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Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules
Elizabeth J. de Koster,1 Lioe-Fee de Geus-Oei,2 Olaf M. Dekkers,3,4 Ilse van Engen-van Grunsven,5 Jaap Hamming,6 Eleonora P.M. Corssmit,3 Hans Morreau,7 Abbey Schepers,6 Jan Smit,8 Wim J.G. Oyen,1,9 and Dennis Vriens2
1Department of Radiology and Nuclear Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; 2Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; 3Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; 4Department of Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; 5Department of Pathology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; 6Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; 7Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; 8Department of Endocrinology, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; and 9Division of Radiotherapy and Imaging, Institute of Cancer Research, and Department of Nuclear Medicine, Royal Marsden Hospital, London SW3 6JJ, United Kingdom
ABSTRACT Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As ~25% of these nodules harbor malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving. This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a preoperative clinical setting, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, computed tomography, 18 sestamibi scintigraphy, [ F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and diffusion-weighted magnetic resonance imaging. The best rule-out tests for malignancy were the Afirma® gene expression classifier and FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques, a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rule-in test. Geographical variations in cytology (e.g., Hurthle¨ cell neoplasms) and tumor genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics. (Endocrine Reviews 39: 154 – 191, 2018)
ndeterminate thyroid cytology is an eyesore to the case of FTC, cytology lacks the insight into the I physicians. It largely corresponds to histopatho- tissue structure like histology does: it does not show logically follicular-patterned lesions, both benign and the capsular and/or vascular invasion that distin- ISSN Print: 0163-769X malignant, including follicular adenoma (FA), non- ISSN Online: 1945-7189 guishes an FTC from a benign FA. In FVPTC, the Printed: in USA invasive follicular thyroid neoplasm with papillary-like growth pattern is follicular and clearly identifying Copyright © 2018 nuclear features (NIFTP), (encapsulated) follicular nuclear features of PTC can usually not be identified Endocrine Society variant of papillary thyroid carcinoma (FVPTC or cytologically (–). Nevertheless, FNAC currently has Received: 18 May 2017 EFVPTC), and follicular thyroid carcinoma (FTC). a most prominent place in the diagnostic workup of Accepted: 27 December 2017 ffi ff First Published Online: These neoplasms are particularly di cult to di er- thyroid nodules. The Bethesda System for the 2 January 2018 entiate on fine needle aspiration cytology (FNAC). In Reporting of Thyroid Cytology was adopted in its
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ESSENTIAL POINTS · Indeterminate thyroid cytology (Bethesda category III and IV) corresponds to follicular-patterned benign and malignant lesions, which are difficult to differentiate on cytology alone · Approximately 25% of indeterminate thyroid nodules harbor malignancy · The value of additional diagnostics is best defined by end points such as desired minimal rates of accurately prevented unbeneficial surgeries (rule-out capacity) or accurately diagnosed carcinomas (rule-in capacity) · None of the diagnostic techniques currently available has near-perfect sensitivity, near-perfect specificity, and cost- effectiveness · A multimodal stepwise approach using a sensitive rule-out and specific rule-in test might offer the most conclusive diagnosis for indeterminate thyroid nodules · The decision favoring or opposing a certain diagnostic technique strongly depends on population-dependent variations in cytology (e.g., Hurthle¨ cell cytology), tumor genetics and prevalence of malignancy, and on the costs and feasibility of the desired diagnostic in the local patient population
current form in , recognizing six diagnostic cat- a more accurate test may eventually replace cytological egories with an incremental risk of malignancy examination completely (, ). At present, however, and clinical management guidelines. Although the a supplemental diagnostic procedure is specifically Bethesda system created a much-used handhold by warranted for cytologically indeterminate thyroid standardizing the cytological diagnosis and consecu- nodules. Diagnostic hemithyroidectomies are still tive management of thyroid nodules worldwide, the customarily performed to obtain a definite histological system does not provide a clear answer for the het- diagnosis. With a benign histopathological result in erogeneous group of nodules with indeterminate cy- approximately three in four cases, surgery was not only tology (, ). This includes cytology with atypia of unbeneficial but also exposed the patient to un- undetermined significance or follicular lesion of un- necessary surgical risks. In the case of malignant le- determined significance (AUS/FLUS, Bethesda III), sions, a second-stage completion thyroidectomy is and cytology (suspicious for a) follicular neoplasm often indicated, which is associated with additional (SFN/FN) or (suspicious for a) H¨urthle cell neoplasm costs and higher risks of surgical complications (SHCN/HCN, Bethesda IV). Similar indeterminate (–). An additional preoperative test or combi- cytological categories are found in the British Thyroid nation of tests for thyroid nodules with indeterminate Association Thy system and classification of the cytology should prevent unbeneficial diagnostic Societ`a Italiana di Anatomia Patologica e Cit- hemithyroidectomies for benign nodules, limit the opatologia Diagnostica/International Academy of number of two-stage surgeries for thyroid malig- Pathology, Italian Division (SIAPEC-IAP): Thya and nancies, or both. With rapidly advancing technology, Thyf, and TIRA and TIRB, respectively (Table ) the possibilities for additional diagnostic techniques (, ). seem endless: the applications of existing diagnostics Alongside a doubled incidence of thyroid carci- such as ultrasound (US), positron emission tomog- noma over the past two decades and a prevalence of raphy (PET)/computed tomography (CT), and im- thyroid nodules stretching far beyond the % for munocytochemistry (ICC) are extended and more palpable nodules, explained by the incidental detection clearly demarcated for use in indeterminate thyroid of nonpalpable nodules and clinically occult thyroid nodules. High-tech molecular tests such as gene cancers on imaging studies, the need for a more ac- mutation panels, gene or microRNA expression curate diagnostic procedure has grown (). This urge profiles, and sequencing techniques are hot-topic (, was further emphasized when other research groups –). Every currently known engagement point were unable to reproduce the prevalence of the cy- from the genotype to the phenotype of the tumor is tological categories and corresponding malignancy being explored. Combined, the various research fields risks proposed by Cibas et al. (), especially those of the encompass an extensive range of investigative AUS category (, , ). Insuperable variations in the methods. Individually they usually focus on one or two worldwide patient populations, and intra- and in- methods only, making one-to-one comparison of terobserver variation in the assessment of thyroid these diagnostics difficult. The American Thyroid cytology, were named as likely underlying causes (, , Association (ATA) guidelines suggested several ad- , ). Yet, it raised questions concerning the overall ditional tests, but a definitive answer or complete approach of thyroid nodule diagnosis and whether overview of all available tests is still lacking (). cytology is the best starting ground. Cost-effectiveness Alongside higher-level expert discussions and lob- is a major benefit of cytological examination, yet bying of med tech companies, clinical endocrinologists
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Table 1. Overview of Classification Systems for Thyroid Cytology Bethesda System for the Reporting British Thyroid Malignancy Proposed Management of Thyroid Cytology (4) Association (BTA) (6) SIAPEC-IAP (Italy) (7) Rate (4) [2015 ATA Guidelines (8)]
Category Description Category Description Category Description
I Nondiagnostic/unsatisfactory Thy1 Nondiagnostic TIR1 Nondiagnostic 1%–4% Repeat FNAC with US guidance Thy1c Nondiagnostic TIR1c Nondiagnostic-cystic cystic lesion
II Benign Thy2 Nonneoplastic TIR2 Nonmalignant/benign 0%–3% No clinical follow-up or treatment required Thy2c Nonneoplastic cystic lesion
III Atypia of undetermined Thy3a Atypical features TIR3a Low-risk indeterminate ~5%–15% Repeat FNAC. If second significance/follicular present lesion Bethesda III result, lesion of undetermined consider additional tests significance (AUS/FLUS) and/or diagnostic hemithyroidectomy
IV Follicular neoplasm/suspicious Thy3f Suspicious of follicular TIR3b High-risk indeterminate 15%–30% Consider additional tests of a follicular neoplasm, neoplasm lesion and/or diagnostic including Hurthle¨ cell hemithyroidectomy (oncocytic) type
V Suspicious of malignancy Thy4 Suspicious of TIR4 Suspicious of 60%–75% Thyroid surgery recommended. malignancy malignancy Consider preoperative additional (molecular) testing to determine extent of surgery
VI Malignant Thy5 Malignant TIR5 Malignant 97%–99% Thyroid surgery recommended
and thyroid surgeons ponder about the best solution will work our way down from genotype to phenotype, for their individual patients. Their choices depend discussing both anatomical and functional techniques, on the characteristics of their patient populations, from the state-of-the-art molecular and imaging availability and costs of a certain test, and personal biomarkers, as well as widely available conventional preference. In any case, a useful additional test should imaging techniques. The ability of a test to distinguish be accurate, accessible, affordable, and affect patient between malignant and benign nodules in a pre- management. operative setting is discussed, focusing on clinical This review aims to provide practical consider- validation and utility, and including the development ations for physicians involved in the management of phase, cost-effectiveness, and availability of each patients with thyroid nodules. It gives an overview of technique, where appropriate. Table provides the available literature on additional diagnostic tests a summarized overview of the discussed diagnostics for thyroid nodules with indeterminate cytology. We and their main attributes.
Molecular Biomarkers mitogen-activated protein kinase (MAPK) signaling pathway (–). Gene mutation analysis and gene expression In the ATA guidelines, the potentially strong In the last decades, researchers have unraveled diagnostic impact of molecular testing is explicitly important molecular mechanisms behind the thy- unfolded, focusing on BRAF testing and the, at that roid tumorigenesis, and designated a great number date, two main commercially available tests: the seven- of genetic alterations that are related to the various gene mutation panel miRInform® thyroid (Asuragen, types of thyroid carcinoma. Several of these mu- Inc., Austin, TX) and the Afirma® gene expression tational markers have found their way to the pre- classifier (GEC) (Veracyte, Inc., South San Francisco, operative diagnosis of indeterminate thyroid CA). The ATA recommends considerate application nodules. The most common markers are the so- of one of these molecular tests for Bethesda III and IV matic BRAF and RAS point mutations, and nodules, provided that the result could change the RET/PTC rearrangement, all of which involve the treatment strategy ().
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In the following chapters, the diagnostic potential than % are reported (, , ). Consequently, of mutation analysis in indeterminate thyroid nodules BRAFV E mutation analysis might have both high is discussed, including the tests mentioned in the specificity and high sensitivity in these populations. guidelines, as well as other individual molecular Studies with higher sensitivities were more often of biomarkers and multigene panels addressed in South Korean origin and frequently demonstrated literature. sensitivity above %, with the prevalence of BRAF mutations reported as high as %to%(, , , BRAF mutation , , –). Conversely, the majority of studies with B-type RAF kinase (BRAF) is a serine–threonine ki- sensitivity below % were conducted in Western nase belonging to the rapidly accelerated fibrosarcoma countries (United States, Europe, or Canada), with (RAF) family, and the most potent MAPK pathway some studies reporting no BRAF mutations at all (, activator. Point mutations in the BRAF proto- –, , , , , , –, , , , , ). oncogene occur in various human cancers. The so- Some South Korean studies based surgical matic BRAFV E mutation is the most common decision-making on the result of the BRAF mutation activating mutation in many carcinomas, including analysis: surgery was relatively less often performed in thyroid carcinoma (). This missense mutation BRAF mutation-negative indeterminate nodules (, consists of a thymine-to-adenine substitution at nu- , , ). Such a surgical management strategy is not cleotide (c.T.A), resulting in an amino acid oncologically safe for Western countries (e.g., Europa substitution where valine is replaced with glutamate at or Northern America), where %to% of thy- codon (hence VE) (, ). BRAF has an roid carcinomas are PTC and reported rates of important function in cell proliferation, differentia- BRAF-mutated PTC vary from %to%(, , tion, and apoptosis. Upregulation of BRAF through ). Moreover, even though the true sensitivity of the BRAFV E activating mutation is associated with BRAF mutation analysis is presumably high in tumorigenesis (). In differentiated thyroid cancer, South Korea for the mentioned epidemiological the BRAFV E mutation is exclusive to PTC, occur- reasons, the conservative management of BRAF ring in %to% of these tumors (, , , mutation-negative nodules likely magnified test –, , , ). The BRAFV E mutation has sensitivity by underestimating the rate of BRAF- been prognostically associated with poor clinico- negative malignant nodules in these studies. Alto- pathological outcomes, such as increased incidence of gether we estimate that approximately one in five extrathyroidal invasion, recurrence of disease, and South Korean patients would benefitfromBRAF distant metastasis of the tumor (, , ). mutationanalysis,oppositemereonein patients BRAF mutation analysis has been extensively from other countries. studied as a rule-in test for thyroid carcinoma. The BRAF mutation is superior to other mutations in its BRAF mutation in papillary microcarcinoma oftentimes % specificity, a positive mutation could Papillary microcarcinoma (mPTC) have lower BRAF prevent two-stage surgery for an indeterminate thy- mutation rates (, , , , , , ). The ATA roid nodule (, –, –, –, –). Even guidelines are reserved with regard to the recom- though the BRAF mutation was found in a majority of mended clinical management of positive BRAF mu- PTC in a number of studies, the prevalence of the tation in mPTC, as its relation to extrathyroidal spread BRAF mutation in indeterminate cytology ranged and positive lymph node metastases is not as clear as in from %to% in individual studies (, , , , , larger thyroid carcinoma. Although there are studies ). Reported sensitivities were therefore heteroge- that associate mPTC to factors of poorer prognosis, the neous and generally poor, ranging from %to%(, guidelines recommend that BRAF-mutated , , ). Other types of thyroid carcinoma occurring mPTC are treated as low-risk malignancies (, ). in indeterminate nodules, including FTC, FVPTC, and H¨urthle cell carcinoma [oncocytic variant of follicular thyroid carcinoma (FTC-OV)], were respectively never BRAFK601E point mutation or infrequently BRAF mutation-positive (, , , , A less common activating BRAF mutation is , , ). Predominated by follicular type carcinoma, BRAFK E (c.A.G), which occurs considerably the BRAF mutation rarely occurs in Bethesda IV less frequently than the BRAFV E variant and is cytology (, , , , , , , , , , , , , associated with FVPTC with high specificity (). , –, , –). Clinically, the characterization of a small cohort of Likely contributors to the observed heterogeneity thyroid malignancies with a BRAFK E mutation are known global variations in the occurrence rates of showed better outcomes than for BRAFV E mutated PTC and BRAF mutations. In South Korea, where tumors: no extrathyroidal tumor extension, recurrence, iodine consumption is high, %to% of thyroid lymph node, or distant metastasis were reported in cancers are PTC. More specifically, the proportion of indeterminate BRAFK E positive tumors with a me- BRAF-mutated PTC is very high: rates of % to more dian follow-up of months (range, to )().
