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Hepatic anisakiasis mimicking metastatic liver tumour

Highlights • Anisakiasis is a parasitic disease caused by anisakid nematode larvae in raw fish.• Anisakiasis may increase with growing consumption of raw fish around the world.• Hepatic anisakiasis presents as small, low density tumours in the liver margin.• The lesions resemble recurrent carcinoma, and can lead to unnecessary surgery.• Dietary investigation is warranted when liver tumour malignancy is not certain.


Introduction
Anisakiasis is the zoonotic disease caused by the third larval stage of anisakid nematodes, most frequently belonging to the Anisakis, Pseudoterranova genera and species of the genus Contracaecum [1]. This zoonotic infection is acquired through the consumption of raw or undercooked squid, mackerel and cod [2]. This is a relatively common diagnosis in East Asia due to the predominant food culture. However, with the increasing popularity of Japanese cuisine, the incidence of anisakiasis has become more frequent around the world due to the increased consumption of raw fish and mackerel [3][4][5]. More than 99% of anisakiasis cases occur in the gastrointestinal tract, specifically in the stomach and small intestine, however the larvae can penetrate the gastrointestinal mucosa or other organs with clinical consequences and potentially allergic reactions [6].
There are two types of allergic reaction, including relaxation type with primary infection and fulminant type with reinfection.
At the time of primary infection, the allergic reaction is weak and there are few symptoms. In extragastrointestinal anisakiasis, anisakis larvae from the primary infection penetrate the wall of the gastrointestinal tract asymptomatically, and sometimes granulomatous tissues are formed in the intraperitoneal organs including the omentum, mesentery, peritoneum, abdominal wall, lymph nodes, liver, pancreas, and ovaries.
Hepatic anisakiasis is said to be about 0.2% of all cases [7][8][9]. To our knowledge, there have been no reports of hepatic anisakiasis outside of Japan, and there is not yet a clear description of the imaging characteristics of the disease. Since the possibility that hepatic anisakiasis will occur in other countries is high, it is important to describe any diagnostic factors. We provide details of our case of hepatic anisakiasis which developed as a tumour at the border of the liver, and summarize the presentations of previously reported cases.
The work has been reported in line with the SCARE criteria [10].

Presentation of case
The patient was a 60-year-old man who had been diagnosed with rectal cancer. He underwent laparoscopic radical low anterior rectal resection and construction of a covering ileostomy. Pathological examination revealed that the rectal cancer was pT3 (A), pN1b       (Fig. 1). Serum tumour markers including CEA and CA19-9 were not elevated, and were similar to the levels before initial chemotherapy. These findings were compatible with a metastatic tumour from rectal cancer. Because the mass was judged to be resectable, laparoscopic partial hepatectomy and ileostomy closure was planned with a diagnosis of liver metastasis from rectal cancer. Intraoperative findings revealed a slight white, crude tumour on the liver segment 8 surface with no other lesions recognized, so partial hepatectomy of segment 8 was performed. The patient recovered postoperatively and was discharged on postoperative day 7. A nodule of approximately 8 mm in diameter was macroscopically identified in the resected specimen (Fig. 2). Necrotic granulation tissue of approximately 5 mm was found in the centre of the nodule, accompanied by a few polygonal giant cells at the margin on the microscopic examination. A parasitic worm body was recognized with Elastica van Gieson staining in a structure suspected to be a vein. Grocott staining did not reveal any fungus or protozoon infection, and the worm body was finally proved to be anisakis simplex by anisakis antibody staining (Fig. 3). It was thought that the anisakis larvae broke through the intestinal wall and invaded the vein from the liver surface. Detailed inquiry after surgery revealed that the patient had a history of eating raw fish. Thereafter, no new lesions have appeared in the liver and there has been no recurrence of rectal cancer.

