Introduction

Hepatic reactive lymphoid hyperplasia (RLH), also known as pseudolymphoma, presents lymphoid follicles with reactive germinal centers and polyclonal reactive proliferation with no atypia in the lymphocytes [1, 2]. No typical imaging of hepatic RLH has been reported. Therefore, preoperative diagnosis of hepatic RLH is difficult and hepatic RLH is mostly diagnosed postoperatively. In this report, we present a rare case of hepatic RLH with characteristic imaging findings.

Case report

A 70-year-old woman had been treated with chemotherapy and radiotherapy for intra-abdominal follicular lymphoma 12 years before, and had been remained in remission. She was followed up by blood tests and positron emission tomography/computed tomography (PET-CT). She was referred to our hospital because of slight elevation of soluble interleukin-2 receptor (sIL-2R) and accumulation of 18F-fluorodeoxyglucose (FDG) in S8 of the liver in PET-CT (Fig. 1a). Laboratory data, including lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, total protein, albumin, and globulin, were within normal range. Hepatitis B virus DNA and hepatitis C virus RNA were negative. Antinuclear antibody and anti-mitochondrial antibody were negative. Tumor markers, including α fetoprotein, protein induced by vitamin K absence or antagonist-II, carcinoembryonic antigen, and carbohydrate antigen 19–9, were within normal range except for slight elevation of s-IL-2R: 592 U/ mL. Abdominal ultrasonography (US) showed a hypoechoic mass, 16 mm in size, in the S8 of the liver, which was well defined and homogeneous (Fig. 1b). Contrast-enhanced computed tomography (CE-CT) showed a pale ring-shaped contrast enhancement in the early phase and washed out in the late phase (Fig. 2). Magnetic resonance imaging (MRI) scan showed hypointense on T1-weighted image and hyperintense on T2-weighted image, and diffusion restriction along the mass and surrounding the portal vein (Fig. 3). Contrast-enhanced MRI (CE-MRI) showed contrast enhancement in the early phase, washed out in the late phase, hypointense in the hepatocyte phase (Fig. 3). The background liver was normal on all imaging findings, and there was no evidence of fatty liver, hepatitis, or cirrhosis. Re-examined CE-CT after 3 months showed that the hepatic mass became well defined and slightly enlarged, and portal vein invasion was suspected (Fig. 4). The mass was strongly suspected to be malignant, such as the recurrence of follicular lymphoma, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma. Although the preoperative diagnosis was difficult because of the lack of typical findings on imaging, liver biopsy was not performed due to the risk of dissemination. Hepatic S8 subsegmentectomy was performed for diagnostic and therapeutic purposes. Macroscopically, multiple white nodules without capsules were observed within an area of 16 mm in diameter (Fig. 5). Hematoxylin and eosin staining of the resected specimen showed small lymphocytes with no atypia and no formation of lymphoid follicles (Fig. 5). There was no hepatitis in the resected specimen. Immunostaining showed CD3-positive cells in the interfollicular region and CD20-positive cells in the lymphoid follicles. Both CD10 and BCL-2 were negative in the follicular germinal center. CD138-positive plasma cells were observed and there was no light chain restriction, because the κ/λ ratio was within normal range (Fig. 6). These results indicated polyclonal growth pattern of lymphocytes in the lymphoid follicles and interfollicular region. Portal vein invasion of the tumor was suspected on the preoperative imaging; however, pathological finding shows many lymphocytes around the portal vein and no direct invasion into the portal vein. Thus, she was finally diagnosed with hepatic RLH.

Fig. 1
figure 1

PET-CT and US images. a: Accumulation of 18F- fluorodeoxyglucose in S8 of the liver; b: a hypoechoic mass in the S8 of the liver, which was well defined and homogeneous

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Fig. 2
figure 2

CE-CT images. A pale ring-shaped contrast enhancement in the early phase and washed out in the late phase

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Fig. 3
figure 3

MRI images. Hypointense on T1-weighted image, hyperintense on T2-weighted image, and diffusion restriction along the mass and surrounding the portal vein (red arrow). Contrast enhancement in the early phase, washed out in the late phase, hypointense in the hepatocyte phase

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Fig. 4
figure 4

Re-examined CE-CT images after 3 months. The hepatic mass became well defined and slightly enlarged, and portal vein invasion was suspected

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Fig. 5
figure 5

Macroscopic and microscopic images. Macroscopically, multiple white nodules without capsules were observed. HE staining showed small lymphocytes with no atypia and no formation of lymphoid follicles

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Fig. 6
figure 6

Immunostaining showed CD3-positive cells in the interfollicular region, CD20-positive cells in the lymphoid follicles. Both CD10 and BCL-2 were negative in the follicular germinal center. CD138-positive plasma cells were observed and there was no light chain restriction, because the κ/λ ratio was within normal range

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Discussion

Hepatic RLH presents lymphoid follicles with reactive germinal centers and polyclonal reactive proliferation with no atypia in the lymphocytes [1, 2]. This disease is thought to be related to autoimmune disease, chronic hepatitis, and malignancies [2,3,4, 19]. To our knowledge, only 87 cases of hepatic RLH/ pseudolymphoma have been reported in the English literature on PubMed. No typical imaging finding of hepatic RLH has been reported. CE-CT and CE-MRI imaging show a variety of findings in each case. Therefore, preoperative diagnosis of hepatic RLH is difficult, and hepatic RLH is mostly diagnosed postoperatively.

