Thyroid Bethesda reporting category, ‘suspicious for papillary thyroid carcinoma’, pitfalls and clues to optimize the use of this category

A. Mahajan, X. Lin and R. Nayar Thyroid Bethesda reporting category, ‘suspicious for papillary thyroid carcinoma’, pitfalls and clues to optimize the use of this category Objective: The Bethesda System of Reporting Thyroid Cytopathology classifies the indeterminate categories based on their differing risks of malignancy, as atypia of undetermined significance (AUS), follicular neoplasm/suspicious for follicular neoplasm (FLUS) and suspicious for malignancy. The vast majority of cases of the last category are suspicious for papillary thyroid carcinoma (PTC). The aim of the present study was to identify the pitfalls and clues to improve the usage of the suspicious category as well as improve its outcome of malignancy. Methods: We reviewed the cytological features on air dried Diff‐Quik® and alcohol‐fixed Papanicolaou smears from 54 thyroid fine needle aspirates (FNAs) with surgical follow‐up that were originally diagnosed as suspicious. Procedure data/specimen adequacy was correlated and follow‐up histology reports were reviewed after our cytological review was completed. Incidental PTC that was not the target of the FNA was excluded from the calculations for correlation. Results: In our cytological review, we retained a diagnosis of suspicious in 18 of the 54 cases and the remaining 36 were re‐categorized as follows: 6 malignant, 10 neoplasm (which is used in our centre instead of FLUS) and 20 AUS. The reasons for overcall of suspicious cases included pseudopapillae, syncytial sheets, nuclear grooves and pinpoint nucleoli in chronic lymphocytic thyroiditis and Hürthle cell neoplasms, and intranuclear inclusions in parathyroid adenoma, hyalinizing trabecular adenoma and mesenchymal repair. The primary reasons for undercall of PTC as suspicious included cystic aspirates with minor features of PTC such as histiocytoid cells, bubblegum colloid, syncytial sheets and cellular swirls. Cases with cytoplasm similar to Hürthle cells were also noted to cause difficulty in accurate classification. Conclusions: Recognition of these pitfalls and clues can help improve diagnosis, patient treatment and consequently reduce the number of unnecessary thyroidectomies.     

Follow‐up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology

N. Dincer, S. Balci, A. Yazgan, G. Guney, R. Ersoy, B. Cakir and G. Guler
Follow‐up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology Objective: To report our experience of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS) rate and outcome. Methods: Among 7658 patients with 19 569 nodules, 524 (2.7%) nodules were diagnosed as AUS/FLUS on fine needle aspiration (FNA). After exclusion of patients with simultaneous nodules that were suspicious for follicular neoplasm or malignancy or that were malignant, 368 (4.8%) patients were diagnosed as AUS/FLUS. The outcome of 146 patients who had undergone surgery or repeated fine needle aspirate at the time of preparation of this study was evaluated. The original FNAs were matched to repeated FNAs and thyroidectomy or diagnostic lobectomy specimens. Results: Seventy‐two (19.6%) of the 368 patients had directly undergone surgery, either a lobectomy or a thyroidectomy: of these, 27 (37.5%) had neoplastic nodules (21 were malignant). Seventy‐four (20.1%) of the 368 patients had repeat FNA. On second FNA, 47 of 74 (63.5%) were benign, three were suspicious for follicular neoplasm, one was malignant and 23 (31.1%) were non‐diagnostic. Four patients had a third FNA: two were AUS/FLUS, one was malignant and one non‐diagnostic. One patient had a fourth FNA, which was diagnosed as AUS/FLUS. Sixteen (21.6%) of 74 patients with repeat FNA had surgery: three of these had neoplastic nodules (two were malignant). Overall, 88 of the 368 (23.9%) patients had a thyroidectomy of which 30 (34.1%) were neoplastic and 23 (26.1%) malignant. The neoplastic rate for patients who were once diagnosed with AUS/FLUS was 8.2% and the malignancy rate 6.3%. The malignancy rate for patients on follow‐up at the time we prepared the study was 15.7% (23/146); 222 remained on follow‐up without surgery or repeat FNA or were managed elsewhere. Conclusions: Although in this category repeat FNA is expected rather than excision, we suggest evaluation of all AUS/FLUS patients in multidisciplinary meetings to decide management and recommend follow‐up of all patients with this diagnosis.     

