Hirotaka Muraoka et al.: Lymphadenopathy Caused by Periodontitis on MRI Journal of Hard Tissue Biology 26[2] (2017) 135-140 © 2017 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved. CODEN-JHTBFF, ISSN 1341-7649 Original

Lymphadenopathy of the Maxillofacial Area Caused by Periodontitis

Hirotaka Muraoka, Takashi Kaneda, Yusuke Kawashima, Naohisa Hirahara, Teruaki Muramatsu and Kotaro Ito

Department of Radiology, Nihon University School of Dentistry at Matsudo, Chiba, Japan (Accepted for publication, December 12, 2016)

Abstract: The purpose of this study was to investigate the appearance of lymph nodes draining areas of periodontitis in the using axial short T1 inversion recovery magnetic resonance imaging, to see if there is a characteristic pattern that may aid in diagnosis and treatment monitoring. The number and short-axis diameter of , submandibular nodes, superior internal jugular nodes, and spinal accessory nodes were measured on magnetic resonance images in 216 subjects (97 patients diagnosed with periodontitis, age 21–81 years and 119 patients undergoing magnetic resonance imaging of the brain without any diseases that would affect the mandible or lymph nodes, age 29-79 years). Between-group differences in the number and diameter of the nodes were analyzed. The size and number of submental nodes, submandibular nodes, and superior internal jugular nodes were significantly different between the periodontitis group and the non- periodontitis group (p < 0.01). The size and number of spinal accessory nodes were not significantly different between the two groups (p > 0.05). Our study found that a definite pattern of lymphadenopathy is associated with periodontitis. These findings indicate that lymphadenopathy should be considered as an inflammation condition commonly associated with periodontitis.

Key words: Bone marrow edema, Lymphadenopathy, Periodontitis, Magnetic resonance imaging

Introduction schematic of the , the lymphatic vessels arise in Periodontitis is an inflammatory disease of the supporting the form of lymphatic capillaries in the soft tissues and merge to tissues of the teeth caused by specific microorganisms, resulting form larger vessels that pass into lymph nodes. The lymph then in progressive destruction of the periodontal ligament and alveolar exits the node in a closed network of ducts, usually extending to bone with increased probing depth formation, recession, or both1). other nodes and then eventually forming the thoracic duct, which At least two of these microorganisms, Porphyromonas gingivalis enters the venous system at the confluence of the left subclavian and Actinobacillus actinomycetemcomitans, are virulent organisms and jugular veins. Thus all lymphatic flow filters through at least that invade the periodontal tissue. The clinical feature that one node, and usually several nodes, before it reaches the thoracic distinguishes periodontitis from gingivitis is the presence of duct or right lymphatic duct9). This is understood to be the clinically detectable attachment loss1). The loss often is nontraumatic portal of entry of most pathogens9). In the oral region, accompanied by periodontal pocket formation and changes in the the submandibular nodes, submental nodes, internal jugular nodes, density and height of subjacent alveolar bone. In recent years, and spinal accessory nodes are especially significant. The questions have arisen about periodontal disease’s influence upon submandibular (submaxillary) nodes are situated in the systemic diseases2-8). Many studies have reported periodontitis as of the , lateral to the anterior belly of a risk factor for chronic medical disorders, including the and near the submandibular gland. The cardiovascular disease, cerebrovascular accidents, and low-birth- submental nodes lie in the of the neck, weight infants. Diabetes mellitus, HIV infection, and cigarette superficial to the and between the anterior smoking have been known as risk factors for periodontitis2-8). bellies of the digastric muscles. The internal jugular (deep cervical) Many lymph nodes are situated in the neck. In the overall chain lies close to the internal jugular vein. The spinal accessory (posterior triangle) chain of nodes follows the course of the spinal Correspondence to: Dr. Hirotaka Muraoka, Department of Radiology, Nihon University School of Dentistry at Matsudo, 2-870-1, Sakaecho- accessory nerve in the posterior triangle of the neck. These nodes Nishi, Matsudo, Chiba, 271-8587 Japan; Tel: +81-47-360-9419; Fax: drain the occipital and mastoid nodes, the parietal and occipital +81-47-364-6295; E-mail: [email protected] 135 J.Hard Tissue Biology Vol. 26(2): 135-140, 2017 Materials and Methods Right side of Left side of the Study Design and Participants mandibular the mandibular We designed and implemented a retrospective cohort study, bone bone which was approved by our university ethics committee (EC12- 009). This study included 108 patients (27 men, 81 women; 21- 81 years of age, mean age 54.5 years) who underwent magnetic resonance imaging (MRI) of the brain at the Nihon University School of Dentistry Hospital, Matsudo, Chiba, Japan, from April 2012 to March 2015. Exclusion criteria were a history of radiotherapy, and disease (e.g., hematological disorders and diabetes mellitus, tumor or cyst of the mandible, inflammatory diseases, lymphomas, metastatic tumors) affecting the mandibular bone marrow and lymph nodes. Figure 1. The mandibular image was divided into two regions: left mandibular and right mandibular. Data Collection regions of the scalp, the nape, lateral portions of the neck, and the MR imaging was performed with a 1.5-T superconductive MR shoulder9). Enlargement of these nodes is known to occur not only unit (Intera Achieva® 1.5 T Nova; Philips Medical Systems, Best, with metastases of malignant tumors but also as part Netherlands) and head coil. Short tau inversion recovery (STIR) of the process of inflammatory conditions or other physiological images were obtained using a spin echo sequence with the defense reactions10,11). following parameters: repetition time, echo time, and inversion There has been little attention devoted to the relationship time were set at 2500, 60, and 180 milliseconds, respectively. between lymphadenopathy and periodontitis. The purpose of this Other study conditions were set as follows: section thickness, 6 study was to characterize lymphadenopathy of the maxillofacial mm; matrix, 320 × 256; field of view, 230 × 195.5 mm; and 1 area associated with periodontitis. acquisition. Analyzing the STIR axial images, the number and short-axis

