**2. Preoperative diagnosis of thyroid carcinoma**

Two diagnostic procedures play a major role in the preoperative diagnosis of thyroid cancer—the ultrasound (US) examination of the neck, revealing one or more thyroid nodules and the fine needle aspiration biopsy (FNAB).With the discovery of a thyroid nodule, a complete history and physical examination focusing on the thyroid gland and cervical lymph nodes should be performed. Family history of thyroid carcinoma, prior head or neck irradiation, a growing or fixed nodule with neck lymphadenopathy, male gender as well as some age groups (< 18 and > 70 years of age are clinical factors that are associated with a higher risk of thyroid carcinoma [11, 12].

The next diagnostic step is the clarification of thyroid function by obtaining a serum TSH. If the serum TSH is subnormal, besides serum levels of free T4 and T3, a radionuclide thyroid scan should be performed to document whether the nodule is hyperfunctioning ("hot"), isofunctioning ("warm") or nonfunctioning ("cold") [12]. Autonomously functioning thyroid nodules (toxic or hyperfunctioning nodules) do not need further cytologic evaluation because the incidence of malignancy is exceedingly low [5, 12]. On the contrary, a higher serum TSH level, even within the upper part of the reference range, is associated with an increased risk of malignancy [13]. Experimental studies have shown that thyroid cell proliferation is TSH dependent and that highly differentiated thyroid carcinomas retain this response to TSH. Suppressive thyroxine treatment for differentiated thyroid cancer is also based on this TSH dependence [14].

#### **2.1. Ultrasound examination**

Most guidelines do not recommend routine population US screening. However, thyroid ultrasound is mandatory for individuals with a family history of thyroid carcinoma, previous head or neck irradiation (e.g., radiotherapy for concomitant lymphoma), palpable nodules in the neck, symptoms of dysphonia, dysphagia, dyspnea and cervical lymphadenopathy [12].

Neck US is a key examination in the management of thyroid nodules and in the last two decades, it has become an indispensable tool for detecting thyroid nodules and for accurately determining their size, number and structure [15]. By definition, a thyroid nodule is a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding thyroid parenchyma [16]. The US examination should select the suspicious nodule for subsequent FNAB according to the "degree of suspicion" determined by the presence of some of the following malignancy-specific characteristics [17]:

• a solid hypoechoic structure and especially marked hypoechogenicity;

USA has nearly tripled from 4.9 to 14.3/100,000 [7]. It is believed that this increase is largely due to the improved diagnosis and detection of carcinomas smaller than 2 cm, whereas the mortality rate of this disease has not changed and remains at a level of 0.5/100,000 [8]. However, an analysis by Lim et al. of 77,276 thyroid cancer patients published in 2017 estimates an increase

The Chernobyl accident in 1986 marked a new era in thyroid carcinoma incidence. The risk of developing thyroid cancer, especially in Ukraine, Belarus, Western Russia and neighboring countries, is estimated to be highest for those who were then under the age of 9, and especially under the age of 5, and probably have taken a large dose radioactive iodine through milk and dairy products [10]. It is estimated that the Chernobyl accident will result in 16,000 new cases of thyroid cancer by 2065 [10]. In the coming years, an increasing number of newly diagnosed thyroid carcinomas is expected in Japan, related to the Fukushima accident in April 2011. All these factors led to the development in 2015 of the American Thyroid Association (ATA) management guidelines for adults with thyroid nodules and differentiated thyroid cancer [5]. Differentiated thyroid carcinoma (DTC), including papillary (classical and variants) and follicular carcinoma, accounts for over 90% of cases of thyroid cancer and is the main subject of this review. Medullary and anaplastic carcinomas are rare and prognostically less favorable.

