Minimally Invasive Follicular Thyroid Carcinoma Research Articles

Long-term oncological outcomes of follicular thyroid cancer in adolescents and young adults: A nationwide population-based study.

Follicular thyroid carcinoma (FTC) in adolescents and young adults (AYAs) is rare and data on long-term oncological outcomes are scarce. This study aimed to describe the long-term recurrence and survival rates of AYAs with FTC, and identify risk factors for recurrence. This is a retrospective cohort study combining two national databases, including all patients aged 15-39years, diagnosed with FTC in The Netherlands between 2000 and 2016. Age, sex, tumor size, focality, positive margins, angioinvasion, pT-stage, and pN-stage were included in a Cox proportional hazard model to identify risk factors for recurrence. We included 192 patients. Median age was 31.0years (IQR 24.7-36.3) and the male to female ratio was 1:4.1. Most patients presented with a minimally invasive FTC (MI-FTC) (95%). Five patients presented with synchronous metastases (2.6%), including two with locoregional metastases (1%) and three with distant metastases (1.6%). During a median follow-up of 12.0years, three patients developed a recurrence (1.6%), of which one patient developed a local recurrence (33%), and two patients a distant recurrence (67%). Five patients died during follow-up (2.6%). Cause of death was not captured. A Cox proportional hazard model could not be performed due to the low number of recurrences. FTC in AYAs is generally characterized as a low-risk tumor, as it exhibits a very low recurrence rate, a high overall survival, and it typically presents as MI-FTC without synchronous metastases. These findings underscore the favorable long-term oncological prognosis of FTC in AYAs.

Selection Criteria for Completion Thyroidectomy in Follicular Thyroid Carcinoma Using Primary Tumor Size and TERT Promoter Mutational Status.

A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial. The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation. A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated. Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p=0.001, p=0.019, and p=0.005, respectively). The data suggest 2cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy.

LBODP092 Proposal Of Indication For Completion Thyroidectomy In Follicular Thyroid Carcinoma Using TERT Promoter Mutational Status

Abstract Background Stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to solve the dilemma of definite characterization of follicular thyroid carcinoma (FTC). However, which patients will be candidates for completion thyroidectomy has been controversial. The aim of this study is to clarify the selection criteria for completion thyroidectomy using TERT promoter mutation. Methods A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the WHO 2017 classifications were calculated. Results Of the 87 patients, 8 patients (9.2%) had initial distant metastasis, and 15 patients (17.2%) had persistent disease or developed structural recurrence. Threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT it was 4cm. Cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification were significantly different only in patients with WT-TERT (P = 0. 001, P = 0. 019, and P = 0. 005, respectively). Conclusions The data suggested that 2 cm may be a critical threshold diameter for deciding completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can be a game changer for selecting candidates for completion thyroidectomy. Presentation: No date and time listed

The Prognostic Impact of Extent of Vascular Invasion in Follicular Thyroid Carcinoma.

Encapsulated angioinvasive follicular thyroid carcinoma (EAFTC) is associated with an increased risk of distant metastasis and reduced survival compared to minimally invasive follicular thyroid carcinoma (MIFTC). There is controversy regarding the extent of surgery and adjuvant radioactive iodine therapy for angioinvasive follicular thyroid carcinoma when stratified by number of foci of angioinvasion. All follicular thyroid carcinoma cases from 1990-2018 were identified from a thyroid cancer database. Primary outcomes were distant metastasis-free survival (DMFS) and disease-specific survival (DSS) with factors of interest being age, gender, tumour size, treatment, foci of angioinvasion and histological subtype. A total of 292 cases were identified; 139 MIFTC, 141 EAFTC and 12 widely invasive follicular thyroid carcinoma (WIFTC). Over a follow-up period of 6.25years, DMFS was significantly reduced (p < 0.001) with 14.2% (EAFTC) and 50% of WIFTC developing metastasis. The risk of metastasis in EAFTC with ≥ 4 foci of angioinvasion was 31.7% (HR = 5.89, p = 0.004), 6.3% for EAFTC with < 4 foci of angioinvasion (HR = 1.74, p = 0.47), compared to 3.6% MIFTC. Age ≥ 50years (HR = 4.24, p = 0.005) and tumour size (HR = 1.27, p = 0.014) were significantly associated with increased risk of distant metastasis. DSS was reduced significantly (p < 0.001), with 7.8% EAFTC patients dying of disease. For EAFTC patients, DSS was 96.8% for < 4 foci and 82.6% for ≥ 4 foci of angioinvasion (p = 0.003). EAFTC is at increased risk of distant metastasis related to the extent of angioinvasion. Tumours with < 4 foci of angioinvasion should be considered for a total thyroidectomy, particularly in older patients.

