Exploring the link: a comprehensive literature review of Schistosoma japonicum infection and its oncogenic potential

Introduction

Background

Blood flukes, or trematode worms, of the genus Schistosoma are the cause of the acute and chronic parasitic disease schistosomiasis. According to estimates, in 2021, at least 251.4 million people would need preventative care (1). Schistosoma japonicum, one of the species of Schistosoma, endemic in China, Philippines and Indonesia causes intestinal schistosomiasis (2). When the skin comes in contact with contaminated freshwater that is home to specific snail intermediate hosts (Oncomelania hupensis quadrasi), an infection result (3).

The elimination of schistosomiasis in Asia may be possible with the use of integrated control measures (1) such as behavioral modifications (4), the construction of infrastructure in Water Sanitation and Hygiene (WASH) programs, and multifaceted interventions that target both human and animal hosts (5). The accomplishments in China, which include the elimination of significant reservoir hosts and a demonstration of government commitment, highlight the significance of strong support for ongoing control initiatives (5,6). In order to implement more thorough and successful control efforts, it is imperative that health education be prioritized (7). Knowledge gaps must be filled and endemic populations’ understanding of parasite-related behaviors must be improved (4).

Rationale and knowledge gap

Schistosomiasis symptoms are brought on by the body’s response to the worms’ eggs rather than the worms themselves (8). The eggs typically end up in the bladder, liver, or intestines where they inflict scarring or inflammation (9). Recurrent infections in children can lead to anemia, malnourishment, and learning challenges (10). The parasite can also harm the liver, gut, lungs, and bladder after years of infection. Eggs can occasionally be discovered in the brain or spinal cord and can lead to inflammation of the spinal cord, paralysis, or convulsions (8).

Chronic Schistosoma japonicum infection can cause numerous complications, including the development of cancer of the liver (11), colon and rectum (12). The parasite’s eggs in the host’s organs, especially the liver, induce tissue damage and chronic inflammation, which is the reason for the connection between schistosomiasis and cancer (13). The immunological reaction triggered by the eggs results in granulomas and fibrosis (14). Long-term tissue remodeling and inflammation raise the risk of genetic abnormalities and abnormal cell proliferation, which aid in the development and spread of cancer (15). The correlation between Schistosoma japonicum and cancer highlights the intricate relationship between oncogenesis and infectious diseases, emphasizing the need to treat the parasitic infection as well as any long-term effects it may have on impacted populations (16). Controlling schistosomiasis through public health initiatives is essential for lowering the disease’s immediate burden as well as the risks of cancer that are linked to it.

Objective

The objective of this review is to thoroughly review and analyze reported cases that associate Schistosoma japonicum infection with particular forms of cancer. We aim to identify the cancer types connected with Schistosoma japonicum and assess the evidence for a possible causative relationship by integrating the research that has already been published. The ultimate objective is to advance knowledge of Schistosoma japoncium’s oncogenic potential, and its effects on public health, in an effort to guide future research and preventive measures. We present this article in accordance with the Narrative Review reporting checklist (available at https://jphe.amegroups.com/article/view/10.21037/jphe-23-174/rc).

Methods

English-written, peer-reviewed journal articles were searched on December 2, 2023, using PubMed, Google Scholar, Embase and Web of Science in order to identify research studies that reported cases of cancers that are associated with Schistosoma japonicum. Three sets of search terms were used in each database following the search terms: (“Schistosoma japonicum”) AND (“case report” OR cases OR reports) AND (cancer OR hepatic cancer OR colon cancer OR colorectal cancer OR oncogenic). See Table 1 for the search strategy summary.

The study included case reports of cancers linked to Schistosoma japonicum infection. There were no restrictions on publication date or case occurrence to guarantee a thorough collection of relevant cases. Only case reports published in English were included, with studies that lacked entire papers but contained detailed clinical histories and diagnoses also being considered. The analysis eliminated studies that did not fit under the category of case reports.

Discussion

Case reports of cancers with the association of Schistosoma japonicum

In this review, we report 14 cases of cancer with the association of schistosomiasis involving the liver, colon and rectum (Table 2). These case reports highlight the different risk factors associated with Schistosoma japonicum infection and accordingly its potential for the development of certain types of cancer.

