- Email: [email protected]
Sonographic diagnosis of Sjögren syndrome: evaluation of parotid gland vascularity as a diagnostic tool
Sonographic diagnosis of Sjögren syndrome: evaluation of parotid gland vascularity as a diagnostic tool Mayumi Shimizu, DDS, PhD,a Kazutoshi Okamura, DDS, PhD,a Kazunori Yoshiura, DDS, PhD,b Yukiko Ohyama, DDS, PhD,c and Seiji Nakamura, DDS, PhD,d Fukuoka, Japan FACULTY OF DENTAL SCIENCE, KYUSHU UNIVERSITY
Objective. To evaluate the usefulness of the vascularity in parotid glands in sonographic diagnosis for Sjögren syndrome. Study design. Sonographic images of 72 cases of previously suspected Sjögren syndrome (including 43 actual cases) were analyzed retrospectively for the abnormal vascularity in the parotid gland parenchyma. The relationships between the vascularity and the results of sialographic, serologic, and histopathologic examinations were analyzed. We also compared the diagnostic accuracy of B-mode only with that of B-mode plus Doppler-mode. Results. Sjögren-positive cases showed significantly higher vascularity. As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower. The highest mean vascular score could be observed both in the initial stage and in the cavitary-destructive stage in the sialographic grades. Sensitivity and accuracy were markedly improved with vascular information. Conclusion. By using vascular information, sonographic diagnosis for Sjögren syndrome can be improved. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:587-94)
Sonography is the most readily applied and inexpensive method among many imaging diagnostic modalities. Since Bradus et al. reported on multiple cystic areas detected on ultrasonography of the parotid glands of Sjögren syndrome patients in 1988,1 there have been many reports on the sonographic features of Sjögren syndrome. Inhomogeneous parenchyma2-6 with characteristic “multiple cystic (hypoechoic) areas”1,3,7-19 and/or “hyperechoic bands (lines or spots)”3,12-14,16-19 has been postulated to be more useful than other sonographic findings, such as the hypoechoic changes of the gland parenchyma and the decrease in gland size by a stepwise analysis.5 We have previously reported that a set of sonographic findings in parenchymal inhomogeniety could be useful in screening for Sjögren syndrome.20 However, it is sometimes difficult to decide whether the gland is inhomogeneous or not, especially when the parenchymal change is slight at an early stage of this a
Assistant Professor, Department of Oral and Maxillofacial Radiology. b Professor and Chairman, Department of Oral and Maxillofacial Radiology. c Assistant Professor, Second Department of Oral and Maxillofacial Surgery. d Professor and Chairman, First Department of Oral and Maxillofacial Surgery. Received for publication Jul 1, 2007; returned for revision Sep 30, 2007; accepted for publication Nov 7, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.11.007
disease. The same fact is also reported with MRI, another noninvasive method for detecting Sjögren syndrome.3,21 We sometimes observed that there was some vascularity in the parotid glands of Sjögren syndrome patients, whereas almost no vascularity was seen in normal parotid glands. There have been a few reports of vascularity in the glands of Sjögren syndrome patients. Martinoli et al. reported that all of the heterogeneous glands in Sjögren syndrome showed a higher number of flow signals.9 Carotti et al. measured resistive index and peak systolic velocity (PSV) in both parotid and submandibular glands and reported that the changes in PSV values before and during lemon juice stimulation were statistically significant only in the control group.17 There have been no reports, however, that investigated the correlation between the glandular vascularity and results of sialographic, serologic, and histopathologic tests of Sjögren syndrome patients. The purpose of the present study was to evaluate the usefulness of the vascularity in parotid glands for sonographic diagnosis of Sjögren syndrome. STUDY DESIGN Patients Seventy-two patients who visited our hospital from October 2003 to June 2005 with suspicion of Sjögren syndrome and who were examined by sonography with both B-mode and Doppler-mode as well as by sialography constituted the study population. All of the pa587
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tients also underwent serologic and histopathologic examinations. Subjects comprised 5 men and 67 women with a mean age of 53.1 years (range 17 to 80 years). Sonographic examinations and evaluations Sonographic examinations were performed by 6 doctors each with more than 1 year experience using an Acuson Sequoia 512 (Mochida Siemens Medical Systems, Tokyo, Japan). B-mode multifoci images were taken with the center frequency of 8 MHz. Dopplermode images were taken with the center frequency of 7 MHz with the flow range of 0.023 m/s. Bilateral parotid glands of each patient were scanned in 2 planes: parallel to the Frankfort-horizontal (F-H) plane at the infra-auricular level and parallel to the retromandibular plane. Bilateral submandibular glands of each patient were scanned in 2 planes: parallel and perpendicular to the submandibular plane. These are the standardized planes for salivary glands. B-mode sonographic images of the parotid glands were analyzed which were scanned parallel to the retromandibular plane, and those of the submandibular glands were analyzed which were scanned parallel to the submandibular plane. Figure 1, A and B, shows normal parotid and submandibular glands in the analyzed planes, where the parotid gland is seen as a spindle-shaped and the submandibular gland as a triangle-shaped aggregation of fine echo signals. Findings compatible with Sjögren syndrome on B-mode sonograms are the following: 1) Multiple hypoechoic areas. 2) Multiple hyperechoic lines and/or spots. 3) Multiple hypoechoic areas surrounded with hyperechoic lines and/or spots (Fig. 2). 4) Obscuration of the gland configuration. Because the posterior border is not clearly observed in the parotid glands, we assessed this last finding only on the submandibular glands. Two observers, with more than 10 years sonographic experience each, evaluated B-mode sonograms independently and under blinded conditions. In clinical cases, we normally diagnose “positive” when 1 or more findings mentioned above were detected. In the present study, however, we adopted only findings 3 and 4 as “positive” to avoid subjective judgment, because these findings showed almost 100% specificity in our previous study.20 When the internal echoes were slightly inhomogeneous but not evident, we scored the case “suspected.” We calculated sensitivity, specificity, and accuracy of sonographic diagnosis only with “positive” cases, and “suspected” cases were included as “negative.”
Fig. 1. A, B-mode sonogram of a normal parotid gland parallel to the retromandibular plane. Left: superior; right: inferior. Internal echoes are homogeneous. B, B-mode sonogram of a normal submandibular gland parallel to the submandibular plane. Left: anterior; right: posterior. Internal echoes are homogeneous.
