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base insertions/de- letions (indels), and gene rearrangements has been reported tohave a sensitivity of 90% for FN/SFN FNA cytology speci- mens from a single-center study (170). A limitation was that the pathologists evaluating the gold standard surgical pathol-ogy specimens were aware of the results of earlier generation molecular tests previously conducted on the FNAs (170). It is not known to what extent differences in techniques used toperform mutational testing by various groups (162,167,170)may affect test performance, and direct, head-to-head compar- isons of these tests within the same population are lacking. The currently available seven-ge ne mutational panels have been proposed to be most useful when surgery is favored. However, this is based on the assumption that the surgical approach would be altered with a positive test, and long-term outcome dataproving the overall beneﬁt of this therapeutic strategy are nee- ded. It is important to acknowledge that algorithms employing seven-gene mutational
testing as a means to inform decision-making on extent of primary thyroid surgery (i.e., lobectomy ortotal thyroidectomy) (162) were developed at a time when the ATA guidelines favored tota l thyroidectomy for most PTCs >1 cm in diameter (25). However, this does not reﬂect recom- mendations in these guidelines (see Recommendation 35 on surgical management of malignant cytology nodules). Fur- thermore, long-term outcome data from a strategy of usingmolecular markers in indeterminate FNA specimens to stratify surgical approach are currently lacking. Use of a 167 GEC has been proposed as a rule-out test due to relatively high sensiti vity (92%) and NPV (93%), as reported in a prospective multicenter study (163). The relatively low speciﬁcity of the 167 GEC test (mean values48%–53% in indeterminate nodules subject to histopatho-logic conﬁrmation) suggests that the test cannot deﬁni- tively rule-in malignancy in indeterminate nodules. In a retrospective analysis of 167 GEC results from
ﬁve insti-tutions, Alexander et al. (171) reported that the prevalence of 167 GEC benign readings by institution varied up to 29%, which was not statistically signiﬁcant. The distribu-tion of recruitment from each of the ﬁve study sites was highly variable (total n=339 nodules), with two sites contributing only 30 and 37 patients, and the other threesites accounting for the majority of the study population. The prevalence of malignancy conﬁrmed by histopathology in 167 GEC ‘‘suspicious’’ nodules ranged from 33% to 80% inthe 48 nodules in the AUS/FLUS group across institutions (no 95% conﬁdence interval [95% CI] reported, p=0.11), and from 33% to 67% in the 65 nodules in the FN cytology group(no 95% CI reported, p=0.87) (171). For the 174 patients with 167 GEC ‘‘benign’’ readings, four patients were advised to undergo surgery (2%), and 41% (71 patients) of this group had short documented follow-up for a mean of 8.5
months (me-dian 8 months, range 1–24 months); ultimately, 6% of patients in this group (11/174) had surgery, with one histopatho- logically conﬁrmed malignancy (171). The reproducibilityof 167 GEC NPV measures in different populations of pa- tients with indeterminate cytology thyroid nodules has re- cently been questioned in three smaller, independent,unblinded studies (172–174). None of these studies reportedany degree of blinding. Furthermore, 95% CI of predictive estimates in indeterminate cytology nodules were not re- ported in two single-center studies (172,173), and onemulti-center study was reported to be a retrospective anal- ysis (174), making it difﬁcult to interpret the ﬁndings. However, such data highlight the need for additional inde-pendent research examining the reproducibility of diag- nostic efﬁcacy of the 167 GEC in more institutions, and the importance of reporting precision estimates for diagnosticaccuracy measures. Furthermore, as in the case of other molecular-based diagnostic tests in the ﬁeld, long-term outcome data from clinical
util ity studies are needed to in- form potential future clinical practice implications of the 167 GEC. Immunohistochemical stains such as galectin-3 and HBME-1 have been examined in multiple studies of histo-logically conﬁrmed thyroid FNA samples with indeterminate cytology, with reports of relatively high rates of speciﬁcity, but low sensitivity, for cancer detection (164,175,176). Twoof these studies were reported to be prospective (164,175), but only one of the studies reported any degree of blinding (blind central histopathologic review) (164). Immuno-histochemical stains require the availability of a cell block toperform the staining. Additional diagnostic molecular marker strategies are also under development. Speciﬁcally, mRNA markers (177–179), as well as miRNA markers (180–185), have shown initial diagnostic utility in FNA samples with in- determinate cytological diagnoses, but they have not been thoroughly validated. A recent study combining seven-genemutational testing with expression of a set of 10 miRNA genes on preoperative FNA sampling from
109 patients with AUS/ FLUS or FN cytology, showed 89% sensitivity, 85% speci-ﬁcity, with a 73% PPV and 94% NPV on this group with a 32% prevalence of malignancy (186). Finally, peripheral blood TSH receptor mRNA assay has been reported to have a 90% PPVand 39% NPV in FNA-based assessment of thyroid noduleswith atypical or suspicious cytology in a single-center, pro- spective validation study (187). In summary, there is currently no single optimal molecular test that can deﬁnitively rule in or rule out malignancy in all cases of indeterminate cytology, and long-term outcome data proving clinical utility are needed. &RECOMMENDATION 14 If intended for clinical use, molecular testing should be per-formed in Clinical Laboratory Improvement Amendments/ College of American Pathologists (CLIA/CAP)-certiﬁed molecular laboratories, or the international equivalent,20 HAUGEN ET AL.
because reported quality assurance practices may be superior compared to other settings. (Strong recommendation, Low-quality evidence) Many molecular marker tests are available in hospital-based molecular pathology laboratories and in reference laboratories. Importantly, all molecular marker tests intended for clinical use should be performed only in CLIA/CAP-certiﬁed molecularlaboratories after appropriate analytical and clinical validation of all assays in each laboratory (158). In a survey of American molecular genetic testing laboratory directors, laboratory pro-cess quality assurance score (for multiple relevant domains) was associated with the presence of CLIA certiﬁcation (188). In a large, international survey of medical genetic testing labo-ratory directors, accreditation of the laboratory was associatedwith a higher quality assurance index score (189). [A17] AUS/FLUS cytology &RECOMMENDATION 15 (A) For nodules with AUS/FLUS cytology, after consider- ation of worrisome clinical and sonographic features, in- vestigations such as repeat FNA or molecular testing may beused to supplement malignancy risk assessment in lieu
ofproceeding directly with a strategy of either surveillance or diagnostic surgery. Informed patient preference and feasi- bility should be considered in clinical decision-making. (Weak recommendation, Moderate-quality evidence)(B) If repeat FNA cytology, molecular testing, or both are not performed or inconclusive, either surveillance or di- agnostic surgical excision may be performed for an AUS/ FLUS thyroid nodule, depending on clinical risk factors,sonographic pattern, and patient preference. (Strong recommendation, Low-quality evidence) Based on the Bethesda System, this diagnostic category is reserved for specimens that contain cells with architectural and/ornuclear atypia that is more pronounced than expected for benign changes but not sufﬁcient to be placed in one of the higher risk diagnostic categories (99,190). Although this diagnostic categoryhas been recommended for limited use and has an expected frequency in the range of 7%, recent reports based on the Be- thesda System have found this cytologic diagnosis to be used in1%–27% of all
thyroid FNA samples (105,191). In studies that utilized the criteria established by the Bethesda System, the risk of cancer for patients with AUS/FLUS nodules who underwentsurgery was 6%–48%, with a mean risk of 16% (191). A second opinion review of the cytopathology slides by a high-volume cytopathologist may be considered for patients with AUS/FLUS cytology. There is some evidence that thisapproach may reclassify many of these patients into the be- nign and nondiagnostic categories (106,192). Furthermore, the overall diagnostic accuracy may be improved. Unfortunately,there is a relatively high intra-observer variability in this dif- ﬁcult diagnostic category (106). A repeat FNA yields a more deﬁnitive cytologic diagnosis in many cases, whereas 10%–30% of nodules are repeatedlyAUS/FLUS (104,193–195). The rate of malignancy on sur- gical follow-up has been shown to be similar for patients witha single AUS/FLUS diagnosis (37/90, 41%), two successive AUS/FLUS diagnoses (22/51, 43%), and patients with a be- nign
cytologic interpretation following the initial AUS/FLUSdiagnosis (2/7, 29%) (196). Use of thyroid core-needle bi-opsy was reported by some to be more informative than re- peated FNA for sampling nodules that were AUS/FLUS on initial FNA (119), and it is reasonably well-tolerated (197). The reﬁnement of risk stratiﬁcation of nodules with AUS/ FLUS cytology using molecular testing has been examined in multiple studies. The interpretation of molecular testing iscomplex, however, and its utility is strongly inﬂuenced by the prevalence of cancer in the tested population of nodules. Only two molecular tests have been separately evaluated and val-idated for the individual AUS/FLUS, FN, and SUSP cate-gories. Mutational testing for BRAF in AUS/FLUS samples has high speciﬁcity for cancer, but low sensitivity (198,199). Testing for a panel of mutations ( BRAF ,NRAS ,HRAS ,KRAS, RET/PTC1 ,RET/PTC3 ,PAX8/PPAR c) offers a signiﬁcantly higher sensitivity of 63%–80% (162,165). In the largest prospective study to date
of nodules with AUS/FLUS cytol-ogy (653 consecutive nodules, of which 247 had surgical follow-up) from a single institution, detection of any of these mutations using RT-PCR with ﬂuorescent melting curveanalysis was reported to convey an 88% risk of cancer among nodules with surgical follow-up; 63% of cancers on ﬁnal histopathology were identiﬁed with a positive mutation pre-operatively (22 of 35), and 94% of nodules that were negativeon mutation analysis had a benign ﬁnal histopathology (209 of 222) (162). Positive testing for BRAF, RET/PTC orPAX8/ PPAR cwas speciﬁc for a malignant outcome in 100% of cases, whereas RAS mutations had an 84% risk of cancer and a 16% chance of benign follicular adenoma. A recent study utilizing RT-PCR with liquid bead array ﬂow cytometry with the seven-gene mutation panel reported on 11 AUS/FLUS cytology nodules that had malignant histopathologic conﬁrmation, of which seven had a negative molecular test and four had
apositive test (167). There were also 11 AUS/FLUS cytologynodules, which were benign on histopathologic evaluation; 9 of 11 had a negative molecular test result and 2 of 11 had a positive result. Interpretation of results from the AUS/FLUSsubgroup is limited by the small reported sample size (167). Molecular testing using the 167 GEC has been studied for its diagnostic use in nodules with AUS/FLUS cytology. Amulti-institutional study of 129 FNA samples with AUS/ FLUS cytology and surgical follow-up reported a 90% sen- sitivity [95% CI 74%–98%] and 95% NPV [95% CI 85%–99%], but only a 53% speciﬁcity [95% CI 43%–63%] and 38% PPV [95% CI 27%–50%] for cancer (163). Although the speciﬁcity of the 167 GEC was low (53% [95% CI 43%–63%]), the negative test result was reported to decrease therisk estimate of malignancy in AUS/FLUS nodules in this study from 24% to 5%. This observation has led to a