Demographic profile

Notably out of the 14 case reports gathered that suggest Schistosoma japonicum associated with cancer, 10 case reports involved male patients, the majority of whom are middle-aged and above. Age, gender and occupation are important risk factors for acquiring schistosomiasis (31). People with occupations involving contact with infested water, such as agricultural-related activities, are considered to have occupational hazards or exposure to Schistosoma infections (1,32). As mentioned in a similar article (33), three-fourths of agricultural workers are male, which is congruent with the data gathered in this review.

Geographic distribution

Moreover, the individuals referred to in the study have been exposed in a schistosomiasis-endemic area or have been previously infected by Schistosoma japonicum. Table 2 depicts nine case reports that have occurred in schistosomiasis-endemic areas, such as Japan and China, otherwise referred to as Asian schistosomiasis. Other Asian endemic countries include Cambodia, Lao People’s Democratic Republic, Myanmar, Indonesia, and the Philippines (34,35). Though Japan was previously endemic for Schistosoma japonicum infection 40 years ago. In 2016, one 90-year-old patient in this study diagnosed with ascending colon cancer was revealed to have numbers of Schistosoma ova in her histological findings (30). Notably, individuals in the case reports who previously served in military in an endemic area also were able to acquire schistosomiasis (22,25).

Date of incidences

The reports collected in this study describe case presentations of Schistosoma japonicum infection and cancer dating from 1940s to 2022. This suggests that Schistosoma infections and the association with cancer is a neglected disease that requires further investigation to advance knowledge of Schistosoma japonicum’s oncogenic potential. The discovery of case reports tying malignancies to Schistosoma japonicum as early as the 1940s has important implications for parasitology and oncology. According to these researches, there has long been a link between this parasite infection and the development of some tumors. Understanding this connection is critical for public health initiatives because it emphasizes the need of controlling and preventing schistosomiasis in order to lower the incidence of related malignancies (36). This early acknowledgment also encourages additional research into the molecular mechanisms underpinning Schistosoma japonicum’s oncogenic potential, which could lead to the development of targeted treatments or preventive measures (37). The historical context of these studies enriches our understanding of the complex interaction between infectious diseases and cancer, underscoring the importance of multidisciplinary collaboration in addressing complex health challenges (38).

Signs and symptoms

The review highlights a relationship between these symptoms and Schistosoma japonicum infection, specifically colorectal and liver malignancies. Abdominal distension, low appetite, weight loss, jaundice, and positive occult blood are some commonalities among reported cases although in some instances the patient is asymptomatic. This study emphasizes the complex link between chronic Schistosoma japonicum infection and the development of colorectal and liver malignancies (12). The clinical presentation indicates the necessity for a thorough medical investigation, including testing for parasite infections and cancers, in order to guide appropriate interventions and improve patient outcomes. Notably, it is important to consider the clinical history, complimentary image diagnosis, fine needle biopsy cytology and immunohistologic studies are useful when attempting to establish an accurate diagnosis (29) as seen in Table 2.

Schistosoma japonicum and cancer association

Schistosomiasis is a systemic illness that damages various organs and systems in the human body (39). Its clinicopathological kinds are diverse, and there may be an “Inflammation-adenoma-carcinoma” pathological transformation process. Some clinicopathological aspects distinguish schistosomiasis-associated digestive system cancers from non-schistosomiasis malignancies.

Schistosoma japonicum and colorectal cancer

Four out of 14 patients included in this study were commonly found to have colon cancer, which was later diagnosed as stage 2 adenocarcinomas. They were typically presented with ulcerating surfaces of the sigmoid colon surrounded with calcified numbers of Schistosoma japonicum eggs deposited in the submucosa of the sigmoid colon. Majority of these cases had a history of being exposed to infested waters in their childhood.

