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Abstract

Objective

To analyze the clinical characteristics of differentiated thyroid cancer (DTC) patients with nasolacrimal duct obstruction (NLDO) after Iodine-131 (¹³¹I) therapy and provide guidance for clinical decision-making.

Methods

Thirty-one DTC patients with NLDO were retrospectively enrolled from the Nuclear Medicine Department of Shanxi Bethune Hospital during follow-up of ¹³¹I therapy between June 2018 and March 2021. Eight hundred and seventy-one thyroid cancer patients during this period without NLDO after ¹³¹I therapy were enrolled as the control group. Clinical characteristics, including sex, age, dose, anti-thyroglobulin antibodies (TGAb), and metastatic lesions, were analyzed by χ² test and logistic multifactor regression.

Results

In the NLDO group and without NLDO group, there were statistically significant differences in gender, age, dose, and whether there was metastasis. Among the NLDO group, the proportion of women, age >55 years old, dose >5.55 GBq, and the presence of metastasis was higher, and the difference was statistically significant; There was no significant difference in the proportion of TGAb positive and negative patients based on ¹³¹I therapy (χ² = 0.27, P = .782).Multivariate logistic regression analysis showed that sex (2.59), age (1.45), dose (2.36), and metastatic lesions (1.93) were all statistically significant influential factors of NLDO after iodine therapy. Significant differences were found in the incidence of NLDO between the number of treatment courses (χ² = 23.541, P < .001). Prevalence rate of repeat radioiodine therapy (2 times or 3 times and more) is higher than 1 time.

Conclusion

Women patients over 55 who had metastatic lesions, and received a dose >5.55 GBq, were more likely to have NLDO. When determining therapeutic doses of ¹³¹I, doctors should weigh multiple factors and then give appropriate dosage and suggest that high risk populations be referred for appropriate ophthalmic surgical consultation, for timely diagnosis and therapy.

Keywords

differentiated thyroid carcinoma iodine therapy multivariate analysis nasolacrimal duct obstruction

Introduction

Thyroid cancer accounts for 3.6% of the world's malignant tumors and its incidence is increasing year by year. Since the 1940s, Iodine-131 (¹³¹I) therapy has been used as adjuvant therapy following thyroid cancer surgery.¹ The first dose of ¹³¹I for thyroid cancer patients can reach 1.11–7.4 GBq and many further rounds may follow, depending on the patient’s condition, leading to ¹³¹I accumulation. Multiple and high dose ¹³¹I 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.^2-4 Estimates based on studies put the number of patients suffering ocular complications at 23% and nasolacrimal duct obstruction (NLDO) may have a causal relationship with iodine therapy and related clinical characteristics. The current study aims to analyze clinical characteristics of patients with NLDO after ¹³¹I therapy for differentiated thyroid cancer (DTC), to provide guidance for clinical decision-making.

Materials and methods

Research participants and grouping

1. Patients: Between June 2018 and March 2021, 31 patients having thyroid cancer with NLDO (the symptom is lacrimation) were selected during follow-up of ¹³¹I therapy in the Department of Nuclear Medicine, Shanxi Bethune Hospital. The male to female ratio was 1:14.5 and mean age of onset was 54 ± 13 years (range: 17–71 years). During this period 871 patients with thyroid cancer and without NLDO were all enrolled. The male to female ratio was 1:4.7 and the mean age of onset was 46 ± 11 years (range 16–78 years). Demographic characteristics of the material obtained are shown in Table 1.

Table 1.

Baseline data of the patient subgroups.

Baseline variables	Patient subgroups
Baseline variables	NLDO (N = 31)	Non-NLDO (N = 871)
Age
Mean ± SD	54 ± 13	46 ± 11
Sex
Female/male	2/29	152/719
Cumulative dose of ¹³¹I (GBq)
Mean ± SD	12.06 ± 4.1	7.77 ± 3.4
Median	11.1	7.4
Period after the first dose of ¹³¹I (months)
Mean ± SD	35.2 ± 7.4	60.1 ± 20.4
Median	31(1–43)	54 (4-94)
Period after the last dose of ¹³¹I (months)
Mean ± SD	10.6 ± 3.7	32.9 ± 16.8
Median	9 (1–15)	29 (4–52)

Patients with and without NLDO symptoms were subdivided into ≤55 years and >55 years old. Groupings were also subdivided by iodine dosage into those receiving ≤5.55 GBq and those receiving >5.5 GBq. Following ¹³¹I therapy, whole-body imaging was performed to evaluate the presence of metastatic lesions.

2. Exclusion criteria were as follows: allergy, nasal cavity/sinus problems, or facial trauma. Patients using contact lenses, autoimmune diseases, medications that may cause tear discharge syndrome, and all eye diseases were also excluded from the study.

