Abstract
Background/Aim: Liver cancer constitutes one of the leading cancers globally. During pregnancy, however, liver cancer is an absolute rarity, with very few cases reported in the international literature. The aim of the present review was to provide a useful update and summarize all case studies of liver cancer in pregnancy published between 2012-2023. Materials and Methods: A literature review was conducted using the MEDLINE, LIVIVO, and Google Scholar databases. Solely case reports and case studies written in the English language that explicitly reported on the presence of histologically confirmed HCC or intrahepatic cholangiocarcinoma during pregnancy were included in the data analysis. Results: After detailed evaluation, a total of 35 reported cases of liver cancer during pregnancy were identified, hence bringing the total number of reported cases globally to 83. Oncological challenges during pregnancy call for an interdisciplinary approach. Although the desire to preserve the pregnancy should be taken into consideration, specialists need to evaluate maternal and fetal well-being and choose the optimal oncological treatment with the least dangers for both the maternal and fetal safety. Conclusion: The present review proves that, despite its scarcity, liver cancer may always occur during pregnancy and clinicians should, therefore, remain vigilant and endeavor to detect and evaluate any hepatic mass or symptoms of liver cancer promptly and exhaustively.
Pregnancy complicated by cancer is considered a rare phenomenon (1). Obstetrical and oncological registries are, however, not uniform worldwide, data regarding miscarriages or abortions are frequently missing, while it is not always clear whether findings across studies are referring to pregnancies or live births (2). Nevertheless, cancer has been proposed as the second leading cause of death during the female reproductive years and complicates an estimated 1 in 1,000 pregnancies (3). The incidence of malignancies increases with age and, given that women in developed countries still tend to delay childbirth for socioeconomic reasons, cancer occurrence in pregnancy will respectively continue to augment (4). Additionally, the implementation of non-invasive prenatal testing with the ability to detect preclinical cancer is anticipated to further promote this increase (5). Cancers diagnosed in pregnancy do not differ from those affecting non-pregnant women of the same age. Melanoma, breast cancer, cervical cancer, lymphomas, and leukemias, represent the most frequently occurring malignancies during pregnancy (3).
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma represent the main types of adult primary liver cancer, with HCC constituting the leading primary liver cancer (6). For 2023, the American Cancer Society estimates the incidence of primary liver and intrahepatic bile duct cancer at 41,210 cases and the related deaths at 29,380 in the United States (7). Excessive alcohol consumption, nicotine abuse, nonalcoholic steatohepatitis (NASH), hepatic cirrhosis, chronic viral hepatitis B or C, as well as aflatoxin ingestion, exemplify the most common causes of liver cancer (8-10). Liver cancer patients typically present with signs of the underlying etiological conditions, whereas symptoms of advanced liver cancer might incorporate cancer cachexia, hepatomegaly, ascites, or jaundice (11). Routine screening for liver cancer in at-risk patients involves alpha-fetoprotein (AFP) blood tests and abdominal ultrasound exams on a six-month basis (12). For patients with early-stage resectable liver cancer, partial hepatectomy or liver transplantation epitomize the first-line therapy (13, 14). For more advanced stage liver cancers, treatment options include radiofrequency ablation, transcatheter arterial embolization, targeted therapy, immunotherapy, chemotherapy, or radiotherapy (13, 15, 16).
Despite its high incidence in the general adult population, liver cancer seems to be extremely uncommon in pregnant women (17). A plausible explanation for this scarcity could be the fact that cirrhosis significantly correlates with infertility (18). In 2011, Choi et al. published the last available retrospective literature review of all 48 case studies globally of HCC in pregnancy and reported poor but improving survival rates over time, particularly due to both earlier diagnosis and surgical intervention (19).
The present work aims at identifying all case studies of liver cancer in pregnancy published between 2012-2023.
Materials and Methods
A literature review was conducted using the MEDLINE, LIVIVO, and Google Scholar databases. Solely case reports and case studies written in the English language that explicitly reported on the presence of histologically confirmed HCC or intrahepatic cholangiocarcinoma during pregnancy were included in the data analysis. The search terms “liver cancer”, “hepatocellular carcinoma”, “cholangiocarcinoma”, and “pregnancy” were employed, and we were able to identify a total of 6589 articles published between 1951 and 2023, after the exclusion of duplicates. A total of 4,977 were discarded in the initial selection process after abstract review due to topic irrelevance. The full texts of the remaining publications were evaluated, and after detailed analysis, a total of 35 relevant studies published between 2012 and 2023 that met the inclusion criteria were selected for the literature review. Figure 1 presents an overview of the aforementioned selection process according to the PRISMA guidelines.
PRISMA flow diagram visually summarizing the screening process.
Results
After detailed evaluation, a total of 35 relevant cases published between 2012 and 2023 that met the inclusion criteria were selected for the literature review.
