Indeterminate Follicular Lesions Research Articles

Impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology Classification of Thyroid Nodules in the Treatment of Indeterminate Follicular Lesions: Five-Year Results at a Single Center.

Purpose Aim of the study was to assess the impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology (SIAPEC) classification of 2014, on the treatment of indeterminate thyroid lesions (TIR3). Methods We retrospectively analyzed patients undergoing thyroid surgery for TIR3 lesions between 2013 and 2018, at the General Surgery Department of Trieste University Hospital. According to the SIAPEC classification, patients were divided into TIR3A and TIR3B groups. All patients treated before 2014 underwent surgical treatment, and surgical specimens were retrospectively classified after revision of fine-needle aspiration cytology. Starting 2014, TIR3A patients were treated only when symptomatic (i.e., coexistent bilateral thyroid goiter or growing TIR3A nodules), whereas TIR3B patients always received surgical treatment. Hemithyroidectomy (HT) was the procedure of choice. Total thyroidectomy (TT) was performed in case of concurrent bilateral goiter, autoimmune thyroid disease, and/or presence of BRAF and/or RAS mutation. Lastly, we analyzed the malignancy rate in the two groups. Results 29 TIR3A and 90 TIR3B patients were included in the study. HT was performed in 10 TIR3A patients and 37 TIR3B patients, respectively, with need for reoperation in 4 TIR3B (10.8%) patients due to histological findings of follicular thyroid carcinoma >1 cm. The malignancy rates were 17.2% in TIR3A and 31.1% in TIR3B, (p = 0.16). Predictability of malignancy was almost 89% in BRAF mutation and just 47% in RAS mutation. Conclusions The new SIAPEC classification in association with biomolecular markers has improved diagnostic accuracy, patient selection, and clinical management of TIR3 lesions.

Utility of subcategorization of atypia of undetermined significance/follicular lesion of undetermined significance category in ultrasound-guided thyroid fine-needle aspiration in a large referral cancer center

Subclassification of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is encouraged in the Bethesda System. In our practice, we subclassified AUS/FLUS into 3 subcategories: atypical follicular cells of undetermined significance (ACUS) for cases with cytologic atypia; follicular lesion (FL) for cellular cases with follicular cells with-minimal or no atypia, arranged in a macro- and micro-follicular pattern with scant colloid; and indeterminate follicular lesion, favor benign (IFL-FB) for cases with few clusters of follicular cells without atypia associated with minimal or no colloid. The objective of our study was to evaluate the prevalence, clinical management, and risk of malignancy for each subcategory. We retrospectively identified ultrasound-guided fine-needle aspiration (US-FNA) of thyroid cases that were subcategorized as ACUS, IFL-FB, and FL at our-institution during 2014-2016. The results of US-FNA were correlated with clinical outcome in the subsequent 2 years including repeat US-FNA, thyroid surgery, and clinical/imaging follow-up. Of 3207 thyroid US-FNA cases, 718 (22.4%) cases were included in the study. Of these 718 cases, 104 (14.5%) were subcategorized as ACUS, 166 (23.1%) as FL, and 448 (62.4%) as IFL-FB. The surgery rate was 39.4% (41 of 104) for ACUS, 13.6% (61 of 448) for IFL-FB, and 27.1% (45 of 166) for FL. The risk of malignancy (ROM) was 25% (26 of 104) for ACUS, and 2.9% (13 of 448) for IFL-FB, 6.0% (10 of 166) for FL. The surgery rate and ROM was significantly higher for ACUS in comparison to IFL-FB (P < 0.05) and FL (P < 0.05). Subclassification of AUS/FLUS into 3 groups based on cytopathologic findings alone not only improved the triage of patients for subsequent clinical management but also effectively stratified the risk of malignancy.

