Article Search
검색
검색 팝업 닫기

Metrics

Help

  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

  • 2. Editorial Board

    Editor-in-Chief + MORE

    Editor-in-Chief
    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
  • 3. Editorial Office
  • 4. Articles
  • 5. Instructions for Authors
  • 6. File Download (PDF version)
  • 7. Ethical Standards
  • 8. Peer Review

    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
    The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.

    The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.

Search

Search

Year

to

Article Type

Original Article

Split Viewer

Limited Role of Bone Marrow Aspiration and Biopsy in the Initial Staging Work-up of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma in Korea

Byung-Hoon Min, Jun Young Park, Eun Ran Kim, Yang Won Min, Jun Haeng Lee, Poong-Lyul Rhee, Jong Chul Rhee, and Jae J. Kim

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Jae J. Kim, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea, Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail: jjkim@skku.edu

Received: July 31, 2013; Revised: October 8, 2013; Accepted: October 21, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2014;8(6):637-642. https://doi.org/10.5009/gnl13284

Published online November 1, 2014, Published date November 29, 2014

Copyright © Gut and Liver.

Background/Aims

The aim of this study was to investigate the frequency of disseminated gastric mucosa-associated lymphoid tissue (MALT) lymphoma and the role of bone marrow study in the initial staging work-up.

Methods

A total of 194 patients with gastric MALT lymphoma was enrolled. The incidence of disseminated disease was evaluated in the initial staging work-up. The demographic data and tumor characteristics were compared according to Helicobacter pylori infection status.

Results

Localized disease of Lugano stage I accounted for 97.4% of the enrolled cases. Abdominal computed tomography revealed abdominal lymph node metastasis in five patients (2.6%). Bone marrow (BM) involvement was found in only one patient without H. pylori infection (0.5%). No patient showed positive findings on chest computed tomography or positron emission tomography. H. pylori-negative cases showed a significantly higher frequency of advanced-stage disease than H. pylori-positive cases (10.0% vs 0.6%). In patients achieving complete remission, no extragastric recurrence occurred during follow-up.

Conclusions

The incidence of disseminated disease, including BM involvement, was very low in Korean gastric MALT lymphoma patients. It might be beneficial to perform BM aspiration and biopsy as a part of staging work-up only in patients with risk factors for advanced disease such as H. pylori negativity.

Keywords: Lymphoma, B-cell, marginal zone, Stomach, Bone marrow, Staging

Mucosa-associated lymphoid tissue (MALT) lymphomas represent about 7% of all non-Hodgkin’s lymphoma.1 The stomach is by far the most common site of MALT lymphoma, accounting for 70% of total cases.2

Gastric MALT lymphoma behaves as an indolent disease and has a favorable long-term prognosis with a 10-year survival of over 90%.2 Most cases remain localized within the stomach for many years. Despite the favorable prognosis, this disease has a limited tendency for distant spread to other organs, such as lung or bone marrow. To date, there have been few reports assessing the frequency of disseminated disease in gastric MALT lymphoma patients.3 In Austrian study that evaluated 61 cases of gastric MALT lymphoma, bone marrow involvement was found in 4.9% of cases.3 Interestingly, previous studies consistently reported that the survival of gastric MALT lymphoma patients was not adversely influenced by the dissemination of the disease, such as bone marrow involvement.3,4 Given the probably limited influence on survival and low incidence of bone marrow involvement, the clinical value of routine bone marrow aspiration and biopsy in initial staging work-up may be limited. Therefore, it remains controversial whether bone marrow aspiration and biopsy should be included in the staging work-up of gastric MALT lymphoma.1,5 The European Society for Medical Oncology guidelines recommend inclusion of bone marrow aspiration and biopsy as an initial staging work-up of gastric MALT lymphoma.1 In the recent European Gastro-Intestinal Lymphoma Study (EGILS) consensus report, however, bone marrow aspiration and biopsy is not recommended as a routine procedure in initial staging work-up. Instead, bone marrow aspiration and biopsy is recommended only when no gastric MALT lymphoma regression is seen after an adequate interval following Helicobacter pylori eradication.5 Since bone marrow biopsy is an invasive procedure and can cause complications, such as pain or bleeding, it might be beneficial to define the patient group at high risk for bone marrow dissemination and make a limited recommendation for selected patients with a high risk of involvement.

In Korea and Japan, the screening endoscopy for gastric cancer is actively performed and consequently gastric MALT lymphomas seem to be diagnosed in early stage in the majority of case. Therefore, the incidence of disseminated gastric MALT lymphoma in Korea and Japan may be lower than that reported in Western countries. To date, however, few efforts have been made to evaluate the frequency of disseminated gastric MALT lymphoma in Far Eastern countries including Korea and Japan.

The aim of this study was to evaluate the incidence of disseminated disease in Korean gastric MALT lymphoma patients and to investigate the role of bone marrow aspiration and biopsy in the initial staging work-up of gastric MALT lymphoma.

