A case of Epstein–Barr virus-positive mucocutaneous ulcer of the hypopharynx: a mimicker of hypopharyngeal squamous cell carcinoma

Abstract

Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) is a new disease, described by the World Health Organization in 2017. It has been recognized as a specific type of immunodeficiency-associated lymphoproliferative disorder. Since patients with EBVMCU present with only cutaneous or mucosal ulcers, it is difficult to clinically distinguish them from carcinoma. A 72-year-old man, who took methotrexate (MTX) (12 mg/week) for rheumatoid arthritis, was referred to our hospital because endoscopy revealed an ulcerated mass in the left pyriform sinus, suggesting hypopharyngeal squamous cell carcinoma. Contrast-enhanced computed tomography and magnetic resonance imaging revealed an ill-defined mass in the left pyriform sinus without lymphadenopathy in the head and neck region. A biopsy of the ulcerative lesion in the hypopharynx was performed, and lymphoproliferative disease was suspected, based on the histopathological findings. Two weeks after MTX withdrawal, the lesions in the hypopharynx disappeared. The patient was diagnosed with EBVMCU, based on the clinical and histopathological findings. This is the first case report of EBVMCU of the hypopharynx. EBVMCU should be considered as a differential diagnosis in immunocompromised patients with hypopharyngeal mucosal ulcers without lymph node or organ involvement.

Introduction

Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described in 2010 as a distinct clinicopathological entity of EBV-positive lymphoproliferative disorders (EBVLPD) with a favorable prognosis [1]. EBVMCU was later described as a new disease concept by the World Health Organization in 2017, which recognized it as a specific type of immunodeficiency-associated lymphoproliferative disorder (LPD) [2]. EBVMCU is characterized by a unifocal mucosal or cutaneous ulcer, occurring in immunosuppressed patients with either age-related or iatrogenic immunosuppression [1, 2]. Since patients with EBVMCU present with only cutaneous or mucosal ulcers, it is difficult to clinically distinguish them from carcinoma. Almost all EBVMCU cases in the head and neck region are located in the oropharynx and oral cavity [2]. Meanwhile, hypopharyngeal lesions have not been reported. The imaging findings of EBVMCU have also not been reported. We present a case of EBVMCU, presenting with an ulcerative lesion in the hypopharynx, which was clinically difficult to differentiate from hypopharyngeal squamous cell carcinoma (SCC). Furthermore, we discuss the imaging characteristics of EBVMCU by comparing them with its pathological findings.

Case report

A 72-year-old man, who took methotrexate (MTX) (12 mg/week) for rheumatoid arthritis, consulted an otolaryngologist for pharyngeal pain lasting 1 month. Endoscopy revealed an ulcerated mass in the left pyriform sinus, and hypopharyngeal carcinoma was suspected. The patient was referred to our hospital for further investigation and treatment. Endoscopy and imaging studies (contrast-enhanced computed tomography [CT] and contrast-enhanced magnetic resonance imaging [MRI]) were performed at our hospital. Endoscopy revealed a mass with a sharply circumscribed mucosal ulcer in the left pyriform sinus (Fig. 1). Contrast-enhanced CT and MRI revealed an ill-defined mass in the left pyriform sinus (Fig. 2). The superficial and deep layers of the mass exhibited different characteristics. The superficial layer exhibited a mildly low signal intensity on T2 weighted images, high signal intensity on diffusion-weighted imaging, and low signal intensity on the apparent diffusion coefficient map, confirming diffusion restriction. CT and MRI showed poor contrast enhancement in the superficial layer of the mass. No enlarged lymph nodes were found in the head and neck region, and no other abnormal findings were found in the chest or abdomen. Blood (Fig. 3) tests revealed a white blood cell count of 6800/µL, C-reactive protein level of 0.62 mg/dL, lactate dehydrogenase level of 138 U/L, and interleukin (IL)-2R level of 345U/L, all within the normal limits. After biopsy of the lesion, additional tests for EBV antibody titers were performed; the EA-IgG titer was less than tenfold, and the Epstein–Barr nuclear antigen titer was tenfold, suggestive of an already infected patient. Based on the endoscopic and imaging findings, hypopharyngeal SCC was suspected, and a biopsy was performed. Histopathological examination of the left pyriform sinus lesion revealed large atypical cell infiltrates. On immunostaining, the lesion was Pax5( +), CD3(-), CD5(-), CD10(-), CD20( +), CD30( +), CD79a( +), EBER-ISH( +), and PD-L1(+ + +). Coagulative necrosis was observed in the pathological tissue. The histological findings suggested diffuse large B-cell lymphoma (DLBCL), but MTX-related lymphoproliferative disease (MTX-LPD) was suspected, based on the infiltration of various cell types (including inflammatory cells), EBER-ISH positivity, and the patient's history. Thus, the patient was diagnosed with EBVMCU, caused by MTX-induced immunosuppression, because systemic examinations, including CT and upper gastrointestinal endoscopy, did not reveal any lesions in the lymph nodes or other organs. MTX was withdrawn, and the patient was kept under observation without treatment. The left pyriform sinus ulcer disappeared after two weeks. Recurrence has not been observed for more than a year later, as at the time of this report.

