A total of 318 FNA samples (199 Hürthle cell + and 119 Hürthle cell -) were used to develop a Hürthle cell Index (HI), which is a binary classifier, determining if a sample is Hürthle cell + or Hürthle cell -. J Endocrinol Invest 42, 1319–1327 (2019). Ann Surg Oncol 21:3522–3527. Classifier score distribution was wider for the Hürthle cell positive case, with a much tighter distribution for Hürthle cell negative cases (Fig. https://doi.org/10.1007/s40618-017-0757-0, CAS c Chromosome-level LOH data from RNA-Seq Hürthle positive, Neoplasm positive or Neoplasm negative samples. Therefore, all mitochondrial genes were included in the gene feature set to undergo feature selection in downstream classifier development. https://doi.org/10.1089/thy.2011.0146, Lee KH, Shin JH, Ko ES et al (2013) Predictive factors of malignancy in patients with cytologically suspicious for Hürthle cell neoplasm of thyroid nodules. In the category III, there were eight non-HC nodules with cytological features of nuclear atypia. The Hürthle identification leverages mitochondrial expression and we developed novel feature extraction mechanisms to measure chromosomal and genomic level loss-of-heterozygosity (LOH) for the algorithm. The FNA outcome in these cases is equivocal and it is usually classified into the category IV: suspicion of follicular neoplasm (SFN), suspicion of Hürthle cell tumor (SHCT) or the category III: follicular lesion of undetermined significance (FLUS)/atypia of undetermined significance (AUS) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) . Finally, the potential gain in the overall Afirma GSC performance due to Hürthle-adjustment was assessed. Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. Hürthle cell negative, Neoplasm positive (H-N+); 4. Due to the complexity of including two types of datasets (one focused on cytologic features, and the other on histopathology labels) and integration of three separate classifiers, complex dynamic parameter optimization was engaged with extensive multi-dimensional grid search to examine the tradeoff in the sensitivity and specificity for each classifier alone, and in combination. The association of tumor size with malignancy in thyroid nodules with indeterminate cytology ... [FLUS], suspicious for follicular neoplasm [SFN]/Hürthle cell neoplasm [HCN], and suspicious for malignancy [SM]) has not been clearly studied. IV • Although FNA is highly sensitive for detecting oncocytic carcinomas, its specificity is low; most nodules diagnosed as FNHCT/SFNHCT are benign (ROM : 10-40%). Walsh PS, Wilde JI, Tom EY, Reynolds JD, Chen DC, Chudova DI, et al. Maximo V, Lima J, Prazeres H, Soares P, Sobrinho-Simoes M. The biology and the genetics of Hurthle cell tumors of the thyroid. There are three mechanisms for arriving at the GSC Benign versus Suspicious binary outcome for a given sample: The result is GSC Benign if the ensemble B/S score is lower than the nominal threshold; otherwise, The result is initially GSC Suspicious but can be reassigned to a benign call by “Hürthle-adjustment” if the sample is predicted as Hürthle cell Index-positive (HI+), and Neoplasm Index-negative (NI-), and the ensemble B/S score is lower than the Hürthle-adjusted threshold; otherwise. The analysis included the results of 25,220 FNA performed in a single center in years 2005–2017. Currently, the classification of a HC nodule into the category II has a higher negative predictive value that is close to the one found for non-HC nodules and exceeds 98%. LOH statistic was calculated both for each chromosome (referred as chromosome-level LOH) and for the entire genome (referred as the genome-level LOH). https://columbiasurgery.org/.../follicular-and-hurthle-cell-thyroid-cancer Interestingly, the LOH was primarily, but not exclusively, enriched in Hürthle cell carcinomas (See Additional file 1: Figure S3 for example of LOH in various tissues). • It is advisable to use the guidelines of the WHO, which consider only those follicular neoplasms that are composed of >75% Hurthle cells to be a Hurthle-cell neoplasm. Samples are first examined by the HI classifier. Thyroid nodules with Hürthle cells: the malignancy risk in relation to the FNA outcome category. This category is not an indication for surgical treatment but for performing control FNA and molecular tests if available, although the efficacy of those tests in the case of nodules with predominant HC is less known [17, 23, 24]. The first group (Cyto-Hürthle) included FNAB for developing Hürthle cell and Hürthle cell Neoplasm indices, where detailed cytologic features were curated by expert thyroid cytopathologists using microscopic examination from FNAB. Performance of the Afirma gene expression classifier in Hurthle cell thyroid nodules differs from other indeterminate thyroid nodules. The classifier is sensitive, but not specific due in part to the presence of non-neoplastic benign Hürthle cells in many FNAB. 25,220 FNA performed in a single center in years 2005–2017 were analyzed. Ross DS. Correspondence to Sangalli et al. CT is rarely accompanied by a large or suspicious goiter that could suggest necessity of the surgical treatment. volume 13, Article number: 27 (2019) Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. Perhaps the greatest limitation to differentiating benign from malignant Hürthle cell nodules is the imperfection of gold-standard surgical histology benign or malignant “truth” labels. 