In addition to colon cancer, rectal cancer has been linked to schistosomiasis. The three cases included in this review showed various clinical manifestations ranging from asymptomatic, change in bowel movements, constipation, submucosal nodule, and to rectal mass. In the case (19), the tumor cells had a small acidophilic cytoplasm with a slightly enlarged nucleus, strongly positive for chromogranin A and focally for synaptophysin. These markers generally indicate carcinoid tumors and neoplasms. In contrast, a rectal mass biopsy revealed extensive infiltration of signet ring cells confirmed using mucicarmine and periodic acid Schiff stain with diastase digestion (PASD) (26). This case was identified as a metastatic signet ring cell carcinoma (SRCC), which is the first occurrence in the context of Schistosoma japonicum chronic infection at this time. Despite the former cases varying in clinical manifestations and types of colorectal cancer, both showed the presence of clusters of calcified Schistosoma japonicum ova. In another case report (19) where colorectal neoplasm was identified, the Schistosoma japonicum ova were found in loose connective tissue that surrounds the thick tumor stroma while the previously mentioned metastatic SRCC (26) were located in lymph nodes. These findings suggest that the location of calcified Schistosoma japonicum ova may cause different types of colorectal cancer.

As early as 1980 (40), 289 cases of colorectal carcinoma were described to be associated with schistosomiasis. There were various colorectal carcinomas deduced, such as mucoid carcinoma. Furthermore, 18% are with combined infection of Schistosoma japonicum among the reported cases of the colorectal cancer patients in West China Hospital between 2006 to 2012 (41). It is likely that a chronic schistosomiasis infestation contributes to the development of colorectal neoplasms (41). In the same year, a case-control study concluded that patients with a history of schistosomal infection were 3 times more likely to develop colon or liver cancer (42). They have observed that 24% of colon cancer patients were attributed to schistosomiasis. Colonic schistosomiasis is one likely independent risk factor for the development of colorectal carcinogenesis (18).

This greatly suggests that Schistosoma japonicum ova can interact with the host microenvironment chronically by causing damage to the mucous membrane and initiating inflammation. This chronic inflammatory response is proposed to produce reactive oxygen species (ROS) and inflammatory cytokines. This results in genomic instability and dysregulation of oncogenes and onco-suppressor genes (17). According to similar studies (43), these genotoxic agents lead to various genomic mutations, such as substitution mutations and missense mutations. This is identical for rectal cancer cases wherein p53 tumor suppressor gene mutations were detected in cases of Schistosoma japonicum infections. In addition to the formerly mentioned genomic mutations also observed point mutations. Several studies agree that the TP53 gene mutation suggests that it plays a role in contributing to Schistosoma japonicum-associated colorectal cancer (26,30). Other factors that are proposed to develop colorectal cancer are TGF-β signaling for metastasis development and amplification of c-MYC, an oncogene. Ulceration, microabscess formation, and carcinogenesis can emerge as a result of this as presented in the mentioned case reports.

Moreover, decreased levels of cytochrome P450 in Schistosoma japonicum infections were eminent in a mouse model (44). This was hypothesized to decrease mutagen processing ability, therefore leading to impairment of immunological surveillance. In addition to a higher risk of Schistosoma japonicum infection and later developing colorectal cancer, this is suggested to render Enterobacteriaceae survivability that further promotes colorectal carcinogenesis (45,46).

Schistosoma japonicum and hepatocellular cancer

The pathophysiology of liver cancer caused by Schistosoma japonicum infection is characterized by chronic inflammation, fibrosis, and complex cellular interactions. The eggs of Schistosoma japonicum become trapped in the host’s liver after being discharged into the bloodstream, prompting a chronic immunological response. Chronic inflammation ensues, resulting in hepatic stellate cell activation and fibrosis (47,48). Prolonged fibrotic alterations lead to cirrhosis, which is a known precursor to hepatocellular carcinoma (HCC). In this inflammatory environment, DNA damage and mutations accumulate in hepatocytes, promoting cancer start and development (14).

