A case of primary hepatic mucosa-associated lymphoid tissue lymphoma incidentally found in the sustained virological response state of chronic hepatitis C: review of the literature of this rare disease

Abstract

A 54-year-old woman finished the treatment for chronic hepatitis C and achieved sustained virological response. She was identified with some tumor lesions at her liver during follow-up observation by ultrasonography. From contrast-enhanced computed tomography, there were four tumors at sub-segment 4/5, S5, S6, and S7. These lesions are slightly enhanced on arterial phase and washed out on delayed phase. Contrast-enhanced magnetic resonance imaging showed slight enhancement on arterial phase and defect on hepatocyte phase. Tumor markers including alpha fetoprotein, Des-Gamma-Carboxy Prothrombin, carcinoembryonic antigen, and carbohydrate antigen (CA19-9) were within normal range. The patient underwent partial hepatectomies of four tumors at S4/5, S5, S6, and S7. The patient was recovering well, so he discharged our hospital after 10 days from the operation. The histological assay of the resected specimen showed accumulation of lymphocyte with hyperplasia of lymphoid follicles accordant with tumor lesions. Immunohistochemical staining assay revealed a positive for CD3, CD20, CD10, and bcl-2. These findings eventually made a diagnosis of all four tumors as mucosa-associated lymphoid tissue lymphoma. Since previously published case reports and our case described nonspecific clinical features of this rare disease, it was difficult to get the certain diagnosis before histological confirmation and non-anatomical partial liver resection may be a good choice for both diagnosis and local therapy.

Introduction

Primary hepatic lymphomas (PHL) are rare tumors with the proportion of less than 1% of malignant lymphomas [1, 2]. The most common histological type is diffuse large B-cell lymphoma, followed by mucosa-associated lymphoid tissue (MALT) lymphoma, Burkitt lymphoma, or Hodgkin lymphoma. MALT lymphoma is a low-grade malignant lymphoma and accounts for around 7% of all non-Hodgkin lymphoma. The most common favorite site is the stomach, which is often associated with Helicobacter pylori. The other favorite sites are lung, thyroid gland, salivary gland, and other gastrointestinal sites [3]. Primary hepatic MALT lymphoma is a relatively rare case and little is known about the causes or the clinical course of the disease and its proper treatment [4, 5]. Primary hepatic lymphoma is confined to the liver with no evidence of lymphomatous involvement of the spleen, lymph nodes, bone marrow, or other lymphoid structures [2, 6]. The etiology of PHL is not clearly established, but chronic inflammation seems to be involved [2, 4]. Hepatitis, cirrhosis and immunosuppressive drugs have been proposed as possible causes. It is so difficult to diagnose from imaging examinations before operation because of its rarity and many cases are diagnosed from surgical specimen [6]. This time which we described a case of surgically resected primary hepatic MALT lymphoma incidentally found in the sustained virological response state of chronic hepatitis C. We also reviewed previous literatures to discuss the management and the treatment of this rare disease.

