Thyroid cancer is present in 5% to 10% of thyroid nodules and is the primary clinical concern in their evaluation.1 Thyroid cancer was projected to be newly diagnosed in 56,460 persons during 2012, and is now the fifth most common cancer diagnosed in women.2 Although the 5-year overall survival rate is 97%, thyroid cancer–associated mortality has increased recently in both men and women. For patients with distant metastatic disease, overall survival decreases significantly to 56% and prompt management offers optimal long-term outcomes.2
The diagnosis of thyroid cancer can be challenging, but it is rarely missed if a systematic strategy is adopted. Cervical ultrasonography is the current diagnostic gold standard for evaluation of thyroid nodules,3,4 and although ultrasonography can differentiate cancer from benign nodules with high sensitivity, it is limited by low specificity.5 Fine-needle aspiration biopsy (FNAB) is currently the most accurate diagnostic test for thyroid cancer. A tiered classification system to report FNAB cytology was proposed at the Bethesda NCI Thyroid Fine-Needle Aspiration State of the Science Conference in 2007 and has been adopted by most large-volume centers. The classification scheme identifies morphological criteria that assign FNAB cytological results into 6 categories: benign, follicular lesion of undetermined significance (FLUS), follicular or oncocytic neoplasm (FN), suspicious for malignancy, malignant, or nondiagnostic.6 The reliability of FNAB is, in part, due to the high diagnostic accuracies of the benign and malignant cytological categories, and the clinical management of patients with these FNAB results is well defined,3,4 but in up to 25% of FNAB specimens, the cytology is indeterminate (FLUS, FN, and suspicious categories). The clinical management of indeterminate FNAB results is further challenged by the wide variability in cancer risk in these categories, which ranges from 5% to 75%.
Repeat FNAB is currently recommended for FLUS results, which carry a low risk of malignancy (5%–20%), yet after repeat FNAB, 50% of FLUS results still require diagnostic thyroid surgery to diagnose or exclude thyroid cancer.7,8 Results in the FN and suspicious categories carry 20% to 30% and 50% to 75% risks of malignancy, respectively, and diagnostic thyroidectomy (Tx) is the current standard of care.3,4 Options for diagnostic Tx include either thyroid lobectomy or total thyroidectomy (TT). Thyroid lobectomy preserves euthyroidism in about two thirds of patients and also avoids the risk of permanent hypoparathyroidism. TT is the recommended treatment of a differentiated thyroid cancer (DTC) of 1 cm or more3; thus, if indicated by final histology, a second operation to complete the TT (“2-stage surgery”) is typically necessary after lobectomy for cancer, incurring additional costs and a higher rate of complications.9
To facilitate the preoperative diagnosis of thyroid cancer, molecular markers have emerged as an adjunct to FNAB cytology. Genetic alterations implicated in thyroid carcinogenesis have been identified in the MAPK and PI3K-AKT pathways and include BRAF V600E and RAS point mutations and RET-PTC and PAX8-PPARγ rearrangements, which together account for about 70% of the known mutations in DTC.10 The clinical utility of FNAB testing for these most frequent mutations was evaluated in the largest study to date with cytological, molecular, and histological correlations.11 The study included 513 FNAB nodules residing in 1 of the 3 indeterminate categories according to the Bethesda tiered classification system. Of the 87 positive results, 70% were RAS mutations. Although the overall risk of cancer in a mutation-negative nodule was still 14%, the overall risk in a mutation-positive nodule was 89%, and when mutation testing was positive for BRAF, RET-PTC, or PAX8-PPARγ, the risk of cancer was 100%.11
The twin goals of thyroid nodule diagnostic testing are to improve patient outcomes by accomplishing an initial definitive TT for all clinically significant thyroid cancers (sTCs) while limiting the extent of surgery to lobectomy for patients with benign neoplasms or papillary thyroid microcarcinoma (PTMC). We hypothesized that the routine use of a clinical algorithm for prospective thyroid FNAB molecular testing (MT) would facilitate both goals.
