Transformed gastric mucosa-associated lymphoid tissue lymphoma originating in the colon and developing metachronously after Helicobacter pylori eradication: A case report

Abstract

BACKGROUND

Helicobacter pylori (H. pylori) eradication treatment for primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma has already been established. However, t (11;18) (q21;q21)/API2-MALT1 translocation-positive lesions are a type of primary gastric MALT lymphoma in which a response to eradication treatment is difficult to achieve. In addition, trisomy 18 may be associated with diffuse large B-cell lymphoma (DLBCL) transformation of gastric MALT lymphoma.

CASE SUMMARY

A 66-year-old man was diagnosed with MALT lymphoma in the ascending colon by colonoscopy and biopsy. Two years later, esophagogastroduodenoscopy revealed chronic atrophic gastritis that was positive for H. pylori, and eradication treatment was administered. Two years and nine months later (at the age of 70), a new ulcerative lesion suggestive of MALT lymphoma appeared in the gastric body, and six months later, a similar lesion was also found in the fundus. One year later (4 years and 3 months after H. pylori eradication), at the age of 72, the lesion in the gastric body had become deeper and had propagated. A biopsy revealed a pathological diagnosis of DLBCL. Both MALT lymphoma lesions in the ascending colon and DLBCL lesions in the stomach were positive for the t (11;18) (q21;q21)/API2-MALT1 translocation, and trisomy 18q21 was also detected. After 6 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, all of the above lesions disappeared [complete remission (CR)], and CR has been maintained for more than 3 years. In addition, both the colonic and gastric lesions were proven to have the same clonality.

CONCLUSION

Because the patient had a MALT1 translocation with trisomy 18q21, it was thought that this gastric MALT lymphoma developed independently of H. pylori infection and progressed.

Key Words: Gastric mucosa-associated lymphoid tissue lymphoma; Transform; Diffuse large B-cell lymphoma; Colonic mucosa-associated lymphoid tissue lymphoma; Helicobacter pylori eradication; MALT1 translocation; Case report

Core Tip: Helicobacter pylori (H. pylori) eradication treatment is expected to be effective for treating mucosa-associated lymphoid tissue (MALT) lymphoma originating not only from the stomach but also from the colon. However, t (11;18) (q21;q21)/API2-MALT1 translocation is difficult to achieve a response to H. pylori eradication treatment for primary gastric MALT lymphoma. In this study, H. pylori eradication treatment performed for chronic atrophic gastritis was not only ineffective against initial colonic MALT lymphoma but also failed to prevent the subsequent development of gastric MALT lymphoma and further transformed diffuse large B-cell lymphoma. Because this lesion had a MALT1 translocation with trisomy 18q21, it was thought that the disease developed independently of H. pylori infection and progressed.

INTRODUCTION

Mucosa-associated lymphoid tissue (MALT) lymphoma, proposed by Isaacson and Wright[1] in 1984, is an indolent lymphoma that develops due to chronic inflammation in various extranodal organs[1]. The stomach is the most common site of occurrence, and MALT lymphoma accounts for approximately half of all primary gastric lymphomas and is dichotomous with diffuse large B-cell lymphoma (DLBCL)[2]. In addition, Helicobacter pylori (H. pylori) is often involved in the development of primary gastric MALT lymphoma, and eradication therapy has long been established as a treatment for this disease[3,4]. Gastric MALT lymphoma independent of H. pylori infection, which is difficult to eradicate, is characterized by: (1) H. pylori negativity; (2) t (11;18) (q21;q21)/API2-MALT1 translocation; (3) Deep gastric wall invasion; and (4) An advanced disease stage[3,5,6]. In addition, trisomy 18 may be associated with DLBCL transformation of gastric MALT lymphoma[7].

On the other hand, primary colorectal lymphoma accounts for < 1% of all colorectal malignancies[8], and colorectal MALT lymphoma is an even rarer disease[9,10]. A study of a small number of patients reported that one-third of those individuals with colonic MALT lymphoma also had gastric MALT lymphoma[11]. In addition, a standard treatment for primary colonic MALT lymphoma has not yet been established, and there are reports that suggest the effectiveness of H. pylori eradication therapy[12,13].

In this study, we reported that MALT lymphoma initially developed in the colon. After H. pylori was eradicated for chronic atrophic gastritis, the colonic lesions remained unchanged, and MALT lymphoma developed metachronously in the stomach, in which multiple lesions were observed, one of which transformed into DLBCL. This case was considered highly suggestive of the mechanism by which gastric MALT lymphoma progresses from its onset.

CASE PRESENTATION

Chief complaints

A 72-year-old man, who was asymptomatic, was transferred to our department for detailed examination and treatment for gastrointestinal lymphomas, as described below.

History of present illness

The biopsy suggested DLBCL, and the patient was referred and admitted to our department.

