Mehrotra, Swati, Al-Abbadi, Mousa, Bigorgne, Claude, Jalalay, Jalal, Krane, Jeffrey F., Perak, Renata B., Vielh, Philippe, Wakely, Paul E., Jr, Wang, He, Wojcik, Eva M., Barkan, Güliz A., Faquin, William C., editor, Rossi, Esther Diana, editor, Baloch, Zubair, editor, Barkan, Güliz A., editor, Foschini, Maria Pia, editor, Kurtycz, Daniel F.I., editor, Pusztaszeri, Marc P., editor, and Vielh, Philippe, editor
Kim, Teresa H., Krane, Jeffrey F., Poretsky, Leonid, Series Editor, Eldeiry, Leslie S., editor, Laver, Nora M. V., editor, Randolph, Gregory W., editor, Sacks, Barry, editor, and Garber, Jeffrey R., editor
Strickland, Kyle C., Eszlinger, Markus, Paschke, Ralf, Angell, Trevor E., Alexander, Erik K., Marqusee, Ellen, Nehs, Matthew A., Jo, Vickie Y., Lowe, Alarice, Vivero, Marina, Hollowell, Monica, Qian, Xiaohua, Wieczorek, Tad, French, Christopher A., Teot, Lisa A., Cibas, Edmund S., Lindeman, Neal I., Krane, Jeffrey F., and Barletta, Justine A.
Wong, Kristine S., Angell, Trevor E., Barletta, Justine A., and Krane, Jeffrey F.
Hürthle cell–predominant thyroid fine needle aspirations (FNA) are encountered frequently in routine practice, yet they are often challenging to diagnose accurately and are associated with significant interobserver variability. This is largely due to the ubiquity of Hürthle cells in thyroid pathology, ranging from nonneoplastic conditions to aggressive malignancies. Although limitations in cytomorphologic diagnoses likely will remain for the foreseeable future, our knowledge of the molecular pathogenesis of Hürthle cell neoplasia and application of molecular testing to cytologic material have increased dramatically within the past decade. This review provides context behind the challenges in diagnosis of Hürthle cell lesions and summarizes the more recent advances in diagnostic tools. Diagnosis of Hürthle cell neoplasia is one of the most challenging areas of thyroid fine‐needle aspiration cytology. This review describes the current state of the art in the cytology of Hürthle cell lesions as well as the clinical, histologic, and molecular findings associated with Hürthle cell tumors. [ABSTRACT FROM AUTHOR]
Johnson, Daniel N., Onenerk, Mine, Krane, Jeffrey F., Rossi, Esther Diana, Baloch, Zubair, Barkan, Güliz, Bongiovanni, Massimo, Callegari, Fabiano, Canberk, Sule, Dixon, Glen, Field, Andrew, Griffith, Christopher C., Jhala, Nirag, Jiang, Sara, Kurtycz, Daniel, Layfield, Lester, Lin, Oscar, Maleki, Zahra, Perez‐Machado, Miguel, and Pusztaszeri, Marc
Background: Fine needle aspiration (FNA) is commonly used for the preoperative evaluation of salivary gland tumors. Tumor grade is a key factor influencing clinical management of salivary gland carcinomas (SGCs). To assess the ability to grade nonbasaloid SGCs in FNA specimens, an international panel of cytopathologists convened to review and score SGC cases. Methods: The study cohort included 61 cases of primary SGC from the pathology archives of 3 tertiary medical centers. Cases from 2005 to 2016 were selected, scanned, and digitized. Nineteen cytopathologists blinded to the histologic diagnosis reviewed the digitized cytology slides and graded them as low, high, or indeterminate. The panelists' results were then compared to the tumor grades based on histopathologic examination of the corresponding resection specimens. Results: All but 2 of the 19 (89.5%) expert panelists review more than 20 salivary gland FNAs per year; 16 (84.2%) of the panelists work at academic medical centers, and 13 (68.4%) have more than 10 years' experience. Participants had an overall accuracy of 89.4% in the grading of SGC cases, with 90.2% and 88.3% for low‐ and high‐grade SGC, respectively. Acinic cell carcinoma and mucoepidermoid carcinoma had the highest degree of accuracy, while epithelial‐myoepithelial carcinoma and salivary duct carcinoma had the lowest degree of accuracy. As expected, the intermediate‐grade SGC cases showed the greatest variability (high‐grade, 42.1%; low‐grade, 37.5%, indeterminate, 20.4%). Conclusion: This study confirms the high accuracy of cytomorphologic grading of primary SGC by FNA as low‐ or high‐grade. However, caution should be exercised when a grade cannot be confidently assigned. This study, which involves an international blinded panel of cytopathologists who reviewed and graded over 60 salivary gland carcinomas using scanned digital slides, shows that grading of primary salivary gland carcinoma via cytomorphology alone has a high degree of accuracy. However, caution is warranted for grading certain carcinomas, including those of intermediate grade. [ABSTRACT FROM AUTHOR]
Renshaw, Andrew A. and Krane, Jeffrey F.
