Clinical Imaging 39 (2015) 396–400
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Clinical Imaging journal homepage: http://www.clinicalimaging.org
Salivary gland dysfunction after radioactive iodine (I-131) therapy in patients following total thyroidectomy: emphasis on radioactive iodine therapy dose☆,☆☆ Han Na Lee a, Ji Young An a, Kyung Mi Lee a, Eui Jong Kim a,⁎, Woo Suk Choi a, Deog Yoon Kim b a b
Department of Radiology, College of Medicine, Kyung Hee University, Seoul, Korea Department of Nuclear Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
a r t i c l e
i n f o
Article history: Received 18 August 2014 Received in revised form 28 November 2014 Accepted 18 December 2014 Keywords: Salivary gland dysfunction Radioiodine therapy Total thyroidectomy Radiation sialadenitis
a b s t r a c t Purpose: The purpose of this study was to retrospectively evaluate symptoms, images of salivary gland dysfunction, and related clinical factors in thyroid cancer patients with total thyroidectomy followed by radioiodine therapy (RIT). Methods: We included 164 patients who underwent thyroid ultrasonography or contrast-enhanced neck computed tomography more than 6 months later after RIT. Correlation between subjective symptoms and various RIT doses was also evaluated. Results: Swelling and decreased salivary volume were the most common symptoms and images. RIT dose was the only factor with a positive correlation (Pb .001). Conclusion: The dose of RIT should be carefully determined to minimize gland dysfunction. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Radioiodine therapy (RIT) has been commonly used after total thyroidectomy for patients with thyroid cancer. It can eradicate normal thyroid remnants and neoplastic microfoci, thereby reducing the risk of cancer recurrence and facilitating follow-up of the patient’s serum thyroglobulin levels and radioactive iodine (I-131) whole-body scans [1,2]. However, there have been reports of several complications of RIT such as salivary gland damage, hematological abnormalities, conjunctivitis, and alopecia. Among these complications, salivary gland dysfunction is the most frequent complication of RIT [3]. Complications in the salivary gland occur when iodine accumulates in the salivary gland and substitutes for CI− as a substrate in the Na/K/Cl cotransport system of the salivary gland [4], which can result in sialadenitis, xerostomia, and taste disturbances [5]. On follow-up ultrasonography (US), which was performed to evaluate the recurrence of thyroid cancer in patients with total thyroidectomy after RIT, we noticed that many patients had symptoms of salivary gland dysfunction and showed abnormal salivary gland findings on US. However, few studies have reported the characteristics and imaging findings of these complications.
☆ Funding sources: none. ☆☆ Conflict of interest: none declared. ⁎ Corresponding author. Department of Radiology, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-872, Republic of Korea. Tel.: +82 2 958 8611; fax: +82 2 968 0787. E-mail address: [email protected] (E.J. Kim). http://dx.doi.org/10.1016/j.clinimag.2014.12.018 0899-7071/© 2015 Elsevier Inc. All rights reserved.
The purpose of this study was to describe the incidence, onset, involved site, and persistence of symptoms related to RIT, and the associated imaging findings of salivary gland dysfunction. Various factors that could affect salivary gland dysfunction, including the various doses of RIT, were also evaluated. 2. Materials and methods 2.1. Patients All aspects of the protocol adhered to the Helsinki guidelines, and the study underwent review and approval by the Kyung Hee University Medical Center Institutional Review Board (KHUHMC IRB 1407-02). The need for informed consent was waived because this study used imaging data retrospectively. Based on a retrospective review of medical records, we enrolled 880 patients who underwent total thyroidectomy followed by RIT with greater than 1100 MBq from March 2009 through December 2011 for histologically confirmed differentiated thyroid cancer. Among the 880 patients, we selected 355 patients who underwent at least one followup examination by thyroid US or contrast-enhanced neck computed tomography (CT) more than 6 months after RIT. Among this population, we excluded 116 patients whose salivary gland scans were not included in the thyroid US after a retrospective review of the images of thyroid US and 239 patients without available data about subjective symptoms by telephone survey, mainly because of incorrect contact information. We finally included the remaining 164 patients (34 males, 130 females; mean age 49.3years, range; 19–79 years). None of the included
H.N. Lee et al. / Clinical Imaging 39 (2015) 396–400
patients were taking drugs that could affect the salivary gland (e.g., anticholinergics, antihistamines, or antispasmodics) or had a stone or tumor of the salivary gland. The demographic data for the 164 included patients are summarized in Table 1. Most of the patients were female, and most had papillary thyroid cancer. There was no recorded TNM stage on the pathologic reports for 16 patients because they underwent surgery at an outside hospital. Therefore, the TNM stage was reviewed in only 148 patients. All patients had RIT following total thyroidectomy, and the average interval between total thyroidectomy and RIT was 3.7 months. We informed the patients of the possibility of salivary gland damage before performing RIT. Low-dose RIT at 1100 MBq was administered to 46 patients, and high-dose RIT at 3700 MBq, 5550 MBq, and 7400 MBq was performed in 45, 62, and 4 patients, respectively. The remaining seven patients had more than two doses of RIT and were analyzed separately. 