Origin and Location of the Oral Activity in Sequential Scintigraphy with 99mTc.Pertechnetate

H.P.van denAkker,E.BusemannSokole,andJ. B.vander Schoot

University of Amsterdam, Amsterdam, The Netherlands

Conflicting views exist regarding the origin and location of the oral radio activity seen in salivary gland scintigraphy with 99@'Tc-pertechnetate. The normal accumulation of oral activity was studied in a series of healthy subjects by sequential scintigraphy (anterior and lateral views) after intra venous injection of 2 mCi of 99―Tc-pertechnetate. Ligation of the parotid ducts and/or cannulation of the submandibular ducts, which prevented their secretions from reaching the oral cavity, established that the oral activity was due entirely to radioactive saliva secreted by the parotid and submandibular glands. Pertechnetate mouthwash studies confirmed that radioactive saliva is adsorbed to and that adsorption to the lingual mucosa is the major contributor to the oral activity. Pertechnetate uptake in sublingual and minor salivary glands of the oral cavity was not visualized, thereby invalidating scintigraphy in the study of these glands. In the diagnosis of salivary gland disorders, oral activity is a useful mdi cator of major salivary gland function. J NuciMed17: 959—964,1976

Scintigraphy of the salivary glands using 9UmTc@ MATERIALS AND METHODS pertechnetate was introduced into clinical practice Sequential scintigraphy was performed in 18 by Bömer et al. in 1965 (1 ). During the ensuing healthy volunteers, none having a history of salivary 10 years both static and dynamic scintigraphy have gland disorder, to study the accumulation of oomTc@ become increasingly popular as noninvasive means pertechnetate in the region of the oral cavity. In of investigating salivary gland disorders, even though formed consent was obtained from each subject the diagnostic limitations have not yet been fully before his participation. A Searle Radiographics established. The major difficulty with these scinti Pho/Gamma III HP scintillation camera and a low graphic studies is the disagreement regarding the energy high-resolution parallel-hole collimator were origin of the “oralactivity,―the radioactivity seen to used, together with a 4,096-channel analyzer and accumulate in the oral region. This activity has been magnetic tape data-processing system. In all sub attributed by some to pertechnetate uptake in the jects sequential studies were carried out in the frontal sublingual and minor salivary glands (1—5)and by view, with the subject in the supine position and with others to radioactive saliva secreted by the parotid the head slightly extended. Immediately after intra and submandibular glands (6,7). To further compli venous injection of 2 mCi of DamTc@pertechnetate, cate the matter, many investigators have accepted consecutive 2-mm scintiscans were made up to 10 both sources, but without reference to their relative mm, followed by 5-mm scintiscans every 10 mm up contributions (8—16). In the present study, the exact origin and location of the oral activity were investigated in a series of Received Dec. 30, 1975; revision accepted March 24, 1976. volunteers in order to establish the significance of For reprints contact: E. BuscmannSokole, Dept. of Nu clear Medicine, University Hospital “WilhelminaGasthuis,― this activity in salivary gland scintigraphy. le Helmersstraat 104, Amsterdam, The Netherlands.

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@ ‘.@

FIG. 1. Normalsequentialimagesin frontal (top) and left lateral (bottom) views after intravenous in@edion of @mTc.per. technetate. Diagrams show locations of (P), (S), central activity (C), lower activity (0), lot eral activity (L), nasal activity (N), and 4-6 MIN 10-15 MIN 40-45 MIN thyroid gland(fl.

to 65 mm after injection. The digitized data were submandibular , the was anes stored on magnetic tape at 2-mm intervals and later thetized with a 2% lidocaine solution. This also replayed to obtain time—activity curves for selected blocked the secretory—motor fibers to the subman regions over the right and left parotid and subman dibular gland, thereby preventing obstructive symp dibular glands (4 cm2) and different parts of the toms from developing. In two other subjects the oral activity (2.5 cm2) . Positional changes resulting orifice of the was located on the scinti from opening the mouth were investigated after com scans using only the tip of a catheter containing a pletion of the sequential series: scintiscans in frontal small 9OmTc marker. and lateral views were obtained with the mouth Frontal and lateral scintiscans were obtained in closed and with the mouth held maximally open with three subjects after a saline mouthwash containing a bite block. In four subjects the position of the 0.5 mCi of oomTc@pertechnetatehad been held in the was established in frontal and lateral views mouth for 10 mm. Scintiscans were then repeated by an acrylic palatal plate containing a small oomTc twice, each time after thoroughly rinsing the mouth marker in the midline. In two subjects, lateral se with saline solution for 10 mm. The data were quential studies up to 65 mm after injection were stored on magnetic tape and replayed to calculate carried out to follow the accumulation of oral activity the percentage of activity retained in the oral cavity in this projection. after each rinse. The effects of radioactive saliva secreted by the major salivary glands were studied in eight subjects. 1500 In five subjects saliva from these glands was pre **—--** C.ntraILower Oi.IOrelActivityActivity C 0—0 LatstaI Oral Activity vented from reaching the mouth by ligation of both S a a Sckground-SkuII ‘4 parotid ducts and cannulation of both submandibular ducts, after which the sequential study was started. U0 The individual contributions of these glands were 1000

