ProGRP as a Novel Biomarker for the Differential Diagnosis of Medullary Thyroid Carcinoma in Patients with Thyroid Nodules

Objective: To investigate the release of progastrin-releasing peptide (ProGRP) in patients with thyroid nodules and the value of ProGRP in fine-needle aspirate washout fluid (FNA-ProGRP) in the differential diagnosis between medullary thyroid carcinoma (MTC) and non-MTC thyroid nodules.Methods: We investigated 2,446 healthy persons and 212 patients with 235 thyroid nodules. They were classified into healthy, nodular goiter, chronic thyroiditis, thyroid follicular neoplasm, papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. The serum ProGRP and FNA-ProGRP were measured.Results: The serum ProGRP median concentration in MTC was 124.40 pg/mL, significantly higher than in other groups. The cutoff value of serum ProGRP was 68.30 pg/mL, leading to 53.85% sensitivity, 96.98% specificity, and 0.51 kappa value in MTC. The FNA-ProGRP median concentration in MTC nodules was 2,096.00 pg/mL, significantly higher than in other groups. A receiver operating characteristic analysis of MTC nodules and non-MTC nodules indicated that the cutoff value was 22.77 pg/mL, leading to 94.12% sensitivity, 98.27% specificity, and 0.85 kappa value.Conclusion: FNA-ProGRP measurement could be served as an ancillary method for the differential diagnosis between MTC and non-MTC thyroid nodules.Abbreviations: CEA = carcinoembryonic antigen; CT = calcitonin; FNAC = fine-needle aspiration cytology; FNA-CT = calcitonin in fine-needle aspirate washout fluid; FNA-ProGRP = ProGRP in fine-needle aspirate washout fluid; MTC = medullary thyroid carcinoma; ProGRP = progastrin-releasing peptide; SCLC = small-cell lung cancer; TM = tumor marker     

Same-Day Diagnosis Based on Histology for Women Suspected of Breast Cancer: High Diagnostic Accuracy and Favorable Impact on the Patient

Background

Same-day diagnosis based on histology is increasingly being offered to patients suspected of breast cancer. We evaluated to which extent same-day diagnosis affected diagnostic accuracy and patients'' anxiety levels during the diagnostic phase.

Patients and methods

All 759 women referred for same-day evaluation of suspicious breast lesions between November 2011–March 2013 were included. Diagnostic accuracy was assessed by linking all patients to the national pathology database to identify diagnostic discrepancies, in which case slides were reviewed. Patients'' anxiety was measured in 127 patients by the State Trait and Anxiety Inventory on six moments during the diagnostic workup and changes over time (< = 1 week) were analyzed by mixed effect models.

Results

Core-needle biopsy was indicated in 374/759 patients (49.3%) and in 205/759 (27%) patients, invasive or in situ cancer was found. Final diagnosis on the same day was provided for 606/759 (79.8%) patients. Overall, 3/759 (0.4%) discordant findings were identified. Anxiety levels decreased significantly over time from 45.2 to 30.0 (P = <0.001). Anxiety levels decreased from 44.4 to 25.9 (P = <0.001) for patients with benign disease, and remained unchanged for patients diagnosed with malignancies (48.6 to 46.7, P = 0.933). Time trends in anxiety were not affected by other patient or disease characteristics like age, education level or (family) history of breast cancer.

Conclusion

Same-day histological diagnosis is feasible in the vast majority of patients, without impairing diagnostic accuracy. Patients'' anxiety rapidly decreased in patients with a benign diagnosis and remained constant in patients with malignancy.     

The Role of Core-Needle Biopsy for Thyroid Nodules with Initially Nondiagnostic Fine-Needle Aspiration Results: A Systematic Review and Meta-Analysis

Objective: This study evaluated the prevalence of nondiagnostic results, diagnostic performance, and complications of core-needle biopsy (CNB) compared with repeat fine-needle aspiration (FNA) for thyroid nodules with previous nondiagnostic FNA findings.Methods: The Ovid-MEDLINE and EMBASE databases were thoroughly searched for studies evaluating CNB or repeat FNA for thyroid nodules with initially nondiagnostic FNA results. Pooled proportions of nondiagnostic results of CNB and repeat FNA were calculated. A meta-analysis was performed to evaluate the diagnostic accuracy of CNB and repeat FNA for a diagnosis of malignancy using a bivariate random-effects model. Complication rates were also evaluated.Results: A review of 52 articles identified 4 eligible articles, involving 1,028 patients with 1,028 thyroid nodules, which were included in the meta-analysis. CNB demonstrated significantly lower rates of nondiagnostic results (6.4%) than repeat FNA (36.5%) (P<.0001). In the 3 studies that analyzed the diagnostic accuracy of CNB in diagnosing malignancy, CNB demonstrated significantly higher summary estimates of sensitivity (89.8%) than repeat FNA (60.6%) (P = .022), but summary specificity did not differ between CNB (99.2%) and repeat FNA (99.0%) (P = .576). None of the patients who underwent CNB or repeat FNA experienced any major complications.Conclusion: CNB demonstrates lower rates of nondiagnostic results and higher diagnostic accuracy than repeat FNA. CNB, rather than repeat FNA, can be utilized to diagnose thyroid nodules previously nondiagnostic on FNA.Abbreviations:CI = confidence intervalCNB = core-needle biopsyFNA = fine-needle aspirationSROC = summary receiver operating characteristicUS = ultrasound     