Review of the English literature of hepatic RLH/pseudolymphoma which referred to imaging findings yielded 23 cases [1, 2, 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21], including this case (Table 1, Table 2). The average age was 60 years and most cases were females (96%) (Table 1). Hepatitis virus infection was present in 33% of them, and 67% were non-infected (Table 1). Elevation of hepatic enzymes were not seen in 87% of the patients (Table1), and hepatic tumor markers were not elevated in all cases (Table 1). The antinuclear antibody was positive in 8 cases, and 3 cases (Case 3, 20, 21) of them had no history of autoimmune disease (Table1). A history of autoimmune disease was observed in 8 cases and malignancy was observed in 6 patients (Table 1). It occurred a little more frequently in the right lobe of the liver (56%) (Table 2). The average size was 15 mm in diameter (Table 2). On imaging, US showed hypoechoic mass (100%). CE-CT and CE-MRI showed contrast enhancement in the early phase and relatively wash out in the late phase (95%). MRI showed hypointense on T1-weighted image (100%) and hyperintense on T2-weighted image (100%), and diffusion restriction (100%) (Table 2). Preoperative diagnoses included HCC (50%), metastatic liver tumor (13%), any malignant tumor (25%), intrahepatic cholangiocarcinoma (4%), RLH (4%), and hepatic adenoma (4%) (Table 2). Eighty-eight percentage of the cases underwent surgery (Table 2), other 12% (Case3, 16, 23) of the cases performed liver biopsy for diagnosis and did not receive hepatic resection (Table 2). In Case 3, percutaneous ethanol injection was performed [5]. In Case 16, radiofrequency ablation was performed [14]. Case 23 was followed up without treatment [21]. These cases has been followed up without recurrence and evidence of malignancy [5, 14, 21].

Table 1 Patient characters
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Table 2 Imaging findings and diagnostic methods
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Hepatic RLH rather than HCC is suspected based on the patient’s background and imaging as follows. Hepatic RLH is mostly middle-aged women. Laboratory data show no elevation of hepatic enzymes or hepatic tumor markers. Autoantibodies, such as antinuclear antibodies, are frequently positive in hepatic RLH. Hepatic RLH is often associated with autoimmune diseases and malignancies [2,3,4, 19], and hepatitis virus infection is less common than HCC.

This case had undergone radiation chemotherapy for intra-abdominal follicular lymphoma 12 years ago and remained in remission. This time, only a hepatic mass was detected on systemic imaging examinations. We also suspected a recurrence of follicular lymphoma due to mild elevation of s-IL2R, but pathology of the resected liver specimen revealed hepatic RLH. The follicular lymphoma has been followed up without recurrence. It is unclear whether a history of lymphoma was associated with hepatic RLH in this case. Although the cause of hepatic RLH is not yet fully understood, an abnormal immune system due to autoimmune disease or malignancy may be involved in hepatic RLH [3, 19].

Contrast CT and MRI findings of hepatic RLH are similar to those of HCC, but hepatic RLH often shows a peripheral contrast effect (Table 2), which is considered to reflect lymphocytes around the portal vein [2] and is consistent with the findings of linear diffusion restriction along the portal vein on DWI [22]. In hepatic RLH, swelling of the portal vein area caused by lymphocytes may show diffusion restriction on MRI, so vascular invasion is often suspected as a finding of malignancy. However, this finding is characterized by linear diffusion limitation along the portal region [22]. Contrast-enhanced US (CE-US) can confirm the contrast enhancement overtime and shows very earlier contrast enhancement and washout than HCC [23], and thus, CE-US is useful for differentiating hepatic RLH from HCC. The timing of CE-CT phase imaging differs by facility, and it creates variety of contrast enhancement. Nevertheless, our data showed that the contrast enhancement was relatively washed out in many cases (95%). Therefore, for a hepatic mass with atypical imaging findings, contrast enhancement of CE-US, peripheral contrast effect of CE-CT/MRI, and diffusion limitation along the portal vein could be useful for the diagnosis of hepatic RLH.

If hepatic RLH is suspected by the patient’s background and imaging, liver biopsy is needed for definitive diagnosis of hepatic RLH. It has been reported that a sufficient amount of liver tissue can be obtained for the diagnosis of this disease by liver biopsy and that immunostaining can determine lymphocyte polyclonality [4]. There have been cases of hepatic RLH with background normal liver or autoimmune disease diagnosed by liver biopsy [4]. In those cases, a reduction in mass size was confirmed during follow-up period [4, 5, 14, 21].

In conclusion, a hepatic mass with atypical imaging findings and backgrounds, hepatic RLH should be considered as a differential diagnosis. Middle-aged women with autoimmune disease or malignancy, and even if not, measuring autoantibodies may help in the diagnosis. Diagnosis of hepatic RLH includes early contrast enhancement and relatively early washed out on CE-CT/US, peripheral contrast effect of CE-CT/MRI, and diffusion limitation along the portal vein on MRI may be useful imaging findings. We suggest that liver biopsy should be considered to avoid surgery in patients who do not have typical risk factors for HCC or other hepatic malignancy, but have characteristics for hepatic RLH as described above.