3. All the patients were diagnosed with NLDO based on lacrimation by an ophthalmologist, according to the following criteria: lacrimal duct irrigation indicating complete obstruction of the lacrimal passage, all flushing fluid flowed back from the upper/lower lacrimal ducts, and the obstruction site was located in the nasolacrimal duct, with or without sticky or purulent secretion. Other secondary factors were excluded. The doctor in charge of lacrimal duct recanalization was not aware of the cumulative dose of radioactive iodine or of the patients’ clinical characteristics.

4. The Institutional Review Board (IRB) approved the experiment.

Methods

1. TGAb values 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, ¹³¹I-whole body scan (WBS) was performed:

1) All patients completed the ¹³¹I-WBS and neck-chest Single-Photon Emission Computed Tomography/Computed Tomography (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 based on SPECT/CT fusion imaging of the neck and chest.

2) ¹³¹I-WBS and SPECT/CT acquisition: The Discovery NM/CT 670 dual probe SPECT/CT instrument (GE, USA) was used. The probe is equipped with a high energy and low-resolution parallel hole collimator. The photopeak was 364 keV, the wiNLDOw width was 20%, the matrix was set at 256 × 1024, and the imaging speed was 5 cm/min.

3) SPECT/CT tomographic fusion imaging: the acquisition parameters were as follows: tube voltage 140 kV, tube current 200 mA, slice thickness 375 mm, and matrices 512 × 512. JET stream workstation (GE Medical Systems) was applied to obtain the SPECT/CT fusion images.

(3) Image analysis: radionuclide images (¹³¹I-WBS and SPECT/CT) were independently evaluated by two experienced nuclear medicine physicians blinded to the patients’ clinical conditions, with consensus of interpretation, using diagnostic software (Compass viewer H 4.0, Medivoly Technology Co. Ltd., Shanghai, China).

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 were analyzed by Statistical Product and Service Solutions (SPSS) version 23.0 for Windows (SPSS Chicago, IL, USA) software, with a P value <.05 being considered statistically significant.

Results

Thirty-one patients had NLDO and the bilateral to 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 rounds, and 5 (16%) received three or more rounds of therapy. 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 NLDO was more than 1 month after the first iodine therapy and the latest was more than 15 months after the second iodine therapy. Before the ophthalmology diagnosis was 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. Among the 871 cases of thyroid cancer after ¹³¹I therapy without NLDO, 3 cases (0.3%) had incomplete tumor resection, 21 (2.4%) had lung metastasis, 9 (1.0%) had bone metastasis, 184 (21.1%) had cervical and/or mediastinal lymph node metastasis, and no definite metastasis was found in the other 554 cases via therapeutic iodine scans. Two hundred and sixty-seven patients (30.7%) received one round of ¹³¹I therapy, 578 patients (66.4%) received two rounds, and 26 (2.9%) received three or more rounds of therapy. The average cumulative dose of ¹³¹I was 7.77 GBq and the median cumulative dose was 7.4 GBq. One hundred and fifty-seven (18.0%) patients were TGAb positive and 714 (82%) were negative.

Independent variables were assigned to factors influencing NLDO occurrence for the purpose of univariate analysis. The dependent variable was the presence or absence of NLDO and the independent variables were as follows: sex, age, dose, presence or absence of metastasis, and TGAb. In patients with NLDO treated with ¹³¹I, there was a statistically significant difference between sex, age, dose, and presence or absence of metastasis. No significant differences were found in the incidence of NLDO after ¹³¹I therapy between TGAb positive and negative patients (χ² = .270; P = .782; Table 2).

Table 2.

Comparative analysis of nasolacrimal duct obstruction after ¹³¹I treatment for thyroid cancer under different clinical characteristics.

Items		Symptom(Number of examples/Composition ratio)		χ2	P
Items		Yes	No	χ2	P
Sex	Male	2(6.5)	153(17.6)	4.489	.046
Sex	Female	29(93.5)	718(82.4)
Age(y)	≤55	11(35.5)	599(68.8)	5.935	.017
Age(y)	>55	20(64.5)	272(31.2)
Dose(GBq)	≤5.55 GBq	1(3.2)	93(10.7)	17.342	<.001
Dose(GBq)	>5.55 GBq	30(96.8)	778(89.3)
Metastases	+	19(61.3)	217(24.9)	23.007	<.001
Metastases	−	12(38.7)	654(75.1)
TgAb	+	7(22.6)	157(18.0)	.270	.782
TgAb	−	24(77.4)	714(82.0)

Note: “−” = Negative,“+” = Positive.

