Improving diagnostics in patients with hepatocellular carcinoma (HCC) demands accurate evaluation of therapy response. Transarterial chemoembolization (TACE) is a possible management of unresectable intermediate-stage HCC according to Barcelona Clinic for Liver Cancer’s staging (BCLC) [1
] and has a central role as an effective treatment according to the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) guidelines [2
], being one of the first therapeutic approaches to primary unresectable HCC in several countries [3
]. A well-recognized imaging phenomenon after local therapies such as TACE and radiofrequency ablation (RFA) is a rim or ring-like enhancement at the border of the therapy, which is most prominently visualized in arterial-phase imaging in CT and MRI [4
]. This common phenomenon presumably represents reactive hyperemia at the margins of the embolized tumor. It is still unclear whether this represents a reactive phenomenon or a potential mimic of residual-tumor tissue and has also been described in association with other local therapy regimens including radiofrequency ablation (RFA) and selective internal radiation therapy (SIRT) [6
]. Depending on the type of interventional therapy, this feature should occur within few weeks, or several months for RFA [7
]. Currently, immediate post-TACE evaluation is rarely performed and therefore data with respect to direct post-TACE effects are only known from conventional digital subtraction angiography, which is known to have limited validity in determining therapeutic efficacy [10
]. Perfusion CT may offer a robust imaging technique that is less prone to artifacts and capable of detecting subtle changes in tumor vascularization and peri-tumoral liver parenchyma induced by these therapies [17
]. In comparison, multi-slice three-phase contrast-enhanced CT consists of multiple repetitive CT scans and thus illustrates the tumor vascularization represented by several arterial as well as mixed arterial–portal-venous enhancement phases that allow for accurate perfusion quantification. The use of dedicated pharmacokinetic models enables separate calculations of hepatic arterial, portal-venous liver and tumor blood supply, thereby enabling differentiation between the two with increased accuracy in detecting residual tumors, e.g., after TACE [20
]. Aided by the HCC characteristics from baseline (pre-TACE), perfusion CT might help to better understand the immediate post-TACE status.
The purpose of this study was therefore to identify the potential occurrence of increased rim enhancement very early after TACE and in mid-term follow-ups, using qualitative and quantitative perfusion-CT-image analysis to assess the role of peripheral changes as a predictor of mid-term response to TACE or as a sign of perifocal hyperemia.
2. Materials and Methods
2.1. Study Population
A total of 52 patients (65.6 ± 9.3 years, range 37–80 years, 12 female) with HCC were treated at our institution and referred to TACE therapy after the interdisciplinary consensus of a dedicated tumor board between January 2010 and December 2015. Two independent imaging modalities (contrast-enhanced CT, MRI, or ultrasound) meeting the diagnostic criteria in accordance with the EASL guideline [2
] had to be presented for the diagnosis of HCC. In five cases with inconclusive imaging, the diagnosis was proven by histology. The therapeutic regimen with the indication for TACE was approved by the local tumor board in accordance with the current EASL guideline [21
], excluding patients with severe hepatic decompensation and tumor burden > 50% of total liver tissue, macrovascular invasion, or portal-vein thrombosis.
Patients underwent PCT before, immediately (within 48 h) after TACE and at follow-up scheduled after three months (95.3 ± 12.5 days after therapy). Patients were enrolled prospectively. Informed consent from every participant was obtained and the study was approved by the local ethical committee.
Residual HCC after TACE was defined as measurable residual contrast enhancing tumor tissue. Recurrence at follow-up was defined as newly measurable tissue enhancement in the TACE region evaluated using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and the PCT results by radiologists with experience in reading oncological imaging and interventional radiology. The cases were interdisciplinarily re-evaluated for defining the following therapeutic regimen.
2.2. CT Protocol
A 128-row and a 256-row CT scanner (Somatom Definition AS+, Definition Flash, Siemens Healthcare, Forchheim, Germany) were used with an initial low-dose non-enhanced CT (60 mAs, 100 kVp, 5 mm slice thickness) to plan the perfusion study. Adaptive spiral-scanning technique with 80 kVp, 100–120 mAs, 64 × 0.6 mm collimation was used. Scan range up to 7 cm coverage with a scan time of 40 s and a resolution in time of 1.5 s per spiral dataset was used. A test bolus using 7 mL contrast agent was used for assessment of the optimal delay time before perfusion start. A dual-head pump injector (Medtron, Saarbruecken, Germany) was used for the administration of 50 mL Ultravist 370 (Bayer, Leverkusen, Germany) with a flow rate of 5 mL/s. Examinations resulted in a mean dose-length product of 478.9 mGy cm.