In 2012, a total of five case reports were published on pregnant women with liver cancer. Chen et al. submitted the case of a 33-year-old pregnant patient with HCC at 28 weeks of gestation, who successfully underwent synchronous cesarean section and right hepatectomy at 32 weeks of gestation (20). Similarly, Russell et al. announced the case of HCC in another 33-year-old pregnant patient, who underwent a synchronous caesarean section and liver resection at 30 weeks of gestation, respectively (17). Furthermore, Hung et al. reported on a 30-year-old patient that suffered from HCC during pregnancy and underwent hepatectomy twice and pulmonary metastasectomy once. A healthy infant was delivered after the first hepatectomy, while she also delivered another healthy infant three years after the resection for pulmonary metastasis (21). The same year, Norouzi et al. described the case of HCC in a 41-year-old pregnant woman who was diagnosed with multiple massive hepatic lesions at laparotomy for termination of pregnancy (22), while Chen et al. submitted the case report of a 28-year-old pregnant woman that was admitted for caesarean section at 38 weeks and underwent segmental hepatectomy for HCC one month later (23).
Two years later, the publication of another three relevant case reports/series followed. Al-Ibrahim et al. reported the case of a 31-year-old pregnant woman with HCC who underwent cesarean section for cephalopelvic disproportion, followed by right lobe hepatectomy three weeks postpartum (24). Moreover, Chen et al. presented the case of a 23-year-old pregnant patient with obstructive jaundice at 38 weeks of gestation due to HCC. After receiving percutaneous transhepatic biliary drainage and caesarean section, right hepatectomy, extrahepatic bile duct resection, and left hepaticojejunostomy were performed upon jaundice improvement (25). Last but not least, Li et al. reviewed their experience with the management of four young pregnant patients with HCC that all underwent hepatectomy during or following caesarian section or abortion (26).
In 2015, three additional case reports were published on pregnant patients with liver cancer. Interestingly, Gerli et al. announced a case of mixed HCC and cholangiocarcinoma during pregnancy in a 30-year-old patient that underwent synchronous cesarean section and right hepatectomy at 31 weeks of gestation (27). Mnyani et al. described the delayed presentation and diagnosis of metastatic HCC in a 30-year-old pregnant woman, who went into spontaneous preterm labor at 32 weeks, but the final diagnosis of metastatic HCC was made postpartum (28). Of note, Manibusan et al. also presented the case of a 23-year-old pregnant lady with fibrolamellar HCC who was first treated with yttrium-90 microspheres (Y90) and was then taken to emergent cesarean section at 32 weeks of gestation (29).
Awuku et al. were the sole study group to publish a case report on a 36-year-old pregnant woman with HCC in 2016, the pregnancy of whom was terminated at 30 weeks by successful labor induction (30).
In 2017, a total of three case reports were published on pregnant women with liver cancer. Malli et al. highlighted the rare case of aggressive cholangiocarcinoma during pregnancy in a 30-year-old patient with primary sclerosing cholangitis (31), while Pencovich et al. described the results of the successful extended left hepatectomy at 30 weeks of gestation, followed by a normal vaginal birth at 38 weeks of gestation, in a 30-year-old patient with intrahepatic cholangiocarcinoma (32). Besides, Vishnu et al. announced the case of a 26-year-old pregnant woman, who underwent a left hepatectomy with extrahepatic bile duct excision for fibrolamellar HCC after an emergency caesarean section at 31 weeks of gestation (33).
The following year, the publication of another six relevant case reports took place. Both Qasrawi et al. and Monteiro de Melo Santos et al. reported two cases of women who were diagnosed with intrahepatic cholangiocarcinoma during their pregnancies (34, 35). Remarkably, Matsuo et al. presented the case of a 33-year-old patient with HCC at 17 weeks of gestation who received radiofrequency ablation for the local control of cancer at 17 weeks of gestation, followed by radical surgery at postpartum (36). Lee et al. claimed to have published the first case of spontaneous rupture of HCC with hemoperitoneum during pregnancy in a 36-year-old patient in Australia (37). Last but not least, both Francis et al. and McCarthy et al. described two separate cases of recurrent liver cancer in pregnancy (38, 39).
In 2019, Green-Thompson et al. underlined the case of a 36-year-old pregnant woman who was diagnosed with HCC late in gestation (40), whereas Das et al. presented a postpartum patient with cholangiocarcinoma who, however, experienced right upper abdominal pain and jaundice from the 20th week of gestation (41).
One year later, a total of six case reports were published on pregnant women with liver cancer. Grubman et al. submitted their case report of a 37-year-old pregnant patient with intrahepatic cholangiocarcinoma complicated by opioid tolerance (42) and Wembulua et al. shared their experience with a 36-year-old patient whose pregnancy was complicated by HCC (43). Furthermore, Maeda et al. reported an additional case of hepatic resection for recurrent HCC during pregnancy (44). Scioscia et al. contributed with an intraoperative photo of spontaneous bleeding of HCC during an emergency caesarean section in a 31-year-old primigravida at 40 weeks of gestation (45). Last but not least, Diakhate et al. announced two cases of HCC associated with pregnancy at the same gynecological and obstetrical clinic in Senegal (46). Sato-Espinoza et al. were the sole study group to publish a case report on a 24-year-old pregnant woman with HCC in 2021, the pregnancy of whom was terminated at 34 weeks by emergency cesarean section (47). In 2022, only Iijima et al. shared their experience with a 40-year-old primipara at 30 weeks of gestation with recurrent and rapidly worsening HCC, who, after delivery at 33 weeks, received chemotherapy (48).
