DOI: https://doi.org/10.21203/rs.3.rs-1819822/v1
Background: The aim was to analyze clinical characteristics of differentiated thyroid carcinoma (DTC) patients with nasolacrimal duct obstruction after 131I therapy and provide guidance for clinical decision-making.
Methods: Thirty one DTC patients with nasolacrimal duct obstruction were retrospectively enrolled from the Nuclear Medicine Department of Shanxi Bethune Hospital during follow-up of 131I therapy between June 2018 and March 2021.Sixty one thyroid cancer patients without nasolacrimal duct obstruction after 131I therapy were also enrolled to act as a control group. Clinical characteristics, including sex, age, dose, positive anti-thyroglobulin antibodies (TGAb), metastasis and nasal uptake, were analyzed by χ2 test and logistic multifactor regression.
Results: Statistically significant differences were found in patients’ nasal uptake after 131I therapy according to gender (11.8% : 38.7%), age (5.6% : 51.1%), dose (3.4% : 47.6%), stage (18.5% : 70.4%) and iodine uptake (83.3% : 30.2%). There was no significant difference in the proportion of TGAb positive and negative patients according to 131I therapy (χ2=0.27, P=0.782). Multivariate logistic regression analysis showed that gender (2.59), age (1.45), dose (2.36), whether there was iodine uptake of metastatic foci (1.93) and whether there was nasal uptake of iodine (1.70) were all statistically significant influential factors of lacrimal discharge symptoms after iodine therapy.
Conclusion: Patients who were over 50, women, had metastatic iodine uptake, received a dose > 5.55GBq and had nasal intake of 131I were more likely to have nasolacrimal duct obstruction. When determining therapeutic doses of 131I, doctors should weigh multiple factors and suggest that high risk populations be referred to the appropriate ophthalmic surgery for timely diagnosis and therapy.
Thyroid cancer accounts for 3.6% of the world's malignant tumors and its incidence is increasing year by year. Since the 1940s,131I therapy has been used as adjuvant therapy [1] following thyroid cancer surgery. The first dose of 131I for thyroid cancer patients can reach 1.11-7.4GBq and many further rounds may follow, depending on the patient's condition, leading to 131I accumulation. Multiple and high dose 131I [2–4] has potential chronic side effects, such as chronic sialopathy, dry mouth, dry eye, chronic conjunctivitis, obstruction of parotid and/or nasolacrimal ducts, infertility, pulmonary fibrosis, myelodysplasia and rare second primary malignant tumors. Literature estimates put the number of patients suffering ocular complications at 23% and nasolacrimal duct obstruction may have a causal relationship with iodine therapy and related clinical characteristics. The current study aimed to analyze clinical characteristics of patients with nasolacrimal duct obstruction after 131I therapy of thyroid cancer to provide guidance for clinical decision-making.
Ethics statement
The present study was approved by the ethics committee of Shanxi Bethune Hospital. All patients provided written informed consent for their clinical information to be reviewed and the study was carried out in accordance with approved guidelines.
1.1 Research subjects and grouping
(1) Patients: Between June 2018 and March 2021, 31 cases of thyroid cancer with nasolacrimal duct obstruction were selected during follow-up of 131I therapy in the Department of Nuclear Medicine, Shanxi Bethune Hospital. The male: female ratio was 1:14.5 and mean age of onset was 54 ± 13 years (range: 17-71 years). 61 patients with thyroid cancer and without nasolacrimal duct obstruction were also enrolled and had mean age of onset of 46 ± 11 years (range 16-78 years). Those with epiphora and those without were subdivided into those ≤ 55 years and those > 55 years old. Groupings were also subdivided by dosage of iodine into those receiving ≤ 5.55GBq and those receiving > 5.5GBq. Following 131I therapy, whole-body imaging was performed to evaluate the presence of metastases and nasal uptake concentrations.
1) Exclusion criteria were as follows: allergy, nasal cavity/ sinus problems or facial trauma. Patients with contact lenses, autoimmune diseases, medications that may cause tear discharge syndrome and all eye diseases were also excluded from the study.
2) Nasolacrimal duct obstruction was diagnosed by an ophthalmologist according to the following criteria: lacrimal duct irrigation indicating complete obstruction of the lacrimal passage, all flushing fluid flowed back from upper/lower lacrimal dots, the obstruction site was located in the nasolacrimal duct, with or without sticky or purulent secretion. Other secondary factors were excluded.
