Clinical Investigation of Diffuse Large B-cell Lymphoma Exhibiting Initial Symptoms in the Maxilla and Mandible

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classied as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is dicult because the disease causes a diverse range of clinical symptoms with no characteristic imaging ndings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL exhibiting initial manifestation in the maxilla and mandible. Of the 2006 at our 27 primary cases with DLBCL based on the chief complaint of symptoms in the gingiva and bone of maxilla and mandible were enrolled. We evaluate on sex, age, whether treatment was provided by a previous physician, symptoms, disease period until seeking treatment, clinical diagnosis, laboratory ndings, and imaging results.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classi ed as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is di cult because the disease causes a diverse range of clinical symptoms with no characteristic imaging ndings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL exhibiting initial manifestation in the maxilla and mandible.

Methods
Of the 2748 patients with malignant tumors of the oral and maxillofacial region examined during a period of 11 years between January 2006 and December 2016 at our hospital, 27 primary cases diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled. We evaluate on sex, age, whether treatment was provided by a previous physician, symptoms, disease period until seeking treatment, clinical diagnosis, laboratory ndings, and imaging results.

Results
There were 15 cases with maxilla involvement and 12 with mandible involvement. The median disease period until seeking of treatment was 60 d (3-450 d). All cases exhibited a tumor or a mass, and hypoesthesia of the chin was con rmed in 8 cases with mandible involvement. The clinical stage was stage I in 8 cases, stage II in 10 cases, and stage IV in 9 cases. Serum lactate dehydrogenase (LDH) levels were elevated in 13 of 22 patients. The overall survival rate was 63%.

Conclusion
The possibility of Malignant Lymphomas (MLs), such as DLBCL, must be considered while treating lesions of the oral and maxillofacial region.

Background
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma that accounts for 30-40% of such lesions [1]. Nodal lymphomas arise within a lymph node, whereas extranodal lymphomas develop in a non-lymph node tissue. Extranodal DLBCLs in the maxilla and mandible are rare, and differential diagnosis is di cult because they often exhibit clinical ndings similar to that in tumors and/or in ammation at other sites.
Some reports have described the clinical characteristics of extranodal DLBCLs of the maxilla and the mandible [2,3]. Therefore, we investigated the clinical characteristics of 27 primary cases of DLBCL de nitively diagnosed after they presented at our facility with the chief complaint of symptoms of the maxilla and mandible. Here we report on these characteristics and present on a review of the literature.

Methods
Of the 2748 cases of malignant tumors of the mouth and jaws examined during the 11 years from January 2006 through December 2016 at our hospital, 27 primary cases de nitively diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled. There were 19 male patients and 8 female patients. The median age at the initial examination was 72 years (37-95 years).
The site of onset was the maxilla in 12 cases, maxillary gingiva in 3, mandible in 10, and mandibular gingiva in 2 (Table 1). Results Table 1 summarizes the clinical ndings at the initial examination.
History of treatment before the initial examination Sixteen patients (59.3%) had previously undergone diagnosis and treatment of the site at a previous dental clinic or another Department of Oral Surgery before the initial examination performed at our department. Tooth extraction had been performed for six cases, resection for four cases, root canal treatment for three cases, and surgical treatment based on another diagnosis for two cases.
Disease period until seeking treatment The median disease period from the time of symptom onset to the time of treatment seeking was 60 d (3-450 d). A signi cant difference was observed between the median disease period until seeking treatment for maxilla cases (60 d) and mandible cases (120 d).

Clinical diagnosis at the initial examination
Based on these clinical symptoms and ndings, the diagnosis made at the initial examination was suspected ML in 6 cases (22.2%), suspected malignant tumor in 14 (51.9%), suspected benign tumor in 2 (7.4%), and suspected in ammation in 5 (18.5%).

Imaging ndings
Characteristic imaging ndings indicating malignant lymphoma in the maxilla or the mandible include permeable bone resorption on computed tomography (CT) images, low apparent diffusion coe cient (ADC) for the mass on magnetic resonance imaging (MRI) [4], and strong uorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT) [5]. Permeable bone resorption on CT was noted in 12/15 patients (80%) who underwent imaging of the maxilla and 5/12 patients (41.7%) who underwent imaging of the mandible. Permeable bone changes were observed when the base of the tumor was in the mandibular body or ramus.
In contrast to those with other tumors, some cases with marked progression into the bone of the maxilla or the mandible or progression into the maxillary sinus with permeable bone resorption, a return to almost normal anatomical structure was con rmed after treatment. The anatomical structure did not recover completely in cases involving progression into the alveolar bone due to teeth movement. Resorption of the alveolar bone was common on the buccal side of the mandible, in particular, in cases with in ammation. Many patients with lesions in the alveolar bone exhibited compression-type bone resorption.
The median ADC was 0.62 × 10 − 3 mm2/s for the 10 cases where con rmation could not be performed using MRI. FDG uptake on PET-CT was observed in all patients who underwent such testing, and the median SUVmax value was 16.7. The FDG uptake was stronger in patients with maxilla involvement than in those with mandible involvement. The mean maximum standardized uptake value (SUVmax) was 29.1 for the cases with maxilla involvement and 13.4 for those with mandible involvement. The SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) increased with larger target lesions, and the values were higher for the patients with maxilla involvement than for those with mandible involvement.