clinical extrapolation suggesting that nodules that have a negative167 GEC test results may be followed without surgery (163). In a recent single-center retrospective study including 68 cases of AUS/FLUS nodules, 16 AUS/FLUS cases were re-ported to have a 167 GEC suspicious result, and the PPV was 61% (11 of 18) for those with surgical pathology conﬁrma- tion (200). There were insufﬁcient data to conﬁrm the NPV ofthe 167 GEC test for AUS/FLUS cytology, since the vast majority of patients with a benign 167 GEC test did not undergo surgery, and no long-term follow-up of such cases was reportedATA THYROID NODULE/DTC GUIDELINES 21
(200). In three other recent studies, there were insufﬁcient data for analysis in the AUS/FLUS subgroup to draw any mean- ingful conclusion on 167 GEC test performance in that sub-group (172–174). In addition, published follow-up for the 167GEC is currently limited to a mean of 8.5 months in a subgroup of 71 patients (171), hence long-term outcome data are needed to ensure durability of benign 167 GEC ﬁndings with corre-lation to clinical and histologic outcomes. Several recent studies (201–205) have examined the feasi- bility of using sonographic features to estimate risk of malig-nancy in nodules with AUS/FLUS cytology. The PPV of suspicious sonographic features has been estimated to range from 60% to 100% depending on the pretest probability ofmalignancy of AUS/FLUS cytology and the speciﬁc sono-graphic criteria selected in respective studies. A limitation of all of these studies is that a gold-standard surgical excisional di- agnosis was not required for
conﬁrmation of malignancy andlong-term follow-up data were generally lacking. The preva- lence of suspicious sonographic features among studies of AUS/ FLUS cytology nodules ranged from 18% to 50%, assumingthat one or more suspicious features were deemed to be sufﬁ- cient to be categorized as a sonographically suspicious nodule. The ﬁndings of these studies must be interpreted in the contextof each study’s overall risk of malignancy for this cytology classiﬁcation because of its effect on the PPVs obtained by subsequent application of sonographic features to cytologicallyAUS/FLUS nodules. From the four Korean studies (overallmalignancy rate 40%–55%), the reported cancer risk in AUS/ FLUS nodules with the high suspicion sonographic pattern is 90%–100% (201–204), and the presence of even one suspi-cious US feature (irregular margins, taller than wide shape, marked hypoechogenicity or microcalciﬁcations) increases the cancer risk to 60%–90%. However, when the reported cancerrate in AUS/FLUS nodules is lower [e.g., 23% in a
study from Brazil (205)], the high suspicion sonographic pattern still raises the risk of malignancy, but the PPV is lower at 70%. None-theless, the incidence of cancer in AUS/FLUS nodules witheither the high suspicion pattern US or just one suspicious US feature is signiﬁcantly higher than that generally accepted for this cytology category. In a secondary analysis of a retro-spective single-center study of indeterminate FNA specimens subject to 167 GEC testing, Lastra et al. studied whether re- examining US characteristics could assist in distinguishingmalignancy in indeterminate cytology nodules with a 167 GEC suspicious result (200). The presence of ‘‘nodular cal- ciﬁcations’’ or hyper- versus hypo-echogenicity did not alterthe prediction of malignancy. It is unclear whether this study was adequately powered because the analysis was limited to a subgroup of 48 cases for analysis of microcalciﬁcations and20 cases for analysis of echogenicity (200). Further researchis needed to examine the impact of
considering clinical and sonographic features on the potential utility and interpreta- tion of molecular testing of FNA specimens. [A18] Follicular neoplasm/suspicious for follicular neo- plasm cytology &RECOMMENDATION 16 (A) Diagnostic surgical excision is the long-established standard of care for the management of FN/SFN cytology nodules. However, after consideration of clinical andsonographic features, molecular testing may be used to supplement malignancy risk assessment data in lieu of proceeding directly with surgery. Informed patient pref-erence and feasibility should be considered in clinicaldecision-making. (Weak recommendation, Moderate-quality evidence)(B) If molecular testing is either not performed or incon- clusive, surgical excision may be considered for removal and deﬁnitive diagnosis of an FN/SFN thyroid nodule. (Strong recommendation, Low-quality evidence) This diagnostic category of the Bethesda System is used for cellular aspirates (i) comprised of follicular cells arranged in an altered architectural pattern characterized by cell crowding and/or microfollicle formation and lacking nuclearfeatures of papillary carcinoma or
(ii) comprised almost ex- clusively of oncocytic (Hu ¨rthle) cells (99,206,207). This is an intermediate risk category in the Bethesda System, with a15%–30% estimated risk of malignancy. Studies that applied the Bethesda System reported the use of this diagnostic cat- egory in 1%–25% (mean, 10%) of all thyroid FNA samples,with the risk of cancer on surgery found to range from 14% to 33% (mean, 26%) (191). The reﬁnement of risk stratiﬁcation of nodules with FN/ SFN/Hu ¨rthle cell neoplasm cytology has been examined using ancillary molecular testing. Testing for a seven-gene panel of mutations (including BRAF ,RAS,RET/PTC ,a n d / PPAR c)i n nodules with follicular or Hu ¨rthle cell neoplasm or SFN has been reported to be associated with a sensitivity of 57%–75%, speciﬁcity of 97%–100%, PPV of 87%–100%, and NPV of 79%–86% (162,165). Many of these benign tumors are follic-ular adenomas driven by oncogenic RAS mutation with
un- certain malignant potential (208). Nodules lacking all of these mutations still have a substantial cancer risk, which is due to thepresence of a subset of tumors that lack any of the mutationstested by this seven-gene panel (162). Expansion of the current panels to include additional mutations and gene rearrangements with this next-generation sequencing assay was associated witha sensitivity of 90% [95% CI 80%–99%], speciﬁcity of 93% [95% CI 88%–98%], PPV of 83% [95% CI 72%–95%], and NPV of 96% [95% CI 92%–100%] in a recent single-centerstudy of 143 consecutive FN/SFN FNA specimens with known surgical outcomes. In this study (170), retrospective ( n=91) and prospective data ( n=52) were combined. A limitation was that the pathologists reviewing the surgical specimens were aware of earlier generation molecular marker seven-gene panel test results, although they were blinded to results of the next-generation mutation panel (162,170). Given the overlap ofsome of the
markers detected in earlier and later generation assays, there is a potential for bias (170), and the results need to be replicated in other studies. Molecular testing using the GEC was reported to have a 94% NPV [95% CI 79%–99%], and a 37% PPV [95% CI 23%–52%] in the FN/SFN/Hu ¨rthle cell neoplasm Bethesda subgroup (163). A recent unblinded study from the Mayo Clinic utilizing a prospective patient registry reported the following diagnostic accuracy estimates in a subgroup of 31indeterminate nodules from the same Bethesda subgroup that were subject to histopathologic conﬁrmation: sensitivity 80% (four of ﬁve nodules), speciﬁcity 12% (3 of 26 nodules), PPV22 HAUGEN ET AL.
15% (4 of 27), and NPV 75% (three of four) (173). In a single- center retrospective study including 64 nodules subjected to 167 GEC testing and a cytology read as FN/FN with oncocyticfeatures, the PPV for a suspicious GEC result was 37% (11 of30), although the PPV was signiﬁcantly higher in the FN group (53%) compared with the FN with oncocytic features group (15%) (200). There were insufﬁcient numbers of pa-tients with benign 167 GEC results who underwent surgery to draw conclusions on NPV; moreover, no long-term follow-up data were reported (200). The relatively small number of in-determinate nodules is an important limitation. Furthermore, precision estimates (95% CIs) for the diagnostic accuracy measures were not reported but could be assumed to be rel-atively wide given the small sample size (173,200). [A19] Suspicious for malignancy cytology &RECOMMENDATION 17 (A) If the cytology is reported as suspicious for papillarycarcinoma (SUSP), surgical management
should be simi- lar to that of malignant cytology, depending on clinical risk factors, sonographic features, patient preference, andpossibly results of mutational testing (if performed). (Strong recommendation, Low-quality evidence)(B) After consideration of clinical and sonographic features, mutational testing for BRAF or the seven-gene mutation marker panel ( BRAF ,RAS,RET/PTC ,PAX8/ PPAR c) may be considered in nodules with SUSP cytology if such data would be expected to alter surgical decision- making. (Weak recommendation, Moderate-quality evidence) This diagnostic category of the Bethesda System is reserved for aspirates with cytologic features that raise a strong suspi- cion for malignancy (mainly for PTC) but are not sufﬁcient fora conclusive diagnosis (99,209). This is the highest risk cate-gory of indeterminate cytology in the Bethesda System, with an estimated cancer risk of 60%–75% (209). Studies that uti- lize the Bethesda System have reported this cytologic diag-nosis in 1%–6% of thyroid FNAs and found malignancy after
surgery in 53%–87% (mean, 75%) of these nodules (191). Due to the high risk of cancer, the diagnosis of suspicious forpapillary carcinoma is an indication for surgery. Mutational testing has been proposed to reﬁne risk prior to surgery, assuming that surgical management would changebased on a positive test result. BRAF mutations have been reported to confer close to 100% probability of malignancy (162,198,210,211). Testing for BRAF mutations in nodules suspicious for malignancy has been reported to have a sen-sitivity of 36% (10 of 28) and speciﬁcity of 100% (24 of 24) in a single-center retrospective study (162). In another single center retrospective study in which FNA slides deemed to besuspicious for PTC were tested after surgery, the sensitivity of BRAF testing for PTC was 45.5% (15 of 33), and speciﬁcity was 85.7% (12 of 14) (212). Testing for a seven-gene panel ofmutations (including BRAF ,RAS,RET/PTC , with or without PAX8/PPAR
c) in nodules with cytology suspicious for ma- lignancy is associated with a sensitivity of 50%–68%, speci-ﬁcity of 86%–96%, PPV of 80%–95%, and NPV of 72%–75%in respective single-center studies (162,165,168). Molecular testing using the 167 GEC has a PPV that is similar to cytol- ogy alone (76%) and a NPV of 85% (163), and it is thereforenot indicated in patients with this cytologic diagnosis. [A20] What is the utility of18FDG-PET scanning to predict malignant or benign disease when FNAcytology is indeterminate (AUS/FLUS, FN, SUSP)? &RECOMMENDATION 18 18FDG-PET imaging is not routinely recommended for the evaluation of thyroid nodules with indeterminate cytology. (Weak recommendation, Moderate-quality evidence) Eight studies have been performed and are the subject of two meta-analyses (213–222). While early data suggested a high NPV for18FDG-PET in this setting, most studies failed to use the Bethesda System for Reporting Thyroid Cyto-pathology and included numerous small nodules <1c m i n
diameter (221). A recent meta-analysis included seven studies, of which ﬁve were prospective (222). The cancerprevalence was 26% inclusive of all combined data, con- ﬁrming a typical study cohort. Sensitivity and speciﬁcity of 18FDG-PET were 89% and 55%, respectively, resulting in a 41% PPV and 93% NPV, which is similar to the perfor-mance of the 167 GEC. Vriens et al. (223) performed a cost- effectiveness analysis using18FDG-PET performance data from their own meta-analysis and 2012 reimbursement ratesof the Dutch system. They showed that18FDG-PET was more cost effective than surgery, the 167 GEC, or mutational testing. A recent prospective analysis of 56 nodules with indetermi-nate FNA cytology used both18FDG-PET and thyroid US to further evaluate the nodules (220). In a multivariate analy- sis, the authors demonstrated no additional diagnostic beneﬁtor improved risk assessment when adding18FDG-PET to that already obtained from thyroid US, bringing into question the incremental beneﬁt of PET imaging
