A forty-nine year old homeless woman with a 35 pack year cigarette smoking history and no significant medical problems presented to primary medical care with complaints of painful oral ulcerations on her gums and palate that had been present for at least 6 months. Her review of systems was unremarkable including an absence of constitutional symptoms, infectious symptoms, rheumatologic symptoms, lymphadenopathy, or history of recurrent infections, as well as a lack of history of or risk factors for HIV or immunosuppression. Her physical exam was notable for hypertrophic gums, a 1 cm ulceration adjacent to the right upper incisor, and a palatal ulceration near the left upper molars. She did not have palpable adenopathy, hepatosplenomegaly, rashes, joint tenderness, or joint effusions. Her differential diagnosis at time of presentation included trauma (necrotizing sialometaplasia), infection (herpes simplex virus/HSV, coxsackie virus, human immunodeficiency virus/HIV, syphilis, tuberculosis), autoimmune (systemic lupus erythematosus, Behcet syndrome, reactive arthritis, Crohn disease orofacial granulomatosis variant, Sweet syndrome, granulomatosis with polyangiitis, mucous membrane pemphigoid), carcinoma (squamous cell, malignant salivary gland tumor), or hematologic malignancy (B-cell lymphoma, T-cell leukemia/lymphoma).
Diagnostic studies included a normal complete blood count and differential with exception of a mild lymphopenia at 950 cells/muL, normal basic metabolic panel, normal liver function test and lactate dehydrogenase, negative autoimmune screen (antinuclear antibody, anti-neutrophil cytoplasmic antibodies), and negative serologies for HIV and viral hepatitis. Her EBV screen by polymerase chain reaction (PCR) of serum was also negative. Computed tomography (CT) of neck, chest, abdomen, and pelvis demonstrated bilateral diffuse lymphadenopathy in the neck with the largest lymph node measuring 2.4 cm (Fig. 1), but no adenopathy in the hilum, mediastinum, axilla, abdomen, retroperitoneum, pelvis, or inguinal region. The spleen size was normal at 9.2 cm and the abdominal viscera appeared radiographically normal. The patient was referred to oral surgery for biopsy of her right maxillary perimolar lesion and left palatal lesion. Pathologic findings are demonstrated in Fig. 2 and Table 1. Extensive mucosal ulceration was noted with an underlying dense infiltration of small lymphocytes and frequent admixed large atypical lymphocytes including rare Hodgkin and Reed-Sternberg (HRS)-like forms that were positive for CD30 (strong), PAX5 (uniform), CD20 (variable), EBER (uniform), and negative for CD3, CD15, and CD79a. Molecular studies demonstrated a clonal immunoglobulin gene rearrangement. The overall findings were consistent with a clonal EBV-driven, B-cell lymphoproliferative disorder. The diagnostic considerations included EBV-positive mucocutaneous ulcer (EBVMCU) and other EBV-positive B-cell lymphomas including EBV-positive diffuse large B-cell lymphoma, however the patient declined excisional biopsy of cervical lymph nodes and bone marrow biopsy.  
Given CD20 expression on the large atypical lymphocytes, the patient received four weekly doses of rituximab (375 mg/m2) with immediate improvement of symptoms and ulcer regression. Unfortunately this response was short-lived. Within 3 months of completion of rituximab therapy the oral ulcers recrudesced and she declined additional diagnostic studies. Over the next 15 months the oral ulcers increased in extent, with multiple maxillary teeth spontaneously loss, increasing pain, and difficulty opening her mouth resulting in an inability to tolerate solid food, a 36-kilogram unintentional weight loss, and aspiration pneumonia and sepsis.
