Clinical and molecular features of mucosa-associated lymphoid tissue (MALT) lymphomas of salivary...

ORIGINAL ARTICLE

CLINICAL AND MOLECULAR FEATURES OFMUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT)LYMPHOMAS OF SALIVARY GLANDS

Andrea Toso, MD,1 Paolo Aluffi, MD,1 Daniela Capello, MD,2 Annarita Conconi, MD,2

Gianluca Gaidano, MD,2 Francesco Pia, MD1

1Department of Otolaryngology-Head and Neck Surgery, Amedeo Avogadro University of Eastern Piedmontand Ospedale Maggiore della Carita, Novara, Italy. E-mail: [email protected] of Hematology, Department of Clinical and Experimental Medicine and IRCAD, Amedeo AvogadroUniversity of Eastern Piedmont and Ospedale Maggiore della Carita, Novara, Italy

Accepted 12 December 2008Published online 9 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21087

Abstract: Background. To analyze clinical features and to

discuss the modality of investigation and treatment of a series

of mucosa-associated lymphoid tissue (MALT) lymphomas. To

investigate the prevalence of aberrant promoter methylation,

responsible for gene inactivation, in a selected panel of genes

potentially involved in the pathogenesis of B-cell malignancies

as O6-methylguanine-DNA methyltransferase (MGMT), p73,

death-associated protein kinase (DAP-k).

Methods. Nine patients with primary MALT lymphoma of

the salivary glands were retrospectively reviewed. MGMT, p73,

DAP-k apoptotic pathways were tested.

Results. Methylation of DAP-k was common (5/8; 63%). His-

tological examination ensured diagnostic confirmation, whereas

fine-needle aspiration cytology was not definitively diagnostic.

Conclusion. Histological assessment is the gold standard

in the diagnosis of salivary gland lesions. Parotidectomy repre-

sents a safe and reliable diagnostic tool leading to a definite

diagnosis of MALT lymphomas in all cases and curative with-

out other treatment in early-stage MALT lymphoma. VVC 2009

Wiley Periodicals, Inc. Head Neck 31: 1181–1187, 2009

Keywords: MALT lymphomas; salivary gland; death-associated

protein kinase (DAP-k); apoptosis; surgical treatment

Mucosa-associated lymphoid tissue (MALT)lymphomas are B-cell extranodal non-Hodgkin’slymphomas (NHLs). They were originally de-scribed by Isaacson and Wright1 in 1983 and inthe World Health Organization (WHO) Classifi-cation of Neoplastic Diseases of the Hematopoi-etic and Lymphoid Tissue represent a distinctclinicopathological entity.2 MALT lymphomasaccount for 5% to 10% of all NHLs and are thevast majority of lymphomas arising in extrano-dal sites.3

The most common presenting site of diseaseis the gastrointestinal tract, but virtually allextranodal, mucosal, or nonmucosal sites can beinvolved. Organs where MALT is physiologicallypresent, like terminal ileum or Waldeyer’s ring,are rarely involved. Most MALT lymphomas areassociated with a predisposing condition, infec-tious or autoimmune, leading to the acquisitionof MALT4 in sites where it is not physiologicallypresent.

Primary lymphomas of salivary glands areuncommon (2% to 5% of salivary glands

Correspondence to: A. Toso

VVC 2009 Wiley Periodicals, Inc.

MALT Lymphomas of Salivary Glands HEAD & NECK—DOI 10.1002/hed September 2009 1181

neoplasms) and usually involve the parotidgland, because of the common presence oflymphoid tissue in its context. First clinicalmanifestation of the disease in the parotid glandand histologically proved involvement of the pa-rotid by lymphoma are strongly indicative of aprimary salivary lymphoma.5

The histologic features of MALT lymphomasare similar regardless of site of origin. The mor-phologic features of MALT lymphomas of salivaryglands are characterized by neoplastic B cellswith a marginal zone-type distribution; lym-phoma cells may colonize the germinal centersand invade glandular structures. The role of apo-ptosis deregulation in the molecular pathogenesisof this type of lymphoma is well documented.