The development of liver cancer is closely connected to a cascade of inflammatory chemicals that coordinate chronic inflammation and contribute to HCC. During chronic schistosomiasis, pro-inflammatory cytokines such as interleukin-1 (49) and tumor necrosis factor-alpha (50) are elevated, creating an inflammatory environment. Chemokines, such as CCL2 and CXCL10, are important in recruiting immune cells to the liver and therefore perpetuating the inflammatory response (51,52). TGF-β, a profibrotic cytokine, leads to the stimulation of hepatic stellate cells and the deposition of collagen, resulting in fibrosis (53,54). Prostaglandins, including prostaglandin E2 (PGE2), have pro-inflammatory actions and may contribute to angiogenesis and immunosuppression, hence promoting tumor growth (55). Furthermore, ROS produced during chronic inflammation cause oxidative stress and DNA damage, increasing the risk of HCC development and progression (56). The intricate interplay of these inflammatory substances emphasizes the complexity of the pathophysiological mechanisms underlying liver cancer caused by Schistosoma japonicum infection, emphasizing the need for targeted therapeutic approaches to target the specific inflammatory pathways involved.

The imbalance of glucose and lipid metabolism was reported to engage in the liver fibrosis generated by the parasite, which gives a unique hint for researching the underlying mechanism of the intestinal pathology of the disease (13,14,56). These findings reveal Schistosoma japonicum infection induces dynamic changes in the expression levels of genes involved in catabolism (glucose uptake, glycolysis and fatty acid oxidation) and suppressing anabolism (glycogen synthesis) in the liver, which could occur via macrophages’ metabolic states (13).

The studies (11,42,57) show that HBsAg and schistosomiasis are both important risk factors for liver cancer, and schistosomiasis may be far more important in the area than hepatitis B virus. The examination of these three factors in combination suggests that each component may be associated with liver cancer in a multiplicative rather than additive manner (58).

Schistosoma japonicum and other cancers

Metastases commonly occur within the abdominal region and nearby organs in the context of liver cancer associated with chronic schistosomiasis, for example, metastases may spread to the lungs, peritoneum, or regional lymph nodes (Table 2). The bones, including the skull, are less common sites for metastases, and their occurrence may be more associated with advanced stages of liver cancer (59) rather than the specific influence of schistosomiasis.

In this review, several cases of cancer including a case of high-grade tubular adenomas in the colon linked (18), SRCC (26) of the rectum and a rare variant of adenocarcinoma (60) associated with chronic schistosomiasis were reported (Table 2). SRCC, a rare variant of adenocarcinoma, is characterized by mucin production (61). The eggs of Schistosoma japonicum in the colon induce mucous membrane damage, triggering an inflammatory response that leads to colitis with ulceration, microabscess formation, pseudopolyps, and ultimately, carcinogenesis (18). In terms of the development of other primary cancers involving the liver in the context of chronic schistosomiasis, while HCC is the most prevalent, other types of primary liver cancers, such as cholangiocarcinoma may occur (21,24) Another case reported developed an uncommon type of Sporadic Porphyria Cutanea Tarda (SPCT) characterized by a liver disorder brought about by Schistosoma japonicum infection (62). In turn, the patient develops cutaneous squamous cell carcinoma (CSCC) on SPCT. A rare case of skull metastasis was reported as liver cirrhosis due to Schistosoma japonicum infection (63). The pathology revealed that circulating tumor cells from the liver had metastasized to the calvaria. Schistosoma japonicum infection causes persistent inflammation and fibrosis, which may lead to the development of numerous liver diseases, including several kinds of liver cancer. An asymptomatic Filipino woman who revealed microcalcifications suggestive of carcinoma in her mammography. Her breast biopsy showed that calcified ova of Schistosoma japonicum was the cause (64).

Greater research into the particular processes and frequency of these metastatic occurrences may be required for a complete understanding. Furthermore, these cases underscore the diverse and intricate pathological manifestations associated with chronic schistosomiasis, emphasizing the need for comprehensive understanding and management of both parasitic infections and their associated malignancies.

Implication to public health

Schistosomiasis caused by Schistosoma japonicum remains a public health concern in endemic areas in Asia. Schistosomiasis control and elimination efforts in Asia have been underway for many years, with national governments (5), international organizations (65), and non-governmental organizations implementing a variety of strategies. These strategies often involve mass drug administration (MDA) using praziquantel, improved sanitation and availability to clean water, snail control measures, health education and awareness programs, and infection rate surveillance and monitoring (66,67).