2.2. Evaluation of subjective symptoms We evaluated the subjective symptoms of salivary gland dysfunction by patient interview and chart review. Subjective symptoms were evaluated from 6 to 27 months after RIT. All patients were interviewed about symptoms related to salivary gland dysfunction including xerostomia, swelling, and pain. The criteria for xerostomia were considered to be satisfied when solid food could not be swallowed without additional drinking. If patients complained of pain or swelling in the salivary gland, the involved periauricular area or submandibular area was also evaluated. All patients with symptoms were asked about the onset of symptoms, and we divided the time period between development of symptoms and RIT into 6-month intervals as follows: immediately (within a week), b 6 months, 6–12 months, N12 months. We also evaluated whether the symptoms persisted. 2.3. Qualitative image analysis Grayscale US was performed with an iU22 scanner and 5–12-MHz linear array transducer (Philips Medical Systems, Bothell, WA, USA) by two thyroid radiologists. We scanned the bilateral parotid and submandibular glands. A diagnosis of sialadenitis on US was considered when one of the following image findings was identified: volume loss, hypoor heteroechogenicity, fatty degeneration, or internal ductal dilatation of salivary gland (Fig. 1). The patients underwent both pre- and postcontrast neck CT using a 64-detector row MDCT (Brilliance 64, Phillips Medical Systems, Cleveland, OH, USA). Sialadenitis was diagnosed by CT when one of the following image findings was observed: volume loss, increased uptake of contrast agent [6], fatty degeneration, and internal ductal dilatation of salivary gland, which were similar to US findings (Fig. 2). The US and CT images of the salivary gland were retrospectively reviewed by the same two radiologists who had previously performed the US. We considered volume loss of the salivary gland to be present when marginal retraction of the salivary gland or a greater than 2-cm discrepancy in transverse diameter compared to the normal parenchyma was observed. The echogenicity or degree of enhancement of the salivary gland was compared with that of the adjacent muscle. The salivary gland was considered heterogeneous when nonuniform echogenicity was shown in the parenchyma. On CT, postcontrast images were compared with precontrast images to identify enhancement of the salivary gland. Fatty degeneration was identified on CT or US when most of the salivary gland parenchyma showed fat echogenicity or attenuation. Finally, diffuse intraductal dilatation of the salivary gland was defined when ducts were obviously seen. 2.4. Data analysis We used univariate analysis (t test for continuous variables and χ 2 or Fisher’s Exact Test for noncontinuous variables) to evaluate the
397
Table 1 Patients demographics Age (years) Sex F/M Dose of RIT 1100 MBq 3700 MBq 5550 MBq 7400 MBq More than two RIT Follow-up period (month) Interval between RIT and latest imaging (month) Remnant thyroid tissue after operation Histology (papillary/follicular) TNM stage *exclusion of 21 patients I II III IVa IVb
49.3 34/130 46 45 62 4 7 24.5 14.4 5 159/5 35 4 34 50 0
relationship between subjective symptoms of salivary gland dysfunction and multiple clinical factors, which included patients’ age, sex, tumor histology, and the dose of RIT. χ2 test with linear by linear association was performed to show the direction of the relationship associated with variable RIT dose. SAS (version 9.2; SAS Institute Inc., Cary, NC, USA) and Microsoft Excel (Redmond, WA, USA) were used for all statistical analyses. P values less than .05 were considered significant. 3. Results 3.1. Symptom evaluation The symptoms of salivary gland dysfunction are outlined in Table 2. Of the 164 patients, 76 (46.3%) complained of symptoms related to salivary gland dysfunction after RIT. Swelling of the salivary gland was the most frequent symptom and was observed in 46 of 76 patients (60.5%). Xerostomia and pain were observed in 41 (53.9%) and 18 (23.7%) patients, respectively. Twenty-five of the 76 patients (32.9%) showed more than two symptoms. In 60 patients who had symptoms of pain and/or swelling, the most frequently involved site was the preauricular area in 28 patients (46.7%), followed by the submandibular area in 16 patients (26.7%). The remaining 16 patients (26.7%) showed involvement of both sites. When we divided the time interval between the development of symptoms and RIT into four periods, as shown in Table 2, the development of symptoms related to salivary gland dysfunction was most frequently observed within 6 months after RIT (28 patients, 36.8%). In univariate analysis, there were no significant differences between patients with and without symptoms after RIT based on age, sex, or tumor histology; however, there was a significant difference in salivary gland dysfunction among the various doses of RIT (1100 MBq, 3700 MBq, 5550 MBq, 7400 MBq, and more than two RIT doses), which showed that salivary gland dysfunction increased as the dose of RIT increased (Pb .001, Table 3). Persistent complaints of salivary gland dysfunction were present in 54.5% of patients who participated in more than 1 year of follow-up and in 60.6% of patients with more than 2 years of follow-up. 3.2. Imaging findings Based on the latest imaging study, 40 patients (24.4%) showed salivary gland changes on US or CT. The mean interval between RIT and the latest follow-up imaging study was 14.4 months. Among 40 patients who underwent US or CT, a decrease in salivary gland volume was the most common finding, observed in 20 patients (50%), followed by a change of echogenicity or density in 15 patients (37.5%), fatty degeneration in 10 patients (25%), and ductal dilatation
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Fig. 1. A 29-year-old woman who underwent two courses of RIT with doses of 5550 MBq and 7400 MBq, respectively, after total thyroidectomy and complained of persistent xerostomia. (A) Follow-up US with longitudinal scan at 1 month after the last RIT showed hypoechoic and swelling of both submandibular glands, suggesting acute sialadenitis. (B) Two years later, both submandibular glands showed a prominent decrease in volume with marginal retraction (arrow) and heterogeneous echogenicity, suggesting progression to chronic sialadenitis.