Communicating the clinical significance of cytologic findings is a vital function of any cytology report. The simplicity and reproducibility of risk of malignancy (ROM), along with the wealth of accumulated data surrounding its use, mean that ROM remains the gold standard for measuring risk in thyroid fine‐needle aspiration specimens, one that is easily understood and has been found to be useful by cytologists, molecular pathologists, clinicians, and patients. [ABSTRACT FROM AUTHOR]
Angell, Trevor E., Heller, Howard T., Cibas, Edmund S., Barletta, Justine A., Kim, Matthew I., Krane, Jeffrey F., and Marqusee, Ellen
Background: For thyroid nodules with indeterminate cytology, the Afirma Gene Expression Classifier (GEC) identified benign nodules to reduce diagnostic surgery, though many nodules classified as suspicious still proved histopathologically benign. The current Afirma Genomic Sequencing Classifier (GSC) demonstrates improved specificity, suggesting more nodules will have a benign result (benign call rate [BCR]), but independent data are needed to confirm this in clinical practice. Methods: Retrospective analysis was performed of all Bethesda III or IV cytology thyroid nodules ≥1 cm tested with GEC (between January 1, 2011, and July 19, 2017) or GSC (between July 20, 2017, and August 27, 2018) at the authors' institution. Afirma testing was not performed reflectively for all nodules with Bethesda III or IV cytology, but rather was applied based on physician–patient decision making. Demographic, sonographic, and cytologic data were collected. The BCR for GEC- versus GSC-tested nodules was compared and further stratified by Bethesda classifications. Results: The study evaluated 600 nodules in 563 patients tested with either GEC (n = 486) or GSC (n = 114). The BCR was 233/486 (47.9%) for the GEC compared to 75/114 (65.8%) for the GSC (p = 0.0006). Hürthle-cell cytology was present in 99/486 (20.4%) nodules in the GEC group compared to 31/114 (27.2%) nodules in the GSC group (p = 0.28). The GSC BCR was significantly higher than the GEC BCR for Bethesda III nodules characterized by Hürthle cells (p = 0.006), but the BCRs were similar for nodules with architectural or cytologic atypia. In Bethesda IV nodules suspicious for follicular neoplasm, BCR for the GEC and GSC were similar (p = 0.68), but for cytology suspicious for Hürthle-cell neoplasm, the GSC BCR was 68.2% (15/22) compared to the GEC BCR of 16.4% (10/61; p < 0.0001). Positive predictive value in resected nodules with a suspicious result was 16/32 (50%) for GSC nodules and 75/221 (33.9%) for GEC nodules (p = 0.1). Conclusions: The higher BCR for the GSC compared to the GEC for indeterminate thyroid nodules, predominantly among nodules with Hürthle-cell cytology, will likely lead to further reduction in surgical management. [ABSTRACT FROM AUTHOR]
Jo, Vickie Y., Krane, Jeffrey F., Pantanowitz, Liron, and Monaco, Sara E.
