# The role of early MRI in assessing the risk of local tumor progression following irreversible electroporation for hepatocellular carcinoma treatment

Lorenzo Carlo Pescatori, Mathilde Dessain, Gisèle N'kontchou, Arthur Petit, Abou Diallo, Lorraine Blaise, Marie-Pierre Rols, Clair Poignard, Jean-Charles Nault, Nathalie Ganne-Carrié, et al.

► To cite this version:

Lorenzo Carlo Pescatori, Mathilde Dessain, Gisèle N'kontchou, Arthur Petit, Abou Diallo, et al. The role of early MRI in assessing the risk of local tumor progression following irreversible electroporation for hepatocellular carcinoma treatment. International Journal of Hyperthermia, 2025, 42 (1), pp.1-8. 10.1080/02656736.2025.2505595. hal-05322273

HAL Id: hal-05322273

https://hal.science/hal-05322273v1

Submitted on 20 Oct 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

# The role of early MRI in assessing the risk of local tumor progression following irreversible electroporation for hepatocellular carcinoma treatment

Lorenzo Carlo Pescatori, Mathilde Dessain, Gisèle N'Kontchou, Arthur Petit, Abou Diallo, Lorraine Blaise, Marie-Pierre Rols, Clair Poignard, Jean-Charles Nault, Nathalie Ganne-Carrié, Pierre Nahon, Olivier Sutter & Olivier Seror

**To cite this article:** Lorenzo Carlo Pescatori, Mathilde Dessain, Gisèle N'Kontchou, Arthur Petit, Abou Diallo, Lorraine Blaise, Marie-Pierre Rols, Clair Poignard, Jean-Charles Nault, Nathalie Ganne-Carrié, Pierre Nahon, Olivier Sutter & Olivier Seror (2025) The role of early MRI in assessing the risk of local tumor progression following irreversible electroporation for hepatocellular carcinoma treatment, International Journal of Hyperthermia, 42:1, 2505595, DOI: 10.1080/02656736.2025.2505595

**To link to this article:** https://doi.org/10.1080/02656736.2025.2505595

<figure><img src="image_3.png" /></figure>

© 2025 The Author(s). Published with license by Taylor & Francis Group, LLC

<figure><img src="image_4.png" /></figure>

Published online: 28 May 2025.

<figure><img src="image_5.png" /></figure>

Submit your article to this journal

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

Article views: 1294

<figure><img src="image_8.png" /></figure>

View related articles

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

CrossMark

View Crossmark data

<figure><img src="image_11.png" /></figure>
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

OPEN ACCESS

<figure><img src="image_14.png" /></figure>

Check for updates

# The role of early MRI in assessing the risk of local tumor progression following irreversible electroporation for hepatocellular carcinoma treatment

Lorenzo Carlo Pescatori<sup>a*</sup>, Mathilde Dessain<sup>a*</sup>, Gisèle N'Kontchou<sup>b</sup>, Arthur Petit<sup>a</sup>, Abou Diallo<sup>c</sup>, Lorraine Blaise<sup>b ID</sup>, Marie-Pierre Rols<sup>d</sup>, Clair Poignard<sup>e#</sup>, Jean-Charles Nault<sup>b</sup>, Nathalie Ganne-Carrié<sup>b</sup>, Pierre Nahon<sup>b</sup>, Olivier Sutter<sup>a ID</sup> and Olivier Seror<sup>a</sup>

<sup>a</sup>Interventional Radiology Department, Avicenne Hospital (APHP), Bobigny, France; <sup>b</sup>Hepatology Department, Avicenne Hospital (APHP), Bobigny, France; <sup>c</sup>Department of Medical Informatics, Avicenne Hospital (APHP), Bobigny, France; <sup>d</sup>Pharmacology and Biology Department, Toulouse University, CNRS, UPS, Toulouse, France; <sup>e</sup>CNRS, INRIA, University of Bordeaux, Talence, France

## ABSTRACT

**Background:** Irreversible electroporation (IRE) in hepatocellular carcinoma (HCC) triggers apoptosis instead of thermal coagulation, resulting in specific modifications within ablation zones. Aim of this study is to evaluate the diagnostic value of MRI performed three days post-IRE (D3MRI).

**Methods:** This single-institution retrospective study examined patients with HCC treated by IRE from 2012-2017. Criteria included no prior HCC treatment, available D3MRI and one-month MRI (M1MRI) without residual tumor and at least one follow-up MRI after 3 months. We measured the peripheral hyperemia (IREPZ) and central necrotic zone (IRECZ) in the ablation area along with the minimum thickness of IREPZ (min.Th/IREPZ) on both D3MRI and M1MRI. The duration of follow-up and instances of local tumor progression (LTP) were recorded.

**Results:** Forty-eight patients (median age: 68 years) with 65 treated nodules (median diameter: 19 mm) were included. The median follow-up was 37 months. D3MRI median dimensions were 67 mm for IREPZ, 19 mm for IRECZ, and 5 mm for min.Th/IREPZ. LTP occurred in 25 nodules after 18 months. 52% had LTP at min.Th/IREPZ. A min.Th/IREPZ ≤ 5 mm on D3MRI indicated a 24-fold higher risk of LTP (95% CI [2.25–255.95], *p* < .01), conversely, the min.Th/IREPZ on M1MRI had no predictive value.

