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Collision Tumors of Gastric Adenocarcinoma and Mucosa-associated Lymphoid Tissue Lymphoma

A 65-year-old woman with a history of treatment for splenic marginal zone B-cell lymphoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma underwent esophagogastroduodenoscopy. A reddish elevated lesion was found in the fundus of the stomach. On image-enhanced endoscopy, several findings, such as glandular structures of varying sizes suggesting well-differentiated adenocarcinoma, pruned blood vessels, and dilated blood vessels in deeper mucosa suggesting MALT lymphoma, were observed. The final pathological diagnosis after surgical resection was collision tumors of well-differentiated adenocarcinoma and MALT lymphoma. The features of both tumors could be observed simultaneously with image-enhanced endoscopy.


Introduction
Gastric adenocarcinoma is the most common type of gastric cancer. Although the number of cases is declining due to a reduction in the Helicobacter pylori (H. pylori) infection rate in Japan, it is still the fifth-most common cancer in the world and has the third-highest mortality; thus, it remains a major cancer. The prognosis of gastric adenocarcinoma varies depending on the stage of the disease, and reports have shown that while stage IV has a 5-year survival rate of only 16.4%, the survival of stage IA can be as high as 91.5% (1)(2)(3). Detection of lesions using endoscopy is very important, and reports have shown the usefulness of imageenhanced endoscopy (IEE), including linked-color imaging (LCI) (4)(5)(6)(7)(8)(9).
Gastric lymphoma accounts for only 0.8%-2.0% of all gastric tumors, making it a relatively rare disease. The most common histological type of gastrointestinal lymphoma is mucosa-associated lymphoid tissue (MALT) lymphoma, accounting for approximately 52% of cases (10,11). Gastric MALT lymphoma shows a good prognosis. Both gastric adenocarcinoma and MALT lymphoma are attributed to H. pylori infection.

Case Report
The patient was a 65-year-old woman. She was referred to our hospital at 49 years old for a detailed examination of splenomegaly and anemia. As a result of the detailed examination, she was diagnosed with splenic marginal zone B-cell lymphoma. Since lymphoma lesions were found in multiple organs, including the stomach, rectum, and bone marrow, the stage of this lymphoma was IVB (Lugano classification). Splenectomy was performed to improve the anemia, and t (11;18)(q21;q21) translocation was detected by a chromosome analysis.
The patient underwent chemotherapy and radiotherapy for endotracheal lesions and submandibular lymphadenopathy, but pulmonary lesions appeared, and the lymphadenopathy relapsed every few years, being treated with chemotherapy.
At 60 years old, esophagogastroduodenoscopy (EGD) revealed an ulcerative lesion in the fundus of the stomach that was diagnosed as MALT lymphoma via a biopsy. The gastric MALT lymphoma and splenic marginal zone B-cell lymphoma were considered pathologically separate tumors. A microscopic examination of the biopsy specimen and a serological test showed negative results for H. pylori. Because bone marrow involvement, parotid gland, and cervical lymphadenopathy associated with splenic marginal zone Bcell lymphoma were also detected, the patient was treated with bendamustine and rituximab.
At 63 years old, after these treatments, a biopsy of the scar on the fundus of the stomach revealed residual MALT lymphoma cells. However, no additional therapy was administered because the other lesions showed no residual lymphoma ( Fig. 1). She declined to undergo EGD for about two years because she had no symptoms.
At 65 years old, the patient experienced stomach discomfort. EGD revealed a reddish elevated lesion with an irregular surface that corresponded to the area of scarring on the fundus ( Fig. 2A, B). The surrounding mucosa was discolored, emphasizing the redness of the lesion compared with the surrounding mucosa. Indigo carmine dye spraying revealed more distinct borders than conventional endoscopy (Fig. 2C). The lesion appeared bright red with LCI and was well contrasted with the surrounding gastric mucosa, creating a distinct boundary (Fig. 2D). Magnifying narrow-band imaging (NBI) endoscopy revealed several findings, including glandular structures of varying sizes, pruned blood vessels, and dilated blood vessels in the deeper mucosa (Fig. 3).
A biopsy revealed the proliferation of cells with enlarged atypical nuclei and increased chromatin forming ductal structures, and she was diagnosed with well-differentiated The dilated blood vessels were also visible. C: A tree-like appearance was observed with magnifying NBI at a different site.