2015;123(12):713–22. The HI classifier first determines if the specimen contains Hürthle cells. Am J Surg 186:702–709, Castro MR, Espiritu RP, Bahn RS et al (2011) Predictors of malignancy in patients with cytologically suspicious thyroid nodules. 133:787–790. [40] and Castro et al. Incidence, malignancy rates of diagnoses and cyto-histological correlations in the new Italian reporting system for thyroid cytology: an institutional experience. 2011;16(10):1380–7. 2016;26(1):1–133. c Hürthle Index Score. The best parameter selected for the final model was 0.001, and the associated number of support vectors was 106. JAMA Surg. In our population, the effect of modified categorization of FNA results could be increased by the effective introduction of iodine prophylaxis. [41] for an Italian population. Nasr CE, Krishnamurthy VD. Hürthle cell nodule: thyroid nodule made of Hurthle cells, which are normal cells found in the thyroid together with the follicular cells. Surgical utility of Afirma: effects of high Cancer prevalence and Oncocytic cell types in patients with indeterminate thyroid cytology. Because RNA-seq data is limited to the exome, only chromosome-wide and genome-wide LOH were examined. Those analyses concerned the results of the last FNA performed before the surgery. HC nodules were classified into categories II (78.2% vs. 91.9%, p < 0.0000) and VI (0.4% vs. 1.2%, p = 0.0017) less often than non-HC nodules, but more frequently to categories III (14.4% vs. 5.8%, p < 0.0000), IV (11.2% vs. 0.9%, p < 0.0000) and V (1.5% vs. 0.8%, p = 0.0013). Google Scholar. We’d like to thank Hajime Matsuzaki, Duncan Whitney, Jing Lu and Ying Shen for their contributions to laboratory studies and algorithm development. Article An additional testing or surgery are required. In: NCCN Clinical Practice Guidelines in Oncology. The neoplasm classifier score distribution is wider for the neoplasm positive samples than the neoplasm negative samples (Fig. 5a and b). For this type of study, archival material was used so that formal consent is not required. Seven samples were rescued by the Hürthle-adjusted threshold (Fig. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. Samples were de-identified prior to cytopathology re-review … Cancer Cytopathol 123:713–722. https://doi.org/10.1016/j.surg.2014.08.026, Boi F, Pani F, Calo PG et al (2018) High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up. Mitochondrial genes were captured during RNA Access library preparation and the same experimental procedures and bioinformatic sequencing pipelines were applied as described in previous sections. Red dashed line indicates the cut-off for NI+ vs. NI-. IARC, Lyon, Díaz Del Arco C, Fernández Aceñero MJ (2018) Preoperative diagnosis of neoplastic or malignant Hürthle cell lesions: a chimera? The Afirma GSC Algorithm Workflow. Sippel RS, Elaraj DM, Khanafshar E, et al. https://doi.org/10.1002/cncy.21396, Shrestha RT, Hennessey JV (2016) Cytologic subclassification of atypia of undetermined significance may predict thyroid nodules more likely to be malignant at surgery. Diagn Cytopathol 31:307–312, Article This analysis included the results of the first FNA only, without considering control examinations. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. We consider this a safer mode of failure. In practice, centers whose Hürthle FNAB included more non-neoplastic samples, or samples that passed through the Hürthle cassette, received an overall benign result among Hürthle FNAB in about one-third of their samples [30, 31], whereas others reported benign results less often [32, 33]. WHO classification of tumours, 4th edn. The authors declare that they have no conflict of interest. Clinical factors influencing the performance of gene expression classifier testing in indeterminate thyroid nodules. Study samples were collected according to protocols that were reviewed and approved by study site institutional review boards (IRB) or central IRBs (Liberty IRB, DeLand, Florida; now Chesapeake IRB, and Copernicus Group Independent Review Board, Cary, North Carolina). The red-dashed lines indicate performance at the selected cutoff. The diagnosis of FLUS or HC-FLUS was made when the specimen showed features from the borders of the categories II and IV. J Clin Endocrinol Metab. b Volcano plots of differential expression. 