Outcomes for Minimally Invasive Follicular Thyroid Carcinoma in Relation to the Change in Age Stratification in the AJCC 8th Edition.

Completion total thyroidectomy with radioactive iodine (RAI) therapy is not uniformly recommended for minimally invasive follicular thyroid carcinomas (MI-FTCs) without distant metastasis, but may be considered for cases with a risk factor of recurrence, such as age ≥ 45years. The present study aimed to investigate the outcomes for patients with MI-FTC using a stratification age of 55years. The records of 478 patients with MI-FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Twenty patients had distant metastasis at diagnosis and were subsequently classified as M1. Among the 478 patients with MI-FTC, univariate analysis identified that age ≥ 55years (p = 0.002) and M1 (p < 0.001) were related to cause-specific survival. In 458 patients with M0 MI-FTC, male sex (p = 0.041), age ≥ 55years (p = 0.001), and tumor size > 40mm (p < 0.001) were related to poor disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that age ≥ 55years (p = 0.005) and tumor size > 40mm (p = 0.005) were independent prognostic factors for DFS. The 10-year DFS rates of patients aged < 45years, 45years ≤ age < 55years, and ≥ 55years were 97.0%, 95.5%, and 86.4%, respectively. The change in the recommended age for completion total thyroidectomy with RAI, from 45 to 55years, seemed reasonable.

Expression of long non-coding RNA H19 predicts distant metastasis in minimally invasive follicular thyroid carcinoma

ABSTRACT Downregulation of lncRNA H19 (H19) expression is associated with an unfavorable prognosis in some cancers. However, little was known as to whether there was an association between H19 and minimally invasive follicular thyroid carcinoma (MI-FTC). In our study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to determine H19 expression in 186 patients with MI-FTC who underwent initial surgery. Of the 186 patients with MI-FTC, 21 patients show distant metastasis （M+）at the initial operation established the diagnosis of MI-FTC. Of the 165 patients who did not show distant metastasis at diagnosis during the follow-up period (≥10 years), 28 patients undergone M+ and 137 patients has no distant metastasis（M-）after the initial operation. Low H19 expression was associated with large tumor size, vascular invasion, and distant metastasis. Univariate analysis showed that gender (male), age (45 years or older), primary tumor size (4 cm or more), vascular invasion and H19 level (<1.12) were significant prognostic factors related to postoperative distant metastases. Multivariate analysis showed that age, primary tumor size (4 cm or more) and vascular invasion was a significant prognostic factor for survival. Patients with low H19 expression showed a poorer outcome in MI-FTC patients. Receiver-operating characteristic (ROC) curve analysis demonstrated H19 could distinguish M+ from M- patientswith a value of area under the curve (AUC). Our findings suggest that H19 is a potential prognostic factor for evaluating prognosis and the metastatic potential of MI-FTC at an initial operation stage.

Hemithyroidectomy for low-risk follicular carcinoma of the thyroid: results from a regional hospital.

Excellent outcomes after conservative thyroid surgery for low-risk follicular thyroid carcinoma (FTC) have been reported from highly specialised centres. However, it is uncertain whether low-volume hospitals can achieve similar treatment results. At our institution, 49 patients with FTC were treated during the period 1991-2014. Patients with minimally invasive FTC (MIFTC) were usually treated with hemithyroidectomy. The demographic data, pathology, treatment modality and oncological outcomes of these patients were retrospectively evaluated. The tumours were classified as Stage I in 40.8% of patients, Stage II in 32.7%, Stage III in 20.4% and Stage IV in 6.1%, according to the TNM classification system. Only 4 (8.2%) patients had widely invasive FTC (WIFTC). Vascular invasion or capsular invasion alone occurred in 9 (19.1%) and 19 (40.4%) patients, respectively, while 19 (40.4%) patients had simultaneous vascular and capsular invasions. 34 (69.4%) patients with MIFTC initially underwent hemithyroidectomy, while 15 (30.6%) patients underwent total thyroidectomy. Ten patients who underwent total thyroidectomy received radioactive iodine ablation. The mean follow-up duration was 86.9 ± 56.6 months. There was no disease-specific mortality, although two patients with WIFTC remained alive with disease at the end of the study. The five-, ten- and 15-year overall survival rates were 95%, 91% and 84%, respectively. Five patients from the hemithyroidectomy group died due to other illnesses with no evidence of FTC. Satisfactory disease control and excellent survival for MIFTC is achievable by hemithyroidectomy in community hospitals. Total thyroidectomy should be reserved for WIFTC or aggressive tumours with nodal or distant metastasis.

