Subclassification of “atypia of undetermined significance” in thyroid fine‐needle aspirates

To identify the subtypes of atypia of undetermined significance (AUS) that confers a different magnitude for the risk of malignancy (RM), thyroid fine‐needle aspiration (FNA) cases carrying a diagnosis of “atypical follicular cells” or “follicular lesion” with surgical pathology followup were included in this study. The direct smears of the aspirates were rereviewed and subclassified into four subgroups based on cytomorphology: AUS cannot exclude follicular neoplasm (AUS‐FN), AUS cannot exclude Hürthle cell neoplasm (AUS‐HCN), AUS cannot exclude papillary carcinoma (AUS‐PTC) and AUS, not otherwise specified (AUS‐NOS). Based on the followup histopathologic findings, RM not including papillary microcarcinoma (PMC), RM including PMC and the risk of neoplasm (RN) were calculated for each of the four AUS subgroups. A total of 138 AUS cases were subclassified into AUS‐NOS (48), AUS‐PTC (41), AUS‐FN (32), and AUS‐HCN (17). RM not including PMC was 32% for AUS‐PTC (P < 0.001), 25% for AUS‐FN, 8% for AUS‐NOS, 0% for AUS‐HCN, and 18% for all AUS cases. RM including PMC was 54% for AUS‐PTC (P < 0.001), 34% for AUS‐FN, 19% for AUS‐NOS, 18% for AUS‐HCN, and 33% for all AUS cases. RN was 63% for AUS‐PTC (P = 0.05), 81% for AUS‐FN (P < 0.01), AUS‐HCN 53%, AUS‐NOS 44% and 59% for all cases. In our study, subclassification enabled us to further divide AUS cases into high‐ and low‐risk groups. The high‐risk group includes AUS‐PTC with a significantly higher risk of malignancy and AUS‐FN with a significantly higher risks of neoplasm. AUS‐HCN and AUS‐NOS subgroups demonstrate a lower risk of malignancy of <10%. Diagn. Cytopathol. 2014;42:23–29. © 2013 Wiley Periodicals, Inc.     

Fine‐needle aspiration of follicular patterned lesions of the thyroid: Diagnosis,management, and follow‐up according to National Cancer Institute (NCI) recommendations

The National Cancer Institute (NCI) State of the Science Conference on thyroid fine‐needle aspiration (FNA) proposed that follicular patterned lesions can be divided into two diagnostic categories; follicular lesion of undetermined significance/Atypia of undetermined significance (FLUS/AUS) and suspicious for follicular neoplasm/follicular neoplasm (SFON/FON). The former group can benefit from repeat FNA (RFNA) to achieve a more definitive diagnosis and the latter should undergo surgical excision for histologic characterization (adenoma vs. carcinoma). In this study, we report the combined experience from our institutions with thyroid FNA cases that can be placed into NCI‐designated thyroid FNA diagnostic categories for follicular patterned lesions. The case cohort comprised of 857 cases in 645 females and 212 males; 509 cases could be classified as FLUS/AUS and 348 as SFON/FON. Histologic follow‐up was available in 273/509 (54%) cases diagnosed as FLUS/AUS and 251/348 (72%) cases diagnosed as SFON/FON. RFNA was performed in 203/509 (40%) patients classified as FLUS/AUS. RFNA diagnoses were: benign (125 cases), FLUS (46 cases), SFON/FON (20 cases), suspicious for papillary carcinoma (7 cases), papillary carcinoma (3 cases) and non‐diagnostic (2 cases). The malignancy rate on surgical excision in the FLUS/AUS group was 27 and 15% with and without RFNA, respectively; and 25% in cases diagnosed as SFON/FON. RFNA is effective in managing thyroid nodules diagnosed as FLUS/AUS since the malignancy rates are different in cases with or without RFNA (27% vs. 15%). The malignancy rate (25%) in cases diagnosed as SFON/FON is similar to reported by other authors. Diagn. Cytopathol. 2010;38:731–739. © 2010 Wiley‐Liss, Inc.     

