Variant Of Papillary Thyroid Carcinoma Research Articles

Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer.

Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals. To delineate interpatient variabilities in RAS variants in thyroid tumors based on the fifth World Health Organization classification of thyroid neoplasms and assess their diagnostic significance in cancer detection among patients with thyroid nodules. This prospective diagnostic study analyzed surgically resected thyroid tumors obtained from February 2016 to April 2022 and residual thyroid fine-needle aspiration (FNA) biopsies obtained from January 2020 to March 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data were analyzed from June 20, 2022, to October 15, 2023. Quantitative detection of interpatient disparities of RAS variants (ie, NRAS, HRAS, and KRAS) was performed along with assessment of BRAF V600E and TERT promoter variants (C228T and C250T) by detecting their variant allele fractions (VAFs) using digital polymerase chain reaction assays. Interpatient differences in RAS, BRAF V600E, and TERT promoter variants were analyzed and compared with surgical histopathologic diagnoses. Malignancy rates, sensitivity, specificity, positive predictive values, and negative predictive values were calculated. A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Median (IQR) follow-up for patients who underwent FNA biopsy analysis and subsequent resection was 88 (50-156) days. Of 438 tumors, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS, 29 (6.6%) with HRAS, and 9 (2.1%) with KRAS. The interpatient differences in these variants were discriminated at VAF levels ranging from 0.15% to 51.53%. The mean (SD) VAF of RAS variants exhibited no significant differences among benign nodules (39.2% [11.2%]), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (25.4% [14.3%]), and malignant neoplasms (33.4% [13.8%]) (P = .28), although their distribution was found in 41.7% of NIFTPs and 50.7% of invasive encapsulated follicular variant papillary thyroid carcinomas (P < .001). RAS variants alone, regardless of a low or high VAF, were significantly associated with neoplasms at low risk of tumor recurrence (60.7% of RAS variants vs 26.9% of samples negative for RAS variants; P < .001). Compared with the sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) for BRAF V600E and TERT promoter variant assays, the inclusion of RAS variants into BRAF and TERT promoter variant assays improved sensitivity to 70.5% (95% CI, 65.4%-75.2%), albeit with a reduction in specificity to 88.8% (95% CI, 79.8%-94.1%) in distinguishing malignant neoplasms from benign and NIFTP tumors. Furthermore, interpatient differences in 5 gene variants (NRAS, HRAS, KRAS, BRAF, and TERT) were discriminated in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 nondiagnostic FNAs (23.7%), and all tumors with follow-up surgical pathology confirmed malignancy. This diagnostic study delineated interpatient differences in RAS variants present in thyroid tumors with a variety of histopathological diagnoses. Discrimination of interpatient variabilities in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.

Clinicopathologic Features and Cytologic Correlation of ALK-Rearranged Papillary Thyroid Carcinoma: A Series of Eight Cases.

Anaplastic lymphoma kinase (ALK) gene fusions are rare in papillary thyroid carcinoma (PTC) but may serve as a therapeutic target. This study aims to evaluate the preoperative cytologic findings and clinicopathologic features of a series of eight ALK-rearranged PTCs from our pathology archives and consultations. All cases were confirmed by ALK D5F3 immunohistochemistry and six with additional targeted RNA-based next-generation sequencing (NGS). The original fine-needle aspiration (FNA) cytology diagnosis included the Bethesda System (TBS) category II in three (37.5%), TBS III in two (25%), TBS V in two (25%), and TBS VI in one (12.5%). Six cases had available FNA cytology and were reviewed. The cytologic features showed microfollicular architecture as well aslimited or reducednuclear elongation and chromatin alterations in all six. Nuclear grooves and pseudoinclusions were absent in two cases, rarely or focally noted in three, and frequently found in one. Two cases initially diagnosed asTBS II, showing microfollicular architecture without well-developed nuclear features, were revised to TBS III (with architectural atypia only). For histologic correlations, four were infiltrative follicular variant PTCs, three as classic subtype PTC with predominant follicular growth, and one as solid/trabecular subtype PTC. All eight cases demonstrated reducedPTC nuclear features with respect to nuclear elongation and chromatin alterations compared to thosetypically identified in "BRAF-like" PTCs. The NGS testing revealed EML4::ALK fusion in three, STRN::ALK fusion in two, and ITSN2::ALK fusion in one. In conclusion, although ALK-rearranged PTCs have been associated with neutral gene expression profile from a BRAF-RAS scoring perspective, the "RAS-like" nuclear features were more commonly identified in this series, resulting in frequent indeterminate diagnosis of preoperative FNA.