in patients with cytolog- ically indeterminate thyroid nodules. [A21] What is the appropriate operation for cytologically indeterminate thyroid nodules? &RECOMMENDATION 19 When surgery is considered for patients with a solitary, cytologically indeterminate nodule, thyroid lobectomy isthe recommended initial surgical approach. This approach may be modiﬁed based on clinical or sonographic char- acteristics, patient preference, and/or molecular testingwhen performed (see Recommendations 13–16). (Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 20 (A) Because of increased risk for malignancy, total thyroidectomy may be preferred in patients with indeter- minate nodules that are cytologically suspicious for ma- lignancy, positive for known mutations speciﬁc forcarcinoma, sonographically suspicious, or large ( >4 cm), or in patients with familial thyroid carcinoma or history of radiation exposure, if completion thyroidectomy would beATA THYROID NODULE/DTC GUIDELINES 23
recommended based on the indeterminate nodule being malignant following lobectomy. (Strong recommendation, Moderate-quality evidence) (B) Patients with indeterminate nodules who have bilateral nodular disease, those with signiﬁcant medical co- morbidities, or those who prefer to undergo bilateral thy-roidectomy to avoid the possibility of requiring a future surgery on the contralateral lobe, may undergo total or near-total thyroidectomy, assuming completion thyroid-ectomy would be recommended if the indeterminate nodule proved malignant following lobectomy. (Weak recommendation, Low-quality evidence) The primary goal of thyroid surgery for a thyroid nodule that is cytologically indeterminate (AUS/FLUS or FN orSUSP) is to establish a histological diagnosis and deﬁnitive removal, while reducing the risks associated with remedial surgery in the previously operated ﬁeld if the nodule proves tobe malignant. Surgical options to address the nodule should be limited to lobectomy (hemithyroidectomy) with or without isthmusectomy, near-total thyroidectomy (removal of allgrossly visible thyroid tissue, leaving only a small amount
[<1 g] of tissue adjacent to the recurrent laryngeal nerve near the ligament of Berry), or total thyroidectomy (removal of allgrossly visible thyroid tissue). Removal of the nodule alone,partial lobectomy, and subtotal thyroidectomy, leaving >1g of tissue with the posterior capsule on the uninvolved side, are inappropriate operations for possible thyroid cancer (224). Decisions regarding the extent of surgery for indeterminate thyroid nodules are inﬂuenced by several factors (225), in- cluding the estimated presurgical likelihood of malignancybased upon clinical risk factors ( >4 cm, family history, and/or history of radiation) (226–229), sonographic pattern (Table 6, Fig. 2) (202–203), cytologic category (Table 8), and ancillarytest ﬁndings (see molecular testing section [A15–19]). Theserisk factors, as well as patient preference, presence of con- tralateral nodularity or coexistent hyperthyroidism, and medical comorbidities, impact decisions regarding thyroidlobectomy with the possible need for subsequent completion thyroidectomy versus total thyroidectomy up front. Nodules that are cytologically classiﬁed
as AUS/FLUS or FN and benign using the 167 GEC, or AUS/FLUS and neg- ative using the seven-gene mutation panel have an estimated 5%–6% risk of malignancy (162,163). Nodules that are cyto-logically classiﬁed as FN and negative using the seven-gene mutation panel have an estimated 14% risk of malignancy, which is slightly lower than the risk based upon the Bethesdaclassiﬁcation alone (162). Nodules that are cytologically classiﬁed as AUS/FLUS or FN and as suspicious using the 167 GEC have an estimated 37%–44% risk of malignancy, which is slightly higher thanthe risk based upon the Bethesda classiﬁcation alone (Table 8) (163,171). Nodules that are cytologically classiﬁed as SUSP cytology and benign using the 167 GEC or negative using the mutation seven-gene panel, also have an estimated 15%–28% risk of malignancy. In contrast, nodules that are cytologically classiﬁed as AUS/FLUS or FN and that are positive for known RAS mu- tations associated
with thyroid carcinoma have an estimated84% risk of malignancy and should be considered in a similar risk category to cytologically suspicious for malignancy (Table 8) (103,230). Nodules that are cytologically classiﬁedas AUS/FLUS or FN or SUSP and that are positive for knownBRAF V600E,RET/PTC ,o rPAX8/PPAR cmutations have an estimated risk of malignancy of >95% and should be con- sidered in a similar category to cytologically diagnosedthyroid carcinoma (198,210,211). Sonographic pattern of nodules with AUS/FLUS cytology may aid in risk stratiﬁcation and management. In one study,sonographically benign or seemingly very low risk nodules with AUS/FLUS cytology were noted to be malignant in only 8% of cases, compared to 58% when sonographic sus-picious was low or intermediate, and 100% when sono-graphic suspicion of malignancy was high (203). Another study supported this ﬁnding with sonographic ﬁndings highly suspicious for malignancy (taller than wide shape, irregularborders, and/or marked hypoechogenicity) having >90% speciﬁcity and PPV
for malignancy (202). The risks of total thyroidectomy are signiﬁcantly greater than that for thyroid lobectomy, with a recent meta-analysis suggesting a pooled relative risk (RR) signiﬁcantly greater for all complications, including recurrent laryngeal nerve in-jury (transient RR =1.7, permanent RR =1.9), hypocalcemia (transient RR =10.7, permanent RR =3.2), and hemorrhage/ hematoma (RR =2.6) (231). Further, total thyroidectomy is associated with the rare but potential risk of bilateral recurrentlaryngeal nerve injury necessitating tracheostomy. Surgeon experience likely inﬂuences the risks of thyroidectomy, with higher volume surgeons having lower complication rates(232,233). Total thyroidectomy necessitates thyroid hormone re- placement, while lobectomy is associated with an incidenceof postoperative biochemical hypothyroidism estimated at 22%, with clinical or overt hypothyroidism estimated at 4% (234). A signiﬁcantly increased risk of hypothyroidism fol-lowing lobectomy has been reported in the presence of auto-immune thyroid disease (e.g., as reﬂected by the presence of thyroid antibodies) or high normal/elevated TSH (231,234).
Hypothyroidism is not an indication for thyroidectomy, andits use as justiﬁcation for total thyroidectomy over lobectomy should be weighed against the higher risks associated with total thyroidectomy. In contrast, coexistent hyperthyroidismmay be an indication for total thyroidectomy depending upon the etiology. Thyroid lobectomy (hemithyroidectomy) provides deﬁni- tive histological diagnosis and complete tumor removal for cytologically indeterminate nodules with a lower risk of complications compared to total thyroidectomy and may besufﬁcient for smaller, solitary intrathyroidal nodules that ul-timately prove malignant. As the likelihood of malignancy increases, the potential need for a second operation also in- creases, if the cytologically indeterminate nodule ultimatelyproves malignant and if completion thyroidectomy would be recommended. Intraoperative evaluation, with or without frozen section, can occasionally conﬁrm malignancy at thetime of lobectomy allowing for conversion to total thyroid- ectomy if indicated. Frozen section is most helpful if the histopathologic diagnosis is classic PTC, whereas its impactis low in
follicular variant of PTC and FTC. The individual patient must weigh the relative advantages and disadvantages of thyroid lobectomy with possible total thyroidectomy or24 HAUGEN ET AL.
subsequent completion thyroidectomy versus initial total thyroidectomy. [A22] How should multinodular thyroid glands (i.e., two or more clinically relevant nodules) be evaluated for malignancy? &RECOMMENDATION 21 (A) Patients with multiple thyroid nodules ‡1 cm should be evaluated in the same fashion as patients with a solitary nodule ‡1 cm, excepting that each nodule that is >1c m carries an independent risk of malignancy and thereforemultiple nodules may require FNA. (Strong recommendation, Moderate-quality evidence) (B) When multiple nodules ‡1 cm are present, FNA should be performed preferentially based upon nodule sono- graphic pattern and respective size cutoff (Table 6, Fig. 2). (Strong recommendation, Moderate-quality evidence) (C) If none of the nodules has a high or moderate suspicion sonographic pattern, and multiple sonographically similar very low or low suspicion pattern nodules coalesce with no intervening normal parenchyma, the likelihood of malig-nancy is low and it is reasonable to aspirate the largest nodules
( ‡2 cm) or continue surveillance without FNA. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 22 A low or low-normal serum TSH concentration in patients with multiple nodules may suggest that some nodule(s) may be autonomous. In such cases, a radionuclide (pref- erably123I) thyroid scan should be considered and directly compared to the US images to determine functionality of each nodule ‡1 cm. FNA should then be considered only for those isofunctioning or nonfunctioning nodules, amongwhich those with high suspicion sonographic patternshould be aspirated preferentially. (Weak recommendation, Low-quality evidence) Patients with multiple thyroid nodules have the same risk of malignancy as those with solitary nodules (32,74). How- ever, when evaluating the risk of cancer per individual nod- ule, one large study found that a solitary nodule had a higherlikelihood of malignancy than did a nonsolitary nodule (p<0.01), although in agreement with the other studies the risk of malignancy per patient was the
same and independentof the number of nodules (77). A recent systematic reviewand meta-analysis conﬁrmed the slightly higher risk of ma- lignancy in a solitary nodule compared with an individual nodule in a MNG. However, this appeared to hold true mostlyoutside of the United States and in iodine-deﬁcient popula- tions (235). A diagnostic US should be performed to evaluate the sonographic risk pattern of each nodule, but if only the‘‘dominant’’ or largest nodule is aspirated, the thyroid cancer may be missed (74). Therefore, multiple thyroid nodules ‡1 cm may require aspiration, based on sonographic pattern (Recommendation 8, Table 6, Fig. 2) to fully exclude clini-cally relevant thyroid cancer. Radionuclide scanning may also be considered in patients with multiple thyroid noduleswith the goal of identifying and aspirating appropriate hy- pofunctioning nodules. Such imaging may prove especially useful when the serum TSH is below or in the low-normalrange. Similarly, sonographic risk assessment of
each nodulecan assist in identifying those nodules with the highest like- lihood of cancer (see section [A10]). [A23] What are the best methods for long-term follow-up of patients with thyroid nodules? [A24] Recommendations for initial follow-up of nodules with benign FNA cytology &RECOMMENDATION 23 Given the low false-negative rate of US-guided FNA cy- tology and the higher yield of missed malignancies based upon nodule sonographic pattern rather than growth, the follow-up of thyroid nodules with benign cytology diag-noses should be determined by risk stratiﬁcation based upon US pattern. (A) Nodules with high suspicion US pattern: repeat US and US-guided FNA within 12 months. (Strong recommendation, Moderate-quality evidence)(B) Nodules with low to intermediate suspicion US pat- tern: repeat US at 12–24 months. If sonographic evidenceof growth (20% increase in at least two nodule dimensions with a minimal increase of 2 mm or more than a 50% change in volume) or development
of new suspicious so-nographic features, the FNA could be repeated or obser- vation continued with repeat US, with repeat FNA in case of continued growth. (Weak recommendation, Low-quality evidence)(C) Nodules with very low suspicion US pattern (including spongiform nodules): the utility of surveillance US andassessment of nodule growth as an indicator for repeat FNA to detect a missed malignancy is limited. If US is repeated, it should be done at ‡24 months. (Weak recommendation, Low-quality evidence) [A25] Recommendation for follow-up of nodules with two benign FNA cytology results (D) If a nodule has undergone repeat US-guided FNA with a second benign cytology result, US surveillance for this nod- ule for continued risk of malignancy is no longer indicated. (Strong recommendation, Moderate-quality evidence) Given that there is a low but discrete false-negative rate for nodules with benign FNA cytology results, is there an opti- mal way to identify these missed malignancies?
