Clinical Cancer Research 13, 182-186, January 1, 2007. doi: 10.1158/1078-0432.CCR-06-0703
© 2007 American Association for Cancer Research
Imaging, Diagnosis, Prognosis |
Risk of Second Cancer in Nongastric Marginal Zone B-Cell Lymphomas of Mucosa-Associated Lymphoid Tissue: A Population-Based Study from Northern Italy
Luca Arcaini1,
Sara Burcheri1,
Andrea Rossi3,
Cristiana Pascutto1,
Francesco Passamonti1,
Ercole Brusamolino1,
Marco Paulli2,
Ester Orlandi1,
Maurizio Buelli3,
Piera Viero3,
Marco Lucioni2,
Francesca Montanari1,
Michele Merli1,
Sergio Cortelazzo3 and
Mario Lazzarino1
Authors' Affiliations: 1 Division of Hematology and 2 Department of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Pavia, Italy and 3 Division of Hematology, Ospedali Riuniti Bergamo, Bergamo, Italy
Requests for reprints: Luca Arcaini, Division of Hematology, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy. Phone: 39-0382-503595; Fax: 39-0382-502250; E-mail: luca.arcaini{at}unipv.it.
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Abstract
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Purpose: The aim of this study was to define the risk of second cancer in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).
Experimental Design: We considered for the analysis 157 patients with a confirmed histology of marginal zone B-cell lymphoma of MALT, presenting with a clinically prevalent extranodal site of disease, except for stomach. All patients came from two hematologic institutions of Northern Italy. We compared the occurrence of second cancer with respect to the general population by calculating the standardized incidence ratio, with the age- and sex-specific incidence rates of a cancer registry of Northern Italy (Lombardia) as a reference.
Results: A history of solid neoplasia was present in 29 (18%) patients for a total number of 30 neoplasms: 25 solid tumors, 2 hematologic diseases (1 Hodgkin's lymphoma and 1 essential thrombocythemia), and 3 nonmelanoma in situ skin cancers. In 4 patients, the site of cancer and lymphoma was the same. In 21 cases the solid tumor preceded the MALToma, in 3 the neoplasm was concomitant, whereas in 6 it was subsequent. For the entire group, the standardized incidence ratio of an additional malignancy was 0.8 [95% confidence interval (95% CI), 0.55-1.17; P = 0.2]. After excluding nonmelanoma skin cancer, the standardized incidence ratio of a second tumor was 0.75 (95% CI, 0.5-1.12; P = 0.2). After excluding all previous malignancies, the standardized incidence ratio of a second cancer was 1.32 (95% CI, 0.69-2.55; P = 0.4). The comparison of risks between males and females was not significant in each group analysis.
Conclusions: Patients with nongastric MALT lymphomas are not at increased risk for other neoplasms compared with the general population of the same geographic area.
Non-Hodgkin's lymphoma patients are at increased risk of developing second cancers compared with the general population (1), and they continue to be at significantly elevated risk of additional neoplasm for up to two decades following non-Hodgkin's lymphoma diagnosis (2). Marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT), especially of stomach, have been studied about the risk of second cancers, considering their peculiar relationship with the triad autoimmunity-infection-immunosuppression (3). Intriguingly, the genetic instability of the host, involving tumor suppressor genes, has been studied in the pathogenesis of gastric MALT lymphoma (4, 5). A high number of additional neoplasms were first described in two observational studies on patients with MALT lymphoma mainly of stomach (6, 7). Successively, two population-based studies did not show a statistically significant rate increase of cancers in patients with MALT lymphomas, mainly of stomach, with respect to the background population (8, 9), despite an apparently high number of second cancers.
To our knowledge, a population-based study on second cancer specifically focused on nongastric MALT lymphomas is still lacking. For this reason, we studied the prevalence of additional neoplasms in a series of 157 patients with nongastric MALT lymphomas consecutively diagnosed in two hematologic institutions of the same geographic area (Lombardia, Northern Italy) and we calculated the risk of second neoplasms in comparison with the background population from the Lombardia Tumor Registry.