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Table 2. Overview of Test Performance and Utility of Main Additional Diagnostics in Indeterminate Thyroid Nodules Sensitivity Specificity Main Advantages Main Limitations Cost-Effectiveness
Molecular biomarkers
Gene mutation analysis and gene expression
BRAF 0%–83% (24–27) 99%–100% Perfect specificity Strong geographical variation in Presumed, though (22, 25–67) at low cost occurrence, clinical utility likely unpublished; V7.50 to limited to gene mutation panels in $123 per test (47, 55, 63, countries other than South Korea 68)
RAS 0%–77% (53, 69) 75%–100% High prevalence, Often found in follicular adenomas Unpublished (53, 69, 70) frequently (false-positive); clinical utility detected limited to gene mutation panels
RET/PTC 0%–29% (30, 43) 73%–100% (28, 30) Specific for PTC Low prevalence; clinical utility limited Unpublished to gene mutation panels
PAX8/PPARg 0%–29% 96%–100% (25, 33, No significant Low prevalence; utility limited to Unpublished (25, 49, 71) 61) advantages gene mutation panels
7-gene mutation panel 18%–69% (23, 26) 86%–99% (26, 33) Comparatively Specificity often insufficient for United States: likely (72); inexpensive surgical decision-making Europe: unlikely (15); mutation panel $425 to $1700 per test (72, 73)
NGS 71%–91% (22, 62) 89%–93% (62, 74) Highly accurate; Limited availability outside the Unpublished; V230 to rapidly advancing United States; limited $3200 per test (75, 76) technology clinical validation studies
Afirma GEC 83%–100% 10%–52% (77, 81) High rule-out Limited availability outside the Unlikely (15, 73, 82–85); ® (77–80) capacity United States; limited high- $3500 ($1750 to $7000) quality clinical validation studies per test (73, 78, 82)
MicroRNA 57%–100% 58%–100% (87, 88) Stable expression Limited clinical validation, Unpublished (23, 86, 87) irrespective of research ongoing preservation medium (87, 89)
ICC
Galectin-3 0%–92% (25, 27, 68%–100% Global availability; Limited current application in Unpublished. Up to 38–68, 70–166) (38, 167–169) inexpensive. cytology; no methodological V20 per test. consensus; limited validation – – HBME-1 61% 100% (166, 75% 96% (166, 168, studies for combinations of 168, 170, 171) 170, 171) immunostains. CK-19 76%–88% (166, 80%–100% 170, 172) (166, 170, 172)
Conventional imaging
Ultrasound Dependent on Dependent on Global availability, Operator dependency; limited Presumed, though (combination (combination of) low cost prospective clinical validation; unpublished. of) feature(s) feature(s) diagnostic accuracy of individual US features insufficient for surgical decision-making
Elastosonography 47%–97% (20, 6%–100% Global availability, Operator dependency; limited clinical Presumed, though 173) (174–176) low cost, easily utility studies; alternative elasticity unpublished. performed during cut-off possibly more useful standard US workup
CT Unavailable Unavailable Unavailable Not investigated in indeterminate NA thyroid nodules (Continued)
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Table 2. Continued Sensitivity Specificity Main Advantages Main Limitations Cost-Effectiveness
Functional and molecular imaging
99mTc-MIBI scintigraphy 56%–79% 52%–96% (20, 61) More widely Limited test performance; limited Unclear. United States (20, 177) available and clinical validation studies; exposure $669–$1156, Europe: lower cost to limited dose of ionizing radiation V119-V500 per scan than PET (84, 178, 179)
FDG-PET 77%–100% 33%–64% (182, 185) High rule-out Exposure to limited dose of United States: (180, 181–184) capacity; ionizing radiation. unpublished. increasing global Europe: likely (15). availability
DW-MRI Unpublished Unpublished No ionizing Limited evidence; no methodological Unpublished radiation consensus; research ongoing Abbreviations: BRAF, BRAF point mutation analysis; NA, not applicable; RAS, RAS point mutation analysis.
Availability, cost-effectiveness, and limitations of thyroid nodules, they are the most common genetic BRAF mutation analysis alteration, due to a strong association of RAS muta- Altogether, the consistent perfect specificity in a large tions with the follicular-patterned lesions that make up number of studies supports the use of BRAF mutation these cytological categories: FA, FTC, FVPTC, and analysis in obviating two-stage surgery. The technique NIFTP (, , , , , ). Originally, two of the is increasingly available in the clinical setting world- three homologous RAS genes were identified as viral wide. A prior meta-analysis of eight studies questioned genes of the oncogenic Harvey (HRAS) and Kirsten the cost-effectiveness of BRAFV E mutation analysis (KRAS) murine sarcoma virus; the third, NRAS, was in indeterminate thyroid nodules based on a mere first identified in neuroblastoma cells (, ). The .% mean prevalence of the mutation (). Cost- genes code for guanosine triphosphate-binding RAS effectiveness studies concerning sole BRAF mutation proteins, which are involved in intracellular signaling analysis in indeterminate thyroid nodules are lacking. in the MAPK/extracellular signal-regulated kinase Regardless, cost-effectiveness is generally presumed, as (ERK) pathway. Mutation causes overactive RAS average costs for testing are relatively low and de- signaling and could ultimately induce malignant creasing over time. Depending on the applied mo- transition (). lecular technique, reported costs for BRAF mutation RAS mutation in thyroid carcinoma has been as- analysis ranged between V. and $ per tested sociated with favorable prognostic factors, such as sample (, , , ). encapsulation of the tumor and absence of lymph Low sensitivity remains the main limitation of node metastases, but also with factors indicative of an BRAF mutation analysis, irrespective of the type of adverse prognosis, such as poor cell differentiation (). indeterminate cytology. Proficiency of the test in RAS mutations are not specific for carcinoma and preoperative patient management depends on the found in both malignant and benign lesions (, , regional occurrence rate of BRAF-mutated PTC; in ). According to the ATA guidelines, Bethesda South Korea, more patients will benefit from BRAF III or IV nodules with a RAS mutation should be mutation analysis, and the probability and extent of treated similar to the Bethesda V category, as ap- cost-effectiveness are likely to increase (). In other proximately four out of five are malignant (, ). health care systems, such as in the United Kingdom, HRAS, KRAS, and NRAS mutations are mutually cost-effectiveness is likely more constrained. None- exclusive. They are each associated with slightly dif- theless, BRAF testing could still save approximately ferent types of cytology and histology, and conse- half the surgical costs in BRAF mutation-positive quently a different clinical course. In general, point carcinoma (, ). These global variations should mutations in NRAS codon and HRAS codon are be considered before local implementation of sole said to occur most frequently (, ). KRAS is asso- BRAF mutation analysis. ciated with oncocytic lesions and a lower malignancy rate than other RAS mutations (). RAS point mutation A RAS point mutation is found in %to% of the Point mutations in the gene family of retrovirus- indeterminate nodules (, ). Moreover, approxi- associated DNA sequences (RAS) together consti- mately one-third of all reported malignancies resulting tute the second most frequently occurring genetic from indeterminate thyroid cytology are RAS muta- alteration in thyroid carcinoma. In indeterminate tion positive, frequently FVPTC or FTC (, , , ,
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). Sporadic cases of RAS mutation-positive FTC-OV of unrelated genes that are expressed in thyroid fol- and MTC are reported (, ). In individual studies, licular cells. Proto-oncogene RET encodes for sensitivity and specificity of RAS mutation analysis a transmembrane receptor with a tyrosine kinase ranged from %to% and from %to%, re- domain; a RET/PTC rearrangement causes in- spectively (, , ). Test performance was similar appropriate overexpression of that domain. It activates for Bethesda III and IV categories, although the the MAPK and PIK/AKT pathways and stimulates mutation occurred more frequently in Bethesda IV malignant transition of the cell through BRAF (, nodules (, , , , , , , , , ). His- ). At least different fusion variants have been topathologically benign nodules carrying a RAS mu- detected until today, of which RET/PTC and RET/ tation are histopathological FA in most cases, but also PTC are the most common. They have a well-known oncocytic variant of FA (H¨urthle cell adenoma) or association with PTC. Cases of both rearrangements in hyperplastic nodules (, , , , ). There is an a single lesion are also reported (, , , ). RET/ ongoing discussion regarding the interpretation of PTC rearrangements, especially RET/PTC, occur a false-positive RAS mutation. It is presumed that an more frequently in PTC in children or patients who oncogenic RAS mutation predisposes a FA for pro- were exposed to ionizing radiation and are clinically gression into follicular carcinoma, an RAS-mutated FA associated with the presence of lymph node metastases should be considered a premalignant preinvasive (). Worldwide variations in frequency of RET/PTC follicular neoplasm. These assumptions put false- rearrangements exist, dependent on demographics positives in a different light, as it would justify re- and ethnicity. The RET/PTC rearrangement is present section of such lesions through hemithyroidectomy. in % of PTC in Western populations with a pre- Consequently, the lesions could also be considered dominance of RET/PTC, and in % of PTC in Asian true-positives, improving the specificity of RAS mu- populations with a predominance of RET/PTC. tation analysis (, , , , , ). However, the Without radiation exposure, in female PTC pa- exact mechanisms behind the malignant potential and tients, RET/PTC is predominant (). The rear- transition for RAS-mutated follicular adenomas are rangements are also found in benign nodules, not yet clarified and difficult to appreciate in a clinical especially in patients who were exposed to ionizing setting. irradiation (, ). Alike RAS mutations, it is as- Similar to BRAF, there was evident global variation sumed to be an activating genetic alteration and it is in the distribution of RAS mutations. Many European argued that a histopathologically benign nodule with and American studies reported a clear predominance an RET/PTC rearrangement should be considered of RAS mutations over BRAF mutations. Solely a precancerous lesion. a Brazilian study of Bethesda III and Bethesda RET/PTC rearrangements are seldom found in IV thyroid nodules reported only BRAF mutations and indeterminate nodules. In many studies, no RET/PTC not a single RAS mutation (). The previously de- translocation was found at all. Most studies in- scribed predominance of BRAF mutations in South vestigated RET/PTC in light of a gene mutation panel Korean populations was confirmed in the sole study and paid it no specific attention (, , , , , , that investigated both point mutations in one pop- , , , , , , , , , , ). Only Guerra ulation (). Combined BRAF/RAS mutation analysis et al. () solely investigated the RET/PTC rear- could be considered, although geographical differences rangement in thyroid nodules of all cytological in the distribution of the two genetic alterations categories. In this Italian study, RET/PTC rear- strongly influence feasibility. A gene mutation panel rangements were found in of the PTC (%) consisting of more genetic alterations (discussed in using reverse transcription polymerase chain reaction a next chapter) is most likely more useful. (RT-PCR) and Southern-Blot. All these RET/PTC- Sole RAS mutation analysis is not accurate in the positive carcinomas were Thy or Thy nodules on preoperative setting. Although specificity is high, only cytology. Among the Thy nodules, two nodules two out of three RAS mutation positive indeterminate with an RET/PTC rearrangement were histopatho- nodules are histopathologically malignant, evidently logically benign (). fewer than assumed and previously described in the Noteworthy, Sapio et al. () detected two RET ATA guidelines. Therefore, RAS mutation positive mutations during their RET/PTC assessments. In indeterminate thyroid nodules should be surgically contrast to the RET/PTC translocation, RET point managed with no more than hemithyroidectomy. mutations are related to sporadic and familial MTC Whether hemithyroidectomy is justified for RAS- (, ). Surgery confirmed histopathological MTC mutated follicular adenomas as a precancerous lesion in the RET-mutated nodules (). is yet under debate. Even though previous histological studies un- deniably associated RET/PTC and RET/PTC rear- RET/PTC rearrangement rangements to PTC, the low prevalence of the Rearrangements of the RET proto-oncogene arise rearrangement in indeterminate cytology is a major from the fusion of the 9 end of RET to the 9 regions downside. Testing exclusively for this genetic alteration
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in indeterminate nodules is not advantageous, even if PAX/PPARg-mutated nodules are likely premalig- issues regarding the number of tested variants and nant lesions, or preinvasive FTC. Eszlinger et al. () sensitivity of molecular techniques are overcome. The observed a microfollicular morphological growth ATA guidelines only advise RET/PTC testing in pattern in two of the PAX/PPARg-positive FA, context of a gene mutation panel (). supporting this hypothesis (). Still, PAX/PPARg rearrangement is a rare rear- PAX8/PPARg rearrangement rangement associated with (encapsulated) follicular The PAX/PPARg rearrangement arises from a fusion tumors. Similar to RET/PTC rearrangements, the of the promoter and 9-coding portion of the thyroid- PAX/PPARg rearrangement should only be assessed specific transcription factor PAX gene to the gene of in indeterminate thyroid nodules in combination with the nuclear receptor peroxisome proliferator-activated more frequently occurring genetic alterations in a gene receptor g (PPARg)(, ). The role of the mutation panel. product of this translocation, the PAX/PPARg fusion protein, is not yet understood, as the DNA binding Other genetic alterations sites of both original proteins are uniquely preserved in the fusion (). In the normal thyroid, transcription Human telomerase reverse transcription factor PAX is involved in differentiation of thyrocytes The enzyme human telomerase is involved in the and regulation of the expression of thyroid-specific maintenance of the chromosomes’ telomeres, which genes encoding thyroperoxidase, thyroglobulin, and are essential for cell life and proliferation. The catalytic the sodium/iodide symporter (). Nuclear receptor subunit of telomerase is human telomerase reverse PPARg has multiple presumed functions, including transcription (hTERT). In normal thyroid cells, it is involvement in the regulation of lipid metabolism, inactive. Inappropriate reactivation is associated with adipogenesis, and insulin sensitivity (, ). malignancy and inflammatory thyroid disease (). The chromosomal translocation PAX/PPARg hTERT promotor mutations were previously observed was first discovered in, and traditionally associated in both PTC and FTC, sometimes together with with, FTC and FA (). It is reported in %to%of a BRAF mutation. The mutation is strongly correlated “ FTC and in up to %ofFA(, –). However, to mortality in differentiated thyroid carcinoma (). PAX8/PPARg is often related to well-differentiated several studies have also uncovered varying amounts hTERT gene expression is potentially accurate in the ff malignancies with a relatively of FVPTC carrying the translocation, with published preoperative di erentiation of indeterminate nodules, favorable prognosis.” rates up to %(, , ). It has not been re- with %to% sensitivity and %to% specificity ported in benign or malignant H¨urthle cell neoplasms demonstrated in two small clinical series of cytological (, ). follicular neoplasms (, ). PAX/PPARg is often related to well-differentiated malignancies with a relatively favorable prognosis. Tyrosine receptor kinase Capsular and vascular invasion are reported to a lesser The tyrosine receptor kinase (TRK) rearrangement extent in FTCs with a PAX/PPARg rearrangement arises from a translocation of the NTRK gene, which than in RAS-mutated tumors (). Widely invasive is normally expressed in the central and peripheral features are not reported. PAX/PPARg-mutated nervous system and involved in cell differentiation. FVPTC are mostly encapsulated, following an indolent The TRK rearrangement is associated with PTC and clinical course with minimal disease recurrence despite presumably with an adverse prognosis, although ev- the presence of some capsular and vascular invasion at idence is limited (). In feasibility studies in in- presentation (–). In contrast to the BRAF, RAS determinate thyroid cytology, not a single TRK and RET/PTC genetic alterations in thyroid carci- rearrangement has been detected; it is most likely not noma, the PAX/PPARg rearrangement does not a useful marker (, , ). involve the RAS-RAF-MAPK pathway. Nikiforova et al. () hypothesized that oncogenesis of follicular- HMGA2 type tumors likely takes place through two different Proteins high mobility group AT-hook (HMGA) molecular pathways: a RAS-mutation driven and and regulate the structure and function of chro- PAX/PPARg rearrangement driven pathway (). matin. Normally only expressed during embryo- Similar to the RET/PTC rearrangement, the PAX/ genesis, the overexpression of HMGA in adult PPARg rearrangement rarely occurred in in- tissues is associated with malignancy (). Lap- determinate thyroid cytology. Approximately two- pinga et al. () demonstrated that HMGA could thirds of the indeterminate nodules carrying the be a promising additional biomarker. Using receiver rearrangement were histopathologically malignant, operating characteristic (ROC) curve analysis, most often FVPTC or FTC (, , , , , , , a ..-fold HMGA overexpression had %sen- , , , , , ). False-positive results corre- sitivity and %specificity in SFN/FN nodules (). sponded to follicular adenomas (, , ). Simi- To date no other studies attempted to validate these lar to RAS mutations, histopathologically benign results.