studied in three subjects in whom, respectively, one ** parotid duct was ligated, both parotid ducts were ligated, and both submandibular ducts were cannu ** ** ** lated. In each subject, the sequential study was con ** * 500 *_ @ tinued up to 55 mm after injection of o9mTc_pertech_ fl,*,* @ netate and compared with a normal study performed /* 1 week previously. Ligation merely involved tying @ a suture around the parotid duct under local anes @@‘**£aaaaaaaaaaaaaaaaaaaaaaaa thesia. The temporary obstruction caused no ad verse effects throughout a 1-year followup. 0 10 20 30 40 50 SO 70 11m stt.r injection (inki) In two subjects, a was located FIG.2. Relativeshapesandmagnitudesoftime—activitycurves by inserting a polyethylene catheter cut to the length from 2.5-cm' regions in oral activity after intravenous injection of of the duct and containing a small 9omTcsource at 2 mCi of [email protected] are averaged from ten normal subjects and ore uncorrected for background activity because of each end. Before introducing the catheter into the its variable magnitude in different oral regions.

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activity ventrally in the oral region (Fig. 1) . Ac tivity in the upper part of the mouth (“central * 1@ activity―) became discernible by 10 mm and in @ , creased until it became the predominant feature, sur passing submandibular gland activity within 20 mm and parotid gland activity within 40 mm after injec tion. In the lateral projection the central activity was seen to be crescent-shaped and nonuniform (Fig. 1), with its most intense part situated posteriorly. The L .@ , @— lower activity gradually seemed to merge with the %@i V increasing central activity, subsequently becoming less distinct. Activity laterally in the oral cavity @ 0 r@ (“lateralactivity―)appeared at the same time as, @ L) LI or slightly later than the central activity and accu mulated to form either separate collections of ac FIG.3. Oralactivityseenfrontally(A)andlaterally(B)innor mal study is absentafter ligation of both parotid ductsand can tivity or lateral extensions of the central activity nulation of both submandibular ducts (C,D). Radioactive saliva in (Fig. 1) . As with the lower activity, the central and submandibular duct catheters is visible on frontal image in mid line, particularly where cathetersrun briefly toward detectorafter lateral activities were preceded by the appearance of emerging from mouth (C arrow). Haze over thyroid region (C,D) is weak diffuse bands extending from the parotid glands due to leakage from catheters onto absorbent paper. Ligation of parotid ducts (without submandibular cannulation) suppresses lateral to the oral region. oral activity, both for bilateral ligation (E) and for right ligation Time—activitycurves of the central, lower, and only (F). Note retention of activity in obstructed glands (C,F). Images obtained 50—65mm after injection. lateral activities generally showed consistent shapes (Fig. 2) . The central activity continuously increased, whereas the lower activity either increased gradually RESULTS to a plateau or decreased after reaching a maximum In all normal frontal and lateral sequential stud at 10—20mm. The two lateral activities were usually ies, radioactivity became visible in the oral region equal and tended to increase gradually. In 8 of the during the first 10 mm after the intravenous injec 18 subjects, sudden decreases were observed in tion of O9mTc.pertechnetate As early as 4 mm after glandular curves. Such a decrease in submandibular injection, the frontal images showed weak diffuse gland activity always correlated with a concurrent bands of activity extending cranially from the sub peak or increase in lower activity; similarly, a sud mandibular glands to the midline. These bands were den decrease in parotid gland activity always corre followed by distinct activity in the midline (“lower lated with a concurrent sharp increase in lateral activity―),which in lateral studies corresponded to activity.

•—eParotid Gland .—. Parotid Gland-Ligated C o—-o Submandibular Gland * .5 0--a Submandibular Gland Cannulat.d E * * C.ntralOralActivity * * C.ntralOralActivity S a a Background-Skull “I a a Background - Skull * * ** ** (.4 C **** * C 3 0 0 U * U ** 1000

@ A 20 30 40 50 10 D 20 30 40 50 10 Tim aft.r inj.ction (mm.) LI Timeaft.rinj.ctlon(mm)

FIG.4. Time—activitycurvesfromsubjectshowninFigs.3A—D.cannulation of both submandibular ducts. All regions of interest (A) Normal study and (B) after ligation of both parotid ducts and are 4 cm2.

