Epstein–Barr virus positive gastric adenocarcinoma with systemic EBV reactivation in a patient with persistently active systemic lupus erythematosus

Introduction

Patients with systemic lupus erythematosus (SLE) have an increased risk of developing specific types of malignancies, with the most data showing an increased incidence of hematological cancers and lower susceptibility for hormonally-based cancers [1, 2]. Dysregulated immune response in lupus patients may cause inadequate control of infections, including those with oncogenic viruses, such as Epstein–Barr Virus (EBV). EBV infection has a high prevalence of over 90% and is associated with nasopharyngeal carcinomas and certain types of lymphoma (Burkitt’s, non-Hodgkin’s and diffuse large B cell lymphoma) [3], [4], [5]. However, 8–16% of gastric carcinomas (GC) have also been associated with EBV infection [4, 6, 7]. Interestingly, the possible role of autoimmunity in developing GC has been suspected for a long time. Although most data related to the association between GC and pernicious anemia, two recent studies demonstrated an increased risk of GC in several other autoimmune diseases, including SLE [8, 9]. Reported standardized incidence rate (SIR) of GC in SLE patients was 1.48 [9].

EBV infection is also implicated in the development of autoimmunity and SLE pathogenesis. Studies have shown increased viral load, elevated anti-EBV antibodies and impaired cellular anti-viral response in lupus patients. Inadequate control of EBV infection leads to frequent viral reactivations [10]. Additionally, EBV may contribute to the development of SLE, as elevated serological markers of EBV reactivation are associated with an increased risk of transitioning to SLE in previously unaffected lupus relatives [11]. Chronic inflammation and immunosuppressive drugs may also contribute to carcinogenesis in lupus patients. However, not all mechanisms have been elucidated. It is assumed that carcinomas develop in a specific interaction between the host, the virus, and lupus itself. We report a case of EBV-positive gastric adenocarcinoma in a patient with persistently active SLE and diagnosed EBV reactivation.

Case presentation

A 52-years old female SLE patient presented in 2021 with a 10-months history of severe fatigue, purpuric lesions, rash, alopecia, polyarthritis, mucosal ulcerations, and weight loss. Diagnosis of SLE was made 10 years ago, and since then, she has experienced several flares with mucocutaneous and musculoskeletal manifestations, successfully treated with antimalarials (used continuously for the treatment of SLE with dose escalation during the active disease) and short courses of corticosteroids. Four years ago, she was evaluated by a hematologist due to the presence of monoclonal IgG kappa in the serum protein detected by immunoelectrophoresis. In addition, bone marrow analysis was performed, resulting in the diagnosis of monoclonal gammopathy of undetermined significance.

Many small hematomas on the trunk and upper and lower extremities were observed on physical examination. In addition, non-palpable purpuric lesions on her lower legs and an erythematous maculopapular rash on her hands and neckline were noted. The patient had moderate polyarthritis (tender and swollen, mostly metacarpophalangeal, interphalangeal, and proximal interphalangeal joints on both hands) and several ulcerations on the buccal mucosa. Laboratory analysis showed moderate elevation of C-reactive protein and estimated sedimentation rate, macrocytic anemia (Hgb 99 g/L, MCV 101.4 fl), and thrombocytopenia (65 × 10⁹/L). The immunological analysis demonstrated the presence of antinuclear antibodies (ANA) with a titer >1:640. A large speckled nuclear pattern was shown using an indirect immunofluorescence assay on Hep2 cells. Other tested autoantibodies were absent (anti-dsDNA, anti-Sm, anti-cardiolipin IgG and IgM antibodies, rheumatoid factor). However, the previous analysis showed positive anti-Sm antibodies. The levels of C4 and C3 were low. During the work-up, the patient was evaluated for several viral infections. Serology testing showed elevation of anti-EBV, anti-CMV, and anti-HSV1/2 IgM antibodies with the presence of IgG antibodies against all mentioned viruses except HSV2. PCR testing from blood samples did not show any detectable EBV, CMV or HSVs DNA (Table 1).

There were no enlarged lymph nodes or splenomegaly on the computed tomography scan of the chest and abdomen. Due to active SLE, corticosteroid therapy (prednisone 30 mg) was escalated, and azathioprine was introduced. As no satisfactory treatment response was achieved and considering the progression of thrombocytopenia (min 43 × 10⁹/L), pulse methylprednisolone therapy (4 g total dose) was given. Although other SLE manifestations gradually resolved over the next six months, significant thrombocytopenia and monoclonal IgG kappa persisted, prompting the performance of sternal puncture. Finally, morphological and immunohistochemical analysis of a bone marrow specimen showed infiltration with metastatic deposits of adenocarcinoma and monoclonal plasmacytosis (10%). Esophagogastroduodenoscopy was performed, visualizing multiple prepyloric erosions of the gastric mucosa, which were biopsied. Pathohistological analysis revealed infiltration of gastric mucosa with poorly differentiated adenocarcinoma, characterized by a “signet ring” type and small anaplastic cells (Figure 1). Helicobacter pylori’s negative status was determined microscopically after histochemical Giemsa staining. Repeated virological analysis after 6 months showed persistence of anti-CMV, anti-HSV1 and anti-HSV2 IgM antibodies without IgG seroconversion of anti-HSV2 antibodies. The detection of viral DNAs in blood samples was all negative again.