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Galectin-3 and CD44v6 None of the subsequent studies matched the ini- One Croatian study used RT-PCR to investigate the tially reported excellent specificity. The next industry- simultaneous expression of galectin- and CDv, sponsored prospective study by Beaudenon-Huibregtse two molecular biomarkers better known for their et al. ()reported% sensitivity and %specificity application in immunohistochemistry (IHC) of their in Bethesda III and IV nodules. Surprisingly, not expression products (). CDv normally func- asingleBRAF mutation was detected (). Valder- tions as the cell-surface receptor for hyaluronic acid. rabano et al. () reported not a single mutation in Overexpression is found in various human cancers, included Bethesda III nodules. Moreover, only of including thyroid (, ). In indeterminate thyroid nodules with H¨urthle cell cytology in this study tested nodules, a positive test for either one of the two positive, suggesting that H¨urthle cell nodules may biomarkers resulted in % sensitivity and % carry different mutations than the ones investigated specificity. It is presumed that similar results for these by the miRInform® thyroid (). Ohori et al. () markers are achieved with the more economical IHC demonstrated that genetic alterations less frequently techniques (, ). occurred in the textbook colloid-poor Bethesda IV cytology compared with the less common colloid- Gene mutation panel rich variant. Differences in etiology are unknown, but Ongoing research in the past years has demonstrated the authors hypothesized that the two types have that assessment of individual oncogenic mutations subtle histopathological differences. The colloid-rich generally has limited clinical utility in indeterminate thyroid carcinomas likely more often develop thyroid cytology. Combining forces of individual ge- through the well-known mutations included in netic alterations into a gene mutation panel, however, the miRInform® thyroid test, whereas mutations likely improves diagnostic accuracy, especially as that elicit colloid-poor thyroid carcinoma are yet mutations are mutually exclusive in most cases. These unknown (). gene mutation panels typically assess the seven genetic Simultaneously with the American miRInform® alterations, gene mutations as well as gene fusions, that studies, five European studies independently in- occur most frequently in differentiated thyroid car- vestigated whether a panel of the same seven genes cinoma, including BRAFV E, BRAFK E, NRAS could reliably be assessed using different methods (, codon , HRAS codon , and KRAS codon - , , , ). In three separate studies, Eszlinger et al. point mutations and RET/PTC, RET/PTC, and (, , ) demonstrated that testing was also feasible PAX/PPARg gene rearrangements (, ). The on routine air-dried FNAC samples from in- best-known panel is the commercially available determinate thyroid nodules. Over the course of these miRInform® thyroid (Asuragen, Inc.), currently studies, sensitivity of this method improved from % rebranded as the ThyGenX® Thyroid Oncogene to % and specificity from %to%, respectively. Panel (Interpace Diagnostics, Parsippany, NJ). The The use of air-dried FNAC samples for mutation miRInform® thyroid tests specific genetic alterations analysis could advance the implementation of muta- in these seven genes (). It is marketed as a rule-in test tion analysis in daily practice, as specific storage for thyroid malignancy. conditions of fresh FNAC samples for mutation The first large clinical utility study to investigate the analysis are no longer required (, , ). Mancini miRInform® thyroid test was published in . et al. () showed that high-resolution melting (HRM) Nikiforov et al. () prospectively included analysis is an accurate screening method for the seven FNAC samples, % of which had sufficient epithelial genetic alterations, with % sensitivity and % cells and nucleic acids to pursue molecular testing. specificity. HRM is a post-PCR procedure that does Residual FNAC material was used for mutation not require substantial additional resources. This analysis; no additional aspirates were required. Un- could reserve the costlier direct sequencing procedures fortunately, surgery was performed for only of solely for samples with abnormal HRM results, (%) indeterminate thyroid nodules, independent of thereby reducing the overall costs of mutation analysis the test outcome; these operated cases were included in (). their final analysis. It is not reported whether non- Overall, reported sensitivities and specificities of surgically managed nodules were mutation-positive or a seven-gene mutation panel in indeterminate thyroid -negative. Sensitivity and specificity were % and % nodules ranges from %to% and %to%, in the Bethesda III nodules, and % and %in respectively (, , ). It is an adequate diagnostic the Bethesda IV nodules, respectively. The authors tool with a high rule-in capacity in indeterminate suggested that the high positive predictive value nodules. Test performance was similar in Bethesda III (PPV) of the miRInform® thyroid in these in- and Bethesda IV nodules, although the latter more determinate thyroid nodules (%and%, re- frequently had a positive test result based on the higher spectively) warrants a direct total thyroidectomy prevalence of RAS mutations (, ). Due to the instead of two-step surgery in patients with a positive common RAS mutations, PPV of the seven-gene test (). mutation panel never exceeds % in a range of
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realistic %to% prevalence of malignancy. As such promotor variants added to its panel. It simultaneously it is debatable whether a positive test warrants im- tested for point mutations in genes and for types mediate single-stage total thyroidectomy. It translates of gene fusion products (). The ThyroSeq® v was into an inappropriate overtreatment in a substantial tested on Bethesda IV thyroid nodules. Forty-two number of patients with a positive test but benign final genetic alterations were found, most frequently NRAS. histology at higher risk of surgical complications and Diagnostic accuracy of the ThyroSeq® v was %, all requiring lifelong levothyroxine supplementation. with astonishing % sensitivity and % specificity Deliberate surgical decision-making should consider (). the underlying positive mutation rather than merely More recently, Nikiforov et al. () tested the the positive test itself. ThyroSeq® v., including point mutations in genes The limited size of the seven-gene gene mutation and gene fusion transcripts, in Bethesda III panel keeps the costs per test low compared with other, nodules. Based on the promising results of the pre- larger molecular panels. Reported prices of the seven- vious study, surgery was withheld for of gene mutation panel all concern the commercial ThyroSeq®-negative patients. In the patients with miRInform® thyroid (or ThyGenX® Thyroid Onco- available histopathology, the ThyroSeq® v. dem- gene Panel) and range between $ and $ (, onstrated % sensitivity and % specificity. Addi- ). Implementation of miRInform® testing for in- tionally, diagnostic accuracy was estimated for determinate nodules theoretically resulted in a % malignancy rates varying between % and %: PPV cost reduction in the United States: the prevented two- would range from %to%, negative predictive step surgical procedures would outweigh the added value (NPV) from %to%. Within reasonable expenses for miRInform® testing and increased limits, the ThyroSeq® v. is highly reliable to rule out number of total thyroidectomies, including those for malignancy (). nodules with a false-positive test (). In a European Le Mercier et al. () retrospectively tested a dif- setting, treatment and hospitalization costs are gen- ferent commercially available -gene NGS panel, the erally lower and miRInform would most likely not be AmpliseqÔ Cancer Hotspot Panel v (ThermoFisher, ff ® ff fi cost-e ective ( ). However, these cost-e ectiveness San Diego, CA), which is a tumor-nonspeci c NGS “Deliberate surgical decision- studies both adopted the unequalled test performance panel for detection of somatic tumor variants. This making should consider the from the initial key publication, true cost-effectiveness panel does not include thyroid-specific RET/PTC, underlying positive mutation may be less optimistic (, , , ). PAX/PPARg, and NTRK rearrangements. Albeit rather than merely the positive ” the study only assessed FNAC samples, with % test itself. Next generation sequencing sensitivity and % specificity in indeterminate thyroid To improve the sensitivity of the miRInform® thyroid nodules, the AmpliseqÔ panel seems less accurate test, the existing seven-gene mutation panel was ex- than the ThyroSeq® (). panded to include additional gene mutations, fusions, The high diagnostic accuracy is also a downside to and translocations, and a microRNA gene expression NGS. Highly sensitive, NGS is able to identify mutant panel. In addition, it adopted promising next gener- alleles at very low levels (,%). A low percentage of ation sequencing (NGS) techniques. NGS enables the mutant alleles might reflect a subclone within the simultaneous targeted testing for multiple mutations nodule, which is not histopathologically identified as in large gene panels and is faster, more sensitive, and carcinoma. This detection of germline or clinically more cost-effective than traditional Sanger sequencing insignificant low-level somatic mutations in benign and other PCR-based methods (, , ). As NGS nodules could decrease NGS specificity (, ). only requires a very small amount ( to ng) of Nikiforov et al. () suggested that the next im- nucleic acids, remainder material from regular FNAC provement of the NGS-related tests should therefore passes suffices and no additional aspirates are required be to determine accurate threshold levels for the (, ). The first thyroid-specific NGS-based gene various gene variations (). panel was the ThyroSeq® v (CBLpath, Ocala, FL), NGS encompasses crucial technology that is rap- presented in . It detected gene variations in of idly advancing. The ThyroSeq® v was recently an- investigated thyroid cancer tissue samples and of nounced, promoting to encompass no less than ~% benign specimens. Unfortunately, indeterminate of genetic alterations occurring in PTC. Extraordinary FNAC samples were not analyzed separately in this diagnostic accuracy above % is anticipated, in- study. Nonetheless, Nikiforova et al. () demon- cluding high accuracy in H¨urthle cell lesions. Results of strated that NGS had a very high success rate and the prospective studies validating this new version will could be a promising molecular technique for thyroid likely be published shortly. Nonetheless, NGS tech- FNAC samples. niques currently have limited global availability, with Following the ThyroSeq® v, the road was paved the exception of some European countries and the for further exploration of NGS-based diagnostics. United States. The ThyroSeq® is available for $ Soon, the ThyroSeq® v (CBLPath, Ocala, FL) was per test (). In contrast, the thyroid nonspe- developed, with a number of primers for TERT cificAmpliSeqÔ panel can be ordered online for only
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V (). Independent prospective studies are needed nodules received any follow-up at all. Despite evident to validate its performance and predicted cost-utility in limitations to the applied reference standards, Alex- different patient populations, and confirm the superior ander et al. () concluded that their results confirm position of the ThyroSeq® and other NGS techniques. both the accurate test performance from their prior study, as well as the large impact that the Afirma® GEC Afirma® GEC has on clinical decision-making for cytologically in- In molecular diagnostics, the chief competitor of the determinate thyroid nodules. seven-gene mutation panel is the commercial Afirma® Yet, physicians indeed seemed reassured by GEC (Veracyte, Inc.). The GEC uses quantification of a negative GEC result based on the first studies alone the messenger RNA (mRNA)-expression of genes (, ). In many institutions in the United States, the and a proprietary classification algorithm to determine Afirma® GEC was immediately implemented in the probabilities of malignancy in the samples’ ex- clinical practice. The retrospective studies that fol- pression patterns. The classification algorithm to lowed were mere postimplementation utility studies, discern a “benign” (negative test) from a “suspicious” and generally reported very high but moderately (positive test) thyroid nodule results from a successful consistent sensitivities. GEC-negative nodules were designer study that trained the GEC in both a tissue set largely managed without surgery and considered true- and diverse FNAC sample sets with known histopa- negative, resulting in possible overestimation of test thology (). Alexander et al. () performed the first sensitivity. Long-term follow-up is not yet available to prospective, blinded, industry-sponsored clinical study endorse a benign diagnosis in these cases (, ). to validate this Afirma® GEC in patients with in- The high degree of missing histology was recognized determinate thyroid nodules. From hospitals by most of these studies as a major limitation (, , Bethesda III, IV, and V FNAC samples were collected, , –). This was confirmed by the ATA obtained by two additional needle aspirates from guidelines: recognizing the Afirma® GEC as a prom- thyroid nodules with a diameter of at least cm. After ising diagnostic tool, the guidelines stress that it is exclusion of over half (/, %) of the samples a major shortcoming that external clinical validation for reasons such as nodules that were not surgically studies with full histological follow-up of Afirma® resected, duplicate specimens from the same nodule, GEC-negative nodules are still lacking (). and issues with specimen shipments to Veracyte, fi- Not all studies were able to confirm the potential of nally FNAC samples were included in the analysis. the Afirma® GEC. Some struggled with a low benign Sensitivity of the Afirma® GEC was % in the call rate (i.e., useful negative test result that could lead Bethesda III as well as the Bethesda IV nodules with to management change) (, ). McIver et al. () a useful GEC-negative test result in %(/), but questioned the cost-effectiveness of the Afirma® GEC specificity was merely % and %, respectively (% in their population, as the mere %(/) negative on average). Despite the relatively high malignancy test rate was much lower than anticipated. Moreover, rate in Bethesda III nodules and the high number of one-quarter of these GEC-negative patients rejected exclusions, this study is well conducted and recognized the proposed conservative treatment of US-based worldwide as the landmark study that demonstrated follow-up and underwent surgery anyway; one of the strength of the Afirma® GEC (). After the them was diagnosed with a .-cm FTC with focal overwhelming results from this key publication, capsular and vascular invasion. Also, % of GEC- popularity of the GEC took flight. It is marketed as positive nodules proved histopathologically benign, a highly accurate rule-out test for malignancy in overall resulting in a disappointing % sensitivity and thyroid nodules with indeterminate cytology. % specificity (). In , the first multicenter study that retro- Besides concerns regarding adequate clinical vali- spectively assessed the clinical utility of the Afirma® dation of test performance, the postimplementation GEC was published. Only % of reported GEC- influence of the GEC on surgical decision-making for negative Bethesda III, IV, and V nodules eventually individual patients was also questioned. In line with underwent surgery, of which one resulted in a -mm the results of their preliminary study, Noureldine et al. mPTC. Unfortunately, data on GEC negative nodules () demonstrated that Afirma® GEC testing had not were only reported on an aggregate level; exact test aided surgical decision-making (, ). In % performance rates in Bethesda III and IV nodules (/) of the included indeterminate nodules, cannot accurately be extracted from the publication. a “benign” or “suspicious” GEC result did not affect Less than half of the GEC-negative nodules without management at all: the surgical strategy would have surgery (/, %) had clinical or radiological been identical had it been based merely on clinical, follow-up, ranging from to months (median cytological, or radiological suspicion. However, if months), a limited duration compared with the management changes were based on the GEC result, natural, indolent course of differentiated thyroid they were more often wrong than right: times GEC- carcinoma. The published paper does not describe positive results inappropriately tempted physicians whether the remaining patients with GEC-negative into more aggressive surgery, and total thyroidectomy