Maximal Stiffness Evaluation by Real-Time Ultrasound Elastography,an Improved Tool for the Differential Diagnosis of Thyroid Nodules

Objective: The aim of the study was to evaluate the diagnostic performance of a new ultrasound elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI) and to investigate their diagnostic performance according to nodule size.Methods: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation, and fine-needle aspiration cytology (FNAC). Thyroid nodules were further stratified into 4 subgroups (G) according to their size (G1, <1 cm; G2, 1–2 cm; G3, >3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI.Results: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity, 0.66 and 0.90, respectively; % Index sensitivity and specificity, 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (odds ratio [OR], 18.68; 95% confidence interval [CI], 6.06 to 63.49; P<.0001 versus OR, 26.15; 95% CI, 8.01 to 102.87; P<.0001, respectively) and in the G1 and G2 subgroups.Conclusion: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to explore both by conventional US and FNAC.Abbreviations: FNAC = fine-needle aspiration cytology % Index = percentage of maximal stiffness within the nodule MCC = Matthew's correlation coefficient OR = odds ratio RTE = real-time elastography SI = strain index US = ultrasound USE = ultrasound elastography     

Autonomously Functioning Thyroid Nodules In Patients &#x003c;21 Years Of Age: The Rhode Island Hospital Experience From 2003&#x00C2;&#x20AC;&#x201C;2013

Objective: This study evaluates the clinical characteristics, workup, treatment, and outcomes of pediatric patients diagnosed with an autonomously functioning thyroid nodule (AFTN) in a large cohort of patients presenting for evaluation of a thyroid nodule. There are few prior studies on AFTN in pediatrics, with limited data on treatment and outcomes. Rates of malignancy in AFTN are perceived as low, but prior studies have varying reports.Methods: This is a retrospective chart review of patients less than 21 years of age at Rhode Island Hospital over an 11-year period (2003&#x00E2;&#x20AC;&#x201C;2013). We reviewed 354 charts, which yielded 242 patients with a diagnosis of thyroid nodule and 17 patients with AFTN.Results: The prevalence of AFTN in patients presenting with thyroid nodules was 7%. Mean age of patients was 15.8 years at diagnosis, and mean nodule size was 3.3 cm. There was female predominance. Thyroid-stimulating hormone levels were suppressed at diagnosis in 87% of patients. Six patients were treated with surgery, 5 patients with radioactive iodine therapy (RAI), 2 patients with medication, and 1 patient was observed without treatment. Three patients treated with RAI required subsequent treatment for hypothyroidism or continued hyperthyroidism. One patient had papillary thyroid carcinoma based on final surgical pathology.Conclusion: Our study found a higher prevalence of AFTN compared to the reported prevalence in adults. We concur with the new guidelines on management of thyroid nodules in recommending surgery for treatment of AFTN, based on the variability of outcomes after treatment with RAI.Abbreviations:AFTN = autonomously functioning thyroid noduleanti-TG = thyroglobulin antibodiesanti-TPO = thyroid peroxidase antibodiesFNA = fine-needle aspirationICD-9 = International Classification of Diseases, Ninth RevisionPTC = papillary thyroid carcinomaRAI = radioactive iodineT₃ = triiodothyronineT₄ = thyroxineTSH = thyroid-stimulating hormoneTSI = thyroid-stimulating immunoglobulin     