Variability in the atypia of undetermined significance/follicular lesion of undetermined significance diagnosis in the bethesda system for reporting thyroid cytopathology: sources and recommendations

Objective: Of the 6 categories in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), the atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category has received the most attention. The objectives of this study were to review the use of the AUS/FLUS category in recent studies, to search for likely sources of the variability in its use, and to address possible methods for improvement. Study Design: A PubMed search was performed to retrieve peer-reviewed articles that have comprehensively detailed the incidence and outcome of AUS/FLUS and other BSRTC categories. Related thyroid cytology articles on the BSRTC were also included. Results: Recent series that reported experiences with the BSRTC categories showed that the AUS/FLUS category exhibited a marked variability in incidence (0.7-18%) and malignant outcome (6-48%) in resection specimens. Review of the literature revealed institutional differences in technical aspects, interpretation and application of criteria, analysis of outcome data, and clinicopathologic interactions. Conclusions: A heightened awareness of technical issues, diagnostic borders of AUS/FLUS, and clinical management may aid in diagnostic refinement and help avoid overuse of this category.     

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 [AUS]/follicular lesion of undetermined significance [FLUS]), IV (follicular neoplasm [FN]/suspicious for a follicular neoplasm [SFN]), V (suspicious for malignancy [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     

The bethesda terminology for reporting thyroid cytopathology: from theory to practice in europe

Objectives: A 2007 conference held at the National Cancer Institute, Bethesda, Md., USA, proposed a new terminology for classifying the results of thyroid fine-needle aspiration (FNA) - The Bethesda System for Reporting Thyroid Cytology (TBSRTC). The need to standardize thyroid FNA terminology was emphasized during the 35th European Congress of Cytology in 2009. An interobserver review study to assess the new terminology for analyzing the results of thyroid FNA was organized by the scientific committee of the European Federation of Cytology Societies. Study Design: Four experts in thyroid FNA examined and classified 116 FNAs according to the 6 levels of TBSRTC which are: nondiagnostic (ND); benign; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), with those of Hürthle cell type reported as follicular neoplasm, Hürthle cell type/suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT); suspicious (SUS), and malignant. Results: The total consensus was 62.1%; the cytopathologists disagreed on 44 cases, including 8 cases of AUS/FLUS and 18 of FN/SFN; 59% of the cases had no consensus. They agreed on 73 and 80% of the cases classified as benign and malignant, respectively, and on 58.3% of the SUS cases. The percentage of no consensus for each expert was between 32 and 39%. Conclusions: Disagreement regarding the use of TBSRTC terminology for classifying the results of thyroid FNA mainly occurred in the most-often criticized categories of AUS/FLUS and FN/SFN.     

Cytologic Features of Focal Papillary Thyroid Carcinoma Arising within Follicular Adenoma: A Masked Cytomorphologic Analysis of 17 Cases

