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doi:10.1111/jgh.12615
GASTROENTEROLOGY
Evaluation of the clinical characteristics and prognostic factors of gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma Xiaoxiao Xu,* Zhenxing Wang,† Yong Yu,* Yafei Wang,* Lianyu Zhang,‡ Baocun Sun,‡ Wanming Da§ and Yizhuo Zhang* Departments of *Hematology, †Gastrointestinal Medical Oncology and ‡Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, and §Department of Hematology, Chinese General Hospital, Beijing, China
Key words gastrointestinal, MALT lymphoma, mucosa-associated lymphoid tissue lymphoma, prognostic factors. Accepted for publication 11 March 2014. Correspondence Yizhuo Zhang, Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, China. Email: [email protected] Zhenxing Wang and Xiaoxiao Xu contributed equally. They are joint first authors. Disclosure: The authors have declared no conflicts of interest.
Abstract Background and Aim: This study was undertaken to evaluate the clinical characteristics, prognostic factors, and long-term outcomes of patients with mucosa-associated lymphoid tissue (MALT) lymphoma in the gastrointestinal (GI) tract. Methods: Clinical and pathological features of patients with MALT lymphoma in the GI tract, who were treated consecutively at Tianjin Medical University Cancer Institute and Hospital from 2001 to 2011, were evaluated retrospectively. Results: Among a total of 99 identified cases, 79.79% of lymphomas were localized in the stomach, 20.20% in the intestinal tract, and disseminated disease was detected in 35.4% of cases. The estimated 5-year overall survival (OS) and 5-year progression-free survival (PFS) rates were 73.1% and 65.1%, respectively. The comparison between stomach and intestinal tract lymphomas demonstrated no significant difference in characteristics, but nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with intestinal tract MALT lymphoma (60%, P = 0.006). The outcomes of gastric and intestinal MALT lymphomas were similar (OS, P = 0.492; PFS, P = 0.408), and so was the survival between proximal and distal gastric lymphomas (OS, P = 0.077; PFS, P = 0.181). Serum lactate dehydrogenase level above normal was identified as the only adverse prognostic factor for both OS and PFS. Conclusion: The clinical characteristics and outcomes demonstrated no significant differences between gastric and intestinal tract MALT lymphomas. Serum lactate dehydrogenase level was an independent prognostic factor for the survival of GI MALT lymphoma.
Introduction Mucosa-associated lymphoid tissue (MALT) lymphoma was first reported in 1983 by Isaacson and Wright,1 and was recognized as a distinct entity of the marginal zone B-lymphoma in the revised European-American lymphoma classification in 1994.2 MALT lymphoma, the most common subset of extranodal lymphoma, accounts for 7–8% of all newly diagnosed lymphomas. Gastrointestinal (GI) tract is the most frequent primary location, although MALT lymphomas can also arise from various non-GI sites, such as salivary gland, conjunctiva, thyroid, orbit, and lung.3 Histologically, MALT lymphomas are characterized by proliferation of clonal marginal zone lymphocytes that invade epithelial structures forming the characteristic lymphoepithelial lesions.4 Histological progression from a low-grade lymphoma to a highgrade occurred in < 10% of the cases.5 Clinically, they behave as 1678
an indolent disease with a prolonged course. Patients with MALT lymphomas have favorable outcomes with a 5-year overall survival (OS) of > 85%.6 Previous studies on GI tract MALT lymphomas were performed either on gastric or non-gastric MALT lymphomas. Investigation of the relationship between gastric and intestinal subsets of MALT lymphomas has been limited. Additionally, prognostic data on these lymphomas remain to be elucidated. Here, we undertook a retrospective study to evaluate the clinical characteristics, prognostic factors, and long-term outcomes for patients with MALT lymphomas in the GI tract.
Materials and methods This is a retrospective study of patients with newly diagnosed GI MALT lymphomas at the Tianjin Medical University Cancer Institute and Hospital from January 2001 to June 2011.
