Incidental diagnosis and surgery outcomes of thyroid cancer in Ecuador

Background: In contrast to the rapid increase in thyroid cancer (TC) incidence, thyroid cancer mortality rates have remained low and stable over the last decades. In Ecuador, however, TC mortality has increased and to determine possible drivers, a retrospective analysis of all patients attending a thyroid cancer referral center in Ecuador was conducted. Methods: From June 2014 to December 2017, a cross-sectional study was conducted at the Hospital de Especialidades Eugenio Espejo (HEEE), a regional reference public hospital for endocrine neoplasia in adults in Quito, Ecuador. We identified the mechanism of detection, histopathology and treatment modalities from a patient interview and review of clinical records. Results: Among 452 patients, 74.8% were young adults and 94.2% (426) of patients were female. 13.7% had a family history of thyroid cancer, and median of tumor size was 2 cm. The incidental finding was 54.2% whereas 45.8% was non-incidental. Thyroid cancer histology reported that 93.3% had papillary thyroid cancer (PTC), 2.7% follicular, 1.5% Hurtle cells, 1.6% medullary, 0.7% poor differentiated, and 0.2% anaplastic carcinoma. The mean MACIS (metastasis, age, completeness, invasion, and size) score was 4.95 (CI 4.15-5.95) with 76.2% of the thyroid cancer patients having MACIS score equal or less than 6. The very low and low risk of recurrence was 18.1% (79) and 62% (271) respectively. An analysis of 319 patients with non-metastatic thyroid cancer showed that 10.7% (34) of patients had surgical complications. Moreover, around 62.5% (80 from 128 patients with thyroglobulin laboratory results) of TC patients had a stimulated-thyroglobulin (sTg) value equal or higher than 2 ng/ml. Overall, a poor surgical outcome was present in 35.1% (112) patients. Out of 436 patients with differentiated thyroid carcinoma (DTC), 86% (n=375) received radioactive iodine (RAI). Conclusion: Thyroid

thyroid cancer histology. However, we observed evidence of overtreatment and poor surgical outcomes that demand additional studies to understand their association with thyroid cancer mortality in Ecuador.

Background
The incidence of thyroid cancer (TC) has increased over the last three decades in most countries around the globe 1 . In the United States, an analysis of the Surveillance, Epidemiology, and End Results (SEER) between 1975 and 2015 found that TC incidence has increased from 4.9 to 15 per 100,000 people 2 . Similar epidemiological changes have been observed in Central and South America. From 2008 to 2012, TC incidence rates in these regions increased 8 to 12 times 3 . In Ecuador, the annual incidence fluctuated from 3 to 22 per 100,000 in the last 16 years, with women having higher incident rates than men 4 .
In contrast with the rapid increased in TC incidence [5][6][7][8] , worldwide thyroid cancer mortality rates have remained low and stable over the last decades [9][10][11] . In Ecuador, however, thyroid cancer incidence and mortality have increased, and Ecuadorian thyroid cancer mortality rates are one of the highest in the world 4,12,13 . Ecuador is a setting with limited epidemiological resources, and the drivers behind this rising incidence and mortality rates are unclear.
Ideally, a large population-based study examining the thyroid cancer characteristics and treatment trends may help clarify the triggers of mortality rate in Ecuador. However, such a study design is not possible with the current TC data infrastructure in Ecuador. Instead, we conducted a retrospective analysis of all patients attending a thyroid cancer referral center in Ecuador to determine possible drivers of high rates of thyroid cancer mortality (type of thyroid cancer diagnosis and surgical outcome). This information might help gain insights into what factors could be contributed to thyroid cancer mortality.

Setting and participants
From June 2014 to December 2017, a cross-sectional study was conducted at the Hospital de Especialidades Eugenio Espejo (HEEE), a regional reference public hospital for endocrine neoplasia in adults in Quito, Ecuador. Ecuador is geographically divided into four major natural regions (Coast, Highland, Amazon, and Galapagos Islands). Due to HEEE is located within the Highland region, its patients come mostly from this area. All the patients who were seen for thyroid cancer at HEEE were included, except the patient who did not have the histopathology report. Patients who had initial management (including surgery) outside HEEE were also included.