in 3 patients (7.5%). Of the 164 patients included in this study, 76 patients (46.3%) manifested more than one symptom related to salivary gland dysfunction. Among the patients with symptoms, 50% showed
positive imaging findings; however, in the 88 patients without symptoms, only 2 (2.3%) patients had abnormal imaging of the salivary gland on US (Fig. 3).
Fig. 2. A 31-year-old women who had xerostomia and taste disturbance after RIT with a dose of 7400 MBq. (A) Axial CT scan of neck in a papillary thyroid carcinoma patient before radiotherapy. The attenuation of the left parotid gland is lower than that of the adjacent masseter muscle (M). (B) On follow-up CT performed 14 months after RIT (7400 MBq), the left parotid gland (arrow) showed increased attenuation compared with the preradiotherapy scan, and attenuation of the left parotid gland was greater than that of the masseter muscle (M).
H.N. Lee et al. / Clinical Imaging 39 (2015) 396–400
399
Table 2 Subjective symptoms of salivary gland Symptoms (Sx)
Location
Swelling Xerostomia Pain N2 Sx
46/76 (60.5%) 41/76 (53.9%) 18/76 (23.7%) 25/76 (32.9%)
Time interval between Sx and RIT
Preauricular Submandibular Both sites
4. Discussion Radiation damage to the salivary gland is recognized as the most common nonthyroidal complication after RIT for patients with thyroid cancer and usually presents as radiation sialadenitis [7–9]. It occurs when the salivary gland concentrates iodine through a carriermediated system of Na 131I, similar to that of the thyroid [10]. Sialadenitis can be classified as an early or late complication, according to the period of first symptomatic appearance. The cause and main symptoms may be slightly different for early and late sialadenitis. Early sialadenitis results from an inflammatory infiltrate that causes increased periductal pressure with duct constriction and salivary retention. Therefore, patients with early sialadenitis usually complain of swelling or pain of the salivary gland, but most cases heal spontaneously [7]. Numerous studies on chronic sialadenitis have been reported. It is assumed that incorporation of damage induced by ionizing radiation into the genetic structure of the cells results in permanent gland damage [11]. In patients with chronic sialadenitis, xerostomia is the most prominent symptom [11,12]. A previous study by Alexander et al. reported the incidence of acute sialadenitis as 33% and that of chronic sialadenitis as 42.9% [3]. Recently, Shin et al. reported a lower incidence of chronic sialadenitis (16.4%) when a minimum of 52 months of followup after RIT was completed. In our study, subjective symptoms of salivary gland dysfunction were observed in 46.3% of the patients. Although we did not evaluate the exact incidence of chronic sialadenitis, we identified 40 of 164 patients (24.4%) showing imaging findings of chronic sialadenitis on US or CT. In patients with symptoms of swelling or pain, the parotid gland was the most frequently involved site at 46.7%, comparable with other studies. This was thought to be because the parotid gland is composed of serous cells that are more susceptible to radiation than the mucous cells of the submandibular gland [7,12]. The most important factor affecting salivary gland dysfunction is known to be the RIT dose [7,8,12]. In the current study, we included patients receiving various doses of RIT, including a low dose (1100 MBq) that was commonly used in outpatients. Subjective symptoms of salivary gland dysfunction rarely developed in patients given 1100 MBq compared to patients who were given more than 3700 MBq. We also demonstrated significant differences in the development of sialadenitis between patients given 3700 MBq and 5550 MBq. We think that this result is important if further studies identify no difference in tumor recurrence between the two groups. Our study showed no correlation
28/60 (46.7%) 16/60 (26.7%) 16/60 (26.7%)
Immediately b6 months 6–12 months N12 months
22/76 (28.9%) 28/76 (36.8%) 16/76 (21.1%) 10/76 (13.1%)