Thyroid Nodule Location on Ultrasonography as a Predictor of Malignancy

Objective: The diagnostic capacity of ultrasonography (US) for differentiating between malignant and benign thyroid nodules is crucial in preventing unnecessary invasive procedures. This is the first study to evaluate whether thyroid nodule location on US has predictive value for malignancy.Methods: We retrospectively reviewed data from 219 patients with thyroid nodules who underwent fine-needle aspiration biopsy in 1 year. Patients' demographics as well as nodule's laterality, polarity, morphology, and multinodularity were analyzed. All malignant lesions were confirmed by surgical pathology.Results: The majority of the patients were female (86.2%). Nodules were evenly distributed between the right lobe (46.3%) and left lobe (49.5%). Eight nodules (4.2%) were located in the isthmus. Most nodules (79.3%) were located in the lower pole, while 9.6% were located in the upper pole and 6.9% in the middle pole. Seventy-five patients (39.9%) had multiple nodules. Fourteen nodules were malignant, representing a prevalence of 7.4%. A significantly higher frequency of malignancy was observed in upper pole (22.2%) compared to lower pole (4.7%) and middle pole (15.4%). A multiple logistic regression model confirmed such association after adjusting for age, body mass index, multinodularity, and laterality. The odds of malignancy in the upper pole were 4 times higher than other locations (odds ratio, 4.6; P = .03).Conclusion: Our study is the first showing that thyroid nodules located in the upper pole can be considered as having higher risk for malignancy. It may enhance the predictive value of malignancy if it is included in thyroid nodule ultrasound classification guidelines.Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; BMI = body mass index; FNA = fine-needle aspiration; TMS = total malignancy score; TTW = taller than wide; US = ultrasonography     

Thyroseq®V2.0 Molecular Testing: A Cost-Effective Approach for the Evaluation of Indeterminate Thyroid Nodules

Objective: Approximately 15 to 30% of thyroid nodules have indeterminate cytology. Many of these nodules are treated surgically, but only 5 to 30% are malignant. Molecular testing can further narrow the risk of malignancy of these nodules. Our objective was to assess the cost effectiveness of ThyroSeq®V2.0 compared to diagnostic thyroidectomy for the evaluation of indeterminate nodules.Methods: Cytology and histopathology slides of Bethesda category III and IV (suspicious for follicular neoplasia [SFN]) nodules obtained between January 1, 2014 and November 30, 2016 were re-reviewed by 2 endocrine cytopathologists. Costs for a diagnostic approach using ThyroSeq® were calculated and compared to those of diagnostic thyroidectomy.Results: We included 8 Bethesda category III nodules that underwent ThyroSeq® and 8 that underwent diagnostic surgery. Of those submitted for ThyroSeq®, 4 were positive for mutations and underwent thyroid surgery. The average cost per nodule evaluated was $14,669 using ThyroSeq®, compared to $23,338 for diagnostic thyroid surgery. The cost per thyroid cancer case detected was $58,674 using ThyroSeq® compared to $62,233 for diagnostic thyroid surgery. We included 13 nodules Bethesda category IV that underwent ThyroSeq® and 11 that underwent diagnostic surgery. Of those submitted for ThyroSeq®, 6 were positive for mutation and underwent thyroid surgery. The average costs per nodule evaluated were $14,641 using ThyroSeq® and $24,345 using diagnostic thyroidectomy. The cost per thyroid cancer case detected was $31,721 when using ThyroSeq® compared to $53,560 for diagnostic thyroidectomy.Conclusion: The use of ThyroSeq® in our institution is cost effective compared to diagnostic thyroid surgery for the evaluation of Bethesda categories III and IV (SFN) nodules.Abbreviations: FNA = fine-needle aspiration; GEC = gene expression classifier; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid cancer; SFN = suspicious for follicular neoplasia     

IS MEASUREMENT OF CIRCULATING TUMOR DNA OF DIAGNOSTIC USE IN PATIENTS WITH THYROID NODULES?

Objective: Circulating tumor DNA (ctDNA), a subset of cell-free DNA (cfDNA), is a potential biomarker for thyroid cancer. We determined the performance of a ctDNA panel for detecting thyroid malignancy in patients with thyroid nodules.Methods: Sixty-six patients with thyroid nodules without a prior history of cancer enrolled in a prospective, 1-year study in which blood was drawn for ctDNA analysis prior to undergoing fine-needle aspiration biopsy (FNAB) of thyroid nodules. The ctDNA panel consisted of 96-mutations in 9 cancer driver genes. The primary outcome measures were the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of our ctDNA panel for the diagnosis of thyroid malignancy as determined by pathologic and/or molecular tissue examination.Results: Results from 10 subjects could not be determined due to inadequate volume or technical issues. The final classifications of the thyroid nodules were 13 malignant and 43 benign lesions. A KRAS G12V mutation was detected in the plasma of 1 patient with stage IVA papillary carcinoma whose tissue contained the same mutation. Two of the 43 patients with benign lesions also had ctDNA detected, giving a sensitivity of 7.7%, specificity of 95.35%, PPV of 33.33%, and NPV of 77.35%. There were no significant differences between benign or malignant lesions in cfDNA levels.Conclusion: Neither cfDNA measurements nor our panel of ctDNA mutations are sensitive or specific enough to provide valuable information over FNAB. An expanded panel and the inclusion of proteomics may improve sensitivity and specificity for thyroid cancer detection.Abbreviations: cfDNA = cell-free DNA; ctDNA = circulating tumor DNA; FNAB = fine-needle aspiration biopsy; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features     

Thyroid Nodules with 2 Prior Inadequate Fine-Needle Aspiration Results: Effect of Increasing the Diameter of the Needle

