Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue of the head and neck area
High rate of disease recurrence following local therapy
Version of Record online: 17 APR 2003
Copyright © 2003 American Cancer Society
Volume 97, Issue 9, pages 2236–2241, 1 May 2003
How to Cite
Wenzel, C., Fiebiger, W., Dieckmann, K., Formanek, M., Chott, A. and Raderer, M. (2003), Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue of the head and neck area. Cancer, 97: 2236–2241. doi: 10.1002/cncr.11317
- Issue online: 17 APR 2003
- Version of Record online: 17 APR 2003
- Manuscript Accepted: 7 JAN 2003
- Manuscript Revised: 1 JAN 2003
- Manuscript Received: 15 NOV 2002
- MALT-type lymphoma;
- head and neck area;
Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct entity with specific clinical and pathologic features that may affect diverse organs. MALT–lymphomas remain localized within their original environment for a long period of time. As recent data have demonstrated a relatively high rate of multiorgan involvement at diagnosis, the authors have retrospectively evaluated 36 patients presenting with MALT-lymphoma in the head and neck area. The authors focused on patients' disease localization, initial treatment, clinical course, and follow-up.
Thirty-six patients with a histologically verified diagnosis of an extranodal marginal zone B-cell MALT-lymphoma arising in the head and neck area were included in this retrospective analysis.
Treatment consisted of surgical resection as the sole treatment in 4 patients (11%), surgical resection with consecutive radiotherapy in 13 patients (36%), radiotherapy alone in 11 patients (31%), chemotherapy in 2 patients (6%), surgical resection plus radiotherapy and chemotherapy in 4 patients (11%), and combined radiation and chemotherapy in 1 patient (3%). Complete and partial disease remissions after initial treatment were achieved in 22 (61%) and 13 patients (36%), respectively, whereas one patient refused any therapy. Four patients (11%) were lost to follow-up and 15 patients (43%) have had disease recurrence after a median time of 11 months (range, 3–80 months).
These data suggest that MALT-lymphomas of the head and neck area are preferentially treated using local modalities such as radiation and/or resection. This practice, however, is associated with an unexpectedly high rate of dissemination or disease recurrence. Obtaining an initial complete response is crucial in these patients. According to previous data, the possibility of understaging in such patients cannot be ruled out. Clinical trials with application of systemic treatment are warranted for these patients. Cancer 2003;97:2236–41. © 2003 American Cancer Society.
Lymphoma of the mucosa-associated lymphoid tissue (MALT-lymphoma) has been recognized recently as a distinct lymphoma entity of B-cell lineage. Initially defined by Isaacson and Wright in 1983,1 the Revised European American Lymphoma and the World Health Organization classification systems have now incorporated this entity under the term extranodal marginal zone B-cell lymphoma of MALT.2, 3 Lymphomas of MALT most frequently occur in the stomach (60–70%) but have also been described in various nongastrointestinal sites (30–40%) such as the salivary glands, conjunctiva, thyroid, orbit, lung, breast, kidney, liver, and prostate.4
In terms of histology, MALT-lymphomas are heterogenous and cover a cytologic spectrum ranging from centrocytelike cells to smaller lymphoid cells or monocytoid cells. An important characteristic is the presence of lymphoepithelial lesions formed by the invasion of individual glands by aggregates of lymphoma cells. Immunhistochemically, MALT-lymphomas share the cytologic feature and immunophenotype (CD20+, CD21+, CD35+, IgM+, IgD−) of marginal zone B cells5, 6 and are CD10−, CD5−, and cyclin D1−, which is important for distinction from follicular lymphoma, small lymphocytic lymphoma/CLL, and mantle cell lymphoma.
As opposed to their lymph node counterparts, MALT-lymphomas are believed to follow a relatively indolent course and show a tendency to remain localized within their original environment for a long period of time.7 However, the presence of a common mucosal immune system and the preferential trafficking of MALT-primed lymphocytes to other mucosal sites8 suggest that these mechanisms might also be operative following malignant transformation. This is further substantiated by anecdotal reports of synchronous occurrence of MALT-lymphoma within different organs or disease recurrence within another typical MALT-organ following successful local therapy of the initially affected site.9–11 In a recently published series, Raderer et al.12 demonstrated a relatively high rate of multiorgan involvement in patients diagnosed with extraintestinal MALT-lymphoma. Up to 50% of patients (the majority of whom had involvement of the head and neck) had a synchronous lymphomatous lesion within another organ, as opposed to only about 30% of patients with gastric MALT-lymphoma.12 According to these findings, we hypothesize that patients with MALT-lymphoma of the head and neck might have a relatively high risk of (at least subclinical) dissemination. These foci of disease might lead to recurrences of the lymphoma following local treatment.