Background/Objective: Focal papillary thyroid carcinoma (PTC) arising within a follicular adenoma (PTCFA) represents a clinically significant, but rare, histopathologic subset of papillary carcinomas whose cytologic features have not been well described. This uncommon presentation of PTC may contribute to a subset of thyroid aspirates interpreted as 'atypia of undetermined significance/follicular lesion of undetermined significance' (AUS/FLUS). Study Design: Seventeen fine-needle aspiration biopsy (FNAB) cases diagnosed as 'PTCFA' on corresponding surgical excision were identified from the archival records of 2 large academic medical centers. A control group of 40 FNAB comprised of 20 follicular adenomas (FA) and 20 PTC was identified (based on the corresponding surgical pathology diagnosis) for comparison. All 57 FNAB were reviewed in a masked fashion and scored for a series of 31 cytomorphologic features. The intraclass correlation between diagnostic categories and overall agreement between cytopathologists was statistically evaluated. Results: Aspirates of PTCFA were originally diagnosed as 'negative' (n = 3), 'AUS/FLUS' (n = 7), 'suspicious for a follicular neoplasm' (n = 3), 'suspicious for malignancy' (n = 3), and 'malignant' (n = 1). On masked review, the most common cytomorphologic features of PTCFA were a nonmacrofollicular cytoarchitectural pattern (71%), medium-large cell size (74%), and micronucleoli (79%). Intranuclear pseudoinclusions and a papillary architecture were absent in 85 and 88% of the cases, respectively. Relative to the 2 control groups, the PTCFA cases demonstrated overlapping features between FA and PTC for the majority of the 31 examined cytomorphologic features. Conclusion: PTCFA represent a rare subset of PTC that is difficult to recognize as PTC by FNAB. Most cases exhibit overlapping features between a benign thyroid nodule and conventional PTC, and they are often interpreted as 'AUS/FLUS'.     

Clinical Impact of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology: A Meta-Analysis of 14,153 Resected Thyroid Nodules

Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category.Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model.Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts.Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules.Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology     

Implementation of a joint protocol for the management of thyroid nodules with a cytological diagnosis of follicular lesion of undetermined significance: experience in one hospital

Background: Follicular lesion of undetermined significance (FLUS) was introduced for fine needle aspiration (FNA) cytology in which there is insufficient evidence to classify the lesion as follicular neoplasm/suspicious of follicular neoplasm or suspicious for malignancy. The recommended management was repeat FNA and correlation with clinical and radiological data. In 2009 we started a joint clinicopathological protocol to improve management of FLUS, recommending follow‐up with repeat FNA at 6 months. The aim of this study was to report on the audit of results of this protocol. Methods: We reviewed the medical records of the patients with FLUS at a single hospital. Between 2007 and 2010 we found 135 cases with this diagnosis (3.6%). We only had long enough follow‐up information for the 95 patients that were included in the present study. Results: FLUS was diagnosed in 74 FNAs before protocol implementation (3.2%) and 61 FNAs after (4.2%), with follow‐up of 46 and 49 patients, respectively. Before 2009, 38/46 (82.6%) patients had surgical excisions, compared with 32/49 (65.3%): a significant reduction of 17% in the number requiring surgery (P = 0.05). We have also shown a reduction in the median time to surgery (11.9 versus 2.9 months). Despite the joint protocol, the FNA was only repeated in two patients. The histological diagnoses were similar in the two periods of time: 31.6% and 31.3% follicular adenomas; 13.1% and 3.1% (P = 0.2) papillary carcinoma (follicular variant). Conclusions: Implementation of a joint protocol reduced the number of surgical operations in patients with FLUS but in most cases FNA was not repeated as recommended. Excision was justified in one‐third of operated patients. Less than 15% of lesions were malignant, which is in accordance with previous reports in the literature.     

Molecular testing of BRAF,RAS and TERT on thyroid FNAs with indeterminate cytology improves diagnostic accuracy

Objective

Liquid‐based (LB)‐FNA is widely recognized as a reliable diagnostic method to evaluate thyroid nodules. However, up to 30% of LB‐FNA remain indeterminate according to the Bethesda system. Use of molecular biomarkers has been recommended to improve its pathological accuracy but implementation of these tests in clinical practice may be difficult. Here, we evaluated feasibility and performance of molecular profiling in routine practice by testing LB‐FNA for BRAF, N/HRAS and TERT mutations.

Methods

We studied a large prospective cohort of 326 cases, including 61 atypia of undetermined significance, 124 follicular neoplasms, 72 suspicious for malignancy and 69 malignant cases. Diagnosis of malignancy was confirmed by histology on paired surgical specimen.

