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FROM BENIGN POLYCLONAL TO MALIGNANT MONOCLONAL LYMPHOPROLIFERATION IN A PATIENT WITH PRIMARY SJ УGREN'S SYNDROME.

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850
BRIEF REPORT
FROM BENIGN POLYCLONAL TO MALIGNANT MONOCLONAL
LYMPHOPROLIFERATION IN A PATIENT WITH PRIMARY
SJOGREN’S SYNDROME
EFRAfN DfAZ-JOUANEN, GUILLERMO J. RUfZ-ARGUELLES, J o s e MANUEL VEGA-ORTfZ,
GUILLERMO VILLAREAL, and DONATO ALARC6N-SEGOVIA
Sjogren’s syndrome (SS) may occur without apparent associated disease (primary Sjogren’s syndrome)
(1,2) or be secondary to other autoimmune diseases,
most notably rheumatoid arthritis (3), systemic lupus
erythematosus (4), scleroderma (9,and liver diseases
(6).
Primary SS may have extraglandular manifestations and seems to be a distinct entity with genetic
markers (7). Lymphoproliferation may occur in patients
with SS and may vary from the benign lymphoepithelial
lesion of SS proper to pseudolymphoma or immunoblastic lymphadenopathy to overt lymphoid malignancy
(8-12). Although most of these stages of lymphoproliferation have been recorded in different subjects, there
have been instances in which one turned into the other
in the same patient (13), suggesting that the spectrum of
lymphoproliferation may occur sequentially in each individual.
No patient studied sequentially through the
three stages has been heretofore reported. We present
here such a patient. Also, all patients previously recorded who developed monoclonal B cell neoplasms
were found to have IgM kappa (14,15), whereas our pa-
From the Department of Immunology and Rheumatology
and the Division of Internal Medicine, Instituto Nacional de la Nutricibn, Mtxico, D.F., Mtxico.
Efrain Diaz-Jouanen, MD: Associate Professor; Guillermo J.
Ruiz-Argiielles, MD: Resident in Hematology; Jose Manuel Vega-Ortiz, MD: Fellow in Rheumatology; Guillermo Villareal, MD: Resident in Medicine; Donato Alarcbn-Segovia, MD: Professor and
Chairman, Department of Immunology and Rheumatology.
Address reprint requests to Efrain Diaz-Jouanen, MD, Department of Immunology and Rheumatology, Instituto Nacional de la
Nutricih, Mtxico 22, D.F., Mtxico.
Submitted for publication July 18, 1980; accepted in revised
form December 1. 1980.
Arthritis and Rheumatism, Vol. 24, No. 6 (June 1981)
tient was found to have intracytoplasmic monoclonal
IgM lambda of the neoplastic B cells.
CASE REPORT
This 85-year-old woman noticed xerostomia 4
years before developing nodular enlargement of the
right parotid gland. Laboratory workup revealed only a
false positive VDRL test. A biopsy showed a benign
lymphoepithelial lesion compatible with Sjogren’s syndrome (Figure 1A).
The parotid gland continued to enlarge and became hard with a small nodule on its lower pole. A scintillation scan revealed decreased and irregular uptake
by the right parotid gland as compared to the left. A
right parotid sialogram showed dilatation of the major
salivary ducts and diffuse punctate sialectasia. Schirmer
and Rose Bengal tests were positive. Erythrocyte sedimentation rate was 38 mm/hour (Wintrobe). Blood hemoglobin was 13.2 gm/100 ml. Rheumatoid factor gave
a titer of 1:163,840 (Singer Plotz); antinuclear antibodies and LE cells were negative. Results of protein
electrophoresis, direct antiglobulin test, and bone marrow aspiration were negative or normal. Serum immunoglobulin levels were also normal (IgG 1062, IgA 165,
IgM 163 mg/100 ml).
The patient was diagnosed as having primary SS
and symptomatic medication was prescribed. Six
months later the right parotid gland had enlarged further, measuring 8 x 10 cm, and was excised together
with the small node on its lower pole. Microscopically,
the parotid gland again showed a benign lymphoepithelial infiltration, but the lymph node showed a typical
immunoblastic lymphadenopathy (Figure 1B). Electron
microscopic studies confirmed the immunoblastic nature of the infiltrating cells (Figure 2).
85 1
BRIEF REPORTS
A
B
Figure 1. A, Biopsy showing a benign lymphoepithelial lesion compatible with Sjogren’ssyndrome. B, Microscopic examination of the lymph node
showed a typical immunoblastic lymphadenopathy (magnification, left to right x 100, X 200, x 320).
The patient returned 2 years later complaining of
general malaise, weight loss, and right cervical and supraclavicular lymph node enlargement forming a large
tumor on the right aspect of the neck that extended to
the right supraclavicular region and right axillae. There
was no splenomegaly. Blood hemoglobin was 9.8 gm/
100 ml, the sedimentation rate was 17 mm/hour (Wintrobe), and although her IgG and IgA levels were similar to the previous testing, IgM levels had fallen to 56
mg/100 ml and the rheumatoid factor titer to 1:10,240.
