ARTICLE
Sjögren's syndrome, both primary and secondary to rheumatoid arthritis
or to other connective tissue diseases, is a chronic, inflammatory, autoimmune
process characterized by a lymphocytic infiltration of lacrimal and salivary
gland parenchyma producing keratoconjunctivitis sicca and xerostomia.
A polyclonal B and T lymphocyte and plasma cell infiltrate is associated
with proliferation of ductal epithelium which produces epimyoepithelial
islands.
The histopathological picture is one of a benign lymphoepithelial lesion
known as myoepithelial sialadenitis (MESA) which may lead to the development
of lymphoma.
In patients with Sjögren's syndrome, the rate of malignant lymphoid
proliferation and the risk of lymphoma development is considerably greater
than in a comparable normal population.
We report a low grade, non-Hodgkin's lymphoma of the skin and oral mucosa
in a patient with Sjögren's syndrome.
Case report
An 81-year-old woman was referred to our department because of purpuric
lesions on both her lower limbs. The patient was referred from the Division
of Internal Medicine where she was being treated for cardiovascular and
respiratory symptoms.
A diagnosis of Sjögren's syndrome related to rheumatoid arthritis
had been made 15 years previously, in accordance with the latest European
classification criteria.
In fact, the woman had a long history of xerostomia, xerophthalmia and
arthralgia in the hands and wrists, and Raynaud's phenomenon.
On clinical examination there was evidence of a bilateral parotid and
minor submaxillary salivary gland enlargement and palpable cervical lymphadenopathy
that caused a marked hard swelling of the cheeks, neck and lower lips
(Fig. 1). Infiltrated
plaques and firm nodules were present at these sites (Fig.
2).
The patient reported that these lesions had
first appeared 1 year before and had gradually enlarged. Moreover, there
was a very marked hepatosplenomegaly.
Laboratory data showed an increased erythrocyte sedimentation rate (ESR),
leukocytopenia, thrombocytopenia, a polyclonal hypergammaglobulinemia
with a high IgM count (3,517 mg/dl) and a marked reduction of complement
factors related to connective tissue disorders.
On the basis of clinical and laboratory data we took an incisional biopsy
from the skin of the lower lip.
Histopathological examination showed a massive nodular infiltrate of
small lymphocytes and plasma cells invading the whole thickness of the
dermis and the hypodermis as far as the muscle (Figs.
3 and 4).
The infiltrate also contained rare, large immunoblastic cells, some of
which were multinucleated (Fig.
5).
Immunocytochemical studies confirmed the B cell phenotype of the small,
irregularly nucleated lymphocytes and suggested the diagnosis of a diffuse,
low grade, non-Hodgkin's lymphoma (NHL) consistent with a MALT origin,
acquired as a result of autoimmune sialadenitis.
The patient died of acute myocardial infarction 2 months after the diagnosis.
Discussion
Sjögren's syndrome is an autoimmune disease characterized by chronic
lymphocytic infiltration of glandular and sometimes extraglandular tissues
without progression to neoplasm in most cases. However, like other chronic
inflammatory conditions, it may occasionally evolve into malignant lymphoproliferative
disease.
This possible progression was first recognized in 1963 by Bunim and
Talal who described three cases of malignant lymphoma and one case of
Waldenström's macroglobulinemia among 58 patients affected by sicca
syndrome [1-2]. Subsequently, many other reports confirmed the suspicion
of an association between Sjögren's syndrome and several lymphoproliferative
disorders belonging to the spectrum ranging from prelymphomas to morphologically
and clinically recognizable malignant lymphomas, most frequently involving
mucosa-associated lymphoid tissue (MALT) [3-10]. Mucosa-associated lymphoid
tissue (MALT) consists of a collection of specialized lymphoid cells found
in the mucosa and ducts of a variety of organs, including the gastrointestinal
tract and lung, along with some endocrine and exocrine glands. The salivary
glands do not normally contain MALT, but its acquisition may occur as
a secondary process resulting from autoimmune inflammatory disorders.
Sjögren's syndrome usually leads to the
histological features of MESA. The lymphocytic infiltrate of MESA is thought
to form a substrate for the possible development of MALT-derived salivary
gland lymphoma [4, 6, 8]. While salivary gland lymphomas represent only
1.7% of all reported salivary neoplasms which are themselves uncommon,
constituting 0.3% of all malignancies [7], they arise approximately 44
times more frequently in patients with Sjögren's syndrome than in
a comparable normal population. The risk of lymphoma in the sicca syndrome
population is approximately 6.4 cases per 1,000 per year [11].
Peculiar clinical features of Sjögren's syndrome, including parotid
swelling, lymphadenopathy and splenomegaly have been indicated as increased
risk factors of lymphoid malignancy. When these conditions are present,
as in our case, it is necessary to perform an incisional biopsy to detect
a possible malignant evolution. According to Isaacson and Wright, lymphomas
derived from MALT appear to have a greater tendency to remain localised
than low grade B cell lymphomas of nodal origin [5, 8, 10].
The literature shows lack of uniformity in the treatment of MALT-derived,
low grade non-Hodgkin's lymphoma of salivary glands. Falzon and Isaacson
suggest a local eradication of the disease by radiotherapy since extrasalivary
lymphoma may occur up to 10 years after initial diagnosis in untreated
cases [12]. Other authors, however, state that chemotherapy and radiotherapy
do not always prevent progression to disseminated lymphoma and could cause
serious local and systemic side effects. Portlock and Rosenberg reported
that survival was not improved by treatment of low grade, non-Hodgkin's
lymphoma and concluded that careful observation without initiation of
therapy is an appropriate management option [8, 13].
CONCLUSION
Acknowledgements
Investigation supported by the University of Bologna, funds for selected
research topics.
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