Data collection and variables
Two sources of data were used to collect the variables of interest. First, a study coordinator interviewed eligible patients during their first postsurgical appointment at the endocrine clinic. During this process, the study coordinator captured: 1) demographic characteristics such as age, degree of education, region of residence (Coast, Highland, Amazon and Galapagos Islands), age at diagnosis, and ethnicity; 2) family history of TC; 3) environmental risk factors; 4) methods of diagnosis (incidental or non-incidental findings).
Second, study team members reviewed medical records of included patients to extract the following information: 1) thyroid gland functionality (euthyroid, hypothyroidism, or hyperthyroidism), thyroid ultrasound characteristics, and thyroid nodule fine-needle aspiration(FNA) cytologic results based on Bethesda System; 2) surgical characteristics such as type and extension of surgery; 3) thyroid gland histopathological features including tumor size, type, focality, minor or gross local invasion, and cervical lymph node involvement or distant metastases; 4) TC markers measured after thyroidectomy and before radioactive iodine therapy, including thyroid-stimulating hormone (TSH), stimulated thyroglobulin (sTg), inhibited (iTg), and anti-thyroglobulin antibodies (aTg); 5) surgical characteristics such as type and extension of surgery, and complications (hypocalcemia <6 months and >6months after procedure, recurrent laryngeal nerve injury); and finally 6) the radioactive iodine treatment, its doses, and scan results.

Data management
Baseline characteristics data were managed as follows: employment and education were classified according to the National Institute of Statistics and Census (INEC) from Ecuador 14 , and thyroid surgery settings were grouped as tertiary (hospitals providing specialized TC management) and non-tertiary hospitals. Furthermore, patients were considered to have a family history of TC when first and second generation-degree relatives had the disease. Based on thyroid histopathologic features, patients were diagnosed as medullar or non-medullar TC, the latter being further classified as differentiated (papillary and follicular), poorly differentiated, undifferentiated (anaplastic), or squamous cell carcinoma 15 . The risk of recurrence in differentiated TC was calculated by using the American Thyroid Association (ATA) 2009 risk stratification system, which classifies patients' risk of recurrence as low, intermediate, or high 16 . Due to the overwhelming increasing incidence of patients with papillary thyroid cancer (PTC) with an intrathyroidal tumor size of < 1 cm, a new category was included to the ATA risk of recurrence calculator: "very low risk" 17 . Furthermore, the risk of mortality in patients with PTC was estimated based on MACIS score (metastasis, age, completeness, invasion, and size) 18 . A cutoff of 6 was employed to group patients as either low (MACIS < 6) or high risk (MACIS ≥ 6) of mortality.
Thyroid cancer method of detection was divided in two groups: non-incidental diagnosis (when the TC was found in asymptomatic patient) and incidental diagnosis when a thyroid nodule harbouring TC is found during the workup of non-nodular thyroid disease, or during an imaging test requested for reasons unrelated to a thyroid disorder or symptom (e.g. preventive ultrasound), or TC is found incidentally in the histological examination of the thyroid gland removed for a benign condition 11 .
We classified the quality of thyroidectomy based on post-operative thyroglobulin sTg levels (at least 6 weeks after the procedure) 19-21 , and the frequency of surgical complications 22-24 . We considered that the quality of surgery was optimal when there were no post-surgical complications and when patients had a sTg ≤2 ng/dl, and poor when patients had at least one permanent surgical complication or post-operative sTg > 2ng/dL. Given that surgical complications and post-operative sTg levels could be affected by the presence of metastatic disease, we limited the assessment of the quality of surgical outcomes to patients with non-metastatic differentiated TC undergoing initial thyroid surgery (total thyroidectomy and central neck dissection).

Statistical methods
For categorical variables, frequencies and percentages were reported. For numerical variables, we used mean and median with their corresponding standard deviation (SD) or interquartile ranges (IQR), as measurements of central tendency and dispersion. Normal distribution was determined by visual inspection and by using the Kolmogorov-Smirnov test. Our dependent variables used for exploratory analysis were incidental findings and quality of surgery, which are dichotomous variables. For our bivariate and multivariate analysis, we decided to use prevalence ratio (PR) instead of odds ratios (OR), due to PR is easier to interpret and OR tend to overestimate the results 25 . To calculate this PR, we planned to use a generalized linear model (GLM) with the binomial family and the log link.
However, convergence problems were found with some of the variables. Such issues are common 26,27 . At the end we chose, from all possible solutions, to use Poisson as the family for the GLM with robust variance. For the multivariate analyses, we decided to include in the models for incidental findings and poor quality of surgery all variables which p-value was smaller than 0.05 and those considered to be important by the investigators.
The results are reported as prevalence ratios (PR) and their respective 95% confidence interval. Statistical analysis was performed with STATA 44 . TCs having MACIS score equal or less than 6 ( Table 1).
Multivariate analysis, controlled for MACIS score, age, the presence of cervical lymph nodes and risk of recurrence, found that a higher tumor size was associated with higher prevalence of people who were incidentally diagnosed with thyroid cancer (PR= 0.96 [CI: 0.94, 0.97]) ( Table 2).