History of past illness

Figure 1 shows the clinical course chart. At the age of 66, owing to a positive fecal occult blood test, the patient underwent a colonoscopy at the hospital in charge of his treatment at that time; a tumor lesion was found in the ascending colon (Figure 2A), and a biopsy suggested MALT lymphoma. Two years later (at the age of 68), esophagogastroduodenoscopy revealed chronic atrophic gastritis that was positive for H. pylori (Figure 2B). Oral administration of vonoprazan fumarate, amoxicillin hydrate and clarithromycin (20 mg, 750 mg and 200 mg, respectively, twice daily) for one week was used for eradication therapy, and urea breath test results were subsequently negative for H. pylori. A repeat endoscopy approximately 1 year later revealed no significant changes. Two years later (at the age of 70), slight erosions appeared on the mucosa of the greater curvature of the gastric body, and nine months later, the lesion had changed to multiple ulcers (Figure 2C). The lesion was biopsied and found to be consistent with MALT lymphoma, and H. pylori was negative histopathologically. Furthermore, 6 months later, a whitish mucosal lesion was observed in the fundus of the stomach (Figure 2D), and a biopsy of this lesion also suggested MALT lymphoma. One year later (4 years and 3 months after H. pylori eradication), the multiple ulcer lesions on the greater curvature of the gastric body were deeper and more widespread (Figure 2E); the biopsy suggested DLBCL.

Figure 1 Clinical course chart. MALT: Mucosa-associated lymphoid tissue; DLBCL: Diffuse large B-cell lymphoma.

Figure 2 Endoscopic findings. Colonoscopy image (A) and esophagogastroduodenoscopy image (B-F). A: This image was taken at the time of discovery of colonic mucosa-associated lymphoid tissue (MALT) lymphoma (at the age of 66); B: This image was taken at the time of the discovery of chronic atrophic gastritis associated with Helicobacter pylori (H. pylori) infection (at the age of 68); C: MALT lymphoma was detected in the greater curvature of the body of the stomach 2 years and 9 months after H. pylori eradication (at the age of 70); D: MALT lymphoma was found in the fundus of the stomach 3 years and 3 months after the eradication of H. pylori (at the age of 71); E: Four years and three months after the eradication of H. pylori (at the age of 72), the lymphoma in the gastric body had progressed and transformed into diffuse large B-cell lymphoma; F: At the time of admission to our department, the lymphoma lesions had further progressed.

Personal and family history

There are no noteworthy points.

Physical examination

The patient had few subjective symptoms, and his performance status was 0. No abnormal findings were observed physically, including in the abdomen.

Laboratory examinations

Blood cell counts and soluble interleukin-2 receptor levels were within the normal range (443 U/mL), and the anti-H. pylori antibody levels were slightly elevated at 10 U/mL.

Imaging examinations

Esophagogastroduodenoscopy and colonoscopy were performed in our department, and the lesions in the fundus of the stomach and ascending colon were almost unchanged from when they were first discovered. A biopsy revealed that the lesion was compatible with MALT lymphoma. In contrast, the lesions in the gastric body had progressed (Figure 2F) within 1 month. Histological findings from the biopsy revealed large atypical lymphoid cells with enlarged nuclei proliferating into the glandular ducts (Figure 3A). Immunostaining revealed that these abnormal cells were positive for CD20 (Figure 3B) and c-myc (Figure 3C), and the MIB-1 index was positive in more than 90% (Figure 3D), indicating that they had DLBCL. Microscopic examination revealed that H. pylori was negative. PET revealed strong accumulation in the gastric body and in swollen lymph nodes around the stomach, with a maximum standardized uptake value (SUVmax) of 10-19 (not shown), which is consistent with DLBCL. The hepatic curvature of the colon had a SUVmax of 6.9, which was unchanged over the previous 6 years, suggesting MALT lymphoma.

Figure 3 Histopathological findings. A: Large abnormal lymphoid cells with enlarged nuclei were proliferating into the glandular ducts (Hematoxylin & eosin staining); B and C: These lymphoid tumor cells were positive for CD20 immunostaining (B) and for c-myc immunostaining (C); D: The MIB-1 index was positive in more than 90% of the tumor cells. Pathological diagnosis of diffuse large B-cell lymphoma was made.

FINAL DIAGNOSIS

On the basis of the above findings, the lesions in the colon and gastric fundus were diagnosed as MALT lymphoma, and the lesion in the gastric body was diagnosed as DLBCL derived from MALT (Lugano-Stage II1, IPI: Low, revised IPI: Very good).

TREATMENT

A total of 6 courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy were administered. The treatment was completed in 3-week cycles without any adverse events.