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oral radioactivity remained the same, although the total activity decreased on the average by 25 % after the first rinse (range, 10—37%) and a further 7% after the second rinse (range, 4—10%).

DISCUSSION Within 2—4 mm after intravenous injection of OOmTc_pertechnetatein normal subjects, areas of in creased activity in the salivary gland region were recognized and could be identified with the parotid and submandibular glands. Increased activity in the region of the oral cavity appeared during the initial 10 mm after injection, but its correspondence with anatomic structures could not be so readily ascer FIG.5. Frontalimageswithmouthclosed(A)andopen(B) show downward displacement of oral activity and separation of tamed. Moreover, this oral activity became greater nasal and central oral activity when mouth is opened. Note tn than either parotid or submandibular gland uptake angular configuration of oral activity when mouth is open. Lateral images with mouth closed (C) and open (D) further elucidate changes and usually was still increasing at 1 hr after injec (see text). (E) Frontal mouth-open image; (F) repeat with pinhole tion, whereas the parotid and submandibular glands collimator. Note almost circular configuration of oral activity and central area of diminished radioactivity. reached their maximum uptake considerably earlier (17) . In the literature,two unrelatedexplanations for the oral activity are presented. Several authors (1—5) attribute the oral activity solely to uptake In sequential studies after ligation of both parotid in the sublingual and the minor salivary glands, par ducts and cannulation of both submandibular ducts, ticularly the palatine glands. They suggest that scm no accumulation of oral activity was observed (Figs. tigraphy provides the only method of investigating 3 and 4). Only ligation of parotid duct(s) resulted minor salivary gland function, and therefore dimin in absence or slight accumulation of lateral activity ished or absent oral activity is interpreted as con (Figs. 3E and 3F). As seen in lateral views, only cannulation of submandibular ducts resulted in ab sence of lower activity. This effect was obscured in frontal views by radioactive saliva in the cannulas (see cannula artifact in Fig. 3C). The scintiscans obtained with the mouth closed and open showed a striking difference both in the configuration and in the position of the oral activity (Fig. 5 ) . In frontal views with the mouth open, the At@ B oral activity as a whole was displaced downwards; in addition, the central and lower activities were separated, leaving an area of diminished activity between them, and the lateral activities lengthened in a downward and medial direction. On lateral im ages, the oral activity shifted in a ventrocaudal direc tion when the mouth was opened with the most intense posterior part changing from a dorsocaudal to a horizontal or even a ventrocaudal direction. @ * •@4 Radioactive markers established the location of the palate, the submandibular duct, and the parotid duct orifice and related these structures to the oral ac @ tivity (Fig. 6). E F @a4 Radioactivity was retained in the mouth after a °9@'Tc..pertechnetate mouthwash. Figure 7 shows that FIG.6. Radioactivemarkerson palate(arrows)appearas small areas of activity separate from and above oral activity when this retained oral activity closely resembles the oral mouth is Open: (A) frontal; (B) lateral. Compare with mouthwash activity seen after intravenous injection not only in images (Figs. 7B and 7D). On frontal (C) and lateral (D) images, markers in catheter show course and length of left submandibular configuration, but also in displacement when the duct (arrows). Early (10—15 mm) frontal image (E) shows marker mouth is opened. After the mouth was thoroughly blocking right parotid duct orifice (arrow). Later (40—45 mm) lat eral oral activity is seen on left side, opposite to marker (F). Note rinsed with saline solution, the distribution of the obstructive retention in right parotid gland.