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was performed instead of the initially recommended Studies of cost-effectiveness yielded variable results, lobectomy for nodules that proved histopathologically but most concluded that GEC testing would not be benign. In contrast, in just four GEC-positive cases the cost-effective over conventional surgical management more aggressive surgery was appropriate and the or other diagnostic modalities in various clinical set- nodule was histopathologically malignant. Also, in just tings (, , –). The first of these studies pro- one patient surgery was withheld specifically due to claimed cost-effectiveness of the GEC even prior to a negative Afirma® GEC result. In the other unresected publication of the first validation study by Alexander GEC-negative nodules, surgery was not clinically in- et al. (), and has been criticized for several important dicated to begin with; the negative GEC-result merely methodological caveats. This study professedly over- endorsed conservative management (). As the GEC estimated test specificity at %, overestimated the rate was still a new technology when this study was of permanent complications from thyroid surgery, and conducted, it is possible that the involved physicians did not consider the regularly reported GEC test were unsure of the correct interpretation of the GEC failures (–, , , , ). A recent study de- results or hesitant to rely on a negative GEC result. termined population-dependent thresholds for feasi- However, clinical suspicions and physician and patient ble cost-effectiveness by comparing GEC performance preference will always be considered when making to conventional surgical management in a local surgical decisions. Bethesda III/IV population. GEC-guided management Yang et al. () elegantly tried to solve the was not cost-effective, adding $ to the $, shortcoming (histological) follow-up by comparing expenses for conventional treatment while hardly their findings of GEC performance to a pre-GEC improving quality-adjusted life years. Sensitivity cohort of similar patients from their hospital in all analysis showed that the GEC would only become of whom surgery was performed (, ). The reported cost-effective if its specificity exceeds %, if it costs malignancy rates were comparable pre- and post-GEC less than $, or if the population malignancy rate implementation (%vs%), and obviously relatively decreases from the actual % to below .%. This more surgeries were performed for benign nodules in price threshold for cost-effectiveness decreases as the the pre-GEC period. Assuming the true malignancy malignancy rate increases, as low as $ per test at “GEC testing was most useful if rates in the successively studied populations are in- % cancer prevalence (). the malignancy rate ranged deed similar, the GEC only modestly reduced the Furthermore, existing interinstitutional differences between 15% and 21%, number of futile surgeries for benign thyroid nodules in test performance have consequences for local ap- comparable to the prevalence ” from %to%(). Altogether, the contribution plicability and effectiveness (, ). Marti et al. () reported by Alexander et al. of the Afirma® GEC to the surgical decision-making compared GEC performance in distinct populations of maybemorelimitedthanexpectedbasedonits two large hospitals. The reproducibility of the tests’ diagnostic accuracy. sensitivity and specificity was good, but utility strongly depended on the local prevalence of malignancy: as the Availability, cost-effectiveness, and limitations of population malignancy rate increased, a rarer negative the GEC GEC became less reliable to rule out malignancy. The Afirma® GEC is currently only available for Oppositely, at low malignancy rates, a negative GEC routine use in the United States. There are high de- merely confirmed that the probability of cancer was mands for the FNAC specimens regarding sample low. In neither situation, the GEC changed the preservation and shipping. Cytology is revised by management strategy. GEC testing was most useful if Veracyte cytologists and declined if not strictly the malignancy rate ranged between % and %, Bethesda III or IV, with %to% discordancy comparable to the prevalence reported by Alexander between local assessment and central review, com- et al. (, ). parable to known interobserver rates for thyroid cy- Finally, the degree of missing histology is a major tology (, , ). Reported rates of nondiagnostic limitation to the performed studies. None of the GEC test results due to insufficient quantity or quality studies following the key publication by Alexander of the mRNA are substantial, varying from %to% et al. () had complete histopathologic follow-up; (, ). Insufficient mRNA quality was often caused histopathological confirmation ranged between % by problems with long duration of the sample ship- and % of specimens. ment to Veracyte (, ). Fourth, Afirma® GEC Missing histology mainly comprised GEC negative testing is expensive and is currently marketed for nodules, likely resulting in overestimated sensitivity $ (range $ to $) per test (, , ). (i.e., missing some malignancies in the many unop- Testing for medullary carcinoma and BRAF mutation erated GEC-negative nodules) and underestimated is not included in the Afirma® GEC, but can be specificity [i.e., relatively more GEC-positive nodules performed by Veracyte at additional costs (). Yet, with benign histology (false-positives) were operated ancillary BRAF mutation testing may not be relevant, on than GEC-negative nodules with benign histology as Kloos et al. () found that it improved sensitivity (true-negatives)]. The trend that studies with higher nor specificity of the GEC. surgical rates for GEC-negative nodules showed more
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moderate results supports these hypotheses (, , Afirma® GEC may soon become obsolete, as an ). updatedversionofthetest,theGeneSequencing A recent meta-analysis by Santhanam et al. () Classifier (Veracyte, Inc.), is currently being put into included seven studies and reported % pooled operation. Improved diagnostic accuracy is antici- sensitivity and % pooled specificity for the GEC in pated, with specific attention to the differentiation of Bethesda III, IV, and V thyroid nodules with histo- H¨urthle cell nodules. pathological follow-up. The authors expected that more than % of patients with a negative test would MicroRNA be treated conservatively (). However, in individual First described in thyroid cytology in , evaluation studies up to % of patients pursued surgery or of the expression levels of microRNA (also called conservative treatment despite GEC-based recom- miRNA) is among the newer and more promising mendation to do the opposite (, ). This obser- approaches to differentiate between benign and ma- vation is crucial to cost-utility analyses. In addition, lignant thyroid neoplasms (, ). MicroRNAs are expensive rule-out tests such as the Afirma® GEC small endogenous noncoding RNAs of ~ nucleo- should not be performed in case surgery is considered tides in length. As negative regulators (i.e., silencers) of for other reasons, such as cosmetic or mechanical protein synthesis at a posttranscriptional level, they are complaints. involved in many intracellular processes, including cell growth, differentiation, and proliferation. Dysregula- GEC in Hurthle¨ cell cytology tion of microRNA expression is found in almost all Brauner et al. ()specifically validated the Afirma® types of human cancers (). It reflects the deregu- GEC in cytology samples suspicious for H¨urthle lated expression of oncogenes and tumor suppressor cell neoplasm. They demonstrated that GEC testing genes (, , , ). MicroRNA overexpression is could accurately have reduced the number of futile present before morphological tissue changes are seen surgeries, although through a less profound re- and therefore considered to be a part of premalignant duction than in nononcocytic indeterminate thyroid changes in carcinogenesis (). MicroRNA expres- nodules (). Similar results were noticed in other sion profiles are tissue-specific and cannot only studies: despite a relatively low risk of malignancy, the identify the tissue of origin, but also the histopatho- majority of H¨urthle cell nodules were GEC-positive. logical subtype of the cancer and whether it concerns Regardless of good sensitivity, this unfavorable be- the primary tumor or a metastasis (, ). nign call rate in H¨urthle cell cytology limits di- MicroRNA expression profiles are similar among agnostic efficacy in these nodules, increasing the the various types of thyroid carcinoma, even though number needed to test and negatively affecting expression levels are often distinctively different (). possible cost-effectiveness (, , , , , ). In histopathological studies, PTC was associated with Diagnostic accuracy of the GEC would likely improve an up to -to-fold upregulation of miR-b, if Bethesda IV cytology suspicious for a H¨urthle cell miR-, miR-, miR-b, miR-, and a down- lesion was excluded from GEC testing. Otherwise, regulation of miR- and miR- compared with similar to the additional testing for medullary car- healthy thyroid tissue and benign nodules. Upregu- cinoma, adaptations should be made to the Afirma® lation of miR-, miR-, and miR- was also GEC to improve its clinical utility for H¨urthle cell found in FTC, FTC-OV, poorly differentiated and lesions. anaplastic carcinoma (, , , , ). Over- In conclusion, it is generally assumed that the expression of miR-b-p, miR-b-p, and miR- Afirma® GEC accurately reclassifies approximately was seen in both PTC and FVPTC (, ). two out of five indeterminate thyroid nodules as Furthermore, expression levels of miR- and miR- benign with published sensitivities ranging between were reported approximately twice as high in %and% and similar test performance in FVPTC as compared with PTC or FTC (). Only Bethesda III and IV nodules. Withholding diagnostic a few microRNAs were differently expressed between surgery from these patients seems safe (–). follicular neoplasm and FTC (). FA was associated However, the diagnostic strength and potential cost- with the expression of miR-a, whereas high ex- utility of Afirma® GEC strongly rely on its NPV, thus pression of miR- was found in H¨urthle cell adenoma on the prevalence of malignancy and benign call rate (). FTC is related to the differential expression of inthetargetedpopulation.Thereareimportant miR-b, miR--p, miR-, miR-, and miR-, concerns regarding the currently insufficient number but results among studies are more heterogeneous (, of clinical validation studies with adequate rates of , ). FTC-OV showed an expression pattern histopathological confirmation or long-term clinical slightly similar to FTC, but also distinct overexpression follow-up. Physicians are strongly advised to locally of other microRNAs, such as miR-, miR-, miR- validate Afirma® GEC test performance before , and miR--p(, ). considering test implementation in daily practice. Accordingly, a diagnostic panel of a carefully se- Nonetheless, further large validation studies on the lected combination of microRNAs and appropriate
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expression levels could aid in the preoperative dis- fivefold in thyroid malignancies. Four microRNAs tinction of indeterminate thyroid cytology (). Re- (miR-, miR-b, miR-, and miR--p) were cent meta-analyses struggled to reconcile the studies significantly downregulated and accurately differen- on microRNA in FNAC, as the investigated set of tiated between benign and malignant follicular and microRNAs was never identical and individual H¨urthle cell neoplasms in the test set. In their vali- microRNA performance was infrequently described. dation set of indeterminate FNAC samples, only In unselected cytology, estimated sensitivity of miR- was moderately distinctive with % NPV. microRNA expression analysis ranged from %to For H¨urthle cell carcinoma, miR- and miR--p % regardless of the investigated set; estimated were both % accurate (). specificity from %to%(–). Finally, in a recent Italian study, only miR- In indeterminate thyroid cytology, different sets of accurately differentiated between benign and malig- microRNAs were evaluated; only several individual nant neoplasms. Subsequently, in TIR cytology ex- microRNAs were analyzed in more than one study. cluding H¨urthle cell lesions, a -fold or higher The selected microRNAs were first assessed in a test set overexpression of miR- perfectly distinguished of cytological and/or histopathological specimens and benign from malignant lesions with % accuracy. It a cut-off for their expression level was determined. was also significantly differently expressed between Subsequently, the significantly up- or downregulated TIRA and TIRB categories and correlated with microRNAs were validated in an independent set of adifferent malignancy risk (). (indeterminate) thyroid FNAC samples. Some studies developed a decision model for the validation step (, Availability and limitations of microRNA , ). expression analysis The most promising results were presented by MicroRNA expression analysis has advantages over Keutgen et al. (). Of the six microRNAs in- other techniques. MicroRNAs are more stable than vestigated in their test set, miR-,miR-b, miR- mRNA at maintaining their expression in formalin- a, and miR- were differentially expressed in fixed paraffin-embedded tissue samples as well as malignant nodules with prior indeterminate cytology. FNAC specimens, irrespective of the preservation The subsequently developed support vector machine method (e.g., archived FNAC slides or nucleic acid “Ongoing research has yet to model incorporated miR-,miR-, and the in- preservation solutions) (, ). Recently microRNA compose the optimal set of significantly expressed miR- and miR-.Pro- expression was even successfully measured in serum microRNAs.” spective validation in an independent set of (). Moreover, microRNA expression levels mea- indeterminate FNAC samples resulted in % sured with generic methods (e.g., quantitative RT- sensitivity and %specificity. Five of the seven false- PCR) correspond well to their biological effect, as positives had H¨urthle cell cytology; excluding these, microRNAs affect biological processes without the raised specificity to %(). Notably, even though additional step of protein synthesis (). overexpression of miR-bisoftenrelatedtothy- However, general limitations of FNAC also roid carcinoma, it proved not useful to Keutgen et al. translate to concerns with microRNA analysis: scant () to include in their prediction model. In contrast, cellularity or low levels of malignant cells in FNAC Agretti et al. ()andShenet al. () included miR- specimens could cause a false-negative microRNA test b as the key differentiators in their models. Agretti result (). Another limitation is the plurality of et al. () assessed a frequently quoted set of microRNAs associated with differentiated thyroid microRNAs consisting of miR-b, miR-,miR- carcinoma in histopathological studies, causing vast ,miR-,miR-,miR-,andmiR- (, heterogeneity between the limited number of studies ). Published in , Nikiforova et al. ()had in indeterminate cytology. Validation studies of the demonstrated that this seven-microRNA set in same microRNA set are lacking. Simultaneously, new FNAC samples had % sensitivity and %spec- microRNAs are still correlated to thyroid carcinoma. ificity if one of the included microRNAs showed an at Ongoing research has yet to compose the optimal set least twofold overexpression. Analytic validation of of microRNAs. Recently, the first commercial test was this model by Agretti et al. ()showeddifferential marketed as the ThyraMIRÔ (Interpace Diagnostics). upregulation in PTC of all of these microRNAs It evaluates the expression levels of miR-b-–p, except miR-.Inparticular,miR-bshowed miR-–p, miR-–-p, miR-–p, miR-b- a .-fold higher expression in PTC. A decision tree p, miR-, miR-–p, miR-–p, miR-, and including miR-b, miR-,andmiR- was % miR-b-p. The ThyraMIRÔ demonstrated % accurate in the test set, but validation in an in- sensitivity and % specificity in Bethesda III and dependent set of indeterminate FNAC samples was IV FNAC specimens (). Prospective clinical vali- unsuccessful, yielding mere % sensitivity and % dation of the ThyraMIRÔ could affirm the diagnostic specificity (). value of microRNA expression profiling in in- Vriens et al. () used a microRNA array to detect determinate thyroid nodules in the preoperative genes that were up- or downregulated by at least setting.
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Immunocytochemistry differentiated follicular adenomas from FTC with Tissue characterization through selective staining of % sensitivity and %specificity if a cytoplasmic expressed proteins, i.e. IHC, is a technique that stain in $% of the cells was considered positive combines histopathology and biochemistry. Exploiting (). The prospective multicenter clinical validation basic antigen–antibody interactions, IHC is able to studybyBartolazziet al. ()demonstrated% visualize the distribution and localization of specific sensitivity and %specificity in Thy nodules if cellular components within the cell and in the proper a cytoplasmic galectin- stain in .% of the cells was tissue context. This includes tissue biomarkers specific considered positive. Nineteen of the false-positive for infection or malignancy. IHC has been fully in- nodules were FA. However, a group of difficult- corporated in the histopathological routine and is to-diagnose (follicular) tumor of unknown malig- crucial to morphological and molecular tissue char- nant potential lesions was disregarded, of which acterization. When ICC, the application of this were galectin- negative. If these neoplasms were immunology-based technique in cytology, became considered malignant, sensitivity dropped to % available, the possibilities were extended to the pre- (). operative setting, too. Specific immunomarkers have been developed to differentiate between benign and HBME-1 malignant thyroid nodules. The ATA guidelines HBME- is a monoclonal antibody targeting an un- acknowledge ICC as a technique under development known antigen on the microvilli of mesothelial cells. It with limited prospective validation studies in in- is usually negative in normal thyroid follicular cells. determinate cytology (). In unselected thyroid cy- Abnormal expression of HBME- shows cytoplasmic tology, the much-used immunomarkers galectin-, location with membrane accentuation. It is associated Hector Battifora mesothelial- (HBME-), and cyto- with, but does not necessarily indicate PTC (, , keratin (CK-) demonstrated %, %, and % , ). Its low detection limit enables assessment in sensitivity, and %, %, and % specificity, re- liquid based cytology (). Reported sensitivity and spectively (). specificity of HBME- in indeterminate nodules ranged from %to% and from %to%, Galectin-3 respectively (, , , ). Approximately two Galectin- is a b-galactosyl-binding protein from the out of five nodules showed positive staining. If only lectin group. It is involved in cell-cycle regulation, nononcocytic follicular neoplasms were selected, including cell migration and adhesion. Its exact Saggiorato et al. () demonstrated that HBME- had function is still to be unraveled, but a role in the excellent % sensitivity and % specificity in in- pathogenesis and progression of PTC is presumed (, determinate thyroid nodules. –). It is related to inhibition of apoptosis, in- duced by abnormal p expression (). Galectin- Cytokeratin 19 can be present both in the intracellular as well as the CK- is a type I keratin. It belongs to the group of extracellular matrix (). Normal thyrocytes do not intermediate filament proteins, which arrange the express galectin-, but the physiological expression of cell cytoskeleton and structural integrity. CK- is galectin- in macrophages, neutrophils, mast cells, and widely present in epithelial cells, but also found in Langerhans cells provides an internal positive control basal cells layers of stratified epithelium (, ). of the investigated FNAC samples (, ). Positive Strong and diffuse abnormal expression of CK- cytoplasmic staining, as opposed to nuclear staining, indicates PTC, including FVPTC. Expression in for galectin- is suspicious for malignancy and mainly FTC is less intense and more variable, warranting associated with PTC (, , ). Galectin- ex- nuanced interpretation of CK- staining intensity. pression has also been associated with the malignant CK- usually shows no or only focal expression in transformation of follicular neoplasms, as it was follicular neoplasms, hyperplastic nodules, and present in FA as well as FTC (, , ). En- adenomatous goiter (, , , ). The re- capsulated FVPTC and minimally invasive FTC ported sensitivities and specificities for CK- showed less frequent and weaker staining (, ). staining in indeterminate cytology ranged from In , Bartolazzi et al. () argued that %to%and%to%, respectively (, , galectin- staining could accurately diagnose thyroid ). Lacoste-Collin et al. ()demonstratedthe carcinoma in unselected thyroid cytology. Sub- importance of an accurate threshold. CK- sequent studies in indeterminate thyroid cytology staining in Bethesda IV nodules accurately di- mostly could not reproduce these promising results. agnosed five out of six malignancies, including With a positive stain in approximately one-third of a PTC, two FTC, and two out of three FVPTC. At all nodules, sensitivity and specificity of galectin- a threshold of $% stained cells, of benign ranged from %to%andfrom%to%, lesions tested false-positive; at a more sensitive respectively (, –). Merely Saggiorato et al. threshold of $%stainedcells, of tested () demonstrated that galectin- accurately false-positive ().