between the development of sialadenitis and age, consistent with a report by Jeong et al. [12]. However, Almeida et al. showed that age was the strongest predictor of parotid gland dysfunction, as demonstrated by salivary gland scan and sialometry [13]. Further studies will be required, including investigation of hydration status, remnant thyroid tissue, and age. Salivary gland scans with Tc-99m pertechnetate have been used to evaluate salivary gland function in patients undergoing RIT [14]. Although this is a sensitive and convenient modality for the evaluation of salivary gland function, only a weak association between the presence of symptoms and objective test results has been suggested [3,10,15]. The absence of subjective symptoms in patients with positive objective results from salivary gland scan was thought to be the result of compensatory function by other salivary glands [9]. In comparison to salivary gland scans, the imaging modalities of CT and US are less sensitive for the evaluation of salivary gland dysfunction. However, imaging modalities of CT and US are usually performed at approximately the same time to evaluate tumor recurrence and thus could be used instead of the salivary scan if abnormal findings of salivary gland are identified on CT or US. We suggest that when performing a postthyroidectomy US or CT scan in thyroid cancer patients, care must be taken to not overlook signs of salivary gland dysfunction when investigating tumor recurrence. In our study, 50% of the patients with symptoms showed normal imaging findings of the salivary gland. We assume that some patients with early sialadenitis heal spontaneously without any objective abnormality and the remaining patients may progress to chronic sialadenitis; however, we did not investigate acute versus chronic sialadenitis, and further studies are therefore necessary. A recent study by Nabaa et al. [14] showed imaging findings of chronic sialadenitis on CT scan. A reduction in the volume of the parotid and submandibular glands and an increase in attenuation of the parotid gland on nonenhanced CT images showed a positive correlation with the severity of salivary gland dysfunction on the salivary scan. To our knowledge, no previous study has reported ultrasonographic findings indicating salivary gland dysfunction. Our data showed similar imaging findings on US, namely, a decrease in volume and heterogeneous echogenicity of the salivary gland. The use of sour candy [15] or lemon juice [16] has been recommended during RIT to reduce complications of the salivary gland. These may increase salivation and thereby decrease the transit time and concentration of I-131 [7]. However, there is controversy regarding the ideal start time of
Table 3 Univariate analysis associating subjective symptoms with clinical variables
Age Sex (M/F) Dose of RIT⁎ 1100 MBq 3700 MBq 5550 MBq 7400 MBq N two RIT Type of tumor Papillary Ca. Follicular Ca.
All patients (n=164)
Sialadenitis (n=76)
No complication (n=88)
P value
49.3 34/130
50.4 13/64
48.4 21/67
.379 .287 b.001
46 45 62 4 7
4 21 43 2 6
42 24 19 2 1
159 5
74 3
86 2
.544
⁎ χ2 test with linear by linear association.
Fig. 3. A diagram of patients' symptoms and imaging findings.
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salivation. Kunihiros et al. [17] claimed that early initiation of lemon candy might cause a significant increase in salivary gland damage, thereby enhancing blood flow to the salivary gland and enabling delivery of a greater amount of I-131 to the salivary glands. Medications such as cholinergic and intravenous amifostine also may be helpful for patients with severe symptoms. Most importantly, clinicians should inform and educate patients about the possibility of salivary gland damage caused by RIT. There are some limitations in this study. First, because of its retrospective nature, the imaging modality, follow-up interval, and followup duration were different for each patient. Second, some selection bias may exist in our study because we only included a small number of patients. However, follow-up images were taken only to evaluate whether cancer recurrence is present, and all of the patients were selected in this study regardless of subjective symptoms of salivary gland dysfunction. Finally, the diagnosis of sialadenitis was based on information that the patients provided, and we did not classify early and late sialadenitis. 5. Conclusion In conclusion, salivary gland dysfunction is a relatively frequent complication after RIT and can result in long-lasting discomfort for patients. Because salivary gland dysfunction showed a positive correlation with RIT dose, clinicians should make a careful decision regarding RIT dose. References [1] Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338: 297–306. [2] Schlumberger M, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012; 366:1663–73.
