Should All Patients With Stage IE Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Receive Antibiotic Eradication Therapy for Helicobacter pylori?

Abstract

PURPOSE

H. pylori eradication therapy (HPE) can lead to tumor regression in H. pylori–positive (HPP) gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, some patients do not have detectable H. pylori (HP) infection (H. pylori–negative [HPN]) and the guidelines differ in their initial approach to HPN patients. The National Comprehensive Cancer Network (NCCN) recommends proceeding to radiation therapy, whereas European Society for Medical Oncology suggests HPE for every patient, even those who are HPN. To address this issue, we evaluated the effectiveness of HPE in limited-stage gastric MALT lymphoma.

MATERIALS AND METHODS

We retrospectively reviewed patients newly diagnosed with stage IE gastric MALT lymphoma between January 2002 and December 2022. The primary outcome was the complete remission (CR) rate defined as no macroscopic findings of lymphoma and negative gastric biopsy at the follow-up gastric endoscopy.

RESULTS

Fifty-two patients were reviewed, and HP infection was detected in 19 (36.5%) patients—14 by immunostaining, three by serology, and one each by stool antigen and urea breath test. All 19 HPP and eight of the 33 HPN patients received HPE treatment. The CR rate was 63% (12/19) in HPP patients and 13% (1/8) in HPN patients (P = .033). After a median follow-up of 89.7 months, only two of the 12 HPP patients achieving CR have relapsed; the one HPN patient who received HPE remains in CR at 12+ months.

CONCLUSION

For limited-stage HPP gastric MALT lymphoma, HPE is an effective and durable first-line treatment and should be used. For HPN patients, the CR rate with HPE is very low in our experience and is thus in support of the NCCN guideline.

Patients with H. pylori-negative stage 1 gastric MALT can proceed to radiotherapy without a trial of antibiotics.

INTRODUCTION

Non-Hodgkin lymphoma (NHL) of marginal zone B cells represent about 7% of all NHL.¹ They are divided into extranodal (EN), nodal, and splenic variants. Within the EN marginal zone lymphoma group, the sites most involved are gastric, lung, and salivary gland.² Gastric mucosa-associated lymphoid tissue (MALT) lymphoma increases in incidence with age and has a favorable long-term outcome.³ Helicobacter pylori (HP) infection is recognized to play a critical role in the pathogenesis of gastric MALT lymphoma and its eradication can lead to tumor remission.^4-8 Therefore, assessment for HP infection should be performed in all patients with gastric MALT lymphomas.

CONTEXT

• Key Objective

• Determine the tumor response to antibiotic therapy when given to patients with extranodal marginal zone non-Hodgkin lymphoma of the stomach (gastric mucosa-associated lymphoid tissue [MALT]) who are negative for Helicobacter pylori (HP) infection.

• Knowledge Generated

• HP infection was documented in only 36.5% of patients and antibiotic therapy induced a complete remission in 63%. Of the HP-negative patients, antibiotics were tried first in eight patients and only one (13%) had a tumor remission.

• Relevance

• Patients with stage I gastric MALT without evidence of HP infection can proceed to definitive treatment with involved site radiation therapy without a trial of antibiotics since the likelihood of response is very low.

There are several methods used to detect HP infection summarized by Dore et al.⁹ Immunostaining for HP infection on the gastric biopsy is the standard of care in all patients with gastric NHL and is highly accurate. If the tissue is negative, then serology in blood, the stool antigen test, and the urea breath test are all noninvasive and have high sensitivity. Test sensitivity varies depending on the type of test, the stage of infection, and recent medication use.¹⁰ Use of bismuth, proton pump inhibitors, and antibiotics can lead to false-negative results on the conventional HP tests. In addition to searching for HP infection, it is now recommended to perform genetic studies on the tissue for the t(11;18)(q21;q21) translocation that is associated with gastric MALT lymphoma^11,12 and has been shown to predict patients who will not respond to antibiotics.^13,14

According to both National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines)¹⁵ and European Society for Medical Oncology (ESMO) guidelines,¹⁶ if HP infection is negative on the basis of histopathologic examination, the above-mentioned noninvasive testing methods should be performed to confirm the negative status before making treatment decisions. The NCCN guideline recommends H. pylori eradication therapy (HPE) as the first-line treatment if HP infection is detected, and the lesion is confined to the gastric wall. HPE therapy has been documented to induce complete remission (CR) in 78% of patients with early-stage disease and 5-year survival of ≥95%.^7,17 Approximately 11% of patients with gastric MALT lymphoma have no evidence of HP infection and are thus designated H. pylori–negative (HPN).¹⁸ These patients are recommended to undergo involved site radiation therapy (ISRT)^19,20 or rituximab (if ISRT is contraindicated). However, the ESMO guideline recommends HPE should be given to all patients with gastric MZL, irrespective of stage.