Multivariate logistic regression analysis showed that sex, age, dose, and metastatic lesions were influencing factors (P < .05). Female patients were 13.363 times more likely to have NLDO after ¹³¹I therapy than male patients. Patients over 55 years were 4.272 times more likely to have NLDO after ¹³¹I therapy than those under 55. NLDO occurred at a 10.54 times higher rate in patients who received a dosage above 5.55 GBq than in those receiving less than 5.55 GBq. There was also a 6.875 times higher probability of NLDO in patients with metastases than in those without metastases (Table 3).

Table 3.

Multivariate logisitic regression analysis of nasolacrimal duct obstruction in patients with thyroid cancer after ¹³¹I treatment.

Clinical characteristics	B	Wald	Sig.	Exp(B)	95% C.I.for Exp(B)
Sex	2.592	5.641	.018	13.363	1.573	113.499
Age	1.452	4.069	.044	4.272	1.042	17.514
Dose	2.355	4.236	.04	10.54	1.119	99.29
Metastases	1.928	6.88	.009	6.875	1.628	29.033

Sex, age, presence of metastases, and TgAb positive or not were analyzed on NLDO and non-NLDO at the same dose. There is significant differences between were found at >5.55 GBq in the incidence of NLDO after ¹³¹I therapy. There is all no significant differences were found at ≤5.55 GBq in the incidence of NLDO after ¹³¹I therapy (Table 4).

Table 4.

Comparative analysis of NLDO and non-NLDO under different clinical characteristics at the same dose of ¹³¹I.

Variables		Dose of ¹³¹I(GBq)(≤5.55)		χ²	P	Dose of ¹³¹I(GBq)(>5.55)		χ²	P
Variables		NLDO	Non-NLDO	χ²	P	NLDO	Non-NLDO	χ²	P
Sex	male	0	86	—	1.000	2	180	11.527	.001
Sex	female	2	313			27	292
Age(y)	≤55	3	298	.614	.433	12	430	46.715	.000
Age(y)	>55	2	98			14	45
Metastases	+	1	72	.003	.957	18	257	4.688	.03
Metastases	−	4	271			8	284
TgAb	+	2	69	.009	.924	5	88	.785	.376
TgAb	−	10	320			14	394

Note:“−”:Fisher’s exact test.

There is significant differences were found in the incidence of NLDO between the number of treatment courses (χ2 = 23.541, P < .001) (Table 5). Prevalence rate of repeat radioiodine therapy (2 times or 3 times and more) is higher than 1 times.

Table 5.

Comparative analysis of nasolacrimal duct obstruction after ¹³¹I treatment for thyroid cancer under different number of treatment courses.

	The number of treatment courses			χ²	P
	1 time	2 times	3 times and more	χ²	P
NLDO	1(0.4%)	25(4.1%)	5(16.1%)	23.541	.000
Non-NLDO	267(99.6%)	578(95.9%)	26(83.9%)	23.541	.000

Discussion

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 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^6-10 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. However, few studies have focused on the side effects of eye discomfort, the most common of which is NLDO.¹¹ A review¹² shows the incidence of NLDO is range from 2.2% to 18% following ¹³¹I therapy, in this study, it was 3.4%. Solans et al.¹³ examined 79 patients after ¹³¹I therapy (.925–18.5 GBq) 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, thereby causing NLDO.¹⁴ Bakheet et al.¹⁵ considered direct uptake by the nasolacrimal duct system to be more likely than indirect radiation through radioactive tears. They found that radioactive tear secretion began 15 minutes after oral ¹²³I and reached a peak after about 60 minutes. During the first four 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 NLDO is direct ingestion, with the effect of radioactive tears being small. Furthermore, hormone and metabolic disorders are also a potential cause of gland dysfunction.