[3] Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 1998;39:1551–4. [4] Helman J, Turner RJ, Fox PC, Baum BJ. 99mTc-pertechnetate uptake in parotid acinar cells by the Na+/K+/Cl− co-transport system. J Clin Invest 1987;79:1310–3. [5] Newkirk KA, Ringel MD, Wartofsky L, Burman KD. The role of radioactive iodine in salivary gland dysfunction. Ear Nose Throat J 2000;79:460–8. [6] Burke CJ, Thomas RH, Howlett D. Imaging the major salivary glands. Br J Oral Maxillofac Surg 2011;49:261–9. [7] Mandel SJ, Mandel L. Radioactive iodine and the salivary glands. Thyroid 2003;13: 265–71. [8] Raza H, Khan AU, Hameed A, Khan A. Quantitative evaluation of salivary gland dysfunction after radioiodine therapy using salivary gland scintigraphy. Nucl Med Commun 2006;27:495–9. [9] Caglar M, Tuncel M, Alpar R. Scintigraphic evaluation of salivary gland dysfunction in patients with thyroid cancer after radioiodine treatment. Clin Nucl Med 2002;27: 767–71. [10] Solans R, Bosch JA, Galofre P, Porta F, Rosello J, Selva-O'Callagan A, et al. Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy. J Nucl Med 2001;42:738–43. [11] Fox PC. Acquired salivary dysfunction. Drugs and radiation. Ann N Y Acad Sci 1998; 842:132–7. [12] Jeong SY, Kim HW, Lee SW, Ahn BC, Lee J. Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Thyroid 2013;23:609–16. [13] Almeida JP, Sanabria AE, Lima EN, Kowalski LP. Late side effects of radioactive iodine on salivary gland function in patients with thyroid cancer. Head Neck 2011;33: 686–90. [14] Nabaa B, Takahashi K, Sasaki T, Okizaki A, Aburano T. Assessment of salivary gland dysfunction after radioiodine therapy for thyroid carcinoma using noncontrast-enhanced CT: the significance of changes in volume and attenuation of the glands. AJNR 2012;33:1964–70. [15] Freitas JE, Gross MD, Ripley S, Shapiro B. Radionuclide diagnosis and therapy of thyroid cancer: current status report. Semin Nucl Med 1985;15:106–31. [16] Spiegel W, Reiners Chr, Börner W. Sialadenitis following iodine-131 therapy for thyroid carcinoma. J Nucl Med 1985;26:816–7. [17] Nakada K, Ishibashi T, Takei T, Hirata K, Shinohara K, Katoh S, et al. Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer? J Nucl Med 2005;46:261–6.
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
Salivary gland dysfunction after radioactive iodine (I-131) therapy in patients following total thyroidectomy: emphasis on radioactive iodine therapy dose☆,☆☆ Han Na Lee a, Ji Young An a, Kyung Mi Lee a, Eui Jong Kim a,⁎, Woo Suk Choi a, Deog Yoon Kim b a b
Department of Radiology, College of Medicine, Kyung Hee University, Seoul, Korea Department of Nuclear Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
a r t i c l e
i n f o
Article history: Received 18 August 2014 Received in revised form 28 November 2014 Accepted 18 December 2014 Keywords: Salivary gland dysfunction Radioiodine therapy Total thyroidectomy Radiation sialadenitis
a b s t r a c t Purpose: The purpose of this study was to retrospectively evaluate symptoms, images of salivary gland dysfunction, and related clinical factors in thyroid cancer patients with total thyroidectomy followed by radioiodine therapy (RIT). Methods: We included 164 patients who underwent thyroid ultrasonography or contrast-enhanced neck computed tomography more than 6 months later after RIT. Correlation between subjective symptoms and various RIT doses was also evaluated. Results: Swelling and decreased salivary volume were the most common symptoms and images. RIT dose was the only factor with a positive correlation (Pb .001). Conclusion: The dose of RIT should be carefully determined to minimize gland dysfunction. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Radioiodine therapy (RIT) has been commonly used after total thyroidectomy for patients with thyroid cancer. It can eradicate normal thyroid remnants and neoplastic microfoci, thereby reducing the risk of cancer recurrence and facilitating follow-up of the patient’s serum thyroglobulin levels and radioactive iodine (I-131) whole-body scans [1,2]. However, there have been reports of several complications of RIT such as salivary gland damage, hematological abnormalities, conjunctivitis, and alopecia. Among these complications, salivary gland dysfunction is the most frequent complication of RIT [3]. Complications in the salivary gland occur when iodine accumulates in the salivary gland and substitutes for CI− as a substrate in the Na/K/Cl cotransport system of the salivary gland [4], which can result in sialadenitis, xerostomia, and taste disturbances [5]. On follow-up ultrasonography (US), which was performed to evaluate the recurrence of thyroid cancer in patients with total thyroidectomy after RIT, we noticed that many patients had symptoms of salivary gland dysfunction and showed abnormal salivary gland findings on US. However, few studies have reported the characteristics and imaging findings of these complications.
☆ Funding sources: none. ☆☆ Conflict of interest: none declared. ⁎ Corresponding author. Department of Radiology, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-872, Republic of Korea. Tel.: +82 2 958 8611; fax: +82 2 968 0787. E-mail address: [email protected] (E.J. Kim). http://dx.doi.org/10.1016/j.clinimag.2014.12.018 0899-7071/© 2015 Elsevier Inc. All rights reserved.
