Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and the third leading cause of cancer‑related deaths worldwide.¹ Unlike other cancers, HCC can be diagnosed based on cross‑sectional contrast‑enhanced imaging findings alone, without biopsy, in the presence of typical features on imaging. Although treatment with direct‑acting antivirals (DAAs), which results in sustained virologic response in almost 100% of cases, has revolutionized the care of patients infected with hepatitis C virus (HCV) by preventing the progression of liver disease, this infection remains the leading etiologic risk factor of HCC in Western countries, surpassing metabolic dysfunction–associated steatotic liver disease and alcohol‑related liver disease.² Since HCV lacks a direct oncogenic effect, HCC occurs almost exclusively in the individuals with advanced cirrhosis, except for a small minority of infected patients with ongoing alcohol use, type 2 diabetes, or obesity.^3,4 In comparison with active HCV infection, virologic cure with DAAs reduces, but does not eliminate, the risk of HCC in a cirrhotic liver.⁵

Treatment of HCC is determined by the Barcelona Clinic Liver Cancer classification. Curative treatments comprise surgical resection and liver transplant (LTx), both of which are restricted to early, asymptomatic stages of HCC. Such patients mostly come from screening surveillance programs (ultrasound every 6 months) of the high‑risk population. Surgical resection can be offered to the individuals who have a single hepatic lesion and well‑preserved liver function, without significant portal hypertension. The risk of HCC recurrence following surgical resection remains high, approaching 50%–60% at 5 years.¹ In Europe, HCC accounts for about a third of all indications for LTx.⁶ Liver transplant is a pertinent option for patients with hepatic dysfunction and HCC who meet the Milan criteria (single tumor ≤5 cm or tumor multifocality up to 3 nodules, each ≤3 cm). In comparison with resection, LTx is associated with a significantly lower risk of cancer recurrence; however, even with adherence to the Milan criteria, HCC recurs in 10%–15% of the patients, being a common cause of death with limited options of salvage therapy.¹ Prediction of HCC recurrence needs a shift from models based on tumor size and nodule number toward biology‑based factors.⁷ Before working out such models, post‑LTx surveillance using contrast‑enhanced imaging methods is strongly advised, and the most widely used approach is biannual thoracic and abdominal computed tomography imaging.^1,8

In the current issue of Polish Archives of Internal Medicine, Zarębska‑Michaluk et al⁹ analyzed the prevalence of HCC recurrence in patients who were treated with DAAs following LTx. Such an analysis is highly welcome as another study showing that, in Poland, HCV‑related liver diseases, particularly in patients not responding to consecutive antiviral treatments or those with HCC, were the primary indication for LTx in the years 2001–2017.¹⁰ It would be interesting to know the proportion of patients treated with DAAs in Poland before and after LTx, as the use of DAAs before the transplant might lengthen the waiting time for a graft, putting the patient at a risk of HCC progression beyond the Milan criteria. The most important message from the current study is that treatment with DAAs is safe and highly effective, with sustained viral response found in 98% of the transplant recipients. The mortality during follow‑up averaging 8 years was 17%, but only 3 patients (5.4%) died from cancer dissemination as a consequence of HCC recurrence. In all 3 cases, HCC recurred in the liver; however, it should be borne in mind that extrahepatic recurrence accounts for a significant proportion of post‑transplant HCCs, with the lung being most common site (approximately 50% of the cases).⁸

In this study, the interval from LTx to DAA treatment initiation ranged from 10 to 42 months (median, 19.5 mo), while HCC recurrence was diagnosed in 2 patients during or shortly after antiviral treatment completion, and in 1 patient within 2 years of DAA therapy. These data confirm that HCC recurrence usually occurs within the first 2 years post‑LTx, but they do not support the role of DAAs in the prevention of HCC recurrence. However, the use of DAAs in transplant recipients prevents hepatitis C recurrence, which, before the advent of this therapy, was an independent predictor of worse post‑LTx survival. In this context, treatment with DAAs might reduce the risk of de novo HCC in the long term.

The lower than expected rate of HCC recurrence in the Polish study might be related to early detection of HCC, undisturbed access to LTx, or pathological characteristics of the tumor. In this study, clinical data could not be adjusted for pathological findings of the explanted liver, including tumor size, tumor differentiation, microvascular invasion, or presence of satellite lesions. Of note, the risk of HCC recurrence is also associated with the selection and dosing of immunosuppressive drugs, which play a role of a double‑edged sword—they are necessary for graft survival, but at the same time increase cancer risk.

An intriguing finding was the presence of cirrhosis in 12 patients at the start of DAA therapy. It is known that reinfection of the graft if viremia is present at time of LTx is the rule, and hepatitis may run a variable course, ranging from gradual (but faster than in immune‑competent patients) progression of fibrosis to a much rarer but severe form, termed fibrosing cholestatic hepatitis, which could be suspected in these 12 patients. This finding warns against a delayed use of DAAs.