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Inclusion criteria. Patients included in the study were histologically diagnosed with MALT lymphoma according to the WHO classification,7 and had not undergone any prior treatment. Histology and immunohistochemistry of all the original histological samples (biopsy or resection specimens) were investigated, and reviewed by at least two histopathologists. Exclusion criteria were as follows: (i) presentation of another histological type of lymphoma, including diffuse large B-cell lymphoma, (ii) human immunodeficiency virus-positive cases, and (iii) multiple types of tumors. Data collection. The following data were collected at diagnosis: age, sex, other diseases, presence of B symptoms, complete physical examination, performance status evaluated according to the Eastern Cooperative Oncology Group (ECOG), and biological parameters, including serum lactate dehydrogenase (LDH), serum β2-microglobulin and hemoglobin. Staging was evaluated by computed tomography scan of the thorax, abdomen and pelvis, endoscopic examination of the GI tract with systematic biopsies, including evaluation of Helicobacter pylori infection status, and bone marrow aspiration and biopsy. Other studies or examinations were performed according to clinical manifestations. Patients were treated with surgery, radiotherapy, chemotherapy, H. pylori eradication, and combinations according to the disease stage and location. Outcome data were collected at 3, 6, and 12 months, and every 6 months thereafter until death or the last scheduled visit. Response to treatment was classified according to the recommendation by the International Workshop to Standardize Response Criteria for non-Hodgkin lymphomas. Statistical methods. Continuous variables were expressed as median (range). Categorical variables were expressed as counts and proportions, and compared using the Fisher’s exact test. Primary endpoints of our survival analysis were OS and progression-free survival (PFS). OS was determined from the date of diagnosis until the date of death due to any cause or the date of final follow up. PFS was calculated from the date of diagnosis to the date of treatment failure, relapse, disease progression, or death due to any cause. The Kaplan–Meier method was used for survival estimations and the log-rank test for survival comparisons. Variables that influenced the prognosis (P < 0.05) and clinically relevant variables were subjected to a multivariate analysis using the Cox regression model to determine independent prognostic factors for survival. A two-sided P value < 0.05 assessed by the log-rank test indicated statistical significance. SPSS 17.0 for Windows software (IBM Corporation, Armonk, NY, USA) was used for all statistical analyses.
Results Of the 122 patients with GI MALT lymphomas, 23 were excluded and 22 were excluded based on the combination of histological presentation of diffuse large B cell lymphoma, and 1 because of inadequate histology. Characteristics of the population at initial presentation. Clinical and pathological characteristics of 99 patients comprising of 52 males and 47 females are listed in Table 1. The
Mucosa-associated lymphoid tissue lymphoma
median age was 52 years (range, 18–85 years). The distribution of patients with MALT lymphomas in the GI tract is shown in Figure 1. The locations of initial lymphomas at diagnosis in the GI tract were gastric (79.8%) and intestinal tract (20.2%). There were no MALT lymphomas from the esophagus and duodenal bulb identified in this series. The most common localizations in stomach and intestine were distal one third of stomach (38.4%) and ileocecal area (10.1%), respectively. The comparison between stomach and intestinal tract lymphomas demonstrated no significant difference in characteristics, but nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with intestinal tract MALT lymphoma (60%, P = 0.006). Outcome. With a median follow up of 30 months for these patients (range, 1–109 months), the median OS was not reached, and the median PFS was 93 months for all patients. Interestingly, the estimated 5-year OS rate was 73.1%, and the estimated 5-year PFS was 65.1%. There was no difference in survival (both OS and PFS) of the gastric and intestinal tract MALT lymphomas (Fig. 2). For the gastric MALT lymphoma, survival of the upper and lower one-third parts of the stomach showed no significant difference (Fig. 3). Prognostic factors. The variables significantly associated with shorter OS included age > 60 years, LDH above normal, high and high-intermediate risk according to International Prognostic Index (IPI) score, bulky disease (tumoral mass > 10 cm), ECOG ≥ 2, anemia, and disseminated disease (Ann Arbor III–IV) (Table 2). Similarly, adverse prognostic factors for PFS included age > 60 years, LDH above normal, high and high-intermediate risk according to IPI score, bulky disease (tumoral mass > 10 cm), ECOG ≥ 2, and disseminated disease (Table 3). Both OS and PFS were not statistically altered by extragastric locations. In multivariate analysis, shorter OS or PFS was associated with LDH above normal (Tables 2,3).
Discussion GI MALT lymphoma is the most common form of extranodal lymphoma, accounting for 30–40% of cases. The most commonly involved site is the stomach (60–75% of cases), followed by the small bowel, ileum, cecum, colon, and rectum.8 The distribution in this study showed that the most common localizations in the GI tract were stomach (78.2%) and ileocecum (11.1%). GI lymphomas are known to be predominant in males (M/F ratio 1.6–1.9).9,10 However, in the case of gastric MALT lymphoma, the previous reports were controversial.3,11,12 Non-gastric MALT lymphomas were reported to be more frequent in females, especially the breast, thyroid, and salivary gland tumors (M/F ratio 0.6–0.87).3,13,14 Our study revealed that gastric lymphomas and intestinal cases were both more common in males. Totally, 35% of patients with MALT lymphoma in the GI tract had a disseminated disease at diagnosis. The proportion of disseminated disease in non-gastric lymphomas is consistent with previous reports (27–52%),13,15,16 and the percentage of patients with gastric lymphoma was similar to the report by Raderer (25%).17 Although Raderer17 reported that non-gastric MALT lymphomas are significantly more prone to disseminated disease as
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1
X Xu et al.