The study of Solans et al showed that the original 10 patients identified with nasolacrimal drainage system obstruction had received a mean cumulative ¹³¹I activity of 12.27 ± 2.92 GBq. The mean individual activity was 6.66 ± 0.55 GBq, whereas the mean individual activity administered just before the onset of symptoms was 7.88 GBq. 6 additional patients who were treated with ¹³¹I for thyroid carcinoma identified with nasolacrimal drainage system obstruction, The average cumulative dose of ¹³¹I preceding symptoms was 19.43 GBq. The average treatment activity was 8.33 GBq, treatment activity immediately preceding symptom onset was 11.95 GBq. All 16 patients received doses significantly greater than 5.55 GBq. Burns et al.¹⁶ have observed at cumulative activities of 5.55 GBq of ¹³¹I or higher that patients are at risk for clinically significant nasolacrimal drainage system obstructions; 4.6% of our patients who received radioiodine therapy have documented or suspected obstruction. This is consistent with the conclusion of this study that NLDO is more likely to occur when the cumulative dose of ¹³¹I >5.55 GBq. Ali et al.¹⁷ found that no patient receiving 3.7 GBq had symptoms but 4% (2/50) of patients receiving more than 5.55 GBq had symptoms. High dose ¹³¹I is therefore associated with NLDO. In the current study, we found that 47.6% (30/63) of patients with and 52.4% (33/63) of patients without NLDO received more than 5.55 GBq. The NLDO incidence was 3.4% (1/29) and 96.6% (28/29). The constituent ratio of NLDO in the group receiving ≤5.55 GBq was significantly less than that in the group receiving >5.55 GBq, which is consistent with previous findings. The review¹² shows they are mostly bilateral and noted in patients who receive more than 150 mCi radioiodine. In this study, there are similar findings, it is 79.3% (23/29) of people have bilateral epiphora in more than 5.55 GBq group. Moreover, patients with Graves’ disease have been reported to have NLDO following ¹³¹I therapy.

In the current study, we found a higher proportion of women with NLDO than men. The incidence of thyroid cancer among women is 2 to 3 times higher than that among men. Positive metastatic lesions mean advanced stage, and a high dose of ¹³¹I is more likely to cause NLDO.

This study shows that people older than 55 are more likely to have NLDO, which is inconsistent with the view of Ju-Yeun Lee et al.¹⁸ They believe that the reason for under 50 years are in higher risk of large for NLDO is based on the following two aspects: More active inflammatory reactions in the younger age group may have led to more severe obstruction of the nasolacrimal duct in their study Moreover, it is also postulated that the younger age group may feel more discomfort even with milder symptoms compared with the older age group, leading to a higher frequency of surgery. Patients over 55 years were also more likely to have increased family and social responsibilities, leading to greater psychological pressures, which may have rendered them more prone to physical dysfunction.¹⁹ There have been some multivariate analyses that have concluded that the ¹³¹I dose was the only cause of obstruction, but these analyses discounted age, gender, and other factors. Thus, it is difficult to exclude the impact of bias in these contrary findings.

Vasily D.Yartsev et al.²⁰ showed that severe tearing considered to be a probable sign of NLDO occurs patients after single-dose and patients after repeated radioiodine therapy (8.8% vs 23.9%), the conclusion is consistent with this study; in the current study, we found that the prevalence rate of repeat radioiodine therapy (2 times or 3 times and more) is 4.1% and 16.1% vs 0.4%. Vasily D.Yartsev et al. think since from the histopathological point of view, alteration is followed by the induction of reparative processes that do not always result in fibrosis. At the same time, repeated alterations can contribute to the chronicity of inflammatory process and make a greater contribution to the damage to mucous glands of nasolacrimal duct and to fibrosis induction than the strength of administered dose.

In many cases, DTC has an indolent course and a generally favorable prognosis. However, recurrences may occur in up to 20% of DTC patients, with 10% of them having a fatal outcome (i.e., overall mortality of 65% at 5 years and 75% at 10 years).²¹ The quality of life of some patients of this type will be seriously affected so that they will not give priority to the occurrence of NLDO symptoms. Therefore as a major issue, quite a few patients were that of metastasis whose life expectancy and other morbidities would defer NLDO. In the non-NLDO group, one case placed an endotracheal tube who had incomplete tumor resection, 2 patients with bone metastasis have severe bone pain symptoms. Whether these obvious discomfort symptoms will cover up the occurrence of NLDO is a question worthy of consideration, which is also the deficiency of this experiment. It needs to carry out more detailed follow-up for this group of people.

Conclusion

¹³¹I therapy may increase the incidence of nasolacrimal drainage system obstruction, especially repeat radioiodine therapy. For female patients over 55 years with metastases, when receiving a dose >5.55 GBq, doctors should be aware of this potential rare complication and multiple factors should be considered when determining appropriate dosages. To reduce the incidence of NLDO, it is suggested that high risk populations are referred for appropriate ophthalmic surgical consultation, for timely diagnosis and therapy.

Footnotes

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This study was conducted with approval from the Ethics Committee of Shanxi Bethune Hospital (No: YXLL-2022-027). This study was conducted in accordance with the declaration of Helsinki. Written informed consent was obtained from all participants.

Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

ORCID iD

Wanchun Zhang

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Clinical characteristics of nasolacrimal duct obstruction after iodine therapy in differentiated thyroid cancer patients

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

Research participants and grouping

Methods

Statistical analysis

Results

Discussion

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

Ethical approval

Data availability

ORCID iD

References