Case Report

Marginal Zone B-Cell Lymphoma of the SalivaryGland Arising in Chronic Sclerosing Sialadenitis(Kuttner Tumor)

Erin Rubin Ochoa, M.D., Nancy Lee Harris, M.D., andBen Zion Pilch, M.D.

We report a case of extranodal marginal zone B-cell lymphomaof mucosa-associated lymphoid tissue (MALT) type of the sali-vary gland arising in a background of chronic sclerosing si-aladenitis. Chronic sclerosing sialadenitis is a common fibros-ing chronic inflammatory lesion of the submandibular gland,which is thought to be the result of sialolithiasis, and is notassociated with a systemic autoimmune disease. SalivaryMALT lymphomas are typically associated with lymphoepithe-lial sialadenitis (LESA) in a patient with or without Sjogren’ssyndrome. Our case of salivary MALT lymphoma was neitherpreceded by Sjogren’s syndrome nor accompanied by LESA.This case suggests that chronic inflammatory processes otherthan Sjogren’s syndrome may provide a substrate for the de-velopment of MALT lymphoma.Key Words: Extranodal marginal zone B-cell lymphoma—MALT lymphoma—Chronic sclerosing sialadenitis—Kuttnertumor—Lymphoepithelial sialadenitis—Salivary gland.

Am J Surg Pathol 25(12): 1546–1550, 2001.

We report a case of extranodal marginal zone B-celllymphoma of mucosa-associated lymphoid tissue(MALT) type of the salivary gland arising in a back-ground of chronic sclerosing sialadenitis, also knownas Kuttner’s tumor. Lymphoma of MALT type is alow-grade B-cell lymphoma first described by Isaacsonand Wright in 1983,10 which is now included in theRevised European-American Classification of LymphoidNeoplasms (REAL) as extranodal marginal zone B-celllymphoma.6 In the salivary gland MALT lymphomausually arises in a background of lymphoepithelial

sialadenitis (LESA) and is often, although not always,associated with Sjogren’s syndrome.2,3,9,12,13 Chronicsclerosing sialadenitis, first described by Kuttner andknown as Kuttner’s tumor, is a common fibrosingchronic inflammatory lesion of the submandibular gland.The etiology of this lesion is thought to be sialolithiasis,and chronic sclerosing sialadenitis is not generally asso-ciated with a systemic autoimmune disease. To ourknowledge, this is the first case of MALT lymphoma ofthe salivary gland associated with Kuttner’s tumor.

CASE REPORT

A 65-year-old man developed painless enlargement ofa right submandibular gland mass that had been presentfor 1.5 years. There was no history of dry eyes or drymouth. His past medical history was significant for dia-betes, hypertension, left lower extremity claudication,asthma, bronchitis, emphysema, hypercholesterolemia,dyspnea on exertion, alcoholism, and a 50 pack-yearcigarette smoking history.

His physical examination revealed a 3 × 3 cm rightsubmandibular mass. No lymphadenopathy or other sali-vary gland enlargement was present.

A fine needle aspiration of the submandibular masswas performed, and 2 months later an approximately 4 ×3 cm, right submandibular gland was removed. Twoyears later the patient is without evidence of recurrentlymphoma, without further therapy.

MATERIALS AND METHODS

Fine Needle Aspiration Biopsy

Fine needle aspiration biopsy was performed using a23-gauge needle. Direct cytologic smears were fixed inalcohol and stained with the Papanicolaou technique.

From the Department of Pathology, Massachusetts General Hospital,Harvard Medical School, Boston, Massachusetts, U.S.A.

Address correspondence and reprint requests to Ben Zion Pilch, MD,Department of Pathology, Massachusetts General Hospital, Warren 2,14 Fruit Street, Boston, MA 02114, U.S.A.; e-mail:pilch.ben@mgh.harvard.edu

The American Journal of Surgical Pathology 25(12): 1546–1550, 2001 © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia

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Flow Cytometry

A portion of the right submandibular gland fine needleaspiration material was analyzed by flow cytometry, aspreviously described.11

Histologic Processing

Sections of the resected tumor and salivary gland werefixed in B5 and formalin. After fixation and processing,4-�m paraffin-embedded tissue sections were stainedwith hematoxylin and eosin. Giemsa and periodic acid-Schiff special stains were performed on selected slides.