1. Patients

Hospital database was searched for gastric MALT lymphoma diagnosed in Samsung Medical Center from January 2000 to December 2010. A total of 232 consecutive patients with gastric MALT lymphoma was identified. Histopathologic diagnosis of gastric MALT lymphoma was made according to World Health Organization classification.6 Patients were excluded from the study subjects if 1) they underwent treatment for gastric MALT lymphoma before visiting our hospital; 2) they had another malignancy at the time of diagnosis; or 3) the follow-up period was shorter than 12 months. After exclusion, a total of 194 patients was finally included in this study. Initial staging procedures included physical examination including Waldeyer ring, complete blood counts, basic biochemical studies, esophagogastroduodenoscopy (EGD), chest radiograph, computed tomography (CT) of abdomen and pelvis, and bilateral bone marrow aspirate and biopsy. In addition, 67 patients (34.5%) underwent chest CT and 54 (27.8%) underwent endoscopic ultrasonography (EUS). 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) was performed in 42 patients (21.6%). The diagnosis of abdominal or mediastinal lymph node (LN) involvement and distant metastasis was made based on imaging studies or histological confirmation, if necessary. The results of initial staging work-up and follow-up examinations were retrospectively reviewed. The H. pylori status was determined by histology, rapid urease test, 13C-urea breath test, and/or serology. H. pylori infection was judged to be positive if one or more of the tests showed a positive result and to be negative when all tests were negative. The clinical stage was determined based on the Lugano staging system, a modification of the Ann Arbor classification.7 The study protocol was approved by the Institutional Review Board at Samsung Medical Center.

2. Treatment

Patients with localized gastric MALT lymphoma (Lugano stage I) associated with H. pylori infection underwent H. pylori eradication therapy using a combination of proton pump inhibitor and antibiotics for 1 to 2 weeks. H. pylori eradication therapy was performed for 153 patients with H. pylori infection and nine patients without H. pylori infection. Other treatment modalities, such as radiotherapy, chemotherapy, or surgery, were used for treatment if 1) the patient had advanced stage disease of Lugano stage II or IV; 2) the patient showed no evidence of H. pylori infection in initial work-up; 3) H. pylori eradication was not achieved even after third-line eradication treatment; or 4) complete remission (CR) was not achieved within 1 year after successful H. pylori eradication.

3. Follow-up after treatment

After H. pylori eradication or other nonsurgical treatments, biopsy specimens were assessed using the Groupe d’Etude des Lymphomes de I’Adult (GELA) histological grading system.5,8 In this study, CR was defined if two consecutive posttreatment biopsy specimens showed complete histological response or probable minimal residual disease by the GELA grading system. For patients with advanced stage disease (Lugano stage II or IV), no visible lesion on imaging studies was also required for a diagnosis of CR.

All patients undergoing H. pylori eradication or other non-surgical treatments were followed up by EGD with multiple biopsies every 3 to 6 months until CR and every 6 to 12 months thereafter. For patients with advanced stage disease (Lugano stage II or IV), follow-up imaging studies including abdominal CT were also performed.

1. Patient characteristics and results of staging work-up

Table 1 summarizes the baseline characteristics of the 194 enrolled patients. Localized disease with Lugano stage I accounted for 97.4% of cases. Abdomen-pelvis CT revealed abdominal LN metastasis in five (2.6%) patients. There was no evidence of metastasis to abdominal organs, such as spleen. Table 2 shows details of work-up and follow-up results of the five patients with abdominal LN involvement. Four patients (80%, 4/5) with advanced stage disease were H. pylori-negative.

In bilateral bone marrow aspirate and biopsy, only one patient (0.5%, 1/194) showed tumor cell infiltration into the bone marrow. The tumor volume in bone marrow biopsy specimens was 5% and 10% in left- and right-side biopsies, respectively. This patient did not show cytopenia or evidence of H. pylori infection at the time of bone marrow biopsy. However, abdomen-pelvis CT demonstrated massive abdominal LN involvement encasing major vascular structures (case 5 in Table 2 and Fig. 1).

None of the patients showed positive findings in either chest CT or PET scan. Among five patients with abdominal LN involvement, three patients underwent chest CT and one patient underwent PET (Table 2).

The majority of patients (83.5%) underwent H. pylori eradication. Radiotherapy and chemotherapy were performed in 11.3% and 4.1% of patients, respectively.

Fifty-four patients received EUS examination. Among them, only 7.4% of patients showed involvement of MALT lymphoma beyond the submucosa layer.

When compared with H. pylori-positive cases, H. pylori-negative gastric MALT lymphoma showed a significantly higher frequency of advanced stage disease and tumor invasion beyond the submucosa layer (Table 3).

2. Outcomes after treatment and pattern of recurrence

Fig. 2 shows the 1-year treatment outcomes according to the initial treatment modalities in 189 patients with Lugano stage I disease. Table 2 summarizes the 1-year treatment outcomes in 5 patients with Lugano stage II or IV disease.

Table 4 shows follow-up results of 153 H. pylori-positive patients who underwent H. pylori eradication therapy as the initial main treatment. All patients had localized disease with Lugano stage I. At the 12-month follow-up examination, CR was achieved in 88.2% (135/153) of cases. During a median 45 months of follow-up, recurrence after CR occurred in three cases (3/135, 2.2%), all of which showed intragastric recurrence. No extragastric recurrence was found during the follow-up period.

A total of 22 patients received radiotherapy as the initial main treatment. All of these patients were H. pylori-negative and had localized disease with Lugano stage I. At the 12-month follow-up examination, the CR rate was 95.5%. During a median 40 months of follow-up, no recurrence occurred after achieving CR.

Chemotherapy was initially administered in eight patients, including five with Lugano stage II or IV disease (Table 2). CR was achieved 12 months after treatment in 50.0% of cases. During a median 71 months of follow-up, no recurrence occurred after achieving CR.