2013;98(5):E962–72. The increase of CT features in the HC group was statistically significant (p < 0.0000). Cytopathology 17:245–250, Rago T, Di Coscio G, Basolo F et al (2007) Combined clinical, thyroid ultrasound and cytological features help to predict thyroid malignancy in follicular and Hürthle cell thyroid lesions: results from a series of 505 consecutive patients. Consequently, the iodine supply influences the numbers of nodules classified into the categories III and IV as well as the risk of malignancy in these groups. Nevertheless, the presence of HC in a smear does not significantly affect the incidence of cancers revealed in the operated patients. Such nodules are classified into categories of equivocal cytological outcomes more often than nodules without HC. The new category III amounted to 6.4% of all FNA results and was more common among HC nodules (14.4%) than non-HC ones (5.8%), unlike the previous category III (Table 1). CAS In this classification, the category I includes non-diagnostic biopsies (ND), the category II—benign lesions (BL), the category III—FLUS and HC-FLUS, the category IV—SFN and SHCT, the category V—suspicious for malignancy (SM), and the category VI—malignant neoplasm (MN). For a given sample i, we denote the scores from HI and NI, and the ensemble B/S classifier as Hi, Ni, and BSi, respectively. c NI classifier scores for HI+ samples from the validation cohort. Similar, independent experiences support this substantial increase in the GSC benign call rate and accuracy of this classifier trio [40, 41]. That decrease was more striking in HC than non-HC group (HC: 56.4% vs. 29.7%, p < 0.0000; non-HC: 82.4% vs. 71.7%, p < 0.0000). This analysis yielded 318 samples, including 119 Hürthle cell-negative and 199 Hürthle cell-positive samples. Until recently, Hürthle cell neoplasm was considered a subtype of follicular neoplasm. Karyotype views of CytoScan data. According to the criteria of the International Council for Control of Iodine Deficiency Disorders, in the 1990s, our country was classified as a moderate iodine-deficient area. Article edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Hum Pathol. FNAs were performed on nodules with a diameter of at least 5 mm (usually over 1 cm), which were palpable or had at least one malignancy risk factor (ultrasonographic or clinical). Purple points are HI+, NI+. Changes in the number of FNA results assigned to the category II were more pronounced in the case of HC nodules (over 10%) than non-HC nodules ( < 1%). While most cytologically indeterminate Hürthle cell FNAB are from benign thyroid nodules, these have historically been recommended for diagnostic surgical resection [20] because of a 9–39% risk of malignancy [18, 22, 23]. https://doi.org/10.1002/cncy.21412, Słowińska-Klencka D, Woźniak E, Wojtaszek M et al (2013) Low malignancy risk of thyroid follicular lesion of undetermined significance in patients from post-endemic areas. (b) Hürthle positive, Neoplasm negative sample. Identification of Hürthle cell cancers: solving a clinical challenge with genomic sequencing and a trio of machine learning algorithms. Cytotechnologist performance for screening Hurthle cell atypia in indeterminate thyroid fine-needle aspirates. Google Scholar, Pu RT, Yang J, Wasserman PG et al (2006) Does Hürthle cell lesion/neoplasm predict malignancy more than follicular lesion/neoplasm on thyroid fine-needle aspiration? Shown are the 13 mitochondrial transcripts present in RNA-seq data. Based on these parameters, the final SVM model was established using the ‘svmLinear’ method from the ‘caret’ R package [36] with all training samples and 1408 genes selected from the differential expression analysis. Red dashed line indicates cutoff for HI+ vs. HI-. However, needle biopsy cannot distinguish between benign and malignant follicular tumors. We additionally thank Virginia LiVolsi and Ronald Ghossein for providing surgical histological diagnoses. Thyroid Carcinoma. The risk was calculated in relation to the cytological diagnostic category of FNA as well as independently of the category of FNA (total RoM—tRoM). Thyroid 19:355–360. volume 42, pages 1319–1327 (2019)Cite this article. J Endocrinol Investig 31:309–313, Yazgan A, Balci S, Dincer N et al (2014) Hürthle cell presence alters the distribution and outcome of categories in the Bethesda system for reporting thyroid cytopathology. Bethesda category III describes the cytological findings as “atypia of undetermined significance” (AUS) and “follicular lesion of undetermined significance” (FLUS), while Bethesda category IV represents “follicular neoplasm/suspicious for follicular neoplasm” (FN/SFN) [1, 4,5,6]. Iodine modifies the relative frequency of non-neoplastic and neoplastic thyroid lesions, as well as the relative incidence of PTC and FTC [27]. In most cases (50-85% depending on indeterminate cytology category) these nodules are found benign after surgery. In our first-generation algorithm, Gene Expression Classifier (GEC), we achieved this goal by using machine learning (ML) on gene expression features. c Neoplasm Index Score. Robinson MD, McCarthy DJ, Smyth GK. