Challenges in Diagnosing Non-Nasal Natural Killer/T-Cell Lymphoma Mimicking Behçet Disease: A Case Report

Introduction

Natural killer/T-cell lymphoma (NKTL), like other non-Hodgkin lymphomas, develops from the transformation of natural killer cells or cytotoxic T-cells. NKTL is relatively common in Asia and, to a lesser extent, in Latin America, but rare in Europe and North America [1]. Most NKTL onset is located in the nasal area; only 20% of NKTLs originate at non-nasal sites, typically involving the gastrointestinal tract, skin, or genital mucosa [2]. These atypical NKTL presentations manifest as repeated ulcerations mimicking Behçet disease, alongside systemic symptoms including unexplained abdominal pain, intestinal obstruction, gastrointestinal hemorrhage, and fever of unknown origin. This substantial clinical overlap creates significant diagnostic ambiguity until histological confirmation.

In this case, we report a 45-year-old patient who experienced the onset of oral and genital ulcers and was subsequently misdiagnosed with Behçet disease. After 5 months of immunomodulatory therapy, the disease became more severe, with severe gastrointestinal hemorrhage alongside shock. Through pathological analysis of hemostatic surgical specimens, the diagnosis of NKTL was ultimately confirmed.

Case Report

A 45-year-old male patient of Han ethnicity was first admitted to the Ear, Nose, and Throat Department in September 4, 2017, suffering from repeated oral ulcers, pain, dysphagia, and external genital ulcers for 1 month. His previous medical history was irrelevant. The patient’s initial laboratory evaluation showed: C-reactive protein (CRP) of 16.1 mg/L, erythrocyte sedimentation rate (ESR) of 58 mm/h, and routine blood parameters, liver and kidney function tests, and coagulation profile within normal limits. Further investigations showed negative results for anti-nuclear antibody, anti-double-stranded DNA antibody, anti-single-stranded DNA (ssDNA) antibody, anti-SSA/Ro antibody, anti-SSB/La antibody, anti-Scl-70 antibody, anti-Jo-1 antibody, anti-centromere antibody, anti-U1RNP/Sm antibody, anti-Ro52 antibody, anti-smooth muscle antibody, and anti-neutrophil cytoplasm antibody. The patient was initially diagnosed with Behçet disease, and his ulcers improved significantly after treatment with dexamethasone 10 mg for 3 days. On September 7, he was discharged.

After discharge, the patient was regularly taking methylprednisolone (6 tablets daily) at home. One month after achieving a stable condition, the dose of methylprednisolone was steadily decreased to 3 tablets per day.

On December 19, 2017, the patient was re-admitted to our hospital with recurrent oral and genital ulcers for 4 months, and with relapse and exacerbation over the past month. Physical examination revealed an approximately 2 cm2 ulcer on the left side of the mouth (Figure 1A), ruddiness in both palms, like liver palms (Figure 1B), and multiple, variably-sized white ulcerative lesions on the genitalia. Despite sustained immunomodulation during admission, therapeutic efficacy remained suboptimal. Subsequent evaluation demonstrated absence of pathergy and a normal ophthalmologic examination. We advised the patient to undergo comprehensive genetic testing for further diagnostic clarification. However, the patient deferred testing due to financial and personal considerations.

The patient developed a high fever (temperature >39°C) on the following day. All routine blood parameters were within normal ranges except for lymphocytopenia (0.71×109/L). The laboratory findings revealed elevated CRP and ESR, with normal procalcitonin and gamma glutamyltransferase test results. There was no significant growth in bacterial/fungal blood cultures, and routine tumor marker screening and autoimmunity-related antibody levels were normal. Notably, however, Epstein-Barr virus (EBV) serology testing was positive for both Epstein-Barr nuclear antigen IgG and Epstein-Barr viral capsid antigen IgG. Bone marrow aspirate smear cytology revealed hypocellular marrow with a decreased myeloid-to-erythroid ratio, coarse granularity in the cytoplasm of some granulocytic cells, and anisocytosis of mature erythrocytes. Chest computed tomography (CT) revealed multiple ground-glass opacities in the right lung. No improvement in fever was observed after empirical antibiotic therapy.

On January 2, 2018, the patient developed a massive gastrointestinal hemorrhage. Active bleeding persisted after 19 days of conservative treatment. On January 21, 2018, he accepted a laparotomy exploration, which showed dilation and distention of the ileocecal colon. The bleeding point was located in the ascending colon of the ileocecum (Figure 2). For hemostatic purposes, the surgeon performed resection of the ileocecal colon and terminal ileum. The result of pathological findings from the resected specimen revealed multiple superficial ulcers with granulation tissue hyperplasia; partial villous atrophy of small intestinal mucosa; and band-like proliferation of small lymphocytes in the submucosa, showing mild monotony and atypia. The pathological examination of the ileocecal ulcer showed positivity for CD3, CD20, CD79a, and BCL-2 (Figure 3A), confirming that this could be considered NKTL.