Although the treatment guideline pathways are consistent with respect to H. pylori–positive (HPP) patients, they diverge with respect to the patient who presents with documented stage I gastric MALT but is HPN. To study this clinical practice dilemma, we performed a retrospective quality assessment study of our experience to guide our clinical practice and inform future guidelines.

MATERIALS AND METHODS

After approval from the Mayo Clinic Institutional Review Board, and the University of Iowa/Mayo Clinic SPORE Lymphoma database committee, we used the database to identify the medical records of consenting patients age 18 years and older who had been diagnosed with stage IE gastric MALT lymphoma between January 2002 and December 2022 and seen at Mayo Clinic. HP infection was detected by immunostaining of gastric mucosa, a serology test, stool antigen, or urea breath test. HP status was identified as positive (HPP) when at least one of those tests showed positive results and as negative (HPN) when all of the performed test results in that patient were negative. The treatment regimen was selected by the attending physician.

Follow-up endoscopy with gastric biopsies to evaluate the tumor response was typically performed 3 months after the completion of treatment and was scheduled every 3-6 months thereafter at the discretion of the patient and clinician. CR was defined as no macroscopic findings of lymphoma and negative biopsy results.²¹ Patients who failed to achieve CR after HPE therapy were either observed or proceeded to therapy with ISRT, immunotherapy (single-agent rituximab), chemotherapy, or surgery.

Continuous and categorical variables are presented as medians (range) and percentages (%), respectively. Differences in clinical characteristics and treatment response were determined using the chi-square test or Fisher's exact test. All statistical analyses were performed using Stata 14 software (College Station, TX, StataCorp LLC), and a P < .05 was considered statistically significant.

RESULTS

Fifty-two patients with stage IE gastric MALT lymphoma were identified and included in the analyses (Table 1). The site of diagnosis and care of the 52 patients was as follows: 46 from Mayo Clinic Rochester, MN, four patients from Mayo Clinic Phoenix, AZ, and two from Mayo Clinic Eau Claire Wisconsin (a Mayo Clinic Health System site). The median follow-up time was 89.7 months (range, 2.9-227.8). HP infection was detected in 36.5% (19/52) of patients. Among these 19 patients, 14 were diagnosed by immunostaining, while in the five patients with negative immunostaining, HP infection was detected by serology (three patients), stool antigen (one patient), or urea breath test (one patient). Of the 33 HPN patients, all were negative by immunostaining; 10 of these 33 did not have any further HP testing. The polymerase chain reaction or fluorescent in situ hybridization (FISH) for t(11;18) was performed in 10 patients (19.2%) and the t(11;18) was detected in two (both were HPN). All HPP patients and 24.2% (8/33) of HPN patients were treated with HPE (Table 1).

TABLE 1.

Clinical Characteristics

Characteristic	Total (N = 52)	HP-Positive (n = 19)	HP-Negative (n = 33)
Age, years
Median (range)	68 (52-87)	68	67
Sex, No. (%)
Male	29 (55.8)	11 (57.9)	18 (54.5)
Female	23 (44.2)	8 (42.1)	15 (45.5)
Methods for detecting HP infection, No. (%)
Tissue immunostaining	51 (98)	14 (73.6)	33 (100)
Serum antibody (serology)	19 (36.5)	3 (15.8)	16 (48.4)
Stool antigen	10 (19.2)	1 (5.3)	9 (27.2)
Urea breath test	6 (11.5)	1 (5.3)	5 (15.1)
PCR or FISH for t(11;18), No. (%)
Detected	2 (3.8)	0 (0.0)	2 (6.1)
Not detected	8 (15.4)	2 (10.5)	6 (18.2)
Unknown	42 (80.8)	17 (89.5)	25 (75.7)
HP eradication therapy, No. (%)	27 (51.9)	19 (100)	8 (24.2)

Abbreviations: FISH, fluorescent in situ hybridization; HP, Helicobacter pylori; PCR, polymerase chain reaction.

