Nasolacrimal duct obstruction following radioactive iodine 131 therapy in differentiated thyroid cancers: review of 19 cases

Introduction

The use of post-thyroidectomy adjuvant radioactive iodine 131 (¹³¹I) therapy is associated with dramatic decreases in locoregional recurrences, distant metastasis, and disease-related mortality in patients with differentiated thyroid carcinomas (DTC).¹ Although generally well tolerated, ¹³¹I therapy is associated with substantial, albeit rare, side effects. While gastrointestinal problems, salivary and lacrimal gland complications, gonadal dysfunction, and second malignancies are well documented side effects of ¹³¹I therapy, there is scant literature addressing nasolacrimal duct obstruction (NLDO).^2,3 Different studies have mentioned that the incidence of NLDO was around 3% among DTC patients treated with ¹³¹I therapy. The common presentation is an excessive overflow of tears (epiphora). Other signs and symptoms are the medial canthus mass, recurrent conjunctivitis, or infection (dacryocystitis).⁴

In the Kingdom of Saudi Arabia, DTC has become the second most common malignancy, behind only breast cancer, accounting for more than 10% of all cancers among women.⁵ The majority of these patients require adjuvant ¹³¹I therapy at some point; only a small proportion of these patients can be at risk of ¹³¹I therapy-acquired NLDO, which was the aim of our study. We also aimed to determine the correlation between NLDO and ¹³¹I therapy along with other clinical and treatment parameters in DTC patients receiving ¹³¹I therapy in our population.

Methods

After formal approval from the institutional ethics committee, the medical records of 864 patients, among a total of 1,192 patients, with confirmed DTC who were treated with ¹³¹I therapy in two major tertiary care hospitals during the period from July 2000–December 2012 were reviewed using a computer-based institutional database system. Patients with NLDO were retrieved in the following manner:

• Demographic information (age at diagnosis and sex), as well as data regarding symptomatology, clinical procedures (anterior rhinoscopy and Jones fluorescein dye test), and ¹³¹I therapy doses in millicurie (mCi) were collected.
• Information on the different diagnostic imaging modalities used, including dacryoscintigraphy, computed tomography (CT) dacryography of the neck, and fluorodeoxyglucose positron emission tomography, was collected.
• Data regarding the surgical intervention used, including balloon dilation, stenting, dacryocystorhinostomy (DCR), type of DCR (external or endoscopic endonasal), symptoms relief, and duration of relief were also recorded.
• Any discrepancies in data acquisition were resolved by directly questioning the patients and treating physicians (ear, nose, and throat, oncology, ophthalmology, and nuclear medicine).
• However, no attempt to systematize other associated sinonasal problems (potential confounders) of the patients was performed.

Statistical analysis

The primary endpoint was the frequency of NLDO. All descriptive data were reported as the mean ± standard deviation, and percentages. The secondary endpoint was the correlation of NLDO with ¹³¹I therapy (as tested by Pearson’s correlation coefficients). Efforts were made to minimize the effects of potential confounders, which were controlled using multivariate analysis. Statistical analyses were performed using the computer program SPSS version 16.0. The Kaplan–Meier method was used to predict the cumulative risk of NLDO in our series.

Results

Among the 864 DTC patients who were treated with ¹³¹I therapy, 19 (2.2%) were identified with NLDO (Table 1). No event of NLDO was seen in any patient who was untreated with ¹³¹I therapy or was treated with ¹³¹I therapy doses below 150 mCi. The mean age of the study population was 51.9±10.5 years (range: 39–72 years), and our population consisted of 15 females (78.9%) and four males (21.1%), with a female-to-male ratio of 3.7:1. The mean individual ¹³¹I dose was 311.1±169.3 mCi (range: 150–600 mCi). The mean duration between the date of ¹³¹I therapy and the occurrence of apparent NLDO was 11.6±4.1 months (range: 6.5–20 months).

Table 1 Patients’ characteristics Abbreviations: 131I, radioactive iodine 131; mCi, millicurie; DSG, dacryoscintigraphy; CT, computed tomography; F, female; PTC, papillary thyroid carcinoma; E-DCR, external dacryocystorhinostomy; FTC, follicular thyroid carcinoma; EE-DCR, endoscopic endonasal dacryocystorhinostomy; M, male.

Fourteen (73.7%) patients had bilateral epiphora. Dacryoscintigraphy allowed for the detection of 16 NLDO with a sensitivity of 84.2% (95% confidence interval [CI]: 60.4–96.4) and a specificity of 99.6% (95% CI: 98.9–99.9), while CT dacryography detected all cases of NLDO with a sensitivity of 100% (95% CI: 82.2–100) and a specificity of 100% (95% CI: 82.2–100).

DCR was performed in 32 completely stenosed nasolacrimal ducts of 18 (94.7%) patients – either bilaterally (63.2%) or unilaterally (26.3%). Three patients (15.8%) had endoscopic endonasal DCR. Observation was planned for one patient; but the patient had partial relief and was considered for DCR. Among the DCR patients, complete recovery was obtained in 14 (73.7%) patients, and partial relief was obtained in three (15.8%) patients. The success rates of external DCR and endoscopic endonasal DCR were 85.7% and 66.7%, respectively.