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Patients and Methods
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We analyzed 157 consecutive cases of extranodal marginal zone B-cell lymphoma of MALT, except for stomach, diagnosed and treated from 1991 to 2004 in two Hematology Units of Northern Italy (Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia and Ospedali Riuniti, Bergamo). The study was conducted in accordance with institutional guidelines established for retrospective studies. The analysis was done in accordance to the Helsinki Declaration of 1964, as revised in 2000. To be included in the analysis, patients were required to have had a confirmed histologic diagnosis of low-grade MALT lymphoma according to the WHO classification (10). Cases with histologic shift in high-grade lymphoma were excluded. By review of the medical records, we identified the cases with histologically proven additional neoplasms. We did not consider noninvasive tumors, such as cervical intraepithelial neoplasia, and we distinguished skin cancers in melanoma and in situ nonmelanoma skin cancers.
Continuous variables were summarized as median and range, and categorical variables as count and relative frequency. The Kaplan-Meier product-limit method was used to estimate the cumulative probability of survival. Standardized cancer incidence ratios were used to compare the cancer incidence of the patients with nongastric MALT lymphoma with that of the general population of Northern Italy. Standardized incidence ratios (equivalent to the relative risk of developing a second cancer) were calculated by determining the ratio of the observed to the expected number of patients with second cancer. The expected number of secondary neoplasms was determined using sex, age, and calendar-year specific rates from the Lombardia Tumor Registry for the period 1993 to 1997 applied to the corresponding person-years at risk. Risks were calculated from date of birth to censorship, either at the date of last follow-up or death, or at the date of a non-MALToma neoplasia. After excluding previous malignancies, we also calculated risks from the date of diagnosis of lymphoma to censorship, either at the date of last follow-up or death, or at the date of a non-MALToma neoplasia. Risks were calculated both including and excluding noninvasive skin cancers. P values (score test) and 95% confidence intervals (95% CI) for the standardized incidence ratios were calculated applying a Gaussian approximation to the Poisson log-likelihood (11).
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Results
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Patients' characteristics, treatment, and outcome. The median age of the patients at diagnosis was 64 years (range, 23-91 years); 94 females and 63 males (ratio, 1.5). Most patients (92%) had a single extranodal mucosal site involvement and 8% had 
2 MALT sites involvement. The primary sites of lymphoma were as follows: 50 (32%) skin, 33 (21%) salivary glands, 24 (15%) orbit, 24 (15%) Waldeyer's ring, 14 (9%) lung and pleura, 6 (4%) breast, 4 (3%) intestine, and 2 (1%) other sites. Seventy-seven (49%) patients had stage I disease, 15 (10%) stage II, 8 (5%) stage III, and 57 (36%) stage IV. Sixty-one (39%) patients showed nodal involvement. Twenty-nine (18%) patients had a monoclonal component of small amount. A watch-and-wait policy was adopted in 23 (15%) cases. The first line treatment consisted into chemotherapy in 78 (50%) patients, surgery in 32 (20%), and radiotherapy in 24 (15%). Chemotherapy consisted of single alkylating agent in 30 patients and polichemotherapy in 48 (containing anthracyclines in 45). The surgical treatments consisted of surgery alone for 23 patients, surgery followed by chlorambucil in 3, and surgery followed by radiotherapy in 6. The radiotherapy was adopted alone in 21 patients and combined with chlorambucil in 3. The median follow-up was 3 years. Median overall survival has not been reached and median event-free survival was 3 years. The estimated 5-year overall survival and event-free survival of all patients were 83% (95% CI, 75-91%) and 37% (95% CI, 30-50%), respectively.
Additional cancer and standardized cancer incidence ratio. A history of 30 additional neoplasms was documented in 29 (18%) patients [18 females and 11 males; median age, 61 years (range, 37-86 years)]. The second cancer antedated the MALT lymphoma in 20 (70%) patients by a median of 118 months (range, 8-339 months). Three (10%) patients had concurrent neoplasms (within 3 months since diagnosis). Six (20%) additional tumors were diagnosed after the MALT lymphoma at a median time of 39 months (range, 6-90 months). Type, sex distribution, and chronology of second cancer are summarized in Table 1
. The malignancies were as follows: 25 solid tumors, 2 hematologic diseases (1 Hodgkin's lymphoma and 1 essential thrombocythemia), and 3 nonmelanoma in situ skin cancers. All the 3 noninvasive skin cancers preceded the MALToma. One patient had two malignancies (breast cancer and essential thrombocythemia), both previous to cutaneous MALT lymphoma diagnosis. Table 2
describes, for each type of neoplasia, the corresponding MALT site of lymphoma. In 4 (14%) patients, the site of cancer and lymphoma was the same (breast cancer 16 months after breast MALToma, melanoma concomitant to MALT lymphoma of the skin, and two in situ skin cancers diagnosed 10 and 7 years before MALT lymphoma of the skin, respectively).
