Follicular Tumor Of Uncertain Malignant Potential Research Articles

EphB3 protein is a potential ancillary diagnostic biomarker for thyroid cancers

ObjectiveTo investigate the expression of ephrin type B receptor 3 (EphB3) in thyroid tumors and its usage as an ancillary diagnostic biomarker for thyroid tumors. MethodsFormalin-fixed and paraffin-embedded (FFPE) tissue samples (78 cases) and FNAC samples (57 cases) were assessed with the EphB3 antibody using immunohistochemistry. PTC and other thyroid follicular tumors were compared regarding their EphB3 expression. Sanger sequencing was used to assess for the presence of a BRAF V600E mutation. ResultsEphB3 was positive in 81.8 % (27/33) of papillary thyroid carcinoma (PTC), 83.3 % (5/6) of medullary thyroid carcinoma (MTC), 25 % (1/4) of hyperplastic/adenomatoid nodule (HN), 14.3 % (1/7) of follicular adenoma (FA), and negative in follicular tumors of uncertain malignant potential (FT-UMP) (0/13), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) (0/7), thyroid follicular carcinoma (TFC) (0/4), Hashimoto's thyroiditis (0/4), and normal thyroid follicular tissues (0/33). In cellular blocks, EphB3 was positive in 87.1 % (20/23) of PTC, 75 % (3/4) of MTC, 20 % (2/10) of HN, and negative in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (0/20) and normal thyroid follicular cells (0/10). ConclusionEphB3 is expressed in the majority of PTC, but less so in benign follicular nodules. EphB3 expression in fine needle aspiration cytology (FNAC) specimens can be used as a diagnostic tool to differentiate thyroid cancer from other follicular lesions in its differential diagnosis, especially AUS/FLUS and PTC.

Possibilities of immunocytochemical staining for HBME-1 expression in the «diagnostic search» of differentiated thyroid cancer. Own investigation

Objective — to investigate HBME-1 expression variants on cytological material classified as doubtful (III, IV, V), according to the Bethesda categories, to evaluate the value of the HBME-1 expression test on the corresponding histological material of nodular goiter, follicular tumor with an uncertain potential for malignancy for the differential diagnosis of thyroid carcinoma (ThC). Materials and methods. The analysis was performed on the data of 14 patients with thyroid nodular lesions and cytological Bethesda categories III, IV, and V (“gray zone“). The HBME-1 expression was determined by the results of immunocytochemical (ICC) and immunohistochemical (IHC) staining with the use of mouse monoclonal antibodies against human HBME-1 (1 : 500; cat № BSB 3459; «Bio SB» «Bioscince for the World» Santa Barbara USA). The HBME-1 expression grade was calculated as the sum of the score for staining intensity and cytoplasmic positive cells square, present in the IHC sample. HBME-1 positive result was considered with an IHC score >6 point. Results. From 14 investigated patients, five were defined as HBME-1 positive. According to the postoperative histological conclusion for the group of HBME-1 positive patients, thyroid carcinoma was diagnosed in four subjects, including three cases of papillary ThC and one follicular ThC; in one patient follicular tumor of uncertain malignant potential (FT-UMP) was reported. Importantly, immunocytochemical and immunohistochemical HBME-1 reactions in the specimens of these patients were of the same intensity. Among 9 HBME-1 preoperative negative patients, none had malignancy according to the final histological study. Nodular goiter was diagnosed in six patients, and tumor of uncertain malignant potential (FT-UMP) was reported for three subjects. Histological specimens of all 9 patients were HBME-1 negative as well. The obtained results demonstrated an increase in cancer detection rates with increasing Bethesda category. Application of statistical software for biomedical research МedCalc revealed that positive predictive value (PPV) of the HBME-1 expression test was 80% (95% confidence interval CI 38.4—96.3%), and diagnostic efficiency was 92.9% (CI 66.1—99.8%). These results suggest the great potential of the test, however, due to the limited observations, the confidence intervals are too wide. Conclusions. HBME-1 can be used as an immuno­cytochemical marker for the differentiation of benign and malignant thyroid nodules, its use will help to reduce the number of unnecessary surgical removals of benign tumors, which will improve the quality of life of patients and reduce the burden on medical services.