Clinical and pathological characteristics of patients with MALT lymphomas in the gastrointestinal tract
Characteristics
Total Age (years) ≤ 60 > 60 Sex Male Female B-symptom Present Absent Nodal involvement Present Absent Serum LDH level Normal Abnormal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Unknown Performance status (ECOG) ≤1 ≥2 Ann-Arbor staging I–II III–IV Anemia Positive Negative Unknown H. pylori infection status Positive Negative Unknown
All patients
Gastric MALT
Intestine tract MALT
n
%
n
%
n
%
99
100
79
79.8
20
20.2
71 28
71.7 28.3
55 24
69.6 30.4
16 4
80.0 20.0
52 47
52.5 47.5
40 39
50.6 49.4
12 8
60.0 40.0
49 50
49.5 50.5
42 37
53.2 46.8
7 13
35.0 65.0
33 66
33.3 66.6
21 58
26.6 73.4
12 8
60.0 40.0
76 23
76.8 23.2
61 18
77.2 22.8
15 5
75.0 25.0
83 16
83.8 16.2
66 13
83.5 16.5
17 3
85 15
59 22 18
59.6 22.2 18.2
54 15 10
68.4 19 12.7
5 7 8
25.0 35.0 40.0
75 24
74.3 25.7
57 22
72.2 27.8
18 2
90.0 10.0
64 35
64.6 35.4
50 29
63.3 36.7
14 6
70.0 30.0
26 61 12
26.3 61.6 12.1
23 45 11
29.1 57.0 13.9
3 16 1
15.0 80.0 5.0
45 14 20
57.0 17.7 25.3
__
__
—
—
Notes: B symptoms, weight loss, fever, and night sweats; Anemia, hemoglobin < 11 g/dL. ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
compared with gastric MALT lymphomas, our data showed no difference between gastric and intestinal tract lymphomas (36.7% in gastric vs 30% in intestine, P = 0.575). The variations in distributions could be due to the different types of examinations and more stringent classification criteria used in different studies, since more thorough examination could lead to more precise staging.18 Survival data from our series confirm the indolent nature of MALT, in spite of the high percentage of disseminated patients. During the follow up, the median OS was not reached, and the median PFS in our series was 74 months. Different prognosis of MALT lymphoma depending on the various anatomical sites of origin has been previously reported,3,12 but a significant difference between gastric and GI (excluding stomach) lymphomas has not been established in our study. Our data demonstrated no significant 1680
difference in survival between gastric and intestinal MALT lymphomas, but durations of survival were shorter as compared with previous reports15,19,20 (5-year OS, 81–89%), which can be attributed to variations in patient population, lesion locations, and treatment options. Additionally, unlike GI multiple lymphomatous polyposis often seen in mantle cell lymphoma patients, surgical, pathological, and laparoscopic examinations revealed that MALT lymphoma is a single site (GI) lesion or involvement in this series. It is well known that the prognosis of patients with gastric cancer in the gastric cardia region is worse as compared with that of patients with distal third gastric carcinoma.21,22 So we explored if this holds true for gastric MALT lymphoma as well. In our study, MALT lymphoma in the proximity of the stomach was found to be associated with poor survival; however, no significant difference was observed.
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
X Xu et al.
Mucosa-associated lymphoid tissue lymphoma
Figure 1 Distribution of primary sites of MALT lymphomas in the gastrointestinal tract.
Figure 2
Comparison of OS and PFS between gastric and intestinal tract MALT lymphomas.
In the present study, nearly all the characteristics of the two groups (gastric and intestinal MALT lymphomas) showed no statistically significant differences. Of note, our study revealed that the local nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with the intestinal tract MALT lymphoma (60%, P = 0.006). However, the difference in the proportions of nodal involvement could be because patients with intestinal lymphomas often receive large surgeries, and more lymph nodes are removed. Additionally, the survival outcome between the subtypes was similar (Fig. 2). Currently, there are no well-established prognostic factors for MALT lymphomas.23 In our analysis, the Ann Arbor stage was demonstrated to be a prognostic factor for both PFS and OS (Fig. 4), consistent with the findings of previous studies.9,14,23–26 In contrast, other
, stomach;
, intestinal tract.
investigators did not observe any correlation between the disease stage and survival.5,13,19 Additionally, other prognostic factors for OS and PFS identified in our study were anemia (only for OS), serum LDH level above normal, poor performance status, high and high-intermediate risk according to IPI score, and bulky disease. Surprisingly, disseminated disease was excluded as an independent prognostic factor in multivariate analysis. A possible reason could be that the use of extensive testing may have shifted some patients with occult distant disease to the advanced disease subset. These patients would likely have similar prognosis to those with localized disease.5,17 Nevertheless, although the relationship between disease dissemination and outcomes may be unclear, awareness of the disease spread was suggested to be important for the decision of local versus systemic treatment.23
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Figure 3 Comparison of OS and PFS between proximal and distal parts of the stomach in MALT lymphoma. stomach.