Doppler-mode sonographic images of the parotid glands were analyzed which were scanned parallel to the retromandibular plane. Images containing motion noise signals were excluded by comparing several images of each patient, and the images containing only dot-like spots were analyzed. Number of the vascular spots (except lines related to the retromandibular vein) in both parotid glands was retrospectively counted by 2 observers with more than 10 years’ sonographic experience each, independently and under blinded conditions (Fig. 3, A). Mean number of vascular spots in both glands counted by the 2 observers was calculated, and we defined it as “mean vascular score.” However, when the gland showed abundant linear vascularity only unilaterally without decrease of internal echo level, it was diagnosed as acute inflammatory change,22 and was excluded from the study (Fig. 3, B). The vascularity of each case was evaluated in 2 ways:
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Fig. 2. Typical B-mode sonogram of a parotid gland with Sjögren syndrome. Multiple hypoechoic areas surrounded with hyperechoic lines can be observed. Left: superior; right: inferior.
1) Mean vascular score (mean number of vascular spots in both glands counted by the 2 observers). 2) Five-grade classification: ⱕ3 spots in both glands, ⱖ4 spots in unilateral gland, 4-6 spots in both glands, 7-9 in both glands, and ⱖ10 spots in both glands. The relationships between the vascularity and the results of diagnosis of Sjögren syndrome, sialography, and serologic and histopathologic examinations were analyzed. We also compared the diagnostic accuracy only by B-mode with that by B-mode plus Dopplermode, with a mean vascular score more than 3 as abnormal. Sialographic examinations and evaluations Sialography was performed with a water-soluble contrast medium, amidotrizoate 76% (Urografin 76%; Schering-Japan, Osaka, Japan). Sialographic images were evaluated by a single observer, based on the classifications by Rubin and Holt23; however, an “initial” stage between normal and “punctate” was added, i.e.: Initial: A few punctate dilatations of the peripheral ducts are suspected or mottled parenchyma is observed. Punctate: Diffuse punctate dilatation of the peripheral ducts less than 1 mm. Globular: The globules of contrast material increase to 1-2 mm.
Fig. 3. A, Doppler-mode sonogram of a parotid gland with Sjögren syndrome (color of the vascular signals is shown here as white). Seven small vascular spots are seen in the periphery. Vasucular line related to the retromandibular vein is excluded from the analysis (arrow). B, Doppler-mode sonogram of a parotid gland with inflammation (color of the vascular signals is shown here as white). Abundant linear vascularity can be seen.
Cavitary: The globules become irregular in size and distribution; cystic dilatation. Destructive: Destruction of the gland parenchyma. When the sialografic images were “punctate” or higher, they were assessed as positive. Diagnosis of Sjögren syndrome Diagnosis of Sjögren syndrome was made based on the revised Japanese Criteria24 (Table I). There are 4 criteria, including serologic, histopathologic, and sialographic examinations. When the patient was positive for more than 2 of the 4 criteria, diagnosis of Sjögren syndrome was made.
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Table I. Revised Japanese Criteria for Sjögren syndrome (1999)3 1. Histopathology Positive for at least 1 of A or B: A) Focus score ⱖ1 (ⱖ50 periductal lymphoid cell infiltration) in a 4-mm2 minor salivary gland biopsy. B) Focus score ⱖ1 (ⱖ50 periductal lymphoid cell infiltration) in a 4-mm2 lacrimal gland biopsy. 2. Oral examination Positive for at least 1 of A or B: A) Abnormal findings in sialography: stage 1 (diffuse punctate shadows of less than 1 mm) or above. B) Decreased salivary secretion (flow rate ⱕ10 mL per 10 min according to chewing gum test or ⱕ2 g per 2 min according to Saxon test) and decreased salivary function according to salivary scintigraphy. 3. Ocular examination Positive for at least 1 of A or B: A) Schirmer test ⱕ5 mm per 5 min and rose bengal test ⱖ3 according to van Bijsterveld score. B) Schirmer test ⱕ5 mm per 5 min and positive fluorescein staining test. 4. Serologic examination Positive for at least 1 of A or B: A) Anti-Ro/SS-A antibody. B) Anti-La/SS-B antibody. Diagnostic criterion: Diagnosis of Sjögren syndrome can be made when the patient meets at least 2 of the above 4 criteria.
Statistical methods Mann-Whitney test was used as the statistical method for comparison of mean vascular score between positive and negative patients in each examination. Kruskal-Wallis test was used to evaluate the differences of mean vascular score among histopathologic grades and among sialographic grades. Sensitivity, specificity, and accuracy of sonographic diagnosis by B-mode only and by B-mode plus Doppler-mode were calculated with regard to actual diagnosis of Sjögren syndrome based on the revised Japanese Criteria.24 RESULTS Forty-three of 72 subjects were positive for Sjögren syndrome based on the revised Japanese Criteria.24 There was 1 case, a unilateral parotid gland of which showed abundant linear vascularity without decrease of internal echo level. This case was diagnosed as an acute inflammatory change22 and was not included in the analyzed 72 cases. Twenty-seven out of 43 Sjögren-positive cases (62.8%) showed abnormal vascularity, i.e., with mean vascular score more than 3. Eight out of 29 Sjögrennegative cases (27.6%) also showed abnormal vascularity. Figure 4, A, shows the relationship between mean vascular score of the glands and results of the revised Japanese Criteria for Sjögren syndrome.