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cavity after the mouthwash, but it maintained the C.'—.. [email protected] 1 same activity distribution. The similarity in activity distributions from mouthwash and intravenous per @ 4A technetate further indicates mucosal adsorption of pertechnetate from radioactive saliva. We are cur A C E rently exploring this further with autoradiographic studies. @ .@‘—. 1 1 Valuable insight into the location of the oral ac tivity was gained from the views obtained when the @&.—. 2 @ @2 :4 mouth was open. The downward displacement of the central activity, resulting in distinct separation from B @D @F the palatal marker, ruled out the palate as the loca tion of this activity. Particularly in the lateral view, FIG.7. Retainedpertechnetatemouthwashactivityviewedfran the configuration and displacement of central activity tally (A,B) and laterally (C,D) with mouth closed (A,C) and open suggests its location on the . This might be (B,D). Markers are on bridge of nose (Arrow 1) and on palate (Arrow 2). Note configuration and displacement of retained activity explained by the numerous lingual papillae which on opening mouth and separate location of palatal marker. Mouth provide a large surface area for mucosal adsorption wash activity (C,D) closely resembles oral activity after intravenous injection of pertechnetate, viewed laterally with mouth closed (E) of pertechnetate. and open (F). The lateral activity originated mainly from parotid secretions, since this activity did not accumulate clusive evidence of minor salivary gland involvement when salivary flow from the parotid gland was ob in systemic glandular disorders, such as Sjogren's structed. The diffuse bands of activity often seen disease. On the other hand, Harden et al. (6) sug between the parotid glands and the mouth repre gest that the oral activity is mainly due to saliva sented radioactive saliva in the parotid ducts. Lat from the major salivary glands; they conclude that eral activity appeared to be situated in the region adsorption of pertechnetate to the oral mucosa takes of the buccal mucosa near the parotid duct orifice, place, since the small volume of radioactive saliva as suggested by Grove and Di Chiro (8) and Sors in the mouth would not account for the oral activity dahl et al. (9) . When seen in frontal images, the seen. While they do not rule out the minor salivary lengthening of the lateral activity in a downward glands altogether, they consider adsorption to be direction corresponds to the stretching of the buccal the more important factor. Most authors accept both mucosa that occurs when the mouth is opened. Ac these explanations for the oral activity (8—16). How tivity in the horseshoe-shaped mandibular sulcus now ever, without a clear indication as to the relative also became discernible due to the change in the contributions of radioactive saliva and minor gland angle between the mandible and the detector. uptake, the oral activity cannot be properly inter Markers placed at each end of a submandibular preted. duct not only located the length and course of the Our ligation and cannulation studies clearly show duct on the scintiscans, but also defined the position that the oral activity visualized during the normal of the , whose medial surface is in sequential studies was entirely dependent on radio close contact with the duct. In our series, no accu active saliva secreted by the parotid and subman mulation of pertechnetate was observed in the sub dibular glands. It follows that scintigraphy cannot lingual glands. Furthermore, in a patient, we were be used to investigate the function of minor salivary able to measure the concentration of pertechnetate glands. However, since pertechnetate concentration in a histologically normal sublingual gland, removed in minor salivary gland tissue does occur ( 18) , our during surgery, in the floor of the mouth at 1 hr after observations show that uptake in these glands does intravenous injection of 2 mCi of GGmTc@pertechne@ not become visible above background. tate. Plasma samples obtained at the time of excision Although we have shown that oral activity is due were also measured, and a gland-to-plasma (G/P) to radioactive saliva, the continuous increase and concentration ratio of 0.69 was found [G/P = (per considerable magnitude of this oral activity cannot cent dose/gm gland)/(percent dose/ml plasma)]. be accounted for solely by saliva circulating in the By comparison, also at 1 hr after injection of per oral cavity. Adsorption of pertechnetate to the oral technetate, Lazarus et al. ( 19) found a mean 0/P mucosa, as suggested by Harden et al. (6) , must ratio of 250 (n = 6) for excised parotid tissue. For therefore be considered. Our pertechnetate mouth rat muscle, Papadopoulos et al. (20) found a tissue wash studies support Harden's thesis, since the radio to-plasma ratio of 0.21 ±0.010 (mean ±s.e.m., activity was not only partially retained in the oral n = 6) . Assuming typical weights of 30 gm for the

