Lymphoma is more common in patients with autoimmune disease, especially those with primary Sjögren’s syndrome
. The relative risk of lymphomas in primary Sjögren’s syndrome was found to be 16–44 times higher than in the general population in 2 large case series studies
[12, 13]. Patients with primary Sjögren’s syndrome have risk factors for progression to lymphoma, such as persistent enlarged parotid glands, splenomegaly, lympadenopathy, palpable purpura, leg ulcers, peripheral nerve involvement, anemia, neutropenia, low-grade fever, low levels of C3 and C4, and mixed cryoglobulinemia
. In this case, risk factors for malignant lymphoma included low levels of C3, anemia, and multiple small lymphadenopathies detected by abdominal CT.
EBV-positive DLBCL is characterized by EBV-positive clonal B cell lymphoproliferation that occurs in patients aged over 50 years without any immunodeficiency or prior lymphoma. It is a recently defined subgroup of DLBCL in the 2008 World Health Organization classification of lymphoid neoplasm
. The pathogenetic role of the EBV in NHL is circumstantial; however, EBV is able to drive cellular proliferation as a potential carcinogen
. In this case, we speculated that this virus assisted in the progression of the malignant lymphoma. Patients with age-related EBV-positive DLBCL are older, have more aggressive clinical features, are rarer (9%)
, and have poorer overall survival, as compared with EBV-negative DLBCL patients. Lymphoma complicated with Sjögren’s syndrome is usually localized in extranodal areas such as salivary glands, the gastrointestinal tract, the thyroid gland, lung, kidney, or orbit
; however, common sites of extranodal involvement in EBV-positive DLBCL are skin, lung, pleural effusion, stomach, and tonsil
. Concurrent primary small-bowel involvement and perforation is a very rare clinical manifestation in patients with EBV-positive DLBCL
, especially in those with accompanying Sjögren’s syndrome.
Interestingly in our case, it is possible that secondary membranous glomerulonephritis was related to primary Sjögren’s syndrome or malignant lymphoma. Clinically significant renal disease is rare in primary Sjögren’s syndrome, but latent involvement is relatively common. Renal abnormalities have been reported at varying rates, from 3% to 67%, in patients with primary Sjögren’s syndrome, according to different studies
[20–24]. Nevertheless, Kaufman et al.
 analyzed 180 case reports of renal involvement in primary Sjögren’s syndrome in a review of the literature; in 89 cases, patients underwent renal biopsies that revealed interstitial nephritis in 49 cases (55%), glomerulonephritis in 33 cases (37%), and both interstitial nephritis and glomerulonephritis in 7 cases (8%). However, renal biopsies been performed in only half of the reported cases; therefore, the true prevalence of membranous glomerulonephritis remains unknown. There have been only 3 previous cases reported of membranous glomerulonephritis and primary Sjögren’s syndrome, to our knowledge
[7, 25]. From a different point of view, patients with NHL manifest a great variety of glomerular lesions, and several case reports on glomerulonephritis associated with NHL have been published
[26–30]. In addition, even if membranoproliferative glomerulonephritis was more common, membranous glomerulonephritis has been reported in 5 of 47 cases (approximately 10%) among glomerulopathies associated with NHL, in a study by Ronco et al.
. Furthermore, the onset of proteinuria occurs with the development of lymphoma, or may slightly precede the clinical detection of lymphoma by several months. There have been several case reports where nephritic syndrome was detected prior to the diagnosis of NHL
[32–36]. In our case, the patient presented with nephritic syndrome more than 3 months prior to the diagnosis of NHL. In this context, we can tentatively propose the possibility that the secondary membranous glomerulonephritis was related to DLBCL in this case.
Serological abnormalities including those of rheumatoid factor, cryoglobulins, ANA, anti-Ro, and anti-La are common in secondary glomerulonephritis with Sjögren’s syndrome; however, serum complement levels are generally normal unless the patient has associated systemic lupus erythematosus. Goules et al. reported the immunological profile of 10 patients with glomerulonephritis in Sjögren’s syndrome; 2 patients demonstrated low levels of C3, 5 patients had decreased C4 serum levels, and there was 1 patient who had low C3 and normal C4 serum levels. These findings are consistent with those of our case, in which the patient had low C3 and normal C4 levels. The underlying mechanisms are still not completely understood, however, there are varying forms of complement abnormalities in renal involvement accompanying Sjögern’s syndrome. Therefore, further study is needed to better understand complement abnormalities.
Although only a few case reports have described treatment with corticosteroid alone or in combination with cyclophosphamide in primary Sjögren’s syndrome with renal disease, such treatment has generally led to good clinical outcomes
. In 1 case report
, Sjögren’s syndrome complicated with membranous glomerulonephritis resulting from malignant lymphoma resolved after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and predinisolone) and radiation. Nevertheless, our patient could not be treated with immunosuppressive therapy or chemotherapy because of her poor general condition. We anticipate that an adequate treatment would be helpful for improvement of the disease.
In conclusion, to the best of our knowledge, we report the first case of primary Sjögren’s syndrome associated with EBV-positive DLBCL and membranous glomerulonephritis. If patients with primary Sjögren’s syndrome show concurrent membranous glomerulonephritis, they should be carefully examined for hidden malignancy, including EBV-positive DLBCL, because of the possibility of malignancy-associated membranous glomerulonephritis.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.