Although therisk of malignancy after two benign cytology results is vir- tually zero (129–133,236), routine rebiopsy is not a viable or cost-effective option because of the low false-negative rate ofan US-guided FNA benign cytology result. Prior guidelines have recommended repeat FNA for nodules that grow during serial sonographic observation. However, nodule growthcan be variably deﬁned. Because of interobserver variation,Brauer et al. (237) reported a 50% increase in nodule volume as the minimally signiﬁcant reproducibly recorded change inATA THYROID NODULE/DTC GUIDELINES 25
nodule size, which is equivalent to a 20% increase in two of the three nodule dimensions. If a 50% volume increase cutoff is applied, only 4%–10% of nodules were reportedto be larger at a mean of 18 months (133,238). However,using cutoffs of a 15% volume increase based upon inter- nally assessed interobserver co efﬁcients of variation, pub- lished series report that 32%–50% of nodules increase insize over a 4–5 year period (239,240). Because of the stringent methodology of these studies, adoption of a 15% volume increase as statistically signiﬁcant is not practically applicable. A recent 5-year prospective multicenter study evaluated outcomes of 1597 nodules from 992 patients with either cy-tologically or sonographically benign nodules (241). Nodules1 cm or larger underwent US-guided FNA and subcentimeter nodules were deﬁned as sonographically benign based upon imaging characteristics equivalent to the ATA low or verylow suspicion US patterns. All nodules were followed by annual
US exams. The false-negative rate of a benign cy- tology diagnosis was 1.1%. Of the four missed cancers, onbaseline US imaging three were hypoechoic and solid and one was isoechoic with microcalciﬁcations; none was spon- giform or mixed cystic solid and noncalciﬁed (ATA very lowsuspicion pattern). During sonographic surveillance, repeat FNA was prompted by either growth (two nodules) or de- velopment of a new suspicious sonographic feature (twonodules). In addition, the shortest time interval to detectchange and repeat the FNA was 2 years. Another critical observation from this study was that only one cancer was detected in 5 years among the 852 subcentimeter nodulesclassiﬁed as sonographicially benign at baseline. This cancer was identiﬁed on the 5-year follow-up US, when its com- position changed from mixed cystic/solid to hypoechoic solidwith irregular margins prompting FNA (241). Currently, there are no follow-up studies of nodule growth that extend observation beyond 5 years to
help inform decision-makingabout long-term surveillance. Additional research would bevaluable because indeﬁnite follow-up of nodules with benign cytology is costly and may be unnecessary. Recent investigations of repeat US-guided FNA in nodules with initial benign cytology show higher detection rates for missed malignancy for those nodules with a high suspicion so- nographic pattern rather than size increase (236,242). Kwak et al. (236) reported a signiﬁcantly higher malignancy rate of 20.4% in nodules with benign cytology that exhibited either marked hy- poechogenicity, irregular border s, microcalciﬁcat ions, or a taller than wide shape versus a 1.4% risk in those that exhibited a 15% volume increase but lacked these US features. Importantly, the low risk of malignancy did not differ between US negativenodules that grew and those that demonstrated no interval sizechange (1.4% vs. 0.5%, p=0.18). Similarly, Rosario et al. (242) detected cancer in 17.4% of nodules with benign cytologic di- agnoses and
suspicious US features versus 1.3% of those withoutsuspicious characteristic that grew, using criteria of a 50% vol- ume increase. These studies indicate that the use of suspi- cious US characteristics rather than nodule growth shouldbe the indication for repeat FNA despite an initial benign cytology diagnosis. Repeat US and FNA should be repeated within 12 months as guided by clinical judgement. Giventhe low false-negative rate of US-guided FNA cytology and the higher yield of missed malignancies based upon nodule sonographic pattern rather than growth, the follow-up ofthyroid nodules with benign cytology diagnoses should be determined by risk stratiﬁcation based upon US pattern as deﬁned in Recommendation 8. If follow-up US for surveil-lance is performed and the nodule size is stable, the utility ofsubsequent US imaging for detection of potential malignancy by nodule growth assessment is very low and if performed, the time interval for any additional US exam should be
at least aslong that between the initial benign FNA cytology result and ﬁrst follow-up. However, even if a repeat US is not indicated based on a benign cytology, US pattern, or stability in nodulesize, larger nodules may require monitoring for growth that could result in symptoms and thus prompt surgical interven- tion despite benign cytology. One recent study evaluated the long-term consequences of a false-negative benign cytology (140). A total of 1369 pa- tients with 2010 cytologically benign thyroid nodules were followed for a mean of 8.5 years. Eighteen false-negativecases were identiﬁed, although only a subset of patients un- derwent repeat FNA or thyroid surgery. Thirty deaths were documented in the entire cohort over this time period andnone were attributable to thyroid cancer. These data sup- port that an initial benign cytology conveys an overall ex- cellent prognosis and a conservative follow-up strategy isreasonable. [A26] Follow-up for nodules that do
not meet FNA criteria &RECOMMENDATION 24 Nodules may be detected on US that do not meet criteriafor FNA at initial imaging (Recommendation 8). Thestrategy for sonographic follow-up of these nodules should be based upon the nodule’s sonographic pattern. (A) Nodules with high suspicion US pattern: repeat US in 6–12 months. (Weak recommendation, Low-quality evidence)(B) Nodules with low to intermediate suspicion US pat- tern: consider repeat US at 12–24 months. (Weak recommendation, Low-quality evidence)(C) Nodules >1 cm with very low suspicion US pattern (including spongiform nodules) and pure cyst: the utility and time interval of surveillance US for risk of malignancy is not known. If US is repeated, it should be at ‡24 months. (No recommendation, Insufﬁcient evidence)(D) Nodules £1 cm with very low suspicion US pattern (including spongiform nodules) and pure cysts do not re-quire routine sonographic follow-up. (Weak recommendation, Low-quality evidence) Ultrasound studies demonstrate that up to 50% of
adults have thyroid nodules. The vast majority of these are subcentimeter, and FNA evaluation is generally not indicated. In addition, based upon both sonographic pattern and size cutoffs (Re-commendation 8), many nodules >1 cm may also be followed without FNA. Although no prospective studies address the optimal cost-effective surveillance strategy for these nodulesthat have not undergone FNA, a recent study by Durante et al. (241) conﬁrms that subcentimeter thyroid nodules corre- sponding to the ATA very low suspicion risk pattern are highly26 HAUGEN ET AL.