Case report

A 54-year-old woman had been treated for chronic hepatitis C by interferon-based therapy and got sustained virological response (SVR). During a follow-up imaging examination, she was identified with some tumor lesions by ultrasonography. She did not state any discomfort, and laboratory investigations including complete blood count, biochemical examination including liver enzymes, coagulation tests, and urine examination were normal. Tumor markers including alpha fetoprotein (AFP), Des-Gamma-Carboxy Prothrombin (DCP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA19-9) were also within normal range. Enhanced computed tomography (CT) demonstrated four lesions which were slightly enhanced on arterial phase and washed out on delayed phase in S (Subsegment) 4/5, S5, S6, and S7 (Fig. 1). Contrast-enhanced magnetic resonance imaging showed slight enhancement at the same lesions of contrast-enhanced CT on arterial phase and defect on hepatocyte phase (Fig. 2). According to the results of the imaging examination, we suspected that these tumor lesions were hepatocellular carcinoma or intrahepatic cholangiocarcinoma. The patient underwent partial hepatectomies of all four lesions S4/5, S5, S6, and S7. When we divided the resected tumors, the divided surface of the tumor showed a whitish and poorly marginated from the macroscopic examination (Fig. 3). Microscopic examinations showed that accumulation of lymphocyte with hyperplasia of lymphoid follicles accordant with tumor lesions and can see follicular colonization (Fig. 4a, b). Immunohistochemistry findings were positive for CD20 both at germinal center and intrafollicular and positive for CD3 only at intrafollicular. Bcl-2 was positive at intrafollicular and negative at germinal center, whereas CD10 was positive at germinal center and negative at intrafollicular (Fig. 4c–f). This means these follicles are not tumor follicles but reactive follicles. And CAM5.2, which was the marker of lymphoepithelial lesion was positive (Fig. 4g). As a result, the patient was diagnosed with primary hepatic MALT lymphoma. The patient was recovered well without remarkable events, so she discharged our hospital after 10 days from the operation. The patients were observed without adjuvant chemotherapy and remain well without any recurrence or the other event for the following 12 months.

Fig. 1.

Nonenhanced axial computed tomography images show nothing special (a). Contrast-enhanced computed tomography demonstrated four lesions which were slightly enhanced on arterial phase (b) and washout on portal phase (c) and delayed phase (d)

Fig. 2.

Contrast-enhanced magnetic resonance imaging showed slight enhancement on arterial phase (a) and defect on late phase (b, c) and hepatocyte phase (d)

Fig. 3.

Gross appearance and the cutting surface of the tumor (S4/5) (a, b)

Fig. 4.

Characteristic of histological examination showed that accumulation of lymphocyte with hyperplasia of lymphoid follicles accordant with tumor lesions and can see follicular colonization (a hematoxylin and eosin, HE × 40 and b HE × 400). Immunohistochemistry findings were positive for CD20 both at germinal center and intrafollicular (c) and positive for CD3 only at intrafollicular (d). Bcl-2 was positive at intrafollicular and negative at germinal center (e), whereas CD10 was positive at germinal center and negative at intrafollicular (f), and CAM5.2 was positive (g)

Discussion

Primary hepatic MALT lymphoma is relatively rare case. A lot of the MALT lymphomas arise in background of chronic inflammation. For example, the stomach, which is the most common site, is known to be related to H. pylori, and removing it is the first line therapy for H. pylori-associated gastric MALT lymphoma [7]. Some previous reports revealed that primary hepatic MALT lymphoma is also related to chronic inflammation including hepatitis C virus, hepatitis B virus, primary biliary cirrhosis, and so on [8–14]. In this case, the patients had hepatitis C virus infection, but she achieved SVR. This case showed that the MALT lymphoma is developed even after curative treatment for HCV infection. Some report showed that the B-cell lymphoma had occurred after curative antiviral therapy of HCV [15–17]. However, little is known about the MALT lymphoma after SVR. Furthermore, in recent years, some patients who have achieved SVR due to significant effects of interferon-based therapy or antiviral therapy developed HCC several years after treatment [18, 19]. This fact makes it difficult to distinguish the between MALT lymphoma and HCC as described below.

In most cases of lymphoma, the mass is not enhanced in the arterial phase compared to hepatocellular carcinoma and tumor margin dose not clear. Even if lymphoma was cited as a differential diagnosis from the imaging examinations, only a few cases were conducted biopsy. In most case, their preoperative diagnoses were atypical hepatocellular carcinoma, and after surgical treatments, they were diagnosed pathologically as MALT lymphoma. Currently, the method of treatment to primary hepatic MALT lymphoma does not established. Surgery, radiotherapy, and chemotherapy alone or multidisciplinary treatment has been commonly selected [6]. In this case, we diagnosed these tumors as malignant tumors such as HCC or ICC rather than the other benign tumors like lymphoma, so we selected the surgical resection. Since it was usually misdiagnosed before histological confirmation, surgical resection may be a good choice for both diagnosis and local therapy [6].