Clinical outcomes of follicular tumor of uncertain malignant potential of the thyroid: real-world data.

Thyroid tumors arising from follicular cells can generally be divided into malignant and benign tumors. However, some cases are difficult to clearly diagnose whether they are benign or malignant. Therefore, in the most recent version of World Health Organization (WHO) classification, some borderline lesions such as follicular tumor of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were proposed. In this study, we investigated the clinical aspects, including the prognosis, of FT-UMP patients. We investigated the clinical features of 339 patients with FT-UMP. On ultrasound, 68% of the tumors were diagnosed as intermediate, and only 5% of those tumors were diagnosed as malignant. On cytology, 40% of the tumors were diagnosed as follicular neoplasm, and only 1% of these were suspected to be or diagnosed as malignancy. The diagnosis was based on questionable capsular invasion for 332 patients, questionable vascular invasion for 2 patients, and both for 5 patients. Eighty-six percent of the tumors showed low cell proliferation activity. To date, five patients (1%) have shown distant recurrence during postoperative follow-up and underwent various treatments such as radioactive iodine therapy, orthopedic surgery, and denosumab injection. None of these patients have died due to thyroid carcinoma. Our findings suggest that FT-UMP is generally an indolent disease, but some patients show distant recurrence. Physicians should carefully follow patients, although it remains unknown how long they should be observed after surgery.

Additional Tissue Sampling Trials Did Not Change Our Thyroid Practice.

Simple SummarySome studies have suggested that the use of additional tissue blocks to diagnose follicular thyroid carcinoma (FTC) could increase the accuracy of diagnosis and improve prognosis, and entire capsule sampling was recommended for a definitive diagnosis of borderline thyroid tumors in 2016. We conducted a study in 2016 to examine whether additional tissue sampling of the encapsulated follicular tumor increases the diagnosis of malignant cases in our patient cohort. Furthermore, the diagnosis was reclassified according to the 4th edition of the World Health Organization’s classification system. The additional tissue sampling only had a slight impact on our thyroid practice and resulted in no benefits to the patient; therefore, we decided to cease it.This study aimed to determine whether additional tissue sampling of encapsulated thyroid nodules would increase the frequency of follicular thyroid carcinoma (FTC) diagnoses. We examined thyroid tissue specimens from 86 patients suspected of FTC (84.9% female; mean age, 49.0 ± 17.8 years). The number of tissue blocks created for pathological assessments ranged from 3 to 20 (mean, 9.1 ± 4.1); the numbers in the previous method recommended by the Japanese General Rules for the Description of Thyroid Cancer and additional blocks ranged from 1 to 12 (mean, 6.0 ± 2.8) and from 1 to 8 (mean, 3.1 ± 2.0), respectively. The additional blocks were subsequently examined to determine whether any diagnoses changed from those based on the previous method. Five patients were diagnosed with FTC using the previous method; however, additional tissue blocks led to the diagnosis of FTC in 6 patients, as 1 diagnosis was revised from follicular adenoma to FTC. It has been reported that increasing the number of tissue blocks used for pathological assessments can increase the frequency of FTC diagnoses; however, this was not clinically significant in thyroid carcinoma, which requires completion thyroidectomy and radioactive iodine treatment. It resulted in no benefits to the patient because all minimally invasive FTCs, follicular tumors of uncertain malignant potential (FT-UMP), and follicular adenomas are treated with lobectomy alone in Japan. Additional tissue sampling only had a slight impact on our thyroid practice; therefore, we decided to cease it.

Distant metastases from pathologically proven benign follicular nodules of the thyroid: clinicopathological features and predictors of long-term survival.