The purpose of this study was to describe the incidence, onset, involved site, and persistence of symptoms related to RIT, and the associated imaging findings of salivary gland dysfunction. Various factors that could affect salivary gland dysfunction, including the various doses of RIT, were also evaluated. 2. Materials and methods 2.1. Patients All aspects of the protocol adhered to the Helsinki guidelines, and the study underwent review and approval by the Kyung Hee University Medical Center Institutional Review Board (KHUHMC IRB 1407-02). The need for informed consent was waived because this study used imaging data retrospectively. Based on a retrospective review of medical records, we enrolled 880 patients who underwent total thyroidectomy followed by RIT with greater than 1100 MBq from March 2009 through December 2011 for histologically confirmed differentiated thyroid cancer. Among the 880 patients, we selected 355 patients who underwent at least one followup examination by thyroid US or contrast-enhanced neck computed tomography (CT) more than 6 months after RIT. Among this population, we excluded 116 patients whose salivary gland scans were not included in the thyroid US after a retrospective review of the images of thyroid US and 239 patients without available data about subjective symptoms by telephone survey, mainly because of incorrect contact information. We finally included the remaining 164 patients (34 males, 130 females; mean age 49.3years, range; 19–79 years). None of the included
H.N. Lee et al. / Clinical Imaging 39 (2015) 396–400
patients were taking drugs that could affect the salivary gland (e.g., anticholinergics, antihistamines, or antispasmodics) or had a stone or tumor of the salivary gland. The demographic data for the 164 included patients are summarized in Table 1. Most of the patients were female, and most had papillary thyroid cancer. There was no recorded TNM stage on the pathologic reports for 16 patients because they underwent surgery at an outside hospital. Therefore, the TNM stage was reviewed in only 148 patients. All patients had RIT following total thyroidectomy, and the average interval between total thyroidectomy and RIT was 3.7 months. We informed the patients of the possibility of salivary gland damage before performing RIT. Low-dose RIT at 1100 MBq was administered to 46 patients, and high-dose RIT at 3700 MBq, 5550 MBq, and 7400 MBq was performed in 45, 62, and 4 patients, respectively. The remaining seven patients had more than two doses of RIT and were analyzed separately. 2.2. Evaluation of subjective symptoms We evaluated the subjective symptoms of salivary gland dysfunction by patient interview and chart review. Subjective symptoms were evaluated from 6 to 27 months after RIT. All patients were interviewed about symptoms related to salivary gland dysfunction including xerostomia, swelling, and pain. The criteria for xerostomia were considered to be satisfied when solid food could not be swallowed without additional drinking. If patients complained of pain or swelling in the salivary gland, the involved periauricular area or submandibular area was also evaluated. All patients with symptoms were asked about the onset of symptoms, and we divided the time period between development of symptoms and RIT into 6-month intervals as follows: immediately (within a week), b 6 months, 6–12 months, N12 months. We also evaluated whether the symptoms persisted. 2.3. Qualitative image analysis Grayscale US was performed with an iU22 scanner and 5–12-MHz linear array transducer (Philips Medical Systems, Bothell, WA, USA) by two thyroid radiologists. We scanned the bilateral parotid and submandibular glands. A diagnosis of sialadenitis on US was considered when one of the following image findings was identified: volume loss, hypoor heteroechogenicity, fatty degeneration, or internal ductal dilatation of salivary gland (Fig. 1). The patients underwent both pre- and postcontrast neck CT using a 64-detector row MDCT (Brilliance 64, Phillips Medical Systems, Cleveland, OH, USA). Sialadenitis was diagnosed by CT when one of the following image findings was observed: volume loss, increased uptake of contrast agent [6], fatty degeneration, and internal ductal dilatation of salivary gland, which were similar to US findings (Fig. 2). The US and CT images of the salivary gland were retrospectively reviewed by the same two radiologists who had previously performed the US. We considered volume loss of the salivary gland to be present when marginal retraction of the salivary gland or a greater than 2-cm discrepancy in transverse diameter compared to the normal parenchyma was observed. The echogenicity or degree of enhancement of the salivary gland was compared with that of the adjacent muscle. The salivary gland was considered heterogeneous when nonuniform echogenicity was shown in the parenchyma. On CT, postcontrast images were compared with precontrast images to identify enhancement of the salivary gland. Fatty degeneration was identified on CT or US when most of the salivary gland parenchyma showed fat echogenicity or attenuation. Finally, diffuse intraductal dilatation of the salivary gland was defined when ducts were obviously seen. 2.4. Data analysis We used univariate analysis (t test for continuous variables and χ 2 or Fisher’s Exact Test for noncontinuous variables) to evaluate the
397
Table 1 Patients demographics Age (years) Sex F/M Dose of RIT 1100 MBq 3700 MBq 5550 MBq 7400 MBq More than two RIT Follow-up period (month) Interval between RIT and latest imaging (month) Remnant thyroid tissue after operation Histology (papillary/follicular) TNM stage *exclusion of 21 patients I II III IVa IVb
49.3 34/130 46 45 62 4 7 24.5 14.4 5 159/5 35 4 34 50 0