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Google Scholar, Sangalli G, Serio G, Zampatti C et al (2006) Fine needle aspiration cytology of the thyroid: a comparison of 5469 cytological and final histological diagnoses. Correspondence to Brauner E, Holmes BJ, Krane JF, Nishino M, Zurakowski D, Hennessey JV, et al. The high specificity of the NI classifier leads to high accuracy in samples called neoplasm positive; the lower sensitivity translates to approximately 30% of truly neoplastic (but not necessarily malignant) samples being falsely identified by as non-neoplastic and therefore invoke the more tolerant GSC classifier threshold. We next sought to identify genomic features associated with Hürthle cell positive, neoplasm positive samples. Cancer Cell. In the first period, FNA was performed in 11,598 patients and their results were classified into the 6 categories described below. In relation to the diagnostic value of the category V, the consequences of the introduction of the category III were also positive: its positive predictive value increased. Similar observations were reported by Yazgan et al. Automatic identification of Hurthle cells and Hurthle neoplasia by two classifiers that coordinate with the core Afirma GSC classifier. Mazzaferri EL. Samples were de-identified prior to cytopathology re-review prior to RNA Access library preparation. 2014;25(3):185–9. Specifically, the risk of malignancy assessed in this way is similar for both HC and non-HC nodules of the categories II, IV, V and VI in the Bethesda system. No further measures were taken beyond those of routine clinical practice. Google Scholar. Fifty-four tissue samples have LOH measured by both Affymetrix CytoScan and RNA-seq. Wu JX, Young S, Hung ML, Li N, Yang SE, Cheung DS, et al. The best parameter selected for the final model was 0.001, and the associated number of support vectors was 51. Another study indicated that the RoM in the subgroup with HC predominance is similar to that observed in the subgroup with nuclear atypia and higher than the one in nodules with architectural atypia [10]. Poller DN, Baloch ZW, Fadda G, Johnson SJ, Bongiovanni M, Pontecorvi A, et al. For this reason, the specimen is not automatically given a final benign result, but rather must still pass the core GSC classifier with an adjusted (more tolerant) benign versus suspicious threshold, rather than having the threshold removed completely. 2015;25(7):789–96. Based on these DNA findings, we sought to recapitulate the LOH signal in RNA-seq data, utilizing SNPs called from expressed genes. Specimens showing a prominent monotonous population of thyroid follicular cells (tfc) arranged in three-dimensional groups and microfollicles with nuclear overlapping and crowding in background of scant or no colloid or containing single cell population of oncocytic cells ( > 75% of cells) with prominent nucleoli arranged in sheets and cohesive groups were classified as SFN or SHCT. But even such a detailed division does not make reported results consistent. A similar RoM of category IV nodules with or without HC was reported by Harvey et al. Bethesda category IV nodules are described as follicular neoplasm or suspicious for follicular neoplasm (FN/SFN). When examined by light microscopy, oncocytes correspond with epithelial cells exhibiting abundant, finely granular cytoplasm around nucleus and a variably conspicuous nucleolus [1]. Article Integrated genomic analysis of Hurthle cell Cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Algorithm training for the NI was carried out similarly to the training for the HI but included novel LOH statistics as features. The algorithms we tested include support vector machine (SVM), elastic net, random forest, as well as SVM with asymmetrical cost to account for class imbalance. Mol Imaging Radionucl Ther. In total, there are 13 protein coding genes, and transcripts from all 13 were captured by the sequencing assay. In its first 6203 cytologically indeterminate specimens, 5779 specimens passed all quality control requirements and received a final result, including 3% BRAFV600E classifier positive, 0.6% parathyroid classifier positive, 0.4% RET/PTC1 or RET/PTC3 fusion positive, and 0.3% medullary thyroid cancer classifier positive. 