Table 2
Table 3
Hazard ratios for overall survival Univariate analysis
Age > 60 years Male sex B-symptom Nodal involvement Serum LDH level above normal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Performance status (ECOG) ≤1 ≥2 Anemia Ann-Arbor staging I–II III–IV
P-value Hazard ratios (95% CI)
8.058 0.005 0.274 1.607 28.570
0.005 0.942 0.601 0.205 0.000
Univariate analysis P-value
5.772 (1.875–17.767) 0.002
22.027 0.000
10.736 0.005
8.045 0.005
3.965 0.046 16.539 0.000
, distal third
Hazard ratios for progression-free survival
Multivariate analysis
χ2
, proximal stomach;
Age > 60 years Male sex B-symptom Nodal involvement Serum LDH level above normal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Performance status (ECOG) ≤1 ≥2 Anemia Ann-Arbor staging I–II III–IV
Multivariate analysis
χ2
P-value Hazard ratios (95% CI)
10.164 0.032 0.697 2.231 32.512
0.001 0.859 0.404 0.135 0.000
P-value
6.554 (2.191–19.600) 0.001
27.668 0.000
10.930 0.004
8.171 0.004
2.375 0.125 16.666 0.000
Notes: B symptoms, weight loss, fever and night sweats; Anemia, hemoglobin < 11 g/dL. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
Notes: B symptoms, weight loss, fever and night sweats; Anemia, hemoglobin < 11 g/dL. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
By multivariate analysis, we found that only LDH was an independent prognostic factor. However, considering the limitations of applying Cox models to small number of events and low death rate (73%, 5-year survival) observed in our study, the results of
the multivariate analysis of prognostic factors should be interpreted with caution. In conclusion, our analysis indicated that gastric and intestinal MALT lymphomas in the GI tract had similar clinical character-
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Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Figure 4
Mucosa-associated lymphoid tissue lymphoma
Comparison of OS and PFS between localized and disseminated MALT lymphomas.
istics and outcomes, and LDH level was an independent prognostic factor for MALT lymphoma. Considering the small number of patients and the nature of retrospective data in our study, more multicenter prospective studies are needed to confirm these findings.
Acknowledgment This work was supported by grants from the National Natural Science Foundation of China 81270603.
References 1 Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983; 52: 1410–16. 2 Harris NL, Jaffe ES, Stein H et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–92. 3 Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: analysis of the Surveillance, Epidemiology, and End Results database. Cancer 2013; 119: 629–38. 4 Dierlamm J, Pittaluga S, Wlodarska I et al. Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Blood 1996; 87: 299–307. 5 Thieblemont C, Bastion Y, Berger F et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J. Clin. Oncol. 1997; 15: 1624–30. 6 Borie R, Wislez M, Thabut G et al. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur. Respir. J. 2009; 34: 1408–16. 7 Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J. Clin. Oncol. 1999; 17: 3835–49.
, localized disease;
, disseminated disease.
8 Psyrri A, Papageorgiou S, Economopoulos T. Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management. Ann. Oncol. 2008; 19: 1992–9. 9 Papaxoinis G, Papageorgiou S, Rontogianni D et al. Primary gastrointestinal non-Hodgkin’s lymphoma: a clinicopathologic study of 128 cases in Greece. A Hellenic Cooperative Oncology Group study (HeCOG). Leuk. Lymphoma 2006; 47: 2140–6. 10 Gobbi PG, Ghirardelli ML, Cavalli C et al. The role of surgery in the treatment of gastrointestinal lymphomas other than low-grade MALT lymphomas. Haematologica 2000; 85: 372–80. 11 Olszewski AJ, Castillo JJ. Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: analysis of the SEER-Medicare database. Ann. Oncol. 2013; 24: 1352–9. 12 Ueda K, Terui Y, Yokoyama M et al. Non-gastric advanced mucosa-associated lymphoid tissue (MALT) lymphoma has worse prognosis than gastric MALT lymphoma even when treated with rituximab-containing chemotherapy. Leuk. Lymphoma 2013; 54: 1928–33. 13 Arcaini L, Burcheri S, Rossi A et al. Nongastric marginal-zone B-cell MALT lymphoma: prognostic value of disease dissemination. Oncologist 2006; 11: 285–91. 14 Zucca E, Conconi A, Pedrinis E et al. Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood 2003; 101: 2489–95. 15 Thieblemont C, de la Fouchardiere A, Coiffier B. Nongastric mucosa-associated lymphoid tissue lymphomas. Clin. Lymphoma 2003; 3: 212–24. 16 de Boer JP, Hiddink RF, Raderer M et al. Dissemination patterns in non-gastric MALT lymphoma. Haematologica 2008; 93: 201–6. 17 Raderer M, Wohrer 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: 3136–41. 18 Siakantaris MP, Pangalis GA, Dimitriadou E et al. Early-stage gastric MALT lymphoma: is it a truly localized disease? Oncologist 2009; 14: 148–54.