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Sjögren-positive cases showed significantly higher vascularity than negative cases (P ⫽ .0082). The similar tendency was also observed regarding mean vascular score between positive and negative cases of the serologic test (P ⫽ .0127; Fig. 4, B), the histopathologic test (P ⫽ .0022; Fig. 4, C), and the sialographic test (P ⫽ .0222; Fig. 4, D). As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower, and there were more Sjögren-negative cases than positive ones only in the lowest vascularity (Fig. 5, A). Similar tendency could be observed in the serologic test (Fig. 5, B), the histopathologic test (Fig. 5, C), and the sialographic test (Fig. 5, D), although there were more negative than positive cases in the second lowest grade of vascularity in the sialographic test (Fig. 5, D). Figure 6, A, shows the relationship between mean vascular score and histopathologic grades. Besides significant differences among the 4 groups (P ⫽ .0197), a clear border between negative (⫺ and ⫹/⫺) and positive (⫹, 2⫹, and 3⫹) cases could be seen. However, sialographic grades were not parallel to the mean vascular score (Fig. 6, B), although there were significant differences among the 5 grades (P ⫽ .0070). The highest mean vascular score could be observed in both the initial stage and the cavitary-destructive stage. There were 7 cases in the initial stage (Fig. 6, B). Abnormal vascularity, i.e., with the mean vascular score more than 3, could be observed in 5 cases of them. Two cases were diagnosed as Sjögren syndrome, because they were positive in both serologic and histopathologic tests. Although the other 3 cases were not diagnosed as Sjögren syndrome, 2 were positive in serologic test, and 1 was positive in histopathologic test. Only 1 out of the 2 cases without abnormal vascularity was positive in histopathologic test. On B-mode sonograms, we diagnosed 20 cases as “positive,” 17 cases as “suspected,” and 35 cases as “negative.” If the “suspected” cases were included as “negative,” the calculated sensitivity, specificity, and accuracy of B-mode sonographic diagnosis were 44.2%, 96.6%, and 65.3%, respectively (Table II). Abnormal vascularity was observed in 14 (70.0%) of the 20 “positive” cases, 9 (52.9%) of the 17 “suspected” cases, and 11 (31.4%) of the 35 “negative” cases. Eight “suspected” cases and 2 “negative” case were rediagnosed as “positive” with vascular information. Sensitivity, specificity, and accuracy of B-mode plus Doppler-mode sonographic diagnosis were 62.8%, 89.7%, and 73.6%, respectively (Table II). Although specificity showed a slight degradation, sensitivity and accuracy were markedly improved when we added vascular information to diagnosis with B-mode.
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Fig. 4. Relationship between mean vascular score and results of the various tests: A, revised Japanese Criteria for Sjögren syndrome; B, serologic test; C, histopathologic test; D, sialographic test. Positive cases of each test showed significantly higher vascularity than negative ones.
DISCUSSION The vascular information in the parotid glands was investigated to evaluate whether it is valuable for the sonographic diagnosis of Sjögren syndrome, especially when inexperienced operators perform sonographic examination. The analysis of vascularity in parotid gland
parenchyma was chosen, because the vascular signals are usually not observed.9 As mentioned earlier, only 2 works on Doppler analysis of parotid glands of Sjögren syndrome were found on reviewing the literature.9,17 Both of these performed waveform analysis, however, and the analysis of vas-
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Fig. 5. Relationship between grades of vascularity of the glands (i.e., 5-grade classification by number of spots) and results of the various tests: A, revised Japanese Criteria for Sjögren syndrome; B, serologic test; C, histopathologic test; D, sialographic test. Grade with asterisk (*) shows the number of spots in the unilateral gland, and other grades show the number in both glands. As the grade of vascularity becomes higher, the rate of negative cases of each test becomes lower. Except in the sialographic test, there are more negative cases than positive ones only in the lowest vascularity.
cularity in parotid gland parenchyma was not detailed. Martinoli et al. reported on abnormal vascularity on sonograms with Sjögren syndrome.9 They reported the number of dot signals and small peripheral vessels randomly scattered throughout the gland. They also stated that the same vascular pattern was seen in sarcoidosis and inferred that this pattern was not specific but common in inflammatory change associated with autoimmune diseases. The vascular pattern observed in the present study had similar scattered dots. Acute inflammation shows abundant vascularity with linear pattern without decrease of internal echo level,22 which is different from the dot-like pattern. Martinoli et al. analyzed 23 Sjögren cases.9 Bmode sonograms of 11 cases showed heterogeneous internal echoes, and all of these cases showed higher vascularity. Only 1 case of normal B-mode sono-
grams showed hypervascular pattern. That meant that 12 out of 23 Sjögren-positive cases (52.2%) showed abnormal vascularity. In the present cases, 27 out of 43 Sjögren-positive cases (62.8%) showed abnormal vascularity. Martinoli et al. inferred that abnormal vascularity was not specific but common in chronic inflammatory change. If that was the case, vascularity can be changed depending on the condition of the glands. When the gland is in chronic condition, the vascularity can be very low22; however, it increases when the gland shows subacute condition. From the results shown here in Fig. 6, B, where the vascular score did not correlate with sialographic stage, that inference can be reasonable. Mean vascular score of positive cases in each test was significantly higher than the negative cases (Fig. 4). When we observed the graded vascular scores,
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Table II. Sonographic diagnostic accuracy (%) with B-mode and Doppler-mode Sensitivity Specificity Accuracy
Fig. 6. Relationship between mean vascular score and: A, histopathologic grades; B, sialographic grades. In contrast to the histopathologic grades, the sialographic grades show the highest mean vascular score in both the initial stage and the cavitary-destructive stage.
