Ann Surg Oncol DOI 10.1245/s10434-014-3508-x

ORIGINAL ARTICLE – ENDOCRINE TUMORS

The Impact of Molecular Testing on the Surgical Management of Patients with Thyroid Nodules Patricia Aragon Han, MD1, Matthew T. Olson, MD2, Roghayeh Fazeli, MD1, Jason D. Prescott, MD, PhD1, Sara I. Pai, MD, PhD3, Eric B. Schneider, PhD1, Ralph P. Tufano, MD, MBA3, and Martha A. Zeiger, MD1 1

Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD; Cytopathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD; 3 Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 2

ABSTRACT Background. The use of molecular tests as an adjunct to FNA diagnosis of thyroid nodules has been increasing. However, the true impact of these tests on surgical practice has not been demonstrated. This study examines the usefulness of molecular testing on surgical management decisions in patients referred for thyroid surgery at a tertiary care center. Methods. Clinical information was collected from patients who presented to Johns Hopkins Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between August 2009 and March 2013. Tests included an RNA-based gene expression classifier, a DNA-based somatic mutation panel, BRAF, NRAS, and/or RET/PTC translocation. A surgical management algorithm was created by consensus of four thyroid surgeons. Postsurgical pathology analysis in each case was then used to judge the appropriateness of the surgical decision-making and the usefulness of preoperative molecular testing, in guiding surgical planning. Results. Of 114 patients assessed by preoperative molecular testing, 87 (72 %) underwent surgery. Surgical management was altered in nine (10 %) patients on the basis of molecular testing. Of these, surgical management

Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3508-x) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 18 July 2013 M. A. Zeiger, MD e-mail: [email protected]

change was appropriate, relative to the postoperative pathology analysis, for three patients and inappropriate for six patients. Conclusions. In this study, molecular testing of thyroid nodule did not alter the surgical management of the majority of patients with thyroid nodules. These results indicate that molecular testing may be overused in patients for whom the results would not change surgical management. Furthermore, our data question the usefulness of the molecular tests examined in guiding preoperative surgical decision-making.

The incidence of thyroid nodules in the United States has risen significantly in the past century, likely as a result of significant improvements in diagnostic imaging modalities.1,2 Fine needle aspiration (FNA) is the standard diagnostic modality for assessment of thyroid malignancy.3 However, because 15–30 % of thyroid FNA samples are classified as indeterminate, the use of novel molecular tests as an adjunct to thyroid FNA has been advocated.4–12 Several different molecular tests for thyroid nodule malignancy analysis have been developed.6–8 The somatic mutation panel (SMP) testing involves assessment of specific genetic alterations and translocations, such as BRAF, RAS, RET/PTC, PAX8/PPARc, and is purported to afford high specificity and positive predictive value for malignancy, but insufficient sensitivity when used in isolation.6,13–17 In particular, BRAF mutation analysis is highly specific but lacks sensitivity to identify carcinoma in a cytologically indeterminate thyroid nodule.11,17–19 The gene expression classifier (GEC) exhibits a high level of sensitivity and negative predictive value when applied to indeterminate cytologic specimens and may facilitate

P. A. Han et al.

identification of patients who may safely avoid surgical management for asymptomatic thyroid nodules.7 Although these molecular markers appear promising to improve cancer detection, their true usefulness in preoperative surgical decision-making has not been demonstrated. In practice, the choice of a surgical procedure takes into account a myriad of clinical considerations beyond cytopathological findings, and no study has yet assessed the use of these clinical factors in the context of molecular marker testing.20–22 Because of this, the true impact of these molecular tests upon the clinical decisions for the management of patients with thyroid nodules remains uncertain. The purpose of this study, therefore, is to examine the usefulness of molecular tests on the correct preoperative selection of surgical procedures for patients who have been referred for thyroid surgery at a tertiary care center. METHODS Patient Selection Under Institutional Review Board approval, clinical information was collected retrospectively from patients who presented to Johns Hopkins Hospital for surgical consultation for a thyroid nodule, had previously undergone molecular testing of associated FNA biopsy material, and who underwent surgery at Johns Hopkins between August 2009 and March 2013. All molecular tests had been ordered by an outside referring physician. Tests included: 1) an RNA-based GEC marketed under the trade name AfirmaÒ; 2) a DNA-based SMP of which the most common commercial version is AsuragenÒ; and/or 3) BRAF 600E mutation analysis only, or performed with NRAS, or RET/ PTC mutation. Results from GEC testing included: suspicious for malignancy (positive), benign (negative), or indeterminate. Indeterminate cases in GEC group included samples with inadequate or suboptimal number of cells to be able to perform the assay by the company. Results from SMP testing were considered mutation positive when at least one mutation from the complete panel, including BRAF, NRAS, KRAS, HRAS, translocation RET-PTC, and/ or PAX8/PPARc was positive. SMP test was considered negative when none of the complete panel of molecular markers was positive. Pathology As part of institutional policy at our hospital, FNA material was reviewed before surgical intervention by inhouse board-certified cytopathologists and was classified according The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as described previously.23