Circulating Tumor Cells in Minimally Invasive Follicular Thyroid Carcinoma and Benign Thyroid Tumors with a Follicular Pattern: Pilot Experience

Minimally invasive follicular thyroid carcinomas (MIFCs) are uncommon; literature offers limited guidance on their natural history and management. Starting January 2015 we measured circulating tumor cells (CTCs) in patients with MIFC (n=22) or benign thyroid tumors with follicular features (n=4). In a retrospective analysis, we assessed detectability of and serial changes in CTC, compared demographic/clinical differences between CTC-positive versus CTC-negative subgroups using Student's t-test, and examined correlations between CTC status and serum thyroglobulin using Spearman's test. CTCs were quantitated via immunomagnetic separation/microscopic inspection. Thirteen patients (50%: 12/22 MIFC, 1/4 benign tumor) were initially CTC-positive; 3 remained CTC-positive in ≥1 subsequent measurement. CTC-positive patients had larger tumors and more frequent multifocality and vascular invasion versus CTC-negative patients (n=13). However, no tested variable differed significantly between the subgroups. After 17.2±10.5 months, neither subgroup showed evidence of disease. Significant correlation was absent (p ≥ 0.263) between CTC and Tg negativity (r = 0.243; n=13 evaluable) or initial CTC positivity and Tg positivity (r = -0.418; n=9 evaluable). In the studied settings, CTC measurement is feasible, has unclear clinical/outcome implications, but may provide different information versus thyroglobulin testing. Lengthier assessment is warranted in larger series.

Prognostic Impact of Further Treatments on Distant Metastasis in Patients With Minimally Invasive Follicular Thyroid Carcinoma: Verification Using Inverse Probability of Treatment Weighting.

The aim of this study was to evaluate the prognostic impact of further treatments in minimally invasive follicular thyroid carcinoma (MIFTC) patients. The risk factors for distant metastases were analyzed, and the impact of surgical extent on distant metastasis was verified by using weighted logistic regression models with inverse-probability of treatment weighting (IPTW). 166 patients including 31 males (18.7%) and 135 females (81.3%), with the mean age of 41.5±13.5years, were enrolled for this study. The median follow-up period was 103.5months (range, 13-244months). Seven patients (4.2%) had distant metastases during follow-up period. The presence of vascular invasion (Hazard ratio [HR]=29.06; 95% Confidence Interval [CI]=3.06-209.08; p=0.015) and extensive vascular invasion≥4 foci (HR=40.57; 95% CI=2.09-789.13; p=0.014) were the independent risk factors for distant metastasis by multivariate analysis. Surgical extent did not influence distant metastasis. Logistic regression with IPTW also demonstrated that there were no statistically significant differences in the development of distant metastasis based on surgical extent (HR=1.28; 95% CI=0.15-10.87; p=0.823). The presence of extensive vascular invasion is the most powerful predictor of distant metastasis. However, it is noteworthy that further treatments do not demonstrate an advantageous effect on preventing distant metastasis during the follow-up period.

Risk Factors for Distant Metastasis in Patients with Minimally Invasive Follicular Thyroid Carcinoma

BackgroundAlthough patients with minimally invasive follicular thyroid carcinoma (MIFTC) generally have an excellent prognosis, distant metastasis occurs in some patients. Risk factors for distant metastasis have been reported, none has been found to be conclusive. This study evaluated risk factors for distant metastasis, including protein markers, in patients with MIFTC.MethodsA review of patient records identified 259 patients who underwent surgery at Asan Medical Center from 1996 to 2010 and were subsequently diagnosed with MIFTC. After review of pathological slides, 120 patients with paraffin blocks suited for tissue microarrays (TMA) were included in this study. Immunohistochemical stain of TMA slides was performed by protein markers; β-catenin, C-MET, CK19, estrogen receptor (ER) α, ER β, HBME-1, MMP2, PPAR γ and progesterone receptor.Results120 patients included 28 males (23.3%) and 92 females (76.7%), of mean age 41.5±10.8 years (range, 13–74 years). Eight patients (6.7%) had distant metastases during follow-up. Univariate analysis showed that age (≥45 years), male sex, and extensive vascular invasion (≥4 foci) were associated with distant metastasis. Multivariate regression analysis showed that extensive vascular invasion was the only independent risk factor for distant metastasis (p = 0.012). Although no protein markers on TMA analysis were directly related to distant metastasis of MIFTC, CK19 expression was more frequent in patients with than without extensive vascular invasion (p = 0.036).ConclusionExtensive vascular invasion was the only independent risk factor for distant metastasis of MIFTC. No proteins markers were directly related to distant metastasis, but CK19 was associated with extensive vascular invasion.

