Non-Surgical Treatment for Hepatocellular Carcinoma: What to Expect at Follow-Up Magnetic Resonance Imaging—A Pictorial Review

Abstract

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, represents a significant global health challenge due to its rising incidence, complex management, as well as recurrence rates of up to 70% or more. Early and accurate imaging diagnosis, through modalities such as ultrasound, CT, and MRI, is crucial for effective treatment. Minimally invasive therapies, including thermal ablation methods such as radiofrequency ablation, microwave ablation, laser ablation, high-intensity focused ultrasound, and cryoablation, as well as non-thermal methods like percutaneous ethanol injection and irreversible electroporation, have shown promise in treating early and intermediate stages of HCC. Some studies have reported complete response in more than 90% of nodules and survival rates of up to 60–85% at 5 years after the procedure. These therapies are increasingly employed and induce specific morphological and physiological changes in the tumor and surrounding liver tissue, which are critical to monitor for assessing treatment efficacy and detecting recurrence. This review highlights the imaging characteristics of HCC following non-surgical treatments, focusing on the common features, challenges in post-treatment evaluation, and the importance of standardized imaging protocols such as the Liver Imaging Reporting and Data System. Understanding these imaging features is essential for radiologists to accurately assess tumor viability and guide further therapeutic decisions, ultimately improving patient outcomes.

1. Introduction

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and a significant contributor to the global cancer burden [1]. With incidence rates rising in many countries and an estimated overall incidence higher than one million cases within the next three years, HCC is a major challenge for healthcare systems worldwide and an important research focus [2].

Patients with liver cirrhosis are screened for HCC with ultrasound and any suspicion of malignancy is clarified based on specific imaging features seen on Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) [3]. Due to the high specificity of imaging findings, the initial diagnosis can be set solely on imaging features without requiring liver biopsy in the majority of cases [4]. However, rare manifestations of HCC and confounding aspects of recurrence of treated HCC may prove to be diagnostic challenges, and the high recurrence rates of up to 70% at 5 years after treatment increase the complexity of the case management [5,6,7,8]. Currently, practice guidelines from various scientific and professional groups are available to assist the radiologist in improving the diagnosis rate and staging accuracy and are updated every few years, with new recommendations made available in 2024 [9,10,11].

The Liver Imaging Reporting and Data System (LI-RADS) is designed to standardize image reporting of HCC nodules, and the 2018 version includes a section on reporting treated HCC, named LI-RADS treatment response (LR-TR) [12]. This includes definitions and precise instructions for size and enhancement measurements of the nodules and the tumor viable tissue, if present. However, the minimally invasive treatment can induce local morphological changes specific to the method, that may represent a challenge for the radiologist in correctly assessing tumor tissue viability.

In terms of HCC management, the Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy is one of the most commonly referred to guides for clinical practice and therapeutic decision-making [13]. As per the 2022 BCLC strategy, minimally invasive treatment is recommended for intermediate-stage patients as well as some early-stage cases. There are multiple therapeutic options classified as minimally invasive, each with specific indications and recommendations [14]. Patients undergoing these treatments will be routinely monitored for tumor viability and recurrence, and since local therapies can induce morphological changes to the adjacent tissues, correctly identifying viability may prove challenging [15].

The purpose of this review is to highlight the most common imaging features of HCC nodules after minimally invasive procedures and to draw attention to critical aspects that may require additional diagnostics steps or close surveillance.

2. Minimally Invasive Therapies for HCC and Their Tissular Effects

A large variety of therapeutic choices are available for HCC patients and selection of the optimal course is usually conducted according to BCLC criteria and patient liver function and concurring health issues [16]. Thermal and non-thermal ablation may be used with curative intent for patients in the very early and early stages of HCC, while patients with intermediate disease may benefit from transcatheter arterial chemoembolization (TACE) [16,17]. Surgical resection, liver transplantation, and molecular therapies, among others, are options for early, intermediate, and advanced stages of the disease [18,19], but do not fall within the scope of this paper.

Regarding the minimally invasive therapies, they rely on local tumor destruction through various mechanisms. In most cases, the result of a successful procedure is obtaining an area of coagulation necrosis that includes the tumor nodule and even goes beyond it by an intended and calculated safety margin [20]. Some procedures, such as TACE, can also induce liquefactive necrosis areas within the coagulation necrosis; this occurs due to the infiltration of neutrophils, which dissolve the necrotic material but fail to completely clear it from the area and this may contribute to hindering the venous or lymphatic drainage from the treated zone [21].

