Exploring the Link between BMI and Aggressive Histopathological Subtypes in Differentiated Thyroid Carcinoma—Insights from a Multicentre Retrospective Study

Simple Summary Our study aimed to investigate the suggested association between body mass index and aggressive histopathological subtypes of thyroid cancer. Thus, we studied 3868 patients who underwent thyroidectomy from 2020 to 2022 at four European centres. We found that overweight and obese patients with papillary thyroid carcinoma had higher rates of aggressive histopathological subtypes, bilateral, multifocal tumours, and larger nodal metastases. These findings suggest that people with higher body mass index may be at an increased risk of developing more aggressive features of thyroid cancer. Abstract Obesity’s role in thyroid cancer development is still debated, as well as its association with aggressive histopathological subtypes (AHSs). To clarify the link between Body Mass Index (BMI) and AHS of differentiated thyroid carcinoma (DTC), we evaluated patients who underwent thyroidectomy for DTC from 2020 to 2022 at four European referral centres for endocrine surgery. Based on BMI, patients were classified as normal-underweight, overweight, or obese. AHSs were defined according to 2022 WHO guidelines. Among 3868 patients included, 34.5% were overweight and 19.6% obese. Histological diagnoses were: 93.6% papillary (PTC), 4.8% follicular (FTC), and 1.6% Hürthle cell (HCC) thyroid carcinoma. Obese and overweight patients with PTC had a higher rate of AHSs (p = 0.03), bilateral, multifocal tumours (p = 0.014, 0.049), and larger nodal metastases (p = 0.017). In a multivariate analysis, BMI was an independent predictor of AHS of PTC, irrespective of gender (p = 0.028). In younger patients (<55 years old) with PTC > 1 cm, BMI predicted a higher ATA risk class (p = 0.036). Overweight and obese patients with FTC had larger tumours (p = 0.036). No difference was found in terms of AHS of FTC and HCC based on BMI category. Overweight and obese patients with PTC appear to be at an increased risk for AHS and aggressive clinico-pathological characteristics.


Introduction
Thyroid cancer (TC) is an increasingly prevalent disease, particularly in high-income countries, and is projected to become the fourth most common cancer in the United States by 2030 [1,2].Environmental and socio-demographic factors, including higher body mass index (BMI) and obesity, have been hypothesised to be linked to this surge in TC incidence [3][4][5][6].Indeed, obesity, a global epidemic affecting 59% of Europeans, has been Cancers 2024, 16, 1429 2 of 15 causally associated with 13 types of cancers, contributing to approximately 200,000 new cases annually [7][8][9][10].The biological plausibility of obesity's role in thyroid carcinogenesis has been speculated to involve low-grade chronic inflammation, altered cytokine levels, and increased oxidative stress found in this condition.Insulin resistance and hormonal changes, part of the pathological landscape of obesity, may also play a pivotal role [11][12][13].However, obesity's impact on aggressive clinico-pathological characteristics of differentiated thyroid cancer (DTC) remains unclear.Indeed, while some studies have suggested an association between higher BMI and aggressive tumour features of DTC, others have failed to demonstrate such a correlation [14][15][16][17][18]. Conversely, studies exploring the possible link between BMI and aggressive histopathological subtypes of DTC are currently lacking.Identifying TCs with aggressive histology or clinico-pathological characteristics that increase the risk of progression or relapse is crucial for directing therapeutic efforts more effectively and ensuring proper resource management.
This study aimed to assess BMI as a potential risk factor for aggressive DTC subtypes or clinico-pathological characteristics.