Results

Mutated LB‐FNAs were significantly associated with malignancy regardless of the cytological classification. Overall sensitivity was 60% and specificity 89%. Importantly, in atypia of undetermined significance and follicular neoplasm patients undergoing surgery according to the Bethesda guidelines, negative predictive values were 85.4% and 90% respectively. TERT promoter mutation was rare but very specific for malignancy (5.5%) suggesting that it could be of interest in patients with indeterminate cytology.

Conclusions

Mutation profiling can be successfully performed on thyroid LB‐FNA without any dedicated sample in a pathology laboratory. It is an easy way to improve diagnostic accuracy of routine LB‐FNA and may help to better select patients for surgery and to avoid unnecessary thyroidectomies.

     

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     

Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules

“The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular” thyroid carcinomas. “Fine-needle aspiration (FNA) of thyroid nodules” can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)γ and “RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas” (more than 70% of cases), which can be used successfully to improve the diagnosis “and the management of patients with thyroid nodules”. The most extensive experience has been accumulated with “the diagnostic use of BRAF mutation”, which is highly specific for malignancy. “Testing FNA samples for a panel of mutations” that typically includes RAS, BRAF, PAX8/PPARγ and RET/PTC could permit to achieve the biggest diagnostic impact. “The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers”.     

BRAF Mutation Analysis of Fine-Needle Aspiration Biopsies of Papillary Thyroid Carcinoma: Impact on Diagnosis and Prognosis

Objective: The BRAF V600E mutation has been associated with aggressive disease in papillary thyroid carcinoma (PTC). Molecular testing has been proposed as a useful adjunct to cytology in the diagnosis of malignancy and for tailoring clinical management. The aims of our study were to evaluate the BRAF mutational status using archived fine-needle aspiration biopsy (FNAB) material from patients with long-term follow-up and to correlate it with the original cytology diagnosis, clinicopathological stage at surgery, and prognosis. Study Design: FNAB material from 52 cases of PTC, with a mean follow-up of 8.4 years, was used in this study. DNA was extracted from archival cytology slides. Mutation analysis was performed by standard sequencing and locked nucleic acid-PCR/sequencing. Results: The BRAF V600E mutation was present in 46% of cases, but it was absent in all FNABs diagnosed originally as atypical and in 14 of 17 suspicious cases. Recurrence was significantly more frequent (p = 0.006) in cases with BRAF mutations and 54% of these cases presented with stage 2 or higher. Conclusion: The BRAF V600E mutation is associated with a higher pathological stage at surgery and a higher rate of recurrence. BRAF mutation analysis did not provide a significant increase in the accuracy of thyroid FNABs diagnosed as suspicious or atypical in our institution.     

Allele-Specific PCR with Competitive Probe Blocking for Sensitive and Specific Detection of BRAF V600E in Thyroid Fine-Needle Aspiration Specimens

Objective: To detect BRAF V600E mutation in thyroid fine-needle aspiration (FNA) slides and needle rinses (NR). Study Design: Tumor-enriched DNA was extracted from FNA smears, formalin-fixed paraffin-embedded (FFPE) sections, or NR specimens from 37 patients with confirmed papillary thyroid carcinoma or benign findings. An allele-specific primer selectively amplified the 1799 T>A BRAF mutation while simultaneously blocking amplification of wild-type (WT) BRAF with an unlabeled probe during PCR. Mutation detection was accomplished by melting analysis of the probe. Results: Allele-specific/blocking probe PCR confirmed the BRAF mutation status for 20 of 24 paired FNA/FFPE samples previously tested by fluorescent probe real-time PCR. For the other 4 cases, the sensitive PCR method detected the BRAF mutation in all paired FNA/FFPE samples. Previously, the mutation had been detected in only the FFPE samples. The BRAF mutation was also detected in some NR specimens. Conclusion: Treatment of patients with thyroid nodules is guided by FNA biopsy, which can be scantly cellular, necessitating a sensitive test that can detect low levels of BRAF V600E mutation in a WT background. We report increased detection of BRAF V600E in FNA specimens using allele-specific/blocking probe PCR, which has an analytical sensitivity of 0.01%.     