A significant correlation between NLDO and ¹³¹I therapy doses above 150 mCi was seen (R=0.92; R²=0.86; P=0.03). Multivariate analysis showed that ¹³¹I therapy doses above 150 mCi and an age >45 years were important prognosticators (Figure 1).

Figure 1 Kaplan–Meier curve of the cumulative hazard risk of 131I-acquired nasolacrimal duct obstruction. Abbreviation: 131I, radioactive iodine 131.

Discussion

Acquired NLDO secondary to ¹³¹I therapy is an extremely rare complication in patients with DTC. In our cohort, the frequency of NLDO of 2.2% is consistent with other reported results (Table 2).^6–10 The incidence rate of NLDO in the general population is lacking, despite a detailed medical literature search. In the majority of cases, the diagnosis is made upon the basis of spontaneous reporting of epiphora by the patients.⁶ This diagnostic delay leads to complete stenosis of the nasolacrimal ducts, and thus renders these patients to aggressive treatment.⁶ In the clinical setting, the Jones fluorescein dye test is of significant value in NLDO patients.One Australian study has demonstrated that a negative single-drop Jones fluorescein dye test is also predictive of symptomatic improvement after DCR in patients with NLDO.¹¹

Table 2 Different case studies and reports of 131I therapy-acquired NLDO reported in the literature Note: Data are presented as mean or mean ± standard deviation, except where otherwise indicated. Abbreviations: 131I, radioactive iodine 131; NLDO, nasolacrimal duct obstruction; N, number; mCi, millicurie; DCR, dacryocystorhinostomy.

The postulated mechanism for ¹³¹I therapy-acquired NLDO is the direct uptake of ¹³¹I in the nasolacrimal duct membrane epithelial cells via the sodium (Na+)/iodide (I) symporter (NIS) leading to radiation-induced cell damage (inflammation and fibrosis/stenosis).⁹ The NIS is a membrane glycoprotein that mediates ¹³¹I uptake in the thyroid gland and several other extrathyroid tissues (salivary glands, lacrimal glands, and ciliary body of the eye).¹² Recently, Morgenstern et al¹³ have reported the overexpression of NIS in the nasolacrimal ducts using reverse transcriptase polymerase chain reaction and immunohistochemical analyses. In addition to the presence of sinonasal disease at the time of ¹³¹I therapy, the treatment may theoretically further decrease the flow in the nasolacrimal ducts and thus increase the exposure to ¹³¹I, which is secreted through the lacrimal system.³

The diagnosis of ¹³¹I therapy-acquired NLDO is challenging. Other possible causes (allergic or viral conjunctivitis, keratoconjunctivitis sicca, trichiasis, canaliculitis, iritis, and functional causes of excessive tears) should be ruled out to reach a definitive diagnosis of ¹³¹I therapy-acquired NLDO.^{14 131}I therapy-acquired NLDO is defined as: 1) the presence of NLDO in ¹³¹I therapy-treated patients; 2) an ¹³¹I dose–NLDO relationship; 3) immediate onset of symptoms after ¹³¹I therapy; and 4) the bilateral nature of NLDO in most of cases. CT dacryography using diluted contrast medium was found to be an easy and highly sensitive tool to evaluate NLDO in our cohort, which endorsed the findings of Garcier et al.¹⁵

Patients with incomplete NLDO have an excellent outlook with the use of balloon dilation and stenting, as complete recovery of symptoms is observed in 100% of cases.³ Although the literature supports the hypothesis of complete symptom recovery with observation alone, in a few cases of incomplete NLDO, we did not find that observation was a feasible option. The reason for this can be explained by the fact that NLDO is possibly a chronic radiation-induced injury that progresses over a period of time.¹⁶ The DCR success rate of 78.9% in our cohort is consistent with the findings of Fonseca et al.⁶ However, the endoscopic endonasal DCR success rate of 60% is much inferior to that reported in the literature, which warrants more personnel training in this area in our region.¹⁷

Because NLDO impairs the quality of life of a patient significantly, prevention of NLDO is a key issue. Currently, there is no mechanism available to stop the blockage of ¹³¹I uptake in the nasolacrimal ducts via the NIS during ¹³¹I therapy,³ and there is scant data available regarding the prophylactic use of 2-(S)-(3-aminopropylamino) ethylphosphorothioic acid (amifostine) during ¹³¹I therapy.¹⁸ Further, the effectiveness of topical saline drops, nasolacrimal duct massage, and delaying ¹³¹I therapy in patients with acute or chronic sinonasal problems as preventive measures needs to tested. Low ¹³¹I therapy doses, whenever possible, can reduce the incidence of NLDO.¹⁹

The limitations of our study were: 1) no systematic attempt to screen for NLDO or the presence of other potential confounders (sinonasal problems) was performed; and 2) the presence of possible selection and recall bias in our cohort.

Conclusion

In conclusion, NLDO following ¹³¹I therapy in DTC patients is an under-recognized and rare complication, especially at higher ¹³¹I doses (>150 mCi). A multidisciplinary approach (nuclear medicine/oncology, ear, nose, and throat, and ophthalmology) is very important in the prevention and treatment of NLDO.

Author contributions

KHAQ and MAA designed the concept of the study. MAT, MAA, and YB carried out data collection; NJA, IM, and AAA carried out manuscript writing. MAT, YB, and AAA performed statistical analysis. All authors read and approved the final manuscript. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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