Immunoperoxidase Staining

Fresh tissue was snap frozen in liquid nitrogen andstored at −70°C. Immunoperoxidase staining was per-formed on 4-�m-thick frozen or paraffin-embedded tis-sue sections by the avidin-biotin complex technique(Vector Laboratories, Burlingame, CA, USA), as previ-ously described (Table 1).8

RESULTS

The fine needle aspiration of the submandibular glandrevealed a monomorphous population of slightly en-larged lymphocytes intermixed with salivary gland epi-thelium. Flow cytometric analysis of the aspirate showed

CD19- and CD20-positive B cells with monotypic � lightchain expression consistent with a B-cell neoplasm(Table 2). The B cells lacked CD5, CD10, and CD23.

Histologic examination of the excised salivary glandrevealed periductal fibrosis and dilated ducts with aprominent lymphoid infiltrate surrounding the areas offibrosis. The submandibular gland parenchyma was atro-phic, but the lobular architecture was preserved (Fig. 1).Intraepithelial lymphoid infiltration and lymphoepithe-lial lesions (epimyoepithelial islands) were absent (Fig.2). The architectural appearance was that of chronic scle-rosing sialadenitis. The lymphoid infiltrate, however,was unusually dense. It contained reactive germinal cen-ters and an interfollicular infiltrate composed of a histo-logically monomorphous population of medium-sizedcells with irregular nuclei and moderate amounts of palecytoplasm consistent with marginal zone B cells (Fig. 3).

TABLE 1. Monoclonal antibodies and immunoperoxidase staining results on frozentissue sections

Antigen Source Results

Kappa 345120 Becton Dickinson (Franklin Lakes, NJ) NegativeLambda Becton Dickinson 345130 PositiveIgM MU046-UC BioGenex (San Ramon, CA) NegativeIgA MU046-UC BioGenex NegativeIgG MU050-UC BioGenex PositiveCD22 550006 Becton Dickinson PositiveCD20 M755 Dako (Carpinteria, CA) PositiveCD21 N784 Dako Focal positive FDCCD10 6602143 Coulter (South San Francisco, CA) NegativeCD43 550044 CAMFolio Becton Dickinson Negativebcl-2 M887 Dako PositiveCD5 6300 Becton Dickinson NegativeCD3 347340 Becton Dickinson Negative

Ig, immunoglobulin.

TABLE 2. Results of flow cytometric analysis of fineneedle aspiration material

T cell B cell

CD3: 14% CD19: 83%CD5: 12% CD20: 84%CD7: 14% Kappa: <1%CD3–8+: <1% Lambda: 83%CD4: 6% CD5: <1%CD8: 8% CD10: <1%

CD23: <1%

FIG. 1. Low power view of the submandibular gland,showing periductal bands of fibrosis, a prominent lym-phoid infiltrate, with preservation of the acinar architecture(hematoxylin and eosin, original magnification ×23).

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There were, however, features of residual chronic scle-rosing sialadenitis such as acute and chronic sialodochi-tis with fibrosis (findings generally absent in salivaryMALT lymphomas) (Fig. 4) as well as glandular atrophywith an infiltrate of non-neoplastic appearing plasmacells without a significant component of monocytoidB-cells (Fig. 5).

Immunoperoxidase staining on frozen tissue with an-tibodies to immunoglobulin heavy and light chains(Table 1) showed monotypic � staining of most lym-phoid cells in a diffuse pattern. With antibody toB-lineage antigens CD20 and CD22, there was stainingof most cells in a diffuse pattern (Fig. 6). The B cellswere negative for antibody to CD5, CD3, CD10, CD43,and immunoglobulin M and positive for bcl-2. With an-tibody to T-lineage-associated antigens CD3, CD5, andCD43, there was staining of rare cells scattered withinthe tissue. With antibody to CD21, there was staining of

multiple dendritic cell aggregates corresponding to re-sidual follicles.

The histologic and immunophenotypic findings con-firmed the diagnosis of extranodal marginal zone B-celllymphoma, arising in a background of chronic sclerosingsialadenitis.