Clinically, MALT lymphomas of salivaryglands have an indolent behavior and tend toremain localized for long periods to primarysites and regional lymph nodes. In low-gradesalivary MALT lymphomas, prognosis is gener-ally excellent but no standard treatment hasbeen defined.6

The purpose of our study was to analyze clin-ical features of a series of consecutive cases ofMALT lymphomas of salivary glands observedin our institution and to discuss the modality ofinvestigation and the opportunity of treatmentin this peculiar lymphoproliferative disorder.

Moreover, we investigated the prevalence ofaberrant promoter methylation, responsible forgene inactivation, in a selected panel of genespotentially involved in the pathogenesis of B-cellmalignancies and representative of genes impli-cated in DNA repair (O6-methylguanine-DNAmethyltransferase, MGMT) and apoptosis regu-lation (death-associated protein kinase, DAP-k).

PATIENTS AND METHODS

Clinical Data. Medical records from patientswith primary neoplasms of the salivary glandsobserved at our institute between 1993 and2002 were retrospectively reviewed to identifypatients with histological diagnosis of MALTlymphoma in accord with the criteria of theWorld Health Organization (WHO) classificationof lymphoid neoplasms.2 In 9 cases, the morpho-logical picture was consistent with a low-gradehistology; in 1 case, the initial diagnosis of low-grade MALT lymphoma was subsequentlyreviewed in diffuse large cell lymphoma, and

the patient was excluded from the present anal-ysis. We collected the information on those pa-rameters known to be of prognostic relevance:age, Eastern Cooperative Oncology Group (ECOG)performance status (PS),7 Ann Arbor stage, se-rum lactate dehydrogenase (LDH), beta2-micro-globulin levels, and International PrognosticIndex (IPI) score. The presence of a hepatitis Cvirus (HCV) infection and a previous autoim-mune disease were also recorded.

Disease in all patients was clinically stagedaccording to the Ann Arbor criteria. The stagingprocedures included CT scans of the head, neck,chest and abdomen, and bone marrow biopsy.Complete remission (CR) was defined as the dis-appearance—lasting at least 1 month—of allclinical evidence of the disease and includingthe normalization of all laboratory values andradiographs that had been considered abnormalbefore starting treatment. Partial remission(PR) was defined as a greater than 50% reduc-tion in the largest dimension of involved sites.Progressive disease (PD) was defined as morethan 25% increase of disease.

Aberrant methylation of MGMT, DAP-k, p73was analyzed in 8 of 9 patients (Table 1).

To exclude the possibility of nonspecific reac-tions and to verify that aberrant methylation ofMGMT, DAP-k, p73 is limited to neoplasticB cells, we tested a panel of nonneoplasticlymphoid tissues represented by normal periph-eral blood leukocytes (n ¼ 10), Epstein-Barr vi-rus (EBV)-immortalized B lymphocytes (n ¼ 5),and samples of reactive polyclonal B-cell hyper-plasia (n ¼ 10).

Molecular Analyses

DNA Preparation. All analyses were performed ontumor specimens collected at diagnosis beforespecific therapy.

Table 1. Aberrant methylation of MGMT, DAP-k, and p73.

Patient MGMT DAP-kinase p73

1 Nonmethylated Nonmethylated Methylated

2 Nonmethylated Methylated Nonmethylated

3 Nonmethylated Nonmethylated Nonmethylated

4 Nonmethylated Nonmethylated Nonmethylated



7 Nonmethylated Methylated Methylated


Abbreviations: MGMT, O6-methylguanine-DNA methyltransferase; DAP-k,death-associated protein kinase.

1182 MALT Lymphomas of Salivary Glands HEAD & NECK—DOI 10.1002/hed September 2009

Genomic DNA was purified by cell lysis fol-lowed by digestion with proteinase K, saltingout extraction, and precipitation by ethanol.

Bisulfite Treatment. DNA from tumor specimenswas subjected to chemical treatment with so-dium bisulfite as previously reported.8 Briefly,1 lg of DNA was denatured by treatment withNaOH and modified by sodium bisulfite treat-ment for 16 hours at 50�C. DNA samples werethen purified using Wizard DNA purificationresin (Promega), desulfonated by incubating ina final concentration of 0.3M NaOH, precipi-tated with ethanol, and resuspended in water.