Categorical TBSRTC diagnoses included: (1) insufficient for diagnosis; (2) benign; (3) atypia of undetermined significance (AUS); (4) suspicious for follicular or Hu¨rthlecell neoplasm (SFN or SHCN); (5) suspicious for malignancy (SFM); and (6) malignant.24 Categories III, IV, and V together represent the indeterminate or suspicious classification. At our institution, pathologists who render the cytopathology diagnosis do not render the surgical pathology diagnosis and vice versa. Final pathology and preoperative FNA were reviewed for each case in order to be certain there was a direct correlation between samples. Papillary microcarcinomas (tumors \1.0 cm in diameter) were only included in our analysis if the preoperative FNA biopsy: (a) was malignant or SFM and/or (b) the FNA had been performed on the same side where only one nodule was present within the upper or lower lobe. Chart Review and Data Collection Data were captured using custom Perl scripts that enabled the interface between the institutional pathology, clinical databases, and a research-oriented FileMaker database (Santa Clara, CA). The internal TBSRTC diagnosis and variables including age, gender, and nodule location and size were populated directly into the FileMaker database after verification with Perl regular expressions and manual review. Patient information including presenting symptom(s), history of radiation exposure, family history of thyroid cancer, associated thyroid disease (e.g., hypothyroidism, hyperthyroidism, multinodular goiter, lymphocytic thyroiditis) was captured from the clinic note through a combination of Perl natural language processing and manual review. The molecular test results were either parsed directly from the pathology report if they were noted or captured as a digital image and recorded in the FileMaker database during manual review. Development of Surgical Algorithm At the beginning of the study, a surgical management algorithm was developed to incorporate TBSRTC diagnosis, associated symptoms, such as hoarseness, dysphagia, discomfort, neck pain, pressure, difficult breathing, hyperthyroidism, tracheal deviation, and cosmetic reasons; family history of thyroid cancer in a first-degree relative, personal history of head or neck radiation exposure, hyperor hypothyroidism, nodule size, and the presence or absence of multinodularity. The algorithm was created by a consensus from four thyroid surgeons and is shown in Fig. 1. The final points on the algorithm were one of five recommended managements: clinical follow-up, repeat FNA, hemithyroidectomy, total thyroidectomy, or total thyroidectomy with lymph node dissection. Only patients

Impact of Molecular Testing on Thyroid Nodules

FIG. 1 Surgical management algorithm. FNA fine needle aspiration, AUS atypia of undetermined significance, SFN suspicious for follicular neoplasm, SHCN suspicious for Hu¨rthle-cell neoplasm,

SFM suspicious for malignancy, MNG multinodular goiter, US ultrasound, Hx history, FHx family history, TT total thyroidectomy, CLND central lymph node dissection

who underwent one of the three surgical options were included in the study.

management algorithm, then the molecular test was considered to have no impact. If the surgeon performed a different surgery than anticipated by the management algorithm, the molecular test was considered to effect a change in management. To evaluate the propriety of any management changes, the histology was correlated with the surgery. If the nodule was histologically malignant and the change in management was from a less to more aggressive surgery, then the change was deemed appropriate. Conversely if the nodule was histologically benign and the change in management was from a more to less aggressive surgery, then the change was deemed appropriate. Other changes were deemed inappropriate.

