Introduction

Primary gastric lymphoma is a rare disease and accounts for approximately 1–5 % of all malignant gastric tumors; the most common histological subtype is diffuse large B-cell lymphoma (DLBCL) and extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) [1, 2]. Some reports demonstrated that stomach-preserving therapy, which comprised a combination of chemotherapy and irradiation, resulted in effects comparable with those of surgical treatment [2–6] and also offered a better quality of life [7, 8]. Among the stomach-preserving therapies, a combination of chemotherapy and radiotherapy achieved better curability in primary gastric lymphoma patients [4, 9, 10]; however, hepatic function is one of the key factors for tolerance to chemotherapy. Because there is a significant relationship between hepatitis C virus (HCV) and lymphoma [11], chemotherapy cannot be administered to patients with severe cirrhosis and a poor hepatic reserve function. To date, there are few reports showing the effects of radiation monotherapy to gastric tumor comparative to those of combination therapy [1, 12–14]. Based on this evidence and poor hepatic reserve function in our case, we performed involved-field radiation monotherapy to the main tumor in the stomach of our patient. Importantly, her symptoms were significantly relieved, and no lymphoma cells were seen in the stomach after radiotherapy although the metastatic lesions outside of the field progressed. Therefore, we report that involved-field radiation monotherapy can be a therapeutic option, although palliative, for patients with a poor hepatic reserve function and with poor prognostic factors and advanced-staged tumors [15].

Case report

A 73-year-old Japanese woman visited our hospital with poor appetite, nausea, vomiting, and low-grade fever in April 2011. She had a history of liver cirrhosis due to HCV infection and had been treated for esophageal varices with endoscopic sclerotherapy in 2007. After this period, no recurrence or liver tumor had been noted. She had lost 6 kg in body weight during the previous month and experienced a temperature of 37–38°C, loss of appetite, nausea, and swelling of left jugular lymph node 2 weeks before admission. Her Eastern Cooperative Oncology Group performance status (PS) was 3 and physical examination upon admission showed mildly anemic conjunctiva, slight tenderness in the epigastric region, mild fluctuation due to the ascites, and marked left jugular lymph node swelling. Laboratory results on admission day showed a decrease in hemoglobin (9.2 g/dL), platelet (6.5 × 104/μL), prothrombin (56 %), and albumin (2.6 g/dL), an increase in aspartate aminotransferase (95 IU/L), lactate dehydrogenase (550 IU/L), and total bilirubin (2.5 mg/dL), positive for anti-HCV antibodies, and a significantly high level of soluble interleukin receptor-2 (sIL-2R; 10527 IU/mL). Based on these results, Child-Pugh grade was determined to be C with a score of 10, indicating poor hepatic reserve function. Other tumor markers were normal including the carcinoembryonic antigen, carbohydrate antigen 19-9, alpha-fetoprotein, and protein induced by vitamin K antagonist II (Table 1). Contrast-enhanced computed tomography (CT) and ultrasonography showed cirrhotic liver, splenomegaly, ascites, diffuse and severe thickening of the gastric wall especially in the antral region, and marked swelling of the gastric and left jugular lymph nodes (Fig. 1a–c).

Table 1 Results of laboratory investigation
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Fig. 1
figure 1

Images and histological findings of the tumor. Computed tomography (CT) showed significant thickening of the gastric wall (a white arrow) and swelling of the gastric lymph nodes (b white arrows) and the left jugular lymph node (c white arrow). Endoscopy showed no tumors or ulcerative lesions in 2009 (d). A large ulcerative lesion in the antral region (e, f) was revealed in 2010. The tumor had deep and sharply demarcated ulcers and caused stenosis in the area. H&E staining of the biopsy specimens from the tumor in the stomach showed a significant number of large lymphoma cells in the tumor (g, h) that stained positive for CD20 (i) and leukocyte common antigen. Magnification: g ×40, h ×400, i ×200