Figure 2.39-year-old women with periodontitis. A: Slight alveolar bone resorption is seen on panoramic radiograph of the mandible(Arrow head). B: Axial STIR MR image shows bone marrow edema (Arrowheads). Prominent superior internal jugular nodes are seen (Arrow). C: Axial STIR MR image shows prominent submandibular nodes (Arrowhead).

136 Hirotaka Muraoka et al.: Lymphadenopathy Caused by Periodontitis on MRI

Figure 3.75-year-old women with periodontitis. A: Severe bone resorption is seen on panoramic radiograph of the mandible (Arrow head). B: Axial STIR MR image shows bone marrow edema (Arrow head). C: Axial STIR MR image shows prominent submandibular nodes (Arrow heads)*** . Prominent superior internal jugular nodes are seen (Arrow).

diameter of lymph nodes in the head and neck region were cerebrospinal fluid (high signal intensity), muscle (intermediate classified into four categories, with the location of lymph nodes signal intensity), and fat (low signal intensity). We classified signal following the description by Rouviere and the level system of intensity into five categories that included intermediate-to-high Som et al12-14). signal intensity and low-to-intermediate signal intensity. 1) Submental lymph nodes: Nodes lying between the medial Normal bone marrow was considered to have low signal margins of the anterior bellies of the digastric muscles. intensity. When bone marrow signal intensity was higher than that 2) Submandibular nodes: Nodes lying above the , of fat, it was considered edematous. In consideration of Muramatsu below the mylohyoid muscle and anterior to the back of the et al.’s report, we defined bone marrow edema as periodontitis in submandibular gland. this study15). 3) Superior internal jugular nodes: Nodes extending from the skull base to the inferior border of the body of the hyoid bone. Data Analysis Nodes located posterior to the back of the submandibular gland Each of the two groups were then compared using the Mann- and anterior to the back of the sternocleidomastoid muscle. They Whitney U-test. Spearman’s correlation coefficients were may lie anterior, medial, lateral or posterior to the internal jugular calculated using bone marrow signal intensity as the criterion vein. variable and the number and short-axis diameter of lymph nodes 4) Spinal accessory nodes: Nodes extending along the spinal as explanatory variables. These analyses were performed with a accessory nerve in the posterior cervical space. Nodes are located statistical package (SPSS version 21.0®, IBM Japan Inc., Tokyo, to interior to the sternocleidomastoid muscle, and posterior to the Japan). p < 0.05 was considered to indicate significance. internal jugular vein (in this study, those superior to the hyoid bone were studied). Results Images including the mandible were divided into two regions: Table 1 shows the lymph node size and number in the presence left mandible and right mandible (Fig. 1). We excluded sites with of periodontitis. The number and size of submandibular nodes missing teeth from evaluation. A total of 216 sites were evaluated. and superior internal jugular lymph nodes were significantly All MR images were evaluated by two radiologists. The baseline different between the periodontitis group and non-periodontitis structures adopted to evaluate STIR MR signal intensity were group. The mean values of the size of submental nodes were 3.4 ± 137 J.Hard Tissue Biology Vol. 26(2): 135-140, 2017

Table1. Relationship between lymph node number and size and periodontitis.