relationship between subjective symptoms of salivary gland dysfunction and multiple clinical factors, which included patients’ age, sex, tumor histology, and the dose of RIT. χ2 test with linear by linear association was performed to show the direction of the relationship associated with variable RIT dose. SAS (version 9.2; SAS Institute Inc., Cary, NC, USA) and Microsoft Excel (Redmond, WA, USA) were used for all statistical analyses. P values less than .05 were considered significant. 3. Results 3.1. Symptom evaluation The symptoms of salivary gland dysfunction are outlined in Table 2. Of the 164 patients, 76 (46.3%) complained of symptoms related to salivary gland dysfunction after RIT. Swelling of the salivary gland was the most frequent symptom and was observed in 46 of 76 patients (60.5%). Xerostomia and pain were observed in 41 (53.9%) and 18 (23.7%) patients, respectively. Twenty-five of the 76 patients (32.9%) showed more than two symptoms. In 60 patients who had symptoms of pain and/or swelling, the most frequently involved site was the preauricular area in 28 patients (46.7%), followed by the submandibular area in 16 patients (26.7%). The remaining 16 patients (26.7%) showed involvement of both sites. When we divided the time interval between the development of symptoms and RIT into four periods, as shown in Table 2, the development of symptoms related to salivary gland dysfunction was most frequently observed within 6 months after RIT (28 patients, 36.8%). In univariate analysis, there were no significant differences between patients with and without symptoms after RIT based on age, sex, or tumor histology; however, there was a significant difference in salivary gland dysfunction among the various doses of RIT (1100 MBq, 3700 MBq, 5550 MBq, 7400 MBq, and more than two RIT doses), which showed that salivary gland dysfunction increased as the dose of RIT increased (Pb .001, Table 3). Persistent complaints of salivary gland dysfunction were present in 54.5% of patients who participated in more than 1 year of follow-up and in 60.6% of patients with more than 2 years of follow-up. 3.2. Imaging findings Based on the latest imaging study, 40 patients (24.4%) showed salivary gland changes on US or CT. The mean interval between RIT and the latest follow-up imaging study was 14.4 months. Among 40 patients who underwent US or CT, a decrease in salivary gland volume was the most common finding, observed in 20 patients (50%), followed by a change of echogenicity or density in 15 patients (37.5%), fatty degeneration in 10 patients (25%), and ductal dilatation
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Fig. 1. A 29-year-old woman who underwent two courses of RIT with doses of 5550 MBq and 7400 MBq, respectively, after total thyroidectomy and complained of persistent xerostomia. (A) Follow-up US with longitudinal scan at 1 month after the last RIT showed hypoechoic and swelling of both submandibular glands, suggesting acute sialadenitis. (B) Two years later, both submandibular glands showed a prominent decrease in volume with marginal retraction (arrow) and heterogeneous echogenicity, suggesting progression to chronic sialadenitis.
in 3 patients (7.5%). Of the 164 patients included in this study, 76 patients (46.3%) manifested more than one symptom related to salivary gland dysfunction. Among the patients with symptoms, 50% showed
positive imaging findings; however, in the 88 patients without symptoms, only 2 (2.3%) patients had abnormal imaging of the salivary gland on US (Fig. 3).
Fig. 2. A 31-year-old women who had xerostomia and taste disturbance after RIT with a dose of 7400 MBq. (A) Axial CT scan of neck in a papillary thyroid carcinoma patient before radiotherapy. The attenuation of the left parotid gland is lower than that of the adjacent masseter muscle (M). (B) On follow-up CT performed 14 months after RIT (7400 MBq), the left parotid gland (arrow) showed increased attenuation compared with the preradiotherapy scan, and attenuation of the left parotid gland was greater than that of the masseter muscle (M).
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Table 2 Subjective symptoms of salivary gland Symptoms (Sx)
Location
Swelling Xerostomia Pain N2 Sx
46/76 (60.5%) 41/76 (53.9%) 18/76 (23.7%) 25/76 (32.9%)
Time interval between Sx and RIT
Preauricular Submandibular Both sites
4. Discussion Radiation damage to the salivary gland is recognized as the most common nonthyroidal complication after RIT for patients with thyroid cancer and usually presents as radiation sialadenitis [7–9]. It occurs when the salivary gland concentrates iodine through a carriermediated system of Na 131I, similar to that of the thyroid [10]. Sialadenitis can be classified as an early or late complication, according to the period of first symptomatic appearance. The cause and main symptoms may be slightly different for early and late sialadenitis. Early sialadenitis results from an inflammatory infiltrate that causes increased periductal pressure with duct constriction and salivary retention. Therefore, patients with early sialadenitis usually complain of swelling or pain of the salivary gland, but most cases heal spontaneously [7]. Numerous studies on chronic sialadenitis have been reported. It is assumed that incorporation of damage induced by ionizing radiation into the genetic structure of the cells results in permanent gland damage [11]. In patients with chronic sialadenitis, xerostomia is the most prominent symptom [11,12]. A previous study by Alexander et al. reported the incidence of acute sialadenitis as 33% and that of chronic sialadenitis as 42.9% [3]. Recently, Shin et al. reported a lower incidence of chronic sialadenitis (16.4%) when a minimum of 52 months of followup after RIT was completed. In our study, subjective symptoms of salivary gland dysfunction were observed in 46.3% of the patients. Although we did not evaluate the exact incidence of chronic sialadenitis, we identified 40 of 164 patients (24.4%) showing imaging findings of chronic sialadenitis on US or CT. In patients with symptoms of swelling or pain, the parotid gland was the most frequently involved site at 46.7%, comparable with other studies. This was thought to be because the parotid gland is composed of serous cells that are more susceptible to radiation than the mucous cells of the submandibular gland [7,12]. The most important factor affecting salivary gland dysfunction is known to be the RIT dose [7,8,12]. In the current study, we included patients receiving various doses of RIT, including a low dose (1100 MBq) that was commonly used in outpatients. Subjective symptoms of salivary gland dysfunction rarely developed in patients given 1100 MBq compared to patients who were given more than 3700 MBq. We also demonstrated significant differences in the development of sialadenitis between patients given 3700 MBq and 5550 MBq. We think that this result is important if further studies identify no difference in tumor recurrence between the two groups. Our study showed no correlation