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Other ICC markers and many other researchers advocate that a panel of IHC studies identified more potential ICC markers. ICC markers should be applied to strengthen the Some, like CDv, have not yet been investigated in suspicion of malignancy (, , , ). Several indeterminate cytology (). Other markers were panels were investigated in literature. Zhang et al. sporadically investigated in preclinical studies, in- () assessed a triple stain of galectin-,HBME- cluding Ki-, TROP-, emerin, keratan sulfate, thy- and p.P is a cyclin-dependent kinase inhibitor roperoxidase, CD, and GLUT-. related to cell life span in normal thyroid cells. Nuclear protein Ki- is expressed in nearly all cell Downregulated in malignancy, positive P stain is cycle phases in proliferating cells. It is associated with related to benign histopathology. In a set of Bethesda poor prognosis in PTC (). The percentage of cells III cytology samples, positive p staining with with Ki- expression is considered the tissues’ pro- negative galectin- and HBME- staining was % liferative index. At a cutoff of $% Ki- was % predictive of a benign nodule and occurred in %of sensitive and % specific for thyroid carcinoma in samples. Loss of p staining in combination with Bethesda IV nodules. A combination of HBME-, CK- positive galectin- and/or HBME- staining was , and Ki- immunomarkers was % accurate to % sensitive and %specific(). Another study diagnose malignancy (). Ki- expression is likely investigated galectin- and HBME- in combination only distinctive for follicular type carcinoma; ex- with a RET proto-oncogene stain, which reflects pression in PTC is generally low (, , ). abnormal intracellular RET proto-oncogene activity Glycoprotein human trophoblast cell surface and presence of the RET/PTC rearrangement. Un- marker (TROP-) is overexpressed on the cell surface fortunately, RET staining was inaccurate in in- of different epithelial carcinoma (e.g., breast, colon) determinate thyroid nodules (). and associated with tumor aggressiveness and poor To find the most accurate combination of prognosis. In indeterminate thyroid cytology, it was immunostains, Saggiorato et al. () explored the only assessed in one small subseries of Bethesda III expression of galectin-, HBME-, thyroperoxidase, samples, correctly diagnosing the three included car- CK-, and keratan-sulfate in cytological follicular cinoma and all but one of the nine benign nodules neoplasms, of which were H¨urthle cell lesions. “ (). Galectin- was not only the most accurate marker The common denominator between all these studies is the Emerin staining emphasizes features of the nu- individually, but also in combination with other stains. combined use of galectin-3 clear membrane often seen in PTC, such as irreg- Sequential HBME- staining of galectin- -negative and HBME-1.” ularities and invaginations. Consequently, the stain cases reached % sensitivity and % specificity in could facilitate the morphological diagnosis of PTC nononcocytic lesions. In oncocytic lesions, sequential and especially the more difficult-to-diagnose FVPTC CK- staining was more preferred with % sen- (, ). In Thy nodules assessed by Asioli sitivity and % specificity (). et al. (), positive emerin staining was highly The common denominator between all these specificforPTC(includingFVPTC),butmis- studies is the combined use of galectin- and HBME-. diagnosed all FTCs. Unfortunately, clinical validation studies regarding Another immunomarker associated with PTC is this combination are limited. Its seemingly promising keratan sulfate, an abnormal glycosaminoglycan diagnostic accuracy warrants further assessment in complex. It was % specific in indeterminate cytology, future prospective studies. but correctly predicted PTC only; its sensitivity was poor at %(). Performance of ICC in Hurthle¨ cell cytology The expression of thyroid peroxidase (TPO) is Expression of ICC markers in H¨urthle cell nodules related to benign follicular neoplasms. A negative TPO differs from nononcocytic indeterminate cytology. stain was % sensitive and % specific for thyroid H¨urthle cell carcinomas were distinguished in the malignancy (). cytological samples by typical overexpression of Finally, CD (Leu) expression is associated with markers associated with a high degree of cell pro- epithelial and nonepithelial malignancies, including liferation, disorganized tissue structure, and in- thyroid carcinoma. Cytological staining was only in- termediate differentiation, such as Ki-, laminin, vestigated in a small series of indeterminate cytology, cyclin D, and cyclin D. Overexpression reflects the but seemed specific for PTC. In the same series, known more erratic behavior of H¨urthle cell carci- GLUT- was not a useful ICC marker, there were no noma (, ). Moreover, markers that were highly positive stains (). diagnostic in indeterminate nodules in general, also seem differently expressed in H¨urthle cell lesions. Combined use of ICC markers Saggiorato et al. () demonstrated that two com- Some research groups have suggested that evident binations of ICC markers were extraordinarily accu- single-marker galectin- positivity is sufficient to rate: galectin- and CK- staining was % sensitive refer a patient for total thyroidectomy (, , ). and % specific; galectin- and thyroperoxidase The ATA guidelines did not adopt these suggestions, staining was % sensitive and % specific().
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In a previous meta-analysis, inclusion of H¨urthle driver mutations, this technique unites the strengths of cell lesions was related to between-study heterogeneity gene mutation analysis and ICC in one technique, (). H¨urthle cell lesions require a biotin-free ICC though likely at lower costs. method, as H¨urthle cells themselves are rich in biotin. In general, ICC is a widely available and relatively Thus, much-used biotin-based methods may conse- inexpensive technique with a reasonable diagnostic quently cause false-positive and highly intensive accuracy. Many immunomarkers seem to have staining in H¨urthle cell neoplasms (, , ). a pronounced association with PTC. Galectin- and HBME- were most frequently investigated, but their Availability, cost-effectiveness, and limitations specificities and sensitivities seem to fall short of of ICC justifying ICC-based surgical decision making. Di- Current application of ICC is limited. Clinical vali- agnostic accuracy of their combined use seems dation studies for all of the described immunomarkers promising, yet current evidence is limited. Prospective are scarce, and no cost-effectiveness studies are validation trials are warranted to confirm the di- available to date. Yet, the technique is widely available, agnostic potential of ICC, including validation of relatively inexpensive and fast in comparison with thresholds for stain positivity, panels of multiple other (molecular) techniques. Costs per immunostain immunostains, and other methodology. vary up to V, partly depending on simultaneous local application of the technique and similar stains for IHC. Conventional Imaging ICC is preferably performed on cell block FNAC specimens, but can be performed in all types of cy- Ultrasound tology, from direct smears to liquid-based cytology US is one of the principal steps in the initial workup of (, ). ICC is impossible when the FNAC spec- thyroid nodules. It is cheap, fast, noninvasive, and imen has poor cellularity or too much obscuring blood globally available, but accurate assessment strongly (). Also, immunostaining of cytology is technically depends on operator experience (). Multiple meta- more difficult than histological staining, especially in analyses showed that well-known US features such as (destained) cytology smears. Technical inconsistency nodule hypoechogenicity, microcalcifications, irregu- and interobserver variation likely lead to false-negative lar margins (including microlobulated or ill-defined results (, ). Stain intensity thresholds or per- margins), and a taller-than-wide shape raise the sus- centage of stained cells necessary to raise suspicion of picion for thyroid malignancy and are mostly asso- malignancy vary in the available literature. Consistent ciated with PTC (, ). Nonetheless, no single US methodology and assessment thresholds should be feature is sufficiently sensitive or specific to accurately determined to improve reproducibility of ICC results. identify a malignant nodule in an unselected pop- Clinical validation studies of existing ICC markers ulation (). Certain combinations of US features, are ongoing. Meanwhile, new markers are also playing however, may offer accurate closure. The current ATA the field, searching for the interfaces between mutation guidelines now include a flowchart recommending analysis of highly specific oncogenic driver mutations FNAC dependent on nodule size and various com- and accessible ICC techniques. For example, Leslie binations of US characteristics with an incremental et al. () investigated ICC of the BRAFV E mutation risk of malignancy (). Despite the obvious importance using the mutation specific antibody VE in a small of both US and cytology, the ATA guidelines do not series of thyroid FNAC samples. Concordance be- provide recommendations regarding (re)interpreta- tween ICC and conventional BRAFV E mutation tion of US characteristics after FNAC has resulted in analysis was %. All samples that were BRAFV E indeterminate cytology. Follicular-type malignancies positive by either method were confirmed as typically have a different US appearance. More often BRAFV E positive PTC on histopathology. Of the FTC may be iso- to hyperechoic, with a spherical eight included indeterminate thyroid nodules, seven shape, smooth regular margins, and no calcifications were histopathologically malignant and BRAFV E (, ). FVPTC may also show FTC-like or benign mutation was detected in two nodules: one by both features rather than the classic suspicious features, methods, one only by molecular analysis. The although microcalcifications may be distinctive BRAFV E specific antibody (VE) stain was much (–). In the past years, Brito et al. () and weaker in cytology than in histology. Moreover, costs Remonti et al. () performed meta-analyses on US of the VE antibody are currently high and optimi- assessment of unselected thyroid nodules. Both also zation of methodology is warranted. Yet, Leslie et al. briefly discussed its diagnostic value in indeterminate () demonstrated that BRAFV E mutation analysis nodules, including a mere limited number of studies using ICC is a promising alternative to mutation and also including cytology suspicious for malig- analysis. If future studies could validate these results in nancy. Increased central vascularization was most larger cohorts of indeterminate thyroid nodules and predictive of malignancy with reported %speci- detect reliable immunomarkers for other oncogenic ficity (). Yet, in general US seemed less accurate in
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indeterminate nodules than in unselected thyroid conservatively. The uniquely balanced rates of PTC, nodules (, ). FVPTC, and FTC resulting from indeterminate cy- In the dozens of available original ultrasound tology may explain why these and various other US studies, individual US features generally demonstrated characteristics have different diagnostic accuracy than limited sensitivity in indeterminate thyroid nodules. in the unselected population. Dependent on the local Only the appearance of a solid thyroid nodule, as case mix, accurate differentiation of indeterminate opposed to varying degrees of cystic content, had high nodules using the classical suspicious US features may sensitivity. Ranging between % and %, multiple or may not be feasible. studies demonstrated sensitivity above %(, , –). Combination of US characteristics A number of classic suspicious US characteristics, A combination of US characteristics likely provides such as a taller-than-wide shape, presence of irregular more accurate differentiation than individual features. margins, and presence of microcalcifications, dem- Different combinations were investigated in multiple onstrated valid specificity in indeterminate thyroid studies (, , , , –, , –). Yoo nodules. Specificities for each of these characteristics et al. () reported % specificity for the combi- ranged from %to%(–), %to%(, nation of marked hypoechogenicity and taller-than- , ), and %to%, respectively (, ). wide shape, a pattern that occurred in .%(/)of Despite the wide range, presence of microcalcifications the included Bethesda III nodules. In the elastoso- was more than % specific in many studies (, , nography study by Rago et al. (), absence of , –, , , –). Large nodule size a hypoechoic halo in combination with presence of (defined as a diameter larger than cm) was only microcalcifications was % specific for thyroid ma- investigated in a limited number of studies. Reported lignancy, but only .% sensitive. Maia et al. () specificities ranged between % and %(, ). found % sensitivity and % specificity in Bethesda Other features, such as a solitary nodule, hypo- III and IV nodules if hypoechogenicity, micro- echogenicity and absence of a hypoechoic halo were calcifications, an irregular margin, and increased associated with thyroid malignancy, but less accurately intranodular vascularity were considered suspicious. “Altogether, diagnostic US differentiated between benign and malignant in- Gulcelik et al. () demonstrated that the US pattern scores or step-by-step fi algorithms could aid the determinate thyroid nodules ( , , , , of a solid, hypoechoic nodule with microcalci cations fi – fi classi cation of US patterns ). Additionally, opposing the results from one had % sensitivity and % speci city. The pattern and consequent risk of of the mentioned meta-analyses, central vasculariza- was seen in % of cytological follicular neoplasms. malignancy.” tion also does not seem very accurate in indeterminate In multiple studies, it was argued that cytological thyroid nodules. Specificity ranged from %to%, follicular neoplasms with a typically benign US pattern although multiple studies demonstrated extremely (a regular shape, isoechoic, homogeneous, with well- poor specificity (, , –). defined margins, cystic components or peripheral Results regarding two US features are remarkably vascularity only, and not a single malignant feature) contradicting. First, the absence of a hypoechoic halo is could be safely followed up clinically instead of un- typically considered suspicious for malignancy, but dergoing diagnostic surgery (, , ). Consid- showed overall poor and very heterogeneous di- eration of more features generally increased the agnostic potential in indeterminate thyroid nodules sensitivity of the US assessment at the cost of its (). Sensitivity and specificity ranged from %to specificity (, ). The terms of their interpretation % and %to%, respectively (, , , , were crucial: Norl´en et al. () demonstrated that US ). Presence of a hypoechoic halo is typically con- was % sensitive and % specific if a Bethesda III sidered a benign feature, but has also been associated nodule had either hypoechoic appearance, irregular with follicular types of thyroid carcinoma (). margins, or microcalcifications. If solely the simulta- Dogan et al. () reported % specificity for presence neous presence of all three features was considered of a halo in AUS/FLUS nodules and % in FN/SFN suspicious for malignancy, sensitivity dropped to % nodules. Second, the ultrasonographic nodule shape but specificity increased to %. seems ambiguous. Similar to the unselected pop- Altogether, diagnostic US scores or step-by-step ulation, a typically suspicious taller-than-wide shape algorithms could aid the classification of US patterns was generally specific for carcinoma, with reported and consequent risk of malignancy (, , ). specificities up to %(, , ). A spherical Best-known and most validated is the Thyroid Im- shape is generally considered benign, but has also been aging Reporting and Data System (TIRADS), a clas- associated with FTC (, , ). In two studies in sification to risk-stratify thyroid nodules, designed by cytological follicular neoplasms, a spherical shape had Horvath et al. () and modified by Kwak et al. () an increased risk of malignancy, with %to% following the example of the similar BIRADS classi- sensitivity and %to% specificity (, ). Chin fication for breast lesions. The TIRADS assigns et al. () even suggested that follicular neoplasms nodules to a risk category based on five suspicious US with a taller-than-wide shape could be treated features: solid appearance, (marked) hypoechogenicity,
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irregular margins, microcalcifications, and a taller- customarily based on the results of the prior US, the than-wide shape. Nodules without any of these fea- prevalence of suspicious US features in indeterminate tures are likely benign and categorized as TIRADS . cytology in these studies is presumably overestimated. Their risk of malignancy is ~.% in a cytologically Nonetheless, several individual US characteristics unselected population. TIRADS includes suspicious seem to have reasonable specificity in indeterminate nodules, which are further classified according to an nodules, although insufficient for accurate diagnosis. A increasing malignancy risk into a (one suspicious US combination of US features is likely more accurate, feature), b (two suspicious features), and c (three or although current evidence does not support US-based four suspicious features). Nodules with all five sus- surgical decision-making. We propose that a future picious US features are classified as TIRADS and meta-analysis should use the individual patient data associated with a high % risk of cancer in an un- from the large number of available original studies to selected population (). Studies that validated the develop a US algorithm specifically for indeterminate TIRADS specifically in indeterminate thyroid nodules thyroid nodules. The existing TIRADS needs pro- showed that diagnostic accuracy depended on the spective validation. chosen cutoff score and type of cytology (, , Even though more advanced and less operator- –). Although TIRADS scores were in- dependent techniques might be preferred, US features frequently assigned in indeterminate nodules, a higher should always be assessed in current clinical practice. TIRADS score (b/c/) was an accurate predictor of The presence of one or more suspicious US features in malignancy, especially in Bethesda IV cytology (, a Bethesda III or IV nodule increases the suspicion of , ). In Bethesda III nodules, lower TIRADS malignancy and underpins the need for a definite scores (/a) could also rule out malignancy (, ). diagnosis. Moreover, to centers or regions with limited Prospective validation studies applying the TIRADS in access to other (molecular) diagnostics, US may def- indeterminate cytology are warranted to assess its initely have clinical utility, pending local validation in possible clinical utility in indeterminate nodules. the indeterminate population.
