T CELL LYMPHOMA OCCURRING IN SJOGREN’S SYNDROME

WILLIAM S. W I L K E . RAYMOND R. TUBBS, RONALD M. BUKOWSKI. THOMAS E. CURRIE, LEONARD H . CALABRESE. ROBERT A. WEISS, RICHAKD. A. SAVAGE, and BRUCE A. S E B E K

This case report documents the occurrence of malignant lymphoma with T cell characteristics in a patient with histologic evidence of Sjogren’s syndrome (SS) diagnosed by parotid biopsy. The case is unusual because recent reports suggest that lymphomas occur- ring in this clinical setting should have B cell rather than T cell characteristics and are derived from B lymphocytes. We offer no hypothesis relating SS to the T cell lymphoma, but simply report that this phenomenon has occurred.

Lymphoma and pseudolymphoma are known to occur in primary and secondary Sjogren’s syndrome. In 1963 and 1964 Bunim and Tala1 (1,2) dcscribed 3 cases of malignant lymphoma and 1 case of Walden- strom’s macroglobulinemia which developed in pa- tients with Sjogren’s syndrome. A subsequent report supported the occurrence of lymphoma with SS (3) . Three recent papers emphasize the B lymphocyte features and origin of lymphoma occurring in Sjo- gren’s syndrome (4-6).

We present a case in which a lymphoma with T cell characteristics developed in a patient with Sjo- gren’s syndrome.’

Case report. A 63-year-old white woman was first evaluated at the Cleveland Clinic in 1975. Her complaint at that visit was bilateral parotid gland swelling which had been present for 1 year. Although

From the Cleveland Clinic Foundation, Cleveland. Ohio. William S. Wilke, MD: Kaymond K. Tubbs. DO; Ronald M.

Bukowski, MD; Thomas E. Currie. DO; Leonard H. Calabrese. DO; Robert A. Weiss. MD: Richard A. Savage. MI>: Bruce A. Sebek. MD.

Addre5s reprint requests to William S. Wilke. MD. Clevc- land Clinic Foundation. 9500 Euclid Avenue, Cleveland, OH 44106.

Submitted for publication December 13, 1982; accepted in revised form March 30. 1984.

she denied having dry eyes or conjunctivitis, she did complain of a dry mouth and mild arthralgias of the knees and hands. A physical examination had normal findings except for bilateral swelling of the parotid glands. N o serologic determinations were obtained. Sialograms were performed and showed diffuse, “BB- sized” calculi, but were not diagnostic of Sjogren’s syndrome. A biopsy of the left parotid gland showed a benign lymphoepithelial lesion in the salivary gland compatible with Mikulicz’s disease (Figure 1).

From 1975 to 1979 she experienced intermittent swelling of the parotid glands which was treated symptomatically with low doses of corticosteroids. She received no other treatment.

On June 1 , 1979 she presented with a new complaint of progressive, non-painful enlargement of the left parotid gland which had been present for 9 months. She denied having dry eyes, conjunctivitis, or arthritis. The left parotid gland was examined and found to be hard, nodular, and nontender on palpation. The right parotid gland was only minimally enlarged. A 0.5-cm, enlarged, left supraclavicular node was felt. Upon examination of the axillae. enlarged nodes of approximately 1 cm were found bilaterally. The rest of the physical examination results were unremarkable and hospitalization was arranged.

The admission chest radiograph showed changes interpreted as bilateral hilar adenopathy. Per- tinent laboratory data included negative or normal values for antibody to extractable nuclear antigens SS- A and SS-B, rheumatoid factor, Clq binding assay, and Westergren sedimentation rate. The antinuclear factor test result was positive at a dilution of 1:20.

A biopsy specimen was obtained from the left parotid gland and interpreted as a benign lymphoepith-

Arthritis and Rheumatism, Vol. 27, No. 8 (August 1984)

952 BRIEF REPORTS

Figure 1. Photomicrograph, parotid biopsy specimen. Typical fea- tures of benign lymphoopithelial lesion. including the pre5ence of myoepithelial islands, arc identified (hcniatoxylin-cosin stained. orig- inal magnification x 64).

elial lesion. The left supraclavicular node was then biopsied (Figure 2). A full description of the histopath- ologic changes appears in the Results section. Lym- phangiograms showed markedly enlarged, foamy lymph nodes throughout the abdomen. The liver biop- sy and bone marrow biopsy specimens were normal.