relatively high number of positive cases showed lower vascularity. On the other hand, there were very few negative cases in higher grades (Fig. 5). Therefore, we have to consider the possibility of Sjögren syndrome
B-mode
B-mode ⫹ Doppler-mode
44.2 96.6 65.3
62.8 89.7 73.6
when we observe scattered vascularity in the gland parenchyma, although the definitive diagnosis only by vascularity may be insufficient. The present results showed that the abnormal vascularity did not correlate with the sialographic grades (Fig. 6, B), although it correlated well with the histopathologic grades (Fig. 6, A). Because many cases in the initial stage were positive in either serologic or histopathologic test, or in both tests, the hypervascularity in the initial stage might represent ongoing process of the histopathologic change in the gland parenchyma. Compared with reported cases by Martinoli et al.,9 the present study observed less abnormal vascularity in B-mode “positive” cases and higher rate of hypervascularity in B-mode “negative” cases. This study also observed abnormal vascularity in about half of the “suspected” cases. We cannot explain why this difference occurred. It may depend on the criteria of vascular abnormality. However, the present results may be more reasonable considering their inference, because the vascularity can be changed depending on the gland condition in case of chronic inflammation; generally low but it increases when the gland shows subacute condition. The present study derived better diagnostic performance with the vascular information than with B-mode only (Table II). Sonographic diagnosis for Sjögren syndrome has had its weak point in detecting slight parenchymal change at an early stage of this disease as well as magnetic resonance imaging (MRI) diagnosis.3 When we use all 4 B-mode criteria, diagnostic accuracy can be improved.20 However, the observer performance of criteria 1 and 2 was highly dependent on the experience of the observers. On the other hand, counting vascular spots does not depend on experience. “Suspected” cases could be diagnosed either “positive” or “negative” with vascular information. Because the sensitivity and accuracy were highly improved with vascular information, vascularity should be useful to make diagnosis of Sjögren syndrome by sonography, and it would make sonography superior to MRI in detecting slight changes in the initial stages of this disease. In conclusion, we performed vascular analysis in parotid gland parenchyma of Sjögren syndrome. Sjögren-positive cases showed significantly higher vas-
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cularity. As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower; therefore, we have to consider the possibility of Sjögren syndrome when we observe scattered vascularity in the gland parenchyma. Sensitivity and accuracy on sonographic diagnosis were markedly improved with vascular information. Thus, vascular information in the parotid gland parenchyma can be an additional objective tool for the sonographic diagnosis of Sjögren syndrome and useful for inexperienced operators. REFERENCES 1. Bradus RJ, Hybarger P, Gooding GAW. Parotid gland: US findings in Sjögren syndrome. Work in progress. Radiology 1988;169:749-51. 2. Makula É, Pokorny G, Kiss M, Vörös E, Kovács L, Kovács A, et al. The place of magnetic resonance and ultrasonographic examinations of the parotid gland in the diagnosis and follow-up of primary Sjögren’s syndrome. Rheumatology 2000;39:97-104. 3. Niemelä RK, Takalo R, Pääkkö E, Suramo I, Päivänsalo M, Salo T, et al. Ultrasonography of salivary glands in primary Sjögren’s syndrome. A comparison with magnetic resonance imaging and magnetic resonance sialography of parotid glands. Rheumatology 2004;43:875-9. 4. Kawamura H, Taniguchi N, Itoh K, Kano S. Salivary gland echography in patients with Sjögren’s syndrome. Arthritis Rheum 1990;33:505-10. 5. De Vita S, Lorenzon G, Rossi G, Sabella M, Fossaluzza V. Salivary gland echography in primary and secondary Sjögren’s syndrome. Clin Exp Rheumatol 1992;10:351-6. 6. Makula E, Pokorny G, Rajtar M, Kiss I, Kovacs A, Kovacs L. Parotid gland ultrasonography as a diagnostic tool in primary Sjögren’s syndrome. Br J Rheumatol 1996;35:972-7. 7. Cvetinovic M, Jovic N, Mijatovic D. Evaluation of ultrasound in the diagnosis of pathologic processes in the parotid gland. J Oral Maxillofac Surg 1991;49:147-50. 8. Traxler M, Schurawitzki H, Ulm C, Solar P, Blahout R, Piehslinger E, et al. Sonography of nonneoplastic disorders of the salivary glands. Int J Oral Maxillofac Surg 1992;21:360-3. 9. Martinoli C, Derchi LE, Solbiati L, Rizzatto G, Silvestri E, Giannoni M. Color Doppler sonography of salivary glands. AJR Am J Roentgenol 1994;163:933-41. 10. Ahuja AT, Metreweli C. Ultrasound features of Sjögren’s syndrome. Australas Radiol 1996;40:10-4. 11. Ching ASC, Ahuja AT. Pictorial essay. High-resolution sonography of the submandibular space: anatomy and abnormality. AJR Am J Roentgenol 2002;179:703-8. 12. Takashima S, Morimoto S, Tomiyama N, Takeuchi N, Ikezoe J, Kozuka T. Sjogren syndrome: comparison of sialography and ultrasonography. J Clin Ultrasound 1992;20:99-109.
13. Ariji Y, Ohki M, Eguchi K, Izumi M, Ariji E, Mizokami A, et al. Texture analysis of sonographic features of the parotid gland in Sjögren’s syndrome. AJR Am J Roentgenol 1996;166:935-41. 14. Yoshiura K, Yuasa K, Tabata O, Araki K, Yonetsu K, Nakayama E, et al. Reliability of ultrasonography and sialography in the diagnosis of Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:400-7. 15. Mandel L, Orchowski YS. Using ultrasonography to diagnose Sjögren’s syndrome. J Am Dent Assoc 1998;129:1129-33. 16. Salaffi F, Argalia G, Varotti M, Giannini FB, Palombi C. Salivary gland ultrasonography in the evaluation of primary Sjögren’s syndrome. Comparison with minor salivary gland biopsy. J Rheumatol 2000;27:1229-36. 17. Carotti M, Salaffi F, Manganelli P, Argalia G. Ultrasonography and color Doppler sonography of the salivary glands in primary Sjögren’s syndrome. Clin Rheumatol 2001;20:213-9. 18. Yonetsu K, Takagi Y, Sumi M, Nakamura T, Eguchi K. Sonography as a replacement for sialography for the diagnosis of salivary glands affected by Sjögren’s syndrome. Ann Rheum Dis 2002;61:276-7. 19. Hocevar A, Ambrozic A, Rozman B, Kveder T, Tomsic M. Ultrasonographic changes of major salivary glands in primary Sjögren’s syndrome. Diagnostic value of a novel scoring system. Rheumatology 2005;44:768-72. 20. Shimizu M, Okamura K, Yoshiura K, Ohyama Y, Nakamura S, Kinukawa N. Sonographic diagnostic criteria for screening Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:85-93. 21. Tonami H, Higashi K, Matoba M, Yokota H, Yamamoto I, Sugai S. A comparative study between MR sialography and salivary gland scintigraphy in the diagnosis of Sjögren syndrome. J Comput Assist Tomogr 2001;25:262-8. 22. Shimizu M, Tokumori K, Saitoh M, Miwa K, Yoshiura K, Kanda S. Sonographic analysis of rat submandibular glands with experimentally induced sialadenitis. Dentomaxillofac Radiol 2000; 29:90-6. 23. Rubin P, Holt FJ. Secretory sialography in disease of the major salivary gland. AJR Am J Roentgenol 1957;77:575-98. 24. Fujibayashi T, Sugai S, Miyasaka N, Hayashi Y, Tsubota K. Revised Japanese Criteria for Sjögren’s syndrome (1999): availability and validity. Mod Rheumatol 2004;14:425-34.