Objective: The major limitation of ultrasound-guided fine-needle aspiration biopsy (US-FNAB) procedures of thyroid nodules are the cytologically nondiagnostic results. The role of increasing the diameter of the needle in the third FNAB (FNAB#3) due to inadequate cytology has as yet not been investigated. The aim of the present study was to evaluate whether increasing the needle diameter could improve the cytologic sampling of thyroid nodules following 2 previous nondiagnostic US-FNAB results.Methods: Between July 2012 and December 2012, 140 consecutive patients with 2 prior nondiagnostic US-FNAB results were enrolled in this prospective investigation. Group 22G consisted of 70 patients (78.5% women; mean age, 52 years) having nodules examined with a 22-gauge (G) needle. Group 27G consisted of 70 patients (75.7% women; mean age, 53 years) having nodules examined with a 27-G needle.Results: The rate of nondiagnostic FNAB results was 42.8% (30 of 70) in group 22G and 64.3% (45 of 70) in group 27G, which was a significant difference (P = .011). The large-bore (22 G) needle was found to be statistically significantly superior compared with the small-bore (27 G) needle in diagnostic ability for predominantly solid (P = .014), irregular (P = .013), and halo-free (P = .021) nodules. The accuracy rate was 64.6 and 38% for large-bore (22 G) and small-bore (27 G) needles, respectively.Conclusion: The results of our study showed that increasing the needle lumen diameter significantly improves diagnostic performance in terms of adequate aspirated material and diagnostic accuracy rate following 2 prior nondiagnostic US-FNABs.Abbreviations: AUS = atypia of undetermined significance FNAB = fine-needle aspiration biopsy G = gauge NPV = negative predictive value PPV = positive predictive value US = ultrasound     

Incidental Thyroid Nodules: Race/Ethnicity Disparities and Outcomes

Objective: Black patients have a significantly lower incidence of well-differentiated thyroid cancer (WDTC) compared to all other race/ethnic groups, while white patients appear to be at greater risk. This study examines incidental thyroid nodules (ITNs) to assess whether racial disparities in WDTC arise from a differential discovery of ITNs—perhaps due to socioeconomic disparities—or reflect true differences in thyroid cancer rates.Methods: A retrospective review was performed of all patients who underwent fine-needle aspiration (FNA) of thyroid nodules by our academic medical center's endocrinology division between January 2006 and December 2010. Medical records were reviewed to identify whether the biopsied thyroid nodule was discovered incidentally through nonthyroid-related imaging or identified by palpation.Results: FNAs were performed on 1,369 total thyroid nodules in 1,141 study patients; 547 (48%) were classified as white, and 593 (52%) were classified as nonwhite. Among this cohort, 36.6% of patients underwent biopsy for an ITN. White patients were 1.6 times more likely to have undergone a biopsy for a nodule that was incidentally identified compared to nonwhites (P<.0001). Indicators of socioeconomic status (SES) did not have a significant association with ITNs. Within the ITN cohort, 4.9% of nonwhite patients were found to have a thyroid malignancy compared to 12.9% of white patients (P<.01).Conclusion: The higher incidence of thyroid cancer in white patients appears to be not only due to diagnostic bias, but also to a true difference in cancer prevalence.Abbreviations: FNA = fine-needle aspiration; ITN = incidental thyroid nodule; SEER = Surveillance Epidemiology and End Results; SES = socioeconomic status; WDTC = well-differentiated thyroid cancer     

The Value of Gross Visual Assessment of Specimen Adequacy for Liquid-Based Cytology During Ultrasound-Guided,Fine-Needle Aspiration of Thyroid Nodules

Objective: Major problems of fine-needle aspiration (FNA) of thyroid nodules arise due to nondiagnostic results caused by inadequately obtained FNA specimens. The purpose of this study was to evaluate the value of visual assessment of liquid-based cytology specimens during FNA of thyroid nodules for predicting sampling adequacy.Methods: For 3 months, visual assessment of FNA specimens was used for 534 consecutive nodules in 534 patients. The FNA specimens were visually graded immediately following aspiration for each nodule, and the visual grades were classified into 2 categories: inadequate (<6 cell groups) and adequate (>6 cell groups). The cytology results were classified as diagnostic or nondiagnostic based on the Bethesda system. We compared the ultrasound features and FNA characteristics between the diagnostic and nondiagnostic results. Multiple logistic regression analysis was used to determine factors independently predictive of nondiagnostic results. We also evaluated the interobserver agreement regarding the visual assessment.Results: Visual assessment was feasible in all patients, and the nondiagnostic rate was 11.6% (62 of 534). Nondiagnostic results were more frequent in the inadequate visual assessment group (38.1%) than in the adequate visual assessment group (10.5%) (P = .001). Independent predictive factors for nondiagnostic results were inadequate visual assessment (odds ratio, 5.18), >50% vascularity (odds ratio, 3.98), and macrocalcification (odds ratio, 3.60). Interobserver agreement for the prediction of visual assessment was good (κ value, 0.767; P<.001).Conclusion: Immediate visual assessment of a specimen during FNA of a thyroid nodule is a feasible method for predicting sampling adequacy.Abbreviations: FNA = fine-needle aspiration LBC = liquid-based cytology US = ultrasound     