Direct antiglobulin test continued to be negative, and
results of a bone marrow aspiration were again normal.
Biopsy of the cervical tumor showed an immunoblastic
sarcoma (Figure 3A and B). Electron microscopy confirmed the immunoblastic nature of the infiltrating cells
(Figure 4). Cyclophosphamide and prednisone were
prescribed, but the patient died 1 month later. Autopsy
was not performed.
Special studies. Indirect immunofluorescence
staining of all 4 paraffin embedded tissues were performed by the method of Bums et a1 (14), and stained
decalcified bone marrow sections of multiple myeloma
patients with known monoclonal proteins were used as
controls. Negative controls were obtained by avoiding
the addition of the first antibody in order to evaluate
nonspecific staining caused by the second antibody. We
also carried out studies on the patient’s tissues and those
of controls using peroxidase labeled antibody by the
method of Taylor and Bums (15). Findings with both
methods were identical and are shown in Table 1.
DISCUSSION
Figure 2. Electron microscopic studies confirmed the immunoblastic
nature of the infiltrating cells in the lymph node (magnification X
6,400).
It has been considered that the lymphoproliferative disorders which appear in S S patients may represent stages of the B cell response to sustained antigenic
stimulus (16). The course of the lymphoproliferative lesion may evolve from a benign and polyclonal lesion to
an intermediate or premalignant polyclonal lesion, and
finally to an overt monoclonal malignancy of B cells.
Until now, all S S patients studied who have developed monoclonal B cell neoplasms were found to
have IgM kappa (16,17). This permitted the consideration of possible genetic implications, although from
the small number of cases studied, results were in-
BRIEF REPORTS
852
B
A
Figure 3. Biopsy of the cervical tumor showed an immunoblastic sarcoma (A, magnification X 300. B, magnification
conclusive (16). The monoclonal malignancy in our SS
patient was IgM lambda. This indicates that either the
IgM kappa neoplasms of the first SS cases occurred by
mere chance or SS patients who develop monoclonal B
cell malignancies have mainly, but not exclusively, IgM
kappa tumors.
Immunoblastic sarcoma is a recently reclassified
lymphoid neoplasia that has been found to be associated with autoimmune diseases in approximately 30%
of the cases (18,19). Among these is at least one instance
of SS in each of the two major series of immunoblastic
sarcomata reported (1 8,19). It is possible that tumors as-
X
640).
sociated with SS described as reticulum cell sarcoma,
histiocytic lymphoma, and poorly differentiated lymphocytic lymphoma could now be classified as immunoblastic sarcomata, according to the classification of lymphoid malignancy of Lukes and Collins (20).
It appears that patients with SS who have recurrent parotid swelling, splenomegaly, and lymphadenopathy are at high risk of developing lymphoid malignancy (9). Our patient did not have splenomegaly when
we saw her, but had recurrent parotid swelling and
lymphadenopathy. She also had a drop in rheumatoid
factor titer and IgM levels upon developing the sarcoma, both of which have also been considered forerunners of lymphoid malignancy in SS (21). Change from
polyclonal to monoclonal intracytoplasmic immunoTable 1. Intracytoplasmic immunoglobulin staining of 4
consecutive tissue specimens in a patient with primary Sjogren’s
syndrome
Intracytoplasmic
immunoglobulin*
Heavy
chain
Specimen
(date)
Parotid gland
(4/29/1976)
Parotid gland
(2/25/ 1977)
Lymph node
(2/25/1977)
Lymph node
(2/ 16/1979)
Figure 4. Electron microscopy confirmed the immunoblastic nature of
the infiltrating cells in the cervical tumor (magnification X 6,400).
Histologic
diagnosis
Benign lymphoepithelial
lesion
Benign lymphoepithelial
lesion
Angioimmunoblastic
lymphadenopathy
Immunoblastic
sarcoma
P
Y
a
K
h
+ + + + +
+ + + + +
+ t + + + +
+
-
* By immunofluorescence and peroxidase staining.
t Intense fluorescent staining.
Light
chain
-
-
+t
BRIEF REPORTS
globulins from one biopsy to the next in SS patients has
previously been recorded (13,16,17); however, to our
knowledge, no study has been recorded of all three
stages of lymphoproliferation in an SS patient.
Patients with Sjogren’s syndrome have not been
found to have decreased suppressor T cell function that
might explain the development of malignancies (22).
However, they have been found to have decreased response in autologous mixed lymphocyte reaction (23);
we have also found these subjects to have decreased autologous rosette forming T cells (24), a subpopulation of
T cells shown to be the responding cell in this reaction
(25). It appears that either primary or secondary SS patients have polyclonal B cell activation that, if and when
prolonged, may become monoclonal and malignant.
ACKNOWLEDGMENTS
We thank Dr. Irmgard Montfort and Dr. Ruy PerezTamayo from the Department of Pathology and Experimental
Pathology for their help in these studies.
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