28/60 (46.7%) 16/60 (26.7%) 16/60 (26.7%)
Immediately b6 months 6–12 months N12 months
22/76 (28.9%) 28/76 (36.8%) 16/76 (21.1%) 10/76 (13.1%)
between the development of sialadenitis and age, consistent with a report by Jeong et al. [12]. However, Almeida et al. showed that age was the strongest predictor of parotid gland dysfunction, as demonstrated by salivary gland scan and sialometry [13]. Further studies will be required, including investigation of hydration status, remnant thyroid tissue, and age. Salivary gland scans with Tc-99m pertechnetate have been used to evaluate salivary gland function in patients undergoing RIT [14]. Although this is a sensitive and convenient modality for the evaluation of salivary gland function, only a weak association between the presence of symptoms and objective test results has been suggested [3,10,15]. The absence of subjective symptoms in patients with positive objective results from salivary gland scan was thought to be the result of compensatory function by other salivary glands [9]. In comparison to salivary gland scans, the imaging modalities of CT and US are less sensitive for the evaluation of salivary gland dysfunction. However, imaging modalities of CT and US are usually performed at approximately the same time to evaluate tumor recurrence and thus could be used instead of the salivary scan if abnormal findings of salivary gland are identified on CT or US. We suggest that when performing a postthyroidectomy US or CT scan in thyroid cancer patients, care must be taken to not overlook signs of salivary gland dysfunction when investigating tumor recurrence. In our study, 50% of the patients with symptoms showed normal imaging findings of the salivary gland. We assume that some patients with early sialadenitis heal spontaneously without any objective abnormality and the remaining patients may progress to chronic sialadenitis; however, we did not investigate acute versus chronic sialadenitis, and further studies are therefore necessary. A recent study by Nabaa et al. [14] showed imaging findings of chronic sialadenitis on CT scan. A reduction in the volume of the parotid and submandibular glands and an increase in attenuation of the parotid gland on nonenhanced CT images showed a positive correlation with the severity of salivary gland dysfunction on the salivary scan. To our knowledge, no previous study has reported ultrasonographic findings indicating salivary gland dysfunction. Our data showed similar imaging findings on US, namely, a decrease in volume and heterogeneous echogenicity of the salivary gland. The use of sour candy [15] or lemon juice [16] has been recommended during RIT to reduce complications of the salivary gland. These may increase salivation and thereby decrease the transit time and concentration of I-131 [7]. However, there is controversy regarding the ideal start time of
Table 3 Univariate analysis associating subjective symptoms with clinical variables
Age Sex (M/F) Dose of RIT⁎ 1100 MBq 3700 MBq 5550 MBq 7400 MBq N two RIT Type of tumor Papillary Ca. Follicular Ca.
All patients (n=164)
Sialadenitis (n=76)
No complication (n=88)
P value
49.3 34/130
50.4 13/64
48.4 21/67
.379 .287 b.001
46 45 62 4 7
4 21 43 2 6
42 24 19 2 1
159 5
74 3
86 2
.544
⁎ χ2 test with linear by linear association.
Fig. 3. A diagram of patients' symptoms and imaging findings.
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salivation. Kunihiros et al. [17] claimed that early initiation of lemon candy might cause a significant increase in salivary gland damage, thereby enhancing blood flow to the salivary gland and enabling delivery of a greater amount of I-131 to the salivary glands. Medications such as cholinergic and intravenous amifostine also may be helpful for patients with severe symptoms. Most importantly, clinicians should inform and educate patients about the possibility of salivary gland damage caused by RIT. There are some limitations in this study. First, because of its retrospective nature, the imaging modality, follow-up interval, and followup duration were different for each patient. Second, some selection bias may exist in our study because we only included a small number of patients. However, follow-up images were taken only to evaluate whether cancer recurrence is present, and all of the patients were selected in this study regardless of subjective symptoms of salivary gland dysfunction. Finally, the diagnosis of sialadenitis was based on information that the patients provided, and we did not classify early and late sialadenitis. 5. Conclusion In conclusion, salivary gland dysfunction is a relatively frequent complication after RIT and can result in long-lasting discomfort for patients. Because salivary gland dysfunction showed a positive correlation with RIT dose, clinicians should make a careful decision regarding RIT dose. References [1] Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338: 297–306. [2] Schlumberger M, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012; 366:1663–73.
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