Helicobacter pylori-positive Colorectal MALT Lymphoma with Repeated Metachronous Recurrence after a Complete Response to Eradication Therapy and Regression after a Watch-and-wait Strategy

Abstract

A 77-year-old man underwent a colonoscopy. A submucosal cecal tumor was found, and localized colorectal MALT lymphoma (Lugano stage I) was diagnosed with a Helicobacter pylori infection. The first-line eradication therapy was successful, and the cecal lesion regressed. However, a new lesion was observed in the lower rectum. The rectal lesion regressed after the second-line eradication therapy. Two new lesions were identified in the sigmoid colon. However, no additional treatment was administered and a watch-and-wait strategy was adopted. Both of the lesions regressed. There are no established treatments for colorectal MALT lymphomas. The watch-and-wait strategy may be effective in cases of recurrence after eradication therapy.

Introduction

In 1983, Isaacson and Wright proposed MALT lymphoma as a low-grade malignant lymphoma derived from mucosa-associated lymphoid tissues (1). Several cases of primary MALT lymphomas of the gastrointestinal tract have been reported. However, most are gastric MALT lymphomas, while colorectal MALT lymphomas are relatively rare (2).

For localized gastrointestinal MALT lymphoma, eradication therapy combined with antibiotics and proton pump inhibitors has been selected as the initial treatment (3), but the outcome depends on the Helicobacter pylori (HP) infection status and the presence of the BIRC3-MALT1 fusion gene.

For gastric MALT lymphoma, the response rate to eradication therapy is low in cases with BIRC3-MALT1 fusion gene positivity. However, eradication therapy is more successful in HP-positive patients (3). It has recently been shown that a response rate of nearly 50% can be achieved even in HP-negative patients (4). Colorectal MALT lymphoma has been reported to respond to HP eradication therapy in some cases, although this has not been studied in a large sample, and the effect may be independent of the HP infection status (5).

The National Comprehensive Cancer Network (NCCN) guidelines (ver2, 2024) recommend surgical resection (surgery), involved-site radiation therapy (ISRT), chemotherapy (rituximab), and watch-and-wait (observation) as initial strategies, although eradication therapy has recently been preferred owing to its low invasiveness. There is no clear consensus regarding treatment. Radiotherapy, chemotherapy, and observation are recommended for the treatment of local recurrence (6).

In this report, we describe a case of HP-positive colorectal MALT lymphoma with repeated metachronous recurrence after a complete response (CR) to eradication therapy that regressed after a watch-and-wait strategy.

Case Report

A 77-year-old man presented with abdominal discomfort and underwent colonoscopy (CS) in December 2013. A 10-mm reddish submucosal tumor (SMT) with a smooth surface and a central depression was found close to the appendiceal orifice in the cecum (Fig. 1a). A type I pit was observed after spraying with indigo carmine (Fig. 1b). Magnifying endoscopy with narrow-band imaging revealed a tree-like appearance of the tumor surface (Fig. 1c, d). Endoscopic ultrasonography showed that the lesion was a hypoechoic mass localized within the first and second layers, with preservation of the third layer. This suggests that the tumor was restricted to the superficial portion of the submucosa (Fig. 1e).

Figure 1.

Endoscopic images of cecal lesions before Helicobacter pylori eradication therapy. (a) A 10-mm reddish lesion with a submucosal tumor-like elevation and central depression in the cecum. (b) A type I pit is observed after indigo carmine spraying. (c, d) Magnifying endoscopy with narrow-band imaging showing a tree-like appearance on the tumor surface with partial disappearance of the normal pit pattern. (e) On endoscopic ultrasonography, the tumor appears as a low-echoic lesion localized within the first and second layers.

Biopsies of the colonic mucosa revealed marked inflammatory cell infiltration within the lamina propria, and intraepithelial lymphocyte infiltration in some areas (Fig. 2a, b). Immunohistochemical studies demonstrated positivity for CD20, CD79a, and bcl-2 and negativity for CD10 and cyclinD1 (Fig. 2c, d).