Methylation-Specific Polymerase Chain Reaction. Themodified DNA was used as a template for MSP,a molecular technique that allows the distinc-tion between methylated and unmethylatedDNA.8 MSP was performed on 50 ng of bisulfite-treated DNA under the following conditions: adenaturing step at 95�C for 7 minutes is fol-lowed by 35 cycles at 95�C (30 seconds per cycle),the annealing temperature being specific foreach reaction (30 seconds per cycle), and 72�C(30 seconds per cycle), in a Hybaid DNA thermalcycler. The polymerase chain reaction (PCR)mixture contained 10�Gold buffer (PerkinElmer), 6.7 mM MgCl2, 10 lM of each primer,1 mM dNTPs, and 0.625 U of Taq Gold (PerkinElmer, 5 U/lL), in a final volume of 25 lL. Pri-mers for MGMT were as follows: 50-TTT GTGTTT TGA TGT TTG TAG GTT TTT GT-30

(sense) and 50-AAC TCC ACA CTC TTC CAAAAA CAA AAC A-30 (antisense) for the unme-

thylated reaction; 50-TTT CGA CGT TCG TAGGTT TTCGC-30 (sense) and 50-GCA CTC TTCCGA AAA CGA AAC G-30 (antisense) for themethylated reaction.9 The annealing tempera-ture for both the unmethylated and the methyl-ated reactions was 59�C. Primers for DAP-k wereas follows: 50-GGA GGATAG TTG GAT TGA GTTAAT GTT-30 (sense) and 50-CAA ATC CCT CCCAAA CAC CAA-30 (antisense) for the unmethy-lated reaction; 50-GGA TAG TCG GAT CGA GTTAAC GTC-30 (sense) and 50-CCC TCC CAA ACGCCG A-30 (antisense) for the methylated reac-tion.10 The annealing temperature for both theunmethylated and the methylated reactions was60�C. Primers for p73 were as follows: 50-AGGGGA TGT AGT GAA ATT GGG GTTT-30 (sense)and 50-ATC ACA ACC CCA AAC ATC AAC ATCCA-30 (antisense) for the unmethylated reaction;50- GGA CGT AGC GAA ATC GGG GTT C-30

(sense) and 5-ACC CCG AAC ATC GAC GTC CG-30 (antisense) for the methylated reaction.11 Theannealing temperature for both the unmethy-lated and the methylated reactions was 58�C. AllMSP analyses were performed with positive andnegative controls for both unmethylated andmethylated alleles. Also, control experimentswithout DNA were performed for each set ofPCR. Ten microliters of each PCR was directlyloaded onto 2.5% agarose gels, stained with ethi-dium bromide, and visualized under ultravioletillumination.

RESULTS

Patient Characteristics at Diagnosis. The charac-teristics of the 9 patients with a primary MALT

Table 2. Patients’ clinical features.

Patient Sex Age, y Extranodal site

Ann Arbor

stage

Serum

LDH

ECOG

PS IPI risk group

Autoimmune

disease HCV

1 F 60 Parotid 1 Normal 0 Low SS �2 F 56 Parotid 1 Normal 0 Low SS �3 F 62 Parotid 1 Normal 0 Low SS, SLE þ4 F 73 Parotid 1 Elevated 0 Low-intermediate SS �5 F 69 Minor salivary gland of the

floor of the mouth

1 Elevated 1 Low-intermediate – �

6 F 81 Minor salivary gland of

the cheek

1 Normal 0 Low – �

7 M 72 Parotid-submandibular gland 2 Normal 0 Low – þ8 F 75 Parotid 1 Normal 1 Low-intermediate – �9 F 50 Parotid 1 Normal 0 low – �Abbreviations: LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; PS, performance status; IPI, International Prognostic Index;HCV, hepatitis C virus; F, female; SS, Sjogren’s syndrome; SLE, systemic lupus erythematosus; M, male.


lymphoma of the salivary glands are reported inTable 2.

The median age was 69 years (range, 50–81),and a female prevalence was observed. In allcases, localized disease was reported corre-sponding to a stage I–II disease according to theAnn Arbor staging system. In 6 cases, a primarylymphoma of the parotid gland was docu-mented; in 2 cases, a minor salivary gland(located in the cheek and in the floor of themouth) was primarily affected; in 1 case, multi-ple salivary glands involvement was recorded(submandibular and parotid gland involve-ment). In this case, lymph node involvementwas present at diagnosis.