1.2 Method
(1) Anti thyroglobulin antibodies (TGAb) were determined by electrochemiluminescence immunoassay (Roche) with a detection range of 10-4000 Ku / L. The upper limit of TGAb normal range is 115 Ku / L. If the upper limit of the normal range was exceeded, TGAb was positive.
(2) After therapy, whole body 131I（131I-WBS） imaging was performed:
1) All patients completed the whole body anteroposterior plane imaging (RX- WBS) and neck-chest SPECT / CT fusion imaging on the third day after oral ingestion of 131I（Atomic HighTech Co. Ltd., Guangzhou, China). After the 131I-WBS, a nuclear medicine specialist evaluated the images on the workstation immediately to decide whether to add other parts of tomographic fusion imaging on the basis of SPECT / CT fusion imaging of neck and chest.
2)131I-WBS and SPECT/CT acquisition: Discovery NM / CT 670 dual probe SPECT / CT instrument (GE , USA). The probe is equipped with high energy and low resolution parallel hole collimator. The photopeak was 364kev, the window width was 20%, the matrix was set at 256x1024 and the imaging speed was 5cm / min.
3) SPECT / CT tomographic fusion imaging: the acquisition parameters were as follows: tube voltage 140 kV, tube current 200 mA, slice thickness 375mm and matrices 512×512.JET stream workstation (GE Medical Systems) was applied to obtain the SPECT/CT fusion images .
(3) Image analysis: radionuclide images (WBS and SPECT/CT) were independently evaluated by 2 experienced nuclear medicine physicians blinded to patients’ clinical condition with interpretation in consensus, using diagnostic software (Compass viewer H 4.0, Medivoly Technology Co. Ltd., Shanghai, China).
1.3 Statistical analysis
Clinical data and imaging features were examined. Normally distributed quantitative data is presented as X ± s with count data being described by constituent ratio. Chi square test was used to analyze count data. Logistic regression model was used to analyze related factors. Variables with statistical significance from univariate analysis were included in multivariate regression analysis. All data was analyzed by SPSS 23.0 for windows (SPSS Chicago, IL, USA) software with a p value<0.05 being considered statistically significant.
1.4 Results
Thirty one patients had epiphora and the bilateral: unilateral ratio was 3.4:1. Nineteen patients had metastases, 6 (19.4%) in the lung, 3 (9.7%) in bone, 1 (3.2%) in bone plus kidney and 9 (29.0%) in the neck and/or mediastinal lymph nodes. No obvious metastasis was found in the remaining 12 cases. One patient (3.2%) received only one round of iodine therapy, 25 patients (80.6%) received two and 5 (16%) received three or more. The mean cumulative dose of 131I was 12.06 GBq and the median cumulative dose was 11.1 GBq. Seven cases (22.6%) were TGAb positive and 24 (77.4%) were negative. The earliest onset of epiphora was more than 1 month after the first iodine therapy and the latest was more than 15 months after the second iodine therapy. 26 cases (83.9%) showed uptake of 131I by the nasal cavity and 5 cases (16.1%) did not. Before the ophthalmology diagnosis had been confirmed, 70% of the patients received at least one form of therapy, including warm compress, eye antibiotics, eye glucocorticoids, artificial tears and ointment, nasal glucocorticoids or eye drops. The doctor in charge of lacrimal duct recanalization was not aware of the cumulative dose of radioactive iodine or of the patients’ clinical characteristics. Among the 61 cases of post-131I therapy thyroid cancer without obstruction of the nasolacrimal duct, 1 case (1.6%) had incomplete tumor resection, 3 (4.9%) had lung metastasis, 1 (1.6%) had bone metastasis, 3 (4.9%) had cervical and/or mediastinal lymph node metastasis and no definite metastasis was found in the other cases via therapeutic iodine scans.13 patients (21.3%) received one round of 131I therapy, 47 patients (77.0%) received two and one (1.6%) received three. The average cumulative dose of 131I was 7.77 GBq and the median cumulative dose was 7.4 GBq. 11 (18.0%) patients were TGAb positive and 50 (82%) were negative. There were 60 cases (98.4%) with 131I uptake by the nasal cavity and 1 case (1.6%) without.
Independent variables were assigned to factors influencing epiphora occurrence for the purposes of univariate analysis. The dependent variable was the presence or absence of tears and the independent variables were as follows: gender, age, dose, presence or absence of metastasis, positive TGAb and nasal 131I uptake. Statistically significant differences were shown between different 131I doses among patients who received 131I therapy after the occurrence of epiphora. No significant differences in the incidence of epiphora after 131I therapy between TGAb positive and negative patients were found（χ2=0.270; p=0.782; Table 1).