3a). Still, mitochondrial and classic DNA mutations, and other cytological, radiological, and laboratory approaches have shown low sensitivity in detecting carcinomas among Hürthle cell FNAB, and imperfect specificity in differentiating benign from malignant nodules [20, 26, 27]. Nodules with benign FNAB results typically undergo clinical and thyroid ultrasound observation as the risk of cancer is < 5%, while nearly all of those with greater cancer risk historically were treated with surgery [13]. Classifier development comprised three sequential steps: (1) differential expression analysis on 21,162 genes, using a statistical software package, edgeR [35], (2) selection of top-ranked genes with a FDR-adjusted p-value < 0.05 and expression fold-change (log2 scale) > 1.5, (3) optimizing parameter setting of multiple state-of-the-art machine learning algorithms with nested cross-validation. The incidence of the category VI for non-HC nodules increased in the second period (5.2% vs. 7.7%, p = 0.0127); HC nodules showed a similar tendency (1.8% vs. 4.3%, p = 0.3009). Both indices are Support Vector Machine (SVM) based. Oncologist. Whether or not the genomic instability of LOH should represent a pre-malignant, or carcinoma in-situ, is unknown and their natural history is unknown since these neoplasms were all surgically resected in our training and validation cohorts. Thyroid 20:1077–1083. Marqusee E, Heller HT, Cibas ES, Barletta JA, Kim MI, Krane JF, et al. Physicians use thyroid ultrasonography to prioritize thyroid nodules whose size and ultrasonographic features warrant fine needle aspiration biopsy (FNAB) for the possibility of a clinically significant thyroid lesion [4,5,6,7]. These oncocytes, or oxyphil cells, occur in multiple tissue types and are characterized by abundant, mitochondria-rich cytoplasm [19]. https://doi.org/10.1007/s40618-019-01055-0, DOI: https://doi.org/10.1007/s40618-019-01055-0, Over 10 million scientific documents at your fingertips, Not logged in The latter group usually includes follicular neoplasm, follicular lesion, and sometimes a more specific diagnosis such as Hurthle cell neoplasm or follicular lesion/neoplasm with Hurthle cell change. The cytology report reads “suspicious for Hurthle cell neoplasm (Bethesda Category IV).” I have an appointment with a surgeon for a more definitive diagnosis. The HI and NI are integrated with the ensemble model to increase overall classification performance (Fig. Samples that did not satisfy the minimum in-house sequencing QC metrics were excluded from downstream analyses. Tumor size predicts malignant potential in Hurthle cell neoplasms of the thyroid. 4a and b). All patients gave their informed consent for FNA in the context of standard clinical care. YH, RTK, GF, JH, QYD, RMH, STT, PMS, and GCK edited and revised the manuscript. The RoM in HC and non-HC nodules of particular categories of the Bethesda system was as follows: II: 1.8% vs. 0.8%, III: 9.7% vs. 3.8% when only the last FNA was considered and 10.8% vs. 6.4% when the category III in any performed FNA was considered; IV: 12.7% vs. 10.9%; V: 41.7% vs. 58.2%; and VI: 100% vs. 96.9%. 6b). With an overall goal of an accurate benign GEC test result, a Hürthle cassette was inserted upstream of the main GEC classifier. Hurthle thyroid cancer requires tissue sample for diagnosis 2017-07-14 - Keith Roach DEAR DR. ROACH: Recently, I underwent a needle biopsy of a thyroid nodule. Mitochondrial genes are shown in purple. Therefore, the elevated number of mitochondria observed microscopically can be detected genomically using RNA Sequencing. © 2021 BioMed Central Ltd unless otherwise stated. The Veracyte database was queried to identify 285 FNAB where Hürthle cell features were noted in the initial cytological reading of the case. Combining the B/S classifier with the HI and NI resulted in a significant performance gain in Hürthle subtypes, with specificity increasing from 11.8% with the GEC to 58.8% with the GSC. https://doi.org/10.1089/thy.2008.0338, Sclabas GM, Staerkel GA, Shapiro SE et al (2003) Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. 6b). For the same reason, the smears with single features characteristic of the thyroid cancer, especially features of PTC, were classified into the category V. In both evaluated periods, when several nodules were examined, the FNAB outcome was classified according to the one related to the highest risk of malignancy. - 202.22.159.243. Dear Dr. Roach: Recently, I underwent a needle biopsy of a thyroid nodule. Prior to the introduction of the Bethesda system, HC nodules diagnosed as benign eventually proved to be cancers more often than cytologically benign non-HC nodules. Straccia P, Rossi ED, Bizzarro T, Brunelli C, Cianfrini F, Damiani D, et al. Thyroid. 5c), with all but two LOH-positive samples classified as neoplasm positive (blue triangles, Fig. QYD, RMH, STT, and PMS performed clinical patient review and/or provided key study feedback. The value of 0.05 was assumed as the level of significance. 2015;59(5):377–83. Loss of Heterozygosity in Hürthle positive samples. The cells are present both in non-neoplastic lesions: nodular goiter (especially in elderly), Hashimoto disease, Graves’ disease, lesions induced by radiotherapy or systemic chemotherapy and in thyroid neoplasms [1, 2]. Almost all the examined patients were exposed to moderate iodine deficiency for most of their lives.
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