Treatment modalities Surgical characteristics and outcomes
All patients were treated with total thyroidectomy. An analysis of 319 patients with non-  Table   3).

Iodine therapy
Out of 436 patients with DTC, 86% (n=375) received radioactive iodine (RAI). The median dose of RAI was 100 mCi (IQR: 100-150) and the median lapse between surgery and RAI therapy was 4 months (IQR: 3-7 months). 95% of people with very low risk and low risk, received RAI treatment (Table 4).

Discussion
We conducted a retrospective analysis of all TC patients receiving care at a regional reference hospital in Ecuador. This analysis revealed that 74.8% of TC patients were between 20 and 54 years old, and the majority was papillary thyroid cancer at low or very low risk of recurrence. Approximately half of these cases were found incidentally (patients without symptoms of TC), and a quarter of TC patients had a poor surgical outcome.
Despite being mostly low-risk cancer, all patients receive total thyroidectomy, and the majority received RAI.
Although this sample only represents a small subset of all thyroid cancers in Ecuador, histological characteristics and method of diagnosis are similar to the ones described in other reports 28-33 . We did not see an increased frequency of aggressive thyroid cancer histological findings that might explain the increase in thyroid cancer mortality in Ecuador. We observed that the majority of thyroid cancer cases were of low risk of recurrence and mortality. Moreover, we found that more than half of thyroid cancers were diagnosed incidentally, and the minority of patients presented with symptoms resembling findings in countries where thyroid cancer overdiagnosis drives increasing incident trends 34-37 .
Even though thyroid cancer histology and mode of presentation did not show any hint to explain thyroid cancer increased mortality, we found that there was evidence of overtreatment and poor surgical outcomes. One-third of patients had either surgical adverse event or a post-surgical Tg value that suggested residual benign or malignant thyroid tissue. The high frequencies of poor surgical outcomes suggest a lack of surgical thyroid cancer expertise 38,39 . In Ecuador, there are no residency programs dedicated to training surgeons about the treatment of TC. The few existing thyroid focused surgeons are insufficient in covering the rising demand for new patients with this tumor. Yet, most TC patients do not receive care or treatment in a reference hospital, and thus, they maybe at higher risk of complications and perhaps unrecognized death due to thyroid cancer surgery. Another driver of the increased thyroid cancer mortality in Ecuador, not assessed in this study, maybe attribution bias. That is, patients with thyroid cancer who died, and the cause of death is attributed to thyroid cancer even if cancer was likely not it due 40 .
This misclassification bias exaggerates cancer-specific mortality. Morticians not familiar with thyroid cancer prognosis may be more willing to allocate cause of death to thyroid cancer when the chain of events leading to death is unclear or unknown. Moreover, we observed that the majority of thyroid cancer cases were of low or very low risk of recurrence, however, most of them received high doses of RAI therapy. Although RAI use would not have a detrimental impact of thyroid cancer mortality, it used adds to the patient's burden of treatment and risk of adverse events. 41-43 .

Conclusions
Considering the paucity of population-based cancer registries in Ecuador, this study provides additional information about the thyroid cancer diagnosis and treatment in a tertiary referral center in Ecuador. We observed thyroid cancer histological characteristics and method of diagnosis are like the ones described in other reports without any evidence of the high frequency of aggressive thyroid cancer histologists. However, we observed evidence of overtreatment and poor surgical outcomes that demand additional studies to understand their association with thyroid cancer mortality in Ecuador.

Limitations
This study has several limitations. This is not a population-based study; therefore, selection bias may influence our results. Furthermore, there were patients with missing data, lowering our sample size and confidence in the estimates. Information about the histopathological characteristics and post-surgical treatment were unavailable because not all patients began the treatment in HEE and some of them came to this hospital after surgery or after radioactive therapy was performed. Moreover, in the interview of the patients, the question of family history was exposed to recall bias. Finally, we were not able to provide information about the outcomes for these patients as this data is currently collected and become material for a subsequent study.

Ethics approval and consent to participate
All data were collected from the patient's medical records after obtaining written informed consent. The study was approved by the Hospital Eugenio Espejo review board. All data was anonymized, and all identifiable information and biological samples were storage according to the local guidelines.

Consent to publish
Written informed consent was obtained from every patient in the study.

Availability of data and materials
Since data came from the medical records where sensitive information is collected, no database is publicly available. Nevertheless, anonymized information can be shared privately upon reasonable request at e.ortizprado@gmail.com or jorgeluismh@hotmail.com.

Funding
This work did not receive financial support of any kind except for the publication fee paid in full by Universidad de las Americas, Quito, Ecuador.      Figure 1 Tumor size by method of diagnosis