As mentioned before, minimally invasive treatments cause significant changes to the tumor and surrounding areas and may produce morphological and physiopathological changes with corresponding imaging features. The remainder of this section addresses the mechanism of action and expected effects on the tumor and adjacent liver tissue.

2.1. Thermal Ablative Therapies

Thermal ablative therapies use extreme temperatures to obtain tumor destruction. A schematic representation of their mechanisms of action is presented in Figure 1.

2.1.1. Radiofrequency Ablation

Radiofrequency ablation (RFA) is commonly reserved for patients with HCC nodules smaller than 5 cm and several randomized trials have shown it to yield a 94% or higher complete response rate as well as a 54% or higher 5-year survival [22,23,24,25,26]. RFA essentially relies on tumor destruction through extreme heat obtained through high-frequency radiowaves between 460 and 480 kHz, but the range may be extended in some cases to 375–500 kHz or beyond [27]. The alternating electrical current travels through the path of least resistance and produces frictional heat (“electrical sink” effect) through ion agitation, which is focused inside the tumor nodule, inducing cellular damage [28]. When temperatures in the tissue reach 60 °C, instant coagulation of proteins and destruction of cellular components is obtained; however, exceeding 100 °C causes fluids to boil with vaporization that implies gas release in the area of ablation; this insulates the tissue and hampers the procedure [28,29]. Moreover, blood vessels can carry away the electrical current from the vicinity of the electrode, thereby decreasing the overall temperature in the region (“heat sink” effect), diminishing the effectiveness of the procedure and allowing for the possibility for some tumor cells to survive [22].

After several seconds of application, RFA induces an ellipsoid volume of coagulation necrosis in the targeted area around the electrode. Animal studies have shown that the histopathological changes induced by RFA are heterogeneous, with a central area of carbonization along the trajectory of the electrode surrounded by an area of necrosis and a peripheric hemorrhagic rim [30]. Moreover, the hemorrhagic rim appears to be surrounded by a fibrovascular halo that thickens over time [31]. There are reports that suggest that cell proliferation is stimulated within the hemorrhagic area and this mechanism could be responsible for the appearance of tumor recurrence [32]. Liver capsule retraction may be observed in the ablation of superficial tumors [33] (Figure 2).

In order to perform a successful procedure and ensure all viable tumor cells are destroyed, a tumor-free margin of at least 1 cm thickness should be obtained around the tumor nodule [28].

2.1.2. Microwave Ablation

Microwave ablation (MWA) was applied in HCC patients with tumors smaller than 5 cm, obtaining complete nodule ablation in around 90% of cases with a 3-year recurrence-free period in around 30% of cases [34,35,36]; the method was also applied in patients with tumors larger than 5 cm, with good response rates [36,37]. MWA uses electromagnetic energy transmitting microwaves into the tissues at frequencies in the range of 300 MHz to 10 GHz, commonly at 915 MHz and 2.45 GHz [22,23]. No current is transmitted through the patient as the energy is focused through dedicated antennas. The passing of the microwaves causes friction of water and nearby molecules, generating heat in the process. Particular to this method is that the heat is instantaneous and homogeneous and is produced in the entire area where microwaves are conveyed (“near field”) [23,38]. Therefore, local factors are less likely to influence the area and effectiveness of the MWA.

Studies on animal models and human liver explants have shown that MWA induces histologic changes consisting of three concentric areas: central necrosis surrounded by a thin brown capsule of cells with damaged membranes and a peripheric hemorrhagic rim [39,40]. Within the central area of necrosis, gas bubbles and cavitation may be observed due to vaporization [41]. As also observed in RFA, blood clots and endothelial injuries may be seen in small and large vessels in the ablated area [40,42]. In the following hours, the ablation area appears to expand and reaches a maximum diameter at 12 h after the procedure, a consequence of the cellular and DNA damage in the margins of the treated zone [40,43]. A fibrous capsule develops around one week after MWA and resorption in the necrosis area causes the lesion to significantly decrease in size after several weeks [43] (Figure 3).

Technological advances in the devices and antennas allowed for improved success rates in treating HCC nodules; however, since vessels with diameters up to 6–7 mm are coagulated, vessel proximity remains a challenge in applying this therapeutic method [40,44].

