Diffuse large B cell lymphoma (DLBCL) is one of the commonest types of lymphoma. Occasionally, hemophagocytic syndrome (HPS) could be an initial manifestation due to tumor factors and Epstein-Barr virus (EBV) infection[4]. Comparatively, Guillain-Barre Syndrome (GBS) is rarely diagnosed before lymphoma[5]. The incidence of GBS in non-Hodgkin’s lymphoma is very low. Almost all studies on lymphoma-related GBS are case reports. Non-Hodgkin’s lymphoma combined with GBS is more common than Hodgkin’s lymphoma. We reported a case in which GBS and HPS were simultaneously confirmed heralding the diagnosis of lymphoma. According to the case reports, lymphoma types of these cases combined with GBS included DLBCL, Burkitt lymphoma, splenic marginal zone lymphoma and peripheral T-cell lymphoma[1-2][6-7]. Only about 10 cases of DLBCL have been reported to date[1,8-18].
GBS is a type of immune-mediated acute inflammatory peripheral neuropathy, manifested as multiple nerve roots and peripheral nerve damages. The main pathological feature is extensive inflammatory demyelination of peripheral nerves. It is a type of motor neuropathy that could progress rapidly and typically recover. The two commonest types of GBS are acute inflammatory demyelinating polyneuropathies (AIDP) and acute motor axonal neuropathy (AMAN). Other types of GBS including acute motor‐sensory axonal neuropathy (AMSAN), Miller‐Fisher syndrome (MFS), acute pan-autonomic neuropathy and acute sensory neuropathy are relatively rare[17]. Although most cases are curable, some patients may progress rapidly with irreversible nerve damage. The case reported herein had typical peripheral neuropathy symptoms before DLBCL was diagnosed. GBS type was considered as AMSAN. GBS-related gangliosides were tested and GD IgM, GD IgM3, GT1a IgM were found to be positive, which seemed to be atypical ganglioside. Gangliosides were positive in two out of five cases of DLBCL, with GBS, GM2 IgM, GM1 IgM and GD1b IgM positive[9,14]. Pathogenesis of GBS remains unclear. Molecular simulation is considered as the main mechanism[19]. Most studies believe that infection, neurotoxicity caused by chemical agents, infiltration of the peripheral nervous system and nerve root cells by lymphoma, vasculitis involving nervous system caused by tumor, lymphoma cells blocking small blood vessels and leading to ischemia, tumor-related protein deposition, and tumor-related bioactive substances may affect their immune system[12,20-21]. Kiyat Atamer A. et al. explained that various factors lead to the activation of T cells, production of antibodies against protein antigens and finally result in damages to the peripheral nerves[22]. In GBS animal models, Th1 and Th17 cytokines are up-regulated in the acute phase, and Th2 cytokines increase in the recovery phase, suggesting that T cell immune regulation disorders play a vital role in the pathogenesis of GBS[26]. Given that the patients present with concomitant GBS and HPS, and HPS is also a clinical syndrome presenting with T cell activation, we hypothesized that tumor-related immune activation may be the main pathogenesis for this patient.
Literature review indicated that DLBCL patients combined with GBS were typically elderly, more than 80% of patients were male and over 60 years old (summarized in Table 1). Neurophysiological examinations showed that both upper and lower extremities could be involved, and both motor and sensory systems could be damaged. GBS could occur before lymphoma is diagnosed. Tumor factors are mainly responsible for this type of GBS. GBS could also occur after lymphoma is diagnosed or treated. Infections or neurotoxicity due to chemotherapeutic agents account for GBS. In these reports, immunoglobulin pulse therapy for GBS widely used glucocorticoids alone or in combination with plasmapheresis. Chemotherapy protocols of CHOP±R and R-DA-EPOCH were most often chosen. Occasionally, radiation therapy was administered. Outcomes were usually unsatisfactory in patients who developed GBS before lymphoma diagnosis and only immunoglobulin pulse therapy was used. GBS could be cured in most patients who developed GBS after chemotherapy. Our patient was immediately treated with immunoglobulin pulse therapy, etoposide, and dexamethasone when GBS and HPS were confirmed. Neurological symptoms slowly recovered and disappeared after R-CHOP chemotherapy. Either GBS or HPS is an emergency event and needs rapid management. Our clinical experience suggests that it is critical to quickly identify the underlying disease and administer directed therapy. We reviewed 12 cases of DLBCL combined with GBS (Table 1), five out of 12 (42.7%) cases suffered from GBS before, and six out of 12 cases suffered from GBS after DLBCL diagnosis. Almost all patients were treated with immunoglobulin, and some were also treated with plasmapheresis or glucocorticoids. All (100%) patients who developed GBS after DLBCL diagnosis, recovered. Comparatively, among patients who were diagnosed with GBS after DLBCL, one out of five patients did not benefit from immunoglobulin therapy and three out of five patients relapsed after GBS treatments. Consistent with literature reports, our patient did not initially respond to immunoglobulin, and his neurological symptoms relieved slowly and finally disappeared after R-CHOP chemotherapy. Therefore, we hypothesized that lymphoma may be the primary cause of GBS, and chemotherapy for lymphoma may be the key to improvement of the patient’s symptoms.
HPS is a rare clinical syndrome with high inflammatory state caused by abnormally activated macrophages and cytotoxic T-cells, resulting in cytokine storms and organ damages. HPS is divided into primary and secondary, and lymphoma is one of the most important secondary factors leading to HPS[23]. EB virus is an important driver of HPS pathogenesis. Lymphoma-associated hemophagocytic syndrome (LAHS), is a clinical process that progresses rapidly and is often life-threatening with poor prognosis[24]. Delayed diagnosis of the underlying diseases may delay life-saving treatments for LAHS. Consequently, it is not enough to only treat HPS without treating aggressive lymphoma. Initially, patients may respond to HPS treatments. However, without further managements, they may relapse more quickly if the underlying lymphoma is not found[23]. As reported, the mean time for lymphoma diagnosis is 22 days[25]. The long diagnosis time (>20 days) is a negative factor of poor prognosis for LAHS patients[25]. Our patient was finally diagnosed as EBV positive DLBCL combined with GBS and HPS in 16 days, which was lower than previously reported[25]. Timely treatments may be crucial to achieve good results.
GBS and HPS heralding the diagnosis EBV DLBCL is clinically rare. Herein, we reported a rare case and shared our clinical experience. Traditional therapies may be effective in patients who develop GBS before lymphoma diagnosis. Fast diagnosis and timely treatment of DLBCL are crucial.