Background: The majority of human papillomavirus (HPV)–associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV–associated neuroendocrine carcinomas (HPV‐NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine‐needle aspiration (FNA) cases of head and neck HPV‐NEC. Methods: Cytology cases of HPV‐NEC were identified over a 3‐year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated. Results: Five FNA cases of HPV‐NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV‐18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5). Conclusions: Head and neck HPV‐NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV‐NEC is also important because of its worse prognosis in comparison with HPV‐associated squamous cell carcinoma. HPV‐associated neuroendocrine carcinoma is an aggressive neoplasm that frequently shows mixed features of small cell carcinoma and large cell neuroendocrine carcinoma, and may pose diagnostic challenges in cytologic samples. Tumors show p16 overexpression, which may be nonspecific in the differential diagnosis; thus, confirmatory testing for high‐risk human papillomavirus is helpful, HPV especially for tumors presenting as cervical lymph node metastases with an unknown primary. [ABSTRACT FROM AUTHOR]
Jo, Vickie Y. and Krane, Jeffrey F.
Salivary gland cytology is challenging, and historically the role of ancillary testing has been limited. However, numerous molecular/genetic advances in the understanding of salivary gland neoplasms during the last decade have facilitated the development of many useful diagnostic markers, such as PLAG1 and HMGA2 immunohistochemistry for pleomorphic adenoma and ETV6 fluorescence in situ hybridization for secretory carcinoma. Numerous salivary gland neoplasms are characterized by specific molecular/genetic alterations, many of which can be identified on cytologic preparations by karyotype analysis, fluorescence in situ hybridization, or immunohistochemical surrogates. Next‐generation sequencing also has potential diagnostic applications, although to the authors' knowledge it currently has no routine role in salivary cytology. The primary goal of salivary fine‐needle aspiration (FNA) is to facilitate appropriate clinical management. Ancillary testing has greatly enhanced the ability for accurate classification as per The Milan System for Reporting Salivary Gland Cytopathology and allows for the definitive diagnosis of many salivary FNA specimens, and also may resolve diagnostic uncertainty for FNAs that may be classified in The Milan System for Reporting Salivary Gland Cytopathology categories of salivary gland neoplasm of uncertain malignant potential or suspicious for malignancy. This review provides an updated discussion of the molecular/genetic features of the more commonly encountered salivary neoplasms by FNA, and discusses the application of available diagnostic immunohistochemical and molecular tests in salivary gland cytology. [ABSTRACT FROM AUTHOR]
Baca, Sylvan C., Wong, Kristine S., Strickland, Kyle C., Heller, Howard T., Kim, Matthew I., Barletta, Justine A., Cibas, Edmund S., Krane, Jeffrey F., Marqusee, Ellen, and Angell, Trevor E.
Liu, Xiaoyun, Medici, Marco, Kwong, Norra, Angell, Trevor E., Marqusee, Ellen, Kim, Matthew I., Larsen, P. Reed, Cho, Nancy L., Nehs, Matthew A., Ruan, Daniel T., Gawande, Atul, Moore, Francis, Barletta, Justine, Krane, Jeffrey F., Cibas, Edmund S., Yang, Tao, and Alexander, Erik K.