The initial staging work-up of lymphoma usually includes the examination for the disseminated disease, such as bone marrow aspiration and biopsy, as patients’ prognoses and the selection of treatment modality are affected by the presence of disseminated disease. However, previous studies consistently reported that the presence of disseminated disease had a limited influence on the survival of patients with gastric MALT lymphoma.3,4 In addition, the incidence of disseminated disease is low in gastric MALT lymphoma. In a Western study, the frequency of bone marrow involvement was 4.9%.3 In the same study, the incidence of lung metastasis and mediastinal LN involvement was 6.6%.3,9 The present study showed an even lower incidence; only one case of bone marrow involvement (0.5%) and no cases of lung or mediastinal LN metastasis (0%) were observed in initial staging work-up. After achieving CR, no extragastric recurrence occurred during follow-up. Considering these factors, Raderer et al.3 argued against the necessity for routine bone marrow biopsy in patients with gastric MALT lymphoma and recommended the individually targeted staging. In the recent EGILS consensus report, bone marrow aspiration and biopsy are not recommended as routine procedures in initial staging work-up of gastric MALT lymphoma.5

In the present study, localized disease (Lugano stage I) accounted for 97.4% of total cases. Among 54 patients who underwent EUS, tumor depth was limited to the mucosa or submucosa layer in 92.6% of cases. This proportion of localized disease is higher than that reported in Western studies, which ranged from 70% to 75%.3,10 However, a recent large Japanese study by Nakamura et al.11 showed comparable results to ours. In their study, 90% of patients had stage I disease and 90% of patients undergoing EUS showed that tumor depth was confined to the mucosa or submucosa layer. This difference between studies from Far Eastern and Western countries might be largely due to the periodic screening endoscopy actively performed in Korea and Japan for the early detection of gastric cancer. Screening endoscopy may result in the detection of gastric MALT lymphoma in early stages and consequently a lower rate of disseminated disease in Far Eastern countries compared to Western countries. Therefore, the value of extensive staging work-up, such as bone marrow biopsy and chest CT, may be more limited in Far Eastern countries than in Western countries.

In addition to above mentioned low incidence of disseminated disease, bone marrow aspiration and biopsy is an invasive procedure and chest CT has several disadvantages, such as cost, radiation exposure, and a high rate of indeterminate lesions. Therefore, it might be beneficial to define the patient group at high risk for disseminated disease and selectively perform bone marrow biopsy and chest CT only in patients with a high risk of involvement. There are few studies evaluating the risk factors for bone marrow and lung involvement that represents disseminated gastric MALT lymphoma. As the incidence of gastric MALT lymphoma itself is low and that of disseminated disease with bone marrow or lung involvement is even lower, no studies have identified definite risk factors by multivariate analysis. Indeed, multivariate analysis to identify risk factors could not be done since the present study included only one case with disseminated disease. Several studies have reported that H. pylori-negative gastric MALT lymphoma presents as advanced disease more frequently than H. pylori-positive disease.12,13 The results of our study support this association (Table 3); 80% of cases with advanced stage disease (Lugano stage II or IV) were H. pylori-negative, including the one case with bone marrow involvement. This might be explained by the high frequency of t(11;18)(q21;q21) in H. pylori-negative gastric MALT lymphoma compared to its H. pylori-positive counterpart13,14 since the presence of t(11;18)(q21;q21) is known to be a significant risk factor for disease dissemination.3 Therefore, patients with H. pylori-negative gastric MALT lymphoma can be reasonable targets for an extensive staging work-up including bone marrow biopsy and chest CT.

There are some limitations in the present study. First, as this was a retrospective study, there could be a selection bias and treatment modalities were not decided under a standardized protocol. Secondly, the number of cases with advanced stage disease was too small to identify definite risk factors for disseminated disease by multivariate analysis. Thirdly, as chest CT and PET were performed only in 34.5% and 21.6% of enrolled cases, our ability to evaluate the role of these examinations in the initial work-up of gastric MALT lymphoma was limited.

In conclusion, our data indicate that the incidence of disseminated disease including bone marrow involvement was very low in Korean gastric MALT lymphoma patients. Given the probably limited influence on survival and low incidence of bone marrow involvement in Korea, the clinical value of routine bone marrow aspiration and biopsy in initial staging work-up of gastric MALT lymphoma may be limited. Therefore, it might be beneficial to define high-risk conditions for disseminated disease, such as H. pylori-negativity or t(11;18)(q21;q21), and selectively perform an extensive staging work-up, such as bone marrow aspiration and biopsy, only in patients with these risk factors. Further large prospective studies are required to identify definite risk factors for disease dissemination and to establish tailored guidelines for initial staging work-up of gastric MALT lymphoma.

Fig. 1.Results of staging work-up in a patient with bone marrow involvement. (A) White light endoscopy image showing nodular mucosal changes and ulcers at the lesser curvature side of the gastric body. (B) Abdominal computed tomography image showing massive lymph node enlargement encasing the aorta, renal vessels, and mesenteric vessels. (C) Pathological findings showing paratrabecular infiltration of lymphoma cells into the bone marrow (H&E stain, ×200). (D) Immunohistochemical staining of bone marrow with CD20.
Fig. 2.Flowchart showing the 1-year treatment outcomes according to the initial treatment modality in 189 patients with Lugano stage I disease. HPE, H. pylori eradication; RTx, radiotherapy; CTx, chemotherapy; SR, surgical resection; CR, complete remission.