Do all Thyroid Nodules >4 cm need to be Removed? An Evaluation of Thyroid Fine-Needle Aspiration Biopsy in Large Thyroid Nodules

Objective: Controversy exists regarding the ability of fine-needle aspiration (FNA) biopsy to rule out malignancy when thyroid nodules exceed 4 cm in diameter. The goal of this study was to provide data regarding FNA accuracy in a clinical setting for detecting/ruling out malignancy in large thyroid nodules (≥4 cm) and discuss FNA utility in guiding surgical decisions.Methods: All thyroid FNA cases performed at Marshfield Clinic from 1/1/2000 to 12/31/2010 followed by complete or partial thyroidectomy on nodules of at least 4 cm were identified. Demographics, medical history, nodule biopsy characteristics, surgical procedures, and diagnosis data were abstracted. FNA was compared to histologic evaluation of surgical specimens.Results: A total of 198 patients with large thyroid nodules were identified. Most had a single large nodule, but ~40% were multinodular, and 206 total nodules were assessed. Females outnumbered males, and the mean age was ~50 years. After surgery, cancer was histologically identified in 49/206 (23.8%) nodules, including 9/123 nodules that had been categorized as benign by FNA, corresponding to a false-negative rate of 7.3%. Sensitivity/specificity for detecting malignancy by FNA was ~80%. The positive predictive value (PPV) was just below 60%, and the negative predictive value (NPV) was 93% but rose to 96% when papillary microcarcinomas were excluded.Conclusion: While FNA sensitivity in large nodules was relatively low, NPV was high, especially if incidental papillary microcarcinomas were excluded. When cancer prevalence and NPV are known, FNA can be a reliable “rule out” test in nodules ≥4 cm. This information is critical and can help guide the surgery decision, especially in high-risk patients. The decision for surgery should not be solely based on nodule size but should consider additional factors including cancer prevalence, clinical history, ultrasound features, surgical risk, and life expectancy.Abbreviations:FNA = fine-needle aspirationNPV = negative predictive valuePPV = positive predictive value     

Utility of Ultrasound Versus Gene Expression Classifier in Thyroid Nodules with Atypia of Undetermined Significance

Objective: Thyroid nodules with fine-needle aspiration (FNA) cytology categorized as atypia of undetermined significance (AUS) often undergo additional diagnostic analysis with the Afirma Gene Expression Classifier (GEC), which classifies these as either high probability of being benign (GEC-B) or suspicious for malignancy (GEC-S). Our goal was to assess the clinical validity and utility of GEC in the evaluation of AUS cytology and evaluate the performance of ultrasonography (USG) for predicting malignancy in this subset.Methods: We conducted a study with a retrospective cohort of patients from January 2012 to January 2014 who had FNA of thyroid nodules >1 cm in size with AUS cytology.Results: Cleveland Clinic Florida has an overall prevalence of AUS of 5%. A total of 119 cases with nodules >1 cm in size were reported as AUS. Forty-eight (40.3%) had a GEC performed after the first FNA (AUS-1), and 27 of these were GEC-S. Of those 27, 21 went for surgery and 14 (66.6%) had thyroid cancer on histopathology. The remaining 71 with AUS-1 were sent for a second FNA: 19 nodules were benign and did not undergo further evaluation, while the remaining 52 were reported as AUS for the second consecutive time (AUS-2). AUS-2 samples were sent for GEC. Of these 52 AUS-2, 38 (73.1%) were reported as GEC-S. Thirty-five went for surgery and 32 (91.4%) had confirmed malignancy on histopathology. Positive predictive value (PPV) was 91.4% for AUS-2 and 66.6% for AUS-1. Moreover, AUS-2 nodules that were hypoechoic and solid on USG showed a PPV of 92% for malignancy.Conclusion: In our practice, the diagnostic accuracy to predict malignancy with GEC for AUS-1 nodules was poor (PPV, 66.6%). The PPV of GEC testing was markedly higher at 91.4% performed after two consecutive AUS cytologies. AUS-2 nodules that were solid and hypoechoic on USG also had a high probability to be malignant (PPV, 92%). We recommend repeat FNA on AUS-1 nodules rather than proceeding directly to GEC testing. Also, we suggest that among AUS-2 nodules, surgery can be recommended when USG shows solid and hypoechoic features with GEC testing reserved for the remainder.Abbreviations:AUS = atypia of undetermined significanceFNA = fine-needle aspirationGEC = gene expression classifierGEC-B = GEC-benignGEC-S = GEC-suspicious for malignancyNPV = negative predictive valuePPV = positive predictive valueUSG = ultrasonography     