US performance in Hurthle¨ cell nodules Elastosonography Cytological H¨urthle cell nodules expressed a large Firm consistency of a thyroid nodule upon palpation is variation of US characteristics (, , , ). considered suspicious for malignancy, an established Many malignant and most benign H¨urthle cell nod- principle during physical examination (). US ules had a benign US appearance (, ). Only elastosonography (USE) is a dynamic US technique three US features possibly predictive of malignancy that is sometimes referred to as “electronic palpation.” were reported in individual studies: both hypo- Tissue elasticity is evaluated by measuring tissue echogenicity and hyperechogenicity (as opposed to distortion while applying a standardized dosed ex- isoechogenicity) (), large nodule size (), and ternal force by the US transducer. It was first applied to microcalcifications (). Despite limited evidence, US the thyroid gland by Lyshchik et al. ()in. evaluation does not seem reliable to differentiate Classic real-time qualitative USE is performed by free- H¨urthle cell lesions. hand compression and a sine-wave or numerical scale showing how much pressure the operator applies with Availability and limitations of ultrasonography the probe. A color-coded elastosonography image is The major advantages of US over other additional superimposed on the grayscale US images: red and diagnostics are its already permanent position in the orange visualizes high tissue elasticity (soft tissue), workup of thyroid nodules, global availability, and low green represents intermediate elasticity, and blue low costs. No additional resources or hospital visits are elasticity (firm tissue). Several score systems are needed to include US interpretations in preoperative available. The original score was developed by Itoh management decisions and the investigation is non- et al. ()in for the evaluation of breast tumors invasive. Nonetheless, besides known limitations and considers scores to benign on a scale of concerning interobserver variability and less reliable (highest elasticity) to (no elasticity). Rago et al. (, interpretation of small nodules, US feasibility in in- ) first applied it to thyroid tumors and modified it determinate thyroid nodules is limited by the pre- to a three-point score. Asteria et al. () derived sumed differences in US appearance of papillary and a modified four-point score. follicular thyroid malignancies, illustrated by the The earliest studies in thyroid nodules reported conflicting results for nodule shape and hypoechoic opportune results of USE as an additional modality to halo in indeterminate nodules. Consequently, local B-mode US, but were heterogeneous in USE technique diagnostic accuracy likely follows variations in the and study population (). A recent meta-analysis by local histopathological case mix. Nell et al. () included studies on qualitative USE In addition, many of the available ultrasound prior to FNAC and concluded that qualitative USE is studies are retrospective, limiting the power of the fit to diagnose benign nodules and safely dismiss evidence. As the decision to perform FNAC is FNAC, provided that the usual elasticity score cutoff is
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abandoned and only completely soft nodules (score cutoff score of in unselected nodules deserves clinical of all systems) are classified as benign. Pooled % validation in indeterminate thyroid nodules. Major sensitivity and % negative predictive value dem- advantages of the technique are the minor extra costs onstrated the ability of USE to reliably rule-out ma- of USE, as it can be performed during regular thyroid lignancy in entirely soft thyroid nodules, composing US with the same equipment, and only adds % of their pooled study population (). ~ minutes to the procedure time per patient. Cost- In individual studies on USE in indeterminate effectiveness will largely depend on performance of nodules, sensitivity and specificity of qualitative USE USE, but no cost-effectiveness studies in indeterminate ranged from %to% and from %to%, re- thyroid nodules are available to date. spectively (, –). Results of several qualitative USE studies stand out. Lippolis et al. () showed an Computed tomography aberrant .% specificity, because they reported only There are no studies that investigated CT scanning in eight nodules with high elasticity, of benign thyroid nodules with indeterminate cytology. Prior nodules were not elastic. The authors themselves studies indicated that CT cannot accurately differen- suggest that a rather homogenous study population tiate thyroid carcinoma (, ). with predominantly small nodules with a solid US pattern, absence of cystic areas, and follicular histology with minimal colloid could be explanatory for the poor Functional and Molecular Imaging specificity rather than operator-dependent causes (). Such possible relations remain undescribed in 99mTc-MIBI other studies. A meta-analysis on the value of USE in Hexakis(-methoxy--methylpropylisonitrile)techne- indeterminate thyroid nodules demonstrated meager tium[ mTc] ( mTc-MIBI) is a Technetium-m- pooled % sensitivity and % specificity (). labeled radiopharmaceutical, primarily known for its As manually applied pressure is difficult to stan- use in myocardial perfusion imaging since the s dardize, qualitative USE is strongly operator de- and more recently the evaluation of hyperparathy- pendent (). Different USE techniques have been roidism. Uptake of mTc-MIBI, a lipophilic cation, “ developed to improve objectivity, such as semi- reflects both perfusion and the number of active mi- As manually applied pressure is difficult to standardize, quantitative tissue-to-nodule strain ratio indices (also tochondria in the cells of the thyroid nodule and thus its qualitative USE is strongly based on manual compression). Studies investigating oxidative burden (, ). ” operator dependent. semiquantitative USE in indeterminate thyroid nod- mTc-MIBI scintigraphy is more suitable for the ules reported sensitivity and specificity ranging from differentiation between benign and malignant thyroid %to% and from %to%, respectively (, nodules than scintigraphy with mTc-pertechnetate m 2 , , ). Furthermore, quantitative shear wave ( TcO ) or radioisotopes of iodide (often 2 2 2 USE measures the propagation velocity of focused I , I or I ). These latter tracers interrogate acoustic pulses, shear waves, from the probe, which the sodium-iodide symporter of the thyrocyte and are correlate to tissue stiffness (Young’s modulus) (, frequently used to assess thyroid nodule functioning ). It had % sensitivity and % specificity in to distinguish autonomous (“hot”)fromhypo- a recent prospective pilot study by Samir et al.(). functioning (“cold”) nodules. They are neither spe- Performance of (semi)quantitative USE seems better cificnoreffective to detect malignancy: benign than qualitative USE, but results are subject to over- nodules can be anything from hyper- to hypo- fitting from the ROC analysis performed to determine functioning, and far outnumber the carcinomas. Still, the strain ratio cutoff value with the highest sensitivity thyroid malignancies are almost always hypo- and specificity. None of the studies applied a pre- functioning: decrease of the sodium-iodide sym- defined cutoff or validated their own cutoff externally. porter or TPO are hallmarks of cell dedifferentiation Consequently, the resulting thresholds were hardly and lead to loss of iodide-trapping function and comparable (, , , ). thus mTc-pertechnetate or radioiodine uptake Altogether, the results from currently available (, –). mTc-MIBI uptake is independent of studies cannot support surgical decision-making in iodide trapping and organification in the thyrocytes. thyroid nodules with indeterminate cytology using Nodules with increased uptake and late retention elastosonography in any of its forms. Whereas color- of mTc-MIBI are suspicious for malignancy coded qualitative USE has insufficient sensitivity and (, ). A meta-analysis by Treglia et al. () specificity, the semiquantitative method lacks valida- demonstrated % sensitivity and %specificity for tion. The power of the available evidence is addi- mTc-MIBI scintigraphy in clinically suspicious, tionally limited by both methodological heterogeneity hypofunctioning, cytologically unselected thyroid and the use of different USE techniques, image pro- nodules. Hyperfunctioning benign adenomas can cessing, and elasticity scoring methods across studies. show false-positive increased uptake of mTc-MIBI Nevertheless, the suggested promising rule-out ca- due to their increased metabolic needs, thereby de- pacity of qualitative USE when applying an alternative creasing test specificity.
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Only three studies investigated the role of mTc- ). Excluding H¨urthle cell nodules from mTc- MIBI in indeterminate thyroid nodules. In all studies, MIBI assessment likely excludes many false-positive evaluation of thyroid nodules was performed by dual- tests while improving benign call rate, specificity, and time planar imaging: an early image was made ranging overall diagnostic accuracy in indeterminate thyroid from to minutes after injection of the radio- nodules. pharmaceutical and a delayed image to minutes post injection. The intensity of the mTc-MIBI uptake Availability, cost-effectiveness, and limitations within the nodule, and possible increased uptake or of 99mTc-MIBI denoting retention on delayed imaging were assessed Imaging of mTc-MIBI requires conventional gamma and compared with the physiological washout of the cameras [with or without single-photon emission tracer from normal thyroid tissue. A visual pattern of computed tomography (SPECT) and CT], which are increased mTc-MIBI uptake on early images that more widely available than PET, especially in non- persisted or further increased on the delayed images Western countries. Furthermore, the tracer itself is was generally considered suspicious for malignancy. more widely available due to relatively simple com- The individual study sensitivity and specificity for this plexation using mTc-MIBI-kits together with the interpretation ranged from %to% and from % favorable half-life of mTc (~ hours) obtained from to %, respectively (, , ). Despite the limited on-site generators. The radiation burden of the number of available studies, the performance of recommended whole-body adult dose is to mil- mTc-MIBI in indeterminate thyroid nodules seems lisievert, but can be lowered by a factor to by insufficient and less accurate than in cytologically partial-body imaging (). However, the system unselected nodules (). resolution of state-of-art gamma cameras is a factor Nonetheless, Giovanella et al. () demonstrated lower than of PET/CT cameras. This decreases the that NPV for this method could increase from %to measured signal of lesions smaller than mm, in- % if only the pattern of mTc MIBI uptake lower creasingly limiting test sensitivity in smaller nodules. than or equal to the pertechnetate uptake within the Average costs of mTc-MIBI scanning range from nodule was considered benign. As few benign lesions V to V in Europe and from $ to $ in expressed this uptake pattern, this would decrease the the United States (, , ). From a German yield of this diagnostic. perspective, mTc-MIBI-based management was cost- Piccardo et al. () did not preselect hypo- effective over Afirma® GEC-testing and conventional functioning lesions, but included all indeterminate management. However, this study inappropriately thyroid nodules. As expected given the explanation extrapolated auspicious performance parameters of above, the specificity of mTc-MIBI was poor: %. mTc-MIBI in unselected thyroid nodules (% Assessment of a retention index of the tracer based sensitivity and % specificity) to the indeterminate on semiquantitative measurements of the lesion to population, and likely underestimated modeled costs nonlesion uptake ratios for early and delayed mTc- for mTc-MIBI scanning and thyroid surgery (, , MIBI images yielded better accuracy. Optimal , , , , ). Therefore, these assumptions thresholds for the retention index were determined regarding cost-effectiveness in indeterminate thyroid using ROC analysis and unfortunately not externally nodules are decidedly questionable and require careful validated (, ). As such, it is unclear whether re-evaluation. semiquantitative mTc-MIBI retention indices are Altogether, there is an increased risk of malignancy truly more accurate than conventional visual assess- in thyroid nodules that show increased mTc-MIBI ment. Moreover, semiquantitative analysis is still uptake, provided that hypofunctioning nodules are operator dependent, as it depends on the manual preselected. Nonetheless, test performance in in- definition of ranges of interest (ROI) (). determinate thyroid nodules seems insufficient. Ex- cluding H¨urthle cell lesions suggests high specificity, 99mTc-MIBI in thyroid nodules with Hurthle¨ but does not resolve the reported poor sensitivity. cell cytology However, the number of studies currently available for Oncocytic cells are rich in mitochondria. Therefore, indeterminate thyroid nodules is limited. We believe H¨urthle cell lesions, malignant as well as benign, prospective validation studies in nononcocytic in- frequently show a more intense and persistent mTc- determinate thyroid nodules should be performed. MIBI uptake (, , ). Boi et al. () in- Future studies should also focus on external vestigated mTc-MIBI in cold thyroid nodules with threshold validation for retention indices to reduce varying proportions of H¨urthle cells in the cytology operator dependency and increase accuracy and samples. A relation between mTc-MIBI uptake and objectivity of mTc-MIBI. Based on the current increased tissue density of oncocytes was suggested evidence, we recommend that mTc-MIBI scanning (). Subsequent studies also concluded that mTc- is not used in surgical management decisions MIBI is not specific enough to differentiate in- in indeterminate thyroid nodules without another determinate lesions with H¨urthle cell cytology (, , adjunctive test.
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18 [ F]-2-fluoro-2-deoxy-D-glucose PET specificity of FDG-PET(/CT) to detect thyroid carci- PET using [ F]--fluoro--deoxy-D-glucose (fluo- noma in indeterminate thyroid nodules ranged from rodeoxyglucose or F-FDG), also known as FDG- %to% and from %to%, respectively. A PET, is an imaging modality that exploits the basic negative index test was reported in ~% of patients principle that (malignant) tumors and inflammatory (, , –, , ). tissues are much more metabolically active than Several reasons for false-negativity were proposed, normal tissues. Whereas normal tissues pre- foremost small nodule size. It is how Traugott et al. dominantly produce energy by low rates of aerobic () explained their % false-negative FDG-PET glycolysis followed by the citric acid cycle in mito- scans: eight lesions were histopathologically smaller chondria, glycolytic rates of rapidly growing cancers than cm. Excluding these, sensitivity and NPV in- can be up to times higher. Subsequent lactic acid creased to %. FDG-avidity in very small nodules fermentation takes place even if oxygen is plentiful may be missed on FDG-PET due to the low volume of (the Warburg effect) (). Similar to regular glucose, malignant cells and due to the partial volume effect: the glucose analog F-FDG is internalized by trans- the detected FDG-concentration is underestimated membranous GLUT transporters and converted by dependent on nodule size in relation to the (limited) hexokinase to F-FDG--phosphate. However, unlike spatial resolution of the scanner. In larger nodules, this the -phosphorylation product of regular glucose, F- effect is negligible (, ). Although the improving FDG--phosphate cannot be metabolized further. It is resolution of state-of-the-art PET scanners pushes the trapped intracellularly and thus accumulates in the detection limit toward mm, PET is less sensitive in tissue. Subsequently, PET scanning can visualize the lesions smaller than mm on US. It is less reliable to increased glucose metabolism of the (abnormal) tissue rule-out microcarcinomas (). Theoretically, the (). Nowadays, FDG-PET is generally performed in improving spatial resolution could also become combination with CT (FDG-PET/CT), mainly to a limitation of the technique: not only will there be less correlate metabolically active regions to their anatomic false-negatives, but likely also more false-positive re- substrates and to correct for tissue-attenuation of the sults, leading to a decrease in the already limited radioactive signal. It is increasingly applied in the specificity over time. In the currently available liter- diagnostic workup, staging, and therapeutic response ature, no such downward trend is noted, but future “Several reasons for false- monitoring of various malignancies. For thyroid studies should monitor this possibility. negativity were proposed, cancer, FDG-PET is frequently used to characterize foremost small nodule size.” recurrent disease, especially if dedifferentiation is ex- Semiquantitative FDG-PET pected in thyroid carcinomas that lost the capacity to Semiquantitative analysis of FDG-PET is performed concentrate radioiodide, yet still have measurable using the maximum standardized uptake value serum values of the tumor marker thyroglobulin. It (SUVmax): the ratio between the maximum radioac- may also be considered in the initial staging of poorly tivity concentration measured within a region of in- differentiated or invasive H¨urthle cell carcinoma. terest on the PET image (the “hottest” voxel) and the Moreover, FDG-avid thyroid incidentalomas require decay-corrected amount injected radiotracer per unit additional workup by FNAC when . cm (, ). In of body mass. It reflects the FDG-concentration factor the current ATA guidelines FDG-PET is not routinely compared with a homogenous distribution of the fi recommended for the diagnostic workup of in- radiotracer ( ). The SUVmax is generally signi cantly determinate thyroid nodules due to limited clinical higher in malignant than in benign lesions (, validation, despite a meta-analysis by Vriens et al. –, , ). There is a possible correlation ( ) that demonstrated % sensitivity and % NPV between higher SUVmax values and increasing size in in indeterminate thyroid nodules larger than mm nodules, insufficiently explained by the above- (, ). mentioned partial volume effect (, ). Also, in Results of available individual studies were mu- FTC a higher SUV was associated with capsular or tually consistent despite limited sample sizes. The first vascular invasion (). Nonetheless, even though studies showed extremely promising results; each Kresnik et al. () demonstrated that all carcinoma – $ reporting % sensitivity ( ). De Geus-Oei and H¨urthle cell adenoma had aSUVmax and all , et al. ( ) argued that implementation of FDG-PET other benign lesions a SUVmax , in multiple other could reduce the number of futile hemithyroidectomies studies the SUVmax of benign and malignant in- for benign nodules by %, likely outweighing the determinate thyroid nodules overlapped. No threshold costs of the extra scans and suggesting cost- could accurately tell them apart (, –, , ff e ectiveness of this technique in the preoperative ). Moreover, as SUVmax calculations strongly de- setting. A subsequent study suggested a less optimistic pend on image acquisition and reconstruction % reduction in futile surgeries, following a lower methods, type of PET-scanner, and other variable benign call rate ( ). More recent studies demon- methodology, reported absolute SUVmax thresholds strated more modest performance of FDG-PET(/CT) are not simply valid for other institutions (). (, , , , ). Overall, reported sensitivity and Standardized optimized FDG-PET protocols are