Baseline Patient Characteristics (n=194)

CharacteristicValue
Age, yr53.3±11.4
 Median (range)53 (30–78)
Gender
 Male88 (45.4)
 Female106 (54.6)
H. pylori infection
 Absent40 (20.6)
 Present154 (79.4)
Abdomen-pelvis CT
 Localized in stomach189 (97.4)
 Abdominal LN involvement5 (2.6)
 Metastasis to organ in abdomen0
Bone marrow involvement
 Absent193 (99.5)
 Present1 (0.5)
Chest CT (n=67)
 No involvement67 (100.0)
 Mediastinal LN involvement0
 Metastasis to lung0
Tumor depth by EUS (n=54)
 Mucosa or submucosa50 (92.6)
 Proper muscle, subserosa, serosa4 (7.4)
PET (n=42)
 No specific findings42 (100.0)
 Findings suggesting metastasis0
Stage by Lugano system
 I189 (97.4)
 II4 (2.1)
 IV1 (0.5)
Initial treatment
H. pylori eradication162 (83.5)
 Radiotherapy22 (11.3)
 Chemotherapy8 (4.1)
 Resection2 (1.0)

Details of Patients Whose Abdominal Computed Tomography Scans Showed Abdominal Lymph Node Enlargement Consistent with Metastasis

CaseSexAge, yrSymptomH. pylori infectionAbdomen-pelvis CTBM involvementChest CTTumor depth by EUSPETStageInitial treatment12-mo outcome
1F40Weight lossNegativeLN (+)NoNot doneNot doneNot doneIIChemotherapyNon-CR
2M39VomitingPositiveLN (+)NoNot doneNot doneNot doneIIChemotherapyNon-CR
3F73NauseaNegativeLN (+)NoNegativeNot doneNegativeIIChemotherapyCR
4M64Epigastric painNegativeLN (+)NoNegativeProper muscleNot doneIIChemotherapyCR
5M51DistensionNegativeLN (+)YesNegativeNot doneNot doneIVChemotherapyNon-CR

Patient Characteristics according to Helicobacter pylori Infection Status

CharacteristicH. pylori-positive (n=154)H. pylori-negative (n=40)p-value
Age, yr53.2±11.353.8±11.70.760
 Median (range)53.0 (30–78)52.5 (33–74)
Gender0.169
 Male66 (42.9)22 (55.0)
 Female88 (57.1)18 (45.0)
Abdomen-pelvis CT0.007
 Localized in stomach153 (99.4)36 (90.0)
 Abdominal LN involvement1 (0.6)4 (10.0)
Bone marrow involvement0.206
 Absent154 (100.0)39 (97.5)
 Present01 (2.5)
Tumor depth by EUS (n=54)<0.001
 Mucosa or submucosa46 (100.0)4 (50.0)
 Proper muscle, subserosa, serosa04 (50.0)
Stage by Lugano system0.007
 I153 (99.4)36 (90.0)
 II or IV1 (0.6)4 (10.0)

Outcomes after Helicobacter pylori Eradication in H. pylori-Positive Cases (n=153)

ParameterValue
Stage by Lugano system
 I153 (100.0)
 II or IV0
Outcomes 12 mo after treatment
 CR135 (88.2)
 Non-CR18 (11.8)
Duration of total follow-up, mo45 (12–126)
Recurrence after CR during follow-up3 (2.2)
Recurrence site
 Stomach3 (100.0)
 Abdominal LN0
 Abdominal organ0
 Bone marrow0
 Mediastinal LN0
 Lung0

  1. Zucca E, Dreyling M. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21;v175-v176.
    Pubmed CrossRef
  2. Du MQ, Atherton JC. Molecular subtyping of gastric MALT lymphomas: implications for prognosis and management. Gut. 2006;55;886-893.
    Pubmed KoreaMed CrossRef
  3. Raderer M, W?hrer S, Streubel B, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24;3136-3141.
    Pubmed CrossRef
  4. Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95;802-806.
    Pubmed
  5. Ruskon?-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus report: gastric extranodal marginal zone B-cell lymphoma of MALT. Gut. 2011;60;747-758.
    Pubmed CrossRef
  6. Isaacson PG, Chott A, Nakamura S, et al. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Swerdlow SH, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 214-217.
  7. Rohatiner A, d’Amore F, Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994;5;397-400.
    Pubmed
  8. Copie-Bergman C, Gaulard P, Lavergne-Slove A, et al. Proposal for a new histological grading system for post-treatment evaluation of gastric MALT lymphoma. Gut. 2003;52;1656.
    Pubmed KoreaMed CrossRef
  9. Raderer M, Vorbeck F, Formanek M, et al. Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer. 2000;83;454-457.
    Pubmed KoreaMed CrossRef
  10. Avil?s A, Nambo MJ, Neri N, Talavera A, Cleto S. Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial. Med Oncol. 2005;22;57-62.
    Pubmed CrossRef
  11. Nakamura S, Sugiyama T, Matsumoto T, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut. 2012;61;507-513.
    Pubmed CrossRef
  12. Chung SJ, Kim JS, Kim H, et al. Long-term clinical outcome of helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma is comparable to that of H. pylori-positive lymphoma. J Clin Gastroenterol. 2009;43;312-317.
    Pubmed CrossRef
  13. Nakamura S, Matsumoto T, Ye H, et al. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a clinicopathologic and molecular study with reference to antibiotic treatment. Cancer. 2006;107;2770-2778.
    Pubmed CrossRef
  14. Ye H, Liu H, Raderer M, et al. High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood. 2003;101;2547-2550.
    Pubmed CrossRef

Article

Original Article

Gut Liver 2014; 8(6): 637-642

Published online November 29, 2014 https://doi.org/10.5009/gnl13284

Copyright © Gut and Liver.