Algorithm Deployment To determine whether the molecular test had an impact on the clinical management, the in-house categorical TBSRTC diagnosis and all clinical variables were integrated into the algorithm and applied retrospectively to yield the recommended surgical management options. The actual surgery was then compared with the recommended surgery. If the surgeon performed the same surgery as anticipated by the

P. A. Han et al. TABLE 1 Patient demographics, FNA biopsy, and molecular test results Demographics and tumor characteristics

N = 87

Female, no. (%)

69 (79.3)

Male, no. (%)

18 (20.7)

Age at diagnosis (year, mean ± SD)

46.7 (13.5)

Tumor size (cm, mean ± SD)

1.6 (1.2)

(±1.2) cm. Twenty-one (24.1 %) cases had associated symptoms, 3 (3.4 %) had a history of radiation exposure, 6 (6.9 %) had a family history of thyroid cancer, 60 (69 %) had multinodular disease, 21 (24.1 %) had hypothyroidism, and 5 (5.7 %) had hyperthyroidism. FNA and Molecular Tests

FNA, no. (%) Insufficient for diagnosis

2 (2.3)

Benign

13 (14.9)

AUS

19 (21.8)

SFN/SHCN

11 (12.6)

SFM Malignant

10 (11.5) 32 (36.8)

Molecular test, no. (%)

N = 89a

GEC

37 (42.2)

SMP

21 (24.4)

BRAF V600E

29 (33.3)

NRAS and BRAF

1 (1.1)

RET/PTC and BRAF

1 (1.1)

FNA fine needle aspiration, AUS atypia of undetermined significance, SFN suspicious for follicular neoplasm, SHCN suspicious for Hu¨rthlecell neoplasm, SFM suspicious for malignancy

FNA diagnoses included: 2 (2.3 %) insufficient for diagnosis, 13 (14.9 %) benign, 19 (21.8 %) AUS, 11 (12.6 %) SFN or SHCN, 10 (11.5 %) SFM, and 32 (36.8 %) malignant. Eighty-nine molecular tests were performed on the 87 cases (2 cases had both GEC and SMP), 36 of 37 (97.3 %) were suspicious by GEC, 10 of 21 (47.6 %) were positive on SMP, 23 of 29 (79.3 %) tested for BRAF V600E only were positive, 1 was NRAS positive and BRAF negative, and 1 was RET/PTC and BRAF negative (Table 1). Of a total of 40 (46 %) indeterminate cases, 22 of 22 were suspicious on GEC, 3 of 11 were mutation-positive on SMP testing, and 3 of 7 were positive for BRAF mutation. Surgical Management

a

For 2 patients with malignant diagnosis on FNA, 2 sets of molecular tests (GEC and SMP) were done which made the total number of tests 89 for a total of 87 patients

Statistical Analysis Sensitivity, specificity, and negative and positive predictive values were calculated with the use of EBM Statistics Calculator.25–27 RESULTS Demographics and Patient History During this time period, 1,967 patients were referred for surgical consultation; from this number, 114 cases had molecular test performed. Of these, 87 (76.3 %) underwent thyroid surgery and were included. Twenty-seven cases (23.7 %) were excluded for the following reasons: 2 (1.8 %) had indeterminate molecular results, 3 (2.6 %) had uncorrelated FNA and molecular test with the histologic diagnosis (for example, cancer was found in the opposite site from where the FNA and molecular marker was performed), 15 (13.3 %) cases had missing follow-up data, and 7 (6.1 %) patients had clinical follow-up only because these patients demonstrated a ‘‘benign history’’: cases with no symptoms, a nodule less than 4 cm and no risk of malignancy (full details are provided in Supplemental Table 1). Of the 87 patients, 69 (79.3 %) were female, with a mean age of 46.7 (±13.5) years, and tumor size was 1.6