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required for interinstitution comparison of study re- FDG-PET/CT was favored over the miRInform® and sults and advancement of PET research (, ). Afirma® GEC (). Contrasting the generally strong sensitivity, spec- FDG-PET in thyroid nodules with Hurthle¨ ificity of FDG-PET is consistently poor. The un- cell cytology derlying mechanism is not yet fully elucidated. The Multiple studies observed aberrant FDG-PET char- negative influence of H¨urthle cell cytology may be acteristics in indeterminate nodules with H¨urthle cell partly responsible. It could also be explained by cel- cytology: both benign and malignant lesions are lular atypia, which was significantly and independently mostly FDG-positive. Twenty-nine H¨urthle cell lesions related to FDG uptake, and found in both benign and were reported by Deandreis et al. (), consisting % malignant lesions. Atypia was also related to the of their study population and providing an explana- presence of H¨urthle cells (). Sebastianes et al. () tion for their limited sensitivity. Moreover, H¨urthle hypothesized that FDG uptake is related to variations cell adenoma generally demonstrated a significantly in gene expression patterns. They suggested that ge- higher SUVmax than other benign lesions ( , netic variations between populations may also explain –, , ). The proportion of H¨urthle cell the varying diagnostic accuracy of FDG-PET between cytology in individual studies is relatively small, but studies. overall FDG-PET seems inadequate in these In conclusion, FDG-PET(/CT) has the potential to neoplasms. accurately rule-out malignancy in all indeterminate nodules except H¨urthle cell lesions. It could prevent Availability, cost-effectiveness, and limitations unnecessary diagnostic surgery for a substantial of FDG-PET number of benign thyroid nodules. Sample sizes of PET systems are less widely available than conven- existing studies are small, but larger prospective trials tional gamma cameras. Moreover, F used for are currently ongoing to settle the diagnostic value of F-FDG synthesis is produced in cyclotrons, and this technique and its utility in clinical practice. We transport distances are limited due to the short half-life recommend that these studies also focus on identifying of this isotope (~ minutes). In Europe, FDG-PET/ (genetic) causes for the occasional false-negativity and CT is ~. to times more expensive than mTc-MIBI generally low specificity of this technique. SPECT/CT. The radiation exposure of FDG-PET/CT is largely accounted for by the FDG dosage at ~ mSv/ Diffusion-weighted magnetic resonance imaging MBq, i.e., ~ to mSv for a typical activity of MBq Diffusion-weighted magnetic resonance imaging administered to an average adult (). Insights re- (DW-MRI) is a functional nuclear magnetic resonance garding common practice total-body FDG-PET/CT imaging technique that evaluates the rate of random imaging are changing (, ). The CT radiation (Brownian) motion of water in tissue, also called dose greatly varies, and can be less than . mSv for diffusivity. By applying diffusion-sensitizing magnetic a low-dose CT of the neck region only. When scanning gradients (the strength and duration of which are the thyroid region only, a longer imaging time can expressed as b-values) different levels of diffusion- compensate for a reduction in FDG dose, which would weighting are obtained: from nondiffusion images lower the radiation burden as well as the costs. Such (b-value = s/mm ) to highly diffusion weighted solutions may counter prevailing reservations re- images (i.e., b-value . s/mm )(). Lesions that garding ionizing radiation exposure. Additionally, show high signal intensity on DW-MRI images with partial-body acquisition could limit the number of a high b-value thus show restricted diffusion. The coincidental PET-positive findings. Much of the apparent diffusion coefficient (ADC; in mm /s) is criticism on FDG-PET focuses on these potential calculated based on the exponential relationship be- incidental findings, which require additional di- tween signal intensity and the corresponding b-value 2 agnostics, are not always clinically relevant and may according to S(b) = S()*e b*ADC. A high ADC rep- negatively impact potential cost-effectiveness (, resents a high degree of diffusion; a low ADC rep- ). Malignant ipsi- or contralateral thyroid inci- resents diffusion restriction (, ). DW-MRI thus dentalomas are reported while the nodule under in- allows noninvasive quantification of tissue properties vestigation was histopathologically benign (, ). without ionizing radiation exposure for the patient. PET-positive incidentalomas are histopathologically Differentiation between benign and malignant tissues malignant in ~% of patients (). Cost-effectiveness by DW-MRI is based on the assumption that increased of FDG-PET/CT was modeled by Vriens et al. (). cell proliferation, cellular-density, and disorganized From a Dutch health care perspective, FDG-PET/CT structures in malignant tissue restrict random motion driven treatment would decrease the rate of unbe- and thus diffusion of water: a lower ADC-value, to- neficial diagnostic hemithyroidectomies for benign gether with high signal intensity at high b-values, is thyroid nodules by % and reduce the costs per more suspicious for malignancy (, ). Oppo- patient by V compared with the V, ex- sitely, increased ADC-values suggest free movement of penses for conventional surgical treatment. Also, water molecules in the tissue. It is found in for example
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edema, colloid follicles, fibrous tissue, hemorrhage, intratumoral hemorrhage (, ). For accurate and calcification, all of which associated with benign ADC measurement, such macroscopic areas should be tissues (). Prior application of DW-MRI in i.e., manually avoided when drawing a region-of-interest. neuroradiology, breast, and lymph nodes showed high However, avoiding microscopic areas of similar origin, diagnostic accuracy (, ). invisible to the human eye, is an impossible task (). Recent exploratory studies in small cohorts of Furthermore, it is hypothesized that the substantial thyroid nodules found distinctively higher ADC amounts of follicular or H¨urthle cells limit the di- values for benign than malignant nodules (–, agnostic accuracy of DW-MRI, specifically in in- –). A recent meta-analysis in cytologically determinate thyroid neoplasms. Follicular and H¨urthle unselected thyroid nodules estimated that DW-MRI cell neoplasms are known for their varying colloid had % sensitivity and % specificity to distinguish tissue involvement. Histologically they contain more thyroid carcinoma (). Among the individual fluid. Thus, DW-MRI would inaccurately provide studies, however, presented optimum ADC thresholds a more benign image (, ). These hypotheses are varied and were not externally validated (–, currently based on very limited evidence. Further –). prospective validation studies are desired to determine Only one small study had assessed DW-MRI in the possible diagnostic value of DW-MRI in in- indeterminate thyroid nodules to date. Nakahira determinate thyroid nodules. Future prospects also et al. () reported a mean ADC value of . 6 include improvements of the technique, including 2 . * mm /s in malignancies opposite . 6 consensus on methodology and standardization of 2 . * mm /s in benign nodules with in- acquisition techniques. determinate cytology. These results were similar to those of their entire study population (n = ), in which 2 a cutoff ADC value of . 6 . * mm /s was Combined and Multistep Diagnostics % sensitive and %specific. The previous sections of this review addressed the Availability and limitations of DW-MRI large number of available diagnostic tools to assess “ DW-MRI is infrequently and only experimentally used indeterminate thyroid nodules. Most studies focused DW-MRI is infrequently and only experimentally used in in the workup of thyroid nodules. Nonetheless, the on a single diagnostic technique only. The elimination ff the workup of thyroid worldwide availability and application of MRI is of between-study population-level di erences is nodules.” growing. As it uses no ionizing but only radio- a major advantage when comparing the performance frequency radiation, the associated risk to the patients of multiple diagnostics independently in one study, is limited, provided that specific measures are taken for optimally in a prospective, independent, and blinded patients with MRI-incompatible implanted devices or fashion. Moreover, assessment of multiple techniques metal. No MRI-contrast is necessary for DW-MRI, in one study allows investigation of the comple- thus avoiding gadolinium-associated toxicity. As the mentary value of multiple techniques as a diagnostic spatial resolution of MRI-scanners is still improving, tool by means of simultaneous or sequential testing technical limitations of DW-MRI with regard to while at the same time aiding to further unravel tumor minimal lesion size are becoming less relevant com- biology as a research tool, especially in the current pared with SPECT and probably also PET. Still, spatial multidisciplinary in-hospital working environment. resolution of DW-MRI sequences is less than that of For example, the question how the presence of conventional anatomical MRI-sequences. a certain oncogenic mutation relates to the (positive) There are several major limitations to DW-MRI. result of an FDG-PET scan could be addressed. MRI is still a rather costly technique; additional se- Piccardo et al. () compared mTc-MIBI, FDG- quences such as DW-MRI adds scanner time (~ to PET/CT, and US plus USE in indeterminate TIR minutes) per patient and thus further increases costs. nodules with a % malignancy rate. FDG-PET/CT DW-MRI methodology is not standardized yet and its was the superior technique with % sensitivity and optimal settings still unsettled, leading to varying ADC % specificity. Following a nonspecific positive FDG- and b-values (, , ). Suboptimal methodology PET result, review of US characteristics offered slight or artifacts cause poor image quality, impede accurate further differentiation; it improved specificity to %. interpretation, and caused undesirable exclusions from However, an additional negative mTc-MIBI scan already small-sized studies, with reported exclusion increased specificity to %; this combination was rates up to %(, , ). Image artifacts are found in % of patients. often caused by inhomogeneity in pathologic tissues or Giovanella et al. () performed both mTc-MIBI by their vicinity to interfaces between soft-tissues and and a seven-gene mutation panel in cold in- bone or air, a source of MRI-artifacts specifically in the determinate thyroid nodules. Combined testing did thyroid region. Besides viable tumor tissue, malignant not improve diagnostic accuracy. Performance of the tumors partly exist of components with high diffu- gene mutation panel was inferior to mTc-MIBI sivity, such as necrosis, cystic components, or imaging. Of the seven (%) mutation-positive
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nodules (four RAS mutations and three PAX/PPARg frequently occurred in thyroid nodules without sus- rearrangements), only four were malignant. It is un- picious US features (, ). In Bethesda III and IV clear whether the low sensitivity of the gene mutation thyroid without suspicious US features, the prevalence panel in this study can be explained by the selected of the BRAF mutation was only .%(/) in the population of hypofunctioning nodules. study by Seo et al. (), very low, particularly for a South Korean population, all while the malignancy Elastosonography and ultrasonography rate was still %(/). Considering the negligible USE is superior to US in indeterminate thyroid yield at additional costs, BRAF mutation analysis nodules, both individual US characteristics as well as might not be contributory in indeterminate nodules combined US patterns described in various articles without suspicious US features. An even lower yield (–, , , , ). Two recent prospective from BRAF mutation analysis in US-unsuspicious studies demonstrated that additional USE evidently nodules is presumed in populations with a lower improved the diagnostic accuracy of US. Garino et al. general prevalence of BRAF mutations. Additionally, () included nodule stiffness as additional char- these results suggest a different US appearance of acteristic into a panel of US characteristics and BRAF mutation-negative malignancies, or a different demonstrated that USE identified eight additional molecular profile of thyroid carcinoma without sus- malignancies that would have been missed by US picious US features. assessment alone. Presence of one or more suspicious RAS mutation analysis and assessment of the US/USE features was % sensitive; two or more % typical suspicious US features could be complemen- sensitive and % specific. Benign test results were tary in the differentiation of indeterminate thyroid found in % of patients. The authors suggested that nodules, as follicular-type thyroid carcinomas are the .% remaining risk of malignancy, similar to the associated with RAS mutations and infrequently benign cytology category, would justify follow-up showed the typically suspicious US features (, , instead of diagnostic hemithyroidectomy in this –). Combined assessment could improve di- group (). In another study of Thy nodules, agnostic accuracy of either technique in indeterminate semiquantitative USE correctly diagnosed % of the thyroid nodules, identifying papillary thyroid malig- histopathologically benign lesions that were consid- nancies through classic suspicious US features and ered suspicious for malignancy on US, and % of the follicular-type carcinoma by RAS mutation analysis. malignancies that were misdiagnosed as benign on US However, challenges for clinical practice continue to (). These results suggest that the existing TIRADS exist in the imperfect specificity of RAS mutation classification could be extended with tissue elasticity analysis, and the interobserver variability and ambi- features. In unselected thyroid nodules, this improved guity of certain US features. TIRADS sensitivity, but not specificity (, ). The combination is a suitable topic for future research in ICC and mutation analysis indeterminate thyroid nodules. Major benefit is that In histopathology samples, certain genetic alterations the two techniques are individually inexpensive and were correlated to positive staining for specific obviously easily combined during one diagnostic immunomarkers: PAX/PPARg rearrangement was procedure. Cost-effectiveness can be anticipated. associated with galectin- reactivity, and RAS point mutation with HBME- (). Only one study inves- US and mutation analysis tigated this combination of techniques in indeterminate US assessment was also reported in various studies on thyroid cytology. Although no significant correlation gene mutation analysis, presumably because US data was demonstrated between positive BRAFV E muta- were usually readily available in clinical studies at no tion and galectin- overexpression, benefitting possible additional costs and thus easily combined with results complementary use, no additional diagnostic value was of more experimental techniques. Even though US demonstrated either (). assessment improved the diagnostic accuracy of both FDG-PET and elastosonography, combined use of US MicroRNA and mutation analysis with the sensitive Afirma® GEC or specific BRAF Combined microRNA expression profiling and mu- mutation analysis demonstrated little additional di- tation analysis could accurately aid diagnosis and agnostic value (). Suspicious US features such as prognosis of thyroid malignancy. Distinct microRNAs hypoechogenicity, presence of calcifications, and have been related to oncogenic mutations. For ex- hypervascularity were not predictors of malignancy in ample, miR-, miR-, and miR-b were more Afirma® GEC-positive nodules (). Also, as expected overexpressed in BRAF- and RAS-mutated PTC. High by their individual association to classic PTC, a posi- expression of miR- was associated with RET/PTC tive BRAFV E mutation was correlated to the rearrangement (, ). The first step toward di- presence of suspicious US features in unselected agnostic integration of the two techniques was taken nodules, including hypoechogeneity and the presence by Laborier et al. (), who tested the com- of microcalcifications (, , ). BRAF mutation less mercially developed -microRNA thyroid classifier
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ThyraMIRÔ simultaneously with the miRInform® Moreover, molecular subtypes of, for example, BRAF- thyroid. The ThyraMIRÔ was designed to increase the mutated PTC were identified and linked to different sensitivity of the miRInform® without affecting its clinical subtypes. The role of microRNA in de- specificity. Combined use demonstrated % sensi- termining cancer phenotype was elaborated, allowing tivity and % specificity (). A recent decision an- better understanding of clinical behavior of various alytics model for Bethesda III and IV nodules genetic variants of PTC. Somatic copy number al- estimated that combined miRInform® and terations were mostly linked to FVPTC. Ultimately, ThyraMIRÔ testing was cost-effective, reducing the the TCGA Research Network envisions a reclassifica- rate of unnecessary surgery (diagnostic hemi- tion of thyroid carcinoma, abandoning the discrimi- thyroidectomy as well as two-step thyroidectomies) nation between PTC and FTC, and classifying from %to% and saving $ per patient in the according to molecular subtypes instead of by histo- first year of treatment or $ per avoided surgery. pathological subtype first (). The identified markers However, it is not described how the economic may not just have an application in the diagnosis of consequences of the % missed malignancies are thyroid carcinoma, but also in better risk-stratification accounted for in this model (). The economic as well of the different cancers and in targeted therapies. The as medical–ethical consequences of such a high plurality of applications is best known for the number of missed malignancies question the current BRAFV E mutation, which has an association with clinical utility of this combination of expensive clinically more aggressive tumor behavior on several techniques. fronts. Also, nonthyroid malignancies carrying a BRAF In brief, the combined or sequential use of multiple mutation are now (experimentally) treated with RAF diagnostics in indeterminate thyroid nodules was inhibitors (, ). infrequently studied. Regrettably, the available studies There is little doubt that molecular classification also mostly remained within their own field of ex- systems are the future of oncology diagnostics in all pertise: comparing tests either within the domain of types of human cancers. The position of histopatho- pathological (molecular) techniques or within the logical assessment is changing, but cannot be re- domain of imaging. Although a sequential combina- nounced. With the current knowledge of thyroid “There is little doubt that tion of a sensitive and an uncorrelated specific test genomics, the need to distinguish the mutated ma- molecular classification might bring the solution that this clinical issue has lignant from the mutated benign, premalignant, systems are the future of been waiting for, the most accurate combination of neoplasms remains, with all due consequences for the oncology diagnostics in all ” tests cannot reliably be determined yet. surgical and postoperative treatment strategy. types of human cancers. Cytological application of the TCGA set was also already investigated in a recent study. Pagan et al. () Recent Developments and Future Prospects validated a panel containing the genomic alterations identified by the TCGA in FNAC samples selected The cancer genome atlas from a previous cohort study, including in- Papillary thyroid cancer was one of the cancers tar- determinate thyroid nodules (, ). In the latter, geted by the cancer genome atlas (TCGA) research % sensitivity and % specificity were demonstrated. network, a large collaborative project by the National In the same set of patients, Pagan et al. () also Cancer Institute and National Human Genome Re- performed the Afirma® GEC. The GEC yielded less search Institute. The incentive of the project is to map false-negatives and a much higher sensitivity. Even genomic alterations occurring in types of cancer in though technical limitations of the applied sequencing , patients and improve the understanding, techniques could leave RNA transcriptions with low classification, and extending possibilities for targeted expression levels undetected and thus negatively in- therapy of these cancers (). Genetic alterations of fluence sensitivity of the TCGA set, the scopes of the all kinds were detected in nearly clinically non- TCGA and GEC most likely explain their difference in aggressive PTCs (classical, follicular, and tall cell performance. The TCGA was developed using PTC variants) using one proteomic and six genomic plat- only. It did not include follicular lesions and their forms. PTC harbored fewer somatic mutations than distinctive genetic alterations. Moreover, in contrast to other human cancer types, but if they were present, the GEC, the TCGA set was not optimized for pre- driver mutations were detected in the majority of the operative diagnostic application in indeterminate cancer cells. As expected, the known driver mutations thyroid nodules (). Consequently, the comparison in the MAPK/ERK pathway were dominant, con- performed by this Veracyte-sponsored study seems firming the mutually exclusive relation for BRAF and unjust: it is obvious that the Afirma® GEC yielded RAS point mutations and RET/PTC rearrangements. better diagnostic performance in this specific clinical Other detected genetic alterations included genetic setting. Yet, the results of this study did prove that variations of the TERT promoter, PIK and PPARg a large panel of genetic alterations such as the TCGA pathways, as well as new alterations of known and new was not useful in clinical practice without further drivers, such as EIFAX, PPMD, and CHEK. expansion of the scope of the panel toward follicular