Reprint requests: Mayumi Shimizu Dept. of Oral & Maxillofacial Radiology Faculty of Dental Science Kyushu University Maidashi 3-1-1, Higashi-ku Fukuoka, 812-8582 Japan [email protected]
Objective. To evaluate the usefulness of the vascularity in parotid glands in sonographic diagnosis for Sjögren syndrome. Study design. Sonographic images of 72 cases of previously suspected Sjögren syndrome (including 43 actual cases) were analyzed retrospectively for the abnormal vascularity in the parotid gland parenchyma. The relationships between the vascularity and the results of sialographic, serologic, and histopathologic examinations were analyzed. We also compared the diagnostic accuracy of B-mode only with that of B-mode plus Doppler-mode. Results. Sjögren-positive cases showed significantly higher vascularity. As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower. The highest mean vascular score could be observed both in the initial stage and in the cavitary-destructive stage in the sialographic grades. Sensitivity and accuracy were markedly improved with vascular information. Conclusion. By using vascular information, sonographic diagnosis for Sjögren syndrome can be improved. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:587-94)
Sonography is the most readily applied and inexpensive method among many imaging diagnostic modalities. Since Bradus et al. reported on multiple cystic areas detected on ultrasonography of the parotid glands of Sjögren syndrome patients in 1988,1 there have been many reports on the sonographic features of Sjögren syndrome. Inhomogeneous parenchyma2-6 with characteristic “multiple cystic (hypoechoic) areas”1,3,7-19 and/or “hyperechoic bands (lines or spots)”3,12-14,16-19 has been postulated to be more useful than other sonographic findings, such as the hypoechoic changes of the gland parenchyma and the decrease in gland size by a stepwise analysis.5 We have previously reported that a set of sonographic findings in parenchymal inhomogeniety could be useful in screening for Sjögren syndrome.20 However, it is sometimes difficult to decide whether the gland is inhomogeneous or not, especially when the parenchymal change is slight at an early stage of this a
Assistant Professor, Department of Oral and Maxillofacial Radiology. b Professor and Chairman, Department of Oral and Maxillofacial Radiology. c Assistant Professor, Second Department of Oral and Maxillofacial Surgery. d Professor and Chairman, First Department of Oral and Maxillofacial Surgery. Received for publication Jul 1, 2007; returned for revision Sep 30, 2007; accepted for publication Nov 7, 2007. 1079-2104/$ - see front matter © 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.11.007
disease. The same fact is also reported with MRI, another noninvasive method for detecting Sjögren syndrome.3,21 We sometimes observed that there was some vascularity in the parotid glands of Sjögren syndrome patients, whereas almost no vascularity was seen in normal parotid glands. There have been a few reports of vascularity in the glands of Sjögren syndrome patients. Martinoli et al. reported that all of the heterogeneous glands in Sjögren syndrome showed a higher number of flow signals.9 Carotti et al. measured resistive index and peak systolic velocity (PSV) in both parotid and submandibular glands and reported that the changes in PSV values before and during lemon juice stimulation were statistically significant only in the control group.17 There have been no reports, however, that investigated the correlation between the glandular vascularity and results of sialographic, serologic, and histopathologic tests of Sjögren syndrome patients. The purpose of the present study was to evaluate the usefulness of the vascularity in parotid glands for sonographic diagnosis of Sjögren syndrome. STUDY DESIGN Patients Seventy-two patients who visited our hospital from October 2003 to June 2005 with suspicion of Sjögren syndrome and who were examined by sonography with both B-mode and Doppler-mode as well as by sialography constituted the study population. All of the pa587
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tients also underwent serologic and histopathologic examinations. Subjects comprised 5 men and 67 women with a mean age of 53.1 years (range 17 to 80 years). Sonographic examinations and evaluations Sonographic examinations were performed by 6 doctors each with more than 1 year experience using an Acuson Sequoia 512 (Mochida Siemens Medical Systems, Tokyo, Japan). B-mode multifoci images were taken with the center frequency of 8 MHz. Dopplermode images were taken with the center frequency of 7 MHz with the flow range of 0.023 m/s. Bilateral parotid glands of each patient were scanned in 2 planes: parallel to the Frankfort-horizontal (F-H) plane at the infra-auricular level and parallel to the retromandibular plane. Bilateral submandibular glands of each patient were scanned in 2 planes: parallel and perpendicular to the submandibular plane. These are the standardized planes for salivary glands. B-mode sonographic images of the parotid glands were analyzed which were scanned parallel to the retromandibular plane, and those of the submandibular glands were analyzed which were scanned parallel to the submandibular plane. Figure 1, A and B, shows normal parotid and submandibular glands in the analyzed planes, where the parotid gland is seen as a spindle-shaped and the submandibular gland as a triangle-shaped aggregation of fine echo signals. Findings compatible with Sjögren syndrome on B-mode sonograms are the following: 1) Multiple hypoechoic areas. 2) Multiple hyperechoic lines and/or spots. 3) Multiple hypoechoic areas surrounded with hyperechoic lines and/or spots (Fig. 2). 4) Obscuration of the gland configuration. Because the posterior border is not clearly observed in the parotid glands, we assessed this last finding only on the submandibular glands. Two observers, with more than 10 years sonographic experience each, evaluated B-mode sonograms independently and under blinded conditions. In clinical cases, we normally diagnose “positive” when 1 or more findings mentioned above were detected. In the present study, however, we adopted only findings 3 and 4 as “positive” to avoid subjective judgment, because these findings showed almost 100% specificity in our previous study.20 When the internal echoes were slightly inhomogeneous but not evident, we scored the case “suspected.” We calculated sensitivity, specificity, and accuracy of sonographic diagnosis only with “positive” cases, and “suspected” cases were included as “negative.”
Fig. 1. A, B-mode sonogram of a normal parotid gland parallel to the retromandibular plane. Left: superior; right: inferior. Internal echoes are homogeneous. B, B-mode sonogram of a normal submandibular gland parallel to the submandibular plane. Left: anterior; right: posterior. Internal echoes are homogeneous.