Risk of Malignancy in Thyroid Cytology: The Impact of The Reclassification of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP)

Objective: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We aimed to compare the risk of malignancy (ROM) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) on fine-needle aspiration cytology (FNAC), before and after the reclassification, in a large cohort of patients.Methods: We analyzed 5,625 consecutive FNAC samples performed in 2012–2014 and selected category III (atypia of undetermined significance &lsqb;AUS]/follicular lesion of undetermined significance &lsqb;FLUS]), IV (follicular neoplasm &lsqb;FN]/suspicious for a follicular neoplasm &lsqb;SFN]), V (suspicious for malignancy &lsqb;SFM]), and VI (malignant) of the BSRTC. We reviewed the histology of operated patients and compared ROM before and after the introduction of the NIFTP category.Results: A total of 772 patients were identified and 45% underwent surgery (n = 348). There were 180 cases of AUS/FLUS (10 NIFTP), 114 cases of FN/SFN (2 NIFTP), 29 cases of SFM (3 NIFTP), and 25 cases of BSRTC VI (no NIFTP). Exclusion of NIFTP from malignant lesions resulted in a relative and absolute decrease in the ROM in AUS/FLUS (15.2% and 5.5%, respectively), FN/SFN (7.6% and 1.8%, respectively) and SFM (14.2% and 10.3%, respectively) categories. Among the NIFTP patients, 93% underwent total thyroidectomy and 20% received radioiodine.Conclusion: Reclassification of noninvasive EFVPTC as NIFTP resulted in a decrease in overall ROM, and the BSRTC categories most affected were III and V.Abbreviations: AUS = atypia of undetermined significance; BSRTC = Bethesda System for Reporting Thyroid Cytopathology; EFVPTC = encapsulated follicular variant of papillary thyroid carcinoma; FLUS = follicular lesion of undetermined significance; FN = follicular neoplasm; FNAC = fine-needle aspiration cytology; FVPTC = follicular variant of papillary thyroid carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid carcinoma; ROM = risk of malignancy; SFM = suspicious for malignancy; SFN = suspicious for a follicular neoplasm     

Quality of Life in Patients with Low-Risk Papillary Thyroid Microcarcinoma: Active Surveillance Versus Immediate Surgery

Objective: This study aimed to compare the quality of life (QoL) and psychological issues of patients with papillary thyroid microcarcinoma (PMC) who were under active surveillance (AS) and those who underwent immediate surgery (OP).Methods: This was a cross-sectional study conducted on 347 patients with low-risk PMC who were under AS (n = 298) or who underwent OP (n = 49). They were asked to complete two questionnaires (thyroid cancer–specific health-related QoL [THYCA-QoL] and the Hospital Anxiety and Depression Scale [HADS]). The results between the AS and OP groups were compared.Results: The mean ages of patients in the AS and OP groups were 58.6 ± 12.5 and 58.4 ± 13.1 years (P =.94), respectively, and the male ratios were 34/298 (11%) and 2/49 (4.1%) (P =.14), respectively. The median follow-up periods from diagnosis in the AS and OP groups were 56.5 months (interquartile range [IQR], 32 to 88 months) and 84 months (IQR, 64 to 130 months) (P<.001), respectively. In the THYCA-QoL questionnaire, the OP group had more complaints about “voice” (P<.001), “psychological” (P =.025), “problems with scar” (P<.001), and “gained weight” (P =.047) than the AS group. Other scales of the THYCA-QoL were comparable in the two groups. In the HADS questionnaire, the AS group had significantly better anxiety (P =.020), depression (P =.027), and total scores (P =.014) than the OP group.Conclusion: PMC patients in the OP group had more complaints and were more anxious and depressed than the AS group. These findings suggest that AS is a reasonable alternative to surgery for patients with low-risk PMC from the point of view of QoL and psychology.Abbreviations: AS = active surveillance; CI = confidence interval; HADS = Hospital Anxiety and Depression Scale; LT4 = levothyroxine; OP = immediate surgery; PMC = papillary microcarcinoma; PTC = papillary thyroid carcinoma; QoL = quality of life; STAI = State-Trait Anxiety Inventory; THYCA-QoL = thyroid cancer–specific health-related quality of life; TSH = thyrotropin     

Predictive Value of Somatic Mutations for the Development of Malignancy in Thyroid Nodules by Cytopathology