We conducted a single-institution retrospective cohort study of all patients who received Tx by 1 of 4 academic endocrine surgeons from October 1, 2010, to March 30, 2012. Patients were included in the study if they had a preoperative thyroid-stimulating hormone, cervical ultrasonography with lymph node mapping, ultrasound-guided FNAB, cytological diagnosis using the 2008 Bethesda criteria, and 1 or more indications for Tx under the 2009 American Thyroid Association (ATA) guidelines. Patients with malignant FNAB cytological results were excluded, as MT results do not yet influence the extent of Tx.3
Prospective MT Protocol
In cohort 1, FNAB was performed at our academic center by standard prospective MT for a panel of markers that included BRAF V600E, BRAF K601E, NRAS codon 61, HRAS codon 61, KRAS codon 12 and 13 point mutations, RET-PTC1, RET-PTC3, and PAX8-PPARγ rearrangements.11 During the study period, MT was routinely performed for all in-house FNAB results in the indeterminate Bethesda cytological categories of FLUS, FN, and suspicious for malignancy and was also performed on the request of the managing physician for selected nodules with either benign or nondiagnostic cytology results. In cohort 2, patients did not have MT results for analysis because (1) their FNAB was done at an outside institution before referral, or (2) the FNAB result was benign or inadequate cytologically, or (3) MT results were uninformative because of GAPDH and KRT7 amplification thresholds that did not meet criteria for sample adequacy as previously described (48 patients; 13%).11
In each cohort, the extent of initial Tx was determined by clinical, radiographical, and cytological results per the 2009 ATA guidelines as previously described,9 except that in cohort 1, positive MT results were also considered to be an indication for initial TT in consenting patients, as illustrated in Figure 1. Performance of prophylactic central compartment (level 6) lymphadenectomy for patients with nonmalignant cytology was determined by intraoperative findings and assessment of malignancy potential, which could include concerning ultrasound appearance, suspicious cytology, and/or positive MT results. Data impacting the decision for and outcomes of initial lobectomy, TT, and reoperative completion Tx were retrieved from clinical, radiological, cytological, operative, and pathological sources under institutional protocol QIIRB-1057. Recurrent laryngeal nerve paralysis was defined as vocal fold immobility diagnosed by direct laryngoscopy persisting 6 months or more postoperatively, and permanent hypoparathyroidism was defined as the need for rocaltrol supplementation to maintain eucalcemia 6 months or more postoperatively. sTC was defined by the presence of DTC of 1 cm or more or DTC of less than 1 cm with cervical lymph node metastasis on final histology. PTMC was defined as the DTC of less than 1 cm.
The χ2 test was used to examine associations between categorical variables, and the unpaired 2-tailed Student t test was used to identify correlation between continuous variables. Statistical analysis was performed using available online calculation tools (http://www.socr.ucla.edu/SOCR.html), and a P value of less than 0.05 was considered significant.
During the study period, 671 patients met criteria for inclusion. These patients have not been previously described, and they do not overlap with the patient population studied to establish the institutional algorithm for prospective FNAB-MT.11 A total of 322 patients comprised cohort 1 and 349 patients comprised cohort 2. The 2 cohorts did not differ significantly by age (P = 0.85), sex (P = 0.56), the type of initial operation (P = 0.08), operative complications (P = 0.88), or the incidence (P = 0.96) or clinical significance (P = 0.34) of malignancy on final histology (Table 1). Regardless of the extent of initial Tx, in the overall study population, an FNAB result in 1 of the 3 indeterminate Bethesda cytological categories (FLUS, FN, and suspicious for malignancy) was the most frequent indication for surgery (TT 71% vs lobectomy 68%; P = 0.5); other indications for surgery included significant nodule growth, compressive symptoms, substernal goiter, concurrent parathyroid exploration, and thyroid nodule size of 4 cm or more.12
Positive MT results were obtained in 56 of 322 cohort 1 patients (17%), and the most common mutation was RAS (42/56; 75%), followed by BRAF V600E (10/56; 18%), BRAF K601E (2/56; 4%), and PAX8-PPARγ (2/56; 4%). In this series of patients with nonmalignant FNAB results, false-positive MT results occurred in 7% of patients (4/56) and were all represented by RAS positivity. Eight of 56 MT-positive cohort 1 patients (14%) had histological PTMC without lymph node metastasis. MT results were the only indication for initial TT in 18 of 202 cohort 1 patients (9%) who otherwise had FNAB results that were FN (8 patients) or FLUS (10 patients), and of these 14 (78%) had sTC histologically.