The patient was treated with a standard proto- col for immunoblastic lymphoma consisting of cyclo- phosphamide, adriamycin, prednisone. and levamisole followed by daily chlorambucil. As a result of this treatment, her disease remained in clinical remission from June 1979 to July 1980, at which time hilar adenopathy reappeared. The treatment protocol was repeated over the next year with less successful re- sults. In October of 1981 she died of progressive disease and pneumonitis. A postmortem examination was not performed.

Materials and methods. The fresh tissue submit- ted was evaluated by a detailed protocol developed for lymphoproliferative disorders. Thin sections of tissue were fixed in zinc-substituted Zenker’s solution and buffered formaldehyde, paragin-embedded, and stained with hematoxylin and eosin, methyl green- pyronine, and periodic acid-Schi8 stains. Segments of tissue 1 .O x 1 .O ml from involved areas in the lymph node were fixed in buffered gluteraldehyde, post-fixed in osmium tetroxide, and dehydrated in graded alco- hols. Spurr-embedded, I p sections were stained with toluidine bluc, and thin sections stained with lead citrate and uranyl acetate, and examined under a Phillips EM400T electron microscope. Fresh-touch

preparations were made from the cut surface of the lymph node and evaluated cytochemically for the expression of acid phosphatase, alpha naphthyl lactate esterase using Garnet bacille Calmette-Guerin and hexazotized pararosaniline as couplers, periodic acid- Schiff, Sudan black. oil red 0. and methyl green- pyronine. Touch preparations were also Wright’s stained.

A 1 .O x I .O-cm segment of fresh tissue was also processed for cell suspension studies using previously described techniques ( 7 ) . All rosette preparations were spun in a cytocentrifuge, Wright’s stained, and exarn- ined for the presence of surface-marked expression by neoplastic subpopulations. Tissue segments I .O x I .O cm were snap-frozen in isopentane at - 150°C in liquid nitrogen, and cryostat frozen sections were air-dried, acetone-fixed for 10 minutes, and evaluated for the expression of immunoglobulin light chains using the direct immunohistochemical technique (8) and the expression of lymphocyte-differentiation antigens us- ing monocloqal antibodies by indirect immunohisto- chemistry (9) (Dako, Santa Barbara. CA). All cryostat frozen section immunohistochemistry (CFSIH) prepa- rations were counterstained with methyl green-pyro- nine and hematoxylin.

Results. The lymph node was diffusely effaced by a polymorphous mononuclear cell infiltrate. Some areas within the lymph node demonstrated residual follicles. The infiltrate in these areas predominantly involved the T cell-dependent paracortex and interfol-

Figure 2. Photomicrograph, supraclavicular lymph node biopsy spccimen. The atypical lymphoid infiltratc consists of cytologically atypical lymphocytes and larger immunoblastic cells (hcniatoiylin- eosin stained, original magnification x 160).

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licular zone. Clusters of epithelioid histiocytes were present throughout the lymph node parenchyma. The proliferating cells consisted of cytologically atypical lymphoid cells and large immunoblastic cells with extensive nuclear lobulation and clefting (Figure 2). These immunoblastic cells were diffusely and intense- ly pyroninophilic. Electron microscopy confirmed these observations, and in addition, the larger immun- oblastic-like cells were shown to have extensively lobulated nuclei with numerous polyribosomes.

Cell suspension analysis disclosed 83 3% sheep red blood cell (E) spontaneous rosettes. A cytospin Wright’s stained preparation demonstrated E-rosetting nucleolated cells (Figure 3). Individual surface immu- noglobulins in cell suspension were as follows: kappa 6.8%, lambda 5%, IgG 5.9%, IgA 3%, IgM 4.9%, IgD 3%. CFSIH disclosed no immunoglobulin light chains within the neoplastic cellular populations. The nucleo- lated immunoblastic cells and the smaller lymphoid cells were positive with monoclonal antibodies specif- ic for peripheral circulating T cells (OKT3) (Figure 4) and cells forming sheep red blood cell rosettes (TI 1).

Clusters of immunoblastic cells which were positive with the monoclonal antibodies having speci- ficity for T cells were also identified in the infiltrate. The complete immunologic phenotype of the neoplasm was kappa-lambda-T3 +TI 1 + T4-T8 -T9+T 10- B 1 - , similar to expanded phenotypes of some other report- ed large cell lymphomas (10). Cytochemical analysis confirmed T cell differentiation, with granular perinu- clear acid phosphatase in a significant number of lymphoid cells (1 1). Histiocytes were prominent with

Figure 3. Photomicrograph, cytospin preparation made from cell suspension prepared from the lymph node biopsy specimen. Both small and larger immunoblastic cells from spontaneous nonimmune E-rosettes with sheep red blood cells (Wright’s stain, original magnification x 640).