Average numbers of nodes (No. ± SD) Average size of nodes (mm ± SD) No periodontitis Periodontitis No periodontitis Periodontitis

Submental nodes 0.464 0.630 2.95 3.428

(± 0.697) (± 0.627) ( ± 0.952) (± 0.886)

* Submandibular nodes 1.845 2.395 4.199 5.210

(± 0.615) (± 0.758) (±0.995) (± 1.453)

**** Superior internal jugular nodes 1.649 2.101 4.931 5.702

(± 0.557) (± 0.803) (± 1.285) (± 1.509)

**** Spinal accessory nodes 2.495 2.555 2.471 2.64 (± 0.577) (± 0.618) (± 0.584) (± 0.561)

* : p < 0.05 ** : p < 0.01 SD = standard deviation ＝ ＝

Table 2. Relationship between the bone marrow signal intensity (Periodontitis classification) and lymph node number and size.

Bone marrow signal intensity (Periodontitis classification)

low-to-inter intermediate-to- Signal intensity low intermediate high R mediate high

mean number ± SD 0.46 0.59 0.65 0.75 0.60 0.122 Submental (± 0.61) (± 0.79) (± 0.67) (± 0.62) (± 0.62) nodes mean size ± SD 2.87 3.31 3.43 4.02 3.83 0.358** (± 0.97) (± 0.87) (± 0.91) (± 0.54) (± 0.54)

mean number ± SD 1.82 2.38 2.46 2.42 2.60 0.350** Submental (± 0.60) (± 0.68) (± 0.82) (± 0.79) (± 1.14) nodes mean size ± SD 4.02 4.87 5.61 6.27 6.02 0.542** (± 0.92) (± 1.15) (± 1.34) (± 1.59) (± 2.01)

mean number ± SD 1.65 1.96 2.15 2.50 2.20 Superior 0.329** internal jugular (± 0.55) (± 0.72) (± 0.79) (± 1.04) (± 0.75) mean size ± SD 4.79 5.58 5.91 6.0 7.04 nodes 0.370** (± 1.2) (± 1.51) (± 1.40) (± 1.66) (± 1.66)

mean number ± SD 2.49 2.57 2.52 2.50 2.80 0.163* Spinal accessory (± 0.58) (± 0.60) (± 0.68) (± 0.50) (± 0.40) nodes mean size ± SD 2.47 2.51 2.61 2.98 2.60 0.046 (± 0.58) (± 0.55) (± 0.50) (± 0.68) (± 0.44)

SD = standard deviation ＝* : p < 0.05 ＝** : p < 0.01

0.9 mm and 3.0 ± 1.0 mm, corresponding to the periodontitis the size of submandibular nodes were 5.2 ± 1.5 mm and 4.2 ± 1.0 group and non-periodontitis group, respectively (p < 0.01). The mm, corresponding to the periodontitis groups and non- mean values of the number of submandibular nodes were 2.4 ± periodontitis group, respectively (p < 0.01). The mean values of 0.8 and 1.8 ± 0.6, corresponding to the periodontitis group and the number of superior internal jugular lymph nodes were 3.1 ± non-periodontitis group, respectively (p < 0.01). Mean values of 0.8 and 2.6 ± 0.7, corresponding to the periodontitis group, and