TT was the initial procedure in 202 of 322 cohort 1 patients (63%) and 241 of 349 cohort 2 patients (69%). Overall, the most common reasons for initial TT were the presence of a contralateral dominant 1 cm or more thyroid nodule (112/443; 43%) and preexisting hypothyroidism (110/443; 25%), and these indications did not differ by cohort (P = 0.1 and P = 0.8, respectively). Central compartment lymph node dissection was performed in 68 of 322 cohort 1 patients (21%) and 54 of 349 cohort 2 patients (15%) (P = 0.06). Lateral lymph node dissection was performed in 2 cohort 2 patients who had FNAB of sonographically suspicious lateral lymph nodes with cytological results that were inconclusive but elevated thyroglobulin levels were detected in the aspirate wash; both proved to have metastatic papillary thyroid carcinoma (PTC).
Altogether in both cohorts, 25% of patients (170/671) proved to have sTC histologically and the overall incidence of sTC did not differ by the type of initial operation (TT, 26% vs lobectomy, 22%; P = 0.3). When the cohorts were compared by the type of initial operative procedure, the incidence of histological sTC after initial TT was considerably higher in cohort 1 (66/202; 33%) than in cohort 2 patients (51/241; 21%) (P = 0.006; Table 2). The incidence of sTC after initial lobectomy was also lower in cohort 1 patients (21/120; 18%), that is, those who routinely had FNAB-MT results available, than in cohort 2 patients who were managed without MT guidance (32/108; 30%) (P = 0.03). Of further note, among the 170 patients who had sTC histologically, the incidence of patients who had initial TT was higher in cohort 1 (66/170; 56%) than in cohort 2 patients (51/170; 44%) (P = 0.04). These data support the hypothesis that routine MT guidance was associated with an increased proportion of correct initial TT in patients with sTC.
Because there was a lower proportion of benign cytological results in cohort 1 patients by study design, we were interested to analyze whether this lower proportion could decrease the pretest probability for sTC and serve as a confounder. The subset of 471 patients who had undergone only surgery for an FNAB result in the FLUS or FN category (Table 2) was further evaluated. In this subset, the incidence of sTC after initial TT was statistically equivalent in both cohorts (cohort 1 vs cohort 2: 28% vs 25%) (P = 0.6; Table 2). However, the incidence of sTC after initial lobectomy was significantly lower for patients managed with MT guidance (cohort 1 vs cohort 2: 17% vs 43%) (P < 0.001). In other words, patients with FLUS/FN cytology who were managed without MT were 2.5 times more likely to require 2-stage Tx for sTC, again verifying the first portion of the study hypothesis.
Overall, 341 of 671 patients (51%) proved to have benign disease histologically, and 160 patients (24%) had a diagnosis of PTMC. When compared by the type of initial operation, the rates of lobectomy performed for benign thyroid histology were equal between cohorts (cohort 1 vs cohort 2: 66% vs 60%) (P = 0.38; Table 2). In the 160 patients with histological PTMC, which is particularly difficult to diagnose by FNAB, lobectomy was also performed at rates that were independent of MT use (cohort 1 vs cohort 2: 17% vs 10%) (P = 0.15). More notably, in the 501 patients with non-sTC (who had either benign lesions or PTMC and for whom lobectomy would be the appropriate extent of surgery under current standards), initial lobectomy was performed more often with routine preoperative MT (cohort 1 vs cohort 2: 99/501, 20% vs 76/501, 15%) (P = 0.001). In other words, patients with non-sTC who had MT guidance were more likely to correctly receive lobectomy than those who did not, and these data support the second portion of the study hypothesis.
To examine the prospective utility of MT, we determined the sensitivities, specificities, positive predictive value (PPV), and negative predictive value (NPV) for FNAB and mutation testing. No patient in this study had cytological results in the benign category, together with positive MT results. In diagnosing sTC, an FNAB result in 1 of the 3 indeterminate categories (FLUS, FN, and suspicious for malignancy) had high sensitivity (89%) and NPV (88%); however, specificity (27%) and PPV (29%) were low, yielding an overall accuracy of 42%. In diagnosing sTC, the addition of MT guidance to FNAB increased the specificity to 95% and the PPV to 82%, with an increased overall accuracy of 82%.