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Endoscopic findings

An upper gastrointestinal endoscopy (Fig. 1d–f) showed a large mass lesion with deeply and sharply demarcated ulcers in the antral region of the stomach. The ulcers showed a few bleeding points with whitish exudates on the surface. The tumor and the thick edematous mucosa appeared to be the stenosis in the stomach that was causing nausea and vomiting (Fig. 1e, f). We carefully reviewed the endoscopic images from the previous year, but no ulcerative lesions were observed (Fig. 1d). Biopsy specimens were obtained from multiple locations in the area. The specimen from the edge of the ulcers showed a remarkable infiltration of the large lymphoma cells with a destructive and infiltrative pattern into vessels and normal gastric tissue, which stained positive for leukocyte common antigen and antigen CD20 (Fig. 1g–i), but negative for antigens CD3, CD5, and CD10 (data not shown). No lymphoma cell infiltration in the duodenum or evidence of Helicobacter pylori infection were seen.

Clinical course

Based on the laboratory data, images, and endoscopic findings, the patient was diagnosed with a diffuse large B-cell primary gastric lymphoma with metastatic lesions in the gastric and jugular lymph nodes. The clinical stage was IVB and her international prognostic index showed score of 5 (age >60 years, elevation of serum lactate dehydrogenase, PS of 2–4, stage III or IV, >1 extra-nodal site) indicating the highest risk for a poor and weekly prognosis. Because of the poor hepatic reserve function due to severe cirrhosis, standard chemotherapy (R-CHOP therapy comprising rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone) could not be administered. Rituximab monotherapy was considered, but because of the high risk for prognosis index, her performance status and HCV-related liver cirrhosis, and her lower appetite and fever, we selected radiation monotherapy combined with 60 mg/day oral prednisone as a palliative treatment to reduce the stenosis in the stomach and improve epigastric pain. Involved-field radiotherapy was carefully planned to target the main tumor and thickened wall lesion in the stomach (Fig. 2a); focal radiotherapy, at a total of 39.6 Gy in 22 fractions, was performed on the gastric lymphoma. The symptoms of nausea and vomiting due to the stenotic change were markedly improved after irradiation with a total of 18 Gy, and her appetite slowly recovered. The administration of prednisone was tapered and concluded and CT showed a reduction in the wall thickness and the size of the mass in the stomach at this time. Further improvement of the gastric wall thickness and tumor lesion in the stomach (Fig. 2b) was observed after irradiation with 39.6 Gy and sIL-2R decreased to 3978 IU/mL. However, metastasis to the gastric and jugular lymph nodes that were outside the irradiation field progressed during this period (data not shown), indicating that administration of prednisone had no effect. Endoscopy showed a remarkable improvement in the stenosis, ulcers, and scars after radiotherapy (Fig. 2c). Because her appetite recovered and gastrointestinal obstructive symptoms disappeared, she left hospital and returned home. Her condition was carefully followed by the clinic, and she visited our hospital with dyspnea after 2 months at home. A chest X-ray showed diffuse infiltration, and she was diagnosed as having acute respiratory distress syndrome with a severe infection. Antibiotics and antiviral agents were administered, and she received the support of mechanical ventilation; however, no response was observed, and she died of respiratory failure. Her sIL-2R level was 4494 IU/mL, showing no significant change since the radiotherapy. With her family’s consent, an autopsy was performed (Fig. 2d); the lungs showed diffuse alveolar injury probably due to the bacterial or viral infection. Interestingly, no lymphoma cells were found in the primary gastric lesion and scars were seen (Fig. 2d–f). In contrast, a large number of lymphoma cells were found in the gastric and jugular lymph nodes with infiltration into vessels and tissue (Fig. 2g, h). These results suggest that the application of radiation monotherapy to diffuse large B-cell primary gastric lymphoma, although palliative, was efficient in improving the patient’s condition and maintaining her quality of life.