Discussion
Two important facts were derived from this case: firstly the existence of hepatic anisakiasis, and secondly, the possibility of hepatic anisakiasis should be considered with low density liver margin tumours of less than 20 mm by contrast CT if the patient has a history of eating raw fish.
The first zoonotic case attributed to the anisakis species was described in the Netherlands by Van Thiel et al. in 1960, and anisakiasis is divided into three types; gastric, intestinal, and extragastrointestinal anisakiasis [11]. Ishikura et al reported that gastric anisakiasis accounts for 95.7% of all cases, intestinal anisakiasis 3.8%, and extragastrointestinal anisakiasis just 0.5% of all cases. Among extragastrointestinal anisakiasis, hepatic anisakiasis is extremely rare. Only 12 cases of hepatic anisakiasis have been reported previously (Table 1). To the best of our knowledge, our case was the 13th case in the world. As in this case, most of extra-gastrointestinal anisakiasis including hepatic anisakiasis are asymptomatic and detected incidentally by imaging studies. In primary infection, anisakis larvae penetrate the wall of the gastrointestinal tract with no symptoms and form abscesses and granulomas in intraperitoneal organs [8].
Hepatic anisakiasis may occur as anisakis larvae migrating from the digestive tract wall into the peritoneal cavity invade the liver surface and form a tumour at the liver margin. It is also speculated that larvae from the gastrointestinal tract might reach the liver via the portal vein, but there are no reports of hepatic anisakiasis invasion routes from any other path than the liver surface.
In our case, anisakis larvae were recognized in the hepatic vein. Although pathological findings could not show clear evidence of invasion from the liver surface, we judged that anisakis larvae penetrated the liver surface from intraoperative findings which confirmed liver surface contractions at the tumour site and pathological findings in which necrotic tissue and granulation tissue spread around the liver surface.
In general, hepatic anisakiasis is difficult to make clinical diagnosis simply by using imaging modalities. In all presented cases including our case, precise diagnosis based on imaging studies was not achieved before pathological examination. Even after pathological examination, to make a definitive diagnosis is also difficult because larva body has often collapsed. The infection in human body is transient and the parasite will die within 14 days, leaving a persistent inflammation forming granuloma. Various immunologic assays like complement fixation test, immunofluorescent-antibody test, immunodiffusion test, immunoelectrophoretic assays, enzyme-linked immunosorbent assay, and radio-allergosorbent test is reliable for obtaining final diagnosis even when the larvae body collapses with time. Use of monoclonal antibodies specific to anisakis antigens also help the definite diagnosis.
Hepatic anisakiasis tumours present as a small low density area of the liver margin on CT. In previously reported cases where there was a description of localization, all tumours were at the liver margin, with an average size of 13.8 mm, and almost all tumour less than 20 mm. Low density areas in contrast CT are thought to reflect granulomas and necrotic tissue. Incidental detection of this lesion is difficult to distinguish from carcinoma recurrence in patients with a history of malignancy, and can lead to unnecessary surgery, chemotherapy, and radiotherapy. Follow-up observation or biopsy can be options for a small low density tumour at the liver margin, unless we positively suspect malignant disease.
In some cases the collapsing worm body may make the final diagnosis difficult, even after resection. Therefore, the exact frequency of hepatic anisakiasis may be higher than suspected. In our case, the dietary history of the patient and the pathological findings, including significant infiltration of inflammatory cells, oedema, formation of granulation tissue, and cuticular structures characteristic of nematodes such as anisakis and gnathostoma, were consistent with a diagnosis of anisakiasis [12].

Conclusion
Changing food cultures, including consumption of raw fish, will likely lead to an increase in anisakiasis cases in the Western countries. Hepatic anisakiasis is rare but should be a consideration if a low density small tumour of the liver margin is detected on contrast CT. The dietary history for the patient should be thoroughly evaluated. When clinical findings do not support positive suspicion of malignant tumours, close observation or biopsy may prevent excessive surgical invasion.

Declaration of Competing Interest
The authors have no conflict of interest.

Sources of funding
This study has not received any funding.

Ethical approval
This case report was approved by the committee of our institute.

Consent
Written informed consent was obtained from the patient.

Registration of research studies
None.

Guarantor
The Guarantor is Ryosuke Kita.

Provenance and peer review
Not commissioned, externally peer-reviewed.