2.1.3. Laser Ablation

Laser ablation (LA) requires the percutaneous insertion of an array of needles into the tumor that allows the passing of optic fibers that will emit near-infrared light. The method may be used for single or multinodular HCC with sizes usually up to 5 cm and yields a response rate of up to 97% and reported overall survival rates at 3 years of up to 68% [45,46,47]. LA commonly uses an Nd-YAG (neodymium: yttrium-aluminum-garnet) laser with either a shorter wavelength of 800–980 nm or a higher-tissue penetrating 1064 nm wavelength [48]. The released infrared energy induces heat in the area around the insertion. Similarly to RFA and MWA, cell death is obtained at temperatures above 60 °C, but exceeding 100 °C induces vaporization, which hinders the effectiveness of the method. Tissue carbonization, which appears at over 300 °C, has even more significant effects in terms of limiting heat conduction [48] (Figure 4).

Literature data regarding the histological effects of laser ablation on either liver explants or animal models is scarce. However, follow-up imaging studies describe similar findings to other thermal ablative therapies such as RFA and MWA [49,50]. Ultrasound examination in the days following LA reveals a central zone of vaporization surrounded by a thin halo of carbonization and a peripheral thick rim of coagulation [45].

Coagulation necrosis is the desired effect and its volume depends on the energy delivered [51]. Incomplete or partial necrosis may be observed in a variety of cases such as tumor subtype, growth pattern, and nodule size [52,53]. Moreover, in vivo animal studies showed LA-induced heat stress-related apoptosis in HCC cells as well as hepatocytes via caspase-3/7 activation [54]. Interestingly, new information suggests that laser ablation might stimulate HCC growth due to heat stress via PI3K/mTOR/AKT signaling [55]. These data must be further analyzed and should also be sought in other thermal ablative methods.

2.1.4. High-Intensity Focused Ultrasound

High-intensity focused ultrasound (HIFU) is based on the transmission of mechanical waves emitted by piezoelectric transducers and focused through acoustic lenses; the ultrasounds are emitted at a low frequency (0.8–1.6 MHz) on a specific target [56]. Single or multi-focal HCC disease may be addressed through this method, though success rates with complete ablation are reported in 50 to 100% of cases [57,58]. Data on the improvement in survival are scarce, and studies on the application of HIFU in HCC generally yield small populations. One of the major advantages of HIFU is that it does not require puncturing the tumor [59] and the heat is quickly generated so dissipation through blood vessels is negligible [23]; however, in order to optimize the ultrasound transmission window, several invasive gestures may be applied, such as rib removal, instillation of saline solution in the pleura or peritoneal cavity, or filling the lumina of the stomach or colon [56]. Conversely, the method might prove useful in patients with advanced liver disease and ascites where other minimally invasive procedures are not indicated.

The effects of HIFU are mixed, and include both thermal and mechanical effects. Thermal effects are caused by the ultrasound energy that raises the temperature and induces coagulative necrosis. Excessive temperatures may be obtained and vaporization may also be achieved through this method [60]. The mechanical effects are represented by acoustic cavitation, a process that implies the creation of microbubbles that subsequently expand and implode, inducing extreme pressure variations that injure the adjacent cells, a process called the “popcorn effect” [60].

HIFU has been deemed safe and effective in ablating small HCC by various studies; despite this, it may face difficulties when attempting the treatment of nodules in areas of the liver that require interventions to optimize acoustic transmission [57,58,61].

2.1.5. Cryoablation

Cryoablation (CA) uses the Joule–Thomson effect to cool the area of ablation by releasing high-pressure argon gas through a cryoprobe [62]. This leads to the formation of an iceball at temperatures below −150 °C that is subsequently thawed [63]. Although cryoablation is not widely used, a randomized controlled trial has shown that 97% of HCC patients undergoing cryoablation had no tumor progression 1 year after the procedure and the overall survival rate at 5 years was 40% [64]. One of the advantages of cryoablation is that real-time observation of the ablated area may be performed through imaging methods, such as CT or US [65]. Technical success is considered when the iceball is at least 5 mm larger than the nodule in any direction [65]. However, small ablation volumes may be achieved with ease using CA in the case of small tumor nodules [66].