unlikely to change during 5-year sonographic follow-up, and the risk of malignancy is exceedingly low. The ﬁndings from studies correlating sonographic features and malignancy risk inaspirated nodules can be extrapolated to inform a follow-upstrategy for this group of nodules that do not meet FNA criteria at the time of their initial detection. For example, the interval for follow-up sonography for a nodule that is hypoechoic andtaller than wide should be shorter than that for an isoechoic solid nodule with smooth borders. US-guided FNA should be performed based upon follow- up US imaging if the nodule subsequently meets criteria based upon Recommendation 8. [A27] What is the role of medical or surgical therapy for benign thyroid nodules? &RECOMMENDATION 25 Routine TSH suppression therapy for benign thyroid nod- ules in iodine sufﬁcient populations is not recommended.Though modest responses to therapy can be detected, thepotential harm outweighs beneﬁt for most patients. (Strong recommendation,
High-quality evidence) &RECOMMENDATION 26 Individual patients with benign, solid, or mostly solid nodules should have adequate iodine intake. If inadequate dietary intake is found or suspected, a daily supplement (containing 150 lg iodine) is recommended. (Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 27 (A) Surgery may be considered for growing nodules that are benign after repeat FNA if they are large ( >4 cm), causing compressive or structural symptoms, or based upon clinical concern. (Weak recommendation, Low-quality evidence)(B) Patients with growing nodules that are benign after FNA should be regularly monitored. Most asymptomaticnodules demonstrating modest growth should be followed without intervention. (Strong recommendation, Low-quality evidence) &RECOMMENDATION 28 Recurrent cystic thyroid nodules with benign cytology should be considered for surgical removal or percutaneousethanol injection (PEI) based on compressive symptoms and cosmetic concerns. Asymptomatic cystic nodules may be followed conservatively. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 29 There are no data to guide recommendations on
the use of thyroid hormone therapy in patients with growing nodulesthat are benign on cytology. (No recommendation, Insufﬁcient evidence) Evidence from multiple prospective, RCTs, and from three meta-analyses suggest that thyroid hormone supplementationin doses that suppress the serum TSH to subnormal levels may result in a decrease in nodule size and may prevent the appearance of new nodules in regions of the world withborderline low iodine intake (239,243–245). However, theeffect is modest, with most studies suggesting an average 5%–15% reduction in nodule volume when treated with suppressive levothyroxine (LT 4) therapy for 6–18 months. Two high-quality meta-analyses conﬁrm that six to eight pa- tients will require suppressive LT 4therapy to achieve one successful treatment response (246,247). The extent of TSHsuppression achieved in high-quality studies is variable, though the majority suppressed TSH to <0.2 mIU/L, with many to <0.1 mIU/L. Hyperthyroidism to this degree has been signiﬁcantlyassociated with an increased risk
of cardiac arrhythmias andosteoporosis, as well as adverse symptomatology. Together, t h e s ed a t ac o n ﬁ r mt h a tL T 4suppressive therapy demonstrates modest (though usually clinically insigniﬁcant) efﬁcacy innodule volume reduction, but increases the risk of adverse consequences related to iatrogenic thyrotoxicosis. One large prospective, randomized trial demonstrated that sufﬁcient die-tary iodine intake (150 lg daily) also reduced nodule size slightly more than placebo (248). The consumption of adequate dietary iodine is recommended for all adults and is without harmwhen not excessive. Data supporting LT 4t h e r a p yi nn o n – T S H - suppressive doses for prevention of thyroid nodule growth are incomplete. One recent cohort analysis suggested non-suppressive doses of LT 4therapy conferred protection from nodule growth over time (249). However, the nonblinded, non- randomized nature of the trial precludes broad translation of the
data, and the efﬁcacy of nonsuppressive LT 4remains unproven. Cystic nodules that are cytologically benign can be monitored for recurrence (ﬂuid reaccumulation), which can be seen in 60%–90% of patients (250,251). For those patients with subse-quent recurrent symptomatic cyst ic ﬂuid accumulation, surgical removal, generally by hemithyroidectomy, or PEI are both rea- sonable strategies. Four controlled studies demonstrated a 75%–85% success rate after PEI compared with a 7%–38% successrate in controls treated by simple cyst evacuation or saline in- jection. Success was achieved after an average of two PEI treatments. Complications included mild to moderate local pain,ﬂushing, dizziness, and dysphonia (250–253). Surgery may be considered for growing solid nodules that are benign on repeat cytology if they are large ( >4 cm), causing compressive or structural symptoms, or based upon clinical concern (254,255). [A28] How should thyroid nodules in pregnant women be managed? [A29] FNA for thyroid nodules discovered during
preg- nancy &RECOMMENDATION 30 (A) FNA of clinically relevant thyroid nodules (refer to section [A10]) should be performed in euthyroid and hy- pothyroid pregnant women. (Strong recommendation, Moderate-quality evidence)(B) For women with suppressed serum TSH levels that persist beyond 16 weeks gestation, FNA may be deferreduntil after pregnancy and cessation of lactation. At thatATA THYROID NODULE/DTC GUIDELINES 27
time, a radionuclide scan can be performed to evaluate nodule function if the serum TSH remains suppressed. (Strong recommendation, Moderate-quality evidence) It is uncertain if thyroid nodules discovered in pregnant women are more likely to be malignant than those found in nonpregnant women, since there are no population-based studies to address this question. Pregnancy does not appear tomodify microscopic cellular appearance, thus standard diag- nostic criteria should be applied for cytologic evaluation (256). Serial evaluation of nodules throughout pregnancy has dem-onstrated that thyroid nodules will enlarge slightly throughout gestation, though this does not imply malignant transformation (257). The recommended evaluation of a clinically relevantnodule in a pregnant patient is thus the same as for a non-pregnant patient, with the exception that a radionuclide scan is contraindicated. In addition, for patients with nodules diag- nosed as DTC by FNA during pregnancy, delaying surgeryuntil after delivery does not affect outcome (258). Surgery
performed during pregnancy is associated with greater risk of complications, longer hospital stays, and higher costs (259). [A30] Approaches to pregnant patients with malignant or indeterminate cytology &RECOMMENDATION 31 PTC discovered by cytology in early pregnancy should be monitored sonographically. If it grows substantially(as deﬁned in section [A24]) before 24–26 weeks ges- tation, or if US reveals cervical lymph nodes that are suspicious for metastatic disease, surgery should beconsidered during pregnancy. However, if the disease remains stable by midgestation, or if it is diagnosed in the second half of pregnancy, surgery may be de-ferred until after delivery. (Weak recommendation, Low-quality evidence) If FNA cytology is consistent with PTC, surgery is gener- ally recommended. However, the decision to performsuch surgery either during pregnancy or after delivery must be individualized. If surgery is not performed, the utility of thyroid hormone therapy targeted to lower serum TSH levelsto improve the prognosis of thyroid
cancer diagnosed during gestation is not known. Because higher serum TSH levels may be correlated with a more advanced stage of cancer at surgery(260), if the patient’s serum TSH is >2 mU/L, it may be rea- sonable to initiate thyroid hormone therapy to maintain the TSH between 0.3 to 2.0 mU/L for the remainder of gestation. Most data conﬁrm that the prognosis of women with well- differentiated thyroid cancer identiﬁed but not treated during pregnancy is similar to that of nonpregnant patients. Because of this, surgery in most pregnant patients is deferred untilpostpartum (258,261), and no further testing is required. However, some studies differ from these ﬁndings. Two Ital- ian cohort studies have investigated women diagnosed withDTC in relation to the timing of pregnancy. Messuti et al. (262) noted a statistically higher rate of persistence/recur- rence when DTC was diagnosed during pregnancy or within 2years postpartum. However, the stimulated Tg
was found tobe>10 ng/mL during 131I ablation in many cases, suggesting the extent of thyroidectomy and/or tumor resection may havebeen limited in this cohort and therefore contributed to bio- chemical persistence of disease. Vannucchi et al. (263) fol- lowed a small cohort of 10 patients with DTC duringpregnancy or within 1 year post partum, again noting a largerate of persistent disease (60%) compared to nonpregnant controls (4.2%–13.1%). Similarly, the majority of cases with persistent disease were attributable to biochemical elevationsin Tg or anti-Tg antibodies, again raising the question of whether the extent of initial resection was limited in com- parison to nonpregnant controls. Given the likelihood thatbiochemical persistence could be attributable to an increased size of remnant tissue or incomplete surgical resection in both studies, these data should not refute previous, larger analysesshowing no increased recurrence rates when DTC is diag-nosed during pregnancy. Theoretically, molecular marker analysis could be helpful
in the evaluation of DTC or clinically relevant, cytologicallyindeterminate thyroid nodules detected during pregnancy. However, the application of molecular testing in pregnant women with indeterminate cytology remains uncertain.There are no published data validating the performance of any molecular marker in this population. Therefore, the committee cannot recommend for or against their use inpregnant women. However, it is theoretically possible that changes in a nodule’s RNA expression may occur during gestation altering performance of the 167 GEC while theseven-gene mutational panel ( BRAF ,RAS,PAX8/PPAR c, RET/PTC ) would be more likely to demonstrate similar performance to that of a nonpregnant population. When surgery is advised during pregnancy, it is most often because of high-risk clinical or sonographic ﬁndings, nodule growth, or change over short duration follow-up or it is based upon physician judgement. To minimize the risk ofmiscarriage, surgery during pregnancy should be done in the second trimester before 24 weeks
gestation (264). However, PTC discovered during pregnancy does not behave moreaggressively than that diagnosed in a similar-aged group ofnonpregnant women (258,265). A retrospective study of pregnant women with DTC found no difference in either recurrence or survival rates b etween women operated dur- ing or after pregnancy (258). Further, retrospective data suggest that treatment delays of <1 year from the time of thyroid cancer discovery do not adversely affect patientoutcome (266). A separate study reported a higher rate of complications in pregnant women undergoing thyroid sur- gery compared with nonpregnant women (267). If FNAcytology is indeterminate, monitoring may be considered with further evaluation may be delayed until after delivery. Some experts recommend thyroid hormone suppressiontherapy for pregnant women with FNA suspicious for ordiagnostic of PTC, if surgery is deferred until the postpar- tum period (259). [B1] DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT GUIDELINES Differentiated thyroid cancer, arising from thyroid follic- ular
epithelial cells, accounts for the vast majority of thyroid cancers. Of the differentiated cancers, papillary cancercomprises about 85% of cases compared to about 12% that have follicular histology, including conventional and onco- cytic (Hu ¨rthle cell) carcinomas, and <3% that are poorly28 HAUGEN ET AL.