Figure 4. Photomicrograph, cryostat frozen section immunohisto- chemical stain for monoclonal antibody with specificity for peripher- al T cells. Both small and large cells demonstrate the reaction product identified, confirming the presence of the T lymphocyte antigen (original magnification x 400).

the expected diffuse acid phosphatase and nonspecific esterase activity.

These observations were considered corrobora- tive of the light microscopic diagnosis of T cell lym- phoma.

Discussion. Sjogren’s syndrome is characterized histologically by mononuclear cellular infiltration of the salivary and lacrimal glands, and serologically by the presence of many tissue component antibodies. In 1964 Tala1 and Bunim documented the clinical course of 58 patients with Sjogren’s syndrome (2). During a 4-year followup period, 3 of these patients developed reticulum cell sarcomas and a fourth developed Wal- denstrom’s macroglobulinemia. The association be- tween Sjogren’s syndrome and lymphoma, Walden- s t rom’s macroglobulinemia, and lymphoid hyperactivity has subsequently been reported in a number of case studies and series (12-15).

Recognition of this relationship has led to the concept that the lymphoepithelial lesion characteristic of Sjogren’s syndrome represents an early stage in a spectrum of lymphoproliferation from benign to malig- nant disease. The spectrum includes SS characterized by mononuclear cellular infiltration of the lacrimal, salivary and other exocrine glands, pseudolymphoma in which immature, but nonmalignant appearing mono- nuclear cells infiltrate extraglandular tissue, and a final step which occurs in a small percentage of patients with the disease, in which the lymphocytes undergo transformation into lymphoproliferative malignancies with varying histologic appearances.

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Explanations for the increased risk of lympho- proliferative disorders in Sjogren’s syndrome have included exposure to ionizing radiation, previous therapy with cytotoxic agents, intense antigenic stimu- lation of the immune system, and/or genetic predispo; sition (12,161. The exact mechanism remains under speculation.

Zulman and associates studied 9 patients with Sjogren’s syndrome who developed malignant lym- phoma (51, In 6 of 9 patients the cellular characteristics of these lymphomas suggested B cell origin. Their report demonstrated a clinical phenomenon that has been proposed by other investigators from the study of the cellular morphology of neoplasms that occur sub- sequent to Sjogren’s syndrome, i.e., that these neo- plasms are derived from B lymphocytes (12).

In this paper we report a different circum- stance, the case of a patient with Sjogren’s syndrome in which an immunoblastic sarcoma with properties suggesting origin from the T lymphocyte has occurred. We th ink this report might be important because previous studies have demQnstrated that lymphomas in these patients were usually B cell in character. Although functional abnormalities of T lymphocytes have been reported in Sjogren’s syndrome ( I7,18), to our knowledge, T cell lymphomas have not been described in this clinical setting.

The criteria which we used to arrive at the diagnosis of SS deserve some comment. Our patient lacked signs and symptoms of keratoconjunctivitis sicca (KCS) and serologic findings of autoantibodies, but did complain of xerostomia and showed histologic findings on the original parotid biopsy consistent with Mikulicz’s disease (19). The absence of symptoms of KCS in SS is not without precedence. Ichikawa (20) has reported 6 cases of SS in which minor salivary histopathology was consistent with a diagnosis, al- though the patients lacked symptoms of the sicca complex. Although autoantibodies are frequently found in patients with SS, (hey are not universally present (21). In our patient, autoantibody tests were not requested at the initial visit and only ordered at the time of the diagnosis of lymphoma. Qualitative and quantitative changes in serologic autoantibodies have been demonstrated at the time of malignant transfor- mation (22), which may explain their absence in our patient.