Background: Since its inception, the Bethesda System for Reporting Thyroid Cytopathology (TBS) has been widely adopted. Each category conveys a risk of malignancy and recommended next steps, though it is unclear if each category also predicts the type and extent of malignancy. If so, this would greatly expand the utility of the TBS by providing prognostic information in addition to baseline cancer risk. Methods: All patients prospectively enrolled into the authors' thyroid nodule database from 1995 to 2013 with histologically proven malignancy were analyzed. The primary ultrasound-guided fine-needle aspiration cytology (AUS, atypia of unknown significance; FN, follicular neoplasm; SUSP, suspicious; M, malignant) was correlated with the type of thyroid cancer and histological features known to impact prognosis and recurrence, including lymph node metastasis (LNM), lymphovascular invasion, and extrathyroidal extension (ETE). Primary cytology was separately correlated with higher risk malignancy. Results: A total of 1291 malignancies were identified, with primary cytology AUS in 130 cases, FN in 241 cases, SUSP in 411 cases, and M in 509 cases. AUS, SUSP, and M cytology were progressively associated with an increasing risk of high-risk disease ( p < 0.001), LNM ( p < 0.001), ETE ( p < 0.001), and margin positivity ( p < 0.001). Notably, 71% of malignancies with AUS cytology were follicular variants of papillary thyroid cancer compared with 63% with SUSP cytology and only 20% with M cytology. In contrast, high-risk malignancies were diagnosed in only 4% with AUS cytology, but 9% and 27% with SUSP and M cytology, respectively. FN conveyed a significantly increased risk of follicular thyroid carcinoma compared with all other types (28% vs. 2%; p < 0.001). A composite endpoint of recurrence, distant metastases, and death similarly increased as cytology progressed from AUS to SUSP to M ( p < 0.001). Conclusion: In addition to predicting cancer prevalence, the TBS also imparts important prognostic information about cancer type, variant, and risk of recurrence. These data extend the utility of TBS classification by fostering an improved understanding of the risk posed by any confirmed malignancy. [ABSTRACT FROM AUTHOR]
Howitt, Brooke E., Sue Chang, Eszlinger, Markus, Paschke, Ralf, Drage, Michael G., Krane, Jeffrey F., Barletta, Justine A., and Chang, Sue
Brauner, Eran, Holmes, Brittany J., Krane, Jeffrey F., Nishino, Michiya, Zurakowski, David, Hennessey, James V., Faquin, William C., and Parangi, Sareh
Background: The recently introduced Afirma gene expression classifier (AGEC) provides binary results (benign or suspicious) to guide management of cytologically indeterminate thyroid nodules. The AGEC is intended to reduce unnecessary surgeries for benign nodules, and management algorithms favor surgery for suspicious results. Limited data are available on the performance of this test for Hürthle cell nodules (HCNs). This study hypothesized that a predominance of Hürthle cells leads to an increased rate of suspicious AGEC results with a potential for overtreatment, despite a relatively low risk of malignancy. Methods: The pathology databases from three tertiary care facilities were queried from 2010 to 2014 for fine-needle aspirates (FNAs) diagnosed as suspicious for Hürthle cell neoplasm (SHCN) or atypia of undetermined significance/follicular lesion of undetermined significance concerning for Hürthle cell neoplasm (AFHCN). Cytology diagnoses were rendered internally prior to AGEC testing. The patient demographics, FNA diagnosis, AGEC result, surgical procedure, and pathologic outcomes were recorded. Results: The cohort consisted of 134 patients with HCNs. Prior to AGEC availability, 62 patients underwent surgery: 81% (50/62) of patients had surgery, and 34% (17/50) of the resected index nodules were malignant. After introduction of the AGEC, 72 patients underwent AGEC testing: 65% (47/72) of patients had surgery, and 13% (6/46) of the resected nodules were malignant. Thirty-two percent (23/72) of patients had a benign AGEC result and did not undergo surgery, and 4% (3/72) had surgery despite a benign AGEC result with benign final pathology, whereas 63% (45/72) of patients had suspicious AGEC results, with 96% of these patients (43/45) undergoing surgery, and 14% (6/43) of these index nodules were malignant. Conclusions: While 32% of tested patients declined surgery based on a benign AGEC, 86% of patients with suspicious AGEC findings had unnecessary surgery, reflecting a substantially lower rate of malignancy from what was previously reported for all indeterminate nodules. Given the approximate pretest malignancy risk of 25-35% for an FNA diagnosis of SHCN or AFHCN, a suspicious AGEC diagnosis does not increase the probability of malignancy in an HCN, and patients should be counseled accordingly. [ABSTRACT FROM AUTHOR]
Pusztaszeri, Marc P., Krane, Jeffrey F., Cibas, Edmund S., Daniels, Gilbert, and Faquin, William C.