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thyroid neoplasms. Still, the genetic alterations and implementation of the ancillary test leads to changes in their relations detected by TCGA are groundbreaking patient management and overall health benefits (). for the progression of research. From these compre- All these requirements directly depend on a plurality hensive sets of biomarkers, we may select new com- of epidemiological and economic factors within the binations of genetic alterations for future clinical tested population, such as the local test availability, research to develop an accurate rule-in or rule-out professional expertise, and case mix—prevalence of molecular test for indeterminate thyroid nodules. malignancy as well as the balance of various sub- types of indeterminate cytology including especially Proteomics H¨urthle-cell neoplasms and BRAF-mutation. Addi- Other molecular advances include protein expression tionally, clinical utility considerations should include diagnostics, or proteomic profiling. These techniques less tangible factors such as physician and patient allow for more detailed insight in the molecular bi- preference, multidisciplinary decision-making, and ology and protein expression of thyroid neo- compatibility with everyday clinical routine and lo- plasms. For example, matrix-assisted laser desorption gistics in endocrine practice. All things considered, ionization/mass spectrometry imaging is able to si- global perspectives regarding the preferred diagnostic multaneously visualize the spatial distribution of for indeterminate thyroid nodules likely greatly differ. proteins and profile up- and downregulated protein expression in relation to the morphological features of Recommendation for clinical use of rule-out tests the thyroid specimen. These and related proteomic The most accurate currently available rule-out tests are techniques could identify new biomarkers for pre- the Afirma® GEC and FDG-PET(/CT) imaging. The operative cytological diagnosis, but require high levels Afirma® GEC had strikingly high sensitivity in nearly of expertise. Application to thyroid cytology has so far all studies (, , , –). However, there are been investigated by few studies (, ). Ex-vivo concerns regarding the lack of strong validation cytology studies show accurate and reproducible dif- studies. With a high degree of missing histology, es- ferentiation between various lesions, including the pecially in GEC negative nodules, there is a potentially currently difficult to diagnose H¨urthle cell neoplasms strong diminution of the tests’ sensitivity if unresected (). No studies investigated the diagnostic value of GEC-negative lesions were less often benign than proteomics in in-vivo indeterminate thyroid cytology presumed. In the United States, physicians should yet. locally validate the tests’ utility prior to implementa- tion. However, with its limited global availability, high costs and low probability of cost-effectiveness, clinical Discussion implementation of the Afirma® GEC outside the United States is currently not favored (, , –). This review provides a comprehensive overview of the FDG-PET/CT may be the preferred rule-out test available literature on molecular and imaging bio- for indeterminate thyroid nodules in a European markers as additional diagnostics for thyroid nodules setting. With sufficient validation studies with com- with indeterminate cytology (Bethesda III and IV) and plete histopathological follow-up, it demonstrated their application in a clinical preoperative setting. consistent high sensitivity and a benign test result in Clinical utility requires more from a diagnostic than % of the patients, although the number of currently mere well-validated test performance and high rule-in published patients is moderate. Cost-effectiveness of or rule-out capacity. The ATA guidelines sug- FDG-PET over other diagnostics is presumed (). Its gested that the ideal rule-out diagnostic for thyroid popularity in the United States is more limited, al- carcinoma should have an NPV similar to a benign though the efficacy of this molecular imaging tech- cytological diagnosis (~.%) and the ideal rule-in test nique could likely compete with molecular biomarkers a PPV that is at least similar to a malignant cytological panels, even if the costs per scan are somewhat higher diagnosis (~.%) (, ). The balance between test than in Europe. The main drawback of FDG-PET/CT sensitivity and specificity, and their prevalence- is its, admitted minor, risk to the patient by using dependent derivatives PPV and NPV, directly re- a limited dose of ionizing radiation. flects on feasibility and cost-effectiveness estimates. A The recently announced version of the Thyro- diagnostic with (near) perfect sensitivity but limited Seq® may become a prime contender. Dependent on specificity is inefficient and unlikely cost-effective: the the case mix, the ThyroSeq® v. anticipated high NPV will be close to %, but the majority of nodules negative predictive value (). However, the number of will test positive. Therefore, instead of focusing on the studies to confirm test performance and clinical utility reproducible highest sensitivity or specificity, a di- in different patient populations is limited. Clinical agnostic is better appreciated by end points such as results for the ThyroSeq® v are eagerly awaited. desired minimal rates of accurately prevented unbe- Semiquantitative elastosonography could be neficial surgeries or accurately diagnosed carcinomas. a suitable alternative, in particular in case a more More importantly, clinical utility demands that economic test is required. However, overfitting and
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lack of external cut-off validation likely overestimated the With the diagnostics currently available in the performance of this technique in the limited number of clinical setting, a multimodality stepwise approach available studies. If future prospective studies can confirm could offer a conclusive diagnosis for indeterminate its performance and thresholds of this operator- thyroid nodules, sequentially combining one sensitive dependent but globally accessible method, USE could rule-out and one specific rule-in test. Unfortunately, become a more important diagnostic in this field. thus far few studies investigated this approach (, ). None of the diagnostic techniques under in- Combinations of (molecular) imaging and somatic vestigation in this review has a perfect NPV or fulfills genetics were especially scarce. There is currently the threshold proposed by the ATA. A number of insufficient evidence to accommodate reliable in- malignant nodules will be misdiagnosed as benign on terpretation of sequentially used tests, as performance first assessment. Considering the typical indolent of the second test is unknown in a population pre- clinical course of differentiated thyroid cancer, follow- selected by the first. Besides choosing two accurate and up of these initially false-negative nodules will most uncorrelated tests to achieve maximum diagnostic likely still result in timely diagnosis without relevant accuracy, the sequence of testing, local availability, and treatment delay and dismal prognostic consequences. costs of the selected diagnostics are crucial. Costs of two or more additional tests may compromise cost- Recommendation for clinical use of rule-in tests utility estimates. Available cost-effectiveness studies The best rule-in performance was unmistakably for individual diagnostic modalities were additionally demonstrated by BRAF mutation analysis, which greatly susceptible to global variations in population- showed perfect % specificity in an abundance of dependent factors such as pretest probability of thy- studies. Yet, strong regional differences in prevalence roid carcinoma and local test performance, and of BRAF mutations have a major impact on its clinical varying health care costs including the surgical re- utility, especially when comparing South Korea to imbursement rates (, , , ). Reported surgical other countries. Moreover, the analysis most likely has and hospitalization costs range from $ to $ very low yield in Bethesda IV nodules, in which the for hemithyroidectomy, $ to $ for comple- mostly follicular type malignancies are more fre- tion thyroidectomy, and $ to $, for initial “ quently RAS-mutated (, , , ). Testing total thyroidectomy. Secondary expenses following Histopathology is classically based on microscopic for individual genetic alterations other than the surgery should be considered as well, including VE assessment of tumor BRAF point mutation is not useful. In American postoperative observation, thyroid hormone replace- phenotype, aided by IHC.” and European settings, a gene mutation panel is likely ment (approximately $ per patient per year), preferred over any individual mutation analysis. treatment of hypoparathyroidism (approximately $ Promising rule-in capacity was also demonstrated for per patient per year), and resolution of rare but po- Galectin- ICC, an infrequently applied technique with tentially serious surgical complications (, , , limited validation studies. Further prospective studies are ). Secondary end points such as quality of life and warranted to validate its performance in indeterminate survival are of minor importance to cost-effectiveness, thyroid nodules and endorse its possible clinical use. due to the generally indolent course of differentiated Besides BRAF mutation analysis, none of di- thyroid cancer, adequate treatment options, and agnostics meet the ATA requirements of an ideal overall low disease-related mortality (, , ). rule-in test. Compared with ruling-out tests, ruling-in tests face an additional challenge. With a generally low Recent discussions in thyroid histopathology frequency of thyroid carcinoma in indeterminate Histopathology is classically based on microscopic thyroid nodules, achieving a reliable PPV (higher than assessment of tumor phenotype, aided by IHC. %) can be a major challenge despite adequate test However, this “gold standard test” is also subject to specificity. Such high demands to a ruling-in test advancing insights regarding tumor phenotype, in- advocate the use of a ruling-out test in populations creasingly aided by knowledge regarding tumor ge- with a limited pretest probability of malignancy. notype. Mutation-negative malignancies resulting from indeterminate cytology were frequently identi- Clinical recommendation for a step-wise approach fied as encapsulated follicular variants of papillary Most of the diagnostic modalities are optimized for thyroid carcinoma without histologic features of ag- either ruling in or ruling out malignancy. gressive behavior (, , , , ). Also, several No single diagnostic addressed in the current re- studies defined a separate intermediate histopatho- view currently has it all: both a near-perfect sensitivity logical category called “(follicular) tumor of uncertain and a near-perfect specificity, and (proven) cost- malignant potential” for encapsulated, well-differentiated effectiveness. It is extremely challenging to develop follicular tumors with questionable PTC-type nuclear such test performance parameters in a single di- changes (, , , ). These examples illustrate agnostic. Even promising new diagnostics, such as the one of the important ongoing discussions in thyroid ThyroSeq® and ThyraMirÔ, require substantial fur- histopathology. In , Nikiforov et al. () pro- ther optimization to get near this diagnostic utopia. posed an official downscaling of the classification of
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proven noninvasive encapsulated FVPTCs, renaming pathway (, ). Rare TP mutations, usually them “noninvasive follicular neoplasm with papillary- associated with poorly differentiated and anaplastic like nuclear features” (NIFTP). The behavior of these carcinoma, were recently also identified in well- neoplasms is benign unlike other thyroid carcinoma differentiated H¨urthle cell nodules (). Also, re- subtypes, showing no evidence of recurrent disease current FTC-OV have shown genome haploidisation, after a median -year follow-up. Approximately one ararephenomenoninothertypesofdifferentiated in four of the neoplasms in the retrospective cohort thyroid carcinoma (). Specificmarkersforthepre- were mutated, most frequently carrying RAS (NRAS) operative molecular differentiation of H¨urthle cell or PAX/PPARg alterations. Presence of a mutation nodules should be developed. Adaptation of existing tests likely predisposes the NIFTP to progress into an in- to additionally suit H¨urthle cell nodules (e.g., the Afirma® vasive encapsulated FVPTC, justifying surgical re- GEC) is a strategy being explored, for example, by the section. Treatment of NIFTP should most likely be ThyroSeq® v and the Afirma® Gene Sequence Classifier. limited to hemithyroidectomy, waiving totalizing Caution should be taken that these adaptations do not thyroidectomy, and radioiodine ablation (). Al- decrease the diagnostic accuracy for nononcocytic le- though revolutionizing, this new nomenclature sions. MicroRNA expression profiling of these lesions is complicates mutation-based preoperative decision- currently also under investigation (, ). making (, , ). The justification to skip two- stage surgery and perform a total thyroidectomy at Strengths and limitations of the current review once for mutation-positive nodules is the driving force There are several important strengths and limitations to of the seven-gene mutation panel and similar tests, but this comprehensive review. This review provides would be overkill for the subgroup of NIFTP (). a complete overview of the available additional di- Nonetheless, most of the undesirable possible over- agnostics for indeterminate thyroid nodules, resulting treatment for NIFTP is likely resolved if RAS-mutated from a careful and systematic literature selection and indeterminate nodules are treated with hemi- instead of quality appraisal. Different types of clinical data of total thyroidectomy, as previously suggested. No com- various levels of evidence were considerately presented. prehensive diagnostic test is currently available to di- Nonetheless, this review is generally prone to inac- agnose mutation-positive NIFTP preoperatively, as curacies from low study quality, study heterogeneity, follicular tumor invasiveness and encapsulation cannot and different types of bias. For some of the assessed be distinguished on cytology. diagnostics, the limited number of available publica- tions and small study cohorts contribute to heteroge- Hurthle¨ cell cytology neity of data and loss of applicability. This mainly The Achilles heel of many diagnostics investigated in concerns studies on nonroutine imaging techniques. By this review is cytology suspicious for a H¨urthle cell nature, these clinical studies need to prospectively in- neoplasm (Bethesda IV SHCN/HCN). H¨urthle cells clude subjects to voluntarily undergo an extra in- are oxyphilic cells with abundant cytoplasm and an vestigation with, at least in the clinical validation phase, enlarged nucleus with a prominent nucleolus. They are no implications for individual patient management. found in benign thyroid diseases such as Hashimoto’s These types of studies require more resources than thyroiditis, but also occur in the notorious H¨urthle cell “further use” tissue biobank studies. Consequently, the adenoma and carcinoma, the oncocytic variant of FA number of studies is more limited and published series and carcinoma (, ). Although H¨urthle cell car- often are small. In contrast, cytological biomarker re- cinomas (FTC-OV) are rare, their aberrant clinical search gratefully profits from available large tissue course and association with invasive features justifies biobanks for initial validation studies. We believe the special attention given to H¨urthle cell cytology by consistent results from properly designed imaging the Bethesda and other classification systems. An studies should not be disregarded due to mere their accurate additional diagnostic is desired. Disap- sample size, but be appreciated by the quality of their pointingly, several studies concluded that the in- study design and statistics. vestigated test was accurate in all except H¨urthle cell Population-level study differences were often ob- lesions (, , , ). ICC handed some solutions, served, not only related to test performance but also although promising results of combined galectin- and strongly varying malignancy rates that were often- CK- staining have not yet been validated (). times much lower or higher than expected from Besides that, BRAF, RAS, RET/PTC, or PAX/PPARg indeterminate thyroid nodules. Besides insupera- alterations are only occasionally found (, ). These ble epidemiological variations, the selection of in- findings support previous presumptions that oncocytic determinate cytology, and the retrospective nature of thyroid nodules are a completely separate entity with many studies may have contributed to these a unique molecular and phenotypic profile (–). discrepancies. Malignant transition in H¨urthle cell nodules most The type of indeterminate cytology included by likely involves the PIKCA-Akt-mTOR and Wnt/ individual studies varied, likely leading to between- b`eta-catenin pathways rather than the MAPK/ERK study heterogeneity. Besides global variations and
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known intra- and interobserver discordance, diverse with indeterminate cytology, all with advantages and definitions of indeterminate cytology were adhered (). disadvantages. This review provided a comprehensive Nowadays, the Bethesda system differentiates in- overview of the available literature on these tech- determinate from benign and suspicious cytology in niques, addressing both molecular and imaging a more standardized manner in both literature and biomarkers, aiming to provide an objective and clinic. Bethesda III and/or IV and similar categories nuanced comparison of their performance and cost- from other classification systems were frequently ap- effectiveness with regard to rightful surgical decision- plied. Unfortunately, some studies also included small making. Many of these diagnostics have either an numbers of Bethesda V nodules without presenting adequate rule-in or rule-out capacity, but no single results for individual categories separately (). Many currently available test seems to serve both purposes other studies adhered to their own definition of in- well. Diagnostics from the different research fields determinate cytology. This especially, but not exclusively, likely complement each other in a multimodality concerns studies published before the introduction of the stepwise diagnostic approach toward. Notwith- Bethesda system in . standing, test performance is always population- Retrospective study designs and subsequent se- dependent. To correctly interpret the results, the lection bias—only including indeterminate thyroid prevalence of malignancy and the performance, costs, nodules that had undergone both thyroid surgery and and feasibility of the desired diagnostic in the local (routine) preoperative testing—likely also caused patient population should be known beforehand. overestimation of the true efficacy of certain tech- Local implementation studies are strongly recom- niques (e.g., BRAF mutation analysis or US). mended to confirm clinical utility. Most importantly, the local decision favoring or opposing a certain diagnostic should be a deliberate and multi- Conclusion and Recommendations disciplinary one. Cooperation between clinical en- docrinologists, endocrine surgeons, pathologists, In current-day practice, there are numerous additional radiologists, and nuclear medicine physicians is diagnostics available to further assess thyroid nodules crucial.
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