Faculty Bibliography

BACKGROUND: Mutations in the RAS gene in the thyroid gland result in the activation of signaling pathways and are associated with a follicular growth pattern and the probability of a carcinoma outcome ranging from 74% to 87%. In the current study, the authors investigated the cytopathologic and histopathologic features of common RAS mutation subtypes. METHODS: Malignant, indeterminate, and selected benign thyroid cytology cases were tested prospectively for the presence of NRAS61, HRAS61, and KRAS12/13 mutations. For each case, the Bethesda System for thyroid cytopathology diagnosis, additional cytologic descriptors, and surgical pathology outcomes were documented. The Fisher exact test and Wilcoxon 2-sample test were used for statistical comparison between the groups. RESULTS: A total of 204 thyroid fine-needle aspiration cases with RAS mutations (93.6% of which were associated with indeterminate cytopathology diagnoses) and corresponding surgical pathology resection specimens were identified. The KRAS12/13 mutation was associated with a significantly lower carcinoma outcome (41.7%) when compared with HRAS61 (95.5%) and NRAS61 (86.8%) mutations (P<.0001). Furthermore, oncocytic change was observed in a significantly higher percentage of cytology and resection specimens with KRAS12/13 mutations (66.7% and 75.0%, respectively) in comparison with those with HRAS61 (4.5% and 4.5%, respectively) and NRAS61 (15.4% and 14.7%, respectively) mutations (P<.0001). RAS mutations also were identified in cases of poorly differentiated carcinoma (NRAS61), anaplastic carcinoma (HRAS61), and medullary thyroid carcinoma (HRAS61 and KRAS12/13). CONCLUSIONS: Subclassification of RAS mutations in conjunction with cytopathologic evaluation improves presurgical risk stratification, provides better insight into lesional characteristics, and may influence patient management. In particular, KRAS12/13-mutated thyroid nodules were found to be different from HRAS61-mutated and NRAS61-mutated nodules with regard to cytopathologic and surgical outcome characteristics. Cancer (Cancer Cytopathol) 2014. (c) 2014 American Cancer Society.

INTRODUCTION: We aimed to determine influence of surgeon volume on (1) frequency of appropriate initial surgery for differentiated thyroid cancer (DTC) and (2) completeness of resection. METHODS: We reviewed all initial thyroidectomies (Tx; lobectomy and total) performed in a health system during 2011; surgeons were grouped by number of Tx cases per year. For patients with histologic DTC >/=1 cm, surgeon volume was correlated with initial extent of the operation, and markers of complete resection including uptake on I(123) prescan, thyrotropin-stimulated thyroglobulin levels, and I(131) dose administered. RESULTS: Of 1,249 patients who underwent Tx by 42 surgeons, 29% had DTC >/=1 cm without distant metastasis. At a threshold of >/=30 Tx per year, surgeons were more likely to perform initial total Tx for DTC >/=1 cm (P = .01), and initial resection was more complete as measured by all 3 quantitative markers. For patients with advanced stage disease, a threshold of >/=50 Tx per year was needed before observing improvements in I(123) uptake (P = .004). CONCLUSION: Surgeons who perform >/=30 Tx a year are more likely to undertake the appropriate initial operation and have more complete initial resection for DTC patients. Surgeon volume is an essential consideration in optimizing outcomes for DTC patients, and even higher thresholds (>/=50 Tx/year) may be necessary for patients with advanced disease.