Distant metastases are rarely observed in patients with initial pathologically proven benign follicular nodules of the thyroid. This study aimed to evaluate the clinicopathological features and independent variables associated with survival in such patients with distant metastases. In total, 10,992 consecutive differentiated thyroid cancer (DTC) patients treated with 131I after total or near-total thyroidectomy from 2000 to 2018 were retrospectively reviewed. Thirty-nine patients with initial pathologically proven benign follicular nodules of the thyroid were enrolled. Among them, 26 were pathologically diagnosed as thyroid adenoma, 8 as benign nodular goiter, 4 as thyroid adenoma combined with benign nodular goiter, and 1 as normal thyroid tissue. Of 26 patients with the initial pathological slides obtained, eight cases were rediagnosed as minimally invasive thyroid carcinoma (MI-FTC), 10 as follicular tumor of uncertain malignant potential (FT-UMP), and five as well-differentiated tumor of UMP (WDT-UMP). Monitoring of thyroglobulin (Tg) changes after initial thyroidectomy and preablation-stimulated Tg (psTg) level were significantly associated with 5-year OS rate (P = 0.007 and P = 0.005, respectively). The presence of radioactive-refractory DTC (RR-DTC), monitoring of Tg changes after initial thyroidectomy, and psTg level had significant effects on 10-year OS rate (P = 0.002, P < 0.001, and P = 0.005, respectively). Lack of monitoring of Tg changes after initial thyroidectomy and RR-DTC were independent factors associated with poor prognosis (P = 0.003 and P = 0.008, respectively). MI-FTC, FT-UMP, and WDT-UMP tended to be ignored and/or misdiagnosed as benign follicular lesions. Lack of monitoring of Tg changes after initial thyroidectomy and the presence of RR-DTC were identified as independent factors associated with poor survival.

Mutation profiles of follicular thyroid tumors by targeted sequencing

BackgroundOne of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant. We aimed to characterize the mutational profiles of follicular thyroid tumor and to identify markers with potential diagnostic and prognostic implications.MethodsTargeted sequencing with a panel of 18 thyroid cancer-related genes was performed on 48 tissue samples from follicular thyroid adenoma (FTA), 32 follicular tumors of uncertain malignant potential (FT-UMP), 17 well-differentiated tumors of uncertain malignant potential (WDT-UMP) and 53 samples from follicular thyroid carcinoma (FTC). The correlation of mutation profiles and clinicopathological features and prognosis were also analyzed.ResultsWe identified 95 nonsilent mutations spanning 14 genes. Specifically, TERT promoter (TERTp) mutations were exclusively detected in FTC. A total of 80% EIF1AX exon 2 mutations (4/5) and 75% TSHR mutations (3/4) occurred in FTA, whereas the rest of them occurred in FT-UMP. KRAS mutations and TP53 mutations were only presented in borderline or malignant tumors. H/N-RAS mutations were detected in all four subtypes, but were most commonly found in WDT-UMP (p = 0.031). All N-RAS mutations were located at codon 61. BRAF V600E and RET fusion were absent in the entire cohort. In FTC cases, EIF1AX mutations were all located at intron 5/exon 6 and correlated with advanced disease (p = 0.032). Both EIF1AX and TERTp mutations predicted shorter disease-free survival (p = 0.007, p = 0.024, respectively). Further analysis revealed that TERTp mutations were correlated with shorter disease-free survival in patients with minimally invasive /encapsulated angioinvasive FTC (p = 0.017), but not in those with widely invasive FTC (p = 0.297).ConclusionTERTp, EIF1AX, TSHR, H/N/K-RAS and TP53 mutations may have diagnostic or prognostic potential in follicular thyroid tumors. TERTp mutations may predict a poor outcome in patients with minimally invasive/encapsulated angioinvasive FTC.

Borderline Thyroid Tumors: a Surgeon's Perspectives

Borderline thyroid tumors are composed of hyalinizing trabecular tumor (HTT), well differentiated tumor of uncertain malignant potential (WDT-UMP), follicular tumor of uncertain malignant potential (FT-UMP) and non-invasive follicular tumor with papillary like nuclear feature (NIFTP) by World Health Organization (WHO) definition. They have different pathological feature from each other. However, it is difficult to diagnose with diagnostic imaging, fine needle aspiration (FNA) or core biopsy preoperatively. Thus, the diagnosis is usually made after diagnostic lobectomy. Main surgical concerns about borderline tumor are not performing total thyroidectomy because of relatively indolent nature of these tumors. Unfortunately, some of these tumors can be diagnosed as malignant tumor preoperatively. The other surgical concern is performing completion thyroidectomy or not after diagnostic lobectomy. Decision making is difficult even though it is generally considered that lobectomy alone is enough. In this article, we will discuss clinical features of borderline malignant tumors and surgical strategy for these tumors.