Minimizing the diagnosis of "follicular lesion of undetermined significance" and identifying predictive features for neoplasia

We used proposed standard morphologic criteria as a guideline to conduct a 10-year retrospective review of thyroid fine-needle aspiration specimens that were originally interpreted as "follicular lesion of undetermined significance" and followed by surgical intervention. We sought to investigate whether the indeterminate diagnosis could be minimized by assessing various cytomorphologic features and identifying the features predictive of neoplasia. Using the standard morphologic criteria, we semi-quantitatively assessed a total of 24 cytomorphologic features in 123 aspirates and recorded an overall interpretation on completion of the review. Cyto-histologic correlation was evaluated and logistic regression model was performed to identify cytomorphologic features predictive of neoplasia. Although 32 of 123 aspirates remained in the indeterminate category, the retrospective review reclassified 64 aspirates as non-neoplasia and 27 aspirates as neoplasia. Histologic confirmation was achieved in 47 (73.4%) non-neoplastic and 15 (55.6%) neoplastic aspirates with a diagnostic accuracy of 68.1%. Furthermore, our analysis demonstrated that neoplasia is positively associated with the presence of syncytial tissue fragments, isolated microfollicles, follicles with scalloped borders, scant cytoplasm, irregular nuclear membranes, nuclear overlapping, coarse chromatin, and increased cellularity. On the contrary, the presence of honeycombing tissue fragments, background colloid, and histiocytes inversely correlated with neoplasia. Overall, using proposed standard morphological criteria can minimize the diagnosis of "follicular lesion of undetermined significance," and allow for more accurate cyto-histologic correlation, and thereby playing a substantial role in reducing unnecessary surgical intervention.     

Follicular neoplasm of the thyroid gland: Unique cytologic appearances in a fine‐needle aspiration biopsy

Fine‐needle aspiration (FNA) biopsy has become a standard first‐line diagnostic procedure for palpable and nonpalpable nodules of the thyroid gland. Six cytologic diagnostic categories have recently been proposed to unify the terminology that is linked to proper clinical management. We report a case of follicular neoplasm diagnosed on FNA specimen that had a very artistic appearance of the microfollicle formation on both Diff‐Quik and Papanicolaou‐stained slides. Diagn. Cytopathol. 2010;38:660–662. © 2009 Wiley‐Liss, Inc.     

Group consensus review minimizes the diagnosis of "follicular lesion of undetermined significance" and improves cytohistologic concordance

We conducted a group consensus review of thyroid aspirates that were previously interpreted as “atypia of undetermined significance/follicular lesion of undetermined significance” (AUS/FLUS) and followed by surgical interventions. The study aimed to investigate if consensus review would minimize the diagnosis of AUS/FLUS with an optimal interobserver agreement and also promote a better cytohistologic concordance. A group of reviewers who were blinded to the corresponding histologic findings simultaneously evaluated a total of 50 aspirates at a multiheaded light microscope. Using the Bethesda System for Reporting Thyroid Cytopathology as a guideline, a consensus interpretation was reached upon review of each aspirate. Interobserver agreement was calculated and recorded. The cytohistologic correlation was then performed between the consensus interpretation and the corresponding histologic diagnosis. The consensus review reclassified 26 (52%) aspirates as non‐neoplasia/benign, 10 (20%) as follicular neoplasm/suspicious for a follicular neoplasm, 1 (2%) as papillary thyroid carcinoma, and 2 (4%) as nondiagnostic. Eleven (22%) aspirates remained AUS/FLUS. The interobserver agreement across the five diagnostic categories ranged from 71.6% to 100% with an average level of 88.8%. Cytohistologic concordance was achieved in 24 of 26 (92.3%) and 9 of 11 (81.8%) aspirates that were reclassified as non‐neoplasia/benign and neoplasia/malignancy, respectively. A diagnostic accuracy of 89.2% (33/37) was obtained in reclassified cases. In conclusion, the group consensus review minimized AUS/FLUS, offered an optimal level of interobserver agreement, and most importantly, promoted excellent cytohistologic concordance in reclassified cases and, therefore, could play a substantial role in the future in reducing reaspiration and/or unnecessary surgeries. Diagn. Cytopathol. 2012. © 2011 Wiley‐Liss, Inc     

