Occult Thyroid Carcinoma Incidence in Multinodular Goiter Experience of a Medium-Volume Center in Romania

Abstract

Background: Multinodular goiter (MNG) is a common thyroid condition characterized by multiple nodules within the thyroid gland. This study aims to evaluate the incidence and clinical features of occult thyroid carcinoma in patients with multinodular goiter, based on the experience from a medium-volume cancer center. Methods: A retrospective analysis was conducted on patients diagnosed with multinodular goiter who underwent thyroidectomy. Clinical, radiological, and histopathological data were reviewed to identify cases of occult thyroid carcinoma. Factors such as age, sex, and histopathological characteristics were analyzed to determine potential risk factors for malignancy in this cohort. Results: A total of 332 patients with MNG were included in the study, with 61 (17.5%) diagnosed with occult thyroid carcinoma. The incidence of occult carcinoma was more frequent in females, with a notable predilection for papillary carcinoma. Regarding age, occult tumors were more frequently encountered in the 20–40 age group, irrespective of gender. Conclusions: In conclusion, we observed that in our center over a 6-year period, the incidence of thyroid cancer after total thyroidectomy for multinodular goiter sits at 17.5%. Thyroid diseases are more frequent in women, which in turn leads to an increased rate of occult carcinomas. Up to 70% of the cancers were papillary. The clinical risk factors associated with a higher probability of cancer were lower age and female gender.

1. Introduction

Thyroid nodules are relatively frequent in daily medical practice, so almost 67% of the general population has them, with variation depending on the mode of detection (palpation, ultrasonography, or autopsy) [1]. The definition of multinodular goiter refers to an increase in the size of the thyroid gland secondary to one or multiple nodules. In the past, this condition has been considered benign [2].

This conception has been reevaluated due to the publication of multiple studies that suggest that thyroid carcinoma can reach an incidence of up to 15% in these patients or even higher if the population is subselected [3]. One such study published by Shruthi et al. in 2023 aimed to evaluate the incidence of occult carcinoma in polinodular goiter and observed a rate of 12% in postoperative specimens [4]. Another large study on 712 patients published by Guillerme et al. observed that the Bethesda index, advanced age, and a reduced size and number of nodules in MNG were associated with occult papillary carcinoma [5].

Thyroid cancers represent 1% of all malignancies according to GLOBOCAN [4,6]. The prevalence of occult thyroid carcinoma in the United States obtained from general autopsy studies is approximately 7.6% [7].

In Finland, a similar study on cadavers observed 35%. Important disparities exist between countries, so screening and treatment must be adapted to the specific population and environmental risk factors [8].

Cancer diagnosis and risk stratification of patients with goiter are related to the clinical and paraclinical evaluation of thyroid nodules. Although both thyroid cancer and MNG involve abnormal growth within the thyroid gland, they have different causes, characteristics, and treatment approaches.

If there is histopathological confirmation of the malignancy a, three-direction treatment is to be adopted and must include: surgery, radioactive iodine, and long-term thyroid suppression hormone [9]. After diagnosis, thyroid cancer can be enlisted in one of three categories: clinically detected, detected at histopathology after resection due to imagery characteristics, and incidental. Occult thyroid cancer is defined as this last type of malignancy and is the focus of our study, which aimed to observe the incidence of occult thyroid carcinoma confirmed postoperatively in patients diagnosed with MNG. The second endpoints were related to the clinical factors that could influence the probability of occult cancer such as age or gender.

2. Materials and Methods

The study protocol was approved by the institutional review board (IRB) of the Prof. Dr. Agrippa Ionescu, Emergency Clinical Hospital, with the number 251 from 1 September 2024. The study covered a period from 1 January 2018 to 1 July 2024. A total of 332 patients underwent thyroidectomy and were retrospectively evaluated. Inclusion criteria were total thyroidectomy for MNG as indicated by the endocrinology department. The indications for thyroidectomy were high-risk nodules according to the Bethesda scale, local compressive complications, and aesthetics. The functional status of the gland was not considered. The surgical treatment was standard. The thyroid gland was extracted through an anterior cervical Kocher incision. The parathyroid and recurrent laryngeal nerves were identified and preserved as a standard procedure with routine visual identification of the recurrent laryngeal nerves and parathyroid glands. Frozen intraoperative evaluation of the nodules/thyroid tissue was not routinely practiced. The thyroid space was routinely drained. All of the patients received T3 supplements in the first postoperative day which was later adjusted by endocrinologists in ambulatory settings. The variables taken into consideration were: age, gender, preoperative diagnosis, histopathological examination including cancer subtype, and clinical type of goiter. Exclusion criteria were related to preoperative cancer diagnosis through fine needle aspiration (FNA). The data obtained for quantitative analysis were structured as minimum or maximum, means, standard deviation, or median. For categorized variables, frequencies were used. To compare quantitative variables between two populations, the Student t-test was used, while for frequencies, the chi-squared test was used. The program used for all of the statistical evaluations was IBM SPSS Statistics version 22.0, 2020 (IBM Corporation, New York, NY, USA). A statistical significance of 5% p < 0.05 was considered significant.