While significant success has been made in reducing the schistosomiasis burden, there are still challenges ahead. Inadequate resources, restricted access to healthcare services in rural places, environmental variables that encourage parasite transmission, and socioeconomic determinants of health all play a role in the persistence of schistosomiasis in specific regions (68,69). In addition, while many schistosomiasis elimination programs focus on reducing parasite transmission and treating infected individuals to alleviate symptoms and prevent severe complications such as organ damage, it may be necessary to include measures that address the potential oncogenic (cancer-causing) effects of chronic schistosomiasis (70). The link between chronic schistosomiasis and the development of certain types of cancer, such as colorectal and liver cancer in the case of Schistosoma japonicum infection, emphasizes the importance of incorporating cancer prevention and control measures into schistosomiasis elimination programs, especially in endemic areas (11,12).

Schistosomiasis-related malignancies are uncommon in non-endemic nations, but their potential influence on public health needs to be recognized, particularly among vulnerable groups with a history of parasite infection. It is alarming to note that there is an emerging increase of prevalence of schistosomiasis and related unspecific chronic complications in European countries due to global migration from schistosomiasis-endemic countries (71,72). Though these studies have focused more on Schistosoma haematobium and Schistosoma mansoni, it is inevitable that the Schistosoma species in general, are emphasized to be neglected and underdiagnosed (72,73). This further suggests that there are underdiagnosed and misdiagnosed cases of cancer, infection, and other complications caused and/or associated by the Schistosoma species (74,75). As a result, initiatives to raise awareness, improve diagnostic capabilities, and adopt effective management methods are critical components of comprehensive medical approaches in these settings (76).

Increasing awareness of the healthcare providers in non-endemic countries between chronic schistosomiasis and development of cancer is important. With this, they may consider screening persons with a history of travel or residence in endemic areas, particularly if they exhibit symptoms or risk factors for schistosomiasis-related malignancies (77). Aside from health practitioners’ awareness, public health education initiatives may focus on migrants, travelers and other at-risk population about the link between schistosomiasis and development of cancer, as well as importance of seeking comprehensive medical evaluation and screening measures (16,78).

By adding efforts to address Schistosoma species’ oncogenic potential into existing elimination programmes, it may be able to lower the burden of schistosomiasis-related cancer and improve the long-term health outcomes of afflicted communities and/or vulnerable population.

Limitations of the study

This study had several limitations. First, selection bias may have been present because the databases used failed to cover all relevant cases. Potential cases may have been overlooked due to publication bias or limitations in the search strategies. Second, the low quality of evidence, resulting from the anecdotal nature of case reports, may have reduced the strength of conclusions. As a result, the case reports’ generalizability to larger populations may be limited. Future research could focus on various areas to increase the evidence basis and address gaps in the understanding of Schistosoma japonicum infection’s oncogenic potential. It would be advantageous to conduct mechanistic research to establish the biological pathways by which Schistosoma japonicum infection leads to the development of colorectal and liver cancer. Furthermore, conducting large-scale epidemiological and longitudinal studies to analyze the connection of Schistosoma japonicum with colorectal and liver cancer patients, as well as understanding the long-term risks of acquiring such diseases, could provide useful insights. Finally, animal model studies or biomarker discoveries that link Schistosoma japonicum to these tumors may provide useful insights into disease mechanisms and potential therapeutic management.

Conclusions

In conclusion, the literature study demonstrates a strong link between Schistosoma japonicum infection and numerous malignancies, including those of the liver, colon, rectum, and rare locations. The cases emphasize demographic risk factors, endemic geographic regions, and a complex interplay of chronic inflammation, fibrosis, and genetic alterations that contribute to cancer development. Many clinical signs and distinct metastatic incidences highlight the complex pathological aspects associated with chronic schistosomiasis. The timeline underscores the long-standing connection, urging further research to uncover the neglected disease’s oncogenic potential. This complete understanding emphasizes the significance of targeted intervention and preventive measures for parasite infections and the associated malignancies.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jphe.amegroups.com/article/view/10.21037/jphe-23-174/rc

Peer Review File: Available at https://jphe.amegroups.com/article/view/10.21037/jphe-23-174/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jphe.amegroups.com/article/view/10.21037/jphe-23-174/coif). The authors have no conflicts of interest to declare.

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