Ectopic Follicular Variant of Papillary Thyroid Carcinoma in Anterior Neck Region with a Normal Thyroid Gland—A Rare Entity

Ectopic Follicular Variant of Papillary Thyroid Carcinoma in Anterior Neck Region with a Normal Thyroid Gland—A Rare Entity

Do extremely large goiters carry a higher risk of malignancy or complications? A case control study

IntroductionThe definition of thyroid goiter remains ambiguous, yet size may impact both malignancy rate and surgical complications' rate. MethodsAll patients with thyroid goiter who underwent thyroidectomy between 1/2015–1/2023 were included. Goiter was defined as lobe ≥4 cm. For analysis purpose, goiters measuring 4–8 cm and ≥8 cm were defined as large and extremely large goiters, respectively. For malignancy definition, tumor<1 cm in their largest diameter were excluded from study. Collected data included demographics, cytology, histology and postoperative complication. Results144 goiters from 111 patients were included. The most common indication for surgery was symptoms (55 %). Compared with large goiter, extremely large goiters demonstrated a trend for tracheal narrowing on pre-operative CT findings (23 % vs. 45 %, p = 0.07 respectively). Overall differentiated thyroid carcinoma (DTC) rate was 17 % (25/144) without statistical difference between groups (p = 0.89). Within goiters with pre-operative benign cytology, the DTC rate was 17 % (7/43). Follicular variant of papillary thyroid cancer was the most common type for both groups. Nodular hyperplasia was significantly associated with extremely large goiters (53 % vs. 73 %, p = 0.03). No significant difference was found in transient hypocalcemia (48 % [15/31] vs. 41 % [5/12], p = 0.6) and other complications' rate between extremely large goiters and the control group. ConclusionWhen discussing management options for patients with goiters, the size of the goiter should not regarded as a higher risk for complications or malignancy, yet the relatively high malignancy rate found should be taken under consideration for resection.

Papillae, psammoma bodies, and/or many nuclear pseudoinclusions are helpful criteria but should not be required for a definitive cytologic diagnosis of papillary thyroid carcinoma: An institutional experience of 207 cases with surgical follow up.

Noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP) was introduced in 2016 replacing noninvasive follicular variant of papillary thyroid carcinoma, with recommendations to label them "noncancer." To avoid reducing risk of malignancy (ROM) and overdiagnosing NIFTP as malignant, some authors required restricted cytologic criteria (RC) for a definitive diagnosis of papillary thyroid carcinoma (PTC), including papillae, psammoma bodies. or≥3 nuclear pseudoinclusions. Since then, NIFTP criteria have been revised, biologic behavior better understood, and incidence reported to be much lower than initially anticipated. This study examines the impact of RC on PTC cytologic diagnoses, ROM, and detection of clinically significant carcinomas (CSC). A total of 207 thyroid FNAs originally diagnosed as PTC and suspicious for PTC (SPTC) with surgical follow-up were evaluated. RC were retrospectively applied to cases as a requirement for diagnosing PTC, and cases that did not meet RC were reclassified as SPTC. ROMs and diagnostic accuracies of pre- and post-RC diagnoses were correlated with followup CSC. RC were met in 118/142 (83%) and 20/65 (31%) of cases originally diagnosed as PTC and SPTC, respectively. Post-RC, 29% (19/65) of CSC originally diagnosed as SPTC were upgraded to PTC, and 17% (24/142) of CSC originally diagnosed as PTC were downgraded to SPTC. No NIFTPs were diagnosed as malignant. RC should not be required for a definitive diagnosis of PTC when other nuclear features of PTC are diffuse and overt. Applying RC, however, helps the pathologist arrive at a more definitive diagnosis of PTC in suspicious cases.

ThyroSeq overview on indeterminate thyroid nodules: An institutional experience.