We developed MT as a preoperative adjunct to FNAB cytology to improve the specificity of FNAB. Ultimately, optimizing the sensitivity of FNAB will also serve to facilitate the future goal of eradicating the need for diagnostic lobectomy for histologically benign disease, but to date, no study has supported the abandonment of using cytological results as the primary guide to clinical management. Using a routine algorithm for prospective MT, we demonstrate here that the likelihood of optimal initial thyroid surgery is increased by the reflexive use of testing a molecular marker panel of BRAF, RAS, PAX8-PPARγ, and RET-PTC on FNAB specimens. We analyzed new data from a single institution that has been prospectively and routinely using FNAB-MT since 2007 and observed that, overall, FNAB-MT facilitated a 30% increase in the appropriate use of initial TT for sTC histology and a 33% increase in the appropriate use of initial lobectomy for non-sTC histology.
The use of molecular markers to help risk stratify nodules with FNAB in the indeterminate cytological category has been studied using 2 novel methods. The first approach uses the MT panel described here to inform decision making at initial surgery. The second approach uses a gene expression classifier (GEC) panel selected to improve the NPV by identifying patterns predictive of benign nodules to potentially reduce or eliminate the need for diagnostic surgery. In an industry-sponsored study of 265 nodules with indeterminate FNAB specimens, GEC results, and histology, the false-negative rate for the GEC panel was 7%, a rate that is higher than most benchmarks for benign cytology alone, and the missed carcinomas were papillary (6/7; size range, 0.6–3.0 cm) and oncocytic (1/7; size range, 3.5 cm) in type. Furthermore, the false-positive rate of the GEC panel was 53% and thus a staged reoperative Tx would still be necessary even with a positive GEC result.13
The molecular marker panel described here is an alternative strategy with different strengths. MT is used for somatic gene changes that are frequently associated with thyroid cancer. BRAF V600E is a point mutation that constitutively activates the downstream targets of the MAPK signaling pathway, and it is the most frequently identified gene mutation in papillary thyroid cancer. A number of studies have prospectively evaluated the benefit of preoperative BRAF testing on FNAB specimens, and the presence of BRAF V600E confers a more than 99% risk of papillary thyroid cancer with rare false-positive cases.14–16 However, BRAF V600E is identified in only 40% to 50% of PTCs and is not present in follicular or oncocytic carcinoma, thus the diagnostic utility of single-gene testing is limited. Additional genetic alterations that have been implicated in thyroid carcinogenesis have been identified and include RET-PTC, PAX8-PPARγ rearrangements, and RAS point mutations.10 A panel that tests for these common mutations in addition to BRAF V600E was evaluated in 2 independent single-institution series and was demonstrated to be highly associated with thyroid cancer in 146 cytologically indeterminate FNAB specimens with histological correlation.17,18 In these studies, 49% of nodules with an identified mutation had one of the non-BRAF mutations and 97% were diagnosed with histological thyroid cancer. Thus, the present multigene panel significantly enhances the diagnostic utility of mutation testing, particularly for nodules with indeterminate FNAB.
Although recommendations to guide clinical thyroid nodule decision making exist, practice in using MT results to guide the initial extent of surgery clearly depends on patient preference and institutional experience. One strength of this study is that we evaluated 2 concurrent cohorts of patients who had their care managed by a coordinated multidisciplinary program; thus, discussions and counseling regarding indications for surgery and extent of Tx were relatively uniform. In addition, all patients had imaging, cytology, and histology interpreted by a consistent group of endocrinologists, radiologists, and pathologists, and because it is not yet our clinical practice to repeat FNAB, specifically for the purpose of MT alone, there was no selection bias with regard to who had MT and who did not.