Serum lactate dehydrogenase (LDH) was ele-vated in 2 cases. No patient had a poor PS at thetime of diagnosis. All patients had a favorable IPIprognostic risk score. In 4 cases, a previous auto-immune disease was reported: in all cases, Sjog-ren’s syndrome, 1 in the context of a systemiclupus erythematosus, diagnosed 2 years before.Two patients had antibodies against HCV, in1 case associated with Sjogren’s syndrome.

At admission, the signs were not specific:most patients showed an asymptomatic enlarge-ment of parotid gland or an indolent submu-cousal oral mass, presenting since 2 to 24months (mean, 8.6 months).

Diagnostic confirmation was obtained in allcases from histological examination of surgicalspecimens, whereas fine-needle aspiration(FNA) and radiological evaluation (ultrasonogra-phy and CT scan) were not definitively diagnostic,leading only to a suspicion of lymphoprolifera-tive lesion. In no case was an open biopsyperformed.

Treatment and Clinical Outcome. All patientswith a parotid gland lesion had primary surgicaltreatment: a superficial parotidectomy in 5 casesand a total parotidectomy in 2 cases (for involve-ment of deep lobe and intraoperative suspicionof carcinoma, respectively); the remaining 2cases, with involvement of a minor salivarygland, had a diagnostic surgical intervention,namely, an incisional biopsy and an enucleation,respectively. After surgery, no major complica-tions, such as permanent facial injury or Frey’ssyndrome, were recorded.

Three patients had systemic therapy: chemo-therapy with single alkylating agent in 1 case,CVP (cyclophosphamide, vincristine, prednisone)in 1 case, and immunotherapy with rituximabin 1 case (Table 3). Three patients had an in-volved field radiotherapy, in 1 case subsequentto rituximab therapy, with total doses of 30, 40,and 48 Gy, respectively.

Different modalities of postoperative adju-vant therapy have been administered in patientswith similar stage of disease because no stand-ard treatment has been settled, and over theyears patients have been treated by differentradiation oncologists and/or hematologists.

Eight patients had a CR after the first-linetherapy, 1 patient achieved a PR. The patientwith a PR after a first-line chemotherapyapproach experienced a local disease progression70 months after treatment and was subse-quently treated with chlorambucil, obtaining anew PR. One patient had a relapse with orbitalinvolvement after 34 months. He was treatedwith radiotherapy (36 Gy), achieving a PR, andhad subsequent second- and third-line systemictherapy with rituximab and rituximab plus CVP

Table 3. Treatment and follow-up.

Patient Stage Therapy Surgery Chemo/RT (dose) Response Follow-up ChemoþRT

1 1 S Superficial parotidectomy – CR NED at 35 mo

2 1 S Superficial parotidectomy – CR NED at 41 mo

3 1 S þ Chemo Superficial parotidectomy Cyclophosphamide CR NED at 22 mo

4 1 S Total parotidectomy – CR NED at 47 mo

5 1 Chemo Biopsy CVP PR PD at 70 mo Chlorambucil

6 1 S þ RT Enucleation IF RT (48 Gy) CR NED at 7 mo

7 2 S Superficial parotidectomy,

submandibular excision,

lymph nodal dissection

– CR PD at 34 mo

8 1 S þ RT Total parotidectomy IF RT (40 Gy) CR DOD at 60 mo

9 1 S þ RT þ Chemo Superficial parotidectomy IF RT (30 Gy), RITUXIMAB CR NED

Abbreviations: Chemo, chemotherapy; RT, radiotherapy; S, surgery; CR, complete response; NED, no evidence of disease; CVP, cyclophosphamide,vincristine, prednisone; PR: partial response; PD, progression of disease; IF, involved field; DOD, dead of other causes.


for disease progression in abdominal lymphnodes.

After a median follow-up of 93 months,1 death was recorded: this patient died 60 monthsafter diagnosis from non–lymphoma-relatedcause. Median overall survival and progression-free survival were not reached.

Molecular Analysis. The sequences of MGMT,DAP-k, and p73 analyzed in our study by MSPare localized in CpG islands spanning the 50

noncoding region of the corresponding genes.The aberrant methylation of these regions hasbeen reported to be associated with transcrip-tional silencing.