Of the 87 patients included in this study, 56 (64.4 %) of them had a thyroid malignancy. As seen in Fig. 2a, molecular testing did not alter the surgical management in 78 of 87 (89.7 %) patients. Thus, molecular test results were not significantly associated with a change in management. Surgical management was altered for nine (10.3 %) patients, and the particular features of these patients are listed in Table 2. As seen in Fig. 2b, management was improved in three (3.4 %) patients as a result of the molecular test results, whereas surgical management was altered inappropriately in six (6.9 %) patients. Seven were GEC-suspicious, and the GECsuspicious status led to two appropriate upgrades in the aggressiveness of the management and five inappropriate aggressive surgeries for benign neoplasms. One patient did not undergo central lymph node dissection (CLND) despite having a 1.3 cm cytologically malignant nodule due to the BRAF-negative status of the cytological material. In retrospect, the downgrade in management was inappropriate because surgical pathology confirmed that the nodule was follicular variant of papillary thyroid carcinoma. Second, it is important to clarify the performance of prophylactic CLND in all patients with PTC is controversial. However, at our institution surgeons routinely do so for tumors C1 cm. Last, one patient underwent total thyroidectomy and central lymph node dissection—despite having a nodule that was cytologically SFM—on the basis of a detected BRAF mutation. Because the surgical pathology demonstrated the nodule to be malignant, this was an appropriate upgrade in the surgical management.

Impact of Molecular Testing on Thyroid Nodules

a b 3 (3.4%)

6 (6.9%)

78 (89.7%)

No impact in the management Appropriate Inappropriate

FIG. 2 Impact of the molecular test on surgical management of patients with thyroid nodules. Results from GEC testing included: suspicious for malignancy (positive), benign (negative), or indeterminate. Indeterminate cases in the GEC group included samples with inadequate or suboptimal number of cells to be able to perform the assay by the company. Results from SMP testing were considered mutation positive when at least one mutation from the panel including BRAF, NRAS, KRAS, HRAS, translocation RET-PTC, and/or PAX8PPAR gamma was positive. SMP test was considered negative when

none of the molecular markers was positive. Cases in which the molecular tests by category were considered to effect or to not effect a change in management of the patients based on the algorithm. Percentages represent the cases in which there was no change in management, appropriate or inappropriate changes. *Two cases in which both GEC and SMP were performed, which resulted in 89 tests for 87 patients. **Case with BRAF and NRAS performed: only NRAS is positive

TABLE 2 Cases with change in the surgical management based on molecular test FNA diagnosis

Nodule History, signs size (cm) and symptoms

Management Molecular based on algorithm test

Actual surgery Final path performed report

1 PTC

1.3

MNG

TT?CLND

BRAF negative TT

FVPTC

2 SFM

2.1

Hypothyroidism

TT

GEC positive

ADN

Overtreatment

3 SFM 4 AUS

1.8 1

MNG Hypothyroidism FHx of thyroid cancer

TT TT

BRAF positive TT?CLND GEC positive TT?CLND

PTC FA

Appropriate Overtreatment

5 AUS

2.1

Uninodular

HT

GEC positive

TT

ADN, and LcT Overtreatment

6 AUS

3.9

Compressive symptoms FHx of thyroid cancer

TT

GEC positive

TT?CLND

FVPTC

Appropriate

7 Benign

1.8

MNG and hypothyroidism Repeat FNA

GEC positive

TT?CLND

FVPTC

Appropriate

8 Benign

1.8

MNG

Repeat FNA

GEC positive

TT

MNH

Overtreatment

9 Insufficient 2.4

MNG

Repeat FNA

GEC positive

TT?CLND

FA, and MNH Overtreatment

TT?CLND

Change in the surgical management Undertreatment

FNA fine needle aspiration, PTC papillary thyroid cancer, AUS atypia of undetermined significance, SFM suspicious for malignancy, MNG multinodular goiter, FHx family history, TT total thyroidectomy, CLND central lymph node dissection, HT hemithyroidectomy, FVPTC follicular variant of PTC, FA follicular adenoma, ADN adenomatoid nodule, MNH multinodular hyperplasia, LcT lymphocytic thyroiditis

Correlation Between Molecular Test and Final Histopathology Correlation between the FNA, molecular test result, and histologic surgical diagnosis was determined in all the cases (Table 3). Of the 37 patients with GEC, 36 were