Subsequently, we also did pathological examinations of the oral ulcers, and found extensive infiltration of atypical lymphoid cells and plasma cells in the lamina propria, with evident epitheliotropism and angiotropism. Immunohistology analysis of the left hard palate ulcer revealed that the tumor cells were strongly positive for CD3 and positive for CD45RO, CD56, CD43, and TIA-1 (Figure 3B). In-situ hybridization showed positivity for Epstein-Barr-encoding RNA. Finally, NKTL was diagnosed based on pathological examination. However, the patient refused chemotherapy and died after 2 months.

Discussion

Behçet disease, first identified by the famous Turkish dermatologist Hulusi Behçet, is a systemic vasculitis characterized by recurrent oral and genital ulcers, skin lesions, and uveitis [3]. Although not fully understood, Behçet’s syndrome pathogenesis is due to a complex interaction between different causal pathways: diet and hygiene habits, bacterial and viral agents, microbiota and their products, genetics and epigenetics, and innate and adaptive immune system dysfunction [4]. Clinical manifestations of this disease include mucocutaneous involvement (recurrent oral and genital ulcers), articular involvement (asymmetric arthralgia), ocular involvement (uveitis), vascular involvement (vasculitic lesions and thrombosis), neurological involvement, and gastrointestinal involvement (terminal ileocecal ulcer with or without perforation or bleeding) [4]. The International Criteria for Behçet’s Disease (ICBD) [5] represent the most current guidelines for Behçet disease in clinical practice (Table 1).

In our case, although the pathergy test was negative, according to the ICBD standard, our patient, who suffered from repeated oral and genital ulcers, had a score of 4 points. The diagnosis of Behçet disease was ultimately established based on clinical manifestation, glucocorticoid responsiveness, and exclusion of alternative autoimmune disorders. Besides, the subsequent development of unexplained fever and gastrointestinal hemorrhage can be fully explained within the spectrum of Behçet disease. That was the root cause of the misdiagnosis.

NKTLs arise mainly from natural killer cells and occasionally cytotoxic T-cells, and are universally infected with EBV. In approximately 80% of NKTLs, the initially involved sites are the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, and upper aerodigestive tract. These lymphomas are collectively referred to as nasal-type NKTL. Approximately 10–20% of NKTLs develop in non-nasal sites, primarily the skin, testes, gastrointestinal tract, muscle, and salivary glands; these are collectively referred to as non-nasal NKTL [6]. In <5% of cases, the lymphomas are disseminated, with hepatosplenomegaly, lymphadenopathy, skin infiltration, and marrow involvement. Occasionally, a leukemia phase may also occur. These disseminated cases are clinically referred to as the aggressive natural killer cell lymphoma/leukemia subtype [7].

The hallmark clinical features of classic NKTL include nasal cavity lesions with adjacent organ invasion and associated EBV infection [8]. In the disease course of our patient, he presented with neither nasal congestion nor epistaxis. Coupled with the absence of active EBV infection and no significant findings in the bone marrow biopsy, this made it difficult to establish the diagnosis of NKTL. Meanwhile, atypical cutaneous and gastrointestinal manifestations of NKTL can closely mimic Behçet disease, creating significant diagnostic confusion. However, no matter how closely the clinical presentations may resemble each other, these 2 diseases exhibit distinct pathological features. Both nasal and non-nasal cases are observed, possessing similar histopathologic features. Lymphoma cells are medium to large, admixed with a polymorphic infiltrate of small lymphocytes, plasma cells, histiocytes, and eosinophils, which are typically positive for cytoplasmic CD3, CD56, cytotoxic markers, and EBV-encoded small RNA on in situ hybridization [9]. Behçet disease mainly shows vasculitic lesions with a marked neutrophilic infiltrate often accompanied by mononuclear infiltration, endothelial cell swelling, and fibrinoid necrosis [10].

Therefore, when encountering Behçet disease refractory to immunomodulatory therapy, a high index of suspicion for non-nasal-type NKTL should be maintained, with prompt EBV testing and histopathological confirmation. In summary, it is necessary to establish a systematic differential diagnostic protocol between the 2 diseases (Table 2).

Conclusions

The coexistence of mucocutaneous lesions with gastrointestinal manifestations should not be readily attributed to Behçet’s disease, and comprehensive diagnostic evaluation through multisite mucosal biopsies and bone marrow aspiration/biopsy is imperative. This approach enables differentiation between malignant processes and autoimmune etiologies, thereby reducing diagnostic ambiguity and preventing complications associated with the use of inappropriate immunosuppressive therapies.