Limited Role of Bone Marrow Aspiration and Biopsy in the Initial Staging Work-up of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma in Korea

Byung-Hoon Min, Jun Young Park, Eun Ran Kim, Yang Won Min, Jun Haeng Lee, Poong-Lyul Rhee, Jong Chul Rhee, and Jae J. Kim

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Jae J. Kim, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea, Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail: jjkim@skku.edu

Received: July 31, 2013; Revised: October 8, 2013; Accepted: October 21, 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

The aim of this study was to investigate the frequency of disseminated gastric mucosa-associated lymphoid tissue (MALT) lymphoma and the role of bone marrow study in the initial staging work-up.

Methods

A total of 194 patients with gastric MALT lymphoma was enrolled. The incidence of disseminated disease was evaluated in the initial staging work-up. The demographic data and tumor characteristics were compared according to Helicobacter pylori infection status.

Results

Localized disease of Lugano stage I accounted for 97.4% of the enrolled cases. Abdominal computed tomography revealed abdominal lymph node metastasis in five patients (2.6%). Bone marrow (BM) involvement was found in only one patient without H. pylori infection (0.5%). No patient showed positive findings on chest computed tomography or positron emission tomography. H. pylori-negative cases showed a significantly higher frequency of advanced-stage disease than H. pylori-positive cases (10.0% vs 0.6%). In patients achieving complete remission, no extragastric recurrence occurred during follow-up.

Conclusions

The incidence of disseminated disease, including BM involvement, was very low in Korean gastric MALT lymphoma patients. It might be beneficial to perform BM aspiration and biopsy as a part of staging work-up only in patients with risk factors for advanced disease such as H. pylori negativity.

Keywords: Lymphoma, B-cell, marginal zone, Stomach, Bone marrow, Staging

INTRODUCTION

Mucosa-associated lymphoid tissue (MALT) lymphomas represent about 7% of all non-Hodgkin’s lymphoma.1 The stomach is by far the most common site of MALT lymphoma, accounting for 70% of total cases.2

Gastric MALT lymphoma behaves as an indolent disease and has a favorable long-term prognosis with a 10-year survival of over 90%.2 Most cases remain localized within the stomach for many years. Despite the favorable prognosis, this disease has a limited tendency for distant spread to other organs, such as lung or bone marrow. To date, there have been few reports assessing the frequency of disseminated disease in gastric MALT lymphoma patients.3 In Austrian study that evaluated 61 cases of gastric MALT lymphoma, bone marrow involvement was found in 4.9% of cases.3 Interestingly, previous studies consistently reported that the survival of gastric MALT lymphoma patients was not adversely influenced by the dissemination of the disease, such as bone marrow involvement.3,4 Given the probably limited influence on survival and low incidence of bone marrow involvement, the clinical value of routine bone marrow aspiration and biopsy in initial staging work-up may be limited. Therefore, it remains controversial whether bone marrow aspiration and biopsy should be included in the staging work-up of gastric MALT lymphoma.1,5 The European Society for Medical Oncology guidelines recommend inclusion of bone marrow aspiration and biopsy as an initial staging work-up of gastric MALT lymphoma.1 In the recent European Gastro-Intestinal Lymphoma Study (EGILS) consensus report, however, bone marrow aspiration and biopsy is not recommended as a routine procedure in initial staging work-up. Instead, bone marrow aspiration and biopsy is recommended only when no gastric MALT lymphoma regression is seen after an adequate interval following Helicobacter pylori eradication.5 Since bone marrow biopsy is an invasive procedure and can cause complications, such as pain or bleeding, it might be beneficial to define the patient group at high risk for bone marrow dissemination and make a limited recommendation for selected patients with a high risk of involvement.

In Korea and Japan, the screening endoscopy for gastric cancer is actively performed and consequently gastric MALT lymphomas seem to be diagnosed in early stage in the majority of case. Therefore, the incidence of disseminated gastric MALT lymphoma in Korea and Japan may be lower than that reported in Western countries. To date, however, few efforts have been made to evaluate the frequency of disseminated gastric MALT lymphoma in Far Eastern countries including Korea and Japan.

The aim of this study was to evaluate the incidence of disseminated disease in Korean gastric MALT lymphoma patients and to investigate the role of bone marrow aspiration and biopsy in the initial staging work-up of gastric MALT lymphoma.

MATERIALS AND METHODS

1. Patients

Hospital database was searched for gastric MALT lymphoma diagnosed in Samsung Medical Center from January 2000 to December 2010. A total of 232 consecutive patients with gastric MALT lymphoma was identified. Histopathologic diagnosis of gastric MALT lymphoma was made according to World Health Organization classification.6 Patients were excluded from the study subjects if 1) they underwent treatment for gastric MALT lymphoma before visiting our hospital; 2) they had another malignancy at the time of diagnosis; or 3) the follow-up period was shorter than 12 months. After exclusion, a total of 194 patients was finally included in this study. Initial staging procedures included physical examination including Waldeyer ring, complete blood counts, basic biochemical studies, esophagogastroduodenoscopy (EGD), chest radiograph, computed tomography (CT) of abdomen and pelvis, and bilateral bone marrow aspirate and biopsy. In addition, 67 patients (34.5%) underwent chest CT and 54 (27.8%) underwent endoscopic ultrasonography (EUS). 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) was performed in 42 patients (21.6%). The diagnosis of abdominal or mediastinal lymph node (LN) involvement and distant metastasis was made based on imaging studies or histological confirmation, if necessary. The results of initial staging work-up and follow-up examinations were retrospectively reviewed. The H. pylori status was determined by histology, rapid urease test, 13C-urea breath test, and/or serology. H. pylori infection was judged to be positive if one or more of the tests showed a positive result and to be negative when all tests were negative. The clinical stage was determined based on the Lugano staging system, a modification of the Ann Arbor classification.7 The study protocol was approved by the Institutional Review Board at Samsung Medical Center.