Background: PAX8/PPARgamma rearrangement is a common genetic alteration in follicular thyroid cancer (FTC) and has been reported with variable frequency in papillary thyroid cancer (PTC). The diagnostic and phenotypic features of thyroid nodules positive for PAX8/PPARgamma on preoperative examination are not well understood. Methods: The prevalence of PAX8/PPARgamma rearrangement was detected in a series of 2015 consecutive thyroid nodules that underwent molecular analysis on cytology specimens and in 446 surgically removed papillary thyroid cancers. For all PAX8/PPARgamma positive cases, cytology and surgical pathology slides were examined and the available clinical records were reviewed. Results: Twenty-two PAX8/PPARgamma rearrangements were identified, including 16 detected preoperatively and 6 postoperatively. The incidence of PAX8/PPARgamma in papillary thyroid cancer was 1.1%. Cytologically, most of these nodules were diagnosed as a follicular neoplasm (73%), followed by the diagnosis of atypical of undetermined significance (19%), and none of the cases was diagnosed as cytologically malignant. All nodules with PAX8/PPARgamma detected preoperatively and surgical follow-up available were found to be malignant, among which the most common diagnosis was the encapsulated follicular variant of PTC. Overall, among 20 PAX8/PPARgamma-positive tumors that were surgically excised, 17 (85%) were PTC and 3 (15%) were FTC. On follow-up available for 17 patients (mean 22.4 months), 16 PAX8/PPARgamma-positive cancers showed no evidence of biochemical or structural recurrence, whereas one patient with FTC developed bone metastasis. Conclusions: In this series, PAX8/PPARgamma rearrangement found in thyroid nodules had a 100% predictive value for differentiated thyroid cancer, and was more predictive of PTC than FTC. However, almost all PTC carrying PAX8/PPARgamma were encapsulated follicular-pattern tumors, being distinguished from FTC only by nuclear features. Although most tumors carrying this mutation appear to be clinical indolent, at least on short-term follow-up, distant metastasis can develop from FTC positive for PAX8/PPARgamma.

OBJECTIVE:: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND:: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS:: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS:: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS:: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARgamma, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

Molecular diagnostics offers great promise for the evaluation of cytologically indeterminate thyroid nodules. Numerous molecular genetic and immunohistochemical tests have been developed that may be performed on thyroid specimens obtained during standard fine-needle aspiration, some of which may greatly improve diagnostic yield. A sound understanding of the diagnostic performance of these tests, and how they can enhance clinical practice, is important. This article reviews the diagnostic utility of immunohistochemical and molecular testing for the clinical assessment of thyroid nodules, and makes recommendations about how these tests can be integrated into clinical practice for patients with cytologically indeterminate thyroid nodules.

Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.

BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a >/=4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules >/=4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the >/=4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules >/=4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all >/=4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules >/=4 cm.

BACKGROUND: Typically, thyroid follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cases show moderate to marked cellularity and scant or absent colloid. Recently, cases have been noted with microfollicular cellularity in the background of moderate to abundant amount of colloid. The purpose of this study was to compare these "colloid-rich" FN/SFN cases to the typical FN/SFN cases. METHODS: Thyroid cytology specimens with the features of FN/SFN were searched in cytopathology files from September 2008 to June 2012. Cases with absent or minimal colloid were designated "typical colloid-poor" FN/SFN and cases with moderate to abundant colloid were designated "colloid-rich" FN/SFN. From these cases, those with surgical pathology resection follow-up were identified. Cytologic, surgical pathology resection, and molecular features (BRAF, RAS, RET/PTC, and PAX8-PPARgamma) were investigated for the typical colloid-poor FN/SFN cases and were compared with those of the colloid-rich FN/SFN cases. RESULTS: Of 431 FN/SFN cases with surgical pathology resection follow-up, 360 (83.5%) cases showed features of typical colloid-poor FN/SFN and 71 (16.5%) cases showed features of colloid-rich FN/SFN. Papillary carcinoma was the most common malignant outcome for the 2 groups. Although the proportion of malignant outcome was similar for the 2 groups, the "colloid-rich" FN/SFN cases showed a greater proportion of nodular hyperplasia among the cases with benign outcome. In addition, the "colloid-rich" FN/SFN cases demonstrated a greater proportion of cases with a mutation. CONCLUSIONS: Approximately one-sixth of cases of FN/SFN show "colloid-rich" features. Comparison to the typical colloid-poor FN/SFN demonstrated similar risk for malignancy but contrasting resection outcome and molecular characteristics.