A A B B C C
adenocarcinoma. In addition to adenocarcinoma, diffuse lymphoid infiltration of small to medium cells was observed in the lamina propria. Immunophenotypically, the tumor cells were positive for CD20 but negative for CD3, CD5, CD10, and Cyclin D1, resulting in a diagnosis of MALT lymphoma. No apparent distant metastases were found on computed tomography (CT). Given these findings, she was diagnosed with double tumors of gastric adenocarcinoma and MALT lymphoma. Although total gastrectomy was an option, the preoperative diagnosis was early gastric cancer, and the patient's quality of life was prioritized, so she underwent laparo-scopic fundectomy and D-1+ dissection. The final pathological diagnosis was well-differentiated adenocarcinoma, pT3, pN2, cM0, pStage IIIb, and MALT lymphoma, Stage II1. Although oral S-1 was administered as postoperative adjuvant chemotherapy, 15 months later, enlargement of the left subphrenic, paraaortic, and hepatoduodenal ligament lymph nodes and liver metastasis were found on CT, and she was diagnosed with recurrence of gastric adenocarcinoma. There was no relapse of MALT lymphoma. Her general condition gradually deteriorated, and she died approximately two years after the operation. The histopathological features of gastric cancer were welldifferentiated adenocarcinoma invading the subserosa. Aside from gastric cancer, histology also revealed invasion by the MALT lymphoma, which was primarily limited to the submucosa (Fig. 5B, C). There was no normal tissue between the two lesions. Small to medium-sized cells with pale cytoplasm and a slightly irregular nucleus, also called centrocyte-like cells, had diffusely infiltrated, and plasmacytic differentiation was observed in some areas. The lymphoid cells were positive for CD20 but negative for CD3, CD5, CD10, and Cyclin D1. In addition, kappa light chain restriction by immunohistochemistry and IgH rearrangement by polymerase chain reaction were detected. It was difficult to determine the t(11;18)(q21;q21) translocation of MALT1 through a chromosomal analysis with fluorescence in situ hybridization (FISH). Well-differentiated adenocarcinoma and metastasis of MALT lymphoma were found in the regional lymph nodes.