Treatment and treatment responses are summarized in Figure 1. All 19 HPP patients were treated for HPE and 63% (12/19) achieved a CR. Only two of these 12 HPP patients achieving CR have relapsed—at 9 months and 2 years after HPE. The seven patients who failed to achieve a CR received further treatment: ISRT in two patients, single-agent rituximab in two patients, chlorambucil in one patient, second-line HPE in one patient, and unknown agent in one patient.

FIG 1.

Clinical course and treatment outcomes of patients with stage IE gastric MALT lymphoma by HP status. CR, complete remission; HP, Helicobacter pylori; HPE, H. pylori eradication therapy; MALT, mucosa-associated lymphoid tissue; NA, not available; PR, partial remission; RT, radiation therapy; SD, stable disease.

In the HPN patient group, 24.2% (8/33) of patients received HPE as the initial treatment and one (12.5%) responded with a CR. This patient remains in CR at 12+ months. The patients who did not achieve CR after HPE proceeded to ISRT in five patients, radioimmunotherapy in one patient, and no available treatment data in one patient. Of the 25 HPN patients who did not receive HPE therapy, the first-line therapy was ISRT in 18 (72%), rituximab monotherapy in three (12%), surgical resection in two (8%), chlorambucil in one (4%), and observation in one (4%). Thus, the CR rate to HPE therapy was significantly higher in HPP patients than in HPN patients (63.2% v 12.5%; P = .033; Table 2).

TABLE 2.

Treatment Outcomes After HP Eradication Therapy With Respect to HP Infection Status

HP Infection Status	Response, No. (%)		P
	CR	No CR
Positive (n = 19; all treated)	12 (63.2)	7 (36.8)	.033
Negative (n = 33; eight treated)	1 (12.5)	7 (87.5)

Abbreviations: CR, complete remission; HP, Helicobacter pylori.

DISCUSSION

The variation in guidelines regarding the approach to HPN gastric MALT led us to review our US clinical practice experience regarding the incidence of HPN gastric MALT and the effectiveness of HPE therapy. Over the past 20 years, we found the incidence of HPP and HPN patients to be 36.5% and 63.5%, respectively. This incidence of HPN gastric MALT lymphoma is higher than the 11% previously reported¹⁸ but similar to that found by the MD Anderson group.²² These differences may be explained in part by a potential false-negative result on the HP immunostain and the lack of a second confirmatory test in 30% (10/33) of our HPN patients. Moreover, wider indications for HPE and the use of over-the-counter proton-pump inhibitors may be decreasing the prevalence of HP infection.²³ Several larger studies^7,24,25 have revealed higher incidences of HP infection in gastric MALT lymphoma. Geographic variation and the differences in HP detection tests may also partially explain these variations. Finally, referral to a center such as ours may have been driven by the finding of HPN gastric MALT, whereas HPP patients would have been easily treated with HPE at the local site.

All the HPP patients in this study received HPE as the standard initial therapy in accordance with NCCN Guidelines and ESMO guidelines. The CR rate of 63.2% was lower than previous reports (70%-95%).^6,17,26-31 For example, in the large systematic review of 1,408 reported patients, the CR rate with HPE was 78%.⁷ Only 19% (10/52) of our patients had a FISH test for the presence of t(11;18), a predictor for antibiotic resistance.^7,13,32 Thus, the lower success rate in our HPP patients may have been due to an unknown higher rate of t(11;18)-positive patients in that cohort. Our results confirm that HPE therapy has high efficacy and durability and should be the first-line treatment for localized HPP gastric MALT lymphoma.

Twenty-four percent (8/33) of HPN patients were given HPE therapy and only one responded and is in early follow-up. There is controversy in the guidelines as to whether HPN patients should receive a trial of HPE. Although the NCCN guideline recommends HPE as initial therapy only in patients with HPP gastric MALT, the ESMO guideline suggests even HPN patients should receive a trial.² Indeed, they recommend HPE as the first-line therapy for every patient with gastric MALT lymphoma irrespective of HP status, leaving radiation therapy or rituximab immunotherapy to HPE failures. They do clearly acknowledge that ISRT can be also be given at physician discretion without waiting for reassessment of the HPE therapy results.²