Objective: The purpose of our prospective longitudinal study was to evaluate the predictive efficacy of genetic testing for malignancies in fine-needle aspiration biopsy samples that are cytologically benign at the time of biopsy.Methods: A total of 779 aspirated cytological samples collected from thyroid nodules of 626 patients were included in a 3-year follow-up study. Consecutive patients with cytologically benign thyroid nodules by the Bethesda System for Reporting Thyroid Cytopathology were enrolled in the study. At enrollment, somatic 1-point nucleotide polymorphisms of BRAF and RAS family genes were tested by melting-point analysis, while RET/PTC and PAX8/PPAR-gamma rearrangements were examined by real-time polymerase chain reaction. The genetic test was considered to be positive if a somatic mutation was found. Malignant cytopathologic diagnoses were confirmed by histopathology.Results: In samples collected from 779 thyroid nodules, there were 39 BRAF, 33 RAS mutations, and 1 RET/PTC rearrangements found at the beginning of the study. No PAX8/PPAR-gamma rearrangement was identified. There were 52 malignant thyroid tumors removed during follow-up, out of which 24 contained a somatic mutation. The specificity of the presence of somatic mutations for malignancies was as high as 93.3%, and sensitivity was 46.2%. The negative predictive value of genetic testing reached 96.0%.Conclusion: Our results show that our set of genetic tests can predict the appearance of malignancy in benign thyroid nodules (at the beginning of follow-up) with high specificity and strong negative predictive value.Abbreviations:BRAF = v-raf murine sarcoma viral oncogene homolog B1FLUS = follicular lesion of undetermined significanceFNAB = fine-needle aspiration biopsyFTC = follicular thyroid carcinomaHRAS = homologous to the oncogene from the Harvey rat sarcoma virusKRAS = homologous to the oncogene from the Kirsten rat sarcoma virusNRAS = first isolated from a human neuroblastoma/neuroblastomaRAS = viral oncogene homologPAX8 = paired box 8PCR = polymerase chain reactionPPAR-gamma = peroxisome proliferator-activated receptor gammaPTC = papillary thyroid carcinomaRAS = rat sarcomaRET = rearranged during transfection tyrosine-kinase proto-oncogeneSM = somatic mutationSNP = single-nucleotide polymorphism     

Quality of Life Following Molecular Marker Testing for Indeterminate Thyroid Nodules

Objective: Thyroid cancer has a disproportionately negative effect on the quality of life (QOL) compared to malignancies with a worse prognosis. The QOL of patients with indeterminate thyroid nodules has not been previously evaluated. We aimed to assess the impact of molecular test results on the QOL of patients with indeterminate thyroid nodules.Methods: A short version of the Thyroid-Related Patient-Reported Outcome (ThyPro-39) was used to assess the QOL of patients who underwent thyroid fine needle aspiration (FNA) biopsy throughout UCLA Health from May, 2016, to June, 2017. All patients with indeterminate biopsy results underwent molecular testing with either Afirma Gene Expression Classifier or ThyroSeq v2 at the time of the initial biopsy. The QOL associated with symptoms of goiter, anxiety, depression, and impaired daily life were analyzed.Results: Of 825 consented patients, 366 completed the assessment (44.4% response rate). FNA results included 76% benign, 7% malignant, and 17% indeterminate. There were no differences in QOL between patients with a benign FNA and patients with an indeterminate result with benign molecular testing. In patients with an indeterminate FNA, symptoms of goiter (20.5 versus 10.4; P = .033) and depression (33.3 versus 21.0; P = .026) were worse for patients with suspicious versus benign molecular test results; however, no significant differences were observed in anxiety or impaired daily life.Conclusion: A benign molecular test result may provide reassurance for patients with indeterminate thyroid nodules that the risk of malignancy is low. Long-term follow-up is necessary to determine if benign molecular test results maintain improved QOL.     

Community Endocrine Surgical Experience With False-Negative Afirma Gec® Results: 2011–2017

Objective: Afirma Gene Expression Classifier® (Afirma GEC) molecular analysis (Veracyte, Inc, San Francisco, CA) is a negative predictive value test developed to reduce the number of thyroidectomies in thyroid nodule patients with indeterminate cytology. GEC technology has reportedly reduced unnecessary thyroid surgery, but few studies have examined Afirma GEC false-negative rates, since usually patients with GEC benign nodules do not undergo surgery for definitive diagnosis. Occasionally, Afirma GEC benign patients require removal of their thyroid nodules for other reasons; this work describes the incidence of malignancy and noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in this population.Methods: We reviewed our community endocrine surgical practice database for patients who had undergone thyroid surgery from January 2011 through April 2017 despite benign Afirma GEC results.Results: Afirma GEC testing was completed for 475 patients during the study period. Surgery was clinically indicated for other reasons in 42 of the 193 patients (22%) with Afirma GEC benign results. Malignancy or NIFTP in the targeted nodule was found in the final histologic evaluation of 14 of the 42 Afirma GEC benign surgical patients. The Afirma GEC false-negative percentage for our incomplete surgical group (FNP-ISG), defined as the surgically proven false negatives divided by the total Afirma GEC benign patients, was 7.3%.Conclusion: Our high surgical rate in Afirma GEC benign nodules reveals an FNP-ISG of 7.3% in our community endocrine surgical patient population; this value exceeds the 5.7% reported in the multicenter 2012 Afirma GEC validation study.Abbreviations: Afirma GEC = Afirma Gene Expression Classifier; FNA = fine-needle aspiration; FNP = false-negative percentage; FNP-ISG = false-negative percentage for an incomplete surgical group; NIFTP = noninvasive follicular thyroid neoplasms with papillary-like nuclear features     

