictive probability of LNM, especially CT. The diagnosis reported negative LNM and stratifies survival results to assist in clinical decision making. Another study also established a predictive model for LNM of cholangiocarcinoma. In the study , 177 patients with cholangiocarcinoma who were undergoing surgical resection and lymph node dissection were selected for the establishment of a predictive model that could extract imaging ensemble features from the CT portal vein. The developed model was internally validated, and high-risk lymph node metastasis was an independent preoperative predictor of disease-specific survival. Lei et al.  proposed the LNM prediction model through the performance evaluation between the developed prediction models. They showed their method was reliable to predict LNM. Recently, however, Navarro et al.  retrospective analysis of 210 patients of ICC who underwent radical surgical resection. The study considered that lymph node dissection did not substantially impact on survival in low-risk patients. Even though radiomics may improve accuracy in predicting LNM risk, it remains controversial whether all patients with lymph node status need lymph node dissection, because some patients with low-risk lymph node status do not benefit from lymph node dissection.
Most of the imaging findings are the qualitative diagnosis, and the differences between observers cannot be disregarded. The study of radiomics tends to measure the quantitative features, which is conducive to the reproducibility of the results. Although standardization of protocols and image scans continue to be a challenge for quantitative imaging analysis, artificial intelligence, and deep learning also play significant roles in the future of radiomics. As an emerging discipline, radiomics accuracy also presents limitations. First, the standard of imaging acquisition protocol, method for extracting imaging features, and acquisition of clinical data may impact the image features and results of the prediction model . Second, tumor segmentation is the most crucial part of radiomics. The standard of segmentation affects the acquisition of quantitative data . Last, the analysis methods and software of radiomics are also variable. Moreover, it has not yet been determined whether there is repeatability between different software. Also, it has no unified standard at present. Further studies are needed to confirm the prognosis of ICC as evaluated by the radiomics model.
Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with a high incidence rate that is second only to hepatocellular carcinoma. Arterial enhancement and delayed enhancement are a good reflection of the biological behavior of the tumor. Arterial enhancement pattern is a practical prognostic factor in evaluating ICC by imaging. Delayed enhancement is associated with a poorer prognosis, and DWI also plays a vital role in the assessment of ICC prognosis. Although tumor radiomics is still in the early stage of development, its noninvasive and quantitative advantages can be refined in subsequent studies to promote the development of precision medicine as well as personalized treatment.
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Grants provided by the National Natural Scientific Foundation of China (81360220) (www.nsfc.gov.cn) and Guangxi Natural Scientific Foundation (2010GXNSFA013189) (https://gxnsf.gxsti.net). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Lin, X., Liao, J. Radiographic imaging assessment of prognosis of intrahepatic cholangiocarcinoma. Chin J Acad Radiol 3, 94–101 (2020). https://doi.org/10.1007/s42058-020-00040-4
- Intrahepatic cholangiocarcinoma
- Enhancement patterns
- Magnetic resonance imaging
- Computed tomography