Ⅰ. INTRODUCTION

Lymphoma is a heterogeneous group of malignant neoplasms of lymphocytes and progenitor cells. Although there are differences according to the literature, Lymphoma accounts for 3.5% of all oral cancers and is the second most common cancer of the head and neck after Squamous cell carcinoma. Lymphoma is further divided into Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL). NHL accounts for 96% of lymphomas, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype accounting for 32% of NHL¹⁾. NHL is usually derived from B lymphocytes and lesions derived from T lymphocytes are rare. HL usually occurs in the cervical and mediastinal lymph nodes and is histologically characterized as Reed-Sternberg cells, whereas NHL often appears in extra-nodal sites in the head and neck regions, less frequent in the para-oral region. Up to 40% of NHL is extra-nodal and 2~3% is in the oral mucosa and jaw. It may develop centrally in the jaws or in the oral soft tissues. Because DLBCL of jawbone is often accompanied by a dental infection, many patients receive endodontic or periodontal treatment. Clinical symptoms are diverse, including no tenderness with diffuse swelling, tooth mobility, numbness of chin area, and ulceration. Most patients are initially asymptomatic, and as the lesion grows in size, various symptoms begin to appear. This may be the reason for the high rate of clinical misdiagnosis and delayed diagnosis^2,3). Misdiagnosis of jaw lymphoma can delay appropriate treatments and worsen the prognosis. Therefore, to avoid delay in diagnosis, clinicians should identify the possible malignancy based on unusual symptoms, clinical findings, radiographic examinations, and histopathological evaluation.

This article aimed to report cases of an early diagnosis of DLBCL in a 64-year-old male patient and a 81-year-old female patient, who were quickly referred to hemato-oncology and have had effective chemotherapy. These cases emphasize that it is important for both pathologists and clinicians to consider malignant lesions such as lymphomas in the differential diagnosis of periapical radiolucency.

Ⅱ. CASE REPORT

1. Case 1

A 64-year-old male patient was referred from local clinic to our department due to severe pain and extra-oral swelling occurred in the right posterior mandible(Fig. 1A). This patient had a past medical history of surgery, radiotherapy, and chemotherapy for rectal cancer in 2017 and was cured in 2022. And he was also significant for hypertension, diabetes mellitus, and dyslipidemia. One month prior, the patient had received root canal treatment on the #47 tooth with local anesthesia in the local clinic (L/C). Two weeks after endodontic treatment, patient came to the L/C with #47 tooth extracted, he still complained of pain and swelling of right posterior mandible. #46 tooth also showed severe mobility and dentist of L/C extracted #46 tooth and performed incision and drainage in the right posterior mandible region. Nevertheless, the pain and swelling did not subside, so the patient was referred to our department.

He reported that his right lower lip was ‘numb'. On intraoral examination, a large gingival swelling associated with extraction site of #46, 47 tooth was noticed, which had a clinical appearance of a pyogenic granuloma(Fig. 1B). The swelling appeared to progress distally to retromolar trigone area. The buccal mucosal tissue and gingiva was firm extending to the bicuspid and the vestibule. The patient was immediately examined with panoramic radiograph, enhanced computed tomography (CT), MRI and PET/CT. The radiographic findings were that of a radiolucent destruction of bone with ill-defined margins around right posterior mandible that extended posteriorly to ramus of mandible(Fig. 1C, 2). The differential diagnosis based on clinical and radiographic finding was an acute apical abscess, acute osteomyelitis or a malignant tumor such as an osteosarcoma. The initial laboratory results showed normal complete blood cell count, and elevations of glucose of 123 mg/dL (reference level: 70~110 mg/dL), HbA1c of 6.8 (reference level: 4.0~6.4 %), and Erythrocyte Sedimentation Rate of 11 (reference level: 0~9 mm/hr). The patient was seronegative for human immunodeficiency virus. Early blood tests revealed no evidence to suggest a hematopoietic malignancy.

Incisional biopsy was done on the swelling lesion of right posterior mandible under local anesthesia. The lymphocytes were intermediate-to-large and atypical with a moderate amount of cytoplasm. The nuclei had finely clumped chromatin with variably prominent nucleoli, and there were abundant mitotic figures throughout the lesion. A panel of immunostains was performed, and the results were positive for CD20, CD79a, Bcl-2, Bcl-6, and negative for CK, CD3, CD56(Fig. 3). As a result of histopathology and immunohistochemical examination, it was finally confirmed as malignant lymphoma, consistent with diffuse large B-cell lymphoma.

Within two weeks of coming to our department, the patient was immediately referred to the department of hemato- oncology for further treatment. He is being treated with two cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) for three months, and the size of tumor mass is significantly reduced.