Focus: Personalized Medicine: Simultaneously Detection of 50 Mutations at 20 Sites in the BRAF and RAS Genes by Multiplexed Single-Nucleotide Primer Extension Assay Using Fine-Needle Aspirates of Thyroid Nodules

Fine-needle aspiration (FNA) is commonly used for primary evaluation of thyroid nodules. Twenty to 30 percent of thyroid nodules remain indeterminate after FNA evaluation. Studies show the BRAF p.V600E to be highly specific for papillary thyroid carcinoma (PTC), while RAS mutations carry up to 88 percent positive predictive value for malignancy. We developed a two-tube multiplexed PCR assay followed by single-nucleotide primer extension assay for simultaneous detection of 50 mutations in the BRAF (p.V600E, p.K601E/Q) and RAS genes (KRAS and NRAS codons 12, 13, 19, 61 and HRAS 61) using FNA smears of thyroid nodules. Forty-two FNAs and 27 paired formalin-fixed, paraffin-embedded (FFPE) tissues were tested. All BRAF p.V600E-positive FNA smears (five) carried a final diagnosis of PTC on resection. RAS mutations were found in benign as well as malignant lesions. Ninety-two percent concordance was observed between FNA and FFPE tissues. In conclusion, our assay is sensitive and reliable for simultaneous detection of multiple BRAF/RAS mutations in FNA smears of thyroid nodules.     

Diagnostic dilemmas of hyalinizing trabecular tumours on fine needle aspiration cytology: a study of seven cases with BRAF mutation analysis

T. Kim, Y. L. Oh, K. M. Kim and J. H. Shin Diagnostic dilemmas of hyalinizing trabecular tumours on fine needle aspiration cytology: a study of seven cases with BRAF mutation analysis Objective: Hyalinizing trabecular tumours (HTTs) are rare follicular‐derived neoplasms that behave in an almost benign manner. HTT is frequently misdiagnosed as papillary carcinoma by fine needle aspiration (FNA) cytology or as papillary or medullary carcinoma on surgical resection. Methods: The authors examined FNA material from seven cases of histologically verified HTT. Cytological findings were reviewed and correlated with ultrasonographic and histological features. In addition, MIB‐1 and calcitonin immunostaining was performed on surgical specimens, and BRAF mutation analysis on three pre‐operative FNA specimens and seven histology specimens. Results: The original cytological diagnosis was either suspicious or positive for papillary carcinoma in all patients. The FNA‐based differential diagnoses included HTT, papillary carcinoma or, less likely, medullary carcinoma in two patients. Aspirates showed oval to spindle‐shaped cells with frequent intranuclear inclusions, isolated in loosely cohesive groups with a trabecular or syncytial pattern in a bloody background. Radiating arrangements of tumour cells surrounding hyaline stroma with serrated calcifications and a lack of papillary or sheet‐like fragments may suggest HTT on FNA. Spherical calcified bodies and possible psammoma bodies were frequently found in three cases. Retrospectively, six of the seven cases showed membranous immunoreactivity for MIB‐1, but none of the seven possessed the BRAF (V600E) mutation or showed calcitonin reactivity. Conclusions: Although the recognition of HTT on FNA cytology is difficult, because of its morphological similarities to papillary and medullary carcinoma, its characteristic cytological features along with ultrasonographic findings may suggest the diagnosis preoperatively and avoid surgical over‐treatment.     

Cytopathology of non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features: A comparative study with similar patterned papillary thyroid carcinoma variants

Objective

Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) is a recently described, indolent thyroid tumor, with well‐defined histopathological diagnostic criteria. Cytology features are not well documented. We reviewed cytology of histologically proven cases of NIFTP and some of its common differentials to look for salient diagnostic features.

Methods

Cases reported on histopathology as follicular variant of papillary thyroid carcinoma (FVPTC), or NIFTP between July 2015 and April 2017 having available cytology smears were retrieved and reclassified as NIFTP, FVPTC, and classical papillary thyroid carcinoma with predominant follicular pattern (PTC‐FP). Cytological features were assessed, classified as per The Bethesda System for Reporting Cytopathology and compared.