For the literature review, we summarized the clinical features of 76 cases with primary liver MALT lymphoma which is previously reported in Table 1 (including the present case). There were 24 females and 31 males, with an age ranging from 30 to 85 years and a median age of 62 years [6, 20–25]. Sixteen cases had HCV infection, but there were no information about the antiviral treatment, and there was little reported about the MALT lymphoma after SVR. Twelve cases had multiple tumors, while 33 cases had solitary tumor. Thirty-nine cases (78%) of 50 cases, which were described about treatment, were selected the surgical resections, regardless of preoperative diagnosis (Table 1). About adjuvant chemotherapy, rituximab is known to effective to CD20 positive extra-gastric MALT lymphoma. In many recurrent cases, rituximab was selected and achieved complete remission [26, 27]. The recurrence of primary hepatic MALT lymphoma after complete resection is rare and only two cases have been reported [24, 28]. One of them was remained in remission a year using idelalisib.

Table 1.

Clinical features of the patients with primary hepatic MALT lymphoma ever reported (including the present case)

Clinical features	Total case (n = 76)
Age, year: median (range)	62 (30–85)
Sex
Male	31
Female	24
NA	21
Symptoms
Asymptomatic	40
Mild elevation of liver enzyme levels	7
Abdominal pain	2
Underlying liver disease
HBV	11
HCV	16
PBC	4
Hepatitis of other reasons	5
Concomitant disease
Malignant tumor	11
Autoimmune disease	8
Helicobacter pylori infection	8
Tumor diameter, cm	3.5 (0.7–9.0)
Tumor number
Solitary	33
Multiple	12
Ann Arbor stage
I	54
II	2
III	4
NA	14
Treatment
Resection	18
Resection + chemotherapy	11
Resection + radiotherapy	1
Resection + rituximab	9
Chemotherapy	5
Radiotherapy	2
Chemotherapy + radiotherapy	1
Liver transplantation	4

For the treatment of this case, surgical resection has been selected, because the patients had no problems in general conditions and relatively better liver functions. Also, we decided to perform the non-anatomical partial liver resection. Some reports showed that the anatomical resection was not superior to non-anatomical partial liver resection in survival outcomes with small solitary HCC [29, 30]. Whereas, in cases which HCC is strongly suspected, such as the solitary tumor and relatively large, or the case which located close to Glissonean pedicle, anatomical resection is an option from the viewpoint of curability. In fact, some cases of primary hepatic MALT lymphoma were selected surgical anatomical resection with suspected HCC [20]. However, in this case, we performed the non-anatomical partial liver resection because of the multiple and relatively smaller tumors, and thus, it was reasonable as a treatment for HCC. Moreover, we did not conduct adjuvant chemotherapy. The reasons were no distinctive evidence about adjuvant chemotherapy to primary hepatic MALT lymphoma and no request from the patient.

If the patient has been chronic inflammatory disease like this case and the imaging findings are nonspecific pattern of hepatocellular carcinoma, we should think MALT lymphoma as one of differential diagnosis before surgical treatment. About treatments, we should select the minimally invasive operation, such as partial hepatectomy as far as possible, and we also need take consideration to adjuvant chemotherapy. Since it was usually misdiagnosed before histological confirmation, surgical resection, especially non-anatomical partial hepatectomy, may be a good choice for both diagnosis and local therapy.

Compliance with ethical standards

Conflict of interest

Authors Tadahito Yasuda, Shigeki Nakagawa, Katsunori Imai, Hirohisa Okabe, Hiromitsu Hayashi, Yo-ichi Yamashita, Akira Chikamoto, Kazutaka Ozono, Yoshiki Mikami, and Hideo Baba declare that they have no conflict of interest.

Ethical standards

The authors comply with the ethical standards of ICCJ.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.