3. Results

We identified 332 patients who underwent total thyroidectomy for MNG over 5 years. The occult tumors were mainly identified in female patients, but this was not statistically significant as the majority of cases with thyroid pathologies were females (

Table A1. Clinical characteristics of occult carcinoma cases.

Variable	Occult Carcinoma (%)		p Value
Age group	Yes	No	0.152
18–40	48	200
40–80	13	91
Gender
Male	8	53	0.134
Female	53	233

). The majority of the malignancies were in the 18–40 age subgroup (Table A1).

The average BMI was 28 kg. Occult carcinoma was observed in 61 cases, which amounts to 17.57%. By far the most frequent cancer was papillary, which if discovered in time has a multitude of resources to treat it (

Table A2. Patients’ demographics.

Variable	Value
Age (years) Mean years (SD)	47 years (+/− 8.3 years)
BMI	28.2 +/− 2.4 kg
Sex
Female	286
Male	61
Occult Carcinoma
Yes	61
No	271
Subtype
Papilar	50
Follicular	4
Medular	3
Anaplastic	2
Oncocitar	1
Angiosarcoma	1

). Out of 61 cases, 50 were papillary (82%). The rarest subtypes of occult tumors observed were oncoplastic and one case of angiosarcoma (young female–28 years). There was a small difference with regards to BMI values for each gender with 27.9 kg/m² ([CI: 0.85–1.75]) and 29.8 in men [CI: 0.79–3.51]). It was observed that women diagnosed with occult carcinoma had a BMI of 24–27 kg/m² ([CI: 1.02–1.68]).

The average age of the entire group with MNG was 47.3 years. The majority of the group consisted of females n = 286 (82%). The median age of females diagnosed with thyroid carcinoma was 38, while in males, this was 40.

4. Discussion

Over the last 20 years, there has been a steady increase in the incidence of thyroid cancer, irrespective of subtype. This has been mostly attributed to the identification of subclinical cases through the widespread use of ultrasonography and fine needle aspiration. An excellent analysis of the causes of this trend has been made by Morris et al. [10].

External factors such as sex hormones, ionizing radiation, or iodine deficiency have also been incriminated [11,12].

Romania presents some geographical particularities when it comes to diseases of the thyroid gland. It has a high incidence of MNG, mainly due to its rich mountainous terrain that offers low iodine water, and also encounters high rates of thyroid cancer due to the Chernobyl disaster in certain geographical areas which are close to the nuclear plant. Interdisciplinary collaboration with other departments such as pathology or endocrinology is mandatory for correct risk stratification, surgical indication, and postoperative treatment [12].

In our department, total thyroidectomy is currently the standard surgical treatment for MNG when complications such as compression, pain, or high risk of cancer exist. Aesthetics can also be considered an indication for surgery as in iodine deficiency, the thyroid gland reaches extreme sizes and causes severe visual deformity. As with any surgical intervention, total thyroidectomy incurs some inherent risks and complications. Due to recent advancements, the rate of complication is as low as 5% in high-volume centers [13]. Until recently, hemithyroidectomy was considered feasible for unilateral pathologies such as high-risk nodules classified as Bethesda 3, 4, or 5 [14,15].

In these cases, if occult cancer is confirmed at histopathology, a totalization is warranted with an even higher risk of surgical complications [15].

If totalization is not required, the remnant thyroid tissue can at some time develop pathologies which will require surgery. One option to avoid a secondary intervention is to have an intraoperative histopathological evaluation of the thyroid tissue, but these cases increase the costs and overall duration of the surgery and do not exempt the patient from future thyroid disease. Another aspect is related to the functionality of the residual thyroid tissue which can only partially secrete the required hormone quantity, making it difficult to correctly adjust the oral dosage of T3. Overall, the complication rate after total thyroidectomy seems to be similar to that of lobectomy or hemithyroidectomy in experienced centers [11].