Implementing Key Changes in The American Thyroid Association 2015 Thyroid Nodules/Differentiated Thyroid Cancer Guidelines Across Practice Types

Objective: This article provides suggestions to help clinicians implement important changes in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma (“ATA 2015”) across diverse settings.Methods: Key ATA 2015 changes are summarized regarding: (1) thyroid nodule management; (2) lobectomy versus thyroidectomy for differentiated thyroid carcinoma (DTC); and (3) surveillance following primary treatment of DTC. Advice to facilitate implementation is based on clinical experience and selected literature.Results: Strategies are described to enhance acquisition of high-quality information that helps identify patients who may possibly avoid fine-needle aspiration (FNA) of thyroid nodules or total thyroidectomy for DTC, or undergo less intense postoperative surveillance. Sonographic imaging of nodules may improve if sonograms are obtained by clinicians ordering or performing FNA or trusted high-volume sonographers. Cytopathologic assessment and reporting can be improved by working with regional or national experts. Pre-operative evaluation by endocrinologists is important so that patients are referred to experienced, proficient surgeons and assisted with well-informed decision-making regarding surgical radicality. Endocrinologists and surgeons should ensure performance of pre-operative neck ultrasonography, voice/laryngeal evaluation, and contrast-enhanced cross-sectional imaging when appropriate. Findings should be disseminated to all healthcare team members, ideally through a comprehensive medical record accessible to the entire team.Conclusion: Optimization of the sequence of specialist visits and assembly of interactive multidisciplinary teams coupled with intensified interdisciplinary and patient communication may enable clinicians to more effectively implement ATA 2015, which calls for more individualized, and often, less “invasive” management of thyroid nodules and DTC.Abbreviations: ATA 2009 = 2009 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; ATA 2015 = 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; DTC = differentiated thyroid carcinoma; FNA = fine-needle aspiration; PET/CT = positron emission tomography/computed tomography     

Comparison of Diagnostic Performance between the American College of Radiology Thyroid Imaging Reporting and Data System and American Thyroid Association Guidelines: A Systematic Review

Objective: We aimed to compare the diagnostic accuracy of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) with the American Thyroid Association (ATA) guidelines in risk stratification of thyroid nodules.Methods: We performed a computerized search of Medline, EMBASE, Web of Science, Cochrane Library, and Google Scholar to identify eligible articles published before July 31, 2019. We included studies providing head-to-head comparison between ACR TI-RADS and ATA guidelines, with fine-needle aspiration biopsy cytology results or pathology results as the reference standard. Quality assessment of included studies was conducted using the Quality Assessment of Diagnostic Accuracy Studies–2 tool. Summary estimates of sensitivity and specificity were calculated by bivariate modeling and hierarchical summary receiver operating characteristic modeling. We also performed multiple subgroup analyses and meta-regression.Results: Twelve original articles with 13,000 patients were included, involving a total of 14,867 thyroid nodules. The pooled sensitivity of ACR TI-RADS and ATA guidelines was 0.84 (95% confidence interval [CI], 0.76–0.89) and 0.89 (95% CI, 0.80–0.95), with specificity of 0.67 (95% CI, 0.56–0.76) and 0.46 (95% CI, 0.29–0.63), respectively. There were no significant differences between the two classification criteria in terms of both sensitivity (P = .26) and specificity (P = .05). For five studies providing direct comparison of ACR TI-RADS, ATA guidelines, and Korean TI-RADS, our analyses showed that the Korean TI-RADS yielded the highest sensitivity (0.89; 95% CI, 0.82–0.94), but at the cost of a significant decline in specificity (0.23; 95% CI, 0.17–0.30).Conclusion: Both classification criteria demonstrated favorable sensitivity and moderate specificity in the stratification of thyroid nodules. However, use of ACR TI-RADS could avoid a large number of biopsies at the cost of only a slight decrease in sensitivity.Abbreviations: ACR = American College of Radiology; ATA = American Thyroid Association; FNAB = fine-needle aspiration biopsy; HSROC = hierarchical summary receiver operating characteristic; SROC = summary receiver operating characteristic; TI-RADS = Thyroid Imaging Reporting and Data System; US = ultrasonography