Fig. 2
figure 2

Clinical course planning of involved-field radiotherapy (a). The main tumor showed a significant reduction in size and wall thickness after 39.6 Gy of irradiation (b white arrow). Endoscopy after 39.6 Gy of irradiotherapy showed improvement of the ulcerative lesions and scarring (c). Autopsy was performed and the stomach showed no stenosis and scars after radiotherapy (d). Swelling gastric lymph nodes were seen (white arrow). No lymphoma cells were seen in the stomach, and scar tissue was revealed by H&E staining (e, f). Gastric (g) and jugular (h) lymph nodes showed diffuse infiltrating large lymphoma cells. Magnification: e ×20, f ×40, g ×200, h ×200

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Discussion

Primary gastric lymphomas are relatively rare malignant gastric tumors and are generally non-Hodgkin lymphomas (NHL) in 60–80 % of cases. The most common histological subtypes are DLBCL and MALT [1, 2]. To date, no standard therapeutic strategies exist for primary gastric lymphoma although they have changed dramatically over the last two decades. The major change has been the abandonment of surgical treatment in favor of conservative therapies, including chemotherapy, radiotherapy, and their combination which have resulted in a high level of curability [2–6, 9, 10]. These stomach-preserving therapies offer a better quality of life and are comparable to surgical treatment in terms of therapeutic effects [3, 7, 8].

The association between HCV infection and the occurrence of B-cell NHL has been reported [11, 16–18] as HCV infects not only hepatocytes but also mononuclear lymphocytes, including B cells that express the CD81 molecule, a putative HCV receptor [19]. Because the cytotoxic chemotherapy to B-cell NHL causes severe damage to hepatic function [20], and reactivation of viral hepatitis with severe hepatitis [21], it is sometimes impossible to administer these agents to elderly patients with liver disease. In 2005, Nakai et al. [22] reported a case of stage I diffuse large B-cell primary gastric lymphoma with a high intermediate prognosis index treated with rituximab monotherapy instead of a combination of cytotoxic agents as the case had a complication of liver dysfunction due to HCV-induced liver cirrhosis. As our case showed lower performance status, more advanced clinical stage and poorer hepatic functional reserve, and activity of chronic hepatitis, the standard R-CHOP or rituximab therapy could not therefore be considered for her gastric lymphoma as there are recent reports showing liver dysfunction [23] and reactivation of HCV [24–27] after rituximab administration. Therefore, we focused on radiotherapy [4, 10] as a palliative therapy.

Based on recent reports, radiation monotherapy is now being used as a standard therapy for MALT lymphoma cases that show insufficient response to eradication chemotherapy and are negative for H. pylori infection [6, 28, 29]. For DLBCL, Herrman et al. [1] first revealed the effectiveness of radiation monotherapy reporting no significant difference between the median relapse-free survival time of patients who received radiation monotherapy and those of the adjuvant radiotherapy following surgical treatment, and this therapeutic efficiency has been confirmed by several reports [12–14]. In addition, it is reported that radiotherapy appeared to benefit patients with poor prognostic factors [15]. Based on this evidence, radiation monotherapy is being considered as a therapeutic option for primary gastric lymphomas with poor prognosis [4, 10], and its planning techniques have undergone significant development from the safety point of view [30, 31].

With advances in the management of HCV infection and supportive therapy for cirrhotic liver, the prognosis of HCV patients is improving [32, 33]. These facts suggest that various HCV-related diseases such as malignant lymphoma, cryoglobulinemia, etc. will increase in aged populations with poor hepatic reserve function, as in our case, and that treatment procedures should be carefully decided.

We report a case of diffuse large B-cell primary gastric lymphoma with a poor prognostic factor and severe liver cirrhosis. The anti-tumor effect of palliative involved-field radiotherapy on the primary tumor significantly improved her symptoms, maintained her quality of life and finally resulted in disappearance of tumor cells in the lesion. These results suggest that the involved-field radiotherapy can be a therapeutic option for primary gastric lymphoma patients with various complications.