Preoperatively undiagnosed papillary thyroid carcinoma in patients thyroidectomized for benign multinodular goiter

ABSTRACT Objective Incidental thyroid cancers (ITCs) are often microcarcinomas; among them, the most frequent histotype is the papillary one. The purpose of this study was to evaluate the rate of papillary thyroid cancer (PTC) in patients thyroidectomized for benign multinodular goiter. Subject and methods We retrospectively evaluated the histological incidence of PTC in 207 consecutive patients who, in a 1-year period, underwent thyroidectomy for benign multinodular goiter. All patients came from an iodine-deficient area (Orleans, France) with three nuclear power stations located in the neighboring areas of the county town. Results Overall, 25 thyroids (12.1%) harbored 37 PTC, of which 31 were microcarcinomas. In these 25 PTC patients, mean age was 55 ± 10 years (range 30-75), female:male ratio 20:5 (4:1). In 10 patients (40% of 25 and 4.8% of 207), PTCs were bilateral, and in 7 (2 with microPTCs) the thyroid capsule was infiltrated. These 7 patients underwent central and lateral cervical lymph node dissections, which revealed lymph node metastases in one and two cases, respectively. Radioiodine treatment was performed in 7 cases. Neither mortality nor transient and permanent nerve injuries were observed. Four (16%) transient hypocalcaemias occurred as early complications. At last follow-up visit (mean length of follow-up 17.2 ± 3.4 months), all patients were doing well and free of any clinical local recurrence or distant metastases. Conclusion With a 12% risk that multinodular goiter harbors preoperatively unsuspected PTCs, which can have already infiltrated the capsule and that can be accompanied by PTC foci contralaterally, an adequate surgical approach has to be considered.


INTRODUCTION
I n the thyroid literature the term incidental has been used to indicate an unsuspected finding; nevertheless, the nature of the incidental finding depends on the clinical context in which the nodules are found.Considering thyroid gland, the identification of thyroid cancer may be classified into 3 broad categories: 1) clinically detected cancer (not incidentally detected), 2) radiologically detected cancer (clinically unsuspected), and 3) pathologically detected cancer (clinically and radiologically unsuspected) (1).Incidental thyroid cancers (ITCs) are often microcarcinomas, most frequently of the papillary histotype (2)(3)(4)(5)(6); the mean tumor size of ITCs decreased during the last decades (3,6).Namely, Boucek and cols.(7) divided ITC diagnoses into four different categories: i) neoplasms found incidentally after thyroidectomy whereas preoperatively only benign pathology was known; ii) neoplasms that were diagnosed incidentally on imaging, mainly ultrasonography (US), and that were evaluated further and confirmed by fine-needle aspiration cytology (FNAC); iii) neoplasms that appeared clinically as lymph node metastases, with primary thyroid carcinoma detected only at histological specimen examination; iv) thyroid cancer that is localized in ectopic thyroid tissue with clinical symptoms or metastases present.Besides these four groups, Liu and cols.(8) proposed another ITC group including patients that presented, Thyroid cancer in patients thyroidectomized for benign multinodular goiter Arch Endocrinol Metab.2018;62/2 despite benign thyroid disease ascertained at imaging and definitive histology, regional or distant lymph node metastases from primary thyroid carcinoma not identified at thyroid pathological examination.
An ITC discovered at histology, after surgical removal of the thyroid for a benign pathology, is the most frequent event (9)(10)(11)(12).In thyroidectomy specimens, ITC prevalence ranges up to 40% (2).In autopsy studies, the reported prevalence of ITC ranges from 0.01% in USA to 35.6% in Finland (7).Recently, a study from U.S.A. have documented that most counties with the highest thyroid cancer incidence are in a contiguous area of eastern Pennsylvania, New Jersey, and southern New York State; radioactive exposures from 16 nuclear power reactors within a 90-mile radius in this area have indicated that these emissions are a likely etiological factor in rising thyroid cancer incidence rates (13).
Over the last 30 years, there has been an increase in the overall incidence of thyroid cancer, from 3.6 (in 1973) to 8.7 (in 2002) per 100,000 inhabitants (14).The incidence rate of papillary thyroid cancer PTC rose up more than any other malignancy (15,16), up to 93% of all thyroid cancers in Japan and up to 85.3% in Western countries (7).PTC is the most common histotype and microPTC represents up to 30% of all forms of papillary cancer (17).
The very recently released American Thyroid Association guidelines on thyroid nodules and cancer underscore that "a recent population based study from Olmsted County reported the doubling of thyroid cancer incidence from 2000-2012 compared to the prior decade as entirely attributable to clinically occult cancers detected incidentally on imaging or pathology" (18)(19)(20).By 2019, one study predicts that papillary thyroid cancer (PTC) will become the third most common cancer in women (21).
The purpose of this study was to evaluate the rate of histologically detected PTC in consecutive patients who were thyroidectomized for benign multinodular goiter (MNG) throughout a 1-year period at a single endocrine surgery unit.Of note, this surgery unit and patients' residence is located near to three nuclear power units.Our data were compared with those of the English language literature on the ITCs.