2. Treatment

Patients with localized gastric MALT lymphoma (Lugano stage I) associated with H. pylori infection underwent H. pylori eradication therapy using a combination of proton pump inhibitor and antibiotics for 1 to 2 weeks. H. pylori eradication therapy was performed for 153 patients with H. pylori infection and nine patients without H. pylori infection. Other treatment modalities, such as radiotherapy, chemotherapy, or surgery, were used for treatment if 1) the patient had advanced stage disease of Lugano stage II or IV; 2) the patient showed no evidence of H. pylori infection in initial work-up; 3) H. pylori eradication was not achieved even after third-line eradication treatment; or 4) complete remission (CR) was not achieved within 1 year after successful H. pylori eradication.

3. Follow-up after treatment

After H. pylori eradication or other nonsurgical treatments, biopsy specimens were assessed using the Groupe d’Etude des Lymphomes de I’Adult (GELA) histological grading system.5,8 In this study, CR was defined if two consecutive posttreatment biopsy specimens showed complete histological response or probable minimal residual disease by the GELA grading system. For patients with advanced stage disease (Lugano stage II or IV), no visible lesion on imaging studies was also required for a diagnosis of CR.

All patients undergoing H. pylori eradication or other non-surgical treatments were followed up by EGD with multiple biopsies every 3 to 6 months until CR and every 6 to 12 months thereafter. For patients with advanced stage disease (Lugano stage II or IV), follow-up imaging studies including abdominal CT were also performed.

RESULTS

1. Patient characteristics and results of staging work-up

Table 1 summarizes the baseline characteristics of the 194 enrolled patients. Localized disease with Lugano stage I accounted for 97.4% of cases. Abdomen-pelvis CT revealed abdominal LN metastasis in five (2.6%) patients. There was no evidence of metastasis to abdominal organs, such as spleen. Table 2 shows details of work-up and follow-up results of the five patients with abdominal LN involvement. Four patients (80%, 4/5) with advanced stage disease were H. pylori-negative.

In bilateral bone marrow aspirate and biopsy, only one patient (0.5%, 1/194) showed tumor cell infiltration into the bone marrow. The tumor volume in bone marrow biopsy specimens was 5% and 10% in left- and right-side biopsies, respectively. This patient did not show cytopenia or evidence of H. pylori infection at the time of bone marrow biopsy. However, abdomen-pelvis CT demonstrated massive abdominal LN involvement encasing major vascular structures (case 5 in Table 2 and Fig. 1).

None of the patients showed positive findings in either chest CT or PET scan. Among five patients with abdominal LN involvement, three patients underwent chest CT and one patient underwent PET (Table 2).

The majority of patients (83.5%) underwent H. pylori eradication. Radiotherapy and chemotherapy were performed in 11.3% and 4.1% of patients, respectively.

Fifty-four patients received EUS examination. Among them, only 7.4% of patients showed involvement of MALT lymphoma beyond the submucosa layer.

When compared with H. pylori-positive cases, H. pylori-negative gastric MALT lymphoma showed a significantly higher frequency of advanced stage disease and tumor invasion beyond the submucosa layer (Table 3).

2. Outcomes after treatment and pattern of recurrence

Fig. 2 shows the 1-year treatment outcomes according to the initial treatment modalities in 189 patients with Lugano stage I disease. Table 2 summarizes the 1-year treatment outcomes in 5 patients with Lugano stage II or IV disease.

Table 4 shows follow-up results of 153 H. pylori-positive patients who underwent H. pylori eradication therapy as the initial main treatment. All patients had localized disease with Lugano stage I. At the 12-month follow-up examination, CR was achieved in 88.2% (135/153) of cases. During a median 45 months of follow-up, recurrence after CR occurred in three cases (3/135, 2.2%), all of which showed intragastric recurrence. No extragastric recurrence was found during the follow-up period.

A total of 22 patients received radiotherapy as the initial main treatment. All of these patients were H. pylori-negative and had localized disease with Lugano stage I. At the 12-month follow-up examination, the CR rate was 95.5%. During a median 40 months of follow-up, no recurrence occurred after achieving CR.

Chemotherapy was initially administered in eight patients, including five with Lugano stage II or IV disease (Table 2). CR was achieved 12 months after treatment in 50.0% of cases. During a median 71 months of follow-up, no recurrence occurred after achieving CR.

DISCUSSION

The initial staging work-up of lymphoma usually includes the examination for the disseminated disease, such as bone marrow aspiration and biopsy, as patients’ prognoses and the selection of treatment modality are affected by the presence of disseminated disease. However, previous studies consistently reported that the presence of disseminated disease had a limited influence on the survival of patients with gastric MALT lymphoma.3,4 In addition, the incidence of disseminated disease is low in gastric MALT lymphoma. In a Western study, the frequency of bone marrow involvement was 4.9%.3 In the same study, the incidence of lung metastasis and mediastinal LN involvement was 6.6%.3,9 The present study showed an even lower incidence; only one case of bone marrow involvement (0.5%) and no cases of lung or mediastinal LN metastasis (0%) were observed in initial staging work-up. After achieving CR, no extragastric recurrence occurred during follow-up. Considering these factors, Raderer et al.3 argued against the necessity for routine bone marrow biopsy in patients with gastric MALT lymphoma and recommended the individually targeted staging. In the recent EGILS consensus report, bone marrow aspiration and biopsy are not recommended as routine procedures in initial staging work-up of gastric MALT lymphoma.5