CA is effective through two distinct mechanisms. On the one hand, it has direct effects on tumor tissue by forming ice crystals in the intra- and extracellular space as well as an increase in osmotic pressure, causing cell destruction and irreversible damage to cell organelles [24,63]. Then, during thawing, the ice crystals converge into larger ones that further advance cellular injuries; moreover, due to osmotic pressure, water is displaced towards the intracellular space, expanding it and rupturing the cell membrane [63]. On the other hand, the indirect effects relate to the altering of blood flow towards the tumor due to damage to the endothelium of adjacent vessels. This leads to blood vessel thrombosis causing ischemia and cell death in the tributary volume of the vessel [24,46]. A “cold sink” effect was described in CA, and therefore lesions near larger blood vessels may be more difficult to treat.

Cryobiology has studied the effects of CA on living tissue and has shown that freezing triggers an anti-tumor response causing a T-cell response to the tumor [67,68]. This effect, labeled “cryoimmunology”, is a secondary advantage to using this ablative technique and the mechanisms involved are still being investigated.

2.2. Non-Thermal Ablative Therapies

Non-thermal ablative therapies rely on various mechanisms to achieve tumor destruction. An overview of the principles is presented in Figure 5.

2.2.1. Percutaneous Ethanol Injection

Percutaneous Ethanol Injection (PEI) was demonstrated to be an effective method in treating HCC nodules smaller than 3 cm in diameter, with an initial complete response of up to 96% and 5-year survival rates of up to 63% in patients with smaller tumors [69]. The injection is generally performed under local anesthesia with US guidance and is repeated in various areas of the nodule until it appears hyperechoic, due to the microbubbles in the solution [70]. Due to the lack of standardization regarding the number and location of the injections, as well as injected quantity and rate, some variance in effectiveness may be observed.

After injection, ethanol diffuses into the cells, causing dehydration and protein denaturation leading to coagulation necrosis [71] (Figure 6). The area of necrosis extends around the injection site and should be observed to reach the periphery of the nodule in order to obtain complete ablation. Repeated injections might be necessary in order to improve efficacy, and stronger substances with a higher infiltrative effect are also in use [72]. In patients with liver cirrhosis, ethanol diffuses with ease in the tumor nodule due to it being relatively soft compared to the hardened adjacent liver parenchyma [73]. Ethanol causes endothelial damage and subsequent thrombosis of the feeding vessels, leading to ischemia in the tumor nodule [74]. Animal studies have shown that necrosis can be observed on the needle track when doses higher than 0.3 mL/kg bodyweight are used; also, a fibroblastic reaction occurs in the periphery of the injected area, and may be observed after 5 to 7 days [75].

The effectiveness of PEI in causing blood vessel occlusion favored its use alongside other ablative techniques such as RFA, where the heat sink effect is diminished, therefore improving the therapeutic success [74].

2.2.2. Irreversible Electroporation

Irreversible electroporation (IRE) is a relatively new, non-thermal therapeutic method for HCC in patients with nodules that usually measure less than 3 cm. IRE is usually reserved for patients that cannot be treated with other minimally invasive methods due to the nodule depth or proximity to major vessels [76]. IRE was successful in obtaining complete ablation in over 90% of nodules and prolonging survival [77,78,79]. From a technical standpoint, the NanoKnife^® system, created by AngioDynamics, which is the widely available commercial solution, uses a direct current of low energy but with high voltage (1000–3000 V) that is generated between the inserted electrodes [80]. The 19-gauge electrodes are parallel-inserted with local anesthesia and under US or CT guidance [81].

The application of IRE causes the appearance of minuscule pores in the cellular membranes in random locations within the ablation area [82]. These pores will expand in size, increasing membrane permeability and ultimately dissolving the membrane while also triggering apoptosis. The procedure seems to be independent of blood flow, hence its application in nodules near blood vessels [82]. The area of ablation is characterized by hemorrhagic necrosis and edema, and apoptosis contributes to the extent of the cell damage [76]. Large blood vessels, bile ducts, and nerves adjacent to the ablation area appear unaffected [83]. However, minor blood vessels may demonstrate vascular congestion [84].

IRE of HCC nodules also triggers an immunological reaction; a recent study has shown that shortly after the application of IRE, an increase in immune cells such as white blood cells, monocytes, neutrophils, and natural killer cells was identified in peripheral blood; a decrease of regulatory T-cells was also noted, signifying that cytotoxic cells are favored and this immune profile might lead to tumor growth restriction [85]. Neutrophil infiltration of the treated region was detected shortly after the procedure [84].