**Conclusion:** D3MRI appears to be a valuable tool for assessing the true ablation margins in HCC nodules treated with IRE and for identifying potential sites of local recurrence. It may, therefore, be considered for integration into the follow-up protocol for patients undergoing IRE treatment for HCC.

## KEYPOINT

Including an early MRI evaluation following electroporation of HCC nodules is beneficial for accurately measuring the size of the ablation zone and for anticipating potential sites of local recurrence.

## ARTICLE HISTORY

Received 29 October 2024
Revised 22 April 2025
Accepted 8 May 2025

## KEYWORDS

Electroporation; liver
ablation; local tumor
progression; hepatocellular
carcinoma; MRI

## Introduction

Hepatocellular carcinoma (HCC) ranks as the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide [1]. Surgical resection and liver transplantation are considered the main curative treatments for hepatocellular carcinoma [2]. However, in patients with HCC nodules smaller than 3 cm, local ablative therapies, like surgery, can serve as a curative option [2].

Most ablative techniques rely on thermal principles to induce necrosis in the target lesion. However, traditional thermal ablation techniques are not recommended when the lesion is near critical structures, such as the main bile duct or neighboring organs, due to the potential for significant complications from thermal injury. Furthermore, the presence of large vascular structures near the lesion can

diminish the effectiveness of thermal ablation due to the heat sink effect [3–5].

Over the past decade, irreversible electroporation (IRE) has been introduced as a treatment for HCC nodules in cases where conventional thermal ablation techniques were contraindicated or deemed ineffective [6]. IRE is a nonthermal ablative technique that causes tumor cell death, by delivering pulsed electric fields through needles positioned around the target lesion, creating pores in the cell membrane, which ultimately mainly lead to apoptosis [7,8]. Importantly, IRE preserves the connective tissue framework, including the basal membrane of biliary and vascular structures, ensuring that their structural integrity remains nearly intact during treatment [9]. Numerous studies have been conducted to interpret radiological findings over time in patients undergoing IRE [1,10–14], as MRI characteristics following IRE differ from

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>
<figure><img src="image_17.png" /></figure>

those observed after thermal ablations. These studies have shown a dual component in the ablation zones after electro- poration, with a tendency for faster tissue shrinkage com- pared to thermal ablation [1,15,16].

Nevertheless, there remains a critical knowledge gap regarding how early imaging findings, particularly the periph- eral ablation zone, reflect irreversible [12] versus reversible [11] tissue damage. Addressing this gap is crucial for optimiz- ing treatment assessment and guiding clinical follow-up. Therefore, accurate imaging interpretation is essential to assess treatment completeness and determine the extent of treatment margins.

The aim of this study is to evaluate the clinical utility of an early MRI performed within three days after IRE, and to investigate the correlation between the early extension of the ablation zone and the risk of local tumor recurrence during the follow-up period.

## Materials and methods

This retrospective study was conducted at a single institution by reviewing all patients who underwent hepatic IRE for HCC between January 2012 and December 2017. The study proto- col adhered to the ethical guidelines outlined in the 1975 Declaration of Helsinki. Written informed consent was obtained from patients and the institutional review board was waived due to the retrospective nature of the study.

The diagnosis of hepatocellular carcinoma (HCC) was established in accordance with the guidelines of the European Association for the Study of the Liver (EASL) [17] or con- firmed through biopsy. Patients were eligible for IRE if they were deemed unsuitable for surgery and presented with up to 3 nodules of HCC, each measuring less than 5 cm in the longest axis, located near the main bile ducts or non-mobilizing viscera. In cases of infiltrative disease with or without tumor vascular invasion, IRE was sometimes consid- ered for lesion diameter below 50 mm to treat both the tumor thrombus and the intraparenchymal part of the lesion.

The inclusion criteria for this study were as follows: (i) IRE as the initial treatment for all target lesions; (ii) Availability of MRI on post-procedure day 3 (D3MRI); (iii) Complete ablation confirmed on 1-month MRI (M1MRI), showing no arterial enhancement or portal venous 'wash- out' phenomenon; (iv) At least one follow-up MRI performed at 3 months post-procedure (M3MRI).

Exclusion criteria: Lack of follow-up imaging, incomplete ablation (M1MRI), or IRE technical failure. Eligible patients could have up to three HCC lesions, with the largest lesion measuring ≤5 cm, located near critical structures such as bile ducts or adjacent organs. For tumors exceeding 3 cm in diameter, a combination of 'non-touch' and direct needle insertion techniques was employed.

Demographic and clinical baseline characteristics were col- lected, including the patients' sex, age, etiology of underlying hepatopathy, Child-Pugh score, as well as the size, location, portal invasion, and infiltrative aspect [18] of the nodules.

### IRE procedure

All procedures were performed under general anesthesia by radiologists with over 5 years of experience in liver tumor

ablation. All patients underwent a pre-operative ultrasound evaluation conducted by the operator one to two weeks in advance, to assess the lesion's visibility.