We have shifted to total thyroidectomy after observing the increasing trend of occult carcinoma even for unilateral lesions/nodules. From this point of view, the authors recommend total thyroidectomy for MNG instead of partial thyroidectomy.

The median age of our study group was 47.3 years with a median of 8.3 years. The youngest patient with thyroid cancer was 28 years and had an aggressive form of angiosarcoma cancer. Moreover, as observed in the results, the most aggressive forms of cancers were in people under 40 years as these are related more to inherited genetic defects than those acquired [16].

When compared to older patients but with similar stages, the disease-free survival (DFS) and overall survival (OS) are higher than in younger subgroups, which reflects a clinical behavior of the disease that is not entirely known [16]. Our results are in line with those presented in the literature. The most frequent subgroup, irrespective of sex, affected by occult thyroid cancer is those aged 18–40 years, but then again, this subgroup formed the majority of the study group. In the literature, the ages with the highest incidence vary: females are placed in the 40–44 subgroup, while males are placed in the 70–74 subgroup [17].

These aspects are not generally available between countries or geographical regions as thyroid malignancy is closely related to environmental factors. Luo et al. observed that in a large study of 600 patients, no correlation was observed regarding age groups [18,19].

Nevertheless, it is the authors’ opinion that these age groups need to be considered when deciding between partial or total thyroidectomy on a patient with MNG who does not have a preoperative diagnosis of thyroid carcinoma [20,21]. Occult carcinoma should always be considered as a possibility.

Regarding gender, our study group is mainly composed of females. These results show a higher incidence of cancer in females. In the 20–40 years subgroup, it has been observed that occult thyroid cancer now can be up to five times more frequent than in males [20]. Overall, in women, thyroid disease is up to 10x times more frequent. This is mainly attributed to the immune system. The majority of thyroid diseases from which cancers evolve are autoimmune mediated [21].

Regarding the subtype of occult cancers, papillary cancers were the most prevalent, but this should come as no surprise as papillary cancers, overall, form the bulk of thyroid cancers (up to 70%). When compound variables were used, we observed no statistical differences between cancer incidence in men and women [22,23].

In our study, the overall incidence of occult cancer was increased, placed at 17.57%. This percentage could be considered high when compared to other studies which place it at 10% [24].

The high incidence, from the authors’ point of view, can be attributed to multiple compound factors such as good screening by the endocrinology department, the overall high incidence of thyroid cancer due to the Chernobyl incident, lack of iodine due to the increased size of the mountainous area in Romania which covers over 27% of the country surface, and characteristics of the goiters operated on, which were in advanced stage (large with multiple heterogeneous nodules). All of these factors increase the risk of occult tumors [25,26].

Other authors observed a similar increased incidence of occult thyroid cancer; Smith et al., in their multi-institutional study on 1523 patients, found the overall incidence was placed at 16% [27].

Gandolfi et al. observed that the overall incidence was 14% [28]. Again these values need to be considered in the context of the population, country, and local geography.

Regarding the indication for surgery in MNG, multiple clinical factors should be taken into consideration such as the number of nodules (historically, solitary nodules are associated with a higher risk of thyroid cancer, but recent studies demonstrated that MNG is also associated with a similar risk. Young age and female gender also collaborate, with a higher risk than the overall population. In MNG, Hoang, in his study, demonstrated that selectively biopsying only the dominant nodule increases the risk of missing thyroid cancer by up to 15% when compared to surgery [29]. Cheng et al. demonstrated that the cumulative risk of the nodules in MNG developing cancer equals that of a solitary nodule [30].

Study Limitations

This study is retrospective—as such, we could not control how the data were introduced in the records or how these were maintained. The patients came from multiple regions of the country and there was not a standard preoperative protocol on how the patients were investigated by the endocrinologists. In Romania, a medical record-keeping database does not exist and the majority of the patients were lost to follow-up.

5. Conclusions

In conclusion, we observed in our center over a 4 year period that the incidence of thyroid cancer after total thyroidectomy for MNG sits at 17.57%. Thyroid diseases are more frequent in women, which in turn leads to an increased rate of cancer diagnosis. Up to 70% of the cancers were papillary. The clinical risk factors associated with a higher probability of cancer were lower age and female gender.