Doppler-mode sonographic images of the parotid glands were analyzed which were scanned parallel to the retromandibular plane. Images containing motion noise signals were excluded by comparing several images of each patient, and the images containing only dot-like spots were analyzed. Number of the vascular spots (except lines related to the retromandibular vein) in both parotid glands was retrospectively counted by 2 observers with more than 10 years’ sonographic experience each, independently and under blinded conditions (Fig. 3, A). Mean number of vascular spots in both glands counted by the 2 observers was calculated, and we defined it as “mean vascular score.” However, when the gland showed abundant linear vascularity only unilaterally without decrease of internal echo level, it was diagnosed as acute inflammatory change,22 and was excluded from the study (Fig. 3, B). The vascularity of each case was evaluated in 2 ways:
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Fig. 2. Typical B-mode sonogram of a parotid gland with Sjögren syndrome. Multiple hypoechoic areas surrounded with hyperechoic lines can be observed. Left: superior; right: inferior.
1) Mean vascular score (mean number of vascular spots in both glands counted by the 2 observers). 2) Five-grade classification: ⱕ3 spots in both glands, ⱖ4 spots in unilateral gland, 4-6 spots in both glands, 7-9 in both glands, and ⱖ10 spots in both glands. The relationships between the vascularity and the results of diagnosis of Sjögren syndrome, sialography, and serologic and histopathologic examinations were analyzed. We also compared the diagnostic accuracy only by B-mode with that by B-mode plus Dopplermode, with a mean vascular score more than 3 as abnormal. Sialographic examinations and evaluations Sialography was performed with a water-soluble contrast medium, amidotrizoate 76% (Urografin 76%; Schering-Japan, Osaka, Japan). Sialographic images were evaluated by a single observer, based on the classifications by Rubin and Holt23; however, an “initial” stage between normal and “punctate” was added, i.e.: Initial: A few punctate dilatations of the peripheral ducts are suspected or mottled parenchyma is observed. Punctate: Diffuse punctate dilatation of the peripheral ducts less than 1 mm. Globular: The globules of contrast material increase to 1-2 mm.
Fig. 3. A, Doppler-mode sonogram of a parotid gland with Sjögren syndrome (color of the vascular signals is shown here as white). Seven small vascular spots are seen in the periphery. Vasucular line related to the retromandibular vein is excluded from the analysis (arrow). B, Doppler-mode sonogram of a parotid gland with inflammation (color of the vascular signals is shown here as white). Abundant linear vascularity can be seen.
Cavitary: The globules become irregular in size and distribution; cystic dilatation. Destructive: Destruction of the gland parenchyma. When the sialografic images were “punctate” or higher, they were assessed as positive. Diagnosis of Sjögren syndrome Diagnosis of Sjögren syndrome was made based on the revised Japanese Criteria24 (Table I). There are 4 criteria, including serologic, histopathologic, and sialographic examinations. When the patient was positive for more than 2 of the 4 criteria, diagnosis of Sjögren syndrome was made.
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Table I. Revised Japanese Criteria for Sjögren syndrome (1999)3 1. Histopathology Positive for at least 1 of A or B: A) Focus score ⱖ1 (ⱖ50 periductal lymphoid cell infiltration) in a 4-mm2 minor salivary gland biopsy. B) Focus score ⱖ1 (ⱖ50 periductal lymphoid cell infiltration) in a 4-mm2 lacrimal gland biopsy. 2. Oral examination Positive for at least 1 of A or B: A) Abnormal findings in sialography: stage 1 (diffuse punctate shadows of less than 1 mm) or above. B) Decreased salivary secretion (flow rate ⱕ10 mL per 10 min according to chewing gum test or ⱕ2 g per 2 min according to Saxon test) and decreased salivary function according to salivary scintigraphy. 3. Ocular examination Positive for at least 1 of A or B: A) Schirmer test ⱕ5 mm per 5 min and rose bengal test ⱖ3 according to van Bijsterveld score. B) Schirmer test ⱕ5 mm per 5 min and positive fluorescein staining test. 4. Serologic examination Positive for at least 1 of A or B: A) Anti-Ro/SS-A antibody. B) Anti-La/SS-B antibody. Diagnostic criterion: Diagnosis of Sjögren syndrome can be made when the patient meets at least 2 of the above 4 criteria.
Statistical methods Mann-Whitney test was used as the statistical method for comparison of mean vascular score between positive and negative patients in each examination. Kruskal-Wallis test was used to evaluate the differences of mean vascular score among histopathologic grades and among sialographic grades. Sensitivity, specificity, and accuracy of sonographic diagnosis by B-mode only and by B-mode plus Doppler-mode were calculated with regard to actual diagnosis of Sjögren syndrome based on the revised Japanese Criteria.24 RESULTS Forty-three of 72 subjects were positive for Sjögren syndrome based on the revised Japanese Criteria.24 There was 1 case, a unilateral parotid gland of which showed abundant linear vascularity without decrease of internal echo level. This case was diagnosed as an acute inflammatory change22 and was not included in the analyzed 72 cases. Twenty-seven out of 43 Sjögren-positive cases (62.8%) showed abnormal vascularity, i.e., with mean vascular score more than 3. Eight out of 29 Sjögrennegative cases (27.6%) also showed abnormal vascularity. Figure 4, A, shows the relationship between mean vascular score of the glands and results of the revised Japanese Criteria for Sjögren syndrome.