When the nodule was visible on ultrasound (US), IRE was performed using simple US guidance (Logiq E9; GE Healthcare, Chalfont St Giles, United Kingdom). In cases where the target lesion was not visible solely on US, a fusion technique was employed. This involved fusion of US images with those obtained from contrast-enhanced Cone Beam CT (Innova IGS540; GE Healthcare), which was performed immediately prior to the procedure, as previously described [19].

The procedures were conducted using an IRE device (NanoKnife, Angiodynamics, Amsterdam, Netherlands) with 2–7 needles placed around the lesion, ensuring that the dis- tance between the needles was less than 2.5 cm. Thus, tumors measuring less than 3 cm were treated using a 'no-touch' ablation method, wherein all needles were placed around the tumor. However, since the recommended maximum distance between needles was 2.5 cm, tumors larger than 3 cm were treated with at least 1 needle inserted inside the tumor while the remaining needles were positioned in the liver paren- chyma adjacent to the tumor's border, as previously described [14,15]. IRE was performed according to our established pro- tocol, which involved the application of 90–120 pulses of 90 µs duration between each pair of needles, with intensity ranging between 30 A and 50 A [20]. The exposed length of the active part of the needle was standardized at 40 mm irre- spective of the tumor size, except in case where shortening was required due to spatial constraints within the liver. In cases where the lesion had a long axis exceeding 3 cm, a pull-back was conducted to ensure an adequate ablation margin. To prevent any rhythm disorders, an ECG synchroni- zation (Accusync Medical Research, Milford, Conn) was employed to deliver the pulses during the refractory period of the cardiac cycle [16].

### Assessment of therapeutic results and follow-up

All patients included in the study underwent imaging evalu- ations using 3DMRI, M1MRI and M3MRI, in accordance with the inclusion criteria. Then, MRI or CT-scan examinations were conducted every 3 months for 2 years, followed by assessments every 6 months for the remaining duration of the follow-up period.

The D3-, M1-, and M3MRI exams were performed using a 1.5 Tesla MRI (Achieva, Philips, Netherlands) with a standard protocol including T1- and T2-weighted sequences, diffusion-weighted imaging (DWI), and the administration of contrast media (Gadoteric acid; Dotarem, Guerbet, Aulnay-sous-Bois, France) during arterial (35s), portal (70s), and late (180s) phases (acquisition parameters are given in Table 1).

All images were initially reviewed by a junior radiologist and subsequently by a senior radiologist. In case of disagree- ment between the two, a consensus reading was performed involving at least two senior radiologists to resolve any dis- crepancies. The treated area was divided into two distinct zones: a peripheral zone (IREPZ) and the central zone (IRECZ) (Figure 1). The IREPZ was characterized on MRI sequences as an area showing hyperintensity on T2 and DWI images, hypointensity on non-contrast T1 images, and progressive enhancement after the administration of gadolinium contrast agent. In contrast, the IRECZ was defined as an area exhibiting
<figure><img src="image_18.png" /><figcaption>**Table 1.** MRI acquisition parameters.</figcaption></figure>

<table><thead><tr><th>Parameter</th><th>T1 (TSE)</th><th>T2 (TSE)</th><th>DW</th><th>3D T1 eTHRIVE</th></tr></thead><tbody><tr><td>TR (ms)</td><td>283</td><td>1600</td><td>4490</td><td>3.91</td></tr><tr><td>TE (ms)</td><td>4.77</td><td>70</td><td>180</td><td>1.83</td></tr><tr><td>Flip angle (°)</td><td>70</td><td>90</td><td>90</td><td>10</td></tr><tr><td>Reconstruction matrix</td><td>512 × 512</td><td>560 × 560</td><td>288 × 288</td><td>400 × 400</td></tr><tr><td>Section thickness (mm)</td><td>8</td><td>4.5</td><td>8</td><td>4</td></tr><tr><td>Intersection gap (mm)</td><td>0.5</td><td>1</td><td>1</td><td>Overlap</td></tr><tr><td>Field of view (mm)</td><td>400</td><td>400</td><td>380</td><td>400</td></tr><tr><td>Acquisition time (s)</td><td>20</td><td>70</td><td>90</td><td>~5 (breath-hold)</td></tr><tr><td>b values (s/mm²)</td><td>N.A.</td><td>N.A.</td><td>50, 600</td><td>N.A.</td></tr></tbody></table>

N.A.: not applicable; TSE: turbo spin-echo; 3D eTHRIVE: a three-dimensional volume-interpolated breath-hold imaging sequence obtained with fat suppression.

hyperintensity on non-contrast T1-weighted images and displaying a variable signal intensity from hypointense to hyperintense on T2 and DWI images, without any enhancement on post-contrast T1-weighted sequences (Figure 2).

The longest axis of IREPZ and IRECZ was measured at D3MRI and M1MRI on the transversal plane of T2, T1, and DWI images at low B-value (<400). Additionally, the longest axis of IREPZ was also measured on the late phase of dynamic T1 [17]. The minimal thickness of IREPZ (min.Th/IREPZ), defined as the smallest distance between the border of IRECZ and IREPZ visualized on the same plane of the T2 weighted sequence, was measured at D3MRI and M1MRI (Figure 1). T2-weighted images were preferred due to the well-defined appearance of the two areas of interest. However, in cases where the demarcation between IRECZ and IREPZ was unclear on T2-weighted images, the natural hyperintensity of IRECZ on T1-weighted images was used for measurement. Any changes in min.Th/IREPZ at D3MRI and M1MRI were recorded.