2.2.3. Transarterial Chemoembolization

Transarterial chemoembolization (TACE) is the standard treatment for patients with BCLC stage B and is one of the most widespread and studied therapeutic options for HCC [86]. The method implies a transarterial approach to the liver nodule under fluoroscopic guidance. Conventional TACE (cTACE) uses a lipiodol drug-charged emulsion followed by an embolizing substance (Figure 7), while a separate technique uses drug-eluting beads (DEB) that release a chemotherapeutic agent over longer periods of time [87] (Figure 8). There are numerous reports of outcomes following TACE, and it appears that DEB-TACE provides a better tumor response than cTACE; the complete response, disease stability, and mortality are overall similar between the two techniques [88].

TACE induces necrosis through a combination of the cytotoxic effect of the injected drugs and the ischemia secondary to the arterial occlusion. The necrosis seems to be greater in supraselective TACE compared to lobar TACE and is directly proportional to the tumor diameter [89]. However, smaller nodules are often hypovascular, a factor negatively affecting the effectiveness of the method [89]. The obtained necrosis is coagulative and is associated with moderate liquefaction and fluid accumulation; infiltration with immune cells may appear in the periphery and areas of cystic changes may be seen after the treatment of larger nodules [90]. The presence of liquefactive necrosis may favor bacterial infection, therefore antibiotics may be required in larger tumors [91].

2.2.4. Yttrium-90 Radioembolization

Yttrium-90 (⁹⁰Y) transarterial radioembolization (TARE) is performed by injecting the microspheres (20–60 µm in diameter) loaded with the isotope through an endovascular arterial approach [92]. The feeding vessel is not occluded in comparison to cTACE and DEB-TACE; after the injection, the microspheres are taken over by the tumor tissue and emit fatal β-radiation for up to 2 weeks but with a small penetrance (smaller than 3 mm), therefore limiting the negative effects on the healthy hepatocytes [92,93,94]. ⁹⁰Y radioembolization has shown objective response rates of up to 88.3% and up to 86.6% overall survival at 3 years [95]. Moreover, ⁹⁰Y radioembolization appears to be better tolerated than cTACE and yields a longer time to progression of the disease than cTACE [96].

After TARE, the treated nodule may be stationary in size, or show either a decrease or increase in diameter; tumoral size increase usually occurs within the first month and is related to the associated edema and hemorrhage [97]. Therapeutic success is defined as the appearance of coagulative necrosis and usually occurs within the first 4 months [98]. However, transient necrotic areas with a patchy pattern may be seen early after the procedure. Also, a thin and smooth granulation tissue forms around the necrotic area and usually resolves after 4–5 months [97]. Capsular retraction may be seen in nodules closer to the liver surface and is considered a consequence of the fibrosis secondary to the radiation [97,99].

A summary of the advantages, limitations, and performance of the thermal and non-thermal ablative therapies is provided in

Table 1. Overview of the minimally invasive treatments for HCC [46,47,63,73,100,101,102,103,104,105,106,107,108,109,110,111].

Ablative Method	BCLC Stage	Advantages	Limitations	Histological (Imaging) Result	Overall Survival at 5 Years
Thermal ablative methods
RFA	0-A	Better control for larger nodules	Not recommended for superficial or near-hilum lesions Heat sink effect	Coagulation necrosis (H-iso T1, hT2)	40–68%
MWA	0-A	Higher ablation volume Minimal heat sink effect	Ablation volume may be difficult to estimate More complications in larger nodules	Coagulation necrosis (H-iso T1, hT2)	50–60%
LA	0-A	Better control for larger nodules Better accessibility to nodules	Relatively small zone of ablation, requiring multiple fibers to achieve sufficient volume	Coagulation necrosis (H-iso T1, hT2)	15–34%
HIFU	0-A	Minimal heat sink effect Less invasive	Possible damage to adjacent structures Longer procedure time	Coagulation necrosis (H-iso T1, hT2)	15–60%
CA	0-A	Less painful Area of CA visible on CT/MRI	Cryoshock syndrome is a possible complication	Coagulation necrosis (H-iso T1, hT2)	23–59%
Non-thermal ablative methods
PEI	0-A	Simple, cheap, accessible	Risk of local progression Difficulty to obtain safety margins	Coagulation necrosis (H-iso T1, hT2)	up to 47%
IRE	0-A	No heat sink effect Applicable to near-hilum lesions	Possible technical difficulty in needle positioning Cardiac gating is required	Coagulation necrosis (H-iso T1, hT2)	14–56%
cTACE	0-B	Combination of local chemotherapy and tumor devascularization	Vascular or biliary complications may occur Difficult in anatomical variants Postembolization syndrome may occur Poor response in hypovascular nodules	Coagulation and liquefactive necrosis (H- and hT1, H- and hT2)	24–54%
DEB-TACE	0-B	Superior chemotherapeutic effect Fewer adverse effects related to the chemotherapeutic drugs		Coagulation and liquefactive necrosis (H- and hT1, H- and hT2)	33–61%
TARE	0-B	Increased radiation dose with curative effect	Radiation-related hepatitis	Coagulation necrosis (H-iso T1, hT2)	up to 40%