Comparative Study between Total Thyroidectomy and Hemithyroidectomy in Treatment of Solitary Thyroid Nodules Diagnosed as Follicular Lesions by Fine-Needle Aspiration Cytology

Background: Thyroid nodular (TN) lesions are a common clinical problem in the world. These are more common in women and in areas of iodine deficiency. Exposure to ionizing radiation in childhood and adolescence increases the risk of solitary thyroid nodule and thyroid carcinoma. Objective: Determination of the optimal surgical approach for individuals undergoing thyroidectomy for solitary thyroid nodule identified as indeterminate follicular lesion on preoperative fine needle aspiration cytology (FNAC) diagnosis and to estimate the long term outcome of patients treated by lobectomy for solitary follicular thyroid nodule. Patients and methods: From June 2017 to June 2019, 50 patients having a solitary thyroid nodule with a cytological diagnosis of “indeterminate follicular lesion” were selected prospectively. Results: There were 26 women and 24 men with a mean age of 56 years (range: 28-83). Hemithyroidectomy (HT) was performed in 25 patients (50%) and a total thyroidectomy (TT) in 25 (50%). Postoperative morbidity was 3.50% in patients who underwent HT and 9.75% in those who underwent TT. At the histological analysis 3 (12%) patients of hemithyroidectomy group had a malignant lesion. Conclusions: Considering the high rate in which HT represents the adequate treatment, and the low rate of reoperation morbidity, HT seems to be the preferable initial surgical approach for indeterminate follicular lesions. Long-term ultrasonographic follow-up seems advisable.

Impact of Italian Society of Anatomic Pathology and Diagnostic Cytology Classification of Thyroid nodules in the Treatment of Indeterminate Follicular Lesions: Results in a Single Center after 3 Years

Impact of Italian Society of Anatomic Pathology and Diagnostic Cytology Classification of Thyroid nodules in the Treatment of Indeterminate Follicular Lesions: Results in a Single Center after 3 Years

Incidence and Significance of Incidental Focal Thyroid Uptake on 18F-FDG PET Study in a Large Patient Cohort: Retrospective Single-Centre Experience in the United Kingdom

Objective: To assess the prevalence and pathological nature of incidental focal thyroid uptake on ¹⁸F-FDG (2-[¹⁸F]-fluoro-2-deoxy-<smlcap>D</smlcap>-glucose) PET (positron emission tomography) and examine the role of the maximum standardised uptake value (SUV_max) to differentiate benign from malignant thyroid pathology. Material and Methods:¹⁸F-FDG PET reports were retrospectively reviewed. Incidental focal tracer uptake in the thyroid was noted in 147 patients (0.5%). Patients with known primary thyroid malignancy were excluded. The final diagnosis was made following ultrasonography of the neck, fine-needle aspiration cytology (FNAC) or histopathology of the surgically resected specimen where surgery was indicated. A Mann-Whitney U test was used to compare the SUV_max of benign and malignant thyroid pathology. Receiver operating characteristic (ROC) analysis was performed to identify an SUV_max cutoff in differentiating benign from malignant pathology. Results: A final diagnosis was achieved in 47/147 (32%) of the patients. The diagnoses included benign lesions in 36 patients and malignancy in 9 patients. In 2 patients, FNAC demonstrated indeterminate follicular lesions; however, surgical excision was not performed. There was a highly significant difference in the mean SUV_max of malignant focal thyroid uptake (15.7 ± 5.9) compared to that of benign lesions (7.1 ± 6.8) with a p value of 0.000123. An SUV_max of 9.1 achieved a sensitivity of 81.6%, specificity of 100% and area under the curve of 0.915 in the ROC analysis differentiating benign from malignant disease. Conclusion: The malignancy potential of incidental focal thyroid uptake remains high and warrants prompt and appropriate follow-up by the clinician. The SUV_max may aid in further characterisation of the lesion and its management.

Using Cancer Gene Profiling to Distinguish Benign from Malignant Follicular Thyroid Lesions

Objective: Fine needle aspiration (FNA) is a procedure used in the diagnosis of thyroid nodules. A definitive diagnosis is not possible when FNA shows follicular cells, and therefore a surgical intervention is necessary. Identifying genetic expression patterns in FNA samples of indeterminate thyroid nodules could assist in distinguishing benign from malignant follicular thyroid lesions. Methods: Patients with follicular cells on FNA and a pathologic diagnosis of either follicular thyroid adenoma (FTA) or carcinoma (FTC) were included. Thyroid tissue was collected at the time of definitive surgery. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used with an array profiler including 84 genes involved in transformation and tumorigenesis. RT2 Profiler PCR array data analysis software identified fold-change based upon ΔΔCt calculations. Gene expression was normalized to five housekeeping genes. Results: Nineteen patients were included: 10 with FTA and 9 with FTC on post-operative pathology. In the FTC group, 11 genes had greater than 2-fold up or down-regulation relative to the adenoma group; and two genes reached statistical significance, caspase-8 and IL-8 (p ≤ 0.05). Utilizing the Sub-Network Enrichment Analysis (SNEA) algorithm, sub-networks of genes involving the transforming growth factor (TGF) family and peroxisome proliferator-activated receptor delta (PPARδ) family were both highly regulated. Conclusions: Our preliminary data identify two potential genes that may aid in differentiating FTC from FTA, and demonstrates a potential role for qRT-PCR of FNA samples. This may contribute to the workup of thyroid nodules to ultimately guide the treatment of indeterminate follicular lesions.