Molecular triage of indeterminate thyroid aspirates offers the opportunity to stratify the risk of malignancy (ROM) more accurately. Here we examine our experience with ThyroSeq v3 testing. We analyzed 276 of 658 (42%) fine needle aspiration samples classified as indeterminate thyroid nodules using ThyroSeq v3 (Sept 2017-Dec 2019). The test provides a ROM and detects specific mutations. Surgical diagnoses were reviewed. Of 276 ThyroSeq-tested cases, 42% (n = 116) harbored genetic alterations, whereas 64% (n = 74) had surgical follow-up. Notably, 79% cases within intermediate to higher risk mutations were highly associated with surgical intervention, resulting in a 77.5% ROM when including both cancer and noninvasive follicular thyroid neoplasia with papillary-like features (cancer+NIFTP) and 68% malignant diagnosis when excluding NIFTP. RAS-like alterations were most common (66%), exhibiting a 73.4% ROM and a 59% malignant diagnosis. Interestingly, this group included 24 encapsulated follicular variant papillary thyroid carcinomas (EFVPTCs), 1 infiltrative FVPTC, 9 follicular carcinomas, and 7 NIFTP. Additionally, three high-risk mutations and eight BRAF/V600E mutations had a 100% ROM, all diagnosed as classic-type papillary thyroid carcinoma (cPTC). Combined analysis of thyroid nodules from Bethesda III and IV categories revealed a 78.2% positive predictive value (PPV) and a 75.9% negative predictive value (NPV). ThyroSeq v3 effectively stratifies the ROM in indeterminate thyroid nodules based on specific genetic alterations, guiding appropriate surgical management. Notably, the BRAFV600E/high-risk group and RAS-like groups exhibited ROM of 100% and 77.5%, respectively, with promising predictive accuracy (PPV of 78.2% and NPV of 75.9%).

Sonographic characteristics of diffuse sclerosing variant of papillary thyroid carcinoma with histopathological correlation: a preliminary study

BackgroundDiffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) is a rare but high invasive subtype of papillary thyroid carcinoma, which mandates an aggressive clinical strategy. Few studies have focused on the sonographic characteristics of DSVPTC and the role of ultrasound in diagnosis and treatment of this variant remains unknown. This study aimed to identify and understand DSVPTC more accurately under ultrasound in correlation with pathology.MethodsThe ultrasound characteristics and histopathologic sections of 10 lesions in 10 DSVPTC patients who underwent thyroid surgery at our center between 2014 and 2020 were reviewed and compared with 184 lesions in 168 classic variant of papillary thyroid carcinoma (cPTC) patients.Results6 DSVPTC cases (60%) showed the “snowstorm” pattern on sonogram and 4 cases (40%) presented hypoechoic solid nodules only. Vague borders (100.0% vs. 18.5%, P = 0.019) and abundant microcalcifications (66.7% vs. 10.9%, P = 0.037) were more common in DSVPTC nodules than in cPTC nodules, corresponding to the infiltrating boundaries and numerous psammoma bodies under the microscope respectively. Most of the DSVPTC cases had a heterogeneous background (80%) and suspicious metastatic cervical lymph nodes (80%) on sonograms. All DSVPTC cases had histopathological metastatic cervical lymph nodes.ConclusionThe sonographic “snowstorm” pattern indicated DSVPTC with whole-lobe occupation. Hypoechoic solid nodules with vague borders and abundant microcalcifications on sonogram suggested DSVPTC lesion with an ongoing invasion. Regardless of which of the two sonograms was shown, the corresponding DSVPTC lesions were aggressive and required the same attention from the surgeons.

