Hepatocellular carcinoma in pregnancy: A systematic review

Abstract Introduction Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor and typically develops in the context of chronic liver disease, such as liver cirrhosis or chronic hepatitis B virus infection. Ultrasound evaluation, CT scan, and MRI are used to detect HCC. α‐fetoprotein (AFP) is a common marker used to detect HCC in the non‐pregnant population, which notoriously increases in pregnant women in relation to gestational age. Treatment is driven by the extent of the disease and the severity of underlying liver disease. Pregnancy may represent an obstacle to diagnosis and appropriate treatment of HCC. The aim of this descriptive systematic review was to describe the clinical features and maternal and neonatal outcomes of HCC in pregnancy. Material and methods We performed a systematic review of the literature about HCC diagnosed in pregnancy and the postpartum period, with signs or symptoms arising in pregnancy. We included case reports and case series describing the clinical features of women diagnosed with HCC, fibrolamellar variant of HCC, and mixed HCC and cholangiocarcinoma during pregnancy or the postpartum period (with onset of symptoms during pregnancy), from inception to March 2023. The study protocol was registered with the PROSPERO database (Registration number: ID CRD42021275584). Results We identified 180 records. The articles included in this systematic review were 47 case reports and 5 case series, for a total of 63 pregnancies. The two most frequent predisposing conditions were hepatitis B virus infection (30/63; 47%) and liver cirrhosis (14/63; 22%). Ultrasound evaluation was the most used technique to detect HCC. AFP was higher than normal in 28/46 patients tested (61%). Surgical treatment was the most used therapy, both during pregnancy and after delivery. Twenty‐six patients (26/63; 42%) died within 6 months of diagnosis. Survival >24 months was 9% (4/46) in symptomatic and 29% (5/17) in asymptomatic women. No patient with cirrhotic liver survived more than 12 months. Thirty‐eight newborns were alive at 28 days of age (38/63; 61%). Conclusions Hepatocellular carcinoma in pregnancy is associated with a high risk of maternal and neonatal mortality. Diagnosis in asymptomatic high‐risk women or following abnormal maternal serum AFP screening is associated with better maternal outcomes.


| INTRODUC TI ON
Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor and typically develops in the context of chronic liver disease, such as liver cirrhosis or chronic hepatitis B virus (HBV) infection.In 2018, the estimated global incidence rate of liver cancer per 100 000 person-years was 9.3 and the corresponding mortality rate was 8.5.The median age at diagnosis among women is 65-69 years. 1 About 75% of primary liver cancers are HCC, and cholangiocarcinoma is the second most frequent neoplasm. 1HCC is more frequent in men than in women, with a ratio of about 3:1. 2 The different sex distribution is thought to be due to differences in hepatitis carrier status, exposure to exogenous toxins, and/or potential effects of estrogens on interleukin-6 (IL-6). 3Inflammation is one of the major contributors to carcinogenesis, and IL-6 is the multifunctional cytokine responsible for the hepatic response to systemic infections or inflammation. 4,5Close ultrasound surveillance is recommended by major guidelines for patients at risk for HCC, liver cirrhosis, chronic active hepatitis B or C infection, and fibrosis.
Biopsy in patients without liver cirrhosis and the use of CT or MRI in patients with cirrhosis allow early diagnosis even with nodules just greater than 1 cm. 6The best long-term survival is observed with surgical treatment, resection and liver transplantation.However, several other non-curative treatments are available for patients who are not candidates for surgery: percutaneous local ablation (thermal or by radiofrequency), transarterial chemoembolization and radioembolization and, rarely, local injection of substances, such as ethanol or acetic acid.Systemic treatments include target molecular therapies, immunotherapy and classical cytotoxic agents. 7The appropriate and tailored treatment is determined by the extent of the disease and the severity of underlying liver disease, which can limit tolerance to therapies.In this context, pregnancy can represent an additional challenge in the choice of proper treatment approach.
According to some authors, estrogens may mediate a protective effect through the inhibition of IL-6 production in Kuppfer cells. 3It remains controversial, considering the small number of cases described in the literature, whether HCC observed during pregnancy differs from that arising in non-pregnant women.In addition, pregnancy can represent an obstacle to diagnosis and appropriate treatment.Lau et al. in 1995 described a more aggressive behavior of HCC during pregnancy, 8 suggesting that pregnancy is an adverse factor for the prognosis of HCC.However, a recent literature review has described an improvement in HCC-related mortality and morbidity during pregnancy, due to improved diagnostic and therapeutic capacity. 9One of the serum markers most commonly used to detect HCC in the non-pregnant population is α-fetoprotein (AFP), 10 which notoriously increases in pregnant women in relation to gestational age. 11This marker can be used to detect possible fetal abnormalities, and for this purpose is generally measured before 20 weeks of gestation. 11e aim of this descriptive systematic review was to describe the clinical features and maternal and neonatal outcomes of HCC in pregnancy.