Improving the diagnostic accuracy of thyroid follicular neoplasms: Cytological features in fine‐needle aspiration cytology

Cytological diagnosis in follicular neoplasms of the thyroid has to surmount some difficulties. Capsular/vascular invasions or metastasis are the histological criteria for follicular carcinoma (FC), and, on fine‐needle aspiration (FNA) samples, marked cytological atypias are only observed in moderately to poorly differentiated FC, while they may be completely lacking in well differentiated angio‐ or capsulo‐invasive FC. To clarify the cytological features and to improve the accuracy and reliability of aspiration cytology, 892 follicular adenomas and 82 FCs were reviewed. A macrofollicular pattern or large sheet pattern of follicular cells with thin colloid in the background were found to be indicators of follicular adenoma. Crowding or irregular arrangement of follicular cells were found to indicate microfollicular lesions but could not discriminate between benign and malignant conditions. High nucleo‐cytoplasmic ratio, nuclear atypia, and coarse granular or dense chromatin were more important criteria for malignancy than nuclear grooves or intranuclear cytoplasmic inclusions. The cytomorphologic features of the follicular neoplasms of the thyroid are described, and the difficulties encountered in the cytodiagnosis of follicular lesions are discussed at length. Diagn. Cytopathol. 2011;39:28–34. © 2010 Wiley‐Liss, Inc.     

Follicular lesion of undetermined significance in thyroid FNA revisited

Controversy exists regarding the validity of follicular lesion of undetermined significance (FLUS), an indeterminate diagnostic category of The Bethesda System for Reporting Thyroid Cytopathology (BSRTC). According to BSRTC, FLUS carries a 5–15% risk of cancer. This study was designed to determine if cytomorphology could stratify FLUS into subgroups with different risks of malignancy. Reports of 127 consecutive FNAs reported as FLUS with subsequent tissue diagnoses were evaluated for the presence of various cytologic features and the results were correlated with histological diagnoses. FLUS cases with focal nuclear atypia (nuclear overlap/crowding, nuclear grooves/membrane irregularities, nuclear enlargement, and/or nuclear pseudoinclusions) were more frequently malignant on excision whereas those with architectural atypia (microfollicles) were more often benign on excision (P < 0.05). The presence of any one or more of these nuclear features increased the risk of carcinoma in subsequent thyroid resection. Papillary carcinomas predominated in excised FLUS cases with focal nuclear atypia whereas most FLUS with architectural atypia were adenomas or hyperplastic nodules on histological evaluation. BSRTC recommends that thyroid aspirates containing follicular cell nuclear and/or architectural atypia insufficient for a diagnosis of suspicious for follicular neoplasm, suspicious for malignancy or malignant be classified as FLUS. Our findings indicate that FLUS cases with focal nuclear atypia carry a risk for malignancy that is substantially higher than that assigned to FLUS and are best classified as suspicious. FLUS cases lacking these atypical nuclear features have a risk for malignancy that approximates the risk BSRTC has assigned to FLUS. Diagn. Cytopathol. 2014;42:18–22. © 2013 Wiley Periodicals, Inc.     