138 Hirotaka Muraoka et al.: Lymphadenopathy Caused by Periodontitis on MRI non-periodontitis group, respectively (p < 0.01). The mean values parameters of alveolar bone loss, gingival bleeding, and probing of the size of the superior internal jugular lymph nodes were 5.7 depth have been used routinely to determine periodontal disease ± 1.5 mm and 4.9 ± 1.3 mm, corresponding to the periodontitis status. The most common cause of bone destruction in periodontal group, and non-periodontitis group, respectively (p < 0.01). The disease is the extension of inflammation from the marginal gingiva periodontitis group showed significantly more lymph nodes, other into the supporting periodontal tissues. The inflammatory invasion than submental nodes and spinal accessory nodes, compared with of the bone surface and the resulting bone loss marks the transition the non-periodontitis group. (Figs. 2, 3 A, B, C). Table 2 shows from gingivitis to periodontitis1). the correlation between bone marrow signal intensity (periodontitis The mandible is a tubular structure of dense cortical bone classification) and the number and short-axis diameter of each filled with trabecular bone and bone marrow1). The bone marrow lymph node. There was significant correlation between bone in the body of a normal adult is known to consist of red marrow marrow signal intensity and the number and short-axis diameter and yellow marrow. Kaneda et al reported marrow conversion of each node other than spinal accessory nodes (p < 0.01). from the immature red to the mature yellow stage was first seen in Increased bone marrow signal intensity was associated with an the anterior region of the mandibular body on MR images17). With increase in the number of lymph nodes. aging, marrow conversion was observed in the premolar/molar region, angle, ramus, and condyle in that order. Muramatsu et al reported bone marrow abnormalities in a high percentage of MR Discussion images of of patients with periodontitis13). Bone marrow Significant differences were observed in the number and short edema is a hallmark of periodontitis in the mandible. Evaluation axis diameter of lymph nodes between the periodontitis group of bone marrow is critical for the diagnosis, treatment, and and the non-periodontitis control group in this study. Significant prognosis of patients with lymphohematopoietic disorders correlations between bone marrow signal intensity (periodontitis including anemias, inflammatory diseases, leukemias, lymphomas, classification) and the number and short-axis diameter of and metastatic tumors. submandibular and superior internal jugular nodes were noted. MRI has been used in lymph nodes to examine their size, Of the approximately 800 lymph nodes in the body, 300 lymph signal intensity, and morphology. It has become an important nodes are situated in the head and neck. Thus, approximately 40% noninvasive imaging technique for bone marrow disorders. of the lymph nodes in the body are located in approximately 20% Therefore, our study investigated relationship between of the body’s volume. This is, in part, understandable, as they lymphadenopathy and bone marrow edema (periodontitis). To drain the nontraumatic portal of entry of most pathogens12-14). The investigate this relationship, we used STIR axial imaging and are often divided into five groups, all of focused on the lymph nodes. STIR sequences are sensitive to which are contiguous with each other. The classification system changes in both T1 and T2; these relaxation time signals are is based on the work of Rouviere12). According to Harnsberger additive and so increase the contrast between different soft tissues. lymphatic drainage in the head and neck region from the mandible, We found a direct correlation between the presence of periodontitis , cheeks, and oral cavity occurs via the submental lymph nodes, and abnormalities of the lymph nodes draining the oral cavity submandibular nodes, and then the deep cervical lymph nodes16). regions. The deep cervical lymph nodes also receive drainage from the In conclusion, our results suggest that lymphadenopathy is parotid gland and the retropharyngeal area. The spinal accessory associated periodontitis. This information may be useful for the nodes receive lymphatic drainage from the occipital, mastoid, differential diagnosis of abnormal lymph nodes. This knowledge parietal scalp, lateral neck and shoulder areas. Submandibular may contribute to the diagnosis of lymphadenopathy and avoid nodes and superior internal jugular nodes of comparatively larger misinterpretation of lymph node disease as primary size than those in other regions are regarded as normal because lymphadenopathy. they receive lymphatic drainage from the oral region, and the oral cavity is a region frequently affected by various diseases such as Conflict of Interest tooth decay and periodontal diseases, which are regarded as The authors have declared that no COI exists. bacterial infections caused by the flora resident in the oral cavity14). On the other hand, periodontitis is a highly prevalent chronic References inflammatory disease caused by primarily by anaerobic gram- 1. Henry HT and Fermin AC. Clinical Diagnosis. In: Carranza’s negative oral infection that leads to gingival inflammation, Clinical Periodontology, 11th Edition, ed by Michael GN, destruction of periodontal tissues, loss of alveolar bone, and loss Henry HT, Perry RK and Fermin AC, Saunders Elsevier Inc., of teeth. This disease is also associated with an increased risk of St. Louis, 2012, pp 340-358. heart attack, stroke, and other serious health problems. The clinical 2. Chambrone L, Preshaw PM, Rosa EF, Heasman PA, Romito

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