Fig. 1.

Endoscopic image obtained during the patient’s first examination at our hospital. Endoscopy shows a mass with a sharply circumscribed mucosal ulcer in the left pyriform sinus (arrowhead)

Fig. 2.

Imaging findings of the lesion in the left pyriform sinus. a Computed tomography (CT) shows an ill-defined mass in the left pyriform sinus. Axial CT shows a homogeneous contrast enhancement in the deep part of the mass (white arrow). Contrast enhancement is poor on the superficial side of the mass (arrowhead). The boundary between the deep part of the mass and the superficial side is clear. b Magnetic resonance imaging (MRI) shows an ill-defined mass in the left pyriform sinus and the deep part of the mass shows moderately high signal intensity on T2 weighted images (WI; white arrow). The superficial side shows mild low signal intensity on T2WI (arrowhead). c Gadolinium contrast-enhanced fat-suppressed T1WI shows a homogeneous contrast enhancement in the deep part of the mass (white arrow), with a poor contrast enhancement on the superficial side of the mass (arrowhead). The border between the deep part and the superficial side is well defined. d The superficial side of the mass shows a high signal intensity on diffusion-weighted imaging, and a strong low signal intensity on the apparent diffusion coefficient (ADC) map, with diffusion restrictions (arrowhead). The deep part of the mass shows a high signal intensity on the ADC map and no apparent diffusion restriction (white arrow)

Fig. 3.

Pathological findings of an ulcer in the left pyriform sinus. a The lesion shows extensive coagulation necrosis (circle) on hematoxylin and eosin staining (× 40). b Atypical lymphoid cells of various sizes are present (arrows) and accompanying a dense polymorphic infiltration by variable inflammatory cells (× 400). c In situ hybridization staining shows atypical cells, positive for EBER (arrows) (× 400)