Based on these findings, we retrospectively evaluated patients initially presenting with localized MALT-lymphoma in the head and neck area, focusing on their initial treatment and follow-up data.
MATERIALS AND METHODS
A retrospective analysis of patients diagnosed with MALT-lymphoma arising in the head and neck area and treated at our institution was performed. Our search disclosed 36 patients with verified MALT-lymphoma of the head and neck treated between January 1995 and July 2002. Histologic diagnosis of MALT-lymphoma was performed according to the criteria outlined by Isaacson.1, 13 Only patients from whom material for histologic reassessment by a reference pathologist (A.C.) was available were included in the analysis. Immunologic phenotyping on paraffin sections was done for demonstration of light-chain restriction and the phenotype CD20+ CD5− CD10− bcl6− cyclinD1−, which, in context with the microscopic appearance, is consistent with extranodal marginal zone B-cell lymphoma of MALT.
We analyzed diagnosis and localization at initial presentation, extent of staging, treatment, response to treatment, duration of response, recurrence, time to recurrence, and survival. Response to therapy was assessed by standard criteria for complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD).14 Only patients with CR and PR, as judged by regular radiologic follow-up, were rated as responders, whereas patients with SD or PD were rated as nonresponders. Overall survival and recurrence-free survival rates were estimated using the Kaplan–Meier product-limit method.15 Data were analyzed as of September 2002.
Thirty-six patients (12 males and 24 females) with MALT-lymphoma of the head and neck were identified and included in this retrospective evaluation (for patient characteristics see Table 1). The median age of the patients was 54 years (range, 31–82 years). The lymphomas were localized as follows: ocular adnexa (n = 20), parotid (n = 14), thyroid (n = 1), and tonsilla (n = 1). For the purpose of this analysis, MALT-lymphomas arising in different ocular adnexa are summarized as a single group. This is based on the fact that, clinically, these lymphomas are remarkably similar and their histologic features are virtually indistinguishable except for minor differences relating to the tissue in which they originate.16
|Patient||Age (yrs)||Gender||Localization||Stage||Treatment||Response||Recurrence||Localization||Time to progression||Follow-up time (mos)|
|7||67||F||OA||III||R,C||PR||Yes||LN (reg) + bone marrow||8||77+|
|10||74||M||OA||II||R||PR||Yes||LN (dd)||25||51 (dead)|
|16||77||F||P||II||R||PR||Yes||LN (dd) lung||10||38 (dead)|
|23||71||F||P||I||S,R,C||CR||Yes||LN (dd) + OA||11||15 (lost)|
|27||51||F||P||I||C||PR||Yes||LN (dd) + stomach||80||105+|
|32||79||F||OA||I||R||PR||Yes||LN (dd)||5||19 (dead)|
Pretherapeutic staging evaluation included full blood counts with a differential white cell count and platelet count, a biochemical profile, β-2-microglobulin, and a physical examination, in addition to chest radiographs and computed tomography (CT) scans of the chest and abdomen in all patients. However, staging procedures were heterogeneous, because some patients were staged at other hospitals before referral to our center. As of the beginning of 1997, standardized staging procedures were established at the Department of Oncology, University of Vienna, including an ophthalmologic examination, otorhinolaryngologic investigation including sonography of the salivary glands or magnetic resonance imaging if indicated, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal (GI) tract, enteroclysis, colonoscopy, a CT scan of the thorax and abdomen, and a bone marrow biopsy. In case of lesions suggestive of lymphomatous involvement, a biopsy was attempted. Thirteen of the patients included in our series underwent this extensive staging procedure before administration of therapy. Staging was performed according to the Ann Arbor staging system.
At diagnosis, 26 patients (72%) presented with Stage I disease, 9 patients (25%) with Stage II, and 1 patient (3%) had Stage III disease. Histologic verification by means of biopsy and immunologic phenotyping on paraffin sections had been performed for all 36 patients included in the analysis.
Eight of the 36 patients (22%) had evidence of autoimmune disease, including Sjogren syndrome (n = 6), dermatomyositis (n = 1), circumscript sclerodermia (n = 1), and chronic polyarthritis (n = 1). One patient refused therapy after having undergone extensive staging following histologic verification of lymphoma of the ocular adnexa. He is currently alive with stable lymphoma 6 months following the initial diagnosis (Table 1, Patient 29).
Therapy consisted of surgical resection as the sole therapeutic modality in 4 patients (11%), surgical resection with consecutive radiotherapy in 13 patients (36%), and radiotherapy alone in 11 patients (31%). Twenty-eight patients underwent local treatment only (or a combination of local treatment modalities). In case of parotid lymphoma, radiation was given to the involved glandular site(s) along with radiation to cervical lymph nodes.