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19 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: 802–6. 20 Nathwani BN, Anderson JR, Armitage JO et al. Marginal zone B-cell lymphoma: a clinical comparison of nodal and mucosa-associated lymphoid tissue types. Non-Hodgkin’s Lymphoma Classification Project. J. Clin. Oncol. 1999; 17: 2486–92. 21 Kim DY, Joo JK, Ryu SY, Park YK, Kim YJ, Kim SK. Clinicopathological characteristics and prognosis of carcinoma of the gastric cardia. Dig. Surg. 2006; 23: 313–18. 22 Craanen ME, Dekker W, Blok P, Ferwerda J, Tytgat GN. Time trends in gastric carcinoma: changing patterns of type and location. Am. J. Gastroenterol. 1992; 87: 572–9.
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23 Papaxoinis G, Fountzilas G, Rontogianni D et al. Low-grade mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 97 patients by the Hellenic Cooperative Oncology Group (HeCOG). Ann. Oncol. 2008; 19: 780–6. 24 Zullo A, Hassan C, Andriani A et al. Treatment of low-grade gastric MALT-lymphoma unresponsive to Helicobacter pylori therapy: a pooled-data analysis. Med. Oncol. 2010; 27: 291–5. 25 Guo Q, Guo S, Zhang Y. Treatment of gastric MALT lymphoma with a focus on Helicobacter pylori eradication. Int. J. Hematol. 2013; 97: 735–42. 26 Morita K, Nannya Y, Yoshizato T, Kurokawa M. Simple but powerful prognostic scoring model for MALT lymphoma: a retrospective study. Ann. Hematol. 2013; 92: 421–3.
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12615
GASTROENTEROLOGY
Evaluation of the clinical characteristics and prognostic factors of gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma Xiaoxiao Xu,* Zhenxing Wang,† Yong Yu,* Yafei Wang,* Lianyu Zhang,‡ Baocun Sun,‡ Wanming Da§ and Yizhuo Zhang* Departments of *Hematology, †Gastrointestinal Medical Oncology and ‡Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, and §Department of Hematology, Chinese General Hospital, Beijing, China
Key words gastrointestinal, MALT lymphoma, mucosa-associated lymphoid tissue lymphoma, prognostic factors. Accepted for publication 11 March 2014. Correspondence Yizhuo Zhang, Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, China. Email: [email protected] Zhenxing Wang and Xiaoxiao Xu contributed equally. They are joint first authors. Disclosure: The authors have declared no conflicts of interest.
Abstract Background and Aim: This study was undertaken to evaluate the clinical characteristics, prognostic factors, and long-term outcomes of patients with mucosa-associated lymphoid tissue (MALT) lymphoma in the gastrointestinal (GI) tract. Methods: Clinical and pathological features of patients with MALT lymphoma in the GI tract, who were treated consecutively at Tianjin Medical University Cancer Institute and Hospital from 2001 to 2011, were evaluated retrospectively. Results: Among a total of 99 identified cases, 79.79% of lymphomas were localized in the stomach, 20.20% in the intestinal tract, and disseminated disease was detected in 35.4% of cases. The estimated 5-year overall survival (OS) and 5-year progression-free survival (PFS) rates were 73.1% and 65.1%, respectively. The comparison between stomach and intestinal tract lymphomas demonstrated no significant difference in characteristics, but nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with intestinal tract MALT lymphoma (60%, P = 0.006). The outcomes of gastric and intestinal MALT lymphomas were similar (OS, P = 0.492; PFS, P = 0.408), and so was the survival between proximal and distal gastric lymphomas (OS, P = 0.077; PFS, P = 0.181). Serum lactate dehydrogenase level above normal was identified as the only adverse prognostic factor for both OS and PFS. Conclusion: The clinical characteristics and outcomes demonstrated no significant differences between gastric and intestinal tract MALT lymphomas. Serum lactate dehydrogenase level was an independent prognostic factor for the survival of GI MALT lymphoma.