differentiated tumors (268). In general, stage for stage, the prognoses of PTC and follicular cancer are similar (266,269). [B2] Goals of initial therapy of DTC The basic goals of initial therapy for patients with DTC are to improve overall and disease-speciﬁc survival, reduce the risk of persistent/recurrent disease and associated morbidity,and permit accurate disease staging and risk stratiﬁcation, while minimizing treatment-related morbidity and unneces- sary therapy. The speciﬁc goals of initial therapy are to 1. Remove the primary tumor, disease that has extended beyond the thyroid capsule, and clinically signiﬁcantlymph node metastases. Completeness of surgical re- section is an important determinant of outcome, while residual metastatic lymph nodes represent the most com-mon site of disease persistence/recurrence (270–272). 2. Minimize the risk of disease recurrence and metastatic spread. Adequate surgery is the most important treat-ment variable inﬂuencing prognosis, while RAI treat-ment, TSH suppression, and other treatments each play adjunctive roles in
at least some patients (273–275). 3. Facilitate postoperative treatment with RAI, where appropriate. For patients undergoing RAI remnant ablation, or RAI treatment of presumed (adjuvant therapy) or known (therapy) residual or metastaticdisease, removal of all normal thyroid tissue is an important element of initial surgery (276). 4. Permit accurate staging and risk stratiﬁcation of the disease. Because disease staging and risk stratiﬁcationshould be used to guide initial prognostication, disease management, and follow-up strategies, accurate post- operative risk assessment is a crucial element in themanagement of patients with DTC (277,278). 5. Permit accurate long-term surveillance for disease re- currence. 6. Minimize treatment-related morbidity. The extent of surgery and the experience of the surgeon both play important roles in determining the risk of surgicalcomplications (232,233,279,280). [B3] What is the role of preoperative staging with diagnostic imaging and laboratory tests? [B4] Neck imaging—ultrasound &RECOMMENDATION 32 (A) Preoperative neck US for cervical (central and
especially lateral neck compartments) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant orsuspicious for malignancy cytologic or molecular ﬁndings. (Strong recommendation, Moderate-quality evidence)(B) US-guided FNA of sonographically suspicious lymph nodes ‡8–10 mm in the smallest diameter should be per- formed to conﬁrm malignancy if this would change man- agement. (Strong recommendation, Moderate-quality evidence)(C) The addition of FNA-Tg washout in the evaluation of suspicious cervical lymph nodes is appropriate in selectpatients, but interpretation may be difﬁcult in patients with an intact thyroid gland. (Weak recommendation, Low-quality evidence) Differentiated thyroid carcinoma (particularly papillary car- cinoma) involves cervical lymph node metastases in 20%–50% of patients in most series using standard pathologic techniques (84,145,281–283), and it may be present even when the primarytumor is small and intrathyroidal (284). The frequency of mi- crometastases ( <2 mm) may approach 90%, depending on the sensitivity of the detection method (285,286). However, theclinical implications
of micrometastases are likely less signiﬁ- cant compared to macrometastases. Preoperative US identiﬁes suspicious cervical adenopathy in 20%–31% of cases, poten-tially altering the surgical ap proach (287,288) in as many as 20% of patients (289–291). However, preoperative US identiﬁes only half of the lymph nodes found at surgery, due to the presence of the overlying thyroid gland (292). Sonographic features suggestive of abnormal metastatic lymph nodes include enlargement, loss of the fatty hilum, a rounded rather than oval shape, hyperechogenicity, cysticchange, calciﬁcations, and peripheral vascularity (Table 7). No single sonographic feature is adequately sensitive for detection of lymph nodes with metastatic thyroid cancer. Onestudy correlated the sonographic features acquired 4 dayspreoperatively directly with the histology of 56 cervical lymph nodes identiﬁed in 19 patients. Some of the most speciﬁc criteria were short axis >5 mm (96%), presence of cystic areas (100%), presence of hyperechogenic punctua- tions representing either colloid or
microcalciﬁcations (100%), and peripheral vascularity (82%). Of these, the onlyone with sufﬁcient sensitivity was peripheral vascularity (86%). The others had sensitivities of <60% and would not be adequate to use as a single criterion for identiﬁcation ofmalignant involvement (292). As shown by earlier studies (293,294), the ultrasonographic feature with the highest sensitivity is absence of a hilum (100%), but this has a lowspeciﬁcity of 29%. Microcalciﬁcations have the highestspeciﬁcity; any lymph nodes with microcalciﬁcations should be considered abnormal (292) (Table 7). The location of the lymph nodes may also be useful for decision-making. Malignant lymph nodes are much more likely to occur in levels III, IV, and VI than in level II (Fig. 3) (292,294), although this may not be true for PTC tumorsarising in the upper pole of the thyroid, which have a higher propensity to demonstrate skip metastases to levels III and II (295). Figure 3 illustrates the
delineation of cervical lymphnode levels I through VI. Conﬁrmation of malignancy in lymph nodes with a sus- picious sonographic appearance is achieved by US-guided FNA aspiration for cytology and/or measurement of Tg in theneedle washout. A Tg concentration <1 ng/mL is reassuring, and the probability of N1 disease increases with higher Tg levels (296). This FNA measurement of Tg is likely valideven in patients with circulating anti-Tg autoantibodies (297,298), although one study challenges the validity of this measurement in patients with anti-Tg autoantibodies (299).Tg washout may be helpful, particularly in cases in which the lymph nodes are cystic, cytologic evaluation of the lymph node is inadequate, or the cytologic and sonographicevaluations are divergent (i.e., normal cytologic biopsy ofATA THYROID NODULE/DTC GUIDELINES 29
a large lymph node with microcalciﬁcations) (300). In a retrospective study of 241 lymph nodes in 220 patients whounderwent US-guided FNA with Tg in FNA (FNA-Tg)washout ﬂuid measurements for suspicious lymph nodes, additional FNA-Tg helped to diagnose a metastatic lymph node with one or two suspicious US features but did not offerincremental beneﬁt for those lymph nodes with highly sus- picious US features in which FNA alone was sufﬁcient for diagnosis. Two recent systematic reviews showed that false-positive Tg washout may occur, particularly in lymph nodes in the central compartment when the thyroid gland is still present (301,302). The review by Pak et al. (302) suggests that an FNA-Tg cutoff of 32 ng/mL has the best sensitivityand speciﬁcity in patients with an intact thyroid gland. Others have suggested interpreting the FNA-Tg in context of the serum Tg and TSH in these patients (303,304). There is nostandardization of FNA-Tg procedures or
assays to date, which makes this additional diagnostic tool sometimes dif- ﬁcult to interpret (305). Future standardization includingmatrix type (phosphate-buffered saline, Tg-free serum, etc.) and volume of diluent matrix would help with interpretation of a Tg washout. Accurate staging is important in determining the prognosis and tailoring treatment for patients with DTC. However, unlike many tumor types, the presence of metastatic diseasedoes not obviate the need for surgical excision of the primarytumor in DTC (306). Because metastatic disease may respond to RAI therapy, removal of the thyroid as well as the primarytumor and accessible loco-regional disease remains an im-portant component of initial treatment even in most patients with metastatic disease. [B5] Neck imaging—CT/MRI/PET &RECOMMENDATION 33 (A) Preoperative use of cross-sectional imaging studies (CT, MRI) with intravenous (IV) contrast is recommended as an adjunct to US for patients with clinical suspicion for advanced disease, including invasive primary tumor, orclinically apparent multiple
or bulky lymph node involve-ment. (Strong recommendation, Low-quality evidence)(B) Routine preoperative 18FDG-PET scanning is not rec- ommended. (Strong recommendation, Low-quality evidence) Since US evaluation is operator dependent and cannot al- ways adequately image deep anatomic structures and those acoustically shadowed by bone or air, alternative imagingprocedures may be preferable or useful as an adjunct in FIG. 3. Lymph node compartments separated into levels and sublevels. Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally on each side by the carotid sheaths. The level II, III, and IV nodes are arrayed along the jugular veins on each side, bordered anteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes arebounded superiorly by the level of the hyoid bone and inferiorly by the cricoid cartilage; levels II and IV
are above and below level III, respectively. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone, and anterior to the posterior edge of the submandibular gland. Finally, the level V nodes are in the posteriortriangle, lateral to the lateral edge of the sternocleidomastoid muscle. Levels I, II, and V can be further subdivided as notedin the ﬁgure. The inferior extent of level VI is deﬁned as the suprasternal notch. Many authors also include the pretracheal and paratracheal superior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neck dissection (341).30 HAUGEN ET AL.
some clinical settings. Patients displaying bulky or widely distributed nodal disease on initial US examination may present with involvement of nodal regions beyond typicalcervical regions, some of which maybe difﬁcult to visualizeon routine preoperative US, including the mediastinum, infra- clavicular, retropharyngeal, and parapharyngeal regions. In a study of 37 consecutive patients who had preoperative CTand US and subsequently underwent total thyroidectomy and neck dissection, the sensitivity of CT was better than US for the evaluation central and lateral compartment lymph nodesexamined together (77% vs 62%, p=0.002), but there were no differences between the two imaging modalities when the central and lateral compartments were examined separately(307). In a series of 299 consecutively registered patientswith pathologically proven PTC who underwent preoperative CT and US, US was more accurate than CT in predicting extrathyroidal tumor extension and multifocal bilobar dis-ease ( p<0.05). The accuracy of staging was better overall with US ( p<0.01),
and US had greater sensitivity than CT at predicting lateral compartment metastases ( p=0.041) (308). However, another study showed that combined preopera- tive mapping with US and CT was superior to US alone in the preoperative detection of nodal disease, especially in thecentral neck (309). The sensitivities of MRI and PET for the detection of cervical lymph node metastases are relatively low (30%–40%) (310). PET can also detect inﬂammatorylymph nodes, which reduces the speciﬁcity of this test inmany patients with DTC. MRI can be used in the detection of cervical nodal metastasis. MRI is affected by respiratory artifacts and may be more difﬁcult to interpret than CTscanning by surgeons in the operating room for low-volume nodal disease (311). Invasive DTC has been reported to occur in 10%–15% of patients at the time of diagnosis (312). For this group of patients, cross-sectional imaging can also be a useful sup- plement for