RFA = radiofrequency ablation, MWA = microwave ablation, LA = laser ablation, HIFU = high-intensity focused ultrasound; CA = cryoablation; PEI = percutaneous ethanol injection; IRE = irreversible electroporation; cTACE = conventional transarterial chemoembolization; DEB-TACE = drug eluting beads transarterial chemoembolization; TARE = transarterial radioembolization; H = hyperintensity, iso = isointensity; h = hypointensity.

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3. Imaging in the Follow-Up of Treated HCC

3.1. Considerations on the MRI Scanning Protocol in HCC Follow-Up

Although each imaging center is free to use a protocol that makes the best use of their MRI machine and equipment, and is most useful for image interpretation, during the last years the LI-RADS recommendations have become standard and are widely applied [112,113,114]. Briefly, the guideline requires T1 in- and out-of-phase images, T2 with or without fat suppression, and 3D thin (less than 5 mm slice thickness) multiphase T1 contrast-enhanced imaging (with unenhanced, late arterial, and portal venous phase) using either gadobenate dimeglumine or gadoxetate disodium with appropriate delayed or transitional and hepatobiliary phases (at approximately 20 min after contrast injection) [12].

Regarding the choice of contrast agent, some authors showed that gadoxetate disodium has superior sensitivity in the diagnosis of HCC, while other studies cite similar lesion-to-liver contrast ratios, therefore yielding similar diagnostic powers [115,116,117,118].

Within LI-RADS, it is also suggested that diffusion-weighted imaging (DWI), subtraction imaging, and multiplanar acquisition are considered as optional images. Increasing the flip angle of the late 3D T1 fat saturated images may increase the contrast between the liver parenchyma and the tumoral lesion [119].

DWI brings a well-recognized advantage in the positive and differential diagnosis of tumors. DWI showed superior reliability compared to analysis of the hepatobiliary phase in the detection of small hypovascular HCCs located in the proximity of blood vessels [120]. Calculation of apparent diffusion coefficient (ADC) values may be useful in predicting the therapeutic response, as significantly lower ADC values were associated with poor or incomplete post-TACE tumor responses [121]. Moreover, ADC was shown to predict survival rates after TACE [122]. However, as shown in the previous sections, the treated nodule may show great inhomogeneity due to the variety of physical and biological processes induced by the treatment. Therefore, when measuring average ADC values in the treated nodule, the heterogeneous structure may influence the findings and lead to false results [123].

Subtraction imaging may be particularly useful in discriminating viable tumor tissue from other T1-WI hyperintensities within the treated nodule, such as the peripheral rim occurring after thermal ablation [124]. A high percentage of patients may show hyperintensity on the non-enhanced T1-WI within the ablation zone and subtraction of the unenhanced set of images from the arterial phase images may be crucial in the differential diagnosis [125,126].

3.2. Expected Post-Treatment Imaging Features in the Absence of Viable Tumor Tissue

Coagulative necrosis is defined as the type of cell death secondary to the decrease or complete stop of blood flow. In consequence, contrast-enhanced MRI will show no uptake. The size of the necrosis should be similar to or larger than the tumor nodule when compared to the pre-therapeutic scans. Within the ablated area, MRI depicts heterogeneous T1-WI hyperintense or isointense areas and a relatively low signal intensity on T2-WI [33]. A target appearance may be seen after thermal ablation, where a central area of T2 hyperintensity corresponding to tissue loss is surrounded by a lower T2-WI intensity and higher T1-WI hyperintense concentric area represented by the coagulation necrosis; the latter may itself be surrounded by a third area of T2-WI hyperintensity with T1-WI isointensity [30]. These target areas evolve with a signal drop in T1-WI in the coagulative necrosis area, while the third concentric area might develop contrast enhancement due to the infiltration by inflammatory cells and may grow thicker over time, while the coagulative necrosis decreases in size [30]. It is commonly accepted that these MRI features of the necrosis are similar in RFA and MWA.