Study Design and Patient Selection
We conducted a multicentre retrospective cohort study including patients with a histopathologically confirmed diagnosis of DTC who underwent surgery between January 2020 and December 2022 at 4 european tertiary referral centres for endocrine surgery: Endocrine Surgery Unit-Verona University Hospital (Verona, Italy), Endocrine Surgery Unit-Pisa University Hospital (Pisa, Italy), General Surgery Unit-Cagliari University Hospital (Cagliari, Italy), and 1st Propaedeutic Department of Surgery-AHEPA University Hospital (Thessaloniki, Greece).
The patients included in the present study underwent either hemithyroidectomy, total thyroidectomy, or completion thyroidectomy with or without lymphadenectomy.Patients younger than 18, with incomplete data or with a histopathological diagnosis of anaplastic or poorly differentiated TC, medullary TC, thyroid lymphoma or metastasis were excluded from the study.Patients who underwent lobectomy and subsequent completion thyroidectomy were considered as a single case for the purposes of this analysis.
A written informed consent to anonymised data collection was signed by each patient included in the study.
The present study is in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Data Collection
Patients' clinical data were collected from computerised medical charts and entered into an anonymized database.Data collected included: patient's age at surgery, gender, BMI, preoperative diagnosis, presence of hyperthyroidism or thyroiditis, type of surgery, number of excised and pathological lymph nodes, histopathological diagnosis, neoplasm diameter, histological variant, multifocality and bilaterality, surgical margin status, vascular infiltration, extrathyroid extension, and American Thyroid Association (ATA) risk score for disease recurrence [19].
Histopathological subtypes and features of DTC were classified as aggressive (aggressive histopathological subtype, AHS) based on the latest WHO guidelines for TC classification [21], i.e., according to the following criteria: tall cell PTC (proportion of subtype features ≥30% of total); hobnail PTC (proportion of subtype features ≥30% of total); solid PTC (proportion of subtype features ≥50% of total); columnar cell PTC; diffuse sclerosing PTC; extensively invasive FTC; or angioinvasive FTC with >4 invasion foci.

Continuous variables were expressed as median values and interquartile ranges [IQR],
while categorical variables were presented as frequencies and percentages.
Collected sociodemographic and histopathological characteristics were compared between BMI categories using Mann-Whitney, Kruskal-Wallis, and Chi Square tests as appropriate.
Differences in histopathological features between different BMI categories were tested separately for patients with papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and oncocytic thyroid cancer (HCC).
A multivariate binary logistic regression analysis was performed to test whether BMI represented an independent predictor of AHS using preoperative data as confounders.
For all tests, a p-value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS (Statistical Package for the Social Sciences, IBM SPSS Statistics for Windows, Version 25.0.IBM Corp.: Armonk, NY, USA).

Results
Out of 3925 patients meeting the inclusion criteria, 57 were excluded from the analysis due to missing data.Consequently, the final analysis included 3868 patients.