preoperative planning to accurately delineate theextent of laryngeal, tracheal, esophageal, or vascular in-volvement (309,313). Endoscopy of the trachea and or esophagus, with or without ultrasonography, at the beginning of the initial operation looking for evidence of intraluminalextension can also be helpful in cases of suspected areodi- gestive tract invasion. Locally invasive primary tumors may be associated with characteristic signs and symptoms including progressive dysphagia, respiratory compromise, hemoptysis, rapid tumor enlargement, signiﬁcant voice change or the ﬁnding of vocalcord paralysis, and mass ﬁxation to the airway or neck structures. Certain sonographic features of the primary tu- mor, including extrathyroidal extension especially withposterior capsular extension and extension into the medias-tinum, may also prompt axial imaging (307). Chest CT is useful in deﬁning the inferior border of disease and in de- termining the extent to which mediastinal structures are in-volved in cases with signiﬁcant caudal spread. CT ﬁndings may inﬂuence management by indicating
the need for ster- notomy and/or tracheal or laryngeal resection/reconstruction,which would likely require assembling additional resources and personnel in preparation for surgery. Neck CT with contrast can therefore be useful in delineating the extent oflaryngeal, tracheal, and/or esophageal involvement in tumors displaying aggressive local invasion, as well as delineating bulky nodal disease, which may harbor signiﬁcant extranodalextension that involves muscle and/or blood vessels. Pre- operative knowledge of these features of the primary tumor or metastases could signiﬁcantly inﬂuence the surgical plan(314). 18FDG-PET scanning may be sensitive in some pa- tients for neck or mediastinal involvement and may reveal distant metastases as well. When cross-sectional imaging is performed, use of IV contrast is an important adjunct because it helps to delineate the anatomic relationship between the primary tumor or metastatic disease and these other structures. Iodine is gen-erally cleared within 4–8 weeks in most patients, so concern about iodine burden from
IV contrast causing a clinically signiﬁcant delay in subsequent whole-body scans (WBSs) orRAI treatment after the imaging followed by surgery is gen-erally unfounded (315). The beneﬁt gained from improved anatomic imaging generally outweighs any potential risk of a several week delay in RAI imaging or therapy. When there isconcern, a urinary iodine to creatinine ratio can be measured. [B6] Measurement of serum Tg and anti-Tg antibodies &RECOMMENDATION 34 Routine preoperative measurement of serum Tg or anti-Tgantibodies is not recommended. (Weak recommendation, Low-quality evidence) Data from a systematic review and meta-analysis sug- gested that high preoperative concentrations of serum Tgmay predict a higher sensitivity for postoperative surveil- lance with serum Tg (316). Preoperative anti-Tg antibodies do not appear to be an independent preoperative predictor ofstage in patients with DTC, but the evidence is limited. In a cross-sectional analysis of 1770 patients with perioperative anti-Tg antibodies status data in the National Thyroid
CancerTreatment Cooperative Study (a large thyroid cancer registry that included 11 North American centers and enrolled pa- tients between 1987 and 2011), serum anti-Tg antibody statuswas not signiﬁcantly associated with stage of disease onmultivariate analysis, or with disease-free or overall survival on univariate or multivariate analyses (317). Evidence that preoperative measurement of serum Tg impacts patientmanagement or outcomes is not yet available. [B7] Operative approach for a biopsy diagnostic for follic- ular cell–derived malignancy &RECOMMENDATION 35 (A) For patients with thyroid cancer >4 cm, or with gross extrathyroidal extension (clinical T4), or clinically appar-ent metastatic disease to nodes (clinical N1) or distant sites (clinical M1), the initial surgical procedure should include a near-total or total thyroidectomy and gross removal of allprimary tumor unless there are contraindications to this procedure. (Strong recommendation, Moderate-quality evidence)(B) For patients with thyroid cancer >1 cm and <4c m without extrathyroidal extension, and without clinical evi-dence
of any lymph node metastases (cN0), the initialsurgical procedure can be either a bilateral procedure (near- total or total thyroidectomy) or a unilateral procedureATA THYROID NODULE/DTC GUIDELINES 31
(lobectomy). Thyroid lobectomy alone may be sufﬁcient initial treatment for low-risk papillary and follicular car- cinomas; however, the treatment team may choose totalthyroidectomy to enable RAI therapy or to enhance follow-up based upon disease features and/or patient preferences. (Strong recommendation, Moderate-quality evidence)(C) If surgery is chosen for patients with thyroid cancer <1 cm without extrathyroidal extension and cN0, the initial surgical procedure should be a thyroid lobectomy unlessthere are clear indications to remove the contralateral lobe. Thyroid lobectomy alone is sufﬁcient treatment for small, unifocal, intrathyroidal carcinomas in the absence of priorhead and neck radiation, familial thyroid carcinoma, orclinically detectable cervical nodal metastases. (Strong recommendation, Moderate-quality evidence) Surgery for thyroid cancer is an important element of a multifaceted treatment approach. The operation must becompatible with the overall treatment strategy and follow-up plan recommended by the managing team. Consideration should be given to referring patients with high-risk features(clinical N1 disease, concern
for recurrent laryngeal nerve [RLN] involvement, or grossly invasive disease) to experi- enced surgeons, as both completeness of surgery and expe-rience of the surgeon can have a signiﬁcant impact on clinicaloutcomes and complication rates (232,233,279,280). Pre- vious guidelines have endorsed total thyroidectomy as the primary initial surgical treatment option for nearly all DTCs>1 cm with or without evidence of loco-regional or distant metastases (25). This was based on retrospective data sug- gesting that a bilateral surgical procedure would improvesurvival (318), decrease recurrence rates (319–321), allow for routine use of RAI remnant ablation, and facilitate de- tection of recurrent/persistent disease during follow-up.However, recent data have demonstrated that in properlyselected patients, clinical outcomes are very similar follow- ing unilateral or bilateral thyroid surgery (322–326). Fur- thermore, since the requirement for routine use of RAIablation was one of the major reasons given in support of total thyroidectomy in low to intermediate risk patients,
our cur- rent more selective approach to RAI ablation in these patientsrequires a critical reassessment of this indication. In some patients, the presence of the remaining lobe of the gland may obviate the lifelong need for exogenous thyroid hormonetherapy. Finally, as our follow-up management paradigm has moved away from diagnostic whole body RAI scanning and toward a greater reliance on neck ultrasonography and serialserum Tg measurements (even in patients that did not receiveRAI remnant ablation), we must also question whether total thyroidectomy and RAI remnant ablation is required to fa- cilitate follow-up in low to intermediate risk patients. In an analysis of 52,173 PTC patients diagnosed between 1985 and 1998 from the National Cancer Data Base (43,227 receiving total thyroidectomy, 8946 undergoing lobectomy),Bilimoria et al. (318) demonstrated a slightly higher 10-year relative overall survival for total thyroidectomy as opposed to thyroid lobectomy (98.4% vs. 97.1%, respectively, p<0.05) and a slightly
lower 10-year recurrence rate (7.7% vs. 9.8%, respectively, p<0.05). When analyzed by size of the primary tumor, statistically signiﬁcant differences in survival andrecurrence were seen for all sizes >1 cm based on the extent of initial surgery. However, data on extrathyroidal extension, completeness of resection, and other comorbid conditions,which could have had a major impact on survival and re-currence risk, were not available. Therefore, it is unclear how often lobectomy was done based on proper selection of low to intermediate risk patients versus how often lobectomy wasdone in high-risk patients because of comorbid conditions, inability to obtain a complete resection, or status of the contralateral RLN. This is an important distinction becausethyroid lobectomy patients were found to have extrathyroidal extension in 7% of cases (325), underwent external beam radiation therapy (EBRT) in 1%–2% (324), and RAI therapyin 12%–18% (318,325), and high-risk features were presentin 8% (325). Given the small magnitude
of differences re- ported for survival and recurrence between the total thyroid- ectomy and the lobectomy patients, it is quite possible that theslightly poorer outcomes seen in the lobectomy group could have been inﬂuenced by lobectomy patients with concurrent high risk features. Adam et al. (327) performed an updated analysis of 61,775 patients in the National Cancer Database who underwent thyroid surgery between 1998 and 2006. The researchers demonstrated that the overall survival advantageseen for patients with 1–4 cm PTC who underwent thyroid- ectomy in the study by Bilimoria et al. (318) disappeared when further adjustment was made for additional variablesrelated to complexity and severity of illness. This lack ofoverall survival advantage was also seen when the group was subdivided into patients with 1–2 cm and 2–4 cm PTC. Previously, Haigh et al. (325) had analyzed 5432 PTC patients from the SEER database (4612 receiving total thy- roidectomy and 820
undergoing lobectomy) and found no difference in 10-year overall survival between total thyroid-ectomy and thyroid lobectomy when risk stratiﬁed by the AMES classiﬁcation system. Interestingly, patients selected for thyroid lobectomy included 7% with extrathyroidal ex-tension, 1% with distant metastases, and 5% with primarytumors >5 cm, and 8% were classiﬁed as having high risk based on AMES. More recently, two additional studies have analyzed the SEER database, and both have failed to demonstrate a sig- niﬁcant difference in survival when comparing total thy- roidectomy with thyroid lobectomy (323,324). Barney et al. (323) included 23,605 DTC patients diagnosed between 1983 and 2002 (12,598 with total thyroidectomy, 3266 with lo- bectomy) and found no difference in 10-year overall survival(90.4% for total thyroidectomy vs. 90.8% for lobectomy) or 10-year cause-speciﬁc survival (96.8% for total thyroidec- tomy vs. 98.6% for lobectomy). Furthermore, in a multivar-iate analysis that included age, T, N, M, sex, year ofdiagnosis,
extent of surgery, and RAI use, no difference in overall survival or cause speciﬁc survival was seen with re- spect to the extent of initial surgery. Mendelsohn et al. (324) analyzed 22,724 PTC patients diagnosed between 1998 and 2001 (16,760 with total thyroidectomy, 5964 with lobecto- my) and found no differences in overall survival or disease- speciﬁc survival in a comparison of total thyroidectomy with lobectomy. Interestingly, of the patients that had lobectomy, 1.6% received external beam radiation therapy, 16% hadextrathryoidal extension, 9% of tumors were >4 cm, and 20% received RAI ablation (once again indicating that lobectomy was done in some high-risk patients).32 HAUGEN ET AL.