Discussion
In this case, gastric MALT lymphoma was observed during treatment of stage IV splenic marginal zone B-cell lymphoma, which had infiltrated multiple organs, and after five years, double tumors of the gastric adenocarcinoma and gastric MALT lymphoma developed. The association between gastric MALT lymphoma and splenic marginal zone B-cell lymphoma was difficult to determine because further investigations, including additional immunostaining, could not be performed due to insufficient specimens; pathologically, however, the gastric lesion was diagnosed as MALT lymphoma.
Double tumors refer to the presence of histologically distinct malignant tumors, and Meyer has classified them into three subtypes (12). Two neoplastic components that develop separately and collide or intersect with each other are defined as collision tumors, two neoplastic components that simultaneously develop from a common stem cell and grow mixed together are defined as contiguous tumors, and two neoplastic components that develop simultaneously but exist independently of each other are defined as independent tumors. The most common of these types is independent tumors, followed by collision tumors and contiguous tumors. Isosaka et al. reported that independent tumors account for approximately 62% of double tumors, followed by collision tumors, which account for approximately 24% (19). In the present case, gastric adenocarcinoma developed after followup of a patient with MALT lymphoma, and the histopathological evaluation of the resected specimen revealed that gastric adenocarcinoma was located at the same place where MALT lymphoma was located. As a result, the patient was diagnosed with collision tumors based on the findings (Fig. 5).
Magnifying IEE is useful for differentiating malignant gastric tumors. Yao et al. reported the VS classification in 2002 for magnifying NBI observation of gastric adenocarcinoma, which markedly improved the ability to diagnose gastric cancer endoscopically (4). Diagnosing the surface structure, vascular structure, and demarcation line makes it possible to differentiate between cancerous and non-cancerous areas as well as between differentiated and undifferentiated adenocarcinoma (5,6). However, abnormal blood vessels with a tree-like appearance (TLA) is a characteristic finding of gastric MALT lymphoma, and this finding is useful for differentiating MALT lymphoma from gastric adenocarcinoma (20)(21)(22). Gastric adenocarcinoma is characterized by findings such as microvasculature with notable irregular di- ameters and an uneven shape; however, there are few abnormal blood vessels with irregular diameters in MALT lymphoma, and the blood vessels tend to diverge like branches from the trunk of a tree. The glandular structures in the present patient varied in size, and the vascular structure was irregular, and although there were endoscopic findings characteristic of adenocarcinoma, the demarcation line was unclear, suggesting the possibility of the coexistence of another disease in addition to typical adenocarcinoma. Furthermore, TLA and dilated vasculature were also found, suggesting the coexistence of MALT lymphoma.
Histopathologically, adenocarcinoma dominated the superficial layer of the mucosa, but the MALT lymphoma had also invaded the superficial and deep layers (Fig. 5). Welldifferentiated adenocarcinoma and MALT lymphoma coexisted on the tumor surface, with both a fine network pattern characteristic of differentiated adenocarcinoma and TLA-like blood vessels characteristic of MALT lymphoma, which were considered to reflect the histological findings (23)(24)(25)(26).
LCI, an image-enhancement technique, has been reported to improve the visibility of gastric adenocarcinoma (7)(8)(9). LCI uses short-wavelength light to emphasize the microvasculature and surface structures on the mucosal surface, which highlights slight differences in reddish areas. Reports have shown that the red color tone in LCI correlates with vessel density (9). In the present patient, LCI not only emphasized the redness of the lesion area but also differentiated the red color tone from the redness due to gastritis in the surrounding mucosa, thereby improving visibility. Nonmagnifying observation with LCI was considered useful for lesion detection in this patient.
Our patient originally developed gastric adenocarcinoma during the course of MALT lymphoma. The development of gastric adenocarcinoma during follow-up of MALT lymphoma has been previously reported, and some of these cases are assumed to be due to chronic irritation of the gastric mucosa by MALT lymphoma (27)(28)(29). However, a report of 12 patients with double primary gastric lymphoma and adenocarcinoma showed that all patients were positive for H. pylori, and the authors concluded that H. pylori infection was associated with the development of these double malignancies (15). The present patient had no general H. pylori infection as the cause of gastric adenocarcinoma. Therefore, it is suspected that this case was preceded by MALT lymphoma, which induced local immunodeficiency and gland duct cell production while damaging the mucosal microvasculature, and thereby triggering adenocarcinoma; however, this is mere speculation (19,(30)(31)(32). Another report indicated that the survival rate of synchronous gastric adenocarcinoma and gastric MALT lymphoma was the same as that of gastric adenocarcinoma alone, and the progression of gastric adenocarcinoma has been shown to often determine the prognosis (15). A previous study also showed that gastric adenocarcinoma tended to be early cancer restricted to the mucosa and submucosa, with gastric lymphomas invading more deeply than adenocarcinoma (15). Despite the long duration of MALT lymphoma, our patient died approximately two years after the diagnosis of gastric adenocarcinoma. If patients with disseminated MALT lymphoma have involvement of the stomach, periodic EGD is recommended over the long term, bearing in mind the possibility of gastric adenocarcinoma.
In summary, we encountered a case of collision tumors of gastric adenocarcinoma and gastric MALT lymphoma. The features of both tumors were able to be observed simultaneously with image-enhanced endoscopy.
The authors state that they have no Conflict of Interest (COI).