Predictive Factors for Malignancy in Cytologically Diagnosed Oncocytic Cell Neoplasm of the Thyroid: A Single-Center Analysis

Predictive Factors for Malignancy in Cytologically Diagnosed Oncocytic Cell Neoplasm of the Thyroid: A Single-Center Analysis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 8 February 2025 V1 Latest version Share on Predictive Factors for Malignancy in Cytologically Diagnosed Oncocytic Cell Neoplasm of the Thyroid: A Single-Center Analysis Authors : tsing hsin yi 0009-0009-8414-4688 and Shih-Lun Chang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173900674.46027215/v1 181 views 56 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Background : Oncocytic (Hurthle) cell neoplasms (OCNs) of the thyroid are follicular-derived lesions characterized by abundant eosinophilic cytoplasm due to mitochondrial accumulation. Fine-needle aspiration (FNA) cytology is a primary diagnostic tool for thyroid nodules but struggles to distinguish benign from malignant OCNs, leading to potential overtreatment. Identifying preoperative predictors of malignancy may improve risk stratification. Methods : A retrospective review was conducted at Chi Mei Medical Center from January 2012 to December 2023. Patients with a FNA diagnosis of OCN and subsequent thyroidectomy were included. Demographic data, ultrasound characteristics (tumor size and TIRADS classification), and final histopathological diagnoses were analyzed. Logistic regression models assessed predictors of malignancy (P < 0.05). Results : Of 1998 patients with thyroid nodules exhibiting oncocytic features on FNA, 174 met the inclusion criteria. Malignancy was confirmed in 28 cases (16.1%), with oncocytic carcinoma accounting for 21% of malignant cases. Gender and TIRADS classification were not significantly associated with malignancy risk. Tumor size was a significant predictor, with a cutoff of 1.83 cm demonstrating an adjusted odds ratio (AOR) of 4.22 (95% CI: 1.18–15.09, P = 0.0268) for malignancy. Conclusion : Preoperative differentiation between benign and malignant OCNs remains challenging. Smaller tumor size is associated with a significant risk of malignancy. Given their potential for distant metastasis and resistance to radioactive iodine therapy, diagnostic lobectomy remains the preferred approach for the management of OCNs. Keywords: Oncocytic cell, Hurthle cell, thyroid Key points 1. FNA remains a crucial preoperative tool for evaluating thyroid nodules, though distinguishing benign from malignant oncocytic neoplasms can be challenging. 2. Histopathologic evaluation is essential for definitive diagnosis, as cytologic findings alone may not reliably predict malignancy. 3. Risk stratification plays a key role in shared decision-making, helping patients and clinicians choose between lobectomy and total thyroidectomy when FNA reveals an oncocytic cell neoplasm. 4. Oncocytic cell carcinoma has a poor prognosis due to its high recurrence rate and poor response to radioactive iodine therapy. 5. This study provides insights into the correlation between FNA findings and final pathologic outcomes, supporting more informed clinical decision-making. Predictive Factors for Malignancy in Cytologically Diagnosed Oncocytic Cell Neoplasm of the Thyroid: A Single-Center Analysis Abstract Background : Oncocytic (Hurthle) cell neoplasms (OCNs) of the thyroid are follicular-derived lesions characterized by abundant eosinophilic cytoplasm due to mitochondrial accumulation. Fine-needle aspiration (FNA) cytology is a primary diagnostic tool for thyroid nodules but struggles to distinguish benign from malignant OCNs, leading to potential overtreatment. Identifying preoperative predictors of malignancy may improve risk stratification. Methods : A retrospective review was conducted at Chi Mei Medical Center from January 2012 to December 2023. Patients with a FNA diagnosis of OCN and subsequent thyroidectomy were included. Demographic data, ultrasound characteristics (tumor size and TIRADS classification), and final histopathological diagnoses were analyzed. Logistic regression models assessed predictors of malignancy (P < 0.05). Results : Of 1998 patients with thyroid nodules exhibiting oncocytic features on FNA, 174 met the inclusion criteria. Malignancy was confirmed in 28 cases (16.1%), with oncocytic carcinoma accounting for 21% of malignant cases. Gender and TIRADS classification were not significantly associated with malignancy risk. Tumor size was a significant predictor, with a cutoff of 1.83 cm demonstrating an adjusted odds ratio (AOR) of 4.22 (95% CI: 1.18–15.09, P = 0.0268) for malignancy. Conclusion : Preoperative differentiation between benign and malignant OCNs remains challenging. Smaller tumor size is associated with a significant risk of malignancy. Given their potential for distant metastasis and resistance to radioactive iodine therapy, diagnostic lobectomy remains the preferred approach for the management of OCNs. Keywords: Oncocytic cell, Hurthle cell, thyroid Key points 1. FNA remains a crucial preoperative tool for evaluating thyroid nodules, though distinguishing benign from malignant oncocytic neoplasms can be challenging. 2. Histopathologic evaluation is essential for definitive diagnosis, as cytologic findings alone may not reliably predict malignancy. 