Conversely, there are several limitations of this study and these include its single-institution and nonrandomized design. The 2 cohorts were equal in mean age, sex distribution, malignancy rate, and the type of surgical procedure (Table 1), yet there may be other sources of unassessed cohort nonuniformity. Another limitation is that histological diagnosis was not blinded to the results of preoperative MT or cytology. Because this was designed as a surgical study and required histology, whether FNAB-MT can prevent surgery for cytologically indeterminate but small, asymptomatic, and sonographically benign lesions is not known. In addition, the clinical impact of false-positive MT results was not quantifiable here, although we did demonstrate that the complication rate is the same between cohorts and did not change with procedure type. A further potential limitation concerns those patients who after initial TT require lifelong L-T4 (levothyroxine), which anecdotally may have an impact on quality of life, although this remains controversial.19,20
Interestingly, in subset analysis, we observed that after initial TT for patients with FLUS or FN cytology, the incidence of sTC was the same in the 2 cohorts (P = 0.6). This may be due to other clinical variables that may increase the clinician's concern for thyroid cancer and lead to a decision for initial TT, such as suspicious ultrasound appearance, family history, rapid nodule growth, or nodule size. More striking is that, in this subset, we observed a significant impact of MT guidance for patients who had initial lobectomy. It is in these patients who had FLUS or FN FNAB cytology and who otherwise did not have any other indications or concerns for thyroid malignancy that MT appeared to have the highest impact on clinical management. Without MT, there was a 2.5-fold higher likelihood of having initial lobectomy for histological sTC requiring a second operative procedure (P < 0.001). The added diagnostic accuracy with MT is also reflected in the 7% of patients who had positive MT results as the only indication for initial TT.
FNAB is to date the best preoperative test to guide thyroid nodule management. In assessing performance parameters, we observed improvements in both specificity (95%) and accuracy (82%) when MT was added to cytological evaluation, with the caveat that FNAB with negative MT results does not reliably exclude malignancy. Our current management strategy still considers mutation-negative indeterminate cytology as an indication for either repeat FNAB or diagnostic thyroid surgery (Fig. 1). In this programmatic algorithm, patients with mutation-positive testing have a high risk of malignancy and definitive initial TT is recommended whereas if mutation-testing results are negative, then a decision for surgery and the extent of initial Tx follows ATA guideline recommendations using clinical, ultrasonographic, and cytological findings.
The added cost of MT to routine FNAB has been closely scrutinized.9 We previously demonstrated in a theoretical decision-tree model that the approximately $650 cost of MT for indeterminate thyroid nodule management was offset by cost reductions achieved by correct initial surgery and reduced use of 2-stage surgery, with a decrease in the number of necessary diagnostic lobectomies and a corresponding increase in appropriate utilization of initial TT. However, limitations to decision-tree modeling included the assumptions that all patients were euthyroid and had a single dominant nodule, which is not always the real-life clinical scenario. Another limitation is that patients and clinicians may choose either lobectomy for a cytologically suspicious nodule or TT for an otherwise low-risk FLUS FNAB result based on other clinical findings or personal preference. Therefore, one aim of this study was to evaluate the efficacy of mutation testing in a large consecutive series of real-time patients.
Additional tailoring of initial surgical treatment will be likely as we further define in long-term follow-up studies how genetic changes correlate with histological phenotype and clinical outcomes. For example, in multivariable analysis of a consecutive series of patients who all had TT for histological PTC, BRAF V600E was the only available preoperative clinical parameter that predicted central compartment lymph node metastasis (odds ratio: 9.7; P = 0.02). Moreover, BRAF negativity was a potent predictor of N0 disease (NPV = 91%).21 In a separate study, BRAF-positive PTC patients were more likely to require cervical reoperation even in short-term follow-up (P = 0.04) and routine preoperative testing could have potentially altered the surgical management in up to 24% of study patients.22 On the contrary, RAS positivity is rarely associated with lymph node positivity.23 Whether prophylactic resection of the central compartment lymph nodes in PTC patients will improve outcome remains to be determined, but preoperative BRAF status, in particular, can be helpful to direct the extent of both Tx and initial lymphadenectomy. The current panel encompasses 70% of the genetic mutations associated with DTC, and augmentation with new gene markers now under study will further increase both the specificity and sensitivity of FNAB-MT.
We demonstrate here that the addition of routine FNAB-MT guidance to a clinical management algorithm for dominant thyroid nodules is associated with increased likelihood that an initial definitive TT is performed for what proves to be clinically sTC, whereas the extent of surgery for benign neoplasms and PTMC is more likely to be correctly limited to lobectomy. MT thus facilitates the goal of succinct and appropriate surgical management for thyroid nodule patients.
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indeterminate nodule; molecular markers; thyroid; thyroid cancer; thyroidectomy
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