Introduction Mucosa-associated lymphoid tissue (MALT) lymphoma was first reported in 1983 by Isaacson and Wright,1 and was recognized as a distinct entity of the marginal zone B-lymphoma in the revised European-American lymphoma classification in 1994.2 MALT lymphoma, the most common subset of extranodal lymphoma, accounts for 7–8% of all newly diagnosed lymphomas. Gastrointestinal (GI) tract is the most frequent primary location, although MALT lymphomas can also arise from various non-GI sites, such as salivary gland, conjunctiva, thyroid, orbit, and lung.3 Histologically, MALT lymphomas are characterized by proliferation of clonal marginal zone lymphocytes that invade epithelial structures forming the characteristic lymphoepithelial lesions.4 Histological progression from a low-grade lymphoma to a highgrade occurred in < 10% of the cases.5 Clinically, they behave as 1678
an indolent disease with a prolonged course. Patients with MALT lymphomas have favorable outcomes with a 5-year overall survival (OS) of > 85%.6 Previous studies on GI tract MALT lymphomas were performed either on gastric or non-gastric MALT lymphomas. Investigation of the relationship between gastric and intestinal subsets of MALT lymphomas has been limited. Additionally, prognostic data on these lymphomas remain to be elucidated. Here, we undertook a retrospective study to evaluate the clinical characteristics, prognostic factors, and long-term outcomes for patients with MALT lymphomas in the GI tract.
Materials and methods This is a retrospective study of patients with newly diagnosed GI MALT lymphomas at the Tianjin Medical University Cancer Institute and Hospital from January 2001 to June 2011.
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
X Xu et al.
Inclusion criteria. Patients included in the study were histologically diagnosed with MALT lymphoma according to the WHO classification,7 and had not undergone any prior treatment. Histology and immunohistochemistry of all the original histological samples (biopsy or resection specimens) were investigated, and reviewed by at least two histopathologists. Exclusion criteria were as follows: (i) presentation of another histological type of lymphoma, including diffuse large B-cell lymphoma, (ii) human immunodeficiency virus-positive cases, and (iii) multiple types of tumors. Data collection. The following data were collected at diagnosis: age, sex, other diseases, presence of B symptoms, complete physical examination, performance status evaluated according to the Eastern Cooperative Oncology Group (ECOG), and biological parameters, including serum lactate dehydrogenase (LDH), serum β2-microglobulin and hemoglobin. Staging was evaluated by computed tomography scan of the thorax, abdomen and pelvis, endoscopic examination of the GI tract with systematic biopsies, including evaluation of Helicobacter pylori infection status, and bone marrow aspiration and biopsy. Other studies or examinations were performed according to clinical manifestations. Patients were treated with surgery, radiotherapy, chemotherapy, H. pylori eradication, and combinations according to the disease stage and location. Outcome data were collected at 3, 6, and 12 months, and every 6 months thereafter until death or the last scheduled visit. Response to treatment was classified according to the recommendation by the International Workshop to Standardize Response Criteria for non-Hodgkin lymphomas. Statistical methods. Continuous variables were expressed as median (range). Categorical variables were expressed as counts and proportions, and compared using the Fisher’s exact test. Primary endpoints of our survival analysis were OS and progression-free survival (PFS). OS was determined from the date of diagnosis until the date of death due to any cause or the date of final follow up. PFS was calculated from the date of diagnosis to the date of treatment failure, relapse, disease progression, or death due to any cause. The Kaplan–Meier method was used for survival estimations and the log-rank test for survival comparisons. Variables that influenced the prognosis (P < 0.05) and clinically relevant variables were subjected to a multivariate analysis using the Cox regression model to determine independent prognostic factors for survival. A two-sided P value < 0.05 assessed by the log-rank test indicated statistical significance. SPSS 17.0 for Windows software (IBM Corporation, Armonk, NY, USA) was used for all statistical analyses.
Results Of the 122 patients with GI MALT lymphomas, 23 were excluded and 22 were excluded based on the combination of histological presentation of diffuse large B cell lymphoma, and 1 because of inadequate histology. Characteristics of the population at initial presentation. Clinical and pathological characteristics of 99 patients comprising of 52 males and 47 females are listed in Table 1. The
Mucosa-associated lymphoid tissue lymphoma
median age was 52 years (range, 18–85 years). The distribution of patients with MALT lymphomas in the GI tract is shown in Figure 1. The locations of initial lymphomas at diagnosis in the GI tract were gastric (79.8%) and intestinal tract (20.2%). There were no MALT lymphomas from the esophagus and duodenal bulb identified in this series. The most common localizations in stomach and intestine were distal one third of stomach (38.4%) and ileocecal area (10.1%), respectively. The comparison between stomach and intestinal tract lymphomas demonstrated no significant difference in characteristics, but nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with intestinal tract MALT lymphoma (60%, P = 0.006). Outcome. With a median follow up of 30 months for these patients (range, 1–109 months), the median OS was not reached, and the median PFS was 93 months for all patients. Interestingly, the estimated 5-year OS rate was 73.1%, and the estimated 5-year PFS was 65.1%. There was no difference in survival (both OS and PFS) of the gastric and intestinal tract MALT lymphomas (Fig. 2). For the gastric MALT lymphoma, survival of the upper and lower one-third parts of the stomach showed no significant difference (Fig. 3). Prognostic factors. The variables significantly associated with shorter OS included age > 60 years, LDH above normal, high and high-intermediate risk according to International Prognostic Index (IPI) score, bulky disease (tumoral mass > 10 cm), ECOG ≥ 2, anemia, and disseminated disease (Ann Arbor III–IV) (Table 2). Similarly, adverse prognostic factors for PFS included age > 60 years, LDH above normal, high and high-intermediate risk according to IPI score, bulky disease (tumoral mass > 10 cm), ECOG ≥ 2, and disseminated disease (Table 3). Both OS and PFS were not statistically altered by extragastric locations. In multivariate analysis, shorter OS or PFS was associated with LDH above normal (Tables 2,3).