GEC-suspicious, and 1 was GEC-benign. The malignancy prevalence was 76 % (16/37). GEC correctly identified all 16 malignant nodules as suspicious (97 % sensitivity; 95 % confidence interval [CI], 77–99.7); however, 20 benign nodules also were identified as suspicious. Thus, the positive predictive value (PPV) was 45 %. In a subgroup

P. A. Han et al. TABLE 3 Correlation between final surgical pathology and the molecular test result, within the different categories of the Bethesda system for FNA diagnosis FNA cytology (n) Final surgical pathology Benign Malignant Benign Malignant Benign Malignant Benign Malignant Benign Malignant Benign Malignant GEC negative GEC positive SMP negative SMP positive BRAF/NRAS/ BRAF/NRAS/ RETPTC negative RETPTC positive Malignant (32)b

1c

0

0

2

1

2a

1a

5

0

3a

0

a

0

2

0

1a

0

3

0

0

0

0

0

1

1

2a

0

0

0

0

0

1a

0

SFM (10)

0

0

0

2

1

1

SFN/SHCN (11)

0

0

4a

4

2

1a

0

AUS (19)

0

0

7a

5

2

1a

0

a

3

0

0

1

a

19

Benign (13)

0

0

8

Insufficient (2)

0

0

1a

0

0

0

0

0

0

0

0

1

Subtotal

1

0

20

16

6

5

2

8

1

6

1

23

Total (89)

37

21

31

SFM suspicious for malignancy, SFN suspicious for follicular neoplasm, SHCN suspicious for Hu¨rthle cell neoplasm, AUS atypia of undetermined significance a

Cases in which (1) the molecular test was positive and the final pathology benign or (2) the molecular test negative and the final pathology malignant

b

For 2 patients with malignant diagnosis on FNA cytology, 2 sets of molecular tests (GEC and SMP) were done which made the total number of tests 34 for a total of 32 FNAs

c

Case in which the FNA was PTC, the GEC negative, and the final pathology, benign

that included Bethesda categories III to V, GEC correctly identified 11 of the 11 cases as suspicious (96 % sensitivity; 95 % CI, 70–99.6); 11 benign cases also were identified as suspicious (4 % specificity; 95 % CI, 0.4–30). The PPV was 50 %. The one GEC-benign nodule was ultimately benign after resection. A negative predictive value could not be obtained from this study, because there were not enough GEC-benign nodules. Of the 21 patients who underwent SMP testing, 10 were mutation-positive, and 11 were mutation-negative. The malignancy prevalence for all patients was 62 % (13/21). Of the 10 mutation-positive cases, 8 were histologically malignant (62 % sensitivity; 95 % CI, 36–82); and of the 11 mutation-negative cases, 5 were histologically malignant (75 % specificity; 95 % CI, 41–93). The negative predictive value (NPV) and PPV were 55 and 80 %, respectively. In a subgroup that included Bethesda categories III to V, SMP correctly identified three of the six malignant cases as mutation-positive (50 % sensitivity; 95 % CI, 20–80); and five benign nodules as mutationnegative (92 % specificity; 95 % CI, 52–99). The NPV and PPV were 61 and 88 %, respectively. Of the 31 BRAF tests performed, including the case with BRAF and NRAS, and 1 case with BRAF and RET/PTC, 24 were mutation-positive, and 7 were mutation-negative. The malignancy prevalence for all patients was 94 % (29/31). Of the 24 mutation-positive cases, 23 were histologically malignant (79 % sensitivity; 95 % CI, 62–90); and of the 7 mutation-negative cases, 6 were histologically malignant