Two patients (6%) received chemotherapy alone, four (11%) underwent surgical resection plus radiotherapy and chemotherapy, and one patient (3%) received combined radiation and chemotherapy. Chemotherapy consisted of cyclophosphamide, doxorubicin, vincristine, and prednisone for two patients. In addition, two patients received cyclophosphamide, vincristine, and prednisone, one patient received cladribine, and one patient had combination chemotherapy comprising mitoxantrone, chlorambucil, and prednisone.
Of the 36 patients, 22 (61%) achieved a CR after initial treatment, 13 (36%) achieved a PR, and 1 patient (3%) refused therapy. Among the Stage I patients, 19 (73%) of 26 patients obtained a CR, 6 patients (23%) had a PR, and in one patient (4%) the tumor was only observed. Three patients (33.5%) presenting with Stage II achieved a CR, whereas the remaining 6 patients (66.5%) obtained a PR. The patient with initial Stage III disease obtained a PR after therapy. Currently, four patients (11%) have been lost to follow-up, two after initial treatment and two after diagnosis of disease recurrence.
After a median follow-up of 40.5 months (range, 3–149 months), information on survival status was obtained for 32 patients, 27 of whom (84%) are still alive. Sixteen (59%) of these 27 patients are alive without evidence of disease at a median follow-up of 28 months (range, 3–79+ months). One patient (4%) died of long-standing CLL 8 months after successful radiotherapy of a parotid MALT-lymphoma, and another patient (4%), age 83 years, died 15 months after initial treatment without evidence of disease.
Fifteen patients (43%) have experienced disease recurrence after a median of 11 months (range, 3–80 months), including 3 of 13 patients who had undergone extensive staging before initiation of therapy. Eight of these patients initially had parotid lymphoma, and seven had involvement of the ocular adnexa. The pattern of disease recurrence was local in three patients (20%): one patient each developed local recurrence following resection of a parotid lymphoma and a MALT-lymphoma of the ocular adnexa, respectively, whereas the third patient presented with local recurrence after surgery and radiotherapy as initial therapy of a parotid lymphoma. The other 12 patients (80%) presented with disseminated disease (Table 1).
Among the 15 patients subsequently diagnosed with disease recurrence, initial treatment consisted of local therapy in 11 patients: surgical resection in 3 patients (20%), surgical resection and consecutive radiotherapy in 3 patients (20%), and radiotherapy alone in 5 patients (33%). In contrast, only three patients with disease recurrence underwent systemic treatment, consisting of chemotherapy only, surgical resection plus radiotherapy and chemotherapy, and combined radiotherapy and chemotherapy in one patient each.
All disease recurrences were documented histologically as MALT-type lymphomas, with the exception of one patient, who developed diffuse large cell lymphoma involving the stomach, the lungs, and mediastinal lymph nodes. Three (20%) of the 15 patients died of PD 19, 38, and 51 months after initial diagnosis, respectively.
Extranodal marginal zone B-cell lymphoma of MALT is a distinctive type of malignant B-cell lymphoma.2, 3 Although data defining the clinical features, natural history, pathology, and molecular genetics of the disease have been accumulating in the last decade, the optimal treatment approach to MALT-lymphoma is still evolving.
A paradigm shift recently has occurred in the management of gastric MALT-lymphoma, where surgery as upfront management is currently being replaced by organ-conserving approaches, which are equally effective.6 Relatively little, however, is known about optimal management of patients with extragastric MALT-lymphomas.
As opposed to gastric MALT-lymphoma, extraintestinal localizations historically have been less liberally subjected to excision. In a retrospective series including 108 patients defined as having MALT-lymphoma, Thieblemont at al.7 found surgery as a part of initial management in 35 of 55 patients (64%) with GI localizations, as opposed to 18 of 53 patients (34%) with non-GI involvement.7 A CR was obtained in 76% of patients with non-GI lymphoma following first treatment, but there was no difference in response or survival rates between various types of treatment. In that study, lymphomas of orbit, salivary glands, thyroid, and the head and neck (without further detailled definition of the latter) were included, but treatment approaches and results were not broken down for the various localizations. Thieblemont et al. reported that patients with localized disease generally were treated with surgery or radiotherapy. A similar therapeutic approach also was reported in 46 patients with ocular adnexal lymphomas by Auw-Haedrich et al.,17 who found radiotherapy to be the predominant form of therapy in patients with MALT-lymphoma.