Abstract 6277: Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching

Abstract The tall cell variant of Papillary Thyroid Carcinoma (TCV-PTC) is the most common aggressive variant of PTC. The impact of TCV-PTC on patients’ prognosis still remains controversial. Moreover, the clinico-pathological and prognostic effect of TCV-PTC from Middle Eastern ethnicity remains unexplored. We aimed to study TCV-PTC in comparison to classical PTC in Middle Eastern patients and their impact on prognosis. We performed a retrospective cohort study of tall cell variant (TCV-PTC) and classic variant of papillary thyroid carcinoma (CV-PTC) after post-surgical radioactive iodine therapy. We used the propensity score matching (1:3 matching ratio) to account for differences between recipients of TCV-PTC vs CV-PTC. Univariate and multivariate analysis were performed to assess the independent factors for persistent/recurrent disease. Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). In total, 174 (16.3%) patients with TCV-PTC and 891 (83.7%) patients with CV-PTC were included. After propensity score matching, 174 pairs of patients were selected (TCV-PTC, n = 174; CV-PTC, n = 522). In the matched analysis, higher proportions of TCV-PTC experienced persistent/recurrent disease compared with CV-PTC (25.7% vs 31.4%; p = 0.0119). In multivariate analyses of clinical and tumor characteristics, histological type of TCV-PTC (odds ratio, 2.09; 95% confidence interval, 1.28-3.40; p = 0.0031) was associated with increased risk of persistent/recurrent disease. The five-year DFS rates for the TCV-PTC and CV-PTC groups were 48.5% and 73.1%, respectively. The Kaplan- Meier analysis indicated that the TCV-PTC group (p &amp;lt; 0.0001) had shorter DFS. In conclusion, when other clinico-pathological factors were similar, this propensity score matched analysis showed that histological subtype TCV-PTC is by itself an independent predictive marker of persistent/recurrent disease in Middle Eastern patients. Therefore, individualized therapeutic approaches might be needed for this aggressive PTC subtype. Citation Format: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari. Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6277.

Abstract 2276: Comprehensive analysis of the genomic landscape of thyroid cancer

Abstract Thyroid cancer, the most common endocrine malignancy, has a high incidence worldwide. Meanwhile, the incidence of thyroid cancer ranks first in Korea. To assess the possible influence of ethnicity on the molecular profile of thyroid cancer, we compared the genomic features of South Korean thyroid cancer with European thyroid cancer. In this study, we performed whole genome sequencing profiling (WGS) for 459 Korean thyroid cancer patients, including papillary thyroid carcinoma (PTC, n = 274), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, n =18), follicular thyroid carcinoma (FTC, n = 16), follicular thyroid adenoma (FTA, n = 63), Hürthle cell adenoma (HCA, n = 22), and invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC, n = 19). We assessed the single nucleotide variant (SNV) and insertions and deletions using Mutect2, Varscan2, and Strelka2. For mutation signature and copy number alterations analysis, we used the Maftools and GISTIC2.0 packages, respectively. Our results revealed that most somatic mutations were similar between the Korean thyroid cancer dataset and the cancer genome atlas program (TCGA). However, the Korean cohort (1%) had a much lower NRAS mutation frequency than the TCGA cohort (8%). Mutation signature analysis showed that SBS6 and SBS2 were highly associated with the TCGA and Korean cohort. SBS6 is related to defective DNA mismatch repair, and SBS2 is characterized predominantly by CC &amp;gt; TT doublet base substitutions. In addition, we identified the NIFTP-specific somatic mutations such as KEAP1 and ZFP36L2. This study presents insights into the genomic landscape of Korean thyroid cancer and reveals some similarities and differences with European thyroid cancer at the molecular level. Citation Format: SooHyun Im, Jong-Lyul Park, Jae-Yoon Kim, Chan-Kwon Jung, Seon-Young Kim. Comprehensive analysis of the genomic landscape of thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2276.

Papillary Thyroid Cancer Trends in the Wake of the COVID-19 Pandemic: Is There a Shift toward a More Aggressive Entity?

Globally, the incidence of papillary thyroid cancer (PTC) has been increasing over the last few decades and it has become the second most common cancer in women in the UAE. There is some evidence to suggest that COVID-19 infection might be directly linked to the development of aggressive variants of PTC. The primary goal of this study was to compare the clinical and pathologic characteristics of thyroid cancer patients treated at the largest endocrine surgery center in Abu Dhabi before and after the COVID-19 pandemic outbreak. This retrospective cohort analysis included patients who underwent elective thyroid surgery at Burjeel Hospital between January 2018 and December 2022. Patients were divided into two groups based on when the COVID-19 outbreak started: group one, comprising patients who had surgery between January 2018 and December 2019 (the "pre-pandemic group"), and group two, comprising patients who had surgery between January 2021 and December 2022 (the "post-pandemic group"). In addition to demographic data, clinicopathological factors, such as aggressive cell type, multifocality, tumor size and location, laterality, lympho-vascular invasion, and extrathyroidal extension, were assessed. We utilized the t-paired test for parametric variables and the Chi-square test for the cross-table analysis. During the study, 1141 people had thyroid surgery, with an annual average of 285 procedures. PTC cases recorded in the final histopathological samples rose from 111 in the pre-pandemic era to 182 in the post-pandemic era. Neither the female-to-male gender ratio, which was 90:21 in the pre-pandemic group and 142:40 in the post-pandemic group (p = 0.532), nor the median age, which was 39.1 and 40.1 years, respectively, varied significantly between the two groups. However, there was a significant increase between pre-pandemic and post-pandemic in the aggressive PTC variants (3% vs. 11.5%, p = 0.001), increased poor prognostic factors such as bilateral multifocality (10.8% vs. 32.4%, p = 0.000), as well as increased capsule-vascular tumor invasion (19.8% vs. 27%); on the other hand, the size of the single foci was 17 mm in the pre-pandemic group compared to 13 mm in the post-pandemic group (p = 0.001). A significant rise in unfavorable prognostic markers and aggressive subtypes of PTC was seen post-pandemic in thyroidectomy patients operated on at a leading endocrine surgery center in the United Arab Emirates.