Consistent with the SEER data analyses, two single-center studies also conﬁrmed that lobectomy is associated with excellent survival in properly selected patients (322,326).After a median follow-up of 8 years, only one disease-speciﬁc death was seen in a cohort of 889 PTC patients with T1–T2 tumors treated with either total thyroidectomy (n=528) or lobectomy ( n=361) (326). Furthermore, Mat- suzu et al. (322) reported a cause-speciﬁc survival rate of 98% after a median of 17 years of follow-up in properly select PTC patients treated with lobectomy and ipsilateral neckdissection. Given the propensity for PTC to be multifocal (often in- volving both lobes), it is not surprising that some studies havedemonstrated a lower risk of loco-regional disease recurrencefollowing total thyroidectomy as compared to thyroid lo- bectomy (319–321). However, with proper patient selection, loco-regional recurrence rates of less than 1%–4% andcompletion thyroidectomy rates of <10% can be achieved following thyroid lobectomy (326,328). Furthermore,
the few recurrences that develop during long-term follow-up arereadily detected and appropriately treated with no impact on survival (322,326,328). Therefore, we conclude that in properly selected low- to intermediate-risk patients (patients with unifocal tumors <4 cm, and no evidence of extrathyroidal extension or lymph node metastases by examination or imaging), theextent of initial thyroid surgery probably has little impact ondisease-speciﬁc survival. While recurrence rates can be quite low in these patients, it is likely that the lowest rates of recurrence during long-term follow-up would be associatedwith a total thyroidectomy. But since salvage therapy is quite effective in the few patients that recur after thyroid lobectomy, a conservative ma nagement approach to com- pletion surgery, accepting a slightly higher risk of loco- regional recurrence, is a reasonable management strategy. Finally, a more selective use of RAI coupled with a greaterreliance on neck US and serial serum Tg measurements fordetection of recurrent
disease is likely to signiﬁcantly de- crease the mandate for total thyroidectomies in low- and intermediate-risk patients done solely to facilitate RAIremnant ablation and follow-up. Near-total or total thyroidectomy is necessary if the overall strategy is to include RAI therapy postoperatively, and thus isrecommended if the primary thyroid carcinoma is >4 cm, if there is gross extrathyroidal extension, or if regional or dis- tant metastases are clinically present. For tumors that arebetween 1 and 4 cm in size, either a bilateral thyroidectomy (total or near-total) or a unilateral procedure (thyroid lobec- tomy) may be suitable as treatment plan. Older age ( >45 years), contralateral thyroid nodules, a personal history ofradiation therapy to the head and neck, and familial DTC may be criteria for recommending a bilateral procedure because of plans for RAI therapy or to facilitate follow-up strategies oraddress suspicions of bilateral disease (270,278,322,326). The relationship between surgeon volume and
patient outcomes has been studied extensively over the last 20 years.Institutional studies examining outcomes following thy- roidectomy by high-volume surgeons have been published demonstrating overall safety. In one of the ﬁrst studies ex-amining the relationship between surgeon volume and thy- roidectomy outcomes at a state level, Sosa et al. (232) found a strong association between higher surgeon volume andfavorable patient outcomes, especially with regard to RLN injury and wound complications. This was especially pro- nounced for patients undergoing total thyroidectomy for thyroidcancer. Others have made simila r observations (233,329,330). In a recent study of patients undergoing thyroidectomy in the Health Care Utilization Project Nationwide Inpatient Sample (HCUP-NIS), surgeons were divided into categories of low ( <10 cases/year; encompassing 6072 surgeons), intermediate (10– 100 cases/year; 11,544 surgeons), and high volume ( >100 cases/ year; 4009 surgeons) (331). Over 80% of thyroid resectionswere performed by low- and intermediate-volume surgeons. On average, high-volume
surgeons had the lowest complication rates for patients who underwent total thyroidectomy for cancerat 7.5%; intermediate-volume surgeons had a rate of 13.4%, andlow-volume surgeons, 18.9% ( p<0.001). From robust population-level data such as these, it can be concluded that referral of patients to high-volume thyroidsurgeons is associated, on average, with superior outcomes. However, such referral is not always possible, given the relative scarcity of high-volume surgeons and their geo-graphic distribution. In addition, there are some data sug- gesting that other factors, such as surgeon age, should be considered (332). Therefore, conclusions at a population le-vel cannot always be applied to individual surgeons and pa- tient circumstances. It may, however, be reasonable to consider sending patients with more extensive disease andconcern for grossly invasive disease to a high-volume sur-geon experienced in the management of advanced thyroid cancer. It is worth noting that even high-volume surgeons have a higher overall postoperative complication
rate when per- forming total thyroidectomy compared with lobectomy (333). Using the HCUP-NIS, these authors found that high-volume thyroid surgeons had a complication rate of 7.6% following thyroid lobectomy but a rate of 14.5% following total thyroidectomy. For low-volume surgeons, the compli-cation rates were 11.8% and 24.1%, respectively. Therefore,patients should carefully weigh the relative beneﬁts and risks of total thyroidectomy versus thyroid lobectomy, even when surgery is performed by high-volume surgeons. [B8] Lymph node dissection &RECOMMENDATION 36 (A) Therapeutic central-compartment (level VI) neckdissection for patients with clinically involved central nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. (Strong recommendation, Moderate-quality evidence)(B) Prophylactic central-compartment neck dissection (ipsilateral or bilateral) should be considered in patientswith papillary thyroid carcinoma with clinically unin- volved central neck lymph nodes (cN0) who have ad- vanced primary tumors (T3 or T4) or clinically involvedlateral neck nodes (cN1b), or if the information
will be used to plan further steps in therapy. (Weak recommendation, Low-quality evidence) (C) Thyroidectomy without prophylactic central neck dissection is appropriate for small (T1 or T2), noninvasive,ATA THYROID NODULE/DTC GUIDELINES 33
clinically node-negative PTC (cN0) and for most follicular cancers. (Strong recommendation, Moderate-quality evidence) &RECOMMENDATION 37 Therapeutic lateral neck compartmental lymph node dis- section should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. (Strong recommendation, Moderate-quality evidence) Regional lymph node metastases are present at the time of diagnosis in a majority of patients with papillary carcinomasand a lesser proportion of patients with follicular carcinomas (290,334,335). Although PTC lymph node metastases are reported by some to have no clinically important effect onoutcome in low risk patients, a study of the SEER database found, among 9904 patients with PTC, that lymph node metastases, age >45 years, distant metastasis, and large tumor size signiﬁcantly predicted poor overall survival outcome in a multivariate analysis (336). All-cause survival at 14 years was 82% for PTC without lymph node metastases and 79%with nodal metastases ( p<0.05). Another SEER registry study concluded that cervical lymph node
metastases con- ferred an independent risk of decreased survival, but only inpatients with follicular cancer and patients with papillarycancer over age 45 years (337). However, characteristics of the lymph node metastases can further discriminate the risk of recurrence to the patient, especially in patients with clinicallyevident metastasis, multiple metastases, larger metastases, and/or extracapsular nodal extension (338,339), compared with those with more limited microscopic nodal disease (335).A recent comprehensive analysis of the National Cancer Data Base and SEER, however, showed a small but signiﬁcantly increased risk of death for patients younger than 45 years withlymph node metastases compared with younger patientswithout involved lymph nodes, and that having incrementally more metastatic lymph nodes up to six involved nodes confers additional mortality risk in this age group (340). This studyunderlines the importance of rigorous preoperative screening for nodal metastases and potentially raises questions about current thyroid cancer staging systems. Common to all ofthese
studies is the conclusion that the effect of the presence or absence of lymph node metastases on overall survival, if present, is small. The cervical node sites are well-deﬁned (341), and the most common site of nodal metastases is in the central neck, which is cervical level VI (Fig. 3). A recent consensus con-ference statement describes the relevant anatomy of thecentral neck compartment, delineates the nodal subgroups within the central compartment commonly involved with thyroid cancer, and deﬁnes the terminology relevant to cen-tral compartment neck dissection (342). In many patients, lymph node metastases in this area do not appear abnormal on preoperative imaging (289,334,343–345) or by inspection atthe time of surgery (335), deﬁning a cN0 group. The role of therapeutic lymph node dissection for treatment of thyroid cancer nodal metastases is well accepted for cN1disease (336,346–348). However, the value of routine pro- phylactic level VI (central) neck dissection for cN0
disease remains unclear. Central compartment dissection (therapeuticor prophylactic) can be achieved with low morbidity by ex- perienced thyroid surgeons (349–351). The value for an in- dividual patient depends upon the utility of the staginginformation to the treatment team in speciﬁc patient cir-cumstances (351,352). Based on limited and imperfect data, prophylactic dissection has been suggested to improve disease-speciﬁc survival (353), local recurrence (345,354),and post-treatment Tg levels (345,355). It has also been used to inform the use of adjuvant RAI (344,347,350,356) and improve the accuracy of the estimates of risk of recurrence(356–358). However, in several studies, prophylactic dis- section has shown no improvement in long-term patient outcome, while increasing the likelihood of temporary mor-bidity, including hypocalcemia, although prophylactic dis-section may decrease the need for repeated RAI treatments (334,346,347,349,359–364). The removal of cN0 level VI lymph nodes detects a sub- stantial number of patients with pN1 disease; however, the direct effect of this
on long-term outcome is small at best (365,366). The use of staging information for the planning ofadjuvant therapy depends upon whether this information will affect the team-based decision-making for the individual patient. For these reasons, groups may elect to include pro-phylactic dissection for patients with some prognostic fea- tures associated with an increased risk of metastasis and recurrence (older or very young age, larger tumor size,multifocal disease, extrathyroidal extension, known lateralnode metastases) to contribute to decision-making and dis- ease control (345,351,355). Alternatively, some groups may apply prophylactic level VI dissection to patients with betterprognostic features if the patient is to have a bilateral thy- roidectomy, and if the nodal staging information will be used to inform the decision regarding use of adjuvant therapy(344,350,356). Finally, for some groups it appears reasonable to use a selective approach that applies level VI lymph node dissection at the time of initial operation only to
patients withclinically evident disease based on preoperative physicalexam, preoperative radiographic evaluation, or intraoperative demonstration of detectable disease (cN1) (335,359,367). The information from prophylactic central neck dissection must be used cautiously for staging information. Since mi- croscopic nodal positivity occurs frequently, prophylactic dissection often converts patients from clinical N0 to path-ologic N1a, upstaging many patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to stage III (334,344–347). However, microscopic nodal positivitydoes not carry the recurrence risk of macroscopic clinically detectable disease (335). Thus microscopic nodal upstaging may lead to excess RAI utilization and patient follow-up.Alternatively, the demonstration of uninvolved lymph nodesby prophylactic dissection may decrease the use of RAI for some groups (344,350,356). These effects may account for some of the existing extreme variability in utilization of RAIfor thyroid cancer (368). Studies of the BRAF V600Emutation have suggested an association between presence of the mutation and the
risk ofnodal disease (369–371), although results across all patients with papillary thyroid carcinoma are mixed (372–375). However, the presence of a BRAFV600Emutation has a limited PPV for recurrence and therefore, BRAFV600Emutation status in the primary tumor should not impact the decision for prophylactic central neck dissection (376).34 HAUGEN ET AL.
The preceding recommendations should be interpreted in light of available surgical expertise. For patients with small, noninvasive, cN0 tumors, the balance of risk and beneﬁt mayfavor thyroid lobectomy and close intraoperative inspectionof the central compartment, with the plan adjusted to total thyroidectomy with compartmental dissection only in the presence of involved lymph nodes. Lymph nodes in the lateral neck (compartments II–V, Fig. 3), level VII (anterior mediastinum), and rarely in level I may also be involved by thyroid cancer (282,335,377,378). Forpatients in whom nodal disease is evident clinically on pre- operative US and nodal FNA cytology or Tg washout mea- surement or at the time of surgery, surgical resection bycompartmental node dissection may reduce the risk of re-currence and possibly mortality (379–381). [B9] Completion thyroidectomy &RECOMMENDATION 38 (A) Completion thyroidectomy should be offered to pa-tients for whom a bilateral thyroidectomy would have beenrecommended had the diagnosis been available before the
initial surgery. Therapeutic central neck lymph node dis- section should be included if the lymph nodes are clinicallyinvolved. Thyroid lobectomy alone may be sufﬁcienttreatment for low-risk papillary and follicular carcinomas. (Strong recommendation, Moderate-quality evidence)(B) RAI ablation in lieu of completion thyroidectomy is not recommended routinely; however, it may be used to ablate the remnant lobe in selected cases. (Weak recommendation, Low-quality evidence) Completion thyroidectomy may be necessary when the diagnosis of malignancy is made following lobectomyfor an indeterminate or nondiagnostic biopsy. In addition,some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease and to allow for efﬁcient RAI therapy. However, sinceintrathyroidal PTC or low-risk FTC can be managed with either lobectomy or total thyroidectomy (see Recommenda- tion 35B), a completion thyroidectomy is not always required.The surgical risks of two-stage thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to those of a near-total or total thyroidectomy
(382–384). The marginalutility of prophylactic lymph node dissection for cN0 disease argues against its application in re-operations. Ablation of the remaining lobe with RAI has been used as an alternative to completion thyroidectomy (385,386).There are limited data regarding the long-term outcomes of this approach. The data suggest similar clinical out- comes with a slightly higher proportion of patients withpersistent detectable Tg. This approach may be helpful in patients for whom completion thyroidectomy carries some i n c r e a s e dr i s ka n df o rw h o mad e l a yi nt h el e n g t ho ft i m erequired to achieve destruction of the normal thyroid, which follows RAI (as opposed to surgical resection), is acceptable. In one unblinded, multicenter, randomizedcontrolled equivalence trial comparing dose activities ina c h i e v i n gs u c c e s