Figure 1:

Pathohistological analysis of the gastric mucosa specimen showing sheets of neoplastic, signet-ring type cells, in lamina propria. H&E (magnification 40×).

Additionally, we tested paraffin-embedded tissue of gastric mucosa for the presence of viral DNA. While CMV DNA and HSVs DNA were expectedly absent, this tissue was positive for the presence of EBV DNA. The patient was directed to the oncologist for further evaluation, confirming gastric adenocarcinoma diagnosis. However, the patient refused oncological treatment and was lost for further follow-up. According to the oncology patient database, our patient died 4 months later.

Discussion

We present a case of a patient with persistently active SLE and serologically diagnosed active EBV infection who developed EBV-positive gastric adenocarcinoma. SLE is an autoimmune inflammatory, multisystem disease with a relapsing-remitting course in most patients. About 15% of patients have persistently active disease, which may present a significant therapeutical challenge [12]. Several studies showed alterations in the control of EBV infection in SLE patients, leading to frequent viral reactivations [13, 14]. Moreover, some authors linked EBV reactivation and lupus disease activity [15]. A higher risk for cancers associated with viral infections in lupus patients was reported in a recent study, whereby cancers not associated with viral infections were decreased [1]. This finding suggests viruses’ causal role, although SLE and immunosuppressive drugs could be contributing factors.

Gastric cancers are the fifth most common globally, representing 5.6% of all new cancer cases [16]. Pathogenesis of GCs is a complex and long-term process that occurs over decades. H. pylori infection has been identified as a major risk factor for the development of GC [17]. Association with EBV infection was first noticed for gastric epithelial lymphatic carcinomas, while subsequent studies also demonstrated an association with gastric adenocarcinomas [18], [19], [20]. Further studies confirmed the role of EBV infection in developing GC and suggested that EBV-positive GC may be a distinct disease entity [21]. Although the precise mechanism behind this process has not been fully elucidated, it has been shown that EBV-encoded nuclear antigen 1 (EBNA1), a viral transcription factor necessary for EBV maintenance, is also a significant oncogenic factor [18]. Frequent viral replications may induce genomic instability in infected cells, facilitating malignant transformation. Other products encoded by EBV genes may enable immune system evasion and survival of premalignant epithelial cells. Inflammatory milieu due to infection and SLE could also contribute to the malignant process [3].

Our patient had persistently active SLE, which was therapeutically challenging, responding only partially to intensive immunosuppressive treatment. Although all clinical manifestations in our patient were typical for lupus, thrombocytopenia could also be considered a paraneoplastic manifestation due to the metastatic bone marrow infiltration. Due to the persistence of thrombocytopenia, monoclonal IgG kappa, and serological signs of active herpesvirus infections, we initially suspected hematological diseases. However, there was a possibility of non-specific synthesis of antibodies due to continuously positive IgM antibodies in initial and repeated samples for all viruses except EBV. This suggested that only EBV serological markers were indicative of actual viral activity. Finally, further PCR testing of biopsied gastric adenocarcinoma revealed the presence of EBV DNA in carcinoma tissue. We speculate that in our patient (with a family history negative for gastric cancer), a complex interplay between active SLE and intensive immunosuppressive therapy led to the impossibility of controlling viral replication, making a potential basis for a virus-associated cell transformation. Based on all the above facts, we recommend particular caution when evaluating herpesvirus reactivation, particularly EBV, towards hematological malignancies and GCs in SLE patients. Early recognition of possible malignant disease significantly improves the outcome. Unfortunately, for the patient described in this Case report, no further follow-up data are available. The patient refused any oncological treatment and died 4 months after diagnosing adenocarcinoma.

Conclusions

In conclusion, the non-specific elevation of serial serological markers of viral infections could indicate the underlying immune disturbance. On the other hand, our case suggests persistent EBV replication as a possible link between SLE and the development of gastric carcinoma. Although the pathogenic mechanism is unclear, reactivations of EBV in our patient could be considered a probable trigger for lupus flares, with consequent chronic autoimmune inflammation additionally contributing to carcinogenesis. Assessment of the herpesvirus infection status in patients with lupus flare, especially those which are therapeutically challenging, may help in the early identification of patients requiring a more detailed approach and extended evaluation for possible malignant disease.