SUBJECTS AND METHODS
All patients of this retrospective cohort were admitted on the same day of the surgical procedures, performed by 3 experienced endocrine surgeons under general anesthesia.Preoperatively, patients were studied by means of neck US and routine blood test, including hormones levels.The American Society of Anesthesiologists (ASA) physical status was assessed in all patients.In order to obtain a more homogeneous cohort of patients, we excluded patients with suspicious characteristics of the thyroid nodule(s) (i.e.irregular margin and/or contour and/or shape, calcifications, hypoechogenicity, vascularity or local invasion/lymph node metastases) at US (n = 19), history of previous neck surgery (n = 7), history of malignancy in other organs (n = 5) and ASA score greater than 4 (n = 2).
Parathyroid glands and recurrent nerves were identified in all cases, and specimens sent to pathologists for the frozen section; no cervical drains were placed systematically.Patients were discharged, generally in the second post-operative day, with a prescription of a weight-adjusted thyroxine treatment.Patients were referred to our endocrinological outpatient surveillance program.We defined microcarcinoma or macrocarcinoma any cancerous nodule up to 10 mm or greater than in maximum diameter, respectively.When multifocality occurred, we considered the largest neoplasm and classified according to its anatomical site.For purpose of comparison with the international literature, we run a PubMed search entering the words "incidental thyroid cancer" or "incidental thyroid carcinoma".The search was updated until November 2016.The search was limited taking into consideration only original papers.The references of the retrieved articles were also checked so as not to miss important clinical studies.Original articles reporting data about patients who underwent surgery for suspicious or preoperatively documented disease, as well as editorials, commentaries, review articles and similar types of articles were excluded.Animal studies were also excluded.Two researchers (A.S., S.B.) independently reviewed the titles and disagreements were resolved in a consensus meeting.

Statistical analysis
Results are expressed as mean ± standard deviation (SD).Laboratory data without normal distribution were described using median and percentile values.Fisher's exact test was used to analyze categorical data.The level for statistical significance was set at P < 0.05.Statistical analysis was performed using Kyplot v2.0 beta 13 version.

RESULTS
In our study from a French endocrine surgery unit, we retrospectively reviewed 207 consecutive patients, 169 were females (mean age of 53.0 ± 12.6 years [range 18 -79]) and 38 males (mean age of 54.9 ± 14.2 years [range 21-78]), who underwent total thyroidectomy (TT) for benign bilateral MNG from January to December 2014.All patients came from an iodinedeficient area (Orleans, France) (22) with three nuclear power stations located in the neighboring areas of the county town (Figure 1).Clinico-laboratory data of all patients are shown in Table 1.Over the 12-month chronological window of our study, in 25/207 patients (12.1%) we discovered 37 preoperatively unsuspected, and therefore ITCs, all being PTCs.Their ASA score of these patients was ASA1 (n = 4), ASA2 (n = 18) and ASA3 (n = 3).Mean hospital stay was 1.1 ± 0.3 days; 23 (92%) were discharged on the 1 st post-operative day and 2 on the 2 nd post-operative day.
Seven supplementary central and lateral cervical lymph node dissections were carried out, because 2 microPTCs and 5 PTCs were infiltrating the thyroid capsule at frozen sections.Lymph node metastases were found in one and two patients, respectively.Radioiodine treatment, with a dose of 100 mCi, was performed in 7 cases, because of the presence of poor prognostic factors such as capsular infiltration, macroPTC and/or multifocality.
Neither mortality nor transient and permanent nerve injuries were observed.Four (16%) transient hypocalcaemias occurred as early complications, and were successfully treated by a 6-week combined cholecalciferol and oral calcium supplementation.At last follow-up visit (mean length of follow-up 17.2 ± 3.4 months), all patients were doing well and free of any clinical local recurrence or distant metastases.
An overview of the literature is summarized in Table 3 .Reported prevalence of ITC at surgery ranges between 2% and 40% (1,2,17,23-68): in Europe it varies from 2.2% to 27.4% and in the United States it varies from 3.3% to 33%.In some European countries, such as Romania, Czech Republic, Ukraine and Poland, the frequency of thyroid cancer showed a lower range (i.e. from 5 to 9.2%); in Turkey, excluding the study from Tasova and cols.(46), there has been a lower variation range in its reported incidence (7-10%).Rates from other European countries were: 12.5 % from Belgium, 10.4-11.1% from Italy and 12.0% from Greece.