DISCUSSION

Extranodal marginal zone B-cell lymphoma is nowrecognized as a distinct clinicopathologic entity.6 Histo-logically, the tumors are composed of neoplastic mar-ginal zone cells, also termed centrocyte-like cells ormonocytoid B cells, with round to irregular nuclei, andabundant pale cytoplasm, and variable numbers of plas-macytoid and/or plasma cells. Reactive follicles are usu-ally present, with monoclonal B cells occupying the mar-ginal zone and/or the interfollicular region. Occasionally,follicles contain an excess of marginal zone cells (follic-ular colonization). In epithelial tissues the marginalzone cells typically invade the adjacent mucosal orglandular epithelium, forming lymphoepithelial lesions.

FIG. 3. Monomorphous sheet of monocytoid B cells withround to irregular nuclei and abundant pale cytoplasm(hematoxylin and eosin, original magnification ×400).

FIG. 5. Small salivary duct with adjacent fibrosis andplasmacytic infiltration with scattered neutrophils.

FIG. 2. There is a prominent lymphoid infiltrate withoutlymphoepithelial lesions (hematoxylin and eosin, originalmagnification ×100).

FIG. 4. Large salivary duct containing mucin and inflam-matory debris, with surrounding fibrosis and chronic in-flammatory infiltration (sialodochitis).

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On immunohistochemical staining the tumor cells ex-press B-cell-associated antigens, are surface immuno-globulin (M > G or A) positive, are immunoglobulin Dnegative, exhibit monotypic light chain restriction, andare CD5 and CD10 negative. Plasma cells are often dis-tributed in distinct subepithelial or interfollicular zones,and are monoclonal in up to 40% of cases.6

MALT is the result of proliferation and differentiationof B lymphocytes in association with mucosal epithe-lium. In normal cases MALT is found predominately inWaldeyer’s ring and in ileal Peyer’s patches. Organizedconcentrated lymphoid tissue is not found in normal gas-tric mucosa or in normal salivary or thyroid gland tissue,although these tissues are common sites of MALT lym-phoma. In these cases the lymphoma is typically pre-ceded by a proliferation of MALT in a background ofchronic inflammation or an autoimmune process.14,15

Salivary MALT lymphomas are typically associatedwith an inflammatory process variously known as benignlymphoepithelial lesion, Mikulicz’s disease, and myoep-ithelial sialadenitis.9,12,13 Recently, the term lymphoepi-thelial sialadenitis (LESA) has been proposed as a moreaccurate reflection of the biologic nature of this process.5

LESA is found in virtually all patients with Sjogren’ssyndrome but may occur without Sjogren’s syndrome.2,3

It is associated with lymphoid infiltration of salivarygland tissue, producing atrophy and destruction of theacini. Lymphoepithelial lesions form as the result of atro-phy of the columnar ductal epithelium and proliferation ofbasal epithelial cells, associated with intraepithelial infiltra-tion of marginal zone B cells. These are analogous to thelymphoepithelial lesions seen in gastrointestinal cases ofextranodal marginal zone lymphoma. Reactive lymphoidfollicles typically surround the altered ducts, and aggre-gates of marginal zone B cells may be present aroundaffected ducts as well as around reactive follicles. Acutesialodochitis and fibrosis are not typical features ofLESA. The development of frank lymphoma is charac-terized by broad sheets of marginal zone cells outside offollicles and lymphoepithelial lesions.7

Kuttner,1 in 1896, described a series of patients with aunilateral, hard, tumor-like mass of the submandibulargland, which histologically showed features of chronicsclerosing sialadenitis. Because of its tumor-like presen-tation, this lesion has come to be known as “Kuttner’stumor.” Patients are more often male than female, with amedian age of 44 years. They present with a rock-hard,unilateral mass, which is often painless but may be as-sociated with pain on food ingestion. It is not associatedwith Sjogren’s syndrome or other autoimmune disease,and progression to lymphoma has not been reported.

The histologic features of chronic sclerosing sialad-enitis in most cases are different from those of LESA.The ducts are typically dilated and filled with inspissatedsecretions; sialoliths are found in 50–80% of the cases.

Prominent periductal fibrosis, associated with a lympho-plasmacytic infiltrate, may contain reactive follicles andgerminal centers. Lobular fibrosis and acinar atrophy areseen in advanced cases. Although the lymphoid infiltratemay be prominent, the presence of marked fibrosis andrelative lack of epithelial proliferation, in most cases,distinguish Kuttner’s tumor from typical LESA.1,4 Theremay be morphologic overlap in some cases, and lympho-epithelial lesions have been described in Kuttner’stumor.