The most recent relevant case report was published in February 2023 by Pakkala et al. about a 23-year-old with primary intrahepatic choriocarcinoma at 28 weeks of gestation that underwent an early cesarean section at 32 weeks, followed by the administration of adjuvant chemotherapy (49). Table I presents a comprehensive overview of the above reported cases of liver cancer in pregnancy.
Studies with liver cancer in pregnancy.
Discussion
Awareness about the complex coincidence of cancer and pregnancy, alongside with the increasing possibilities of treatment, have led to the expansion of research to large-scale registries. Overall, obstetric outcome has improved in the recent decades, with fewer terminations of pregnancy and fewer deliveries being prematurely induced to initiate maternal cancer treatment. As a consequence, more women are efficiently treated for cancer during pregnancy nowadays (50).
Liver cancer occurs very rarely in pregnancy, with a total of 48 reported cases described in the international medical literature till 2011 (19). The present review adds 35 relevant cases of liver cancer in pregnant women published between 2012 and 2023, hence bringing the total number of reported cases globally to 83. Under the cases published between 2012 and 2023, liver cancer occurred in an age range from 23 to 41 years with a mean age of 31.6 years. Most cases of liver cancer during pregnancy were reported in Eastern Asian and sub-Saharan countries. This distinct distribution may be partly attributed to the typical prevalence of hepatitis B and C viruses, which in general constitute major risk factors for the development of liver cancer (51).
Liver cancer diagnosis during pregnancy may be challenging, as tumors usually remain asymptomatic in the early disease stages, physiologic symptoms of pregnancy such as fatigue, nausea, or emesis, resemble those of liver cancer, whereas palpable liver masses become less evident upon pregnancy progression. Significantly, even the typical combination of right upper quadrant abdominal discomfort, hepatomegaly, and jaundice, may be misinterpreted and falsely attributed to the pregnancy per se. In the same context, liver function tests and maternal alpha fetal protein levels show profound alterations in pregnancy and other conditions (52), thereby further complicating the diagnosis of liver cancer. Fortunately, ultrasonography may accurately detect suspicious liver masses, while Magnetic Resonance Imaging (MRI) may provide clinicians with essential information for both the diagnosis and the treatment plan, without any adverse effects on the fetus. Consequently, liver cancer may be discovered early in pregnancy, thus permitting for the conceptualization of the most appropriate treatment plan for both the mother and the fetus.
Liver resection seems to represent the main stay of liver cancer therapy in pregnancy. More precisely, either synchronous or subsequent hepatectomies are the most preferred treatment modalities for localized liver cancer, where possible, with preservation of the pregnancy. Especially in cases where liver cancer is diagnosed during the second or third trimester, clinicians seem to prioritize a safe labor induction or elective cesarean section after the 32 weeks of gestation, with the administration of surfactants or steroids playing a most important role in terms of fetal lung maturity. Most authorities will, nonetheless, prefer termination of pregnancy in the first trimester in patients with advanced liver cancer, so that the mothers may benefit from all available treatment modalities including chemotherapy, radiotherapy, RFA, etc.
Early and precise diagnosis of localized liver cancer, alongside with a successful complete surgical excision of the tumor, account for the good prognosis and promising postoperative course of both the mother and the newborn. Nevertheless, survival rates seem to significantly drop in cases of advanced and/or metastatic liver cancer.
Conclusion
Oncological challenges during pregnancy call for an interdisciplinary approach. Even though the desire to preserve the pregnancy should be always considered, specialists need to weigh maternal and fetal well-being and opt for the optimal oncological treatment with the least dangers for both the maternal and fetal safety. Regardless of the epidemiologic figures, oncological treatment in pregnant women should adhere to treatment guidelines used for non-pregnant patients in order to safeguard maternal prognosis. The present review proves that, despite its scarcity, liver cancer may always present during pregnancy and clinicians, therefore, need to remain alert and endeavor to detect and evaluate any hepatic mass or symptoms of liver cancer early and exhaustively.
Footnotes
Authors’ Contributions
IP, NG and CD designed the study. IP, NG, AG and CD wrote the article. IP, NG, AG, KV, PS, EK, KN and CD collected the data. NG, KV, EAA, DD, GK, MVK, NN, KK and CD offered scientific advice. IP, NG, and CD revised the manuscript. CD critically revised the manuscript and was the supervisor.
Conflicts of Interest
All the Authors declare that there are no conflicts of interest.
- Received April 10, 2023.
- Revision received May 18, 2023.
- Accepted May 30, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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