Two diagnostic procedures play a major role in the preoperative diagnosis of thyroid cancer—the ultrasound (US) examination of the neck, revealing one or more thyroid nodules and the fine needle aspiration biopsy (FNAB).With the discovery of a thyroid nodule, a complete history and physical examination focusing on the thyroid gland and cervical lymph nodes should be performed. Family history of thyroid carcinoma, prior head or neck irradiation, a growing or fixed nodule with neck lymphadenopathy, male gender as well as some age groups (< 18 and > 70 years of age are clinical factors that are associated with a higher risk of

The next diagnostic step is the clarification of thyroid function by obtaining a serum TSH. If the serum TSH is subnormal, besides serum levels of free T4 and T3, a radionuclide thyroid scan should be performed to document whether the nodule is hyperfunctioning ("hot"), isofunctioning ("warm") or nonfunctioning ("cold") [12]. Autonomously functioning thyroid nodules (toxic or hyperfunctioning nodules) do not need further cytologic evaluation because the incidence of malignancy is exceedingly low [5, 12]. On the contrary, a higher serum TSH level, even within the upper part of the reference range, is associated with an increased risk of malignancy [13]. Experimental studies have shown that thyroid cell proliferation is TSH dependent and that highly differentiated thyroid carcinomas retain this response to TSH. Suppressive thyroxine treatment for differentiated thyroid cancer is also based on this TSH dependence [14].

Most guidelines do not recommend routine population US screening. However, thyroid ultrasound is mandatory for individuals with a family history of thyroid carcinoma, previous

in the mortality rate for advanced-stage papillary thyroid cancer [9].

**2. Preoperative diagnosis of thyroid carcinoma**

thyroid carcinoma [11, 12].

50 Thyroid Disorders

**2.1. Ultrasound examination**


Other US characteristics are still debatable, for example, an increase in nodular size/volume (50% increase in volume), large coarse and irregular-shaped dystrophic calcifications (frequently seen in all types of nodules and may reflect previous hemorrhage and tissue necrosis) and rim or "egg-shell" calcifications (malignancy is suspected if the "egg-shell" is interrupted, with small extrusive soft-tissue component). According to most studies, the nodule size and number (solitary nodules or multinodular goiter) are not suggestive of malignancy, although a meta-analysis of Campanella indicates a higher malignancy risk for single nodules (OR, 1.43) and for nodule size ≥4 cm (OR, 1.63) [11].

There are also some US features suggestive of benignity of the nodule—pure cysts with anechoic structure, spongiform nodules, halo sign, smooth margins, dorsal acoustic enhancement, presence of a gentle continuous halo, dorsal acoustic enhancement, hyperechoic structure, uninterrupted eggshell calcifications as well as significant decrease in size over time [22].

Apart from the interobserver variation in the assessment, the US criteria associated with malignancy have various sensitivity and specificity, and unfortunately, none of them alone is strong enough to prove or rule out malignancy efficiently (**Table 1**). This is why some teams have tested certain combinations of US features to increase the diagnostic accuracy of this imaging technique. The concurrent presence of two sonographic criteria doubles the probability of malignancy; a combination of three raises the malignancy risk to 72.7% [30]. According to Papini et al. the combination of a hypoechoic structure and at least one of the following US features—irregular borders or microcalcifications or intranodular blood flow—reaches 87% sensitivity and would miss only 13% of the carcinomas among the nonpalpable nodes [25].

**US feature Author Year Nodules**

Solid Kim et al. [23] 2002 155 26.5 94.3 hypoechoic Peccin et al. [24] 2002 289 44.0 83.0 structure Papini et al. [25] 2002 494 87.1 43.4

Irregular Kim et al. [23] 2002 155 55.1 83.0 margins Peccin et al. [24] 2002 289 56.0 80.0

Microcalci- Kim et al. [23] 2002 155 59.2 85.8 fications Peccin et al. [24] 2002 289 56.0 94.0

Intra- Papini et al. [25] 2002 494 74.2 80.8 nodular Capelli et al. [26] 2007 5198 62.0 50.0 blood flow Brito et al.\* [28] 2014 18288 48.0 53.0