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study

BackgroundThe effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk.MethodsThis study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined.ResultsThere was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 1.61, 95% CI, 1.09, 2.38; p for trend = 0.05) and significantly decreased risk of follicular variant PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 0.38, 95% CI, 0.16, 0.91; p for trend = 0.04). Further stratified by sex, risk of classical PTC was higher for females (third tertile above LOD vs. <LOD, OR = 2.23, 95% CI: 1.23, 4.06; p-trend = 0.02) than for males (OR = 1.22, 95%CI: 0.72–2.08; p-trend = 0.56), though the test for interaction by sex was not statistically significant (p-interaction = 0.30). Similarly, β-hexachlorocyclohexane (β-HCCH) was associated with a higher risk for classical PTC for women with concentrations ≥LOD versus <LOD (OR = 1.76, 95% CI: 1.07, 2.89), while the effects were null for men. There were no consistent trends when stratified by race or birth year. ConclusionsThe U.S. Environmental Protection Agency has classified HCB and other OCPs we studied here as probable human carcinogens. Our findings of increased risks for classical PTC associated with increased concentrations of HCB and β-HCCH, which were stronger among females, should be replicated in future studies of other populations.

Diagnostic and prognostic utility of TROP-2, SLP-2, and CXCL12 expression in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignancy. Histopathological examination is widely accepted as the gold standard test for the diagnosis of PTC. However, the histopathological examination sometimes can't differentiate PTC from other thyroid diseases. Differentiating PTC from other thyroid diseases is essential for a therapeutic approach and prognosis. The current study was performed to investigate the utility of TROP-2, SPL-2, and CXCL12 mRNA and protein expression in discriminating PTC from other thyroid diseases that mimic PTC. The current study was performed on 75 cases of surgically resected thyroid glands. The cases were distributed in two groups: the PTC group and the non-PTC group. The PTC group consisted of 35 cases (25 patients of the classic PTC variant and 10 patients of the PTC follicular variant). The non-PTC group consisted of 40 cases (10 cases were multinodular goiter, 5 cases were Graves' disease, 5 cases were Hashimoto thyroiditis, 15 patients were follicular adenoma (FA) and 5 cases were follicular carcinoma). TROP-2, SPL-2, and CXCL12 mRNA expression were estimated by qRT-PCR, and protein expression was estimated by immunohistochemistry. There were upregulated TROP-2, SPL-2, and CXCL12 mRNA and protein expressions in PTC compared to non-PTC (P< 0.001, for each). There was a statistically significant upregulation in the mRNA expression of the three genes among PTC cases with larger tumor sizes (P< 0.001, for each), those with tumor stages III and IV (P= 0.008, 0.002 and < 0.001 respectively), and those with LN metastasis (P< 0.001, for each). Moreover, there was a statistically significant upregulation in CXCL-12 gene expression among PTC cases with extra-thyroid extension (P< 0.001). mRNA expression of TROP-2, SPL-2, and CXCL12 among PTC cases increased in larger tumor size, tumor stages III and IV, and LN metastasis. Moreover, there was an increase in CXCL-12 gene expression among PTC cases with extra-thyroid extension. Thus, TROP-2, SPL-2, and CXCL12 expressions could be possible diagnostic and prognostic markers in PTC.

Accuracy of World Health Organisation-grade parameters (necrosis and mitotic activity) and foci of vascular invasion in predicting prognosis of papillary thyroid carcinoma. A case-control validation study.