Table1 Comparative analysis of epiphora symptoms after 131I treatment for thyroid cancer under different clinical characteristics
|
|
symptom（Number of examples/Composition ratio） |
χ2 |
P |
||
|
Yes |
No |
||||
|
Gender |
Male |
2(11.8) |
15(88.2) |
4.489 |
0.046 |
|
|
Female |
29(38.7) |
46(61.3) |
|
|
|
Age(y) |
≦50岁 |
7(15.6) |
38(84.4) |
12.974 |
0.000 |
|
|
＞50岁 |
24(51.1) |
23(48.9) |
|
|
|
Dose(GBq) |
≦5.55GBq |
1(3.4) |
28(96.6) |
17.342 |
0.000 |
|
|
＞5.55GBq |
30(47.6) |
33(52.4) |
|
|
|
Stage |
I |
10（17.2） |
48（82.8） |
19.019 |
0.000 |
|
|
II |
21（61.8） |
13（38.2） |
|
|
|
metastases |
No |
12(18.5) |
53(81.5) |
|
|
|
|
Yes |
19(70.4) |
8(29.6) |
23.007 |
0.000 |
|
TgAb |
Negative |
24(77.4) |
50(82.0) |
|
|
|
|
Positive |
7(38.9) |
11(61.1) |
0.270 |
0.782 |
|
Nasal uptake |
Negative |
5(83.3) |
1(16.7) |
|
|
|
|
Positive |
26(30.2) |
60(69.8) |
- |
0.016 |
“-”=No value.
Multivariate logistic regression analysis showed that gender, age, dose, metastatic foci and nasal uptake were influencing factors for lacrimal symptoms (all p < 0.05). Female patients were 13.363 times more likely to have tears after 131I therapy than male patients. Patients over 55 years were 4.272 times more likely to have epiphora after 131I therapy than those under 55. Epiphora occurred at a 10.54-fold higher rate in patients who received a dosage above 5.55GBq than in those receiving less than 5.55GBq. Similarly, epiphora occurred at a 5.458-fold higher rate in patients with positive nasal uptake than in those with negative nasal uptake. There was also a 6.875-fold higher probability of epiphora in those with metastases than in those without (Table 2).
Table 2 Multivariate Logisitic regression analysis of epiphora symptoms in patients with thyroid cancer after 131I treatment
|
clinical characteristics |
B |
Wald |
Sig. |
Exp(B) |
95% C.I.for Exp(B) |
|
|
Gender |
2.592 |
5.641 |
0.018 |
13.363 |
1.573 |
113.499 |
|
Age |
1.452 |
4.069 |
0.044 |
4.272 |
1.042 |
17.514 |
|
Dose |
2.355 |
4.236 |
0.04 |
10.54 |
1.119 |
99.29 |
|
Nasal uptake |
1.697 |
4.345 |
0.037 |
5.458 |
1.107 |
26.922 |
|
Stage |
2.179 |
8.129 |
0.004 |
8.837 |
1.976 |
39.523 |
|
metastases |
1.928 |
6.88 |
0.009 |
6.875 |
1.628 |
29.033 |
B= Partial regression coefficient;Wald= Chi-square value; SE= Partial regression coefficient; df= degrees of freedom; Sig= salience; Exp ( B) = OR value.
Radioiodine has been used to treat thyroid diseases for more than 70 years. Besides thyroid tissue itself, sweat and salivary glands and the nasal cavity also have the ability to uptake and store iodine through their sodium iodide transporters. Body fluids such as gastric juice, cerebrospinal fluid, breast milk and fetal blood can also incorporate 131I [14] leading to an impact of 131I therapy for DTC on gonadal function and reproductive health. As a result, the effects of 131I therapy have attracted a great deal of attention [5].