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Sjögren-positive cases showed significantly higher vascularity than negative cases (P ⫽ .0082). The similar tendency was also observed regarding mean vascular score between positive and negative cases of the serologic test (P ⫽ .0127; Fig. 4, B), the histopathologic test (P ⫽ .0022; Fig. 4, C), and the sialographic test (P ⫽ .0222; Fig. 4, D). As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower, and there were more Sjögren-negative cases than positive ones only in the lowest vascularity (Fig. 5, A). Similar tendency could be observed in the serologic test (Fig. 5, B), the histopathologic test (Fig. 5, C), and the sialographic test (Fig. 5, D), although there were more negative than positive cases in the second lowest grade of vascularity in the sialographic test (Fig. 5, D). Figure 6, A, shows the relationship between mean vascular score and histopathologic grades. Besides significant differences among the 4 groups (P ⫽ .0197), a clear border between negative (⫺ and ⫹/⫺) and positive (⫹, 2⫹, and 3⫹) cases could be seen. However, sialographic grades were not parallel to the mean vascular score (Fig. 6, B), although there were significant differences among the 5 grades (P ⫽ .0070). The highest mean vascular score could be observed in both the initial stage and the cavitary-destructive stage. There were 7 cases in the initial stage (Fig. 6, B). Abnormal vascularity, i.e., with the mean vascular score more than 3, could be observed in 5 cases of them. Two cases were diagnosed as Sjögren syndrome, because they were positive in both serologic and histopathologic tests. Although the other 3 cases were not diagnosed as Sjögren syndrome, 2 were positive in serologic test, and 1 was positive in histopathologic test. Only 1 out of the 2 cases without abnormal vascularity was positive in histopathologic test. On B-mode sonograms, we diagnosed 20 cases as “positive,” 17 cases as “suspected,” and 35 cases as “negative.” If the “suspected” cases were included as “negative,” the calculated sensitivity, specificity, and accuracy of B-mode sonographic diagnosis were 44.2%, 96.6%, and 65.3%, respectively (Table II). Abnormal vascularity was observed in 14 (70.0%) of the 20 “positive” cases, 9 (52.9%) of the 17 “suspected” cases, and 11 (31.4%) of the 35 “negative” cases. Eight “suspected” cases and 2 “negative” case were rediagnosed as “positive” with vascular information. Sensitivity, specificity, and accuracy of B-mode plus Doppler-mode sonographic diagnosis were 62.8%, 89.7%, and 73.6%, respectively (Table II). Although specificity showed a slight degradation, sensitivity and accuracy were markedly improved when we added vascular information to diagnosis with B-mode.
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Fig. 4. Relationship between mean vascular score and results of the various tests: A, revised Japanese Criteria for Sjögren syndrome; B, serologic test; C, histopathologic test; D, sialographic test. Positive cases of each test showed significantly higher vascularity than negative ones.
DISCUSSION The vascular information in the parotid glands was investigated to evaluate whether it is valuable for the sonographic diagnosis of Sjögren syndrome, especially when inexperienced operators perform sonographic examination. The analysis of vascularity in parotid gland
parenchyma was chosen, because the vascular signals are usually not observed.9 As mentioned earlier, only 2 works on Doppler analysis of parotid glands of Sjögren syndrome were found on reviewing the literature.9,17 Both of these performed waveform analysis, however, and the analysis of vas-
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Fig. 5. Relationship between grades of vascularity of the glands (i.e., 5-grade classification by number of spots) and results of the various tests: A, revised Japanese Criteria for Sjögren syndrome; B, serologic test; C, histopathologic test; D, sialographic test. Grade with asterisk (*) shows the number of spots in the unilateral gland, and other grades show the number in both glands. As the grade of vascularity becomes higher, the rate of negative cases of each test becomes lower. Except in the sialographic test, there are more negative cases than positive ones only in the lowest vascularity.
cularity in parotid gland parenchyma was not detailed. Martinoli et al. reported on abnormal vascularity on sonograms with Sjögren syndrome.9 They reported the number of dot signals and small peripheral vessels randomly scattered throughout the gland. They also stated that the same vascular pattern was seen in sarcoidosis and inferred that this pattern was not specific but common in inflammatory change associated with autoimmune diseases. The vascular pattern observed in the present study had similar scattered dots. Acute inflammation shows abundant vascularity with linear pattern without decrease of internal echo level,22 which is different from the dot-like pattern. Martinoli et al. analyzed 23 Sjögren cases.9 Bmode sonograms of 11 cases showed heterogeneous internal echoes, and all of these cases showed higher vascularity. Only 1 case of normal B-mode sono-
grams showed hypervascular pattern. That meant that 12 out of 23 Sjögren-positive cases (52.2%) showed abnormal vascularity. In the present cases, 27 out of 43 Sjögren-positive cases (62.8%) showed abnormal vascularity. Martinoli et al. inferred that abnormal vascularity was not specific but common in chronic inflammatory change. If that was the case, vascularity can be changed depending on the condition of the glands. When the gland is in chronic condition, the vascularity can be very low22; however, it increases when the gland shows subacute condition. From the results shown here in Fig. 6, B, where the vascular score did not correlate with sialographic stage, that inference can be reasonable. Mean vascular score of positive cases in each test was significantly higher than the negative cases (Fig. 4). When we observed the graded vascular scores,
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Table II. Sonographic diagnostic accuracy (%) with B-mode and Doppler-mode Sensitivity Specificity Accuracy
Fig. 6. Relationship between mean vascular score and: A, histopathologic grades; B, sialographic grades. In contrast to the histopathologic grades, the sialographic grades show the highest mean vascular score in both the initial stage and the cavitary-destructive stage.
