Peri‐Implant Epstein–Barr Virus (+) Mucocutaneous Ulcer in an Immunocompetent Patient: Case Report and Review of the Literature

ABSTRACT

Epstein–Barr virus (+) mucocutaneous ulcer (EBVMCU) is an uncommon benign lymphoproliferative lesion that develops in immunocompromised patients. We present a special case of EBVMCU located in the peri‐implant mucosa and we review the oral cases published to date. An 88‐year‐old man with no medical history of interest was attended in the dental clinic due to an ulcerated tumor located in the peri‐implant mucosa. The lesion showed an atypical lymphoid proliferation, positive for CD3, CD20, CD30, PAX‐5, and MUM1. Positive EBV and favorable patient evolution confirmed the final diagnosis of EBVMCU. Oral EBVMCU reports related to immunosenescence mainly develop in the gingiva of advanced age patients. Our case highlights the importance to perform a complete clinicopathological study of all peri‐implant lesions. Although most peri‐implant pathologies are inflammatory‐reactive disorders, sometimes they can also correspond to other entities.

1. Introduction

Epstein–Barr virus (+) mucocutaneous ulcer (EBVMCU) is a specific lymphoproliferative lesion first introduced by [1] that affects the oropharyngeal mucosa, gastrointestinal tract, and skin. EBVMCU occurs in patients with specific immunodeficiencies, mainly induced by solid organ or bone marrow transplantation, infections such as human immunodeficiency virus or pharmacological therapies (azathioprine, methrotexate, micophenolate, or cyclosporine) [1]. Cases related to immunosenescence are rare. The prognosis of this particular lesion is good, with no relapses after the immunological recovery [2].

In 2022, the World Health Organization described EBVMCU as a new clinicopathological entity within the group of “lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation” [3]. EBVMCU is characterized by a proliferation of polymorphic CD30 (+) and EBV (+) B‐lymphocytes, some of which morphologically mimic Hodgkin cells. Due to the complex immunophenotype of the lymphocytic proliferation, clinicopathological, molecular, and evolutionary correlation of each case is necessary in order to achieve the correct diagnosis [4]. Currently, several intraoral clinical cases of EBVMCU have been reported, mostly in patients with pharmacological immunosuppression, and only one case has been described in the peri‐implant region [5].

Overall, most peri‐implant disorders correspond to inflammatory reactive lesions (peri‐implantitis, fibroepithelial hyperplasia, pyogenic granuloma, etc.). However, other neoplastic lesions like squamous cell carcinomas, lymphomas, sarcomas, metastases, or melanomas can also arise in this region. Therefore, histopathological diagnosis is key in all peri‐implant lesions [6].

The aim of this study is to present a particular case of peri‐implant EBVMCU in an immunocompetent patient, and to review the oral cases published to date of this condition.

1.1. Case Report

An 88‐year‐old man with no medical history of interest was attended in the dental clinic due to a 2‐month‐old painless ulcerated tumor located in the peri‐implant mucosa. Two dental implants had been placed 10 years ago in that region. The lesion was soft and measured 3 × 1.5 cm (Figure 1A). The radiological study showed an extensive and destructive radiolucent lesion penetrating into the maxillary sinus (Figure 1B,C). With the clinical suspicion of malignancy, two incisional biopsies were performed under local anesthesia.

FIGURE 1.

Clinico‐radiographical aspect: (A) Ulcerated tumor in the peri‐implant mucosa. (B, C) Destructive radiolucent lesion in the peri‐implant region penetrating into the maxillary sinus. (D) Patient follow‐up with the healing process.

The study was approved by the UPV/EHU Research Ethics Committee (CEISH: M10/2016/057, CEIAB/2016/180), for which the patient signed an informed consent form.

Histopathologically, the lesion showed a diffuse and polymorphic lymphoid proliferation, in which two cell populations could be recognized, focally invading muscle bundles: one “atypical,” immature and lymphoblastic (Hodgkin cell‐like), and another one mature and lymphocytic (Figure 2). The immunohistochemical analysis of the polymorphic lymphoid infiltrate was positive for CD20, CD30, PAX‐5, and MUM1 (Figure 3); and negative for CK AE1/AE3, CD10, CD15, CD34, CD68, Bcl2, Bcl6. Cells displayed a Ki‐67 proliferation index of 50% and were positive for EBER (Epstein–Barr virus‐associated non‐coding RNA) (Figure 3). Areas of necrosis and vascular thrombosis were also seen, as well CD3 (+) T lymphocytes which could be reactive.

FIGURE 2.

Histopathological data: (A) Diffuse and polymorphic lymphoid proliferation (H&E, 4×). (B, C) Areas of the lesion with thrombosed vascular structures and foci of necrosis (H&E, 10×). (D) Pleomorphic cell proliferation showing lymphoid morphotype (H&E, 10×). (E, F) Detail of the two cell populations, focally invading muscle bundles: One “atypical,” immature and lymphoblastic; and another one mature and lymphocytic (H&E, 20×).

FIGURE 3.

Immunohistochemical profile. (A) CD20 (+), (B) CD3 (+), (C) CD30 (+), (D) MUM‐1 (+), (E) PAX‐5 (+), (F) ki‐67 (50%), (G) EBER (+).