2. Case 2

A 81-year-old female patient was referred from local clinic to our department due to severe pain and mobility occurred in the right posterior maxilla. This patient had no systemic diseases other than hypertension. This patient did not receive treatment related to her chief complaint, and was referred after receiving a antibiotic prescription from a local clinic on the day of visit. To resolve the chief complaint, surgical extraction of #17 was planned after 1 week discontinuation of taking plavix related to hypertension. The initial laboratory results showed normal complete blood cell count without any abnormal findings. The patient was seronegative for human immunodeficiency virus. Early blood tests revealed no evidence to suggest a hematopoietic malignancy. Surgical extraction of #17 was done aseptically but additional 2 weeks of antibiotics were prescribed as the inflammatory findings remained even after 1 week after tooth extraction. A month after tooth extraction, the pain disappeared. But the patient complained that 'mass remained' in #17 area(Fig. 4). Therefore, cone beam CT (CBCT) was taken and irregular osteolysis of the alveolar bone around #17 extraction socket was observed. Cortical bone loss was also observed in the maxillary sinus floor and nasal floor. Therefore, it was necessary to differentiate between osteomyelitis and malignancy. Further enhanced maxilla CT was taken. On enhanced CT, bone destruction, loss of the maxillary sinus floor, and erosive resorption of the medial wall of the right maxillary sinus were also observed in the #16 palatal root apex. In addition, a minimally enhancing lesion was observed inside the right maxillary sinus and on the buccal cheek adjacent to #17 area(Fig. 5). Finally, incisional biopsy under local anesthesia of right posterior maxillary area was performed. The lymphocytes were intermediate-to-large and atypical with a moderate amount of cytoplasm. A panel of immunostains was performed, and the results were positive for CD3, L26, Ki-67 and negative for CD138, EBV(Fig. 6). As a result of histopathology and immunohistochemical examination, it was finally confirmed as malignant lymphoma, consistent with diffuse large B-cell lymphoma.

Within 8 weeks of coming to our department, the patient was immediately referred to the department of hemato- oncology for further treatment. She has been treated with four cycles of R-CHOP for three months, and the department of hemato-oncology confirmed a state of remission.

Ⅲ. DISCUSSION

The clinical staging of both HL and NHL derives from the Ann Arbor (AA) staging system. The staging system is based on the extent of involvement of nodal groups. From stage I to stage IV, the condition gets worse. According to Michi, Yasuyuki, et al, the 5-year survival rate was 63% for the overall study population of DLBCL (n = 27), 75% for stage I patients, 70% for stage II patients, and 44% for stage IV patients. For a good prognosis, a quick and accurate diagnosis is necessary above all else⁴⁾. But, oral extranodal DLBCL can mimic some malignant or benign disorders, which make it difficult to diagnose correctly. When affecting the gingiva, DLBCL may present a similar aspect of pyogenic granuloma or dental abscess. Finally, DLBCL may present as an ulcer and may clinically suggest squamous cell carcinoma or other malignancy. Intraosseous lymphoma is very rare and may mimic periapical or periodontal disease in addition to other osteolytic lesions. Differential diagnosis may be difficult based on radiographic findings, and if the diagnosis is incorrect, the patient's prognosis will be poor. Misdiagnosis and subsequent delayed treatment can lead to cortical bone perforation, and the formation of soft tissue masses in the oral cavity. Tumors are usually aggressive, grow quickly and cause severe bone destruction⁵⁾. Diagnosis of lymphoma is based on histological tissue examination. DLBCL is a heterogeneous neoplasm with diverse clinical, morphological and immunophenotypic features. Microscopically, DLBCL consists of large tumor cells with large nuclei that are more than twice the size of normal lymphocytes. These tumor cells display centroblastic or immunoblastic characteristics. Centroblasts have round or irregular nuclei and membrane- bound nucleoli, whereas immunoblasts have a rounded nucleus and prominent centrally located nucleoli³⁾. CHOP, which refers to a cocktail medication of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone, is the most commonly used first-generation chemotherapy regimen used for aggressive NHL. The R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncobin, prednisone) treatment protocol is a modification of CHOP and is a group of targeted therapies including rituximab, a monoclonal antibody agent. If remission is not maintained, bone marrow transplant is considered. Surgical treatment is limited in the treatment of DLBCL. In most cases, the disease is widespread at the time of diagnosis and the prognosis for NHL is poor, with a 5-year survival rate of 73% for head and neck and 65% for extranodal NHL.

Hematopoietic malignancies such as DLBCL can mimic periodontal disease and dento-alveolar abscesses in clinical findings. We, Oral and maxillofacial surgeons should try to identify the possibility of malignancies based on abnormal symptoms expressed in the oral cavity, clinical findings, and radiological examination, so that patients can receive an appropriate treatment as soon as possible. These presenting cases were referred and diagnosed effectively rather early, preventing significant patients’ morbidity and mortality.