Local tumor progression (LTP) was defined as the reappearance of any arterial enhancement with subsequent wash-out on delayed phase on M3MRI or subsequent imaging examinations. The distance of any occurrences of LTP from the min.Th/IREPZ was recorded.

## Statistical analysis

Categorical variables were presented as counts (percentages), while continuous data were expressed as medians (interquartile range [IQR]). The paired and unpaired Student's t-test was utilized for comparing continuous variables and the Freeman-Halton extension of Fisher's exact test was utilized for comparing dichotomous variables. To assess the association between categorical variables, odds ratios were calculated. A *p* value of less than .05 was considered statistically significant.

## Results

During the analysis period, 1147 patients with HCC nodules were treated at our center with percutaneous ablation (all techniques combined); among them, 130 patients underwent IRE for hepatic HCC nodules.

Among them, seventy patients were deemed completely treated based on the M1MRI assessments. However, 22 patients were excluded from the study due to a lack of available D3MRI

or M3MRI (Figure 3). Ultimately, 48 patients (median age: 68 years; IQR 61–73 years; 39 males) were included in the analysis, with a total of 65 nodules treated with IRE. The nodules had a median longest axis of 19 mm (IQR 14–28 mm). Among the cases, there were 8 infiltrative tumors, 7 tumors with partial invasion, and 15 tumors larger than 30 mm in the longest axis. Twelve patients had 2 concomitant lesions, one patient had three lesions and one patient had four lesions. The rest of the population had a single HCC.

Nodules were treated with 3, 4, 5, 6 or 7 needles in 47%, 26% 6%, 20% and 1% of cases, respectively. Needle tip exposition was of 2, 2.5, 3, 3.5 or 4 cm in 6%, 3%, 10%, 9%, 72% of cases, respectively. One to 3 cm pull-back of the needles was performed in 32% of cases, in order to treat the whole lesion. Table 2 provides the baseline clinical and biological characteristics of the study population.

## Post procedure MRI findings

MRI findings revealed that, after treatment, the IRECZ was consistently surrounded by the IREPZ.

There were no significant differences observed in the measurements of the longest axis for the same area across different sequences at D3MRI or M1MRI. However, there was a significant decrease in the longest axis of IREPZ, IRECZ, and the min.Th/IREPZ from D3MRI to M1MRI (*p* < .01) for every pair of sequences (Table 3).

Specifically, when considering the sequence showing the maximum extension of the longest axis among the different surfaces, the longest axis of IREPZ decreased from 67 mm (57–75 mm) to 48 mm (38–59 mm), with a percentage decrease of 29% (IQR: 15–34) (*p* < .01). The longest axis of IRECZ decreased from 19 mm (14–28 mm) to 16 mm (13–22 mm), with a percentage decrease of 21% (IQR: 12–29) (*p* < .01) and min.Th/IREPZ passed from 5 (2–10) mm to 3 (0–6) mm (*p* < .01), with a percentage decreasing of 33% (IQR: 14–67).

## Local tumor progression assessment

The median follow-up duration was 37 months [IQR: 22–56]. Local tumor progression (LTP) was observed for 25 nodules,

<figure><img src="image_19.png" /><figcaption>**Figure 1.** Measurements of different components of ablation zone induced by IRE.</figcaption></figure>
<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /><figcaption>**Figure 2.** Pre-therapeutic CT showing HCC at the arterial phase (a) with wash out at the portal phase (b). MRI performed 3 days after IRE with T2 weighted MR showing hyperintense round Central area surrounding by hyperintense peripheral area (c) and T1 weighted MR at arterial phase gadolinium injection showing complete ablation with no remaining enhancement of the tumoral area (d). T2-weighted MRI performed 30 days after IRE showing decreasing of both Central and peripheral IRE area (e). T1-weighted MRI performed 12 months after IRE showing nodular LTP (arrow) on MT-IRE<sub>PZ</sub> (f).</figcaption></figure>

<figure><img src="image_22.png" /></figure>

HCC: hepatocellular carcinoma; IRE: irreversible electroporation; D₃, M₁, M₄MRI: MRI at day 3, one-month and four-months after IRE procedure

<caption>**Figure 3.** Flowchart of included patients.</caption>

occurring at a median interval of 18 months [7–22] after IRE. Nodules that exhibited LTP had a median main axis measurement of 23 mm (16–30 mm), whereas nodules without LTP

had a main axis measurement of 16 mm (14–26 mm) (p = .05). Out of 25 nodules, 13 (52%) LTP were located at the min. Th/IREPZ. A total of 33 nodules had a min.Th/IREPZ of <
<figure><img src="image_23.png" /></figure>

5mm at D3MRI. Among them, 16 nodules (48%) exhibited LTP, and 12 out of the 16 (75%) specifically showed LTP on the min.Th/IREPZ. Thus, nodules with a min.Th/IREPZ ≤ 5mm on D3MRI had an odds ratio of 1.05 for LTP within the first 36 months after the IRE procedure (95% CI [0.34–3.24], *p* = .94) but they had an odds ratio of 24 for developing LTP on the min.Th/IREPZ (95% CI [2.25–255.95], *p* < .01). Conversely, a min.Th/IREPZ ≤ 5mm on M1MRI did not show significant predictive value for LTP on the min.Th/IREPZ (OR 6, 95% CI [0.56–63.99], *p* = .1). The presence of portal invasion and/or the infiltrative aspect of the nodule did not show any correlation with the development of LTP on the min.Th/IREPZ.