How to handle borderline/precursor thyroid tumors in management of patients with thyroid nodules.

Thyroid carcinomas originating from follicular cells have the prognosis of heterogeneous diseases, but pathologists classify them all as malignant disease. Epidemiologists have issued a stern warning regarding over-diagnosis and overtreatment of patients with indolent thyroid tumors that cause no harm to the patients. Review of the literature revealed that there were several proposals of borderline/precursor tumors to some indolent thyroid carcinomas. Thyroid tumor of uncertain malignant potential (UMP) was first proposed by Williams for encapsulated follicular pattern thyroid tumors to solve problems due to observer variation. Rosai et al. proposed to rename papillary microcarcinoma (PMC) to papillary micro-tumor as the overwhelming majority of them are of no clinical significance. Liu et al. proposed well-differentiated tumor with uncertain behavior (WDT-UB) which covered WDT of UMP (WDT-UMP) and non-invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). The EFVPTC without invasion was renamed as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) by an international panel of pathologists. A new prognostic classification of thyroid tumors was proposed by Kakudo et al., in which extremely low risk tumors were grouped in a borderline tumors category. The borderline/precursor thyroid tumors included encapsulated tumors [capsular invasion only follicular carcinoma, encapsulated papillary carcinoma without invasion, WDT-UMP and follicular tumor of UMP (FT-UMP)] and non-encapsulated tumors (PMC). The UMP and NIFTP were incorporated in the 4th edition WHO classification of thyroid tumors as a new tumor entity in chapter 2-2A: other encapsulated follicular patterned thyroid tumors. Their behavior codes were decided to be 1 (borderline or uncertain behavior), and not 0 (benign), 2 (in situ carcinoma) or 3 (malignant). These borderline/precursor thyroid tumors are indolent tumors biologically and should be treated more conservatively than as previously recommended for thyroid follicular cell carcinomas [total thyroidectomy (TTX) followed by radio-active iodine (RAI) treatment] by western clinical guidelines.

High Ki-67 index in fine needle aspiration cytology of follicular thyroid tumors is associated with increased risk of carcinoma

PurposePreoperative distinction of follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA) is a diagnostic challenge. Our aim was to investigate whether the Ki-67 proliferation index in fine needle aspiration material can contribute to the diagnosis of FTC.MethodsWe analyzed retrospectively cytological Ki-67 index determined in routine clinical setting and clinical data for 61 patients with FTC, 158 patients with FTA and 15 patients with follicular tumor of uncertain malignant potential (FT-UMP) surgically treated and diagnosed by histopathology at Karolinska University Hospital 2006-2017 (Cohort A). A previously published cohort of 109 patients with follicular tumors was re-analyzed as well (Cohort B).Results:In Cohort A, patients with FTC had a higher Ki-67 index (p < 0.001), larger tumor size (p < 0.001) and higher age at diagnosis (p = 0.036) compared to patients with FTA or FT-UMP. Hürthle cell differentiation, present in 50 FTA, 20 FTC and 8 FT-UMP, was associated with higher Ki-67 index (p = 0.009). Multivariate analysis of Cohort A identified a high Ki-67 index (odds ratio [OR]: 1.215, p < 0.001) and large tumor size (OR: 1.038, p < 0.001) as independent predictors of FTC. Results remained consistent after exclusion of Hürthle cell tumors and in pooled analysis of Cohort A + B. The area under curve of the Ki-67 index for predicting FTC was 0.722 and a cut-off for Ki-67 index at above 5% resulted in a specificity at 93% and sensitivity at 31%. Subgroup analysis of FTCs in Cohort A showed an association of higher Ki-67 index to extrathyroidal extension (p = 0.001) as well as widely invasive subtype (p = 0.019) based on the WHO 2017 classification.ConclusionsPre-operative Ki-67 index may add diagnostic information for a subset of patients with follicular thyroid tumors.