Discussion

EBVMCU was first described as an LPD by Dojcinov et al. in 2010. It was newly classified as a mature B-cell tumor by the World Health Organization classification in 2017 [1, 2]. EBVMCU affects immunocompromised patients, including those who have an advanced age, iatrogenic immunosuppression, or primary immune disorders. It is characterized by mucosal or cutaneous ulcers with sharp borders, and it is not usually accompanied by enlarged lymph nodes or organ involvement. Unlike the other EBV-associated LPDs, EBVMCU has a good prognosis. It resolves spontaneously or when medication is withdrawn. It should be noted that other disease concepts, such as MTX-LPD and EBVLPD, overlap with EBVMCU. Given that most EBVMCUs do not require chemotherapy, prioritizing the diagnosis of EBVMCU over other immunodeficiency-related LPD may be beneficial for patients with overlapping disease concepts. The histopathological feature of EBVMCU is the proliferation of EBV-positive atypical lymphoid cells, accompanied by dense polymorphic infiltration of various inflammatory cells. EBV-positive atypical cells vary in size and may resemble Hodgkin and Reed–Sternberg-like cells. Angioinvasion and necrosis are often observed in EBVMCU [2, 3]. These features were consistent with the patient’s histopathological findings. He developed EBVMCU due to immunosuppression, caused by MTX, which was used to treat his rheumatoid arthritis. The clinical course was typical for EBVMCU, and the lesions resolved after MTX discontinuation. Among the reported EBVMCU cases, 66.1% were associated with iatrogenic immunodeficiency, while 27.3% were associated with age-related immunosuppression [4]. MTX, tacrolimus, and infliximab are reportedly causative agents of iatrogenic immunodeficiency, and the frequency of EBVMCU, caused by MTX, is high in Japan. Ikeda et al. reported that 72%, 17%, and 19% of EBVMCU cases occurred in the oropharynx, skin, and gastrointestinal tract, respectively [5]. EBVMCU of the hypopharynx has not been reported previously, and this is the first case report. EBVMCU develops from any site in the pharynx and has also been reported to occur in the nasopharynx [4]. Therefore, EBVMCU should be considered in immunosuppressed patients, who present with ulcerative lesions in the pharynx.

Previous reports have not discussed the imaging findings of EBVMCU. The CT scan of the patient showed a poorly contrast-enhanced area on the superficial side of the mass in the left pyriform sinus. MRI also showed a poorly contrast-enhanced area on the superficial side of the mass with diffusion restriction in the same area. These imaging findings reflected the coagulation necrosis observed in the pathological examination. The presence of necrosis in pathological tissues is one characteristic of EBVMCU. Previous studies have reported that the frequency of coagulative necrosis was significantly higher in EBV-positive LPD than in EBV-negative LPD [6]. Although there were no available studies on the imaging findings of EBVLPD, lymph node and lung lesions of EBVLPD reportedly exhibited necrotic findings on imaging [7]. Therefore, the poorly contrast-enhanced area on the superficial side of the mass in this patient reflected necrosis, a characteristic imaging finding of EBVMCU. High signal intensity on diffusion-weighted images and increased apparent diffusion coefficient (ADC) values of the deep part of the mass is presumed to reflect inflammation and edema. Diffusion restriction was not observed in the deep part of the mass, which may be one of the points to distinguish EBVMCU from lymphoma. Approximately 60% of hypopharyngeal cancers were accompanied by lymph node metastasis. However, EBVMCU is typically not accompanied by lymph node involvement. Therefore, EBVMCU should be considered in immunosuppressed or elderly patients with imaging findings of necrosis in the hypopharynx lesion without lymphadenopathy. However, since it is difficult to make a definitive diagnosis on imaging, a biopsy is necessary in patients suspected of EBVMCU.

Histologically, EBVMCU is difficult to differentiate from malignant lymphomas, such as EBV-positive DLBCL and classical Hodgkin lymphoma [3]. Since EBVMCU is characterized by lesions confined to the mucocutaneous region, it is necessary to differentiate them by performing a systemic examination using imaging and endoscopy, to assess lesions in other organs. Chemotherapy is usually not required to treat EBVMCUs. Immunosuppressed patients with mucosal or cutaneous ulcer lesions only need to be followed up sometimes for EBVMCU, even when the histological findings are suggestive of malignant lymphomas.

In conclusion, we reported the first case of EBVMCU in the hypopharynx. EBVMCU should be considered as a differential diagnosis in immunocompromised patients, presenting with a sharply circumscribed hypopharyngeal mucosal ulcer without lymph node involvement.

Funding:

None.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from the patient in the study.