Volume 17,Number 11 963 VAN DEN AKKER, SOKOLE, AND VAN DER SCHOOT

parotid gland and 5 gm for the sublingual gland, we 5. FOURESTIERJ, GAçON,J, LE STIR A, et al. : Localisa calculated that total pertechnetate uptake of the tion de la captation buccale en scintigraphie salivaire. Rev parotid should be about 20 times that of the sub Stomatol Chir Man/b/ac 75: 530—533,1974 6. HARDEN RM, HIwrrcH TE, KENNEDY I, et al. : Up lingual gland. From these data it is understandable take and scanning of the salivary glands in man using that sublingual gland uptake is not visualized on pertechnetate-@'4Tc. C/in Sci 32: 49—55,1967 @ scintiscans. The submandibular duct markers showed 7. ENFORSB, Ln@ M, SöDERBORGB: Salivary gland scan definitely that the lower activity could not be attrib ning with @mtechnetium. Ada Otolaryngol (Siockh) 67: uted to uptake in the sublingual glands, as suggested 650-654, 1969 8. GROVE AS, DI CHIR0 G : Salivary gland scanning with by zum Winkel et al. (15). In agreement with Sors technetium 99m pertechnetate. Am J Roenigenol Radium dahl et al. (9), we consider the lower activity to TherNuclMed 102:109—116,1968 represent radioactive saliva in the floor of the mouth 9. SORSDAHLOA, WILLAMS CM, BRUNO FP: Scintillation near the orifices of the submandibular ducts. Radio camera scanning of the salivary glands. Radiology 92: 1477— active saliva in the duct itself is usually seen early 1480, 1969 10. JANSSENS A : Exploration scintigraphique des glandes during the study as a weak diffuse band of activity. salivaires. Acta Stomatol Belg 67 : 25—75,1970 The relation between submandibular gland saliva and 11. SCHALL GL, ANDERSON LG, WOLF RO, et al. : Xero the lower activity was also supported by the time stomia in Sjögren's syndrome : Evaluation by sequential activity curves that showed peaks or sharp increases salivary scintigraphy. JAMA 2 16: 2109—2116, 1971 in the lower activity concurrent with sudden de 12. SCHALL GL, ANDERSON LG, BUCHIGNANIJS, et al.: Investigation of major salivary duct obstruction by sequen creases in submandibular gland activity. tial salivary scintigraphy: Report of 3 cases. Am I Roent In clinical practice, oral activity is not due to genol Radium Ther Nuci Med 113: 655—659,1971 pertechnetate uptake in sublingual and minor sali 13. SCHALL GL, Di CHIRO G: Clinical usefulness of sali vary glands and should only be regarded as a useful vary gland scanning. Semin Nuci Med 2 : 270—277,1972 indicator of major salivary gland function. 14. BöRNERW: Szintigraphische Darstellung der Kopf speicheldrüsen.Med K/in 66: l496—1501, 1971 ACKNOWLEDGMENTS 15. ZUM WINKEL K, SCHMIDTL, AMMON J, Ct al. : Phar macodynamic studies of the salivary glands with the scm The authors wish to thank G. Samson for his many help tillation camera and data storage and processing system. In ful suggestions during the preparation of this paper. This Medical Radioisotope Scintigraphy, vol 2. Vienna, IAEA, work was presented in part at the 2nd Congress of the 1973,pp 147—154 European Association for Maxillo-Facial Surgery, Zurich, 16. LAFAYE M, LAFAYE C, MEYNIEL G, et al. : Apport de Sept., 1974, and at the 13th International Annual Meeting Ia scintigraphie au diagnostic des affections des glandes of the European Society of Nuclear Medicine, Copenhagen, salivaires. Ann Otolaryngol Chir Cervicofac 90: 67—89,1973 Sept. 1975. 17. VAN DENAKKER HP, SOKOLEEB: Sequential scintigra phy of the salivary glands with special reference to the oral REFERENCES activity. ml I Oral Surg 3: 321—325,1974 I. BöRNERW, GRÜNBERGH, MOLL E: Die szintigra 18. STEPHEN KW, ROBERTSONJWK, HARDEN RM, et al.: phische Darstellung der Kopfspeicheldrüsen mit Techne Concentration of iodide, pertechnetate, thiocyanate, and tium@'4.Med Welt 42: 2378—2380,1965 bromide in saliva from parotid, submandibular, and minor 2. GRUNBERG H, BöRNERW: Multicentric sialoangiec salivary glands in man. I Lab C/in Med 81: 219—229,1973 tasis: Investigated by scintigraphy. I Laryngol Otol 82: 871— 19.LAZARUS JH, STEPHEN KW, HARDEN RM, et al.: 881, 1968 Simultaneous quantitative measurement of ‘9-iodine and 3. KESSLER L, SCHMIDTW, Orro HJ : Die Kamera-Szin @mTc-pertechnetateuptake by human salivary glands using tigraphie der Kopfspeicheldrüsen mit Technetium@m-Pertech scintiscanning with validation by direct estimation in biopsy netat. Arc/i K/in Erp 0/ire,, Nasen Kehlkopfheilkd 193: samples. Eur I C/in invest 3: 156—159,1973 329—336,1969 20. PAPADOPOULOS5, MACFARLANE S, HARDEN RM : A 4. FOURESTIER J, GAçONJ, BRISOU B, et al. : La scm comparison between the handling of iodine and technetium tigraphie des glandes salivaires dans les bouches sèches.Rev by the thyroid gland of the rat. I Endocrinol 38: 38 1—387, Stomato! Chir Man/b/ac 73: 504—516, 1972 1967

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