OUTCOME AND FOLLOW-UP

All lesions, including those in the stomach, colon, and lymph nodes, disappeared, resulting in complete remission (CR). More than 3 years have passed since the end of treatment, and the patient has maintained CR to date. He is now 76 years old and leads a healthy daily life.

Molecular biological analysis

Fluorescence in situ hybridization (FISH) revealed MALT1-positive lymphoma cells in both the stomach and colon, and 3 copies of the MALT1 gene were found in the nucleus of a small number of tumor cells (Figure 4A). The FISH results for p53 and c-myc were negative. We also investigated the IgH gene rearrangement of tumor cells in lymphoma lesions in the stomach and colon by polymerase chain reaction-based single-strand conformational polymorphism (PCR-SSCP) analysis[14]. As a result, the bands indicating monoclonality matched, revealing that the two lesions had the same clonality (Figure 4B).

Figure 4 Molecular biological analysis. A: Three copies of the MALT1 gene were detected in the nuclei of lymphoma cells (Fluorescence in situ hybridization); B: The bands indicating monoclonality (orange arrows) matched, revealing that the colonic and gastric lesions had the same clonality (polymerase chain reaction-based single-strand conformational polymorphism).

DISCUSSION

Considering the comprehensive safety of the treatment itself, its effectiveness against colonic MALT lymphoma[12,13], and its ability to reduce the risk of developing gastric adenocarcinoma later in life[15], we believe that H. pylori eradication is a reasonable treatment option. However, it was not only ineffective against colonic MALT lymphoma but also failed to suppress the development of gastric MALT lymphoma and subsequent DLBCL. It is also possible that MALT lymphoma was already occurring histologically at the time of eradication. Gastric MALT lymphomas that are positive for MALT1 translocation, as in this case, are not associated with H. pylori infection, and eradication is often ineffective[3,5,6]. In addition, it was believed that the development of DLBCL approximately 2 years later was not de novo but rather was due to transformation from H. pylori-independent MALT lymphoma.

Extra copies of chromosome 3 or 18 (trisomy) are chromosomal abnormalities that may be associated with DLBCL transformation in patients with gastric MALT lymphoma[7]. Additionally, there is a report[16] that extra copies of MALT1 (18q21 trisomy), as in our case, are an independent factor for poor event-free survival in patients with gastric MALT lymphoma. Although our patient did not exhibit c-myc translocation by FISH, the c-myc protein was expressed. “MYC-driven B-cell lymphoma” has been proposed as a general term for lymphomas whose pathogenesis is presumed to involve the activation of MYC[17]. Magnoli et al[18] reported that high c-myc protein expression is a poor prognostic factor in extranodal DLBCL[18]. The patient was reexamined at age 76 (10 years after MALT lymphoma was first found) and confirmed to be in CR in both the stomach and colon more than 3 years after the end of treatment. We intend to continue to monitoring him closely.

Owing to the rarity of colonic MALT lymphoma, there are few comprehensive reports on this disease[9-11]. Its treatment has not been established, and there are reports that the eradication of H. pylori is expected to be effective even in H. pylori-negative patients[13], but objective evidence is still lacking[9,11]. It is unclear whether eradication therapy will be less effective in colonic MALT lymphomas that are positive for MALT1 translocation, as in the case of the stomach. This time, CR was achieved with R-CHOP chemotherapy. We previously reported a case of multiple lesions of colorectal MALT lymphoma that were successfully treated with chemotherapy, including R-CHOP, and achieved long-term CR[19]. Bendamustine is also likely to be used more often in the future as a therapeutic drug[19,20].

Previously, it was reported that out of 9 patients with colonic MALT lymphoma, 3 had synchronous MALT lymphoma in the stomach[10]. To the best of our knowledge, our patient is the first reported case in which the clinical course of MALT lymphoma, which first developed in the colon and then metachronously developed in the stomach, was followed in real time, and analysis via the PCR-SSCP method demonstrated that both lesions had the same clonality.

CONCLUSION

In this study, eradication treatment for H. pylori was not only ineffective against newly diagnosed colonic MALT lymphoma but also failed to suppress the onset of gastric MALT lymphoma from chronic atrophic gastritis and the subsequent development of transformed DLBCL. Because these lesions had MALT1 translocations accompanied by trisomy 18q21, it was thought that MALT lymphoma developed independently of H. pylori infection and further worsened. Furthermore, although both the colonic and gastric lesions had metachronous onset, PCR-SSCP proved that they had the same clonality.

ACKNOWLEDGEMENTS

The authors would like to thank Ikuo Sato (Sapporo Clinical Laboratory Inc.) and Kyoko Fujii (Department of Cancer Pathology, Faculty of Medicine, Hokkaido University) for the technical support provided in the laboratory aspects of this study and Dr. Sosuke Kato (Department of Gastroenterology, NTT Medical Center Sapporo) for providing detailed information as the attending physician at the hospital where the patient was previously followed.