After HIFU-treated HCC, it was reported that a discrepancy between the predicted ablation area and the area identified by MRI may occur, the latter being almost half of the expected size [127]. There is a paucity of studies regarding the MRI features after HIFU due to the limited application of this method.

MRI imaging features after CA are similar to findings after RFA or MWA. Generally, in the days after the procedure, the ablation zone appears hypointense in T1-WI and hyperintense in T2-WI, with heterogeneous areas represented by focal hemorrhage [128]. If large vessels are not punctured, the bleeding is small and evolves in the weeks after the procedure; it can be identified as iso- to hyperintense T1-WI foci and is usually hypointense in T2-WI [129]. The coagulation necrosis appears similar to other thermal ablative procedures; however, a significantly intense T2-WI signal could suggest fluid accumulation within the nodule [129]. A peripheral area of inflammatory response is seen after CA, evolving into fibrosis within the following months. Vascular changes may be identified around the nodule in the form of wedge-shaped areas of increased contrast uptake, which are produced by the arterial hyperperfusion secondary to portal venous flow reduction [130]. If imaging follow-up is performed at 24 h after the procedure, persistent tumor enhancement may be seen; the contrast uptake is gradual and is thought to be caused by reperfusion through injured vessels within the ablation area [131]. This is specific to cryoablation due to the mechanism of inducing the coagulative necrosis. Contrast enhancement after cryoablation within the tumor nodule may be a normal finding if the uptake is less intense and slower than in the adjacent unablated areas, and this usually resolves within the following months [132].

HCC nodules successfully treated with PEI will show iso- or hyperintensity on T1-WI and uniform hypointensity on T2-WI [71]. However, PEI-treated nodules are associated with persistent fan-shaped T2-hyperintense areas in the vicinity caused by perfusion abnormalities; this was found to be secondary to ethanol infiltration in the peritumoral normal tissues, which caused arterioportal shunts that lasted several months [133]. Additionally, ethanol-related direct toxic effects on healthy liver cells around the treated nodule were identified, causing coagulative necrosis and secondary fibrosis [134]. These T2-hyperintense areas might partly obscure the presence of viable tumor tissue, so careful analysis of these areas is recommended [135].

Imaging follow-up after successful HCC treatment with IRE may show features distinctive to those after thermal ablations. More specifically, persistent contrast enhancement may be seen in the absence of tumor tissue within the ablation zone in the peritumoral liver parenchyma [136]. This may make it difficult to properly assess the ablation area; however, the necrotic area should not present enhancement if no viable tissue is present. An animal study has shown that using IR-prepared images can help delineate a central area of IRE and a peripheral area of reversible electroporation [137]. The same study concluded that temporary contrast enhancement is possible in the IRE zone due to the formation of membrane pores that permitted the uptake of the contrast agent, as well as in the reversible electroporation zone, where the contrast persists in the intracellular space due to electrotransfer [138].

Nodules treated with ⁹⁰Y present specific MRI findings. The peripheral rim often seen around the area of necrosis due to granulation tissue developing adjacent to the coagulative necrosis can measure up to 5 mm after ⁹⁰Y; after thermal ablative techniques, a thickness of around 1 mm is expected [139]. This is considered to appear due to the effect of radiation emitted in the peripheral vessels and may be seen for up to 6 months after the procedure [140,141]. Small areas of contrast enhancement may be identified within the ⁹⁰Y treated nodule and should be monitored unless they are larger than 5 mm, when it is considered to be viable tissue [98].

3.3. Transient Hyperemia

Transient hyperemia is usually visualized as a T2-WI hyperintense rim; the rim might show contrast enhancement, and corresponds to a hemorrhagic area within the congested sinusoid vessels that surround the necrosis [30]. This may be seen in most local regional therapies due to the extension of the aggressive factor (heat, cold, radiation) beyond the treated margins (Figure 9). On DWI, this rim may appear hyperintense with corresponding hypointensity on the ADC map due to the associated cytotoxic edema [142]. Transient hyperemia usually resolves within 6 months when the agent is long-lasting, such as ⁹⁰Y microspheres, or sooner if the effects are limited to the procedure event [143,144,145].