Taller-than- Kim et al. [23] 2002 155 32.7 92.5 wide shape Moon et al. [27] 2008 8024 40.0 91.4

Size >10 mm Papini et al. [25] 2002 494 61.3 32.0

**Table 1.** Sensitivity and specificity of different US characteristics, studied by different research groups.

\*a metaanalysis of 31 studies \*\*a meta-analysis of 41 studies **(number)**

Capelli et al. [26] 2007 5198 81.0 47.0 Moon et al. [27] 2008 8024 41.4 92.2 Brito et al.\* [28] 2014 18288 73.0 56.0 Remonti et al \*\* [29] 2015 12786 62.7 62.3

Papini et al. [25] 2002 494 77.5 85.0 Capelli et al. [26] 2007 5198 53.0 81.0 Moon et al. [27] 2008 8024 48.3 91.8 Brito et al.\* [28] 2014 18288 56.0 79.0 Remonti et al \*\* [29] 2015 12786 50.5 83.1

Papini et al. [25] 2002 494 29.0 95.0 Capelli et al. [26] 2007 5198 72.0 71.0 Moon et al. [27] 2008 8024 44.2 90.8 Brito et al.\* [28] 2014 18288 54.0 81.0 Remonti et al \*\* [29] 2015 12786 39.5 87.8

Remonti et al \*\* [29] 2015 12786 49.5 78.0

Brito et al.\* [28] 2014 18288 53.0 93.0 Remonti et al \*\* [29] 2015 12786 26.7 96.6

Capelli et al. [26] 2007 5198 77.0 35.0 Brito et al.\* [28] 2014 18288 57.0 40.0

**Sensitivity (%)**

Thyroid Cancer: Diagnosis, Treatment and Follow-Up http://dx.doi.org/10.5772/intechopen.77163

> **Specificity (%)**

53

In 2017 the European Thyroid Association (ETA) created a novel European Thyroid Imaging and Reporting Data System, called **EU-TIRADS**, providing a risk stratification of thyroid nodules [31]. It consists of a 6-point scale for risk stratification with increasing risks of malignancy and is based on the "classic pattern" concept [31]:



Apart from the interobserver variation in the assessment, the US criteria associated with malignancy have various sensitivity and specificity, and unfortunately, none of them alone is strong enough to prove or rule out malignancy efficiently (**Table 1**). This is why some teams have tested certain combinations of US features to increase the diagnostic accuracy of this imaging technique. The concurrent presence of two sonographic criteria doubles the probability of malignancy; a combination of three raises the malignancy risk to 72.7% [30]. According to Papini et al. the combination of a hypoechoic structure and at least one of the following US features—irregular borders or microcalcifications or intranodular blood flow—reaches 87% sensitivity and would miss only 13% of the carcinomas among the nonpalpable nodes [25].

In 2017 the European Thyroid Association (ETA) created a novel European Thyroid Imaging and Reporting Data System, called **EU-TIRADS**, providing a risk stratification of thyroid nodules [31]. It consists of a 6-point scale for risk stratification with increasing risks of malig-

• **EU-TIRADS 1** category refers to a US examination where no thyroid nodule is found; there

• **EU-TIRADS 2** category comprises benign nodules with a risk of malignancy close to 0%, presented on sonography as pure/anechoic cysts (**Figure 1A**) or entirely spongiform nodules (**Figure 1B**). Both of these US appearances are sufficient to rule out malignancy without the need for FNAB, unless the last is performed for therapeutic purposes—that is, cyst evacuation in case of compressive symptoms. The benign cyst is a purely cystic nodule which does not have any wall thickening or any solid component that could be identified by Doppler US. Cysts which are divided into separate compartments by septa also belong to this benign category. Bright echogenic spots with posterior comet-tail artifact represent a benign finding, in fact a reverberation of the US signal related to presence of microcrystals in colloidal nodules. The spongiform nodule (also "puff pastry" structure) is composed of tiny cystic spaces involving the entire nodule, separated by numerous isoechoic septa, and