Discussion GI MALT lymphoma is the most common form of extranodal lymphoma, accounting for 30–40% of cases. The most commonly involved site is the stomach (60–75% of cases), followed by the small bowel, ileum, cecum, colon, and rectum.8 The distribution in this study showed that the most common localizations in the GI tract were stomach (78.2%) and ileocecum (11.1%). GI lymphomas are known to be predominant in males (M/F ratio 1.6–1.9).9,10 However, in the case of gastric MALT lymphoma, the previous reports were controversial.3,11,12 Non-gastric MALT lymphomas were reported to be more frequent in females, especially the breast, thyroid, and salivary gland tumors (M/F ratio 0.6–0.87).3,13,14 Our study revealed that gastric lymphomas and intestinal cases were both more common in males. Totally, 35% of patients with MALT lymphoma in the GI tract had a disseminated disease at diagnosis. The proportion of disseminated disease in non-gastric lymphomas is consistent with previous reports (27–52%),13,15,16 and the percentage of patients with gastric lymphoma was similar to the report by Raderer (25%).17 Although Raderer17 reported that non-gastric MALT lymphomas are significantly more prone to disseminated disease as
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1
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Clinical and pathological characteristics of patients with MALT lymphomas in the gastrointestinal tract
Characteristics
Total Age (years) ≤ 60 > 60 Sex Male Female B-symptom Present Absent Nodal involvement Present Absent Serum LDH level Normal Abnormal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Unknown Performance status (ECOG) ≤1 ≥2 Ann-Arbor staging I–II III–IV Anemia Positive Negative Unknown H. pylori infection status Positive Negative Unknown
All patients
Gastric MALT
Intestine tract MALT
n
%
n
%
n
%
99
100
79
79.8
20
20.2
71 28
71.7 28.3
55 24
69.6 30.4
16 4
80.0 20.0
52 47
52.5 47.5
40 39
50.6 49.4
12 8
60.0 40.0
49 50
49.5 50.5
42 37
53.2 46.8
7 13
35.0 65.0
33 66
33.3 66.6
21 58
26.6 73.4
12 8
60.0 40.0
76 23
76.8 23.2
61 18
77.2 22.8
15 5
75.0 25.0
83 16
83.8 16.2
66 13
83.5 16.5
17 3
85 15
59 22 18
59.6 22.2 18.2
54 15 10
68.4 19 12.7
5 7 8
25.0 35.0 40.0
75 24
74.3 25.7
57 22
72.2 27.8
18 2
90.0 10.0
64 35
64.6 35.4
50 29
63.3 36.7
14 6
70.0 30.0
26 61 12
26.3 61.6 12.1
23 45 11
29.1 57.0 13.9
3 16 1
15.0 80.0 5.0
45 14 20
57.0 17.7 25.3
__
__
—
—
Notes: B symptoms, weight loss, fever, and night sweats; Anemia, hemoglobin < 11 g/dL. ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
compared with gastric MALT lymphomas, our data showed no difference between gastric and intestinal tract lymphomas (36.7% in gastric vs 30% in intestine, P = 0.575). The variations in distributions could be due to the different types of examinations and more stringent classification criteria used in different studies, since more thorough examination could lead to more precise staging.18 Survival data from our series confirm the indolent nature of MALT, in spite of the high percentage of disseminated patients. During the follow up, the median OS was not reached, and the median PFS in our series was 74 months. Different prognosis of MALT lymphoma depending on the various anatomical sites of origin has been previously reported,3,12 but a significant difference between gastric and GI (excluding stomach) lymphomas has not been established in our study. Our data demonstrated no significant 1680
difference in survival between gastric and intestinal MALT lymphomas, but durations of survival were shorter as compared with previous reports15,19,20 (5-year OS, 81–89%), which can be attributed to variations in patient population, lesion locations, and treatment options. Additionally, unlike GI multiple lymphomatous polyposis often seen in mantle cell lymphoma patients, surgical, pathological, and laparoscopic examinations revealed that MALT lymphoma is a single site (GI) lesion or involvement in this series. It is well known that the prognosis of patients with gastric cancer in the gastric cardia region is worse as compared with that of patients with distal third gastric carcinoma.21,22 So we explored if this holds true for gastric MALT lymphoma as well. In our study, MALT lymphoma in the proximity of the stomach was found to be associated with poor survival; however, no significant difference was observed.
