Postgraduate Medical Journal (1989) 65, 323 - 326

Lymphoplasmacytoid lymphoma elaborating lambda chainparaprotein with amyloid deposition in Sjogren's syndrome

A.W.G. Savage, D.S. Shareef, E.J. Maher, M.H. Bennett and D.J.B. Thomas

Departments ofMedicine, Radiotherapy and Histopathology, Mount Vernon Hospital, Northwood, MiddlesexHAJ2RN, UK.

Summary: A woman presented with painful enlargement of her parotid and submandibular glands.She was shown to have the previously unreported combination of idiopathic thrombocytopenic purpura,Sjpgren's syndrome, Hashimoto's disease, and myasthenia gravis. Parotid gland biopsy and bone marrowexamination showed the presence ofa rare lymphoplasmacytoid lymphoma. There was amyloid depositioqkin the parotid glands, gums and on muscle biopsy. Immunohistochemical staining ofthe parotid lymphomaand amyloid was monotypic for lambda light chains, and there was also a lambda chain paraprotein. It isfelt that the lymphoplasmacytic lymphoma was responsible for the light chain amyloidosis.

Introduction

Sjogren's syndrome is a multisystem disease that oftenoccurs with connective tissue disorders.'"2 It may alsobe associated with auto-immune thyroid disease andmyasthenia gravis.3 It is well known that thyroiddisease can complicate idiopathic thrombocytopenicpurpura (ITP) and more recently myasthenia gravishas been reported in a patient with chronic ITP.4However the case we describe appears to be the firstreport of a patient who developed ITP, auto-immunethyroid disease, Sj6gren's syndrome, and myastheniagravis. This patient then re-presented with a rareparotid lymphoma associated with light chain amy-loidosis.

Case report

A woman presented in 1967 at the age of 39 withidiopathic thrombocytopenic purpura which was suc-cessfully treated by splenectomy. In 1976 Sj6gren'ssyndrome was diagnosed after she developed dry eyesand a dry mouth. During the same year she underwenta partial thyroidectomy for a large goitre, histology ofwhich showed Hashimoto's disease. In 1981 thepatient developed diplopia followed by systemic weak-ness. A positive edrophonium test supported thediagnosis ofmyasthenia gravis and she responded wellto oral prednisolone and pyridostigmine therapy.

In 1986 the patient noticed a painful increase in thesize of her parotid and submandibular glands(Figure 1), and complained ofprofound weakness and

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Figure I The patient with marked enlargement of theparotid and salivary glands.

D The Fellowship of Postgraduate Medicine, 1989

Correspondence: D.J.B. Thomas, M.D., M.R.C.P. (UK)Accepted: 1 November 1988

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weight loss. Physical examination revealed that shewas emaciated with marked enlargement of hersalivary glands. There was no hepatomegaly or lym-phadenopathy. Rectal and jejunal biopsies were car-ried out to exclude a gastro-intestinal cause for weightloss. They were considered normal at the time and onreview later. In 1987 her weakness persisted and shewas investigated further.

InvestigationsSerum IgA level 16.1 g/l (normal range 1-1.3 g/l).There was no evidence of immunoparesis. Lambdaparoprotein was present in serum and urine. ChestX-ray was normal. ANF positive titre 1/80, DNAdouble strand antibody negative. Renal and hepaticfunction were normal.

Parotid gland biopsy showed dense deposition ofamyloid (Figure 2). High power magnification of thesalivary gland tissue showed that it was markedlyatrophic and consisted mainly of ductules and a fairlydense lymphoplasmacytic infiltrate (Figure 3), sugges-ting a lymphoma. Immunohistochemical stainingshowed that the cytoplasm of these cells and much ofthe amyloid tissue stained monotypically for lambdalight chain (Figure 4), confirming the presence of amalignant lymphoma. Bone marrow examinationshowed early involvement by lymphoma. A gingivalbiopsy revealed amyloid deposition in submucosalvessels and quadriceps muscle biopsy also showedvessel amyloid.

Review of the original thyroid histology showedHashimoto's thyroiditis but also revealed excessiveplasma cell infiltrate, which stained monotypically for

lambda light chain. The sections from the splenectomyspecimen showed the nonspecific changes ofidiopathic thrombocytopenic purpura. The patientwas treated with chlorambucil 10 mg daily and localradiotherapy which resulted in a partial improvementin her symptoms.

Discussion

Patients with enlarged parotid glands due to Sjogren'ssyndrome run a high risk of developing a lymphoma,estimated to be 48;3 times higher than the expectedincidence.5 These lymphomas are usually non-Hodgkin's B cell types with lymphocytic lymphomasbeing the commonest salivary manifestation andWaldenstrom's macroglobulinaemia being the com-monest extrasalivary lymphoma. Lymphoplasmacyticlymphomas appear to be a very rare complication.