3. Risk stratification plays a key role in shared decision-making, helping patients and clinicians choose between lobectomy and total thyroidectomy when FNA reveals an oncocytic cell neoplasm. 4. Oncocytic cell carcinoma has a poor prognosis due to its high recurrence rate and poor response to radioactive iodine therapy. 5. This study provides insights into the correlation between FNA findings and final pathologic outcomes, supporting more informed clinical decision-making. Introduction Oncocytic (Hurthle) cell neoplasms of the thyroid represent a distinct subset of follicular-derived thyroid lesions characterized by abundant eosinophilic cytoplasm due to the accumulation of mitochondria. [1, 2] The term ”oncocyte” specifically refers to this change, while ”oxyphil,” though commonly used, is less precise. Oncocytic transformation represents a metaplastic process commonly observed with aging in various organs, such as the parathyroid and pituitary glands. In the thyroid, however, this change is more often associated with inflammatory processes or neoplastic transformation, particularly within follicular epithelial cells. [3] Fine needle aspiration (FNA) cytology, a cornerstone diagnostic tool for evaluating thyroid nodules, often encounters limitations in distinguishing between benign and malignant oncocytic neoplasms. [4, 5] Oncocytic change is observed in follicular nodular disease and thyroid adenomas, with malignancy characterized by nuclear atypia, invasive behavior, and distinct molecular alterations; However, due to overlapping features between benign and malignant lesions, the definitive diagnosis requires thyroidectomy for histopathological evaluation.[3] As the definitive diagnosis of malignancy requires histopathological evaluation following thyroidectomy, patients may undergo surgery based on indeterminate or suspicious cytological findings, leading to potential overtreatment. [3, 5] Thus, identifying predictive factors that can enhance malignancy risk stratification in oncocytic neoplasms is critical to optimizing patient management and reducing unnecessary surgical interventions. Emerging evidence suggests that certain clinical and demographic characteristics may serve as predictors of malignancy in oncocytic thyroid neoplasms. Recent reports highlight that advanced age and male sex are associated with a higher likelihood of malignancy in these lesions. [6, 7] Furthermore, tumor size, as assessed via ultrasonography, has been identified as an independent predictor of malignancy in Oncocytic cell neoplasms. [7] Understanding the role of these and other potential predictive factors could provide valuable insights into preoperative risk assessment and improve decision-making in the management of oncocytic thyroid nodules. This study aims to conduct a retrospective review at our institution to evaluate the diagnostic performance of FNA cytology in oncocytic thyroid neoplasms and to investigate potential predictors of malignancy, including gender, age, tumor size and the TIRADS classification. By addressing these critical knowledge gaps, this research seeks to contribute to the refinement of diagnostic and management strategies for this challenging subset of thyroid lesions. not-yet-known not-yet-known not-yet-known unknown Materials and Methods Study Design and Setting This retrospective study was conducted at Chi Mei Medical Center, encompassing three departments located in Tainan, Taiwan. The study period spanned from January 2012 to December 2023. Preoperative cytology results from thyroid nodules were reported according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) employed at the time of each patient’s fine needle aspiration (FNA). [16] Patient Selection Patients were identified using the search terms “Hürthle cell” or “oncocytic cell.” According to the definitions outlined in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), oncocytic (Hürthle) cell neoplasm was defined as a nodule composed of classified as Category I (nondiagnostic), Category II (benign), and Category VI (malignant) were excluded, as the study aimed to evaluate cases with a cytologic differential diagnosis of oncocytic (Hürthle) cell neoplasm. Only patients who subsequently underwent thyroidectomy (either total or hemithyroidectomy) during the study period were included. not-yet-known not-yet-known not-yet-known unknown Data Collection Data collected for each patient included demographic variables, such as age at diagnosis and sex. Preoperative ultrasound including size (long axis) and TIRADS grade were collected. Surgical and pathological outcomes were recorded, including the type of thyroidectomy performed (hemithyroidectomy or total thyroidectomy) and the final histopathological diagnosis. Statistical Analysis Descriptive statistics were used to summarize demographic and clinical data. Continuous variables were reported as mean ± standard deviation or median (interquartile range), as appropriate, while categorical variables were expressed as frequencies and percentages. Categorical variables are calculated using Pearson’s chi-square or Fisher’s exact test; continuous variables are estimated using Independent two sample t test. Logistic regression analysis was employed to assess the association between tumor size and malignancy. A size cutoff value predictive of malignancy was determined based on the regression model’s output. Statistical significance was set at *P* < 0.05. All analyses were conducted using SPSS (version X, IBM Corp.) or a similar statistical software platform. Result Initial data included 1998 patients who underwent fine needle aspiration and the cytology results with “hurthle” or “oncocytic” lesion, of which 1727 patients did not undergo surgery and were excluded. Of remaining 271 patients, 97 patients were excluded due to cytology not fulfilling the definition of oncocytic cell neoplasm. 