(50 % specificity; 95 % CI, 10–91). The NPV and PPV were 14 and 96 %, respectively. In a subgroup that included Bethesda categories III to V, BRAF mutation was positive in three of the six malignant cases (50 % sensitivity; 95 % CI, 20–80) and negative in one benign case (75 % specificity; 95 % CI, 20–97). The NPV and PPV were 30 and 88 %, respectively. DISCUSSION This study examined the ability of different commercially available molecular tests to accurately assist in the selection of surgical procedures for patients presenting with thyroid nodules and is the first to do so in the context of clinical information used to guide preoperative decision making. While complete accuracy should not be expected of these tests, the molecular assays described here are unique in that their goal is to simplify clinical management in a particularly nuanced multidisciplinary field of medicine. It appears that these expectations have not been met given that management changes are more often wrong than right. However, in a broader sense, the most remarkable finding in this study is that for the overwhelming majority of our study group, they did not add information that changed the type of surgery that the patient would have received based on conventional medical and pathological methods. At the very least, these results indicate that molecular testing is no substitute for the multidisciplinary approach currently in place for thyroid nodule

Impact of Molecular Testing on Thyroid Nodules

management. Unfortunately, none of the tests examined proved to be uniformly accurate in preoperatively predicting the presence or absence of malignancy. Only in a small number of cases it helped with the surgical decisionmaking process; in some it hindered the process. It is important to point out that indeterminate and suspicious cytological categories were the reasons for the development of molecular testing. However, our results showed that the molecular tests are often not utilized for their intended purposes, namely to differentiate benign from malignant in the indeterminate or suspicious cases. An example of this included molecular tests utilized in patients with malignant FNA, presumably to advocate for a total thyroidectomy or CLND (Table 3). In addition, there were 15 patients with benign or insufficient results who had inappropriate ordering of molecular testing as well. These findings also suggest that it may be prudent for surgeons to be consulted before the initiation of molecular testing. That way, unnecessary testing could be avoided. An alternative solution would be to agree on an algorithm for surgical management and have the laboratory deny testing for cases in which no change in management would ensue as a result of the molecular testing. Regardless, the need for a consideration of all clinical and pathological variables in the use of molecular testing is important, because these tests add significant incremental cost and have the potential not to be appropriately utilized or interpreted by the clinician. This includes inappropriate ordering of molecular tests by referring physicians, misinterpretation by the surgeon of the molecular test results as well as the limitations of molecular testing itself. Regardless, it is important to note that of the 87 patients referred for surgical consultation who also had molecular testing, in the majority no impact from that testing appeared to occur on the surgical decision-making. This study has several limitations: (1) the data collected are retrospective and subject to biases both known and unknown; (2) several different molecular tests were included in the study and therefore precise evaluation of the individual markers cannot be made; (3) because all the molecular testing was initiated by the referring physicians, selection bias is likely; for example, a greater suspicion about the thyroid nodule; (4) it is likely that those patients having negative molecular testing results were less likely to be referred for surgical management, thus biasing our study population. Also, patients who had indeterminate FNA results and negative molecular testing were likely not referred for surgical consultation, nor were those patients who had a surgical consultation but did not undergo surgery at our institution or who were medically managed included; (5) although the surgeons universally agreed upon the surgical algorithm into which the markers were incorporated, it is not possible to capture the decision-

making process with 100 % accuracy as well as the realtime intention to treat decision in a retrospective fashion, and intraoperative findings may direct surgical decision making away from this algorithm, thus introducing bias; and (6) because the algorithm was formalized after the fact, it may not be correct to assume that any deviation from that algorithm was inappropriate care. Despite these limitations, our study included all consecutive patients referred to our institution for surgical consultation for a thyroid nodule who also had molecular tests ordered by the outside referring physician. Our results suggest that it is very important that we carefully evaluate when and how a molecular test is incorporated into a surgical algorithm and its true impact on surgical care before we can accurately state how efficacious the added testing truly is. CONCLUSIONS This preliminary study indicates that molecular testing for thyroid nodule diagnosis may be overused given that most patients undergoing surgery for thyroid nodule management do not benefit from this testing. The minimal difference in justified and unjustified changes in surgical management clearly warrants additional investigation using a larger-powered, prospective study. ACKNOWLEDGMENTS

The authors have nothing to disclosure.

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The impact of molecular testing on the surgical management of patients with thyroid nodules.

The use of molecular tests as an adjunct to FNA diagnosis of thyroid nodules has been increasing. However, the true impact of these tests on surgical ...
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