• **EU-TIRADS 3** is the low-risk category (malignancy risk: 2–4%) which includes ovalshaped, isoechoic or hyperechoic nodules with smooth margins and no high-risk features (**Figure 1C** and **D**). FNA is recommended only for nodules >20 mm [31, 32]. For nodules with an inhomogeneous structure, the presence of any hypoechoic areas classifies the nod-

• **EU-TIRADS 4** is the intermediate-risk category with an estimated risk of malignancy between 6 and 17% [31, 32]. This category is presented by mildly hypoechoic nodules with oval shape, smooth margins and without any features of high risk (**Figure 1E**). FNA should be performed if nodule's diameter is >15 mm. As it is evident, the difference between the low-risk (EU-TIRADS 3) and the intermediate-risk category (EU-TIRADS 4) lies in the echogenicity of the solid part of the nodule. The estimated risk of malignancy varies between 6 and 17% and some US features may modulate it. For example, cystic areas, the presence of comet-tail artifacts, peripheral vascularity or high elasticity lowers the malignancy risk, whereas interrupted rim macrocalcifications, a thick or discontinuous halo, predominantly

central vascularity, and low elasticity may increase the risk [31].

nancy and is based on the "classic pattern" concept [31]:

is no need for FNAB.

52 Thyroid Disorders

is considered benign [5, 12, 22, 31].

ule as intermediate risk (see below).

**Table 1.** Sensitivity and specificity of different US characteristics, studied by different research groups.

• **EU-TIRADS 5** encompasses the high-risk category nodules with at least one of the following US features: marked hypoechogenicity, nonoval shape, irregular margins and microcalcifications. The risk of malignancy varies between 26 and 87% [33, 34], generally increasing with the number of suspicious US characteristics. FNA is recommended for high-risk nodules if they exceed 10 mm in size. In case of benign cytology of such a suspicious nodule, FNAB should be repeated within 3 months to reduce the rate of false-negative samples. Patients with subcentimeter nodules with highly suspicious US features (microcarcinomas) and no abnormal lymph nodes can have the choice of active surveillance or FNAB. The last is recommended if the nodule shows enlargement or is accompanied by abnormal lymph node/s, highly suspicious of lymph node metastatic disease [31].

increased incidence of thyroid carcinoma is mainly due to detection of microcarcinomas ≤ 1 cm as incidentalomas [36]. The estimated risk of malignancy varies according to the method of discovery. In the absence of clinical risk factors, the risk of malignancy in thyroid incidentalomas diagnosed on neck US, CT or MRI is 5–13%, which is more or less the same as the risk among all thyroid nodules [31, 32, 36, 37]. This implies а mandatory US assessment before the decision for FNAB. In contrast, the risk of malignancy when diagnosed by focal FDG uptake on a PET scan (F-18 fluoro-deoxy-glucose positron emission tomography) is much higher, around 30% [38]. Although the FDG PET is performed in the context of another oncological disease, most FDG PET-positive thyroid incidentalomas are differentiated thyroid cancers and not intrathy-

Thyroid Cancer: Diagnosis, Treatment and Follow-Up http://dx.doi.org/10.5772/intechopen.77163 55