Discussion
Recent evidence has suggested that obesity may increase the risk of various cancers, including TC.However, the specific role of individual obesity-related factors in carcinogenesis remains uncertain [12,22,23].The association between BMI and TC is believed to be linked to shared hormonal and metabolic factors related to central adiposity, as well as potential interactions with genetic variants of the fat mass and obesity-associated (FTO) gene.Certain FTO gene variants, particularly in combination with higher BMI, have been associated with an elevated risk of TC [24].Moreover, obesity itself may contribute to chronic low-grade inflammation and altered insulin signalling, promoting tumorigenesis [8].However, the current understanding lacks data on the correlation between BMI and aggressive histopathological subtypes of thyroid cancer.
Our study identified significant associations between BMI and the AHS of PTC.Overweight and obese patients exhibited a higher proportion of AHSs of PTC compared to their normal/underweight counterparts.This association was consistent across genders.
In other cancer types, BMI has been identified as a risk factor for the emergence of more aggressive subtypes.For instance, in premenopausal women, obesity is associated with an elevated risk of the triple-negative breast cancer subtype and non-luminal subtypes [25,26].Similarly, a high BMI is linked to an increased risk of borderline serous, invasive endometrioid, and invasive mucinous ovarian cancer subtypes [27].The authors postulated a potential correlation between different cancer subtypes and the inflammatory adipose microenvironment rich in IL-6 and TNF-alpha, along with heightened levels of IGF-1 observed in obese patients.We speculate that similar molecular pathways may play a role in the development of distinct and more aggressive subtypes of PTC in obese individuals.Such molecular pathways may either act independently or interact with other known drivers of PTC tumorigenesis exacerbating tumor aggressiveness in obese individuals.Further in vivo and in vitro studies are needed to investigate the potential effects of adipose-tissue-derived factors on PTC tumorigenesis in obese patients.
Our data indicate that BMI could serve as a predictor of AHS, irrespective of gender.While the strength of the association is modest, we believe that clinicians should not overlook this finding and should consider incorporating BMI monitoring as part of the routine risk assessment for PTC.
In our study, overweight/obese patients with PTC had a higher proportion of bilateral, multifocal tumours, and larger nodal metastases than normal/underweight patients.Additionally, in younger patients (<55 years old) with PTC > 1 cm, the BMI predicted a higher ATA risk class.These associations were not observed in patients with FTC and HCC.
Studies investigating the relationship between BMI and aggressive histopathological features of TC have yielded conflicting results.While some studies have found no positive association between BMI and aggressive tumour features or recurrence [14,28], others have reported a significant association between higher BMI and extrathyroidal extension, multifocality, and lymph node metastasis in PTC [15,16,29].Recent evidence suggests that obese patients with TC may activate different pathways compared to normal-weight patients.In a study by Basolo et al. [30], genes involved in metabolic pathways and immune-cell-related mechanisms were expressed differently in the thyroid tissue of obese patients compared to normal-weight patients.Furthermore, in a study on murine animal models by Kim et al., obesity exacerbated TC progression, resulting in increased tumour growth and a more aggressive type of TC [31].
We hypothesise that obesity may be a potential risk factor for the development of aggressive clinicopathological features in PTC, especially in younger patients.Although the exact mechanisms are not fully understood, it is conceivable that specific molecular pathways and gene expression profiles within adipose tissue, along with low-grade chronic inflammation, could play a role in the emergence of these aggressive features in PTC.
The lack of similar associations in patients with FTC and HCC may be attributed to various factors.We can speculate that the molecular mechanisms leading to the expression of aggressive features in TC among obese individuals could be specific to PTC.Additionally, the relatively small sample size of FTC and HCC patients should be considered, potentially impacting the ability to identify comparable associations in these subgroups.Furthermore, the retrospective nature of our study introduces inherent selection bias, potentially limiting the generalizability of these findings to a broader population.Lastly, in the present study, BMI was used as the primary metric for assessing obesity and overweight status, according to WHO definitions.However, although BMI is a widely accepted and practical measure, future research exploring obesity-related associations with cancer subtypes may also benefit from considering additional measures to provide a more comprehensive evaluation.
A significant strength of this study lies in the inclusion of a multicentric, large, diverse and representative sample, enhancing the external validity of our findings.Furthermore, the robustness of our study is underscored by a meticulous data collection process that systematically included a wide range of histopathological features in the analysis.This comprehensive approach contributed to a more nuanced understanding of the subject and improved our possibilities of identifying meaningful associations within the data.
Although our study supports the correlation between BMI and aggressive histopathological variants, further multicentric prospective studies with homogeneous samples are needed to confirm our results.

Conclusions
Our study contributes insights into the relationship between obesity and DTC, specifically focusing on the potential role of BMI in predicting AHS and aggressive clinicopathological features of PTC.Caution should be used in generalizing these results to other TC subtypes, as the molecular dynamics may vary.Prospective studies are needed to confirm our findings.
Institutional Review Board Statement: This research study was conducted retrospectively from data obtained for clinical purposes.Ethical approval was waived in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.The present study is in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent Statement:
A written informed consent to anonymised data collection was signed by each patient included in the study.

Figure 1 .
Figure 1.Bar chart and pie charts depicting the relative proportion of differentiated thyroid cancers included in the study and each histopathologic subtype within each neoplasm.

Figure 1 .
Figure 1.Bar chart and pie charts depicting the relative proportion of differentiated thyroid cancers included in the study and each histopathologic subtype within each neoplasm.

Table 1 .
Sociodemographic and surgical characteristics of the whole population.

Table 2 .
Pathological characteristics of the whole population.

Table 3 .
Differences in sociodemographic and pathological characteristics of PTC patients between BMI categories.

Table 4 .
Differences in sociodemographic and pathological characteristics of FTC patients between BMI categories.

Table 5 .
Differences in sociodemographic and pathological characteristics of HCC patients between BMI categories.

Table 6 .
Univariate and multivariate logistic regression to identify predictors of AHS.