Minimally invasive follicular thyroid carcinomas: prognostic factors.

Although minimally invasive follicular thyroid carcinoma (MI-FTC) is regarded as an indolent tumour, treatment strategies remain controversial. Our aim was to investigate the outcome for patients with MI-FTC and to identify prognostic parameters to facilitate adequate treatment and follow-up. This retrospective follow-up study involved all cases of MI-FTC operated at the Karolinska University Hospital between 1986 and 2009. Outcome was analysed using death from MI-FTC as endpoint. Fifty-eight patients (41 women and 17 men) with MI-FTC were identified. The median follow-up time was 140 (range 21–308) months. Vascular invasion was observed in 36 cases and was associated with larger tumour size [median 40 (20–76) compared with 24 (10–80) mm for patients with capsular invasion only (P = 0.001)] and older patients [54 (20–92) vs. 44 (11–77) years; P = 0.019]. Patients with vascular invasion were more often treated with thyroidectomy (21/36 compared to 7/22 with capsular invasion only; P = 0.045). Five patients died from metastatic disease of FTC after a median follow-up of 114 (range 41–193) months; all were older than 50 years (51–72) at the time of the initial surgery; vascular invasion was present in all tumours and all but one were treated with thyroidectomy. Univariate analysis identified combined capsular and vascular invasion (P = 0.034), age at surgery ≥50 years (P = 0.023) and male gender (P = 0.005) as related to risk of death from MI-FTC. MI-FTC should not be considered a purely indolent disease. Age at diagnosis and the existence of combined capsular and vascular invasion were identified as important prognostic factors.

Does completion thyroidectomy improve the outcome of patients with minimally invasive follicular carcinoma of the thyroid?

The diagnosis of minimally invasive follicular thyroid carcinoma (MIFTC) is often made histologically after thyroid lobectomy. We attempted to determine whether completion thyroidectomy should be considered necessary for all patients diagnosed with MIFTC after thyroid lobectomy. The subjects of this study were a total of 324 patients who underwent thyroid lobectomy as initial surgery at our institution between 1989 and 2010 and diagnosed histologically as MIFTC. Completion thyroidectomy was performed on 101 patients, and the other 223 patients were followed up without further treatments. Cumulative cause-specific survival (CSS) rates and distant-metastasis-free survival (DMFS) rates were calculated by the Kaplan-Meier method. Differences between groups were analyzed for statistical significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards model. During the follow-up period, 39 patients were diagnosed with distant metastasis, and 7 patients died of their disease. Age at the initial surgery was found to be a significant factor related to DMFS in both the univariate and multivariate analysis and to also be related to CSS in the univariate analysis. Completion thyroidectomy did not have a significant effect on DMFS or CSS according to the results of the univariate analysis, but it had significant effect on DMFS according to the results of the multivariate analysis. Although we were unable to demonstrate sufficient statistical evidence that completion thyroidectomy improved the outcome of MIFTC patients, it is noteworthy none of the patient who underwent completion thyroidectomy died of the disease.