174 total patients were included in the final analysis. There were 30 males and 144 females with an average age (SD) of 51.12 (13.53) years (Table 1). Pre- operative ultrasonographic imaging was available for 62 patients. Table 1. Age, Gender and Size of nodules distribution Surgical pathology Overall, 28 patients (16.1%) were found to have thyroid malignancy (6 Oncocytic cell carcinoma, 2 follicular carcinoma, 19 papillary carcinoma, 1 medullary carcinoma—summarized in Figure 1). Carcinoma was found in 8 of the 90 patients that underwent a hemi- thyroidectomy and 27 of the 85 patients that underwent a total thyroidectomy. Total thyroidectomy 8 of 85 was accidentally found carcinoma, not the target lesion. Of the 146 patients who did not have malignancy, 26 (17.81%) had Oncocytic cell adenoma, 8 (5.48%) had follicular adenoma, 89(60.96%) had nodular goiter, 16 (10.96%) had lymphocytic thyroiditis, 5 (3.42%) had Hashimoto’s thyroiditis, and 2 (1.37%) had other benign findings or fibrosis. Figure 1. Surgical pathology results of 174 patients following hemithyroidectomy or thyroidectomy for patients with thyroid nodules which underwent fine-needle aspiration and were found to be suspicious for Oncocytic (Hurthle) cell neoplasm. n, number of patients Demographic associations Among individuals younger than 65 years, benign pathology was observed in 124 cases, with a higher proportion in females (86.07%) compared to males (76.00%) (Table 2). Malignant pathology in this age group was more evenly distributed, with 24.00% of males and 13.93% of females affected; the difference in gender distribution was not statistically significant (p = 0.2293). In individuals aged 65 years or older, benign pathology was similarly predominant, observed in 22 cases, with females accounting for 86.36% and males 60.00%. Malignant pathology in this age group showed a higher relative proportion in males (40.00%) compared to females (13.64%), although this difference also did not reach statistical significance (p = 0.2207). Overall, the results suggest a non-significant association between gender and thyroid pathology outcomes across both age groups. Table 2. Stratification of Age. Preoperative Ultrasonography Preoperative ultrasonography was available in 62 patients. 11 of the 62 patients were found to have carcinoma upon thyroidectomy. TI-RADS scoring did not significantly predict malignancy (p= 0.76) (Figure 2.). Binary logistic regression did not reveal significant independent predictive factors for the diagnosis of carcinoma on final surgical pathology. Figure 2. Number of patients by TI-RADS Grade The mean size of benign and malignant tumors was 2.65 cm and 2.98 cm, respectively. In the subgroup analysis of oncocytic adenomas and oncocytic malignancies, the mean sizes were 3.18 cm and 3.56 cm, respectively. The comparison of nodules ≥1.83 cm versus <1.83 cm (reference) yielded an AOR of 4.22 (95% CI: 1.18–15.09), with a statistically significant p-value of 0.0268, indicating that larger nodules in this range were significantly associated with an increased risk of malignancy. The AUC for this model was 0.6734, suggesting moderate discriminatory ability. For nodules ≥2 cm compared to <2 cm, the AOR was 1.32 (95% CI: 0.52–3.33), with a non-significant p-value of 0.55 and an AUC of 0.6026. Similarly, nodules ≥2.5 cm versus p-value of 0.64 and an AUC of 0.6086. For nodules ≥3 cm compared to 0.56 and an AUC of 0.6106. In our center’s analysis, we found that a nodule size of 1.83 cm demonstrated predictive value for malignancy. Compared to other reference thresholds, the forest plot (Figure 3.) highlighted statistical significance for this size cutoff, further supporting its clinical relevance in malignancy risk stratification. Figure 3. Forest Plot of Tumor Size and Adjusted Odds Ratios for Malignancy Relative to the Reference Threshold *AUC (Area Under Curve) 1 Giorgadze, Tamar et al(2004)；2Lee, Kwang Hwi et al. (2013)；3 Pisanu, Adolfo et al(2010) Discussion Recent studies have consistently reported that the incidence of malignancy in oncocytic (Hürthle) cell neoplasms (OCNs) ranges from 15% to 33% [7,8,9,22]. Our single-center analysis identified a malignancy rate of 16.1% among patients with OCN who underwent surgical intervention, a figure that closely aligns with previously reported data. Among these malignant cases, 21% were classified as oncocytic cell carcinoma, further corroborating the malignant potential of OCNs, as documented in the contemporary literature. Our analysis did not demonstrate a statistically significant association between gender or TIRADS classification and malignancy risk, a finding consistent with prior studies [8,9,19]. While some reports have suggested that male