Discussion

This study evaluates the utility of MRI conducted 72 h post-IRE (D3MRI) in predicting the development of local tumor progression (LTP) during the follow up. In all cases, D3MRI revealed an ablation zone consisting of a central necrotic area attributed to the tumor 'ghost', surrounded by a conges- tive peripheral zone. After a median follow-up of 37 months. Among the 25(38%) nodules that exhibited LTP, 52% had LTP in the area where the minimum distance between the central and peripheral zone (min.Th/IREPZ) was the thinnest on the 72-h MRI and nodules with a min.Th/IREPZ thinner than 5mm had a significantly higher odds ratio of LTP occurrence in regard of the min.Th/IREPZ itself.

<table><caption>Table 2. Clinical and morphological characteristics of the lesions.</caption><tbody><tr><td>Age</td><td>68 y.o.[61–73]</td></tr><tr><td>Gender</td><td>39 M : 9 F</td></tr><tr><td>Cirrhosis</td><td></td></tr><tr><td>Alcohol</td><td>46%</td></tr><tr><td>HCV</td><td>44%</td></tr><tr><td>NASH</td><td>6.3%</td></tr><tr><td>HBV</td><td>2.1%</td></tr><tr><td>Other</td><td>2.1%</td></tr><tr><td>Child-Pugh Score</td><td></td></tr><tr><td>A</td><td>33 (68.7%)</td></tr><tr><td>B</td><td>15 (31.3%)</td></tr><tr><td>C</td><td>0 (0%)</td></tr><tr><td>N° of nodules</td><td>65</td></tr><tr><td>Longest axis</td><td>19(14–28)mm</td></tr><tr><td>Portal invasion</td><td>7 (11%)</td></tr><tr><td>Infiltrative HCC</td><td>8 (12%)</td></tr><tr><td>Liver distribution</td><td></td></tr><tr><td>Segm I</td><td>7 (10%)</td></tr><tr><td>Segm II</td><td>5 (8%)</td></tr><tr><td>Segm III</td><td>5 (8%)</td></tr><tr><td>Segm IV</td><td>15 (23%)</td></tr><tr><td>Segm V</td><td>9 (14%)</td></tr><tr><td>Segm VI</td><td>8 (12%)</td></tr><tr><td>Segm VII</td><td>3 (5%)</td></tr><tr><td>Segm VIII</td><td>13 (20%)</td></tr></tbody></table>

HCV: Hepatitis C Virus; NASH: nonalcoholic steatohepatitis; HBV: Hepatitis B virus; Segm: liver segment.

Our findings suggest that the peripheral ablation zone observed on the D3MRI has clinical significance, as a thin peripheral zone correlates with an increased risk of incomplete ablation and subsequent LTP, while this correlation is lost on MRI performed lately.

Early MRI enables the measurement of the ablation zone (i.e., IRECZ and IREPZ) at its maximal dimensions. The 'target' appearance is well described after thermal ablations as well [21]. Nevertheless, the pictorial aspect induced by IRE shows greater thickness and more rapid changes of the peripheral zone, while the central zone shows characteristics strongly indicative of coagulative necrosis, as per MRI after thermal ablations.

Padia et al. [11], in a retrospective study involving 20 patients with HCC treated using IRE and subjected to MRI follow-up at day 1, day 30, and subsequently every 90 days, concluded that, as the peripheral zone disappear during follow up, it is related to the surrounding penumbra of reversible electroporation changes. In other words, based on this conclusion, the peripheral zone observed a day after the ablation should not be considered as the ablative margin. However, typically, reversible electroporation changes endure only for several tens of minutes, shorter than 24 h [22,23]. Furthermore, numerical simulations of dose deposition during IRE for HCC demonstrated that the peripheral zone, which is the closest to the needles, receives levels of energy well above the electroporation reversibility threshold [9,24].

Studies based on animal models that correlate histopathological and MRI findings have provided additional insight into understanding the nature of the IREPZ [12,14,25]. All of these studies confirm that the central zone comprises a mixture of coagulative necrosis and, as evidenced by the TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) method, a high ratio of apoptotic hepatocytes. Interestingly, Felker et al. using a simplified IRE setup consisting of a single bipolar coaxial needle, demonstrated through MRI and pathological examinations of pig livers performed 50 h after ablation that the peripheral zone seen on MRI corresponded histopathologically to an inner, thick congestive and hemorrhagic zone surrounded by a thin inflammatory layer [12]. Apoptosis was observed in the congestive and hemorrhagic zone but absent in the outer inflammatory layer. Furthermore, their MRI protocol, which included a hepatobiliary phase sequence, revealed a lack of gadoxetate disodium uptake within both the central and peripheral zones of ablation. These findings support our conclusion that the changes induced in hepatocytes within the peripheral zone, as observed with MRI a few days after IRE, including apoptosis and the loss of transmembrane transport of gadoxetate disodium, are irreversible and indicative of cell death.