‘Indeterminate for malignancy’ (Tir3/Thy3 in the Italian and British systems for classification) thyroid fine needle aspiration (FNA) cytology reporting: morphological criteria and clinical impact

The British system (Thy1-5), the Bethesda system for reporting thyroid cytopathology (BSRTC) and the Italian Society of Anatomic Pathology and Cytology (SIAPEC) classification represent the most important international classifications for thyroid cytopathology. Irrespective of the system used, the 'indeterminate' categories are still debated among cytopathologists, particularly with regard to diagnostic criteria, clinical impact of subclassification and role of molecular techniques. We aimed to find answers to the following questions: Are there shared criteria in cytological preparations that allow the division of indeterminate follicular lesions into subcategories? What is the true clinical impact of this possible subclassification? Among 1150 consecutive thyroid fine needle aspiration (FNA) specimens, 80 patients had nodules with a final cytological report of Tir3 (SIAPEC)/Thy3. These 80 cases were re-evaluated and subclassified according to morphological criteria into three groups: pure follicular proliferations, Hürthle cell follicular lesions and atypical proliferations. Sixteen (20%) cases were categorized as pure follicular proliferations, 40 (50%) as Hürthle cell follicular lesions and 24 (30%) as atypical proliferations. Surgery was performed in 57 cases (71%). Cyto-histological correlation showed that follicular adenoma was the most frequent final diagnosis in the cases treated by surgery (24/57, 42%). The overall malignancy rate in the Tir3 category was 28% (16/57). Atypical proliferations were more often malignant than either of the follicular groups (53% versus 19%, P=0.019). A five-tiered classification, subdividing the 'indeterminate for malignancy' class into 'follicular proliferations' and 'atypical lesions' could be adopted. As a result of their higher risk of malignancy, surgical management of the atypical lesions would be justified. In future, the introduction of a genetic panel might contribute to their stratification, to the determination of a more accurate risk of malignancy of the atypical lesions and to the verification of follicular proliferations that are benign.

An antibody-like peptide that recognizes malignancy among thyroid nodules

There is an urgent need for biomarkers to identify malignant thyroid nodules from indeterminate follicular lesions. We have used a subtractive proteomic strategy to identify novel biomarkers by selecting ligands to goiter tissue from a 12-mer random peptide phage-displayed library using the BRASIL method (Biopanning and Rapid Analysis of Selective Interactive Ligands). After three rounds of selection, two highly reactive clones to the papillary thyroid tumor cell line NPA were further evaluated, and their specific binding to tumor proteins was confirmed using phage-ELISA. The antibody-like peptide CaT12 was tumor-specific, which was further tested by immunohistochemistry against TMAs (tissue microarrays) comprised of 775 human benign and malignant tissues, including 232 thyroid nodular lesions: 15 normal thyroid tissues, 53 nodular goiters (NG), 54 follicular adenomas (FA); 69 papillary thyroid carcinomas (PTC); and 41 follicular carcinomas (FC). CaT12 was able to identify PTC among thyroid nodular lesions with 91.2% sensitivity and 85.1% specificity, despite its non-specificity for thyroid tissues. Additionally, the CaT12 peptide helped characterize follicular lesions distinguishing the follicular variant of PTC (FVPTC) from FA with 91.9% accuracy; FVPTC from NG with 83.1% accuracy; FVPTC from the classic PTC with 57.7% accuracy; and FVPTC from FC with 88.7% accuracy. In conclusion, our strategy to select differentially expressed ligands to thyroid tissue was highly effective and resulted in a useful antibody-like biomarker that recognizes malignancy among thyroid nodules and may help distinguish follicular patterned lesions.