Figure 2.

Pathological and immunohistochemical findings in MALT lymphoma. (a, b) High inflammatory cell infiltration within the lamina propria and intraepithelial infiltration by lymphocytes in some areas. (a) Hematoxylin and Eosin (H&E) staining at ×40 magnification, (b) H&E staining at ×100 magnification. (c) Immunohistochemically, the tumor cells were positive for CD20 (CD20 staining at ×100 magnification). (d) Tumor cells are positive for CD79a (CD79a staining at ×100 magnification). (e) Polymerase chain reaction (PCR) revealed immunoglobulin heavy chain gene rearrangement [VH (FR1)/JH]. (f) BIRC3-MALT1 chimeric transcripts were not detected by reverse transcriptase PCR (MALT1 Probe signal is red, BIRC3 Probe signal is green).

Based on an analysis of tumor specimens, the results of an immunoglobulin heavy chain gene rearrangement analysis were VH(FR1)/JH(+), VH(FR2)/JH(-), VH(FR3)/JH(-), DH1-6/JH(-), and DH7/JH(-). The BIRC3-MALT1 fusion gene was negative (Fig. 2e, f). Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue was diagnosed. Upper endoscopy showed O-2 type atrophy according to the Kimura-Takemoto classification (7). No other abnormal findings, including MALT lymphoma in the esophagus, stomach, duodenum, colon, or rectum, were observed.

The patient tested positive for anti-HP antibodies (82 U/mL). The patient underwent staging positron emission tomography-computed tomography (PET-CT), which revealed no ¹⁸F-fluorodeoxyglucose accumulation in the tumor lesion or other organs, including the lymph nodes. A bone marrow biopsy showed no lymphomatous involvement. Based on the above findings, we diagnosed stage I localized colorectal MALT lymphoma according to the Lugano classification, with HP infection but without the BIRC3-MALT1 fusion gene.

Eradication therapy consisting of oral amoxicillin 1,500 mg/day, clarithromycin 400 mg/day, and rabeprazole 20 mg/day for seven days was administered as the initial treatment (December 2013; month 0), and HP eradication was successful.

The primary tumor (Lesion A shown in Fig. 3) located in the cecum regressed endoscopically and pathologically nine months later (September 2014; month 9). Simultaneously, a new 8 mm SMT (Lesion B shown in Fig. 3) was detected in the lower rectum and it was pathologically diagnosed to be colorectal MALT lymphoma. A retrospective examination revealed that the rectal lesion was absent at the time of the initial CS. The second-line eradication therapy consisted of amoxicillin (1500 mg/day), metronidazole (500 mg/day), and rabeprazole (20 mg/day) for 7 days. The rectal lesion regressed endoscopically and pathologically 16 months later (January 2016; month 25).

Figure 3.

Treatment progress chart for colorectal MALT lymphoma.

A new 10-mm SMT (Lesion C shown in Fig. 3) and a 5-mm SMT (Lesion D shown in Fig. 3) were detected in the sigmoid colon 13 months later (February 2017; month 38). The patient was pathologically diagnosed with colorectal MALT lymphoma. We therefore proposed four treatment options to the patient : surgery, radiation therapy, chemotherapy, and watch-and-wait. The patient selected a watch-and-wait strategy for two new lesions (lesions C and D). Lesion C regressed after eight months (October 2017; 46 months). Lesion D persisted with little change in its morphology for another 39 months (May 2020; month 77) and regressed after 51 months (May 2021; month 89).

The detailed course of all the lesions is shown in Fig. 3. The last surveillance endoscopy was performed in May 2024 (month 125) and no MALT lymphoma was detected.