In the present study, localized disease (Lugano stage I) accounted for 97.4% of total cases. Among 54 patients who underwent EUS, tumor depth was limited to the mucosa or submucosa layer in 92.6% of cases. This proportion of localized disease is higher than that reported in Western studies, which ranged from 70% to 75%.3,10 However, a recent large Japanese study by Nakamura et al.11 showed comparable results to ours. In their study, 90% of patients had stage I disease and 90% of patients undergoing EUS showed that tumor depth was confined to the mucosa or submucosa layer. This difference between studies from Far Eastern and Western countries might be largely due to the periodic screening endoscopy actively performed in Korea and Japan for the early detection of gastric cancer. Screening endoscopy may result in the detection of gastric MALT lymphoma in early stages and consequently a lower rate of disseminated disease in Far Eastern countries compared to Western countries. Therefore, the value of extensive staging work-up, such as bone marrow biopsy and chest CT, may be more limited in Far Eastern countries than in Western countries.

In addition to above mentioned low incidence of disseminated disease, bone marrow aspiration and biopsy is an invasive procedure and chest CT has several disadvantages, such as cost, radiation exposure, and a high rate of indeterminate lesions. Therefore, it might be beneficial to define the patient group at high risk for disseminated disease and selectively perform bone marrow biopsy and chest CT only in patients with a high risk of involvement. There are few studies evaluating the risk factors for bone marrow and lung involvement that represents disseminated gastric MALT lymphoma. As the incidence of gastric MALT lymphoma itself is low and that of disseminated disease with bone marrow or lung involvement is even lower, no studies have identified definite risk factors by multivariate analysis. Indeed, multivariate analysis to identify risk factors could not be done since the present study included only one case with disseminated disease. Several studies have reported that H. pylori-negative gastric MALT lymphoma presents as advanced disease more frequently than H. pylori-positive disease.12,13 The results of our study support this association (Table 3); 80% of cases with advanced stage disease (Lugano stage II or IV) were H. pylori-negative, including the one case with bone marrow involvement. This might be explained by the high frequency of t(11;18)(q21;q21) in H. pylori-negative gastric MALT lymphoma compared to its H. pylori-positive counterpart13,14 since the presence of t(11;18)(q21;q21) is known to be a significant risk factor for disease dissemination.3 Therefore, patients with H. pylori-negative gastric MALT lymphoma can be reasonable targets for an extensive staging work-up including bone marrow biopsy and chest CT.

There are some limitations in the present study. First, as this was a retrospective study, there could be a selection bias and treatment modalities were not decided under a standardized protocol. Secondly, the number of cases with advanced stage disease was too small to identify definite risk factors for disseminated disease by multivariate analysis. Thirdly, as chest CT and PET were performed only in 34.5% and 21.6% of enrolled cases, our ability to evaluate the role of these examinations in the initial work-up of gastric MALT lymphoma was limited.

In conclusion, our data indicate that the incidence of disseminated disease including bone marrow involvement was very low in Korean gastric MALT lymphoma patients. Given the probably limited influence on survival and low incidence of bone marrow involvement in Korea, the clinical value of routine bone marrow aspiration and biopsy in initial staging work-up of gastric MALT lymphoma may be limited. Therefore, it might be beneficial to define high-risk conditions for disseminated disease, such as H. pylori-negativity or t(11;18)(q21;q21), and selectively perform an extensive staging work-up, such as bone marrow aspiration and biopsy, only in patients with these risk factors. Further large prospective studies are required to identify definite risk factors for disease dissemination and to establish tailored guidelines for initial staging work-up of gastric MALT lymphoma.

Fig 1.

Figure 1.Results of staging work-up in a patient with bone marrow involvement. (A) White light endoscopy image showing nodular mucosal changes and ulcers at the lesser curvature side of the gastric body. (B) Abdominal computed tomography image showing massive lymph node enlargement encasing the aorta, renal vessels, and mesenteric vessels. (C) Pathological findings showing paratrabecular infiltration of lymphoma cells into the bone marrow (H&E stain, ×200). (D) Immunohistochemical staining of bone marrow with CD20.
Gut and Liver 2014; 8: 637-642https://doi.org/10.5009/gnl13284

Fig 2.

Figure 2.Flowchart showing the 1-year treatment outcomes according to the initial treatment modality in 189 patients with Lugano stage I disease. HPE, H. pylori eradication; RTx, radiotherapy; CTx, chemotherapy; SR, surgical resection; CR, complete remission.
Gut and Liver 2014; 8: 637-642https://doi.org/10.5009/gnl13284

Table 1 Baseline Patient Characteristics (n=194)

CharacteristicValue
Age, yr53.3±11.4
 Median (range)53 (30–78)
Gender
 Male88 (45.4)
 Female106 (54.6)
H. pylori infection
 Absent40 (20.6)
 Present154 (79.4)
Abdomen-pelvis CT
 Localized in stomach189 (97.4)
 Abdominal LN involvement5 (2.6)
 Metastasis to organ in abdomen0
Bone marrow involvement
 Absent193 (99.5)
 Present1 (0.5)
Chest CT (n=67)
 No involvement67 (100.0)
 Mediastinal LN involvement0
 Metastasis to lung0
Tumor depth by EUS (n=54)
 Mucosa or submucosa50 (92.6)
 Proper muscle, subserosa, serosa4 (7.4)
PET (n=42)
 No specific findings42 (100.0)
 Findings suggesting metastasis0
Stage by Lugano system
 I189 (97.4)
 II4 (2.1)
 IV1 (0.5)
Initial treatment
H. pylori eradication162 (83.5)
 Radiotherapy22 (11.3)
 Chemotherapy8 (4.1)
 Resection2 (1.0)

Data are presented as mean±SD or number (%).