Journal of Gastroenterology and Hepatology 29 (2014) 1678–1684 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Figure 1 Distribution of primary sites of MALT lymphomas in the gastrointestinal tract.
Figure 2
Comparison of OS and PFS between gastric and intestinal tract MALT lymphomas.
In the present study, nearly all the characteristics of the two groups (gastric and intestinal MALT lymphomas) showed no statistically significant differences. Of note, our study revealed that the local nodal involvement was significantly lower in gastric MALT lymphoma (26.6%) as compared with the intestinal tract MALT lymphoma (60%, P = 0.006). However, the difference in the proportions of nodal involvement could be because patients with intestinal lymphomas often receive large surgeries, and more lymph nodes are removed. Additionally, the survival outcome between the subtypes was similar (Fig. 2). Currently, there are no well-established prognostic factors for MALT lymphomas.23 In our analysis, the Ann Arbor stage was demonstrated to be a prognostic factor for both PFS and OS (Fig. 4), consistent with the findings of previous studies.9,14,23–26 In contrast, other
, stomach;
, intestinal tract.
investigators did not observe any correlation between the disease stage and survival.5,13,19 Additionally, other prognostic factors for OS and PFS identified in our study were anemia (only for OS), serum LDH level above normal, poor performance status, high and high-intermediate risk according to IPI score, and bulky disease. Surprisingly, disseminated disease was excluded as an independent prognostic factor in multivariate analysis. A possible reason could be that the use of extensive testing may have shifted some patients with occult distant disease to the advanced disease subset. These patients would likely have similar prognosis to those with localized disease.5,17 Nevertheless, although the relationship between disease dissemination and outcomes may be unclear, awareness of the disease spread was suggested to be important for the decision of local versus systemic treatment.23
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Figure 3 Comparison of OS and PFS between proximal and distal parts of the stomach in MALT lymphoma. stomach.
Table 2
Table 3
Hazard ratios for overall survival Univariate analysis
Age > 60 years Male sex B-symptom Nodal involvement Serum LDH level above normal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Performance status (ECOG) ≤1 ≥2 Anemia Ann-Arbor staging I–II III–IV
P-value Hazard ratios (95% CI)
8.058 0.005 0.274 1.607 28.570
0.005 0.942 0.601 0.205 0.000
Univariate analysis P-value
5.772 (1.875–17.767) 0.002
22.027 0.000
10.736 0.005
8.045 0.005
3.965 0.046 16.539 0.000
, distal third
Hazard ratios for progression-free survival
Multivariate analysis
χ2
, proximal stomach;
Age > 60 years Male sex B-symptom Nodal involvement Serum LDH level above normal IPI ≤2 ≥3 Tumoral mass (cm) ≤ 10 > 10 Performance status (ECOG) ≤1 ≥2 Anemia Ann-Arbor staging I–II III–IV
Multivariate analysis
χ2
P-value Hazard ratios (95% CI)
10.164 0.032 0.697 2.231 32.512
0.001 0.859 0.404 0.135 0.000
P-value
6.554 (2.191–19.600) 0.001
27.668 0.000
10.930 0.004
8.171 0.004
2.375 0.125 16.666 0.000
Notes: B symptoms, weight loss, fever and night sweats; Anemia, hemoglobin < 11 g/dL. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
Notes: B symptoms, weight loss, fever and night sweats; Anemia, hemoglobin < 11 g/dL. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IPI, the International Prognostic Index; LDH, lactate dehydrogenase.
By multivariate analysis, we found that only LDH was an independent prognostic factor. However, considering the limitations of applying Cox models to small number of events and low death rate (73%, 5-year survival) observed in our study, the results of
the multivariate analysis of prognostic factors should be interpreted with caution. In conclusion, our analysis indicated that gastric and intestinal MALT lymphomas in the GI tract had similar clinical character-
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Figure 4
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Comparison of OS and PFS between localized and disseminated MALT lymphomas.
istics and outcomes, and LDH level was an independent prognostic factor for MALT lymphoma. Considering the small number of patients and the nature of retrospective data in our study, more multicenter prospective studies are needed to confirm these findings.
Acknowledgment This work was supported by grants from the National Natural Science Foundation of China 81270603.
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