With all this data, the final diagnosis was Epstein–Barr virus mucocutaneous ulcer. The patient underwent resective surgery and 4 years later has not developed any more lesions or lymphoproliferative disorders (Figure 1D).

2. Discussion

“Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation” represent a heterogeneous group of lymphoid disorders whose clinicopathological features differ depending on the immunosuppressive etiological factor [1, 3]. Among these EBV‐related entities, post‐transplant polymorphous lesions, Hodgkin's lymphoma‐like, or similar lesions in patients treated with methotrexate, diffuse large B‐cell lymphoma and isolated EBVMCU stand out [4].

EBVMCU is most frequently associated to immunosuppressive drugs (methotrexate, azathioprine, micophenolate, or cyclosporine) or systemic immunosuppression due to human immunodeficiency virus infection [3]. The particularity of our patient is that immunosenescence was his only immunosuppressive factor. Thus, we performed a literature review of all intraoral EBVMCU cases associated with immunological senescence published to date, which corresponded to 5 men and 9 women with an age range between 64 and 89 years (64.3% older than 80 years) (Table 1). Lesions were located on the gingiva, tongue, palate, lip, vestibule, and floor of the mouth [1, 2, 7, 8, 9].

TABLE 1.

Clinical data of patients with intraoral EBVMCU related to immunosenescence.

	Location	Age/Sex	Treatment
[1]	Lip	82 male	Spontaneous remission, chemotherapy, radiotherapy
	Lip	82 female
	Palate	80 female
	Floor of the mouth	84 female
	Tongue	64 female
	Tongue	68 female
	Tongue	89 female
	Tongue	76 male
[9]	Vestibule	83 female
[7]	Palate	81 female	Spontaneous remission
[8]	Gingiva	79 female
[2]	Gingiva	80 male	Spontaneous remission
	Gingiva	69 male
Current case	Gingiva	88 male	Surgery

Immunosenescence secondary to aging is associated to monoclonal TCD8 cell accumulation that show a mature immunophenotype and a restricted number of specific epitopes [1]. These lymphocytes provide a much lower responsiveness than lymphocytes from a young immunocompetent patient, inducing a higher risk of lymphoproliferative lesions [10, 11].

The histopathological differential diagnosis of oral EBVMCU includes ruling out other disorders, preferably B‐cell non‐Hodgkin's lymphomas, for which it is mandatory to know the immunohistochemical profile. EBVMCU shows positivity for both T‐cell (CD3) and B‐cell (CD20, PAX5) markers. B‐lymphocytic cells are positive for MUM1, and negative for CD10, Bcl6, and Bcl2. This profile confirmed the post‐follicular phenotype (activated B cells) and ruled out B cell lymphoma [5, 12]. CD30 and EBER positivity confirm the EBVMCU suspicion. However, the key data to reach the final diagnosis is the benign and nonaggressive evolution of the patient.

A special feature of our case was its peri‐implant location. Although several cases of malignant lymphoproliferative lesions have been described surrounding dental implants, only two EBVMCU cases has been reported so far, all in patients treated with immunosuppressive drugs (chloroquine and prednisone) or chemotherapy [5, 13]. It is known that the presence of an inflammatory microenvironment could be linked to the development of several malignancies [14, 15]; nevertheless, there is no scientific evidence regarding the relationship between dental implants and oral oncogenesis. Chronic infection by different periodontopathogens can cause genetic and epigenetic alterations that facilitate abnormal cell proliferation [16]. Therefore, an important pathogenic factor in our patient could have been the immunosurveillance response, trying to stop the microbial invasion and peri‐implant bone destruction, and sadly leading to the lymphocyte proliferation of EBVMCU.

Another important aspect of our case is EBV virus infection. EBV is an oncogenic pathogen that infects and reprograms resting human B‐lymphocytes and induces their continuous proliferation. Upon EBV infection, B cells exit quiescence to enter a germinal center‐like differentiation program, which culminates in immortalized, proliferating cells [17]. Since EBV seems to show a greater presence in the peri‐implant sulcus of patients with peri‐implantitis, a chronic peri‐implant EBV infection could have also favored the appearance of this lymphoproliferative disorder [18, 19].

Most commonly, EBVMCU undergoes spontaneous remission after incisional biopsy, although radiotherapy, chemotherapy, and surgical resection have also been used as treatment if choice. Purposely in our case, implant explantation surgery served as both diagnostic procedure and debridement of the maxillary necrotic tissue. With all this, patient prognosis is very favorable, as no cases of recurrence, dissemination, or metastasis have been reported [2].

3. Conclusions

In summary, this is the first report of immunosenescence‐related peri‐implant EBVMCU in an elderly patient, which demonstrates the importance of always analyzing peri‐implant lesions mimicking peri‐implantitis. Overall, EBVMCU possesses a complex differential diagnosis and good prognosis, which requires a complete clinicopathological and immunohistochemical study.

Author Contributions

Irene Lafuente‐Ibáñez de Mendoza: methodology, investigation, formal analysis, writing – original draft; Pablo Aguirre‐Echevarria: methodology, validation, writing – review and editing; Tulio Mateo Silva‐Soria: methodology; Francisco Javier Vallejo Aisa: methodology; Aitor Fernández de Larrinoa: methodology; José Manuel Aguirre‐Urizar: methodology, investigation, supervision, writing – original draft, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.