In no patient, methylation of the MGMT pro-moter was observed. On the contrary, methyla-tion of DAP-k was common in MALT lymphomaof salivary glands (5/8; 63%). Only a minority ofour cases presented methylation of p73 pro-moter (2/8; 25%).

DISCUSSION

Non-Hodgkin’s lymphomas constitute 2% to 5%of salivary glands neoplasms; MALT lymphomais the most frequent histotype among the pri-mary salivary glands lymphomas.12

A constitutive activation of nuclear factor-kappa B (NF-jB), a major transcription factor re-sponsible for the expression of a variety of genesinvolved in the immune response, inflammation,and apoptosis, is now considered the commonfinal pathway of the most common nonrandomgenetic lesions associated with MALT lympho-mas.13 DAP-k aberrant methylation is the com-monest epigenetic alteration identified in ourcohort of primary salivary gland MALT lym-phoma, further confirming the role of apoptosisderegulation in the molecular pathogenesis ofthis type of lymphoma. In fact, in lymphomacells, DAP-k inactivation results in disruption ofthe extrinsic pathway of apoptosis initiated byinterferon c, tumor necrosis factor a, and FASligand.10 Thus, inactivation of the extrinsic path-way of apoptosis through DAP-k methylationmay reinforce and possibly cooperate with thesurvival advantage conferred to lymphoma cellsby NK-kB activation.13

The hypothesis that inactivation of DAP-k iscritical in the deregulation of the apoptotic path-ways in lymphomas with impaired apoptosis issupported by the observation that, among B-NHL, the higher frequency of aberrant methyla-

tion of DAP-k is observed in follicular lymphomaand chronic lymphocytic leukemia.14,15

The relevance of MGMT inactivation in thepathogenesis of B-cell lymphomas is related tothe genetic instability subsequent to the acquisi-tion of DNA point mutations, as MGMT is impli-cated in DNA repair function.9 Among B-NHL,aberrant methylation of MGMT inactivation isprevalent in aggressive lymphomas, and in dif-fuse large B-cell lymphomas, MGMT methyla-tion is a useful marker for predicting survival.16

Based on our results, epigenetic inactivation ofMGMT is not involved in the pathogenesis ofsalivary MALT lymphoma.

Our data show that the pathogenetic rele-vance of p73 promoter methylation, a candidatetumor suppressor gene sharing structural andfunctional similarities with p53 and involved incell cycle control and apoptosis,17 could be lim-ited to a subset of MALT lymphoma cases.These results reflect what observed has been inother neoplasia derived from mature B-cells,where p73 methylation is restricted to a smallfraction of cases.14

None of the nonneoplastic samples displayedmethylation of MGMT, DAP-k, or p73 CpGislands (data not shown), confirming that aber-rant methylation of these genes is not related tocell culture, viral transformation, cell activation,or proliferation.

In 20% of cases, MALT lymphomas are asso-ciated with Sjogren’s syndrome or myoepithelialsialadenitis. Myoepithelial sialadenitis is char-acterized by epithelial infiltration of centrocyte-like cells surrounding myoepithelial islands andleading to destruction of the glandular paren-chyma; about 50% of patients with myoepithe-lial sialadenitis have a diagnosis of Sjogren’ssyndrome, and all the patients with Sjogren’ssyndrome virtually present with myoepithelialsialadenitis.13

Different levels of evidence suggest a multi-step progression in the pathogenesis of MALTlymphomas, which ranges from the lymphopro-liferation without the characteristic of malig-nancy to the manifest lymphoma.

Some studies suggest that myoepithelial sia-ladenitis and Sjogren’s syndrome may be a set-ting in which oligoclonal populations of B cellsmay grow, 1 of which eventually become domi-nant resulting in manifest lymphoma. The lim-its between the reactive or autoimmune andneoplastic lymphoproliferation are not alwaysclear, and above all, the intermediate frames are