Results

There were 23 NIFTP cases, 18 FVPTC and 8 PTC‐FP. A microfollicle‐predominant pattern was seen in all. Nuclear score was 2 in most NIFTP cases (61%). Pseudoinclusions were absent. NIFTP showed features of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (III) in 61%, follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN) (IV) in 35% and suspicious for malignancy (SFM) (V) in 4%. Most of the FVPTCs were also called FN/SFN (IV) (56%) or AUS/FLUS (III) (22%). Nuclear features did not statistically differ from NIFTP. PTC‐FP showed high‐grade cytology in 75%, and higher nuclear score (3 in 75%) in contrast to NIFTP (P = .003).

Conclusion

NIFTP and FVPTC show a similar distribution among the Bethesda categories hence precluding conclusive distinction on cytology. PTC‐FP, in contrast, was found to have a statistically significant higher nuclear score and more commonly showed malignant cytology.

     

Increased Pleiotrophin Concentrations in Papillary Thyroid Cancer

Background

Thyroid nodules are common, and approximately 5% of these nodules are malignant. Pleiotrophin (PTN) is a heparin-binding growth factor which is overexpressed in many cancers. The expression of PTN in papillary thyroid cancer (PTC) is unknown.

Method and Findings

74 subjects (age 47 ± 12 y, 15 males) who had thyroidectomy with a histological diagnosis: 79 benign nodules and 23 PTCs (10 classic, 6 tall cell, 6 follicular variant and 1 undetermined). Fine-needle aspiration (FNA) samples were obtained ex vivo from surgically excised tissue and assayed for PTN and thyroglobulin (Tg). Immunohistochemistry (IHC) was performed on tissue sections. In FNA samples, PTN concentration normalized to Tg was significantly higher in PTC than in benign nodules (16 ± 6 vs 0.3 ± 0.1 ng/mg, p < 0.001). In follicular variant of PTC (n = 6), the PTN/Tg ratio was also higher than in benign nodules (1.3 ± 0.6 vs 0.3 ± 0.1 ng/mg, P < 0.001, respectively). IHC showed cytoplasmic localization of PTN in PTC cells.

Conclusion

In ex vivo FNA samples, the PTN to thyroglobulin ratio was higher in PTCs, including follicular variant PTC, than in benign thyroid nodules. The findings raise the possibility that measurement of the PTN to Tg ratio may provide useful diagnostic and/or prognostic information in the evaluation of thyroid nodules.     

Mastopathic fibroadenoma of the breast: a pitfall of aspiration cytology

OBJECTIVE: To assess the correlation between cytological diagnoses and histological subtypes of fibroadenoma (FA) and to clarify the cytological features of a specific group of FA displaying variable features similar to fibrocystic disease (mastopathic type, MFA), and to evaluate the significance of this subtype in cytological diagnosis. METHODS: A review of 141 cases of histologically proven FA was performed. We re-classified them into four subtypes according to Kinoshita's criteria [Jpn J Breast Cancer6 (1991) 377] and further selected 92 cases for which both fine needle aspiration (FNA) smears and histological specimens were available. Among them, 18 cases of MFA and their cytological smears were selected for the present study. RESULTS: There was significant correlation between MFA and cytological diagnosis of 'indeterminate' or 'suspicious for malignancy' (P < 0.01). Although no false-positive diagnosis was experienced in our series, 56% of the MFAs (10/18) had cytological diagnoses of indeterminate or were included in the category 'suspicious for malignancy'. Smears from MFA revealed high cellularity (9/18 smears had more than 10 epithelial clusters each composed of more than 50 cells), presence of cellular discohesiveness (13/18, 72.2%), but only mild nuclear atypia (5/18, 27.8%). Anisonucleosis was present in fewer than half the cases and no apparent condensed chromatin was identified. CONCLUSION: We highlight the significance of subclassification of MFA in aspiration cytology of breast. MFA had a significantly higher chance of falling into the 'suspicious for malignancy' or 'indeterminate' diagnostic category in aspiration cytology. It might be a diagnostic challenge for cytopathologist to identify this subtype of FA in FNA smears.     