As early as 1968, Albrecht and Kreutzig reported salivary gland damage due to high-dose radioactive iodine radiation, leading to dry mouth syndrome and other long-term side effects. Since then, many studies have confirmed this finding and suggested acidic food and parotid gland massage to promote salivary secretion and reduce radiation damage [6–10]. However, few studies have focused on the side effects of eye discomfort, the most common of which is xerophthalmia [11]. Solans [12] and others examined 79 patients after 131I therapy (0.925-18.5GBq) and found that 17.7% developed dry eye symptoms in the first year after therapy. There were also patients with epiphora, the most common cause of which was stenosis or obstruction of the lacrimal passage. The cause of epiphora in thyroid cancer patients is considered to be obstruction of the nasolacrimal duct. The lacrimal gland may secrete radioactive iodine which directly contacts the lacrimal sac and nasolacrimal duct mucosa, resulting in chronic fibrosis of nasal mucosa and causing nasolacrimal duct obstruction [13]. Kloos RT et al. considered direct uptake by the nasolacrimal duct system to be more likely than indirect radiation through radioactive tears. These researchers found that radioactive tear secretion began 15 minutes after oral 123I and reached a peak after about 60 minutes. During the first 4 hours, the total secretion was about 0.01% of the dose. The turnover rate of the lacrimal film system is about 12–16%/min. Therefore, the main cause of nasolacrimal duct obstruction is direct ingestion with the effect of radioactive tears being small. Hormone and metabolic disorders are also a potential cause of gland dysfunction.
In two studies performed by Kloos RT et al., 563 patients with DTC received high-dose 131I therapy, of whom 26 cases (4.6%) developed tears. Sixteen cases had unilateral or bilateral stenosis with lacrimal drainage system obstruction confirmed by ophthalmologists. Ali MJ et al. [14] found that no patient receiving 3.7 GBq had symptoms but 4% (2 / 50) of patients receiving more than 5.55 GBq did. High dose 131I is therefore associated with nasolacrimal duct obstruction. The current study found that 47.6% (30/63) of patients with and 52.4% (33 / 63) of patients without epiphora symptoms received more than 5.55 GBq. The epiphora incidence was 3.4% (1/29) and 96.6% (28/29), respectively. The constituent ratio of epiphora in the group receiving ≤ 5.55 GBq was significantly less than that in the group receiving > 5.55 GBq, a conclusion which is consistent with previous findings. Moreover, patients with Graves' disease have been reported to have nasolacrimal duct obstruction following 131I therapy.
In a study [15] which used single photon emission computed tomography (SPECT) imaging to locate nasal tissue, 131I uptake by the nasal cavity was classified as low, medium or high. For nasal cavity 131I concentrations in excess of 5.55 GBq, the risk of nasolacrimal duct obstruction was increased. The current study found that 83.9% of patients with epiphora had taken in iodine through the nasal cavity. In anatomical terms, the location of the nasolacrimal duct opening in the nasal cavity predisposes it to obstruction on nasal iodine intake which will cause symptoms of lacrimal discharge.
The current study found a higher proportion of women with epiphora than men. The incidence of thyroid cancer among women is 2–3 times higher than that among men. More advanced stage and iodine uptake metastases, combined with the patient's condition, mean that a high dose of 131I is more likely to cause epiphora. Patients over 55 years were also more likely to have epiphora and increased family and social responsibilities, producing greater psychological pressures, may have rendered them more prone to physical dysfunction [16].There have been some multivariate analyses that have concluded that the 131I dose was the only cause of obstruction and which have discounted age, gender and other factors [4]. However, it is difficult to exclude the impact of bias in these contrary findings.
131I therapy may increase the incidence of nasolacrimal drainage system obstruction. For patients over 55 years, female, with 131I uptake metastases, receiving a dose > 5.55 GBq and with nasal uptake of 131I, doctors should be aware of this potential rare complication and multiple factors should be considered when determining appropriate dosages. In order to reduce the incidence of epiphora, it is suggested that high risk populations should be referred to appropriate ophthalmic surgery for timely diagnosis and therapy.
-Ethics approval and consent to participate
The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Liu Xiansheng. Written informed consent was obtained from individual or guardian participants.
-Consent for publication
Not applicable.
-Availability of data and materials
All data generated or analysed during this study are included in this published article.
-Competing interests
The authors declare that they have no competing interests.
-Funding
Not applicable.
-Authors' contributions
Na Li contributed to conceptualization, referencing, and writing of the draft. Wanchun Zhang contributed to editing and providing clinical insight of the manuscript.All authors read and approved the final manuscript.
-Acknowledgements
The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn ) for the expert linguistic services provided.
-Authors' information (optional)
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences,Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University,Taiyuan, 030032, China.
Phone: +86 15835137043 ;E-mail：[email protected]
2.Wanchun Zhang*
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences,Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University,Taiyuan, 030032, China.
Phone: +86 13935131789 ;E-mail：[email protected]