Sonoelastography is a noninvasive dynamic technique that uses US to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force. US elastography has been applied to study the hardness/elasticity of nodules to differentiate malignant from benign lesions [39]. Real-time ultrasound elastography (RTE) is the most commonly used method in thyroid clinics. The nodule chosen by the operator and taken in to the area of interest is subjected to repeated pressure pulses applied by the probe. Tissue distortion is then processed by a special software and presented by a US elastogram over the B-mode image in a color scale that ranges from red, for components with greatest elastic strain (*i.e.,* softest components), to blue for those with no strain (*i.e.,* hardest components). The US elastographic image is then matched with an elasticity color scale and classified as: score 1—elasticity in the whole nodule; score 2—elasticity in a large part of the nodule; score 3—elasticity only at the periphery of the nodule; score 4—no elasticity in the nodule; score 5—no elasticity in the nodule and part of the surrounding tissue [39, 40]. The probability of malignancy raises with increasing hardness of the nodule and decreasing elasticity, respectively. A strain index (SI) could be calculated as a ratio of the nodule strain divided by the strain of the softest part of the surrounding normal tissue. The cut-off of SI for malignancy was estimated to be 2.9 in a study of Magri in 661 nodules [41]. Others proposed

Fine needle biopsy (with or without aspiration) is the most accurate preoperative diagnostic method for distinguishing malignant from benign thyroid nodules [43]. It is a minimally invasive and safe method, which can be performed to hospitalized patients as well as in outpatient settings. It is recommended that the yielded cytological material is then evaluated according

**1. Nondiagnostic or unsatisfactory** are specimens that do not meet the criteria for adequacy due to different reasons—an insufficient number of follicular cells, obscuring blood or clotting artifact, thick smears, air drying of alcohol-fixed smears and others. A thyroid FNA specimen is considered satisfactory for evaluation if it contains at least six groups of follicular cells, each group composed of at least 10 cells [45]. Cyst-fluid-only (CFO) cases

a higher cut-off of 3.85 for detecting malignant thyroid nodules [42].

**2.2. Fine needle aspiration biopsy (FNAB) with cytology assessment**

to the Bethesda classification in one of the following six categories [44]:

roidal metastases from other malignancies [38].

*2.1.2. US elastography*

#### *2.1.1. The problem of thyroid incidentalomas*

A thyroid incidentaloma is defined as an unexpected, asymptomatic thyroid tumor discovered during the investigation of an unrelated condition. The widespread use of various high-sensitive imaging methods (US, CT, MRI, FDG PET) leads to accidental detection of nonpalpable thyroid nodules, some of which may prove to be malignant [35]. It is believed that the

**Figure 1.** US images of different thyroid nodules, classified according to EU-TIRADS. A. A pure cyst in the left thyroid lobe (EU-TIRADS 2). B. A spongiform nodule with comet-tail artifacts (EU-TIRADS 2). C. An isoechoic nodule with continuous halo (EU-TIRADS 3). D. A hyperechoic nodule with a hypoechoic halo (EU-TIRADS 3). E. A hypoechoic nodule with borderline anterio-posterior to transversal ratio (EU-TIRADS 4). F. A highly suspicious nodules with marked hypoechogenicity, non-oval shape, irregular margins, and microcalcifications (EU-TIRADS 5).

increased incidence of thyroid carcinoma is mainly due to detection of microcarcinomas ≤ 1 cm as incidentalomas [36]. The estimated risk of malignancy varies according to the method of discovery. In the absence of clinical risk factors, the risk of malignancy in thyroid incidentalomas diagnosed on neck US, CT or MRI is 5–13%, which is more or less the same as the risk among all thyroid nodules [31, 32, 36, 37]. This implies а mandatory US assessment before the decision for FNAB. In contrast, the risk of malignancy when diagnosed by focal FDG uptake on a PET scan (F-18 fluoro-deoxy-glucose positron emission tomography) is much higher, around 30% [38]. Although the FDG PET is performed in the context of another oncological disease, most FDG PET-positive thyroid incidentalomas are differentiated thyroid cancers and not intrathyroidal metastases from other malignancies [38].