18F-Fluorodeoxyglucose Uptake in Thyroid from Positron Emission Tomogram (PET) for Evaluation in Cancer Patients: High Prevalence of Malignancy in Thyroid PET Incidentaloma

To investigate the prevalence of incidental thyroid F-fluorodeoxyglucose (FDG) uptake in positron emission tomogram (PET) scan for evaluation in cancer patients and the role of standard uptake value (SUV) measurement in differentiation of thyroid malignancy from benign disease. Retrospective single-center study. Four thousand one hundred thirty-six subjects had been given FDG-PET scan for evaluation of known malignancies not associated with thyroid. The maximum SUVs of the thyroid lesions were recorded and reviewed. Fine needle aspiration was performed in patients with definite nodule by palpation or ultrasonography. Ninety-four (2.2%) were identified to have focal (n = 45, 1.1%) or diffuse (n = 45, 1.1%) thyroid FDG uptake. The incidence of focal or diffuse thyroid FDG uptake was higher in women (2.7% or 1.9%) than in men (0.4% or 0.7%). Cytologic diagnosis was available in 32 of 45 focal thyroid FDG uptakes. In 16 (50%) patients, the tumor was found to be malignant; 14 were papillary thyroid carcinoma (surgically confirmed in 7 cases), 2 were metastatic tumor from breast and esophagus. Sixteen were cytologically diagnosed as follicular cell lesions: follicular neoplasm (n = 2), nodular hyperplasia (n = 7), indeterminate follicular lesion (n = 7). There was no significant difference in maximum SUV between benign and malignant nodules. From 45 patients with diffuse thyroid FDG uptake, presumptive diagnosis of chronic thyroiditis was possible in 34 patients by clinical and laboratory findings. Our data suggest that a cytologic diagnosis of focal thyroid FDG-PET incidentaloma regardless of SUV is mandatory considering the very high prevalence of thyroid malignancy.

Prevalence of malignancy within cytologically indeterminate thyroid nodules

Background The optimal management of cytologically indeterminate thyroid nodules is controversial given the variable malignancy rates reported in this patient population. We examined the prevalence of malignancy within cytologically indeterminate follicular thyroid lesions in an attempt to predict malignancy based on cytologic features. Methods Cytopathology reports obtained after fine-needle aspiration biopsy (FNAB) examination of indeterminate follicular thyroid lesions were examined over a 4-year period. The prevalence of malignancy on final histology was determined in 4 indeterminate cytologic categories. Results A total of 107 records were available (91 women, 16 men). The mean patient age was 45.4 ± 16 years. Forty-eight patients (45%) underwent surgery and had histopathologic diagnosis, while 57 patients did not have surgery. The prevalence of malignancy in patients who underwent thyroidectomy was 42% (20 of 48). Conclusions The high prevalence of malignancy within indeterminate follicular lesions may necessitate thyroidectomy for patients with indeterminate follicular lesions on FNAB examination.

Recent experience with preoperative fine-needle aspiration biopsy of thyroid nodules in a community hospital.

The application and reliability of fine-needle aspiration (FNA) biopsy in community hospitals may be less efficacious in the clinical assessment of patients with thyroid nodules than in tertiary referral centers. Retrospective review. One community teaching hospital. One hundred eighty-three patients who underwent thyroidectomy after FNA biopsy. Preoperative FNA biopsy cytopathologic testing and thyroidectomy and postoperative histopathologic testing. Preoperative cytopathologic reports were compared with postthyroidectomy histopathologic reports. Thyroid cancer was confirmed postoperatively in 70 patients (38%). An FNA biopsy diagnosis of papillary carcinoma (in 29 patients) correlated with a predictive accuracy of 93% (27 patients). Suspicious for papillary carcinoma (n = 14) correlated with malignancy in 8 patients (57%). Indeterminate follicular lesion (n = 60) correlated with malignancy in 18 patients (30%), of whom 16 (89%) had papillary carcinoma (10 patients had follicular variant) and 2 (11%) had follicular carcinoma. Indeterminate Hürthle cell lesion (n = 20) correlated with malignancy in 7 patients (35%). Atypical cell clusters (n = 5) did not correlate with malignancy. Benign FNA biopsy findings (n = 44) in patients who underwent thyroidectomy for other clinical features correlated with malignancy in 8 (18%). Of 11 patients who underwent thyroidectomy for insufficient number of cells after repeated FNA biopsy attempts, 2 (18%) had carcinoma. The accuracy of an FNA biopsy of thyroid nodules in a community hospital setting is comparable to results from major endocrine referral centers. An indeterminate follicular lesion was the most common FNA biopsy indication for thyroidectomy and correlated with the presence of differentiated thyroid cancers in 18 (30%) of 60 patients.