Tumour necrosis and/or increased mitoses define high-grade papillary thyroid carcinoma (PTC). It is unclear whether angioinvasion is prognostic for PTC. Cut-offs at five or more mitoses/2 mm2 and four or more angioinvasive foci have been empirically defined based upon data from all forms of aggressive non-anaplastic thyroid carcinomas. Performance of tumour necrosis, mitoses and vascular invasion in predicting distant metastases when specifically applied to PTC is undefined. We analysed 50 consecutive PTC cases with distant metastases (DM-PTC): 16 synchronous and 34 metachronous. A total of 108 non-metastatic PTC (N-DM-PTC, 15.0-year median follow-up) were used as controls. Invasive encapsulated follicular variant PTC was excluded. Necrosis, mitoses and angioinvasion were quantified. Receiver operating characteristics (ROC) and area under the curve (AUC) analyses determined best sensitivity and specificity cut-offs predictive of distant metastases. Metastases correlated with necrosis (any extent = 43.8% all DM-PTC, 53.1% metachronous DM-PTC versus 5% N-DM-PTC; P < 0.001), mitoses (P < 0.001) and angioinvasion (P < 0.001). Mitoses at five or more per 2 mm2 was the best cut-off correlating with distant metastases: sensitivity/specificity 42.9%/97.2% all DM-PTC (AUC = 0.78), 18.8%/97.2% synchronous DM-PTC (AUC = 0.63), 54.6%/97.2% metachronous DM-PTC (AUC = 0.85). Angioinvasive foci at five or more was the best cut-off correlating with distant metastases: sensitivity/specificity 36.2%/91.7% all DM-PTC (AUC = 0.75), 25%/91.7% synchronous DM-PTC (AUC = 0.79) and 41.9%/91.7% metachronous DM-PTC (AUC = 0.73). Positive/negative predictive values (PPV/NPV) were: necrosis 22.6%/98.2%; five or more mitoses 32.3%/98.2%; five or more angioinvasive foci 11.8%/97.9%. After multivariable analysis, only necrosis and mitotic activity remained associated with DM-PTC. Our data strongly support PTC grading, statistically validating World Health Organisation (WHO) criteria to identify poor prognosis PTC. Angioinvasion is not an independent predictor of DM-PTC.

In silico annotation of follicular thyroid neoplasm associated metabolic pathways and involved biomarkers: An aid to diagnosis

The follicular thyroid neoplasm (FTN) is like an unsolved puzzle at some stage in preoperative diagnosis. Usually, for preliminary characterization of thyroid lesions, clinicians depend much on fine-needle aspiration cytology (FNAC). However, in the case of FTN, FNAC cannot distinguish between benign and malignant entities, as both are exhibiting predominant follicular architecture. Cytological/ architectural/ or cellular criteria alone is not enough to differentiate Follicular adenoma (FA), Follicular thyroid carcinoma (FTC), Follicular variant of papillary thyroid carcinoma (FVPTC) together with Non-Invasive Follicular variant of Papillary Thyroid Carcinoma (NIFTP), Encapsulated FVPTC (EFVPTC) and well-differentiated neoplasm of uncertain malignant potential. Thus, the genetic analysis can be used as a novel diagnostic approach that should be applied with the traditional method for easy diagnosis of follicular thyroid neoplasm, which reduces the risk of unnecessary surgeries. This present study tried to explore the current genetic assessment of FTN through review of the genetics of FTN studied from 2009 to 2019 which showed the characterization of differential gene expression in these follicular neoplasms some extent. Also, pathway analysis has potentially implemented to minimize the diagnosis dilemma. In addition to the previously identified pathways and associated target genes, some novel endocrine cancer-related pathways with putative target genes of FTN have been remoted from characterizing tumor with follicular pattern. The observed genes might be considered as diagnostic biomarker in the respective FTN associated metabolic pathways.