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Table 1. Type, sex distribution, and chronology of additional cancers in 157 patients with nongastric marginal zone B-cell lymphoma of MALT
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Table 2. Correspondence between the sites of second cancers (left column) and the sites of lymphoma (right column)
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Table 3
details the features of MALT lymphomas and second cancers (anatomic sites, age at diagnosis, treatments, time interval between the two diagnoses, follow-up, and survival). For 10 of 20 patients with a previous neoplasia, treatment was as follows: surgery alone in 6, surgery followed by radiotherapy in 2, surgery followed by chemotherapy in 1, surgery followed by hormonal therapy in 1. Three patients relapsed for solid neoplasia before the lymphoma diagnosis; two of them were treated with radiotherapy. In the six patients with a subsequent neoplasia, two were followed with a watch-and-wait policy and four had received therapy for the lymphoma before the diagnosis of second cancer [two lines of radiotherapy in one, cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) chemotherapy followed by chlorambucil in one, surgery followed by CHOP in one, and CHOP alone in one]. At the time of the diagnosis of the solid neoplasia, three patients had stable disease (those followed with a watch-and-wait policy and the patient treated with radiotherapy), two patients were in complete remission and one patient had lymphoma progression. The three patients with concurrent malignancies were treated surgically for solid neoplasia whereas two received radiotherapy and one CHOP chemotherapy for lymphoma. The median time from diagnosis of lymphoma to death was 37 months (range, 2-119 months) whereas the median time from diagnosis of second cancer to death was 63 months (range, 4-368 months). For the entire group, the standardized incidence ratio of an additional malignancy was 0.8 (95% CI, 0.55-1.17; P = 0.2). The relative rate of an additional malignancy was 0.7 for males (95% CI, 0.39-1.26; P = 0.2) and 0.89 for females (95% CI, 0.55-1.46; P = 0.6); the comparison of risks between males and females was not significant (standardized incidence ratio, 1.28; 95% CI, 0.59-2.76; P = 0.5). After excluding nonmelanoma skin cancer, the standardized incidence ratio of a second tumor was 0.75 (95% CI, 0.5-1.12; P = 0.2). The relative rate of a second tumor was 0.6 for males (95% CI, 0.31-1.15; P = 0.1) and 0.89 for females (95% CI, 0.54-1.47; P = 0.6); the comparison of risks between males and females was not significant (standardized incidence ratio, 1.49; 95% CI, 0.65-3.4; P = 0.3). After excluding all previous malignancies, the standardized incidence ratio of a second cancer was 1.32 (95% CI, 0.69-2.55; P = 0.4). All concomitant and subsequent malignancies were invasive tumors. The relative rate of a second cancer was 1.46 for males (95% CI, 0.61-3.51; P = 0.4) and 1.19 for females (95% CI, 0.44-3.16; P = 0.7); the comparison of risks between males and females was not significant (standardized incidence ratio, 0.81; 95% CI, 0.22-3.02; P = 0.8).
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Table 3. Features of MALT lymphomas and second cancers (anatomic sites, age at diagnosis, treatments, time interval between the two diagnoses, follow-up, and survival)
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Discussion
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Epidemiologic studies have shown a nonaccidental association between second cancers and non-Hodgkin's lymphomas (1). Studies in long-term survivors have found a significantly elevated risk of second cancer for up to two decades following non-Hodgkin's lymphoma diagnosis (2), underlining the importance of a continued medical surveillance in the non-Hodgkin's lymphoma population.