Repeat CT (Fig. 3) demonstrated irregular enhancing soft tissue deep to the left nasolabial region and anterior premaxilla, encroaching on the left nasal vestibule. The tumor invaded the left maxilla. There was diffuse enhancement around the maxilla, palate, and upper oral mucosa. There were shotty bilateral cervical lymph nodes and small subcentimeter bilateral retropharyngeal nodes, but none clearly pathologic. On clinical exam, there was obvious left facial swelling along the left medial cheek and premaxillary region extending into the lip (Fig. 4a). She had limited oral opening due to pain. An ulcerative indurated mass was visible eroding the left maxilla and palate (Fig. 4b, c). It extended to the hard palate-soft palate junction with normal appearing soft palate mucosa. There was fullness and induration suggestive of submucosal extension to the sublabial region and to the buccal mucosa from the lip commisure back to the retromolar trigone. A second ulcer was apparent on the right upper inner gum line extending from the incisors to molars (Fig. 4d) with gum hypertrophy (Fig. 4e) and induration of the right buccal mucosa extending about halfway back. The oral tongue appeared normal. A swab of her ulcers was negative for HSV by PCR and her screen for HIV and EBV was again negative by PCR of peripheral blood. She continued to be resistant to repeat biopsy and bone marrow evaluation. Given the brief response to prior rituximab therapy, four weekly infusions of rituximab dosed at 375 mg/m2 were administered; however, the patient failed to experience treatment response. Her oral ulcers persisted and increased in size resulting in an almost total inability to tolerate oral intake with subsequent worsening weight loss, lethargy, and weakness.  
Her large left palatal ulcer was biopsied with overall pathologic findings similar to that seen in her initial biopsy. Again noted was ulcerated mucosa with underlying dense inflammatory infiltrate of small lymphocytes, eosinophils, neutrophils, histiocytes, and scattered large atypical lymphocytes with rare HRS-like forms. Sheets of large cells were not seen. Large atypical lymphocytes were uniformly positive for CD30, PAX5, MUM1, EBER, EBV LMP (Fig. 5), and negative for CD3, CD10, and CD20 (in the setting of recent rituximab exposure). The Ki-67 proliferation rate of the atypical lymphocytes was 70-80 %. Given the absence of lymphadenopathy or other systemic involvement of disease, a diagnosis of EBVMCU was rendered. 
Although HIV testing had been repeatedly negative and the patient had no prior history of recurrent infections or exposure to immunosuppressive agents, a potential underlying immunodeficiency syndrome was considered. Quantitative immunoglobulin (Ig) and T-cell subset analysis was performed and her IgG and IgM were found to be mildly depressed at 544 mg/dL (reference range 620-1490 mg/dL) and 29 mg/dL (reference range 40-350 mg/dL), respectively, while her IgA was normal at 122 mg/dL (reference range 65-420 mg/dL). Her mild hypogammaglobulinemia was likely secondary to recent rituximab exposure, although pre-treatment quantitative immunoglobulins had not been evaluated. Interestingly her CD4 and CD8 T-cell counts were both depressed with an absolute CD4 T-lymphocyte count of 125 cells/muL (reference range 733-2250 cells/muL) and an absolute CD8 T-lymphocyte count of 168 cells/muL (reference range 250-1240 cells/muL). Her CD4/CD8 ratio was relatively preserved at 0.73. Rituximab can cause B-lymphocyte depletion and subsequent hypogammaglobulinemia, however it is generally not observed to cause either primary of secondary T-cell depletion. Unfortunately T-cell subset analysis was not performed in our patient prior to rituximab exposure, and we were unable to determine whether she had an underlying immunodeficiency.
Given our patient's poor response to recent systemic therapy, radiotherapy was considered as a therapeutic option given case report of excellent clinical response to radiation. Details of radiotherapy including dose were not described; however, extrapolating from radiation approaches with other lymphoproliferative conditions such as low grade lymphomas, we expected doses in the range of 20-45 Gy in conventional fractionation (1.8-2 Gy per fraction) to be associated with a high rate of clinical response and local control with a favorable toxicity profile. Regional nodal dissemination is not characteristic of EBVMCU, so elective nodal irradiation was not deemed necessary. Our patient received external beam radiation therapy using a three-dimensional conformal plan and a three-field approach (opposed lateral and anteroposterior fields; Fig. 6). The gross disease in the oral cavity was treated to 30 Gy in 15 fractions. She experienced a very brisk and complete clinical response with resolution of all oral ulcers and gum hypertrophy (Fig. 7) durable to 6 months.