Presentation and treatment of two cases of malignant struma ovarii

BackgroundMalignant Struma Ovarii (MSO) is a rare type of germ cell tumour which is diagnosed postoperatively on surgical pathology specimens by the presence of differentiated thyroid cancer in mature cystic teratomas in the ovaries. Treatment and follow-up procedures are not clearly established due to the paucity of MSO cases.Case 1A 44-year-old multiparous female presented with an irregular period. Ultrasound showed a left ovarian lesion mostly a dermoid cyst, however, CT showed a 3.8 × 2.7 × 4 cm complex cystic lesion with thick septation and enhancing soft tissue component. Laparoscopic left salpingo-oophorectomy was performed and histopathology showed a follicular variant of papillary thyroid carcinoma arising in a mature cystic teratoma. Peritoneal cytology was positive for malignancy. A thyroid function test was normal before surgery. Total thyroidectomy was performed followed by radioactive (RAI) iodine therapy. Later, a total laparoscopic hysterectomy and right salpingo-oophorectomy were performed. There is no evidence of recurrent disease during the 26-months follow-up.Case 2A 46-year-old single female presented with left lower abdominal pain that had persisted for 2 months. Imaging revealed an 8 × 9 × 9.5 cm left ovarian mass. Laparoscopic left salpingo-oophorectomy was performed and histopathology showed mature cystic teratoma with small papillary thyroid cancer. CT showed no evidence of metastatic disease. Later, the patient had a total thyroidectomy followed by radioactive (RAI) iodine therapy. She was started on thyroxine and later had total abdominal hysterectomy and right salpingo-oophorectomy.ConclusionMSO is a very rare tumour. Preoperative diagnosis is very difficult because of the nonspecific symptoms and the lack of specific features in imaging studies. Also, there is no consensus on the optimal treatment of women with MSO. Our two cases add to the limited number of MSO cases.

The Role of 5-Hydroxymethylcytosine as a Potential Epigenetic Biomarker in a Large Series of Thyroid Neoplasms.

Cytosine modifications at the 5-carbon position play a critical role in gene expression regulation and have been implicated in cancer development. 5-Hydroxymethylcytosine (5hmC), arising from 5-methylcytosine (5-mC) oxidation, has shown promise as a potential malignancy marker due to its depletion in various human cancers. However, its significance in thyroid tumors remains underexplored, primarily due to limited data. In our study, we evaluated 5hmC expression levels by immunohistochemistry in a cohort of 318 thyroid tumors. Our analysis revealed significant correlations between 5hmC staining extension scores and nodule size, vascular invasion, and oncocytic morphology. Nuclear 5hmC staining intensity demonstrated associations with focality, capsule status, extrathyroidal extension, vascular invasion, and oncocytic morphology. Follicular/oncocytic adenomas exhibited higher 5hmC expression than uncertain malignant potential (UMP) or noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), as well as malignant neoplasms, including papillary thyroid carcinomas (PTCs), oncocytic carcinomas (OCAs), follicular thyroid carcinomas (FTCs), and invasive encapsulated follicular variants of PTC (IEFV-PTC). TERT promoter mutation cases showed notably lower values for the 5hmC expression, while RAS (H, N, or K) mutations, particularly HRAS mutations, were associated with higher 5hmC expression. Additionally, we identified, for the first time, a significant link between 5hmC expression and oncocytic morphology. However, despite the merits of these discoveries, we acknowledge that 5hmC currently cannot segregate minimally invasive from widely invasive tumors, although 5hmC levels were lower in wi-FPTCs. Further research is needed to explore the potential clinical implications of 5hmC in thyroid tumors.

Warthin-like variant of papillary thyroid carcinoma with lymph node metastases: a case report and review of the literature