The reported effectiveness of HPE in HPN gastric MALT varies by geography. Three studies from Korea showed a high response rate of approximately 40%-60%,^25,33,34 while a multicenter cohort study in Japan reported a 13.6% response rate after HPE.¹⁷ A systematic review with pooled analysis including 11 studies (110 patients) with early-stage HPN MALT lymphoma revealed a CR rate of 15.5% (95% CI, 8.7 to 22.2).³⁵ In addition, the recent meta-analysis of 25 studies that reported treatment responses to HPE as an initial treatment for patients with HPN gastric MALT lymphoma revealed the overall pooled CR rate of 29.3% (95% CI, 22.2 to 37.4; I² = 41.5%).³⁶ There are several possible reasons why antibiotics could work in HPN patients. First, the false-negative results during the diagnosis of HP infection. Second, patients with HPN gastric MALT lymphoma who achieved CR after HPE showed negative results in serologic tests but showed histologic evidence of chronic atrophic gastritis, suggestive of past HP infection.^5,37 Third, antibiotics may eradicate microorganisms other than HP, such as H. heilmannii, which is also associated with the development of MALT lymphoma.³⁸ Finally, potential immunomodulatory or even direct anti-neoplastic effects of antibiotics, especially clarithromycin, may contribute to the responsiveness to eradication therapy.

Although eradication of HP infection might lead to CR in some patients, gastric MALT lymphoma may persist in nearly 20% of patients, necessitating further therapeutic strategies. Management should be individually tailored because delayed histologic regression of lymphoma after successful HPE, even after a 24-month interval, has been reported.³⁰

In our study, only one of the eight HPN patients who received HPE achieved CR, which was a significantly lower rate than in HPP patients. The remainder of HPN patients proceeded to other standard first-line treatments with ISRT, immunotherapy (rituximab), or chlorambucil, which gave an excellent response (92% CR). On the basis of these findings, we do not advocate HPE as the initial therapy for limited-stage HPN gastric MALT lymphoma primarily because of the low success rate. We acknowledge that HPE therapy is inexpensive but when the definitive treatment is so effective and associated with minimal side effects, it is favored in this HPN situation. In addition, the high failure rate of HPE in HPN patients prolongs definitive therapy by 3 months, the typical time point for repeat endoscopy after HPE. Other disadvantages are the persistence of symptoms during this time and the need for repeat endoscopy and tumor imaging to ensure that stage had not changed. Instead, the patients should be considered for ISRT or single-agent rituximab if ISRT is contraindicated. Long-term follow-up data from clinical studies including this one indicate that ISRT is an effective treatment modality in gastric MALT lymphoma as an initial treatment for patients with HPN disease or after HPE failure.^19,20,39-44

This study had several limitations. First, despite a retrospective review of 20 years of practice, this 52-patient cohort is still relatively small because of the low incidence of gastric MALT lymphoma, and we only included stage IE patients. The lack of secondary testing in gastric HPN patients could have missed some HP infections. The strength of this study was the interesting finding of more HPN patients with gastric MALT than previously realized. The low chance of responding to HPE in this group and the excellent results with ISRT will be helpful in making treatment decisions in these patients. These data will also be useful for groups such as ESMO and NCCN Guidelines in refining guidelines for this condition in the future.

From a quality perspective, we learned that in our past practice, we were not always pursuing secondary noninvasive HP testing in gastric MALT that are HPN by tissue immunostaining. Although our pathologists now routinely apply FISH testing for the t(11;18), this was missing in the earlier years of our study and serves as a reminder for clinicians to review the pathology report for this information.

AUTHOR CONTRIBUTIONS

Conception and design: Chonlada Laoruangroj, Thomas E. Witzig

Financial support: Chonlada Laoruangroj, Thomas E. Witzig

Administrative support: Chonlada Laoruangroj, Thomas E. Witzig

Provision of study materials or patients: Chonlada Laoruangroj, Thomas M. Habermann, Yucai Wang, Thomas E. Witzig

Collection and assembly of data: Chonlada Laoruangroj, Thomas M. Habermann, Yucai Wang, Carrie A. Thompson, Thomas E. Witzig

Data analysis and interpretation: Chonlada Laoruangroj, Yucai Wang, Rebecca L. King, Scott C. Lester, Thomas E. Witzig

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Should All Patients With Stage IE Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Receive Antibiotic Eradication Therapy for Helicobacter pylori?

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