In our clinical study, the central zone often appeared as a necrotic 'ghost' of the tumor, suggesting that differing sensitivities to IRE between tumor and healthy tissue may

<table><caption>Table 3. Evolution of the measurement of the IRE ablation area.</caption><thead><tr><th rowspan="2"></th><th colspan="2">IRECZ</th><th colspan="2">IREPZ</th><th colspan="2">min.Th/IREPZ</th></tr><tr><th>D3MRI</th><th>M1MRI</th><th>D3MRI</th><th>M1MRI</th><th>D3MRI</th><th>M1MRI</th></tr></thead><tbody><tr><td>T2</td><td>18(15–28)</td><td>16(12–22)</td><td>p < .01</td><td>64(55–73)</td><td>47(37–59)</td><td>p < .01</td></tr><tr><td>T1</td><td>19(14–28)</td><td>16(13–22)</td><td>p < .01</td><td>67(57–75)</td><td>48(38–59)</td><td>p < .01</td></tr><tr><td>DWI</td><td>15(17–27)</td><td>15(10–23)</td><td>p < .01</td><td>66(58–74)</td><td>48(38–57)</td><td>p < .01</td></tr><tr><td></td><td>p > .05</td><td>p > .05</td><td></td><td>p > .05</td><td>p > .05</td><td></td></tr></tbody></table>

IRECZ: central zone of the electroporation area; IREPZ: peripheral zone of the electroporation area; Min.Th/IREPZ: minimum distance between IRECZ and IREPZ; T2, T1 and DWI: MRI sequences. All measures are given in millimeters.
<figure><img src="image_24.png" /></figure>

influence the therapeutic outcomes of the technique [26]. Distinct effects of IRE on abnormal tumor and normal liver microvascular structures, such as the 'vascular lock' effect and vasculitis changes, possibly combined with specific membrane sensitivities of tumor cells and normal hepatocytes, could explain the differential responses in the center and periphery of the ablation zone [6,9]. Moreover, these mechanisms could also account for some discrepancies between the features of IRE ablation zones reported in *in vivo* studies without a tumor model and those observed in clinical practice. This is an important point of discussion because IRE is a multibipolar ablative technique that necessitates the insertion of several needles (at least three) around the tumor [27]. Therefore, in contrast to other ablative techniques, which rely on intratumoral centrifugal radiating energy deposition, IRE delivers a relatively high amount of energy to the periphery of the tumor. In these locations, MRI reveals small foci of necrosis due to the thermal effect of high levels of pulsed RF energy. However, in the remainder of the peripheral zone, a few millimeters away from the needle tracts, despite the persistence of a high electric field magnitude, no necrotic changes are observed, unlike in tumorous tissue exposed to equivalent energy deposition [20].

Furthermore, in the 'no-touch' approach, the needles are placed around the tumor rather than through it, thereby including a layer of apparently healthy liver tissue within the ablation zone. This practice mirrors the principle of achieving negative surgical margins: a seemingly larger area is targeted to ensure complete ablation of the tumor and its peritumoral margins. Rather than representing unnecessary damage to the healthy liver, this additional zone serves to decrease the likelihood of residual disease, much like wide resections in surgery. Consequently, although the central necrotic region represents the tumor 'ghost', the irreversible peripheral zone (IREPZ) is equally vital for long-term local control [28-30].

Additionally, in interpreting our results, it is important to emphasize that IRE was deliberately chosen for selected patients presenting with challenging tumor locations or compromised liver function, rather than being indiscriminately applied. The absence of heat generation in IRE bypasses the heat sink effect, offering crucial protection for vascular and biliary structures situated near the tumor. This 'niche' application targets lesions not easily managed by conventional thermal ablative methods like radiofrequency or microwave ablation. While our study does reveal notable residual disease and local progression rates, these findings must be considered considering the inherent complexity of the cases—such as patients with advanced cirrhosis or poorly located lesions—who are predisposed to poorer prognoses [31,32]. Notably, for a portion of the observation period, our center was among the very few routinely offering IRE in France, and thus we also received referrals from other institutions whose patients were not appropriate candidates for thermal ablation and had no local IRE options. Further, the literature underscores a steeper learning curve for IRE, with experience in electrode placement and procedural protocols markedly influencing outcomes. As IRE techniques evolve, and as adjunctive measures (e.g., chemotherapy or repeated sessions) become more standardized, there is strong potential for improved local control and minimized collateral damage [31-35]. We therefore view IRE not as an overextended modality, but as a strategic alternative for patients in whom thermal ablation might

pose undue risk, reinforcing its role in a comprehensive, patient-tailored approach to HCC management.

Our study has several limitations that should be acknowledged. Firstly, its retrospective design and relatively small sample size limit the strength of our findings. Additionally, we did not use a hepatospecific contrast medium agent, as Felker et al. did in their study [12], which could have provided additional information for evaluating the ablative margin. Finally, due to the absence of histopathological correlation inherent to the study's design, enrolling patients from a clinical cohort, we had to draw speculative conclusions based on indirect evidence.