sex may be a risk factor for malignancy in specific age groups, the evidence remains inconclusive, with conflicting findings across studies [8,9,13]. Within our cohort, patients aged over 65 years with malignant pathology exhibited a higher relative proportion of males (40.0%) compared to females (13.6%). Given that our study represents the largest cohort of OCN cases reported in the Asian population to date, these findings may provide valuable data for future meta-analyses aimed at refining risk stratification models. The optimal nodule size threshold for predicting malignancy in OCNs remains a subject of debate [21], with previous studies proposing cutoffs ranging from 2.0 cm [7] to 3.0 cm [12]. Some predictive models have incorporated a 2.9 cm cutoff as one of multiple parameters [11]. In our cohort, we identified 1.83 cm as a potential size threshold for malignancy prediction. This finding suggests that even smaller nodules may warrant closer clinical scrutiny and could have implications for refining current surgical decision-making algorithms. Overdiagnosis and overtreatment are predominantly concerns in papillary thyroid carcinoma; however, due to the rarity of oncocytic cell carcinoma, its metastatic behavior, and reduced avidity to radioiodine therapy, the management of OCNs may require a more tailored approach [20]. The 2015 American Thyroid Association (ATA) guidelines classify oncocytic thyroid carcinoma (OTC) as a variant of follicular thyroid carcinoma (FTC) and recommend risk stratification based on established parameters. [18] For nodules <4 cm, diagnostic lobectomy is preferred unless specific clinical factors necessitate a more extensive procedure [17,23]. Among 174 patients in our cohort who underwent surgery, 28 were confirmed malignant. Contralateral malignancy was identified in four patients, suggesting that total thyroidectomy at initial surgery may benefit select cases. A patient who underwent lobectomy followed by total thyroidectomy three months later experienced no significant complications. A case-matched study of 295 patients with Hürthle cell carcinoma found no impact of thyroidectomy extent on recurrence-free or overall survival [10]. These findings emphasize individualized surgical planning and the need for further research on the optimal extent of resection. Conclusion The preoperative diagnosis of oncocytic thyroid carcinoma (OTC) remains challenging, as neither fine-needle aspiration (FNA) nor intraoperative frozen section analysis can reliably distinguish benign from malignant lesions. Definitive diagnosis requires histopathological evaluation of the entire tumor to assess for vascular and/or capsular invasion. Although OTC exhibits distinct biological behavior compared to other thyroid malignancies, current clinical management guidelines largely mirror those for follicular thyroid carcinoma (FTC) [14,15]. In our cohort, smaller nodule size and male sex were associated with a potential risk of malignancy. The perioperative complication rate was low, and diagnostic lobectomy was the preferred surgical approach. Study Limitations This study is subject to inherent limitations due to its retrospective design, which introduces potential selection bias. Additionally, a subset of patients did not undergo surgery, precluding definitive histopathological confirmation of malignancy in those cases. However, among patients who underwent thyroidectomy, long-term follow-up and comprehensive clinical records were available, strengthening the reliability of our findings. Despite the relative rarity of OCNs, our study includes a substantial number of cases, representing the largest single-center cohort reported in the Asian literature to date [9,19]. Future prospective studies with larger, multicenter cohorts are warranted to further validate these findings and optimize management strategies for OCNs Reference: 1. LiVolsi V, Baloch ZW, Sobrinho-Simoes M, Tallini G. Hurthle (oncocytic) cell tumors. In: Lloyd RV, Osamura RY, Kloppel G, Rosai J, eds. WHO Classification of Tumors of Endocrine Organs. Lyon, France: IARC; 2017. 2. Maximo V, Sobrinho-Simoes M. 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Suspicious thyroid nodules 4 cm require a diagnostic lobectomy regardless of their benign fine needle aspiration results. Asian J Surg. 2022;45(6):1113-1116. During the preparation of this work, the author used ChatGPT to assist with language refinement and manuscript drafting. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the final version of the publication. Information & Authors Information Version history V1 Version 1 08 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations tsing hsin yi 0009-0009-8414-4688 Chi Mei Medical Center View all articles by this author Shih-Lun Chang [email protected] Chi Mei Medical Center View all articles by this author Metrics & Citations Metrics Article Usage 181 views 56 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation tsing hsin yi, Shih-Lun Chang. Predictive Factors for Malignancy in Cytologically Diagnosed Oncocytic Cell Neoplasm of the Thyroid: A Single-Center Analysis. Authorea . 08 February 2025. DOI: https://doi.org/10.22541/au.173900674.46027215/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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