H. pylori, Helicobacter pylori; CT, computed tomography; LN, lymph node; EUS, endoscopic ultrasonography; PET, positron emission tomography.


Table 2 Details of Patients Whose Abdominal Computed Tomography Scans Showed Abdominal Lymph Node Enlargement Consistent with Metastasis

CaseSexAge, yrSymptomH. pylori infectionAbdomen-pelvis CTBM involvementChest CTTumor depth by EUSPETStageInitial treatment12-mo outcome
1F40Weight lossNegativeLN (+)NoNot doneNot doneNot doneIIChemotherapyNon-CR
2M39VomitingPositiveLN (+)NoNot doneNot doneNot doneIIChemotherapyNon-CR
3F73NauseaNegativeLN (+)NoNegativeNot doneNegativeIIChemotherapyCR
4M64Epigastric painNegativeLN (+)NoNegativeProper muscleNot doneIIChemotherapyCR
5M51DistensionNegativeLN (+)YesNegativeNot doneNot doneIVChemotherapyNon-CR

H. pylori, Helicobacter pylori; CT, computed tomography; BM, bone marrow; EUS, endoscopic ultrasonography; PET, positron emission tomography; F, female; LN, lymph node; CR, complete response; M, male.


Table 3 Patient Characteristics according to Helicobacter pylori Infection Status

CharacteristicH. pylori-positive (n=154)H. pylori-negative (n=40)p-value
Age, yr53.2±11.353.8±11.70.760
 Median (range)53.0 (30–78)52.5 (33–74)
Gender0.169
 Male66 (42.9)22 (55.0)
 Female88 (57.1)18 (45.0)
Abdomen-pelvis CT0.007
 Localized in stomach153 (99.4)36 (90.0)
 Abdominal LN involvement1 (0.6)4 (10.0)
Bone marrow involvement0.206
 Absent154 (100.0)39 (97.5)
 Present01 (2.5)
Tumor depth by EUS (n=54)<0.001
 Mucosa or submucosa46 (100.0)4 (50.0)
 Proper muscle, subserosa, serosa04 (50.0)
Stage by Lugano system0.007
 I153 (99.4)36 (90.0)
 II or IV1 (0.6)4 (10.0)

Data are presented as mean±SD or number (%).

CT, computed tomography; LN, lymph node; EUS, endoscopic ultrasonography.


Table 4 Outcomes after Helicobacter pylori Eradication in H. pylori-Positive Cases (n=153)

ParameterValue
Stage by Lugano system
 I153 (100.0)
 II or IV0
Outcomes 12 mo after treatment
 CR135 (88.2)
 Non-CR18 (11.8)
Duration of total follow-up, mo45 (12–126)
Recurrence after CR during follow-up3 (2.2)
Recurrence site
 Stomach3 (100.0)
 Abdominal LN0
 Abdominal organ0
 Bone marrow0
 Mediastinal LN0
 Lung0

Data are presented as number (%) or median (range).

CR, complete remission; LN, lymph node.


References

  1. Zucca E, Dreyling M. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21;v175-v176.
    Pubmed CrossRef
  2. Du MQ, Atherton JC. Molecular subtyping of gastric MALT lymphomas: implications for prognosis and management. Gut. 2006;55;886-893.
    Pubmed KoreaMed CrossRef
  3. Raderer M, W?hrer S, Streubel B, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24;3136-3141.
    Pubmed CrossRef
  4. Thieblemont C, Berger F, Dumontet C, et al. Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed. Blood. 2000;95;802-806.
    Pubmed
  5. Ruskon?-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus report: gastric extranodal marginal zone B-cell lymphoma of MALT. Gut. 2011;60;747-758.
    Pubmed CrossRef
  6. Isaacson PG, Chott A, Nakamura S, et al. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Swerdlow SH, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 214-217.
  7. Rohatiner A, d’Amore F, Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994;5;397-400.
    Pubmed
  8. Copie-Bergman C, Gaulard P, Lavergne-Slove A, et al. Proposal for a new histological grading system for post-treatment evaluation of gastric MALT lymphoma. Gut. 2003;52;1656.
    Pubmed KoreaMed CrossRef
  9. Raderer M, Vorbeck F, Formanek M, et al. Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer. 2000;83;454-457.
    Pubmed KoreaMed CrossRef
  10. Avil?s A, Nambo MJ, Neri N, Talavera A, Cleto S. Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial. Med Oncol. 2005;22;57-62.
    Pubmed CrossRef
  11. Nakamura S, Sugiyama T, Matsumoto T, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut. 2012;61;507-513.
    Pubmed CrossRef
  12. Chung SJ, Kim JS, Kim H, et al. Long-term clinical outcome of helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma is comparable to that of H. pylori-positive lymphoma. J Clin Gastroenterol. 2009;43;312-317.
    Pubmed CrossRef
  13. Nakamura S, Matsumoto T, Ye H, et al. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: a clinicopathologic and molecular study with reference to antibiotic treatment. Cancer. 2006;107;2770-2778.
    Pubmed CrossRef
  14. Ye H, Liu H, Raderer M, et al. High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood. 2003;101;2547-2550.
    Pubmed CrossRef
Gut and Liver

Vol.16 No.6
November, 2022

pISSN 1976-2283
eISSN 2005-1212

qrcode
qrcode

Share this article on :

  • line

Popular Keywords

Gut and LiverQR code Download
qr-code

Editorial Office