BACKGROUND Benign thyroid nodules with papillary hyperplasia (BTN-PH) are sometimes misinterpreted cytologically as papillary thyroid carcinoma (PTC). We evaluated a fine-needle aspiration biopsy (FNAB) series of BTN-PH to identify the causes of diagnostic error and to better define its cytologic criteria. METHODS A total of 48 FNAB cases of histologically confirmed BTN-PHs from 44 patients were identified from our archives. The available cytological and histological slides were reviewed and scored for 10 cytomorphological features. Fifteen FNAB cases of classical PTC were also reviewed for comparison. RESULTS The FNAB diagnoses for the 48 BTN-PHs were: benign, 18; suspicious for malignancy (S-PTC), 12); atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 10; follicular neoplasm, 5; malignant (PTC), 2; and nondiagnostic, 1. The extent of PH in the corresponding histology was highest in FNAB cases diagnosed as S-PTC/PTC versus all other categories (54% vs 27%; P = .0084). Papillary cytoarchitectural features were present in 53% of FNAB cases overall and in 89% of cases diagnosed as S-PTC/PTC ( P = .0093). Nuclei were smaller in FNABs of BTN-PH compared with PTC (mean diameter/range, 8.2/6-12 vs 14.2/7-26 μm, respectively; P = .0001). Twenty-six percent of BTN-PHs contained cytoplasmic pigment. All FNAB cases diagnosed as S-PTC/PTC had focal nuclear atypia including grooves (87.5%), enlargement and crowding (75%), and chromatin pallor and pseudoinclusions (25%); however, the extent of nuclear atypia was significantly less than in the control group of PTCs ( P < .0001). CONCLUSIONS BTN-PH represents a significant pitfall in thyroid FNABs in which it can be misinterpreted as S-PTC/PTC. Cytologic clues to this pitfall include limited and variable nuclear atypia, small nuclear size, and cytoplasmic pigment. Cancer (Cancer Cytopathol) 2014;122:666-677. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]
VanderLaan, Paul A., Marqusee, Ellen, and Krane, Jeffrey F.
The diagnostic category of atypia of undetermined significance (AUS) in the Bethesda System for reporting the results of thyroid fine-needle aspirations (FNAs) is intended to encompass findings associated with a low risk of malignancy. It is unclear if there are patterns within this evolving, heterogeneous category associated with differing risk of malignancy that might warrant alternative classification or clinical management. Therefore, a retrospective review of 512 AUS FNAs from January 2005 to May 2009 was done. Most malignancies associated with AUS were papillary carcinoma (86/96 [90%]), of which 85% (73/86) were follicular variants. Atypia qualifiers were correlated with the follow-up rate of malignancy. The risk of malignancy for architectural atypia alone was approximately half that observed for cytologic, both cytologic and architectural, or unspecified atypia. Architectural atypia alone was less likely to be papillary carcinoma and more likely to be follicular adenoma. The lower risk of malignancy associated with isolated architectural atypia compared with other patterns of AUS should be considered in clinical decision making and in future management guidelines. [ABSTRACT FROM AUTHOR]
VanderLaan, Paul A., Marqusee, Ellen, and Krane, Jeffrey F.
In the Bethesda System for reporting thyroid fine-needle aspirations (FNAs), atypia of undetermined significance (AUS) is a category with limited reported follow-up and outcome data. We report a retrospective analysis of our institution's experience during nearly 4.5 years with a tiered classification scheme conforming to the Bethesda System in which repeated FNA was recommended for most patients with an initial AUS diagnosis. Of 4,691 thyroid FNAs, 512 (10.9%) had a diagnosis of AUS. Cytologic or histologic outcome data were available for 331 cases (64.6%), of which 240 (72.5%) were benign and 91 (27.5%) were malignant. Of patients with a surgical diagnosis, there was no statistically significant difference in malignancy rate among patients who went directly to surgery after a single AUS diagnosis (37/90 [41%]), patients having 2 successive AUS FNA diagnoses (22/51 [43%]), and patients with a benign aspirate after AUS (2/7 [29%]). Although AUS confers an intermediate risk of malignancy, guidelines recommending repeated FNA for most cases should be reevaluated. [ABSTRACT FROM AUTHOR]
Krane, Jeffrey F.
Costigan et al help to refine what constitutes an atypical thyroid aspirate by describing the distinction between spherules and true microfollicles. In doing so, the authors highlight significant advances that have been made since the initial implementation of The Bethesda System for Reporting Thyroid Cytopathology. [ABSTRACT FROM AUTHOR]
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