We believe the histopathologic findings at biop- sy are the most crucial elements in the diagnosis. To argue that this case is simply one of Mikulicz’s disease may be to argue that this is a case of SS. Morgan (23)

reviewed the literature in 1954 and addressed this issue. He suggested that Mikulicz’s disease be classi- fied as “a less highly developed variant of a larger symptom complex, Sjogren’s syndrome.” If the his- tologic changes seen in the parotid gland of our patient were encountered in labial salivary glands, the changes would be consistent with a focus score of 3-4 (24). diagnostic of Sjbgren’s syndrome. Pittsley et al (25) presented data which show that biopsy evidence was far superior to clinical signs and symptoms in the diagnosis of SS and suggested a new definition of SS based on biopsy findings. We conclude that the pres- ence of dry mouth and the characteristic histologic changes seen in the parotid gland of our patient are sufficient criteria for the diagnosis of SS.

We cannot propose a cause and effect relation- ship between SS and T cell lymphoma at present. Whatever the explanation of this phenomenon, this case report again documents the occurrence of lym- phoma in patients with primary SS, reaffirms the need for regular and close followup of patients with this connective tissue disease, and further emphasizes the role of immunologic markers in the precise classifica- tion of lymphomas occurring in SS.

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2. T‘alal N, Bunim JJ: The development of malignant lymphoma in the course of Sjogren’s syndrome. Am J Med 26:529-540, 1964

3. Hornbaker JH, Foster EA, Williams GS, Davis JS: Sjagren’s syndrome and nodular reticulum cell sarcoma. Arch Intern Med 118:449-452, 1966

4. Faquet GB. Webb H H , Agee JF , Ricks WB, Sharbaugh AH: lmmunologically diagnosed malignancy in Sjo- gren’s pseudolymphoma. Am J Med 65:424-429, 1978

5 . Zulman J , Jaffe R, Talal N : Evidence that malignant lymphoma of Sjogren’s syndrome is a monoclonal B-cell neoplasm. N Engl J Med 299:1215-1220, 1978

6. Diaz-Jouanen E, Ruiz-Arguclles GJ, Vega-Ortiz JM. Villareal G , Alarcon-Segovia D: From benign polyclonal to malignant monoclonal lymphoproliferation in a pa- tient with primary Sjogren’s syndrome. Arthritis Rheum 24:850-853, 1981

7. Tubbs RR, Valenzuela K, Savage RA, Deodhar SD: The nature of surface immunoglobulin in pure monocytic (M5) leukemia. Am J Clin Pathol 72:614-617. 1979

8. Tubbs RR, Sheibani K , Weiss RA, Sebek BA: Immuno-

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histochemistry of fresh lymphoid tissue using the direct immunoperoxidase procedure. Am J Clin Path01 72: 172- 174, 1981

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1 1 . Savage RA, Valenzuela R, Hoffman GC: Acid phospha- tase staining patterns an indicator of T-celi acute leuke- mia. Am J Clin Pathol 76:760-764, 1981

12. Anderson LG, Talal N: The spectrum of benign to malignant lymphoproliferative Sjogren’s Syndrome. Clin Exp Immunol 10:199-21 I . 1972

13. Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R. Kimberly RP, Budman DR, Costa J , Decker J L , Chused TM: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89:888-892, 1978

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19. Godwin JT: Benign lymphaepithelial lesion of the parot- id gland (adenolymphoma, chronic inflammation, lym- phoepithelioma, lymphocytic tumor, Mikulicz’s dis- ease): report of eleven cases. Cancer 5: 1089-1 103, 1952

20. Ichikawa Y , Takaya M, Saitoh H: Characterization of sicca symptoms in patients with Sjogren’s syndrome and reports of six cases lacking subjective sicca features (“subclinical Sjogren’s syndrome”). Tokai J Exp Clin Med 6:229-240, 1981

21. Martinez-Lavin M, Vaughan JH, Tan EM: Autoanti- bodies and the spectrum of Sjogren’s syndrome. Ann Intern Med 91:185-190, 1979

22. Anderson LG, Talal N: The spectrum of benign to malignant lymbhoproliferation in Sjogren’s syndrome. Clin Exp Immunol 9: 199-21 I , 1971

23. Morgan WS: l h e protiable systemic nature of Mikulicz’s disease and its relation to Sjogren’s syndrome. N Engl J Med 251:5-10, 1954

24. Greenspan JS, Daniels TE, Talal N , Sylvester RA: The histopattiology of Sjogren’s syndrome in labial salivary gland biopsies. Oral Surg 37:217-229, 1974

25. Pittsley RA, Daniels T E , Fye K H , Michalski JP, Tala1 N: Autoimmune exocrinopathy: a new definition of Sjogren’s syndrome confirmed by labial salivary gland biopsy (abstract). Arthritis Rheum 21 :584, 1978

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