Using the Ata and Acr Ti-Rads Sonographic Classifications as Adjunctive Predictors of Malignancy for Indeterminate Thyroid Nodules

Objective: Thyroid nodules with indeterminate cytology pose management challenges in clinical practice. The aim of this study was to determine the efficacy of ultrasound features in navigating clinical decision making in thyroid nodules with indeterminate cytology.Methods: We retrospectively reviewed ultrasound imaging from 186 adult patients with thyroid nodules and indeterminate cytology who underwent thyroidectomy at a quaternary hospital from 2010–2017. All nodules were classified based on the American Thyroid Association (ATA) and 2017 American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS). Nodules were included if good quality pre-operative ultrasound imaging and surgical pathology were available.Results: A total of 202 thyroid nodules were included. The median age was 57 years; 82.8% were female. Risk of malignancy (ROM) in resected nodules with Bethesda 3 and 4 cytology was 19.4% and 30.3%, respectively. ATA high-suspicious and TI-RADS 5 nodules had high ROM, 100% in both systems for Bethesda 3 nodules; 66.7% and 50.0%, respectively, for Bethesda 4 nodules. For ATA very-low suspicious/TI-RADS 1 and 2, ROM was 0%. ROM in ATA low-suspicious/TI-RADS 3 nodules with Bethesda 3 cytology was lower (15.2% and 16.0%, respectively) than Bethesda 4 cytology (33.8% and 34.3%, respectively). ATA intermediate-suspicious/TI-RADS 4 nodules with Bethesda 4 cytology had a lower ROM (11.1% and 18.2%, respectively) than Bethesda 3 cytology (28.6 % and 31.6%, respectively).Conclusion: Using either the ATA or the TI-RADS system to risk-stratify nodules with indeterminate cytology may help clinicians plan better for additional diagnostic testing and treatment.Abbreviations: ACR = American College of Radiology; ATA = American Thyroid Association; AUS = atypia of undetermined significance; FLUS = follicular lesion of undetermined significance; FN = follicular neoplasm; PPV = positive predictive value; ROM = risk of malignancy; SFN = suspicious for follicular neoplasm; TI-RADS = Thyroid Imaging Reporting and Data System     

Overview of Molecular Biomarkers for Enhancing the Management of Cytologically Indeterminate Thyroid Nodules and Thyroid Cancer

ObjectiveTo provide information on molecular bio markers that can help assess cytologically indeterminate thyroid nodules.MethodsPublished studies on immunohistologic, somatic mutation, gene expression classifier, microRNA, and thyrotropin receptor messenger RNA biomarkers are reviewed, and commercially available molecular test pan els are described.ResultsThyroid nodules are common, and clinical guidelines delineate an algorithmic approach including serum thyroid-stimulating hormone measurement, diagnostic ultrasound examination, and, when appropriate, fine-needle aspiration (FNA) biopsy for determination of a benign versus malignant status. In clinical practice, approximately 20% of FNA-derived cytology reports are classified as “indeterminate” or follicular nodules that do not fulfill either benign or malignant criteria. In this set ting, the actual risk for malignancy of a cytologically indeterminate nodule ranges from approximately 15% to 34%. Research describing molecular biomarkers from thyroid cancer tissue has been applied to FNA-derived thyroid nodule material. There is also a serum molecular marker that has been reported with goals similar to those for the FNA-derived molecular markers: to enhance the preoperative diagnosis of thyroid cancer and reduce the large number of patients who have a diagnostic surgical procedure for benign thyroid nodules.ConclusionProgress toward the foregoing goals has been made and continues to evolve with the recent appearance of molecular biomarker tests that can be selectively applied for further assessment of cytologically indeterminate thyroid nodules. (Endocr Pract. 2012;18:611-615)