Hematological ndings
Serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) are biomarkers of malignant lymphoma. Serum LDH was higher than the normal upper limit in 13 patients. The measurement of sIL-2R was performed only for three patients, and one patient exhibited an abnormally high value for sIL-2R. patients, and best supportive care (BSC) for 4 patients. Reasons for BSC included di culty in the treatment procedure, patient refusal to undergo treatment, or dementia. The 5-year survival rate was 63% (Fig. 1a) for the overall study population (n = 27), 75% for stage I patients, 70% for stage II patients, and 44% for stage IV patients (Fig. 1b). All the patients in the group classi ed as high as per the NCCN-IPI were elderly; only one patient could undergo chemotherapy, and all patients had a poor prognosis. All the patients in the low-intermediate group demonstrated disease-free survival. The sample size was relatively small; therefore, no signi cant differences were noted among the groups.

Discussion
Malignant lymphoma is the third most common malignant lesion of the oral cavity and the maxillofacial region after squamous cell carcinoma and salivary gland cancer [5,6]. Malignant lymphomas can be broadly classi ed based on the histopathological ndings as either Hodgkin's lymphoma or non-Hodgkin's lymphoma [7]. Majority of the lymphomas that develop in the oral cavity region are non-Hodgkin's lymphomas.
Diffuse large B-cell lymphoma, not otherwise speci ed (DLBCL, NOS) as de ned in the 2017 World Health Organization (WHO) classi cation, accounts for > 30% of all non-Hodgkin lymphomas in Japan, making it the most prevalent form of NHL [8]. Approximately 40% of DLBCLs involve extranodal lesions [9]. Oral cavity DLBCLs mainly arise in the gingival and palate mucosa, and few studies have reported such lesions arising in the jaw bone [10]. Our data indicated that most of these cases arose in the jawbone, whereas few developed in the gingiva.
Lesions were more common in men than in women (2.4:1), with a higher proportion of male cases being reported than in previous trials [1,11,12]. The mean age in our study (69 y) was equivalent to that in earlier studies [1,11,12].
As DLBCLs arising in the jawbone often also involve dental infections, many patients undergo treatments such as root canal therapy and periodontal treatment [10]. We found that 59.3% of our patients had undergone some type of dental treatment before the initial examination performed at our department.
Clinical symptoms are diverse, including painless tumors, tooth instability, desensitization of the buccal or chin region, and ulceration. Most patients are asymptomatic in the initial stages, with various symptoms appearing with increase in lesion size. This could be the reason for the high proportion of clinical misdiagnosis and delayed diagnosis [13].
With respect to the imaging ndings, bone destruction was not clearly observable on panoramic radiography images; however, careful observation revealed diffuse bone destruction as well as disappearance of the maxillary sinus border in the maxilla and unclear cortical bone in the mandible, with increased X-ray permeability. On CT images, relatively little cortical bone destruction is observable and masses wherein a permeative pattern of bone destruction prevail with no clear periosteal reaction are noted [14]. In our study, 80% of the cases with maxilla involvement exhibited permeable bone resorption on CT images; this percentage was higher than that in those with mandible involvement. We believe that this re ects the fact that the tumor diameter in the cases with maxilla involvement was larger than that for those with mandible involvement. Hypointense signals on T1-weighted MRI and moderate enhancing effects on fat-suppressed contrast-enhanced T1-weighted MRI are common observations. In jawbone DLBCL, ADC is low on diffusion-weighted images and, in contrast to many other squamous cell carcinomas in the oral cavity, strong diffusion is observed [15]. On FDG-PET, the FDG uptake localized to the tumor region was observed. Similar to that in other tumors, SUVmax is unrelated to malignancy or prognosis, being dependent on the tumor size. The SUVmax was smaller for patients with maxilla involvement and a large tumor diameter (median: 42 mm) than for those with mandible involvement and a small tumor diameter (median: 33 mm).
The serum LDH activity and sIL-2R levels are measured as biomarkers for lymphoma patients [16]. However, these are rarely measured in patients who are not initially diagnosed with malignant lymphoma in the clinical setting. The LDH levels were elevated in approximately 50% of our patients who underwent hematological testing in the early stages. The serum LDH levels often rise non-speci cally; therefore, we believe that it should be used as an auxiliary aid for diagnosis.
Many DLBCLs of the oral cavity and the maxillofacial region are believed to be stage I or II at the onset [12]; however, about one-third of our patients were classi ed into stage IV. This ratio was higher than that reported in previous studies. B symptoms are generally uncommon and were noted in only 7.4% of our patients. While the OS of 63% could not be described as highly favorable, it was consistent with previous reports. NCCN-IPI result closely re ected the prognosis. In the future, treatment methods for patients with poor prognosis need to be developed.

Conclusions
The possibility of MLs, such as DLBCL, must be considered while treating lesions of the oral and maxillofacial region.

Consent for publication
Informed consent for publication of this article and its contents was obtained from the patients.

Availability of data and materials
The data is available through e-mail from the corresponding author.

Competing interests
The authors report no nancial or other con ict of interest relevant to this article, which is the intellectual property of the authors.