In conclusion, we confirm that the central zone corresponds to a necrotic area centered on the HCC nodule and, in light of both the current literature and our considerations regarding the risk of local tumor progression (LTP) reported in this study, we believe that the peripheral zone is an area of irreversible alteration in the peritumoral liver tissue, which can be considered as ablation margins. The disappearance of the peripheral delayed enhanced zones is more likely related to tissue remodeling rather than the restoration of cell membranes in the peripheral zone, which might have hypothetically received energy below the irreversibility threshold. In this context, early MRI can be a valuable tool in assessing the effectiveness of IRE for HCC, especially in evaluating the risk of LTP based on the minimum thickness of the ablation margin. Therefore, we propose that early MRI, conducted within 3 days after the IRE procedure, should be considered as part of post-treatment follow-up guidelines for this ablative technique. Nevertheless, further prospective studies with larger sample sizes are required to validate our findings and optimize the assessment of post-treatment images in HCC patients.

## Generative artificial intelligence (AI) statement

The authors acknowledge the use of ChatGPT, a generative language model developed by OpenAI (San Francisco, CA, USA), for assistance in the syntactic and grammatical revision of the manuscript. The model was not used for content generation, data analysis, or interpretation of scientific results.

## Disclosure statement

No potential conflict of interest was reported by the author(s).

## Funding

The author(s) reported there is no funding associated with the work featured in this article.

## ORCID

Lorraine Blaise http://orcid.org/0000-0001-5344-1625

Olivier Sutter http://orcid.org/0000-0002-2802-9652

## Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.
<figure><img src="image_25.png" /></figure>

References

[1] Barabasch A, Distelmaier M, Heil P, et al. Magnetic resonance imaging findings after percutaneous irreversible electroporation of liver metastases: a systematic longitudinal study. Invest Radiol. 2017;52(1):23-29. doi: 10.1097/RLI.0000000000000301.

[2] Eresen A, Zhou K, Sun C, et al. Early assessment of irreversible electroporation ablation outcomes by analyzing MRI texture: pre-clinical study in an animal model of liver tumor. Am J Transl Res. 2022;14(8):5541-5551.

[3] Lee EW, Loh CT, Kee ST. Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation. Technol Cancer Res Treat. 2007;6(4):287-294. doi: 10.1177/153303460700600404.

[4] Charpentier KP, Wolf F, Noble L, et al. Irreversible electroporation of the liver and liver hilum in swine. HPB. 2011;13(3):168-173. doi: 10.1111/j.1477-2574.2010.00261.x.

[5] Aycock KN, Davalos RV. Irreversible electroporation: background, theory, and review of recent developments in clinical oncology. Bioelectricity. 2019;1(4):214-234. doi: 10.1089/BIOE.2019.0029.

[6] Lavee J, Onik G, Mikus P, et al. A novel nonthermal energy source for surgical epicardial atrial ablation: irreversible electroporation. Heart Surg Forum. 2007;10(2):E162-E167. doi: 10.1532/HSF98.20061202.

[7] Davalos RV, Mir ILM, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng. 2005;33(2):223-231. doi: 10.1007/s10439-005-8981-8.

[8] Kingham TP, Karkar AM, D'Angelica MI, et al. Ablation of perivascular hepatic malignant tumors with irreversible electroporation. J Am Coll Surg. 2012;215(3):379-387. doi: 10.1016/j.jamcollsurg.2012.04.029.

[9] Gallinato O, De Senneville BD, Seror O, et al. Numerical workflow of irreversible electroporation for deep-seated tumor. Phys Med Biol. 2019;64(5):055016. doi: 10.1088/1361-6560/AB00C4.

[10] Seror O, Poignard C, Gallinato O, et al. Irreversible electroporation: disappearance of observable changes at imaging does not always imply complete reversibility of the underlying causal tissue changes. Radiology. 2017;282(1):301-302. doi: 10.1148/RADIOL.2017161809.

[11] Padia SA, Johnson GE, Yeung RS, et al. Irreversible electroporation in patients with hepatocellular carcinoma: immediate versus delayed findings at MR imaging. Radiology. 2016;278(1):285-294. doi: 10.1148/RADIOL.2015150031.

[12] Felker ER, Dregely I, Chung DJ, et al. Irreversible electroporation: defining the MRI appearance of the ablation zone with histopathologic correlation in a porcine liver model. AJR Am J Roentgenol. 2017;208(5):1141-1146. doi: 10.2214/AJR.16.17207.

[13] Guo Y, Zhang Y, Nijm GM, et al. Irreversible electroporation in the liver: contrast-enhanced inversion-recovery MR imaging approaches to differentiate reversibly electroporated penumbra from irreversibly electroporated ablation zones. Radiology. 2011;258(2):461-468. doi: 10.1148/RADIOL.10100645/-/DC1.

[14] Pan L, Sun C, Zhou K, et al. Transcatheter intraarterial perfusion MRI approaches to differentiate reversibly electroporated penumbra from irreversibly electroporated zones in rabbit liver. Acad Radiol. 2020;27(12):1727-1733. doi: 10.1016/J.ACRA.2020.01.008.