2.3. DCE-CT Analysis
Syngo.via body perfusion (version VB10B, Siemens Healthineers, Forchheim, Germany) was used for subsequent motion correction, noise reduction and threshold-based exclusion of bone, fat and air [22
]. A volume of interest (VOI) was drawn at the site of maximal arterial-liver perfusion of the tumors as well as at the tumor margins after TACE and apart from the tumor in the normal liver parenchyma avoiding larger vessels (Figure 1
). Residual tumor at the location of TACE or recurrent enhancement at follow-up was measured accordingly. The largest lesion was evaluated in all cases.
The following perfusion parameters were quantified: arterial-liver perfusion (ALP; mL/100 mL/min), portal-venous perfusion (PVP; mL/100 mL/min) and hepatic-perfusion index (HPI; %) using the maximum-slope model. ALP and PVP are calculated by taking the dual blood supply of the liver by the hepatic artery and portal vein into account. The time of peak splenic enhancement is used to separate the arterial- and portal-venous phase using ROIs in the portal vein and spleen. ALP is calculated by dividing the maximum arterial slope by the maximum aortic enhancement derived from the arterial time–density curve. PVP is calculated by dividing the maximum portal-venous slope by the maximum portal-vein enhancement derived from the portal-venous time–density curve. HPI represents the quotient from ALP and the sum of ALP and PVP.
All data were analyzed by three readers with 5, 9 and >20 years of experience in oncologic imaging in a consensus reading.
Catheter angiography of the hepatic and mesenteric artery was performed to evaluate liver and tumor vascular anatomy and for detection of possible arteriovenous shunts. Interventions were performed by an experienced interventional radiologist at the lowest possible radiation dose [23
]. Feeding arteries were supra-selectively catheterized with a microcatheter (2.0-French Progreat α Terumo, Europe N.V, Leuven, Belgium). DC beads loaded with Epirubicin (BTG, Langweid/Augsburg, Germany) with a diameter of 100–300 µm were used with an average dose of 26.7 mg ± 13.5, range 10–75 mg. Beads were mixed with an equal volume of non-ionic contrast medium before delivery.
2.5. Statistical Analyses
Statistics were calculated with Prism (GraphPad 8 software, La Jolla, CA, USA). All data are reported as mean ± standard deviation (SD). Normal distribution was not given in the study data (D’Agostino & Pearson omnibus normality test, p < 0.05 for all datasets) and Mann–Whitney test or Kruskal–Wallis test were used for comparisons between groups. p values were corrected for multiple tests, and values smaller than 0.025 were considered significant.
This study examined imaging findings in and around HCC treated with TACE by using PCT very early after TACE (within 48 h) and at mid-term (three months), focusing on a possible occurrence of rim enhancement in initially successfully embolized HCCs as a potential mimic of viable tumor mass or reactive hyperemia. Additionally, PCT maps were analyzed at the edges of the embolized tumor area for mid-term HCC relapse. PCT has a broad spectrum of applications, including characterization of liver lesions, especially in cirrhosis, as well as early response assessment for anti-VEGF therapy of HCC [24
]. As PCT is also suitable for assessing response to TACE, we hypothesized that this modality might also be suitable to differentiate very early responses to TACE and residual hyperemia after the intervention. In contrast to MRI and CT studies performed several weeks after intervention, we did not observe any significant rim enhancement, neither shortly after TACE nor at mid-term follow-up. The tumor-free margins of the embolization areas were found to be even less arterially supplied compared to the normal liver parenchyma. This presumably reflects the impact of local transarterial embolization on the perilesional arterial supply of normal liver parenchyma following particle dispersion or embolization of marginal tumor areas. Previous reports stated that rim enhancement following local therapy for liver tumors could be a potential mimic of a residual tumor [6
]. Guo et al. pointed at potential difficulties when assessing early response to intra-arterial therapies as related to reactive edema or granulation tissue formation [11
]. Other studies emphasize that only a smooth homogenous rim should be visual, and that any nodular aspect should raise the suspicion of viable tumor tissue [6
]. An inflammatory reaction to the thermal injury has been implicated in the transitory ring-like enhancement after RFA, whereas in SIRT patients the ring enhancement was found to correlate well with complete pathologic necrosis [12
]. Following TACE, transient hyperemia has been considered a physiologic response to embolization of liver parenchyma surrounding the tumor itself. Chung et al. found 24% ring enhancement in HCCs treated with TACE, of which 83% proved to be benign at mid-term follow-up [6
]. Their study design differed, as the follow-up CT was performed one month after TACE and the imaging technique used for perfusion assessment was a three-phase abdominal-CT protocol.