The pathogenesis of chronic sclerosing sialadenitis ispostulated to be duct obstruction by abnormal secretions,termed “obstructive electrolyte sialadenitis.” However,the presence of reactive follicles in most cases indicatesan immunologic component to the process. Thus, it ispossible that the setting of chronic immune stimulationresulting from mechanical duct obstruction and releaseof antigens from parenchymal cells provided a substratefor the development of MALT lymphoma in this case.

The absence of lymphoepithelial lesions may reflectbiologic differences in the epithelium of the subman-dibular gland duct epithelium compared with the parotid,which is the site of most salivary MALT lymphomas.Even in Sjogren’s syndrome, the lesions of the subman-dibular and intraoral salivary glands often show less epi-theliotropism than those in the parotid. Furthermore,MALT lymphomas of other epithelial sites (lacrimalgland, skin, breast) often lack prominent lymphoepithe-lial lesions. It is also possible that the nature of the im-mune stimulus in Kuttner’s tumor is different from thatusually present in Sjogren’s syndrome/LESA, resultingin neoplastic cells with different epitheliotropism or thatthe damage to the ducts by the obstructive sialadenitismay alter the relationship of the neoplastic marginal zonecells to the epithelium. �

FIG. 6. Diffuse positive staining with antibody toB-lineage antigen CD20 (original magnification ×200).

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REFERENCES

1. Seifert G, Miehlke A, Haubrich J, et al. Chronic sclerosing sialad-enitis (Kuttner tumor) of the submandibular gland. Diseases of theSalivary Glands: Pathology–Diagnosis–Treatment–FacialNerve Surgery. Stell PM, translator. Berlin, Germany: Georg ThiemeVerlag, 1986:140–6.

2. DiGiuseppe JA, Corio RL, Westra WH. Lymphoid infiltrates of thesalivary glands: pathology, biology and clinical significance. CurrOpin Oncol 1996;8:232–7.

3. Diss TC, Wotherspoon AC, Speight P, et al. B-cell monoclonality,Epstein Barr virus and t(14;18) in myoepithelial sialadenitis andlow-grade B-cell MALT lymphoma of the parotid gland. Am JSurg Pathol 1995;19:531–6.

4. Ellis GL, Auclair PL. Atlas of Tumor Pathology: Tumors of theSalivary Glands, 3rd series, fascicle 17. Washington, DC: ArmedForces Institute of Pathology, 1996:387–402, 419–21.

5. Harris NL. Lymphoid proliferations of the salivary glands. Am JClin Pathol 1999;111(suppl 1):2094–2103.

6. Harris NL, Jaffe ES, Stein H, et al. A revised European-Americanclassification of lymphoid neoplasms: a proposal from the Inter-national Lymphoma Study Group. Blood 1994;84:1361–92.

7. Hsi ED, Zukerberg LR, Schnitzer B, et al. Development of extra-salivary gland lymphoma in myoepithelial sialadenitis. Mod Pathol1995;8:817–24.

8. Hsu S, Raine L, Fanger H. Use of avidin-biotin-peroxidase com-

plex (ABC) in immunoperoxidase techniques: a comparison be-tween ABC and unlabeled antibody (PAP) procedures. J Histo-chem Cytochem 1981;29:577–80.

9. Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma ofsalivary glands and its relationship to myoepithelial sialadenitis.Hum Pathol 1988;19:766–76.

10. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue: a distinctive type of B-cell lymphoma.Cancer 1983;52:1410–6.

11. Preffer FI. Flow cytometry. In: Colvin RB, Bhan AK, McCluskeyRT, eds. Diagnostic Immunopathology, 2nd ed. New York: RavenPress, 1993:725–49.

12. Quintana PG, Kapadia SB, Bahler DW, et al. Salivary gland lym-phoid infiltrates associated with lymphoepithelial lesions: a clini-copathologic, immunophenotypic, and genotypic study. HumPathol 1997;28:850–61.

13. Schmid U, Helbron D, Lennert K. Development of malignant lym-phoma in myoepithelial sialadenitis (Sjogren’s syndrome). Vir-chows Arch A 1982;395:11–43.

14. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of pri-mary low-grade B-cell gastric lymphoma of mucosa-associatedlymphoid tissue type after eradication of Helicobacter pylori. Lan-cet 1993;342:575–7.

15. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacterpylori-associated gastritis and primary B-cell gastric lymphoma.Lancet 1991;338:1175–6.

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