A case of hepatic pseudolymphoma in a patient with primary biliary cirrhosis

Abstract Hepatic pseudolymphoma is a very rare benign reactive lymphoid hyperplasia associated with autoimmunity and chronic inflammatory liver diseases such as primary biliary cirrhosis and may mimic hepatocellular carcinoma. This diagnosis should be suspected in female with a suspicious single tumor. Close monitoring is needed in view of its premalignant nature.


| BACKGROUND
Pseudolymphoma is a rare disease that forms a mass-like lesion and is characterized by the proliferation of non-neo plastic, polyclonal lymphocytes forming follicles with an active germinal center. 1 Pseudolymphoma is also termed reactive lymphoid hyperplasia or nodular lymphoid lesion. Pseudolymphoma is most commonly described in the skin 2 and gastrointestinal tract. 3,4 Hepatic pseudolymphoma (HPL) is an extremely rare disease, and it is very difficult to distin guish HPL from other malignant diseases, such as hepato cellular carcinoma (HCC), based on imaging examinations. HPL is often confirmed and diagnosed based on postoper ative pathologic evaluation. Even though the etiology and pathogenesis of HPL are unknown, the association with a chronic infection or inflammatory process suggests an as sociation with an immunologic response. 5 We describe a case of HPL associated with primary biliary cirrhosis (PBC) and review the literature to reveal the clinicopathologic characteristics.

| CASE PRESENTATION
A 70-year-old woman was shown to have a mass, 10 mm in diameter, in segment Ⅷ of the liver during a follow-up evaluation for PBC. Her social and family histories were un remarkable. She had chronic rheumatoid arthritis in addition to PBC, and she was prescribed oral steroids and methotrex ate. She had no abnormal physical findings.
Laboratory testing was negative for hepatic virus, and hepatic function was in the normal range, although the an timitochondrial antibody titer was positive. Tumor markers, including carcinoembryonic antigen, carbohydrate antigen 19-9, alpha-fetoprotein (AFP), and protein induced by vitamin K absence or antagonist Ⅱ(des-gamma-carboxy prothrombin [PIVKA-Ⅱ]), were within normal limits. In addition, the ICG 15 min value was 9.8% and the Child-Pugh classification was A at 5 points (Table 1).
Abdominal ultrasonography showed a hypoechoic mass, 13.4 mm in diameter, in segment Ⅷ of the liver ( Figure 1). An abdominal computed tomography (CT) scan showed a mass, 10 mm in diameter, which was slightly enhanced in the early phase and washed out in the late phase ( Figure 2). On gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), the mass was enhanced in the arterial dominant phase and washed out in the late and he patocyte phases ( Figure 3).
Based on the preoperative diagnosis of HCC, a laparo scopic-assisted S8 subsegmentectomy was planned. The op eration began with laparoscopic right liver mobilization with the camera port and three ports under the right brow arch, fol lowed by right subcostal oblique incision for hepatic resection.
A gray-white solid tumor with a maximum diameter of 9 mm was observed macroscopically (Figure 4). The tumor in the liver consisted of a dense lymphocytic infiltration, in cluding multiple lymphoid follicles with germinal centers, microscopically. The interfollicular areas were expanded and filled with small-to-medium lymphocytes without cellular atypia ( Figure 5). Immunohistochemical staining revealed that the follicles were CD20 (+), CD79a (+), CD10 (+), and Bcl-2 (−), and the interfollicular area was CD3 (+) and CD5 (+). Taken together, a diagnosis of pseudolymphoma was favored ( Figure 6).
The postoperative course was good, and she was dis charged on postoperative day 7.

| DISCUSSION
Pseudolymphoma, which is also termed reactive lym phoid hyperplasia or nodular lymphoid lesion, is a rare disease, especially in the liver. Based on a review of the PubMed database from 1981 to 2017 using the key words "pseudolymphoma," "lymphoid hyperplasia of the liver," and "nodular lymphoid lesion," we found 80 cases of pseudolymphomas, including our case ( Table 2). F I G U R E 2 On abdominal computed tomography (CT) scan, a mass, 10 mm in diameter, was demonstrated, which was slightly enhanced in the early arterial phase and subsequently washed out in the late phase after contrast material injection, but was not consistent with a HCC. Other organs, including regional or para-aortic lymph nodes, showed no abnormal findings