In our series, we examined the local effects of TACE within 48 h post-TACE and found no single case of ring enhancement with PCT. Moreover, we used a liver-perfusion protocol, which is expected to be more sensitive in detecting residual-tumor vascularization or reactive peritumoral hyperemia. To account for the lack of peripheral ring enhancement, we quantified the perfusion in a rim of liver parenchyma surrounding the embolization area, calculating the degree of arterial supply. Perfusion parameters knowingly differentiate between liver parenchyma and the tumor due to their different blood supply (arterial vs. portal venous) with HPI representing the percentage of arterial- to portal-venous supply in liver tissue and tumors.
Changes after interventions can be highly variable and misleading irrespective of progressive or responding disease. To address these issues, the use of standardized assessment criteria for follow-up imaging and case assessment by expert radiologists in interventional and oncological radiology is essential [31
]. In our series, 42 HCCs showed complete embolization at the end of their respective TACE sessions and the following PCT revealed no evidence of residual-tumor enhancement or reactive ring enhancement in these cases. Hence, according to our results, TACE seems to have no imminent stimulatory impact on the perfusion of surrounding liver parenchyma—at least at this early time point—thus excluding reactive hyperemia as a potential differential for a persisting viable tumor after TACE. Furthermore, classifying ring enhancement as reactive hyperemia seems misplaced as there was no increase in perilesional perfusion at any time point, also whilst accounting for physiological intra-liver fluctuations. Another possible explanation for rim enhancement could be subsequent tissue scaring at the margins of the embolization area occurring later at follow-up.
Unfortunately, immediate post-TACE results are no guarantee of a relapse-free survival. Using CECT for post-RFA evaluation, Lu et al. reported a sensitivity of CT for the depiction of viable residual-tumor tissue of only 36% [33
]. This is confirmed in recent studies from Müller et al. and Fronda et al. investigating the delayed percentage attenuation ratio from three- or four-phase CT and found this parameter helpful to determine early response [34
]. However, similar to our results, this was not predictive for mid-term recurrence in the study of Müller et al. Conversely, peripheral, nodular, highly perfused areas of incomplete embolization always indicated early relapse due to viable tumor tissue at the margins after TACE. According to our results, they exhibited similar perfusion values as the pre-TACE tumor tissue or locally relapsed HCCs. As a potential future perspective, the possibilities for post-processing features such as convolutional neural networks, the pre-processed perfusion maps may present an easier dataset for artificial networks to operate on compared to the anatomical CT datasets, potentially allowing for predictions of disease recurrence based on baseline imaging alone or additional inclusion of post-TACE images. This might be a possible future integration of the PCT protocol to further implement it in clinical routine processes as previously described for other indications [36
While PCT comes with an additional radiation burden and thus the indication must be critically validated, it has some advantages over MRI for specific cases. In addition to the use in patients with contra-indications for MRI, PCT can have advantages in cases with pronounced perihepatic ascites, where MRI artifacts can lead to improper liver signal. Compared to MRI, PCT examinations are relatively short with benefits for patients with reduced compliance and difficulties for breath hold examinations. Additionally, attempts to further reduce the PCT radiation dose are important [28
]. This might be especially relevant in attempts to implement improved surveillance programs in several countries to identify early and even very early stages of HCC [40
] to overcome the proposed limitations of ultrasound screening [41
]. The identification of multiple characteristic small lesions with PCT or MRI could thus increase the demand for TACE in unresectable situations. As the vascular architecture and blood supply of very small lesions is substantially different from larger lesions, the presence of rim enhancement might be different compared to the investigated cohort. Future investigations of these phenomena will be of increasing relevance not only for patients treated with TACE but also for SIRT, where post-interventional response assessment might be even more complex, and a tendency towards response or failure of treatment might not be reliably accessible with imaging until several months after treatment [42
Our study has some limitations. First, our cohort was small and therefore our results may not reflect the definite absence of a rim-enhancement phenomenon with PCT at the chosen time points. Second, the measured absolute values at the edges of tumor-embolization areas might have been influenced to some minor degree by partial volume averaging of the normal liver tissue or even the necrosis core despite robust motion-correction algorithms. Third, a possible limitation might be the fact that in this cohort, 21/42 patients showed recurrent enhancement at interim follow-up, which is suggestive of a residual or recurrent tumor. Despite this number, we still did not encounter cases of rim enhancement and unfortunately, this is not uncommon among TACE patients after the first treatment.