DISCUSSION
The increased incidence of thyroid carcinoma seems to be related to an improved diagnostic approach, given by a widespread use of US and cytology, but also by the employment of new imaging techniques, such as 18 F-fluoro-deoxyglucose positron emission tomogram/computed tomography ( 18 F-FDG-PET/ CT) (69)(70)(71).Among patients who performed neck US for suspected parathyroid disease, incidental thyroid nodules were found in 46% of them (72).Similarly, thyroid incidentalomas discovered during CT or magnetic resonance imaging that had been carried out for other reasons have been reported with an incidence of 16% (73,74); moreover, 9% to 13% were discovered during carotid US (75,76), and 2% to 3% at 18 F-FDG-PET/CT scan (77)(78)(79).The prevalence of incidental thyroid nodules on US in the general population ranges between 42% and 67% (80,81).In thyroidectomy specimens, ITC prevalence ranges up to 40% (2).In autopsy studies, the reported prevalence of ITC ranges from 0.01% in USA to 35.6% in Finland (7).
The overview of the literature (Table 3, refs., has shown that one-third (n = 16) of the studies are on cohorts of thyroidectomized patients smaller than ours (n = 50 to 191, compared to 207), and oneseventh of the studies (n = 7) are on cohorts slightly greater than ours (256 to 8,132).Prevalence of ITC at surgery ranges between 2% and 40% (1,2,17,.In Europe, the frequency of ITC varies from 2.2% to 27.4%, and a similar wide range (3.3% to 33%) is observed in the United States.Interestingly, in Eastern Europe (Romania, Czech Republic, Ukraine, Poland), the frequency of thyroid cancer is relatively low (range 5-9.2%).In Turkey, excluding the study from Tasova and cols.(46), there is a lower variation range in the reported incidence of thyroid cancer (7-10%).
One comment deserves the coexistence of ITCs with HT.We found a 33% rate of ITCs (always microPTCs) in patients with histologically confirmed HT.This rate is greater than that reported in one recent retrospective study from Serbia (37).Slijepcevic and cols.(37) also investigated the prevalence of microPTC in patients operated for benign thyroid diseases in a retrospective study of 2,466 patients who underwent thyroid surgery from 2008 to 2013.The overall prevalence of microPTC was 16.3%, the highest being in HT.Smith and cols.( 63) examined cancer frequency in patients referred for removal of benign thyroid disease in a multiinstitutional series of 2,551 patients.Indeterminate/ malignant FNA diagnoses were excluded (n = 1,028).Overall, 238 (15.6%) cancers were found, and 275 patients had thyroiditis (18%).Presence of thyroiditis was not associated with cancer, because there were 47 ITCs in the 275 patients compared with 191 ITCs in 1,247 patients without thyroiditis (17.1% vs 15.3%).Our rate of 33.3% was highly significant as well as the 22.7% (χ 2 = 10.80,P < 0.001) of Slijepcevic and cols.(37), whereas the rate of 17.1% (χ 2 = 0.388, P = 0.533) reported by Smith and cols.did not reach statistical significance.The limitations of this study are due to its retrospective nature.Another limitation is the natural history of thyroid cancer, which is a slow growing tumor, so that extended follow-up is needed to evaluate the long-term outcomes.The strength of the study lies in its short course, avoiding that a variable number of pathologists histologically examined the specimens using different methods of evaluation.
Our 12.1% rate is comparable to rates from other European countries, including Belgium, Italy (25,30,33) and Greece (17).Because Italy and Greece have no nuclear plants, we tend to exclude that our rate was influenced by the relative vicinity of our medical center and residence of patients to three nuclear plant units (82).A systematic review and meta-analysis on this issue does not support an association between living near nuclear power plants and risk of thyroid cancer.However, sensitivity analysis by exposure definition demonstrated that living less than 20 km from nuclear power plants was associated with a significant increase in the risk of thyroid cancer (83).Additionally, with a 12% risk that MNG harbors preoperatively unsuspected PTCs which can have already infiltrated the capsule and that are accompanied frequently by other PTC foci contralaterally, an adequate surgical approach has to be considered.
The operative management of benign thyroid diseases includes partial and total thyroidectomy: the first one preserves thyroid function, sparing patients the need for lifelong thyroid hormone replacement (84); moreover, microPTCs can have an excellent prognosis not requiring completion thyroidectomy.On the other hand, total thyroidectomy may present complications, such as hypoparathyroidism (often transient) (85) and recurrent laryngeal nerve injury (84), which occurs in 6% and 1% of patients, respectively (84).However, reoperation after partial thyroidectomy can be needed in cases with multifocal thyroid cancer or for radioactive iodine ablation.
In our experience, total thyroidectomy showed neither mortality nor transient and permanent nerve injuries, avoiding the risk of recurrence and necessity of completion thyroidectomy, with its known technical difficulties and increased risk of complications, and also avoiding the risk of ITC presence in remnant tissue.
Disclosure: no potential conflict of interest relevant to this article was reported.

Figure 1 .
Figure 1.Topography of nuclear power plants in the neighboring areas of Orleans, France (ring).

Table 1 .
Demographic and clinico-laboratory characteristics of patients undergoing total thyroidectomy for benign multinodular goiter SD: standard deviation; Tg: thyroglobulin.
Thyroid cancer in patients thyroidectomized for benign multinodular goiter

Table 3 .
Summary of the literature on thyroid cancers that were discovered incidentally at thyroidectomy in patients underwent surgery for benign thyroid disease Thyroid cancer in patients thyroidectomized for benign multinodular goiter Tabulated data taken from the abstracts written in English and/or illustrative material. * Thyroid cancer in patients thyroidectomized for benign multinodular goiter