relatively high number of positive cases showed lower vascularity. On the other hand, there were very few negative cases in higher grades (Fig. 5). Therefore, we have to consider the possibility of Sjögren syndrome
B-mode
B-mode ⫹ Doppler-mode
44.2 96.6 65.3
62.8 89.7 73.6
when we observe scattered vascularity in the gland parenchyma, although the definitive diagnosis only by vascularity may be insufficient. The present results showed that the abnormal vascularity did not correlate with the sialographic grades (Fig. 6, B), although it correlated well with the histopathologic grades (Fig. 6, A). Because many cases in the initial stage were positive in either serologic or histopathologic test, or in both tests, the hypervascularity in the initial stage might represent ongoing process of the histopathologic change in the gland parenchyma. Compared with reported cases by Martinoli et al.,9 the present study observed less abnormal vascularity in B-mode “positive” cases and higher rate of hypervascularity in B-mode “negative” cases. This study also observed abnormal vascularity in about half of the “suspected” cases. We cannot explain why this difference occurred. It may depend on the criteria of vascular abnormality. However, the present results may be more reasonable considering their inference, because the vascularity can be changed depending on the gland condition in case of chronic inflammation; generally low but it increases when the gland shows subacute condition. The present study derived better diagnostic performance with the vascular information than with B-mode only (Table II). Sonographic diagnosis for Sjögren syndrome has had its weak point in detecting slight parenchymal change at an early stage of this disease as well as magnetic resonance imaging (MRI) diagnosis.3 When we use all 4 B-mode criteria, diagnostic accuracy can be improved.20 However, the observer performance of criteria 1 and 2 was highly dependent on the experience of the observers. On the other hand, counting vascular spots does not depend on experience. “Suspected” cases could be diagnosed either “positive” or “negative” with vascular information. Because the sensitivity and accuracy were highly improved with vascular information, vascularity should be useful to make diagnosis of Sjögren syndrome by sonography, and it would make sonography superior to MRI in detecting slight changes in the initial stages of this disease. In conclusion, we performed vascular analysis in parotid gland parenchyma of Sjögren syndrome. Sjögren-positive cases showed significantly higher vas-
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cularity. As the grade of vascularity became higher, the rate of the Sjögren-negative cases became lower; therefore, we have to consider the possibility of Sjögren syndrome when we observe scattered vascularity in the gland parenchyma. Sensitivity and accuracy on sonographic diagnosis were markedly improved with vascular information. Thus, vascular information in the parotid gland parenchyma can be an additional objective tool for the sonographic diagnosis of Sjögren syndrome and useful for inexperienced operators. REFERENCES 1. Bradus RJ, Hybarger P, Gooding GAW. Parotid gland: US findings in Sjögren syndrome. Work in progress. Radiology 1988;169:749-51. 2. Makula É, Pokorny G, Kiss M, Vörös E, Kovács L, Kovács A, et al. The place of magnetic resonance and ultrasonographic examinations of the parotid gland in the diagnosis and follow-up of primary Sjögren’s syndrome. Rheumatology 2000;39:97-104. 3. Niemelä RK, Takalo R, Pääkkö E, Suramo I, Päivänsalo M, Salo T, et al. Ultrasonography of salivary glands in primary Sjögren’s syndrome. A comparison with magnetic resonance imaging and magnetic resonance sialography of parotid glands. Rheumatology 2004;43:875-9. 4. Kawamura H, Taniguchi N, Itoh K, Kano S. Salivary gland echography in patients with Sjögren’s syndrome. Arthritis Rheum 1990;33:505-10. 5. De Vita S, Lorenzon G, Rossi G, Sabella M, Fossaluzza V. Salivary gland echography in primary and secondary Sjögren’s syndrome. Clin Exp Rheumatol 1992;10:351-6. 6. Makula E, Pokorny G, Rajtar M, Kiss I, Kovacs A, Kovacs L. Parotid gland ultrasonography as a diagnostic tool in primary Sjögren’s syndrome. Br J Rheumatol 1996;35:972-7. 7. Cvetinovic M, Jovic N, Mijatovic D. Evaluation of ultrasound in the diagnosis of pathologic processes in the parotid gland. J Oral Maxillofac Surg 1991;49:147-50. 8. Traxler M, Schurawitzki H, Ulm C, Solar P, Blahout R, Piehslinger E, et al. Sonography of nonneoplastic disorders of the salivary glands. Int J Oral Maxillofac Surg 1992;21:360-3. 9. Martinoli C, Derchi LE, Solbiati L, Rizzatto G, Silvestri E, Giannoni M. Color Doppler sonography of salivary glands. AJR Am J Roentgenol 1994;163:933-41. 10. Ahuja AT, Metreweli C. Ultrasound features of Sjögren’s syndrome. Australas Radiol 1996;40:10-4. 11. Ching ASC, Ahuja AT. Pictorial essay. High-resolution sonography of the submandibular space: anatomy and abnormality. AJR Am J Roentgenol 2002;179:703-8. 12. Takashima S, Morimoto S, Tomiyama N, Takeuchi N, Ikezoe J, Kozuka T. Sjogren syndrome: comparison of sialography and ultrasonography. J Clin Ultrasound 1992;20:99-109.
13. Ariji Y, Ohki M, Eguchi K, Izumi M, Ariji E, Mizokami A, et al. Texture analysis of sonographic features of the parotid gland in Sjögren’s syndrome. AJR Am J Roentgenol 1996;166:935-41. 14. Yoshiura K, Yuasa K, Tabata O, Araki K, Yonetsu K, Nakayama E, et al. Reliability of ultrasonography and sialography in the diagnosis of Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:400-7. 15. Mandel L, Orchowski YS. Using ultrasonography to diagnose Sjögren’s syndrome. J Am Dent Assoc 1998;129:1129-33. 16. Salaffi F, Argalia G, Varotti M, Giannini FB, Palombi C. Salivary gland ultrasonography in the evaluation of primary Sjögren’s syndrome. Comparison with minor salivary gland biopsy. J Rheumatol 2000;27:1229-36. 17. Carotti M, Salaffi F, Manganelli P, Argalia G. Ultrasonography and color Doppler sonography of the salivary glands in primary Sjögren’s syndrome. Clin Rheumatol 2001;20:213-9. 18. Yonetsu K, Takagi Y, Sumi M, Nakamura T, Eguchi K. Sonography as a replacement for sialography for the diagnosis of salivary glands affected by Sjögren’s syndrome. Ann Rheum Dis 2002;61:276-7. 19. Hocevar A, Ambrozic A, Rozman B, Kveder T, Tomsic M. Ultrasonographic changes of major salivary glands in primary Sjögren’s syndrome. Diagnostic value of a novel scoring system. Rheumatology 2005;44:768-72. 20. Shimizu M, Okamura K, Yoshiura K, Ohyama Y, Nakamura S, Kinukawa N. Sonographic diagnostic criteria for screening Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:85-93. 21. Tonami H, Higashi K, Matoba M, Yokota H, Yamamoto I, Sugai S. A comparative study between MR sialography and salivary gland scintigraphy in the diagnosis of Sjögren syndrome. J Comput Assist Tomogr 2001;25:262-8. 22. Shimizu M, Tokumori K, Saitoh M, Miwa K, Yoshiura K, Kanda S. Sonographic analysis of rat submandibular glands with experimentally induced sialadenitis. Dentomaxillofac Radiol 2000; 29:90-6. 23. Rubin P, Holt FJ. Secretory sialography in disease of the major salivary gland. AJR Am J Roentgenol 1957;77:575-98. 24. Fujibayashi T, Sugai S, Miyasaka N, Hayashi Y, Tsubota K. Revised Japanese Criteria for Sjögren’s syndrome (1999): availability and validity. Mod Rheumatol 2004;14:425-34.
Reprint requests: Mayumi Shimizu Dept. of Oral & Maxillofacial Radiology Faculty of Dental Science Kyushu University Maidashi 3-1-1, Higashi-ku Fukuoka, 812-8582 Japan [email protected]