of difficult diagnostic interpretation. It is some-times very difficult to histologically differentiatemyoepithelial sialadenitis from MALT lympho-mas. No clear correlation has been reportedbetween immunoglobulin gene clonality andclinical or morphologic evidence of lymphoma.Thus, adequate sampling is of paramount im-portance in differentiating MALT lymphomasfrom nonneoplastic lymphoproliferations. In ourseries with a high prevalence of cases with pre-vious history of Sjogren’s syndrome, a superfi-cial parotidectomy represented a safe andreliable diagnostic tool leading to a definite di-agnosis of MALT lymphomas in all cases. Infact, FNA cytology usually does not provide suf-ficient material to achieve an accurate and de-finitive diagnosis (in our experience, FNA of thesalivary glands, performed in 7 of 9 cases, wasnever helpful to reach a histological confirma-tion of MALT lymphoma diagnosis). Moreover,incisional ‘‘blind’’ biopsies of a parotid mass,without isolating and exposing the facial nerve,must be avoided to prevent a seeding of the neo-plastic cells and/or a damage to the facial nerve.

Some authors reported FNA as an appropri-ate diagnostic tool for extranodal salivary lym-phoma, although MALT lymphoma showshistopathological characteristics posing particu-lar diagnostic difficulty; in some cases, it isimpossible to distinguish MALT lymphoma frommyoepithelial sialadenitis solely on cytomorpho-logic features.18

FNA can be useful in the preliminary evalu-ation of a parotid mass; however, in cases inwhich it is not possible to achieve a definitivediagnosis, a histological assessment should beobtained. A role for FNA cytology could be todetect recurrence of lymphoma, as reported bysome authors, avoiding further surgicalintervention.19

Some authors perform in selected cases openincisional biopsy, with facial nerve monitoring,to achieve histological diagnosis in parotidtumors.20 In our experience, MALT parotid lym-phoma usually does not show as a well-definedmass but as a parotid swelling, where the majordifferential diagnosis is with reactive lymphoidproliferation caused by myoepithelial sialadeni-tis. In such conditions, there is the risk of sam-pling a nondiagnostic part. In our series, asuperficial parotidectomy provided, in all cases,an accurate histological diagnosis with low riskof major complications and, in 3 stage I cases, aCR without other treatment.

In our experience, a definitive diagnosis canbe achieved only with histological examinationafter parotidectomy.

For intraoral submucosal masses, excision-biopsies may reveal a MALT lymphoma of minorsalivary glands, as experienced in 2 cases of ourseries.

Treatment of MALT lymphoma of salivaryglands depends on the site of lesion and thestage of the disease. Patients with localized lym-phomas (stages I and II) are usually treatedwith local therapy, surgery, and/or radiotherapywith excellent local control. However, radiother-apy may exacerbate mucositis and xerostomia inpatients with a preexisting sicca syndrome. Inour hand, the superficial parotidectomy repre-sented an efficacious mean of local disease con-trol spearing in the majority of cases toxicitiesrelated to radiotherapy. Nevertheless, MALTlymphoma is considered as an indolent diseasewith good prognosis, but a reported high rate oflate relapses (37%) has suggested the need for alifelong observation21 and probably for systemictherapy.22 In our series, after median follow-upof 93 months, 1 patient with stage II diseaseand submandibular and parotid gland involve-ment at diagnosis had a relapse after 34months; another patient experienced diseaseprogression after an initial partial remission af-ter 70 months.

The 4 patients with stage I disease, treatedwith only surgical excision (superficial paroti-dectomy in 3 cases, total parotidectomy in 1 sub-ject), did not show any recurrence to date, witha disease-free follow-up period ranging from 6 to47 months (mean, 32.2 months). Our result con-firms the data reported by Takahashi et al23

showing no clinical progression of disease in 9patients who underwent surgical excision (pa-rotidectomy) without further treatment. No re-currence of disease for up to 7 years afterexclusive superficial parotidectomy was alsoobserved by Isaacson and coworkers.24

Because of the indolent clinical behavior andfavorable prognosis, a conservative parotidec-tomy, in the absence of other treatment, may beconsidered curative in cases of low-grade stage 1MALT lymphoma of the parotid gland. Radio-therapy is usually performed after a positive bi-opsy of a localized salivary glands MALTlymphoma. A more aggressive therapy (chemo-therapy alone or in association with RT or sur-gery) should be considered in patients withspread to regional lymph nodes or disseminated


disease. Prolonged follow-up should be per-formed in these patients to assess possible laterelapses.

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