Biliary Parasitic Diseases Associated with Hepatobiliary Carcinoma Free

The fluke is in the class Trematoda and consists of groups of parasitic flatworms. Some of the fluke species can infect and reside in the human intestine, bile duct, and liver [1]. Despite much effort in preventing and controlling flukes by health authorities, their prevalence remains high, and many people suffer from fluke infections in endemic areas in eastern or southeastern Asia [2]. While the symptoms caused by fluke infection are mild to minimal in general, the infection tends to be prolonged and can cause serious late complications such as developing malignancy. In fact, according to the International Agency for Research on Cancer (IARC), some flukes are classified as group 1, 2A, or 2B carcinogens [3], which are considered “definitely,” “probably,” or “possibly” carcinogenic to humans, respectively. In this mini review, we focus on three common flukes in eastern and southeastern Asia and describe the association between fluke infection and the risk of hepatobiliary cancer.

Schistosomiasis is a neglected disease caused by infection with blood fluke trematodes of the genus Schistosoma. Schistosomiasis is considered the most important helminth parasite in humans in terms of morbidity and mortality. This disease affects 200 million people worldwide. Schistosoma japonicum (SJ) is one of the five species of Schistosoma that infect humans, and others include S. haematobium, S. mansoni, S. intercalatum, and S. mekongi.

SJ, so-called blood fluke, was originally discovered in Japan in 1904. Although SJ was successfully eradicated from Japan in the 1990s by a public health campaign for the prevention and control of this disease, it remains endemic in China, the Philippines, and Indonesia, and its new incidence has been reported as thousands each year worldwide [4].

The cercariae of SJ grow in the snail and are transmitted to humans by direct contact to the skin. Once cercariae infect the human body, they move to the gut and then the liver via the portal circulation, where they produce eggs, which cause local immune reactions developing granulomas. As a result, patients with SJ infection develop skin rash, fever, diarrhea, or abdominal pain as acute symptoms. The granuloma or the egg itself can cause the obstruction of small vessels in the liver, and patients can develop liver cirrhosis at a later stage of this disease. The diagnosis of SJ is confirmed by a serological test or a stool test for the detection of eggs, and praziquantel is an effective anthelmintic to eradicate SJ infection.

There is a much higher prevalence of hepatocellular carcinoma (HCC) in the local endemic areas of SJ than in non-endemic areas. Therefore, an association between SJ infection and carcinogenesis of HCC is suspected. In an epidemiological study reported by Inaba et al. [5], 62 patients with HCC in an endemic area of SJ in Japan were evaluated for risk factors and compared with other populations with or without other liver disease. This study showed that a history of SJ infection was an independent risk factor for HCC. A similar study from China also showed that SJ infection was associated with an increased risk of HCC in patients without a history of hepatitis B virus infection [6]. Although there are no data available yet to address the possible cofounding of SJ infection with hepatitis C virus infection, SJ infection was classified as possibly carcinogenic to humans (group 2B) by the IARC [3].

Clonorchis sinensis (CS), so-called Chinese liver fluke, is the third most prevalent worm parasite and is currently endemic in China and Korea. Approximately, 35 million people are estimated to be infected by CS worldwide, and most of them are in China. Liver flukes have three distinct hosts in their life cycles. The eggs produced by the adult worms are excreted into the hosts’ stool and ingested by snails when they reach a freshwater body. They grow as cercariae in the snails and then swim in the water, transmitting to various freshwater fishes, where they become infectious metacercariae. Humans or other fish-eating animals are infected by ingesting raw or undercooked fish containing metacercariae. The flukes live in the bile duct system for a long time and keep feeding eggs in the bile (up to 10–24 years). Most hosts are asymptomatic, but some may develop biliary symptoms when they develop cholangitis. The diagnosis of CJ is made by a serological test or a stool test for the detection of eggs, and CJ infection can be eradicated by praziquantel.

In addition to many case reports for concomitant CS infection in patients with cholangiocarcinoma (CCA), a lot of evidence for the association between CS infection and an increased risk of CCA has been reported. Two epidemiological studies from South Korea described a higher incidence of CCA in endemic local areas with a higher prevalence of CS than that in any other areas in the country [7, 8]. Shin et al. [9] evaluated the risk factors for CCA by analyzing 41 patients with CCA compared with 203 patients with other liver disease and 203 healthy controls. They showed that a history of CS infection was a risk factor for CCA with a relative risk of 5.0. In a much larger case-control study reported by Lee et al. [10] including 622 patients with CCA compared with 2,488 healthy controls, CS infection increased the risk of CCA 14 times. Infection with CS was classified as probably carcinogenic to humans (group 2A) by the IARC [3].

Opisthorchisviverrini (OV) is another common liver fluke called the South East liver fluke. OV is endemic in north Thailand and 10 million people are estimated to be infected by OV. Similar to CS, OV causes infection in humans by the ingestion of raw or undercooked fish containing its metacercariae. Most infections are subclinical, and acute symptoms caused by OV infection are usually minimal and include vague gastrointestinal discomfort, diarrhea, and constipation. The diagnosis of OV is made by a serological test or the detection of eggs in stools. Similar to the other species mentioned above, praziquantel is also effective to eradicate this disease.

OV is one of the most studied parasites for the risk of CCA, and there is robust evidence for the association between OV infection and CCA. Sriamporn et al. [11] showed a positive correlation between the incidence of CCA and the prevalence of OV in an epidemiological study including more than 18,000 people from 20 endemic areas in Thailand. In a case-control study by Kurathong et al. [12] which included 13 patients with CCA and 479 control patients without hepatobiliary disease, OV infection was associated with an increased risk of CCA with a relative risk of 11. In another larger case-control study by Honjo et al. [13] which included 129 patients with CCA and 129 population-based controls, the infection of OV confirmed by a serological test was associated with an increased risk of CCA with a relative risk of 27. Infection with OV was classified as definitely carcinogenic to humans (group 1) by the IARC [3]. The characteristics of these three flukes are summarized in Table 1.

Surgery is the best available therapy with the potential to cure patients with HCC and CCA. Resection of the tumor should be considered whenever it is limited to locoregional disease and complete resection is feasible. The data regarding long-term outcomes after resection for fluke-associated cancers have been limited to several reports of relatively small case series. Watanapa et al. [14, 15] reported their experience of 30 patients with hilar CCA associated with OV. While only 7 patients underwent resection for curative intent, the 2-year survival rate after resection was 43%, and they claimed that this rate was similar to that in those with perihilar CCA without liver fluke infection. In contrast, Matsuda et al. [16] reported a poor long-term outcomes in patients with HCC with chronic SJ infection. Among 198 patients with HCC who underwent resection, 44 patients had chronic SJ infection. The 5-year survival rate in patients with SJ infection was 25% compared with 31% in those without SJ infection. Notably, in the multivariate analysis of prognostic factors, SJ infection was one of the significant factors associated with poor outcomes. The mechanism by which SJ infection causes worse long-term outcomes remains to be determined. There are no data available to date regarding the long-term outcomes after resection for CCA associated with CS.

Flukes remain clinically important in East Asia because they lead to an increase in the incidence of hepatobiliary cancer and mortality in this endemic area. Early treatment and prevention of the disease spread can reduce the incidence of deadly cancers. The manuscript was presented at DDW 2017 from the 5th to the 8th of May in Chicago, IL, USA.

We thank Ellen Knapp, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

The authors have no conflicts of interest to declare.

None.

The contribution of each author was as follows: T.H.: conception or design of the report and drafting the manuscript; H.I.: conception or design of the report, drafting the manuscript, and critical revision of the manuscript.