3.4. TACE-Associated Necrosis

As previously mentioned, due to its complex therapeutic mechanisms, TACE may induce a mix of coagulative and liquefactive necrosis. Coagulative necrosis shows a typical T2-WI hypointensity. However, T2-WI focal hyperintensities may be seen when hemorrhage, inflammation, or liquefactive necrosis are associated [146]. Furthermore, after TACE, HCC nodules commonly show variable unenhanced T1-WI intensity, a combined effect of areas of hyperintense hemorrhage and hypointense necrosis [147]. The lipiodol used in cTACE also appears hyperintense on T1-WI in the days following the procedure and increases the contrast-to-noise ratio (CNR); however, it appears that T2-WI is not affected by lipiodol [148]. The extent of lipiodol uptake within the tumor nodule is considered to correlate with therapeutic success [149]. However, this is easily assessed through CT due to the composition of iodine. MRI is not an equally reliable instrument in this regard, although gradient echo images can provide good approximation [150]. Therefore, volumetric techniques have been developed for the prediction of cTACE-induced necrosis extension using MRI contrast enhancement and CT lipiodol volume measurements [151].

DWI also plays an important role in the post-therapeutic assessment of cTACE. Highly vascularized lesions will show prominent restricted diffusion with lower values on the ADC map. This will likely correlate with better results of the TACE [152]. However, necrotic tumors will likely show higher values on the ADC map, which may lead to a poorer prognosis and correlate with higher aggressiveness [153,154]. Regarding DEB-TACE, DWI proved to be useful in predicting treatment response, as increases in ADC after the procedure correlate with longer survival [155].

3.5. Post-Treatment Imaging Features of Tumor Viability

According to LI-RADS, tumor viability is defined as a nodular or thick concentric lesion that either presents contrast wash-in, wash-out, or contrast dynamics similar to pretherapeutic imaging examinations [12] However, viable tumor tissue after treatment can take on different forms (Figure 10).

However, there are several distinctive features and recurrence profiles of interest to radiologists and clinicians alike. Hypovascular recurrences can be identified after treatment and their imaging features may be different than the original more vascularized primary tumor [156]. While it is commonly accepted that hypervascularization of a recurrence is an additional risk factor and that hypervascular primary nodules are associated with a poorer prognosis, it is uncertain how to interpret and manage hypovascular recurrences, especially due to their rarity [157,158]. Another notable HCC subtype is nodule-in-nodule, which is regarded as a morphological marker of early HCC dedifferentiation [159,160]. While, apparently, the prognosis of patients with this unique subtype is better than the “conventional” appearance, knowledge of the imaging features and aspects at post-therapeutic follow-up is essential for correctly identifying tumor recurrence [5,161].

3.6. Current and Future Perspectives in Targeting Tumor Nodules

Considering the advent of minimally invasive procedures and liver surgery for HCC, augmented reality training is gaining interest as an instrument that can aid the interventional radiologist or surgeon [162,163]. The technology can overlay preoperative imaging onto the surgical field and can increase the spatial awareness, reducing risks related to critical adjacent structures or anatomical variations [164,165]. Moreover, integrating image-guided simulation systems in minimally invasive procedures has demonstrated improved patient outcomes, allowing for precise targeting of tumor nodules [166,167].

Looking forward, preoperative planning and additive technologies have an increasingly important role, as 3D-printed anatomical models based on patient-specific imaging can offer the opportunity to plan and practice the procedure with high accuracy [168,169]. Innovations in digital planning as well as augmented reality and artificial intelligence can assist image-guided simulation, can be integrated with surgical robots, and will likely further improve the precision in targeting the tumor nodules while minimizing invasiveness and complications [170,171,172].

4. Conclusions

Minimally invasive therapies for HCC significantly alter the morphological features of tumor nodules. Each type of therapy induces distinct morphological changes in the treated lesions, such as variations in size, shape, and internal architecture, as well as alterations in contrast enhancement patterns. The proper understanding and interpretation of these imaging characteristics are essential in evaluating treatment efficacy and detecting early signs of recurrence.

Future research perspectives should include the standardization of imaging protocols across different centers in order to consistently identify these morphological features. Advanced imaging techniques, including radiomics and artificial intelligence, offer promising avenues for improving the interpretation of post-treatment imaging features. Moreover, integrating imaging biomarkers with morphological analysis could further enhance the assessment of tumor response and long-term prognosis. Additional research is needed to validate these approaches in larger, multi-institutional studies, which may ultimately lead to personalized treatment strategies for HCC patients.