BackgroundWe present a rare case of thyroid lesion marked as the Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) with lymph node metastases. A proper preoperative identification is difficult because of unspecific cytology features and common ultrasound characteristics of this malignant tumor. The long-term prognosis cannot be thoroughly described due to the scarcity of data. The purpose of the presentation is to show common characteristics and long-term survival rates of an uncommon variant of differentiated thyroid cancer (DTC). Therefore, the data represented in this article can make a significant contribution to future investigations.Case presentationA 40-year-old Ukrainian woman had a lesion in the thyroid gland, which was accidentally diagnosed during medical checkup. Ultrasound (US) features were similar to the common suspicious nodule. It had typical signs of suspicion for malignancy (TI-RADS-4) on the background of thyroiditis. A thorough investigation of the neck showed lymph nodes with nonspecific US features on both lateral compartments. Lymph nodes were hypoechoic, oval-shaped and 10 mm wide, with regular contours, low central vascularity, with preserving hilar fat, without cystic formation. The patient did not have any complaints or changes in the hormone status. No hereditary findings linked with cancer were discovered. The woman had been living for a long time in the country with a high level of insolation, which was atypical for the ordinary environment of the patient. Fine-needle aspiration (FNA) of the lesion was done and the Bethesda system 6 result was obtained. Total thyroidectomy with central lymph node dissection was accomplished. The histological conclusion was WLV-PTC on the background of lymphocytic infiltration of the gland with metastasis to the lymph nodes. The inpatient radioactive iodine (RAI) ablation (100 mCi) was subsequently performed. Hormone withdrawal was used followed by RAI. In one year after the surgery the level of thyroglobulin (Tg) was 0.2 ng/ml. Up to the present time the five-year follow-up has not demonstrated any signs of recurrence relying on a level of Tg (< 0.04 ng/ml), Tg antibodies (< 14 IU/ml), neck US without any structural disease.ConclusionWLV-PTC resembles salivary gland tumors with similar histological features. This variant is not well known, but often associated with a stroma lymphocytic infiltration and a low risk of lymph node metastases. It is regarded that this rare subtype has similar long-term survival rates as classic papillary thyroid cancer (PTC).

Clinical and morphological features and unsolved issues in diagnosis of aggressive forms of papillary thyroid carcinoma

Differentiated thyroid cancer (DTC) is a disease with a favorable clinical course and high survival rate compared to other epithelial tumors. The majority of DTC (up to 85 %) is represented by various subtypes of papillary thyroid cancer (PTC). Aggressive forms of PTC characterized by early lymphogenous and hematogenous metastasis, low avidity to radioiodine therapy (RIT), low relapse-free survival rates and high mortality rate compared to other types of PTC occur among them. Preoperative diagnosis of PTC is based on the results of ultrasound (US) examination and fine-needle aspiration biopsy (FNA) with cytological examination of the aspirate. At the same time, the capabilities of cytological examination in determining the histological type of PTC are limited and it does not allow to predict its aggressiveness and plan adequate treatment. Molecular genetic tests of the tumor cytological and morphological material are effective in prognosis of aggressiveness of PTC due to the determination of specific mutations in the BRAF, TERT, RAS genes and the quantitative expression of oncogenic and tumor suppressive microRNAs. Some of these indicators are already used in the morphological classification of tumors of the endocrine system.&#x0D; At the same time, there are contradictory data concerning the connection of the molecular genetic portrait of PTC, the clinical manifestations of its aggressiveness (extrathyroidal invasion, early metastasis, and radioiodine resistance) and its pathomorphological structure. We tried to summarize and analyze the literature data regarding the diagnosis of aggressive variants of PTC.

A Case of Concomitant Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma and Graves’ Disease with Ophthalmopathy Appeared After Coronavirus Disease 2019 Vaccine

A Case of Concomitant Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma and Graves’ Disease with Ophthalmopathy Appeared After Coronavirus Disease 2019 Vaccine

Hirurško lečenje solidne varijante papilarnog karcinoma štitaste žlezde - petnaestogodišnje iskustvo tercijarnog centra

Aim: Papillary thyroid carcinoma (PTC) is a well differentiated, highly curable cancer, with a wide variety of histological forms. Although most of these variants are indolent, aggressive variants of PTC have been described. These variants include tall cell variant (TCV), hobnail variant (HV), columnar cell variant (CCV), diffuse sclerosing variant (DSV) and solid variant (SV). Solid variant represents one of the rarest forms of papillary thyroid carcinoma, with an incidence of about 2.6% according to retrospective studies. Methods: In this retrospective study, data of all patients that underwent thyroid surgery in our Clinic between January 2008 and January 2018 were analyzed. All relevant information was obtained from a prospectively maintained institutional database. Results: Of total of 1867 consecutive patients operated for follicular derived thyroid carcinomas during ten-year period, 38 had solid variant PTC as a definitive pathohistological finding (14 male and 24 female). The incidence of solid variant PTC is 2.04% in our series. Patient follow-up ranged from 36 to 168 months, disease specific five-year survival rate was 97.4%. Conclusion: Considering the scarcity of research discussing the prognosis of this variant of PTC, we believe that the treatment plan should be decided based on the extent of tumor and the experience of clinicians. WHO classification of thyroid neoplasms from 2022,may shed some light as to why the prognosis of solid variant PTC may be less aggressive than previously thought.