F I G U R E 3 On gadoxetic acid (Gd-
EOB-DTPA)-enhanced magnetic resonance imaging (MRI), abbreviated as EOB-MRI, the mass was enhanced in the arterial dominant phase and washed out in the late phase and hepatocyte phase F I G U R E 4 On macroscopic examination, there was a gray-white solid tumor measuring 9 mm in the largest diameter. The tumor was completely excised F I G U R E 5 On microscopic examination, the tumor in the liver was composed of dense lymphocytic infiltration, including multiple lymphoid follicles with germinal centers. The interfollicular areas were expanded and filled with small-tomedium lymphocytes without cellular atypia F I G U R E 6 Immunohistochemical staining revealed that the follicles were CD20(+), CD79a(+), CD10(+), and Bcl-2(-), and the interfollicular area was CD3(+) and CD5(+). Taken together, a diagnosis of pseudolymphoma was favored In the previously reported cases, images of HPL depicted a hypoechoic lesion on ultrasonography and varied from hyper-to hypovascular on contrast CT, MRI, and angiog raphy. 6,7 The preoperative diagnosis of HPL has features similar to those of hepatocellular carcinoma. Many cases of HPL have been misdiagnosed as HCC or metastatic tumors. The preoperative diagnosis was described in 65 cases, 33 of which were diagnosed as hepatocellular car cinoma and 16 were diagnosed as metastatic liver tumors. Although the preoperative diagnosis is difficult, when ex amining the characteristics of HPL, 86.3% of the reports described a single tumor. The average age of the patients was 56.6 years (range = 15-81 years). The frequency of fe males was greater (F:M = 74:6 [92.5%]). The average size of the tumor was 17.4 mm (range, 3-60 mm), and 88.8% of the tumors were ≤20 mm in size.
In this case, HPL appeared during the course of PBC, but there were also 13 cases (16.3%) of HPL associated with PBC (Table 3). 816 Because the lesion had been misdiag nosed as HCC or another malignant tumor, 10 HPL patients associated with PBC underwent hepatic resections. Three tumors were found in the liver and resected by transplanta tion for PBC.
Primary biliary cirrhosis is a chronic progressive choles tatic liver disease. The pathogenesis of PBC is presumed to have an underlying autoimmune mechanism. Histologically, the interlobular bile ducts are primarily damaged and show characteristic findings, such as chronic nonsuppurative de structive cholangitis (CNSDC), followed by progressive bile duct loss. 15,16 Some of the HPL patients present with extrahepatic autoimmune diseases, such as Sjogren's syn drome, 10,12,17 autoimmune thyroiditis, 6,9,18 Takayasu aortitis with antiphospholipid syndrome, 9 or calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and tel angiectasia (CREST syndrome; 13). Because HPL has a rel atively large number of autoimmune disease complications, it is suggested that an autoimmune mechanism is involved in the increase in HPL. 17,18 In addition, many of the HPL pa tients were shown to have chronic liver diseases, such as PBC and viral hepatitis, representing 27.5% of affected patients. It is also suggested that the pathogenesis of HPL might involve a chronic reaction. 19 In contrast, PBC is rarely complicated by HCC. According to the data of all reviewed PBC patients in Japan, the inci dence of HCC was 2.4%. 20 PBC is pathologically charac terized by CNSDC, thus inflammatory lesions of PBC are mainly present on cholangiocytes, and it is thought that HCC is less frequent in PBC patients due to poor inflammation in hepatocytes, as is seen in viral infections. So, the possibility of HPL should be considered if a woman with PBC is shown to have a liver tumor <20 mm in size.
Because the diagnosis often is established from sur gery, the natural history of HPL is not well understood.
Malignant conversion of pseudolymphoma has been re ported in the lungs, stomach, and skin. 2123 With respect to the liver, one case report is available, 10 with the possibility of transformation of HPL into hepatic MALT lymphoma. This case was HPL in a patient with PBC. HPL is generally regarded as a benign disease, but because there is the pos sibility of malignant conversion, it is important to follow the patient closely.