The miR-221/222 cluster, miR-10b and miR-92a are highly upregulated in metastatic minimally invasive follicular thyroid carcinoma

Minimally invasive follicular thyroid carcinoma (MI-FTC) is characterized by limited capsular and/or vascular invasion with good long-term outcomes. However, some cases of MI-FTC show a poor prognosis because of severe distant metastasis (i.e., metastatic MI-FTC). Nonetheless, no method has been established for predicting the prognosis of MI-FTC. This study was conducted to identify novel prognostic factors for metastatic MI-FTC by the use of microRNA (miRNA). Thirty-four patients with MI-FTC were categorized into two groups: the metastatic group, M(+) (n=12) and the non-metastatic group, M(−) (n=22). In the M(+) group, distant metastasis was recognized after the initial operation established the diagnosis of MI-FTC. In the M(−) group, no distant metastasis was recognized postoperatively for ≥10 years. Using laser micro-dissection followed by quantitative real-time PCR and PCR arrays, we performed a comprehensive expression profiling of 667 miRNAs in formalin-fixed, paraffin-embedded samples from the initial MI-FTC operation. Furthermore, we assessed the potential use of miRNAs as novel biomarkers for the metastatic potential of MI-FTC by logistic regression analysis. Comprehensive quantitative analysis of miRNA expression in MI-FTC samples revealed that the miR-221/222 cluster (i.e., miR-221, miR-222 and miR-222*), miR-10b and miR-92a were significantly upregulated in the M(+) group compared with the M(−) group. Interestingly, the expression levels of these miRNAs were also shown to be upregulated in widely invasive FTC (WI-FTC; n=13) that has distant metastasis and worse prognosis, indicating a close similarity in the miRNA expression between metastatic MI-FTC and WI-FTC. Logistic regression analysis revealed that miR-10b made a significant contribution to prognosis (OR 19.759, 95% CI 1.433–272.355, p= 0.026). Our findings suggest that miR-10b is a potential prognostic factor for evaluating the metastatic potential of MI-FTC at an initial operation stage.

Differentiation of widely invasive and minimally invasive follicular thyroid carcinoma with sonography

Purpose We evaluated the sonographic findings that can help differentiate widely invasive follicular thyroid carcinomas (WIFTC) from minimally invasive follicular thyroid carcinomas (MIFTC). Methods We retrospectively compared the sonographic and clinical findings of 24 patients (M:F = 5:19) with 24 MIFTCs and 12 patients (M:F = 1:11) with 13 WIFTCs that were confirmed pathologically and available in sonography at our institution between 1995 and 2007. Results WIFTC was more common in elderly patients than MIFTC ( p < 0.0001). WIFTC was seen with a larger size than MIFTC ( p = 0.0092). The best cut-off values for age and size were 49 years and 5.6 cm, respectively. On sonography, all tumors were seen as a well-defined oval or round mass. Heterogeneous mulberry-like echotexture was more common for WIFTC than for MIFTC (77% vs. 25%) ( p = 0.0046). The presence of calcifications was more frequent in WIFTC than in MIFTC (54% vs. 8%) ( p = 0.0041). Ring calcifications (86%) were the most common type for WIFTC. WIFTC was commonly hypoechoic (70%) and rarely cystic change (8%), but without statistical differences. When WIFTCs represented tumors with two or more findings with a statistical difference, the specificity was 96%. Conclusion WIFTC is distinguishable from MIFTC by sonography for patients with an age ≥49 years, a tumor ≥5.6 cm, a heterogeneous mulberry-like echotexure, or the presence of calcifications. The sonographic impression of a WIFTC can support a preoperative or intraoperative diagnosis of a difficult case as determined by FNA or with a frozen section.

Molecular analysis of minimally invasive follicular carcinomas by gene profiling

While the majority of minimally invasive follicular thyroid carcinoma (MIFTC) behave like follicular adenomas, some recur or metastasize. These studies were conducted to determine if molecular profiling can enhance our understanding of MIFTC and to perhaps offer a better classification schema. Microarray analysis was performed on 27 follicular neoplasms. Thirteen follicular adenomas (FAs) were compared with 7 widely invasive follicular thyroid carcinomas (WIFTCs) to generate a list of differentially expressed genes. Next, 7 MIFTCs were analyzed along with the other samples in a cluster analysis. The MIFTCs were then compared directly against both the adenoma and WIFTC groups to investigate genetic relatedness. FAs and WIFTCs have distinct genetic profiles, with 401 differentially expressed genes. The 7 MIFTCs were added to the analysis. Six of 7 of the MIFTCs were grouped with the adenomas, 4 of which created their own subgroup. When analyzed directly, MIFTCs had 223 differently expressed genes, compared with FAs, and 365, compared with WIFTCs. Molecular profiling illustrates that the majority of MIFTCs comprise a subclass of follicular neoplasms, and, while most MIFTCs are genetically similar to adenomas, our patient data suggest that these tumors may deserve greater suspicion of malignant potential. Gene profiling can provide insight into the molecular pathogenesis of MIFTC.