In gastric MALT lymphoma, a high number of additional malignancies have been reported (6, 9). It is well known that both gastric adenocarcinoma and gastric MALToma are related to Helicobacter pylori infection (12–15) and, interestingly, cases of simultaneous gastric MALT lymphoma and adenocarcinoma have been reported (16). The genetic susceptibility of the host makes the difference between the high number of patients with H. pylori infection and the small number of patients who develop gastric MALToma. In the sequence of events from H. pylori–positive chronic gastritis to lymphoma transformation and to progression, several tumor suppressor gene alterations, such as p53 (17) and p16 (18) mutations, have been found, characterizing a tumor-prone phenotype (19), as well as defects in DNA repair mechanisms and allele imbalance at microsatellites for the tumor suppressor genes DCC and APC (4). Trisomy 3 is the most frequent chromosomal aberration in gastric MALT lymphoma (5); because several tumor suppressor genes are located on the short arm of chromosome 3, they are thought to be involved in the development of many solid tumors. The genetic instability of the host might explain the high prevalence of other malignancies. However, this hypothesis has not been definitely confirmed from an epidemiologic point of view; in fact, although Zucca et al. (6) found a 20% prevalence of additional neoplasms in a series of patients with low-grade gastric MALT lymphoma, in a Spanish population-based study of patients with gastric MALT lymphoma, only in the subgroup of patients under 50 years of age an excess of second cancers was close to significance (9). Some studies analyzed mixed series of MALT lymphomas including both gastric and nongastric cases; Luppi et al. (7) reported 11% of additional neoplasms in a small series whereas, in a population-based study from British Columbia Cancer Agency, the incidence of second malignancies resulted to 21% without a statistically significant rate increase of cancers with respect to the background population (8).
Nongastric marginal zone lymphomas of MALT are a heterogeneous group of disorders with distinct clinical behavior (20, 21). They represent 7% of all non-Hodgkin's lymphomas. In a recent multicenter Italian study on 208 patients, the median age at diagnosis was 64.4 years with a 5-year overall survival of 83% (21). The issue of second cancer in this lymphoma subtype has not yet been addressed; in the British Columbia Cancer Agency study, the relative rate of second malignancies for the subgroup of 95 patients with nongastric MALT lymphoma was 0.82 (8).
On such bases, we did a population-based study specifically focused on the risk of second cancers in nongastric MALT lymphomas. We determined whether there was an excess of additional neoplasms both during the whole clinical history of the patients and after the MALToma diagnosis. Despite an elevated number of additional malignancies (18%), especially solid tumors (83%), our data show that the relative rates for second cancers are not increased in patients with nongastric MALT lymphomas, independently of the timing of the additional cancer diagnosis. In particular, the standardized incidence ratio of an additional malignancy was not significant for the entire group, after excluding nonmelanoma skin cancers and after excluding all previous malignancies.
Actually, our results in nongastric MALT lymphomas do not differ from those in gastric MALT lymphoma; in fact, among the above-mentioned studies, only in the Spanish study (9) the subgroup of patients under 50 years of age showed an excess of second cancers close to significance (standardized incidence ratio, 2.59; 95% CI, 0.98-6.88). In our series of 29 patients with second cancer, 27 were >50 years old at the diagnosis of non-Hodgkin's lymphoma; the paucity of patients aged <50 years does not consent to elaborate an informative analysis for this subset of younger patients.
We did not a priori exclude a treatment-related pathogenesis of additional cancers in nongastric MALT lymphomas but we could not calculate a specific standardized incidence ratio for the only three patients treated with chemotherapy because the standardized incidence ratio would have not been informative. Given the relatively short follow-up of our series and the long latency in developing therapy-related second cancers, a role for treatment cannot be completely ruled out. Concerning this point, it should be noted that the median follow-up of our series is longer or equal to those reported by previous studies on gastric MALT lymphoma: 17.6 months in British Columbia Cancer Agency study (8) and 36 months in the Spanish series (9). Moreover, the advanced age of MALToma patients is related to a higher incidence of solid tumors and is itself a limit to a long follow-up, if compared with epidemiologic studies in younger populations like Hodgkin's lymphoma patients (22).
In conclusion, our data show that patients with nongastric MALT lymphomas are not at increased risk for second cancer compared with the general population of the same geographic area. However, because nongastric MALT lymphoma is a long-lasting disease typical of advanced age and with high probability of relapse (23), a careful oncohematologic follow-up is always warranted.
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Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: L. Arcaini and S. Burcheri contributed equally to this study.
Received 3/21/06;
revised 7/31/06;
accepted 9/19/06.
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Abstract
Patients and Methods