Combined clinical and ultrasound follow-up assists in malignancy detection in Galectin-3 negative Thy-3 thyroid nodules.

The use of galectin-3 ThyroTest in the preoperative evaluation of cytologically indeterminate (Thy-3) thyroid nodules has been largely validated by retrospective and prospective multicentre studies. Here we report the results of galectin-3 ThyroTest routinely applied in the management of Thy-3 nodules in combination with clinical and ultrasonography (US) examination, in which galectin-3 positive nodules were directly referred to surgery whereas galectin-3 negative lesions were considered for clinical and US long-term follow-up. A cohort of 331 patients, bearing 340 thyroid Thy-3 nodules, was enrolled and subjected to galectin-3 expression analysis. A total of 256 galectin-3 negative nodules were directed to periodical clinical and US examination, while 84 galectin-3 positive cases were referred to surgery. Excluding 63 dropout patients plus 15 patients that were operated because of clinical reasons the remaining 176 galectin-3 negative nodules were followed with clinical and US examination for an average period of 31months. During the follow-up, the volume of galectin-3 negative nodules was unchanged in 85 cases (48%), reduced in 47 (27%), and increased in 44 (25%). Based on combined clinical features and US follow-up results, a total of 36 out of 191 galectin-3 negative nodules (19%) were referred to surgery, with a final histological finding of 28 benign lesions, three follicular tumor of uncertain malignant potential (FT-UMP), and five malignant lesions, corresponding to a 7% false negative rate. In the group of 84 galectin-3 positive nodules, we detected 65 thyroid cancers with a prevalence of 77%, 12 FT-UMPs, and 7 false positive lesions, corresponding to a 4% false positive rate. A total of 150 patients were not operated and are still under clinical and US monitoring while surgery was performed in 118 patients with a final 70 thyroid cancers diagnosed, corresponding to a 59% prevalence of malignancy detected at surgery and to a 26% prevalence of malignancy among the entire Thy-3 nodule population. Galectin-3 ThyroTest is an easy and cheap diagnostic procedure that integrates conventional fine-needle-aspiration cytology, reduces the number of unnecessary thyroidectomies and increases the rate of malignancy at surgery. Clinical and US follow-up of galectin-3 negative lesions allows to further reduce false negative cases.

Classification of thyroid follicular cell tumors: with special reference to borderline lesions [Review

We propose a new classification of thyroid follicular cell tumors which is correlated with patient's prognosis. It is unique as to two new categories: borderline malignancy between benign and malignant, and moderately differentiated adenocarcinoma (MDA) as a differentiation classification to stratify tumor aggressiveness. As to diagnostic criteria, we recommend invasiveness (capsular and vascular invasion) to separate benign and malignant and it should not be based on presence or absence of papillary thyroid carcinoma (PTC) type nuclear features (PTC-N). Thus borderline malignancy in our new classification includes some of the formerly malignant tumors and they are 1) papillary microcarcinoma, 2) encapsulated conventional PTC (EncPTC), 3) encapsulated follicular variant PTC (EnFVPTC), 4) well differentiated tumor of uncertain malignant potential (WDT-UMP), 5) follicular tumors of uncertain malignant potential (FT-UMP), and 6) capsular invasion only follicular thyroid carcinoma (FTC). Review of the literature revealed that those thyroid tumors have consistently excellent outcome. Well differentiated follicular cell adenocarcinoma (WDA) in our classification includes common type PTC and low-risk follicular carcinoma (FTC). They are invasive (diffuse infiltrative) common type PTC and minimally invasive type FTC with less than 4 foci of angioinvasion. Moderately differentiated follicular cell adenocarcinoma (MDA) includes FTC with angioinvasion (more than 4), aggressive variants of PTC, such as tall cell, columnar cell, solid, loss of cellular polarity/cohesiveness (hobnail) variants and encapsulated carcinoma with high grade histology. Poorly differentiated carcinoma (PDC) includes PDC of WHO definition, insular carcinoma, tumors with minor anaplastic transformation and tumors with distant metastasis at presentation.