Discussion

This was a case of colorectal MALT lymphoma with concurrent HP infection but without the BIRC3-MALT1 fusion gene. A new lesion was found in the rectum after regression of the primary cecal lesion following first-line eradication therapy but regressed after second-line eradication therapy. Multiple new lesions developed in the sigmoid colon and a watch-and-wait strategy was adopted. Several cases of colorectal MALT lymphoma with simultaneous lesions have been reported (8). However, reports of metachronous recurrence are limited (9), and the colorectal MALT lymphoma reported herein is a rare case of both simultaneous lesions and metachronous recurrence.

According to the NCCN guidelines, colorectal MALT lymphoma is classified as an extranodal MZL of nongastric sites. The guidelines for extranodal MZL of non-gastric sites include surgery, ISRT, rituximab, and observation as initial treatment options in parallel with stage IE or contiguous stage IIE (6). However, the efficacy of eradication therapy for colorectal MALT lymphoma has been widely reported (10). Considering its low invasiveness, eradication therapy has been reported to be effective as an initial therapy in clinical practice (11).

In our case, eradication treatment was administered after obtaining informed consent from the patient. Previous reports have shown that a proportion of patients with colorectal MALT lymphoma achieve CR with eradication therapy in both HP-positive and HP-negative cases (11). Higher CR rates have been reported in HP-positive cases than in HP-negative cases (11). In contrast, a higher CR rate has been reported for HP-negative cases [Hp-positive: 50.0% (7/14) vs. Hp-negative: 66.7% (8/12)] (12). Thus, eradication therapy is considered effective for MALT lymphoma with mechanisms other than the eradication of HP infection (13,14); mechanisms via modification of the gut microbiota or tumor immunity have been speculated (15).

In this case, we suggested surgery, ISRT, chemotherapy, and observation as treatment options when lesions C and D were detected after regression of lesions A and B, and the patient preferred observation. Owing to the regression of Lesion C within a short period, we continued the watch-and-wait strategy for a long period, and the patient achieved CR after 51 months.

For gastric MALT lymphoma, several cases of CR following a long period of eradication therapy have been reported, and it takes time for treatment to be effective (3,16). In this case, it is possible that modification of the gut microbiota due to eradication therapy delayed regression. However, this may not have been direct because another lesion recurred after CR was achieved. Modification of gut microbiota may also influence the appearance of new lesions.

Spontaneous regression has been reported in extranodal malignant lymphomas of the rectum, stomach, thyroid, and lungs (17-20). The mechanism is unclear, but a possible mechanism involving modification of the host immunity due to biopsy injury or complete shedding due to ulceration has been reported (21-24). In the current case, several biopsies were performed during the follow-up endoscopy to monitor the lesion. Therefore, tissue injury caused by biopsy may have modified host immunity; however, it is difficult to elucidate a clear mechanism based on this case alone, and further study and accumulation of cases are needed.

MALT lymphoma has a high recurrence rate (25), and there have been reports of extranodal malignant lymphoma that recurred after spontaneous regression (19,26). Therefore, further follow-up was considered crucial in the present case. Although there is no consensus according to the NCCN guidelines, we considered it important to conduct follow-up examinations every 3-6 months for 5 years and annually thereafter. However, at our patient's request, we scheduled follow-up examinations with CS and PET-CT at least once a year.

In cases involving metachronous recurrence, genetic analysis of all lesions would be useful to confirm whether the origin was the same. Unfortunately, in the present case, a genetic analysis was only performed for the first lesion. Because retrospective assessment of lesions after regression is difficult, multifaceted evaluation, including genetic analysis, should be considered during the follow-up of colorectal MALT lymphomas.

In conclusion, we herein described a case of HP-positive colorectal MALT lymphoma with repeated metachronous recurrence after CR and eradication therapy. It regressed after the watch-and-wait strategy. Malignant lymphomas tend to develop into metachronous and multifocal lesions. All patients treated for MALT lymphoma require appropriate long-term follow-up even after CR.

The authors state that they have no Conflict of Interest (COI).

Financial Support

Open Access funding was provided by Hiroshima University. No financial support was received for this study.