[15] Granata V, Fusco R, Catalano O, et al. Percutaneous ablation therapy of hepatocellular carcinoma with irreversible electroporation: MRI findings. AJR Am J Roentgenol. 2015;204(5):1000-1007. doi: 10.2214/AJR.14.12509.

[16] Granata V, Fusco R, Salati S, et al. A systematic review about imaging and histopathological findings for detecting and evaluating electroporation-based treatments response. Int J Environ Res Public Health. 2021;18(11):5592. doi: 10.3390/IJERPH18115592.

[17] Galle PR, Forner A, Llovet JM, et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019.

[18] Seror O, N'Kontchou G, Haddar D, et al. Large infiltrative hepatocellular carcinomas: treatment with percutaneous intraarterial ethanol injection alone or in combination with conventional

percutaneous ethanol injection. Radiology. 2005;234(1):299-309. doi: 10.1148/RADIOL.2341031008.

[19] Sutter O, Fihri A, Ourabia-Belkacem R, et al. Real-time 3D virtual target fluoroscopic display for challenging hepatocellular carcinoma ablations using cone beam CT. Technol Cancer Res Treat. 2018;17:1533033818789634. doi: 10.1177/1533033818789634.

[20] Tasu JP, Tougeron D, Rols MP. Irreversible electroporation and electrochemotherapy in oncology: state of the art. Diagn Interv Imaging. 2022;103(11):499-509. doi: 10.1016/J.DIII.2022.09.009.

[21] Bréhier G, Besnier L, Delagnes A, et al. Imaging after percutaneous thermal and non-thermal ablation of hepatic tumour: normal appearances, progression and complications. Br J Radiol. 2021;94(1123):20201327. doi: 10.1259/BJR.20201327.

[22] Vogel JA, van Veldhuisen E, Alles LK, et al. Time-dependent impact of irreversible electroporation on pathology and ablation size in the porcine liver: a 24-hour experimental study. Technol Cancer Res Treat. 2019;18:1533033819876899. doi: 10.1177/1533033819876899.

[23] Giardino R, Fini M, Bonazzi V, et al. Electrochemotherapy a novel approach to the treatment of metastatic nodules on the skin and subcutaneous tissues. Biomed Pharmacother. 2006;60(8):458-462. doi: 10.1016/J.BIOPHA.2006.07.016.

[24] Leguèbe M, Silve A, Mir LM, et al. Conducting and permeable states of cell membrane submitted to high voltage pulses: mathematical and numerical studies validated by the experiments. J Theor Biol. 2014;360:83-94. doi: 10.1016/J.JTBI.2014.06.027.

[25] Shangguan AJ, Sun C, Wang B, et al. DWI and DCE-MRI approaches for differentiating reversibly electroporated penumbra from irreversibly electroporated ablation zones in a rabbit liver model. Am J Cancer Res. 2019;9(9):1982-1994.

[26] Frandsen SK, Gehl J. A review on differences in effects on normal and malignant cells and tissues to electroporation-based therapies: a focus on calcium electroporation. Technol Cancer Res Treat. 2018;17:1533033818788077. doi: 10.1177/1533033818788077.

[27] Nault JC, Sutter O, Nahon P, et al. Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations. J Hepatol. 2018;68(4):783-797. doi: 10.1016/J.JHEP.2017.10.004.

[28] Lee DH, Lee M, Kim P, et al. Outcome of no-touch radiofrequency ablation for small hepatocellular carcinoma: a multicenter clinical trial. Radiology. 2021;301(1):229-236. doi: 10.1148/radiol.2021210309.

[29] Han S, Lee MW, Lee YJ, et al. No-touch radiofrequency ablation for early hepatocellular carcinoma: 2023 Korean Society of image-guided tumor ablation guidelines. Korean J Radiol. 2023;24(8):719-728. doi: 10.3348/kjr.2023.0423.

[30] Seror O, N'Kontchou G, Nault J-C, et al. Hepatocellular carcinoma within milan criteria: no-touch multibipolar radiofrequency ablation for treatment-long-term results. Radiology. 2016;280(2):611-621. doi: 10.1148/radiol.2016150743.

[31] Mafeld S, Wong J, Kibriya N, et al. Percutaneous irreversible electroporation (IRE) of hepatic malignancy: a bi-institutional analysis of safety and outcomes. Cardiovasc Intervent Radiol. 2019;42(4):577-583. doi: 10.1007/s00270-018-2120-z.

[32] Cannon R, Bolus D, White JA. Irreversible electroporation as a bridge to liver transplantation. Am Surg. 2019;85(1):103-110. doi: 10.1016/j.hpb.2017.02.357.

[33] Niessen C, Beyer L, Pregler B, et al. Percutaneous ablation of hepatic tumors using irreversible electroporation: a prospective safety and midterm efficacy study in 34 patients. J Vasc Interv Radiol. 2016;27(4):480-486. doi: 10.1016/j.jvir.2015.12.025.

[34] Cheung W, Kavnoudias H, Roberts S, et al. Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. Technol Cancer Res Treat. 2013;12(3):233-241. doi: 10.7785/tcrt.2012.500317.

[35] Lyu T, Wang X, Su Z, et al. Irreversible electroporation in primary and metastatic hepatic malignancies. Medicine. 2017;96(17):e6386. doi: 10.1097/MD.00000000000006386.