| Main outcomes measures
Clinical features, diagnostic and treatment approaches, and fetal and maternal outcomes.

| Eligibility criteria
Given the rarity of HCC in pregnancy, we included case reports and case series describing the clinical features of women diagnosed with HCC, the fibrolamellar variant of HCC, and mixed HCC and cholangiocarcinoma during pregnancy or the postpartum period (with onset of symptoms during pregnancy).Studies with a presumptive diagnosis of HCC were included, even without certain histological data.To assess the methodological quality and risk of bias, we used the tool reported by Murad et al. 12 based on the domains of selection, ascertainment, causality, and reporting.

| Data collection and analysis
The titles and/or abstracts of the identified studies were screened independently by two authors (IP and FM).Subsequently, the same authors recovered the entire texts of screened papers and assessed the eligibility.The reference lists of all identified articles were systematically reviewed to identify other eligible publications.For all unavailable articles or incomplete data, we contacted the corresponding authors.Every disagreement on the eligibility of the data was resolved with consensus.The systematic review was performed following PRISMA guidelines.From each study, the following data For statistics, we used descriptive analysis.Comparative analyses were not performed because of the small number of patients, spread over a large period of time.
The study protocol was registered with the PROSPERO database (Registration number: ID CRD42021275584).

| General characteristics of the studies
We identified 180 records and screened 135 articles for evaluation.
We excluded 78 records, and then analyzed the remaining 57 articles, from which we excluded 5 other records that did not meet the inclusion criteria, leaving 52 articles that met the inclusion criteria.
The articles included in this systematic review were 47 case reports  S1.The assessment of the quality and risk of bias of each article is summarized in Table S2.The citations of the excluded studies are listed in Table S3.

| Synthesis of the results
From the records, we extracted data of 63 pregnant women.
Maternal characteristics are summarized in Table 1.The two most frequent comorbidities were HBV infection (30/63; 47%) and liver cirrhosis (14/63; 22%).We included 25 women from East Asia (40% of the sample), of whom 23 had a previous diagnosis of HBV infection (23/25; 92%).Three women (3/63; 5%) had a previous diagnosis of HCC, and one (1/63; 2%) had a diagnosis of recurrent HCC during pregnancy (all of them unplanned).One of them terminated the pregnancy; one had a vaginal birth at 33 weeks of pregnancy; and the last one died during hospitalization before any treatment could be performed.
The signs and symptoms of HCC are several, and include abdominal pain, ascites, gastrointestinal symptoms, jaundice, hypoglycemic coma, hemoperitoneum, rectal bleeding, and hemorrhagic shock.
The gestational age at delivery also differed in the two groups.

Termination of pregnancy was performed in one symptomatic
woman and in those without symptoms in whom HCC was discovered after AFP analysis.Fifteen women who delivered by cesarean section underwent hepatic surgery at the same time (15/63; 23.8%).
The maternal and fetal outcomes are described in Table 2.We cannot estimate an overall survival rate of women who had HCC during pregnancy because of the differences in follow-up data between the reports.The results show that 52% of symptomatic women died within 6 months after diagnosis (23/46), whereas women without symptoms with survival >24 months were 29% (5/17).Notably, no patient with a cirrhotic liver survived more than 12 months.The cause of death was described in 23 women only: 15 of them (15/23; 65%) died from hepatic insufficiency and multi-organ failure; five died from lung failure (5/23; 22%); and three from hemorrhagic shock (2/23; 13%).Thirty-eight (66%) newborns survived after delivery, 28 (67%) in the symptomatic group and 10 (63%) in women without symptoms (Table 2).

| DISCUSS ION
Hepatocellular carcinoma is a rare condition, especially in young women.In this systematic review, we identified 63 cases in pregnant women from 47 case reports and 5 case series, distributed over 70 years.Overall, 42 women (68%) died within 24 months of diagnosis, and we did not have information about 11 women (18%).Fifty percent of symptomatic women died within 6 months after diagnosis.
F I G U R E 1 PRISMA 2020 flow chart and steps of studies selection.Citations of excluded studies are provided in Table S3.Reports not retrieved (n = 4) were extracted: maternal ethnicity, clinical features, histological data, maternal serum AFP concentrations, coexistence of previous chronic liver disease (cirrhosis and chronic hepatitis virus infection), gestational age at diagnosis, diagnostic and treatment approaches, gestational age at childbirth, maternal and neonatal morbidity and death.Both IP and FM assessed the methodological quality of all the papers.
and 5 case series, for a total of 63 pregnancies.The study selection process is shown in Figure 1.The characteristics of each patient are summarized in Table