Our retrospective evaluation confirmed that Stage I or II MALT-lymphomas outside the GI tract were preferentially treated with local approaches. Of 36 patients, 28 (78%) underwent local therapy only consisting of surgery, radiation, or a combination of both modalities. This approach is based on the assumption that MALT-lymphoma, which is an indolent disease, remains localized for a prolonged period of time.
Anecdotal reports of synchronous occurrence of MALT-lymphoma or recurrence of disease in various organs following successful local therapy of the initially affected site are scattered throughout the literature.9–11 Recently, systematic evaluations of the dissemination pattern of MALT-lymphoma have been published. For example, Thieblemont et al.7 analyzed 158 patients with MALT-lymphoma and found dissemination at diagnosis in about one-third of cases. At our institution, Raderer et al.12 used an extensive staging routine and also demonstrated a higher than expected rate of multifocal disease at diagnosis in patients with MALT-lymphoma. That rate approached 50% in patients with extragastric origin. According to these data, this propensity for dissemination could cause undertreatment when applying local therapies in patients with undetected multifocal disease. Given the relatively indolent nature of the disease, lesions that become clinically apparent months after initial diagnosis may simply reflect untreated synchronous lesions that are not detected by initial staging rather than true instances of disease recurrence. In fact, 9 of 15 disease recurrences observed in our patients occurred within 12 months after the initial diagnosis. In the remaining six patients, disease recurrences were observed after a relatively long time span. These were demonstrated after an interval as long as 80 months. The rate of recurrences might probably increase with an even longer follow-up. In our study, the median follow-up time was 40.5 months, which is comparable to the results of other studies on extragastric MALT-lymphomas. Zinzani et al.4 reported a follow-up time of 47 months and have estimated a recurrence rate of 30% at 5 years. The exact follow-up of patients with lymphoma localized in the head and neck area, was not provided. No clear differences between various approaches were found in this study, which is most likely due to the small number of patients in the various subgroups and localizations. Conversely, Jenkins et al.18 found a higher rate of recurrence when analyzing data from 192 patients with lymphoma of the ocular adnexa. They reported that 47% of patients with MALT-lymphoma of the ocular adnexa had at least one extraorbital recurrence after 5 years. This lends further support to the notion that not only extensive staging, but also meticulous and prolonged follow-up are necessary in these patients. In our study, 8 of 13 patients who developed disseminated disease only had a PR following initial therapy, indicating that achieving an initial CR might be an important factor for disease control.
It is noteworthy that in our study, of 15 patients with subsequent disease recurrence, only 3 had received chemotherapy as part of their therapy. The majority of patients were managed with surgery and/or radiotherapy. The number of patients who received chemotherapy in our study is too small to perform statistical comparisons.
These data suggest that local approaches, in spite of effective local control, might be insufficient to prevent subsequent disease recurrence and dissemination. This assumption also agrees with results reported by Tsang et al.19 Although these authors found no recurrences in gastric and thyroid MALT-lymphomas following irradiation, recurrences occurred in 8 of 62 patients (original sites: 2 salivary, 3 orbit, 1 nasopharynx, 1 larynx, and 1 breast). Three of these patients had recurrence in the nonirradiated contralateral paired organ, four had disease recurrence in distant sites, and one had disease recurrence in both local and distant sites.
Given the biologic properties of MALT-lymphoma, especially the homing properties of lymphocytes involved in MALT,8 and recent data on multifocal occurrence,12 this fact is not surprising. According to the limited experience with chemotherapy in patients with MALT-type lymphoma,6 clinical trials of systemic therapies are strongly warranted.
Our data suggest that patients with MALT-lymphoma of the head and neck are at a relatively high risk for early dissemination and subsequent distant recurrence when only local therapies are applied. Extensive staging is mandatory before considering radiotherapy to rule out synchronous distant disease. Although the current study does not allow a clear interpretation of the efficacy of chemotherapeutic intervention, the results strongly warrant trials investigating systemic approaches to MALT-lymphoma of the head and neck. Given the fact that recurrences also occur after a relatively long period, these patients should be monitored closely for a prolonged time.
- 6Extranodal lymphoma of mucosa associated lymphoid tissue (MALT)-type: the perspective at the beginning of the 21st century. Expert Rev Anticancer Ther. 2001; 1: 89–101., .
- 13Mucosa-associated lymphoid tissue (MALT) and the MALT-lymphoma concept. In: IsaacsonPG, NortonA.J, editors. Extranodal lymphomas. Edinburgh: Churchill Livingston, 1994: 5–14., .
- 16Lymphomas of the ocular adnexa and eye. In: IsaacsonPG, NortonAJ, edit. Extranodal lymphomas. Edinburgh: Churchill Livingstone, 1994: 117–130., .