Medullary thyroid carcinoma presenting as rectangular cell type on fine‐needle aspiration

Medullary thyroid carcinoma typically presents as dyscohesive plasmacytoid, spindled, or polygonal cells on fine‐needle aspiration smears. We recently encountered a case of sporadic medullary thyroid carcinoma that presented as a hypercellular aspirate composed of cohesive aggregates of rectangle‐shaped cells. The case was mistakenly reported as a hypercellular follicular neoplasm on cytology. Subsequent thyroidectomy revealed medullary carcinoma. We draw attention to this distinctive rectangular cell type as an additional morphology for medullary thyroid carcinoma. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification

The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub-classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (IN(a)) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (IN(b)). We reviewed these indeterminate cases to document the follow-up trend using this two-tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine-needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow-up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy-one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 IN(a), 64 IN(b)). Records of follow-up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the IN(b) (56%) compared to the IN(a) (7%) cases. A diagnosis of "IN(a)" does not carry the same implication as that of "IN(b)". The IN(b) category needs a more aggressive follow-up than the IN(a) category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (<7%).     

Evidence‐based evaluation of the risks of malignancy predicted by thyroid fine‐needle aspiration biopsies

A National Cancer Institute (NCI) “Thyroid Fine‐Needle Aspiration (FNA) State of the Science Conference” recently proposed standardized nomenclature and “risks of malignancies” associated with various diagnostic categories. We evaluated the evidence levels of the data used by NCI to predict malignancy risks and whether those estimates had clinical validity in our patient population. Eight hundred seventy‐nine patients underwent thyroid FNA during 2006. FNA diagnoses were translated into NCI diagnostic categories, and 2‐year follow‐up retrospective information was obtained. Four percentages of malignancies were calculated for each diagnostic category using follow‐up information from FNA, thyroidectomy, both, and all patients as denominators. 95% confidence intervals (CI) were estimated for all proportions, and results were analyzed with chi‐square statistics. “Relative risk” calculations were performed using the percentage of malignancies in the entire population under study as a denominator. Most of the studies cited by the NCI provided incomplete and variable level III evidence based mainly on surgical follow‐up. Among our patients, the percentages of malignancies calculated with follow‐up data from all patients as the denominator were similar to the “risk estimates” proposed by the NCI, but estimates based on surgical follow‐up overestimated the probability of thyroid malignancy for patients with FNA diagnosis of “benign” and “follicular lesions of undetermined significance” (FLUS). Relative risk and 95% CI calculations suggested that the NCI classification could be simplified into three categories: “benign,” “FLUS + neoplasm,” and “suspicious + malignant.” Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Cytologic features of pancreatic adenocarcinoma with “vacuolated cell pattern.” report of a case diagnosed by endoscopic ultrasound‐guided fine‐needle aspiration

The “vacuolated cell pattern” has only been recently described as a distinct morphologic variant of pancreatobiliary adenocarcinoma. Herein, we report the endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) cytologic features of a case of pancreatic adenocarcinoma with “vacuolated cell pattern” occurring in a 60‐year‐old man. The aspirate smears and cell block sections from the EUS‐FNA of a 23.5 mm hypoechoic pancreatic head mass were highly cellular, showing variably‐sized crowded three‐dimensional cell clusters, flat sheets, and numerous highly atypical single cells. The background was bloody and showed necrotic debris, but no discernible mucus. The most striking feature of the aspirate was the presence of numerous very large (20–50 µm) vacuoles, occupying the entire cytoplasm, pushing the nuclei to the side and indenting them, that imparted a cribriform appearance to the sheets of neoplastic cells. The non‐vacuolated neoplastic cells were large, had abundant dense (squamoid) cytoplasm, irregularly contoured hyperchromatic nuclei, and prominent macronucleoli. Histologic evaluation of the pancreatectomy specimen showed a “vacuolated cell pattern” adenocarcinoma composed of poorly formed glands, solid sheets, and infiltrating single cells with pleomorphic nuclei and large cytoplasmic vacuoles. To our knowledge, this is the first report describing the cytologic features of this rather uncommon morphologic variant of pancreatic adenocarcinoma. Recognition of this morphologic variant of pancreatic adenocarcinoma in ESU‐FNA samples allows its differentiation from primary and metastatic signet‐ring cell carcinomas. Diagn. Cytopathol. 2014;42:302–307. © 2014 Wiley Periodicals, Inc.