In Sj6gren's syndrome the lymphoma is probablypreceded by benign lymphoepithelial lesions (BLL),which consist of lymphocyte infiltrates with progres-sive destruction of glandular acini and disruption ofductal epithelium which may become metaplastic.Salivary gland BLL may occur in Sj6gren's syndrome,auto-immune thyroid disease, systemic lupuserythematosus, and a wide range of other auto-immune conditions. The more sinister nature of BLLwas discovered when the British Salivary GlandTumour Panel reviewed 36 cases and found that5 patients had developed salivary lymphomas and2 had extrasalivary gland lymphomas.6 Schmidt hasidentified a subgroup of BLL in patients withSjogren's syndrome which has a high incidence ofmalignant lymphoma development. These lesions are

Figure 2 Dense deposits of amyloid in atrophic salivary gland (x 15, haematoxylin and eosin).

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Figure 3 Atrophic salivary gland tissue with ductules and dense lymphoplasmacytic infiltrate (x 60, haematoxylinand eosin).

characterized by extensive confluent lymphoid pro-liferation and have been termed 'manifest malignantlymphoma'.7

It is not clear whether the high incidence of salivarygland lymphoma in Sj6gren's syndrome is increasedfurther by the presence of other auto-immune diseaseswhich are known to be associated with salivary BLL.This patient had auto-immune thyroid disease butthere was insufficient evidence to diagnose systemiclupus erythematosus. Myasthenia gravis is associatedwith salivary gland periductal lymphocyte infiltratesbut their significance in this condition is unclear.8

Parotid gland, muscle and gum biopsy showedamyloid infiltration in this patient which had not beenpresent in rectal and jejunal biopsies two years earlier.The onset ofamyloidosis seems to have occurred as theparotid gland enlarged presumably due to the lym-phoma infiltration. The lymphoplasmacytoid lym-phoma, and much of the amyloid stained immuno-histochemically for lambda light chain, and lambdalight chain paraprotein was found in the serum. Lightchains can be amyloidogenic, a phenomenon mostcommonly observed with lambda light chains as in thispatient.9 Review ofthe patient's thyroid histology with

Figure 4 Immunohistochemical staining for light chain showing monoclonal population of lymphoplasmacyticinfiltrate (x 24, immunoperoxidase method).

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immunostaining showed an excess of lambda lightchain containing plasma cells. This is compatible withstudies of serum immunoglobulins in patients withautoimmune disease which have shown that organ-specific auto-antibodies are predominantly of onelight chain type, either lambda, or kappa in a givenpatient. Thus plasma cells in patients with Graves'disease and tissue plasma cell infiltrates in patientswith Sjogren's syndrome demonstrate lambda chainbias.'0"12The evolution of lymphoma is probably slow but

early stages can be recognized by focal lymphocyteproliferations which demonstrate light chain biasimmunohistochemically. The process of neoplasticchange in B cells is not understood, but possiblemechanisms may include hyper-responsiveness of Bcells involved in auto-antibody production to growthfactors." An alternative hypothesis is that neoplasticchange may result from prolonged local anti-idiotypicresponse to pathogenic auto-antibody producing Bcells within the target auto-immune organ.'2

References

1. Bloch, K.J., Buchanan, W.W., Wohl, M.J. & Bunim, J.J.Sj6gren's syndrome. A clinical, pathological, andserological study of sixty two cases. Medicine 1965, 44:187-231.

2. Moutsopoulis, H.M., Chused, T.M., Mann, D.L. et al.Sj6gren's syndrome. Ann Intern Med 1980, 92: 212-226.

3. Downes, J.M., Greenwood, B.M. & Wray, S.H. Auto-immune aspects of myasthenia gravis. Q J Med 1966,137: 85-105.

4. Anderson, M.J., Woods, V.L., Tani, P., Lindstrom,J.M., Schmidt, D. & McMillan, R. Autoantibodies toplatelet glycoprotein IIb/Illa and to the acetylcholinereceptor in a patient with chronic idiopathic throm-bocytopenic purpura and myasthenia gravis. Ann InternMed 1984, 100: 829-831.

5. Kassan, S.S., Thomas, T.L., Moutsopoulis, H.M. et al.Increased risk of lymphoma in the sicca syndrome. AnnIntern Med 1978, 89: 888-892.

6. Gleeson, M.J., Cawson, R.A. & Bennett, M.H. Benignlymphoepithelial lesion: a less than benign disease. ClinOtolaryngol 1986, 11: 47-51.

7. Schmidt, U., Hebron, D. & Lennert, K. Development ofmalignant lymphoma in myoepithelial sialadenitis(Sjogren's syndrome). Virchows Arch 1982, 395: 11-43.

8. Lindahl, G., Karilefvert, A. & Hedfors, E. Periductallymphocytic infiltrates in salivary glands in myastheniagravis patients lacking Sj6rgren's syndrome. Clin ExpImmunol 1986, 66: 95- 102.

9. Cohen, A.S. & Connors, L.H. The pathology andbiochemistry of amyloidosis. J Pathol 1987, 151: 1-10.

10. Jasani, B., Smith, C. & Williams, E.D. Lambda chainrestriction in the diffuse thyroid lymphoid infiltrate inuntreated Graves' disease. J Endocrinol Invest 1986, 9(suppl 3): 101.

11. Theofilopoulos, A.N. & Dixon, F.J. Murine models ofsystemic lupus erythematosis. Adv Immunol 1985, 37:269-390.

12. Jasani, B. Immunohistologically definable light chainrestriction in autoimmune disease. J Pathol 1988, 154:1-5.

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