*4.1.4.1. Percutaneous ethanol injection (PEI)*

PEI induces cell necrosis through dehydration, protein denaturation, and small vessel disruption. It is not often used since it can only be performed in lesions <2 cm and it has a higher recurrence ratio than percutaneous ablation. It has indication only in lesions that are not considered safe for ablation due to their localization [54].

Compared to PEI, RF has shown better outcomes in terms of overall survival, survival at 1, 2, and 3 years, and cancer-free survival at 1, 2, and 3 years. This is probably due to the better performance of RF in terms of complete necrosis of the lesion and the low percentage of local recurrence [54].

RF requires fewer treatment sessions and shorter hospitalization than ethanol injection: although the quality of life of these patients was not evaluated, there was a decrease in hospitalization rates [54].

#### *4.1.4.2. Cryoablation*

Cell death with cryoablation is different than that with thermal ablation. The freezing process results in both intracellular and extracellular ice formation, both of which can result in cellular death, but by different mechanisms. Since the ablation zone is reperfused after the ice ball melts, the result is a rapid release of cellular debris into the systemic circulation. This probably explains the systemic complications of cryoablation (i.e., cryoshock) that are rare with heat-based ablation. Thermoablation is the preferred ablation method for treating HCC in patients with cirrhosis because of the increased risk of bleeding and of disseminated intravascular coagulation-like reaction (called cryoshock) associated with cryoablation [55, 56]. Therefore, although many studies have shown that small-volume cryoablation is feasible in patients with cirrhosis and HCC, it is difficult to justify the additional risk of cryoablation in these patients when viable heat-based alternatives are available [55].

#### *4.1.4.3. Laser ablation (LA)*

The term laser ablation refers to the thermal tissue destruction by conversion of absorbed light (usually infrared) into heat. Infrared energy penetrates tissue for 12–15 mm in depth; heat is conducted beyond this range thereby creating a larger ablation area. Optical penetration has been shown to be increased in malignant tissue compared to normal parenchyma [57].

Local tissue properties, in particular perfusion, have a significant impact on the size of the ablation zone. Highly perfused tissue and large blood vessels act as a heat sink, since infrared energy is absorbed by erythrocytic heme and transported away from the target area. This phenomenon makes normal liver parenchyma relatively more resistant to LA than tumor tissue and this is the rationale for using hepatic inflow occlusion techniques such as arterial embolization (TACE) in conjunction with laser therapy [57].

Light transmission into tissues and the size of the ablation zone increase with higher laser power, as does the local tissue temperature reached during ablation, with consequent higher risk of overheating and carbonization of the adjacent normal tissue.

The use of water-cooled laser application sheaths allows the use of a higher laser power output while preventing carbonization [58]. When using multiple water-cooled higher power fibers, ablation zones of up to 80 mm diameter can be obtained.

Major complications of LA are liver failure, segmental infarction, hepatic abscess, cholangitis, bile duct injury, and hemorrhage. The technique is considered safe by rates of 1.8% for major complications and a mortality rate of 0.1% [59] and can also be used safely in elderly patients with advanced liver disease up to Child–Pugh class B [57]. Tumor seeding after percutaneous biopsy and ablative therapies is a well-known phenomenon, but it has rarely been reported following laser ablation [57].

A recent study compared LA and TACE in patients with a single large HCC and found a significant superiority in multifiber-LA vs. TACE in terms of recurrence rates, especially in nodules >4 cm, while OS was similar between both groups [60].

Ablation size is critical to predict outcome; patients with lesions >6 cm or with multifocal disease (more than five nodules) are usually managed with other treatment modalities.

LA can be used with a curative intent only in patients with early-stage HCC. In this setting, it has shown similar outcomes compared to RFTA when treating nodules <3 cm [57, 60].

In patients with advanced local HCC, LA should only be used as a palliative treatment. The use of laser ablation is not currently extensively adopted for the treatment of HCC, but given the promising outcomes shown in recent studies and the expected technical advancements, it could become an increasingly more important treatment modality for HCC in the near future.