#### *2.1.2. US elastography*

• **EU-TIRADS 5** encompasses the high-risk category nodules with at least one of the following US features: marked hypoechogenicity, nonoval shape, irregular margins and microcalcifications. The risk of malignancy varies between 26 and 87% [33, 34], generally increasing with the number of suspicious US characteristics. FNA is recommended for high-risk nodules if they exceed 10 mm in size. In case of benign cytology of such a suspicious nodule, FNAB should be repeated within 3 months to reduce the rate of false-negative samples. Patients with subcentimeter nodules with highly suspicious US features (microcarcinomas) and no abnormal lymph nodes can have the choice of active surveillance or FNAB. The last is recommended if the nodule shows enlargement or is accompanied by abnormal lymph

A thyroid incidentaloma is defined as an unexpected, asymptomatic thyroid tumor discovered during the investigation of an unrelated condition. The widespread use of various high-sensitive imaging methods (US, CT, MRI, FDG PET) leads to accidental detection of nonpalpable thyroid nodules, some of which may prove to be malignant [35]. It is believed that the

**Figure 1.** US images of different thyroid nodules, classified according to EU-TIRADS. A. A pure cyst in the left thyroid lobe (EU-TIRADS 2). B. A spongiform nodule with comet-tail artifacts (EU-TIRADS 2). C. An isoechoic nodule with continuous halo (EU-TIRADS 3). D. A hyperechoic nodule with a hypoechoic halo (EU-TIRADS 3). E. A hypoechoic nodule with borderline anterio-posterior to transversal ratio (EU-TIRADS 4). F. A highly suspicious nodules with

marked hypoechogenicity, non-oval shape, irregular margins, and microcalcifications (EU-TIRADS 5).

node/s, highly suspicious of lymph node metastatic disease [31].

*2.1.1. The problem of thyroid incidentalomas*

54 Thyroid Disorders

Sonoelastography is a noninvasive dynamic technique that uses US to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force. US elastography has been applied to study the hardness/elasticity of nodules to differentiate malignant from benign lesions [39]. Real-time ultrasound elastography (RTE) is the most commonly used method in thyroid clinics. The nodule chosen by the operator and taken in to the area of interest is subjected to repeated pressure pulses applied by the probe. Tissue distortion is then processed by a special software and presented by a US elastogram over the B-mode image in a color scale that ranges from red, for components with greatest elastic strain (*i.e.,* softest components), to blue for those with no strain (*i.e.,* hardest components). The US elastographic image is then matched with an elasticity color scale and classified as: score 1—elasticity in the whole nodule; score 2—elasticity in a large part of the nodule; score 3—elasticity only at the periphery of the nodule; score 4—no elasticity in the nodule; score 5—no elasticity in the nodule and part of the surrounding tissue [39, 40]. The probability of malignancy raises with increasing hardness of the nodule and decreasing elasticity, respectively. A strain index (SI) could be calculated as a ratio of the nodule strain divided by the strain of the softest part of the surrounding normal tissue. The cut-off of SI for malignancy was estimated to be 2.9 in a study of Magri in 661 nodules [41]. Others proposed a higher cut-off of 3.85 for detecting malignant thyroid nodules [42].

#### **2.2. Fine needle aspiration biopsy (FNAB) with cytology assessment**

Fine needle biopsy (with or without aspiration) is the most accurate preoperative diagnostic method for distinguishing malignant from benign thyroid nodules [43]. It is a minimally invasive and safe method, which can be performed to hospitalized patients as well as in outpatient settings. It is recommended that the yielded cytological material is then evaluated according to the Bethesda classification in one of the following six categories [44]:

**1. Nondiagnostic or unsatisfactory** are specimens that do not meet the criteria for adequacy due to different reasons—an insufficient number of follicular cells, obscuring blood or clotting artifact, thick smears, air drying of alcohol-fixed smears and others. A thyroid FNA specimen is considered satisfactory for evaluation if it contains at least six groups of follicular cells, each group composed of at least 10 cells [45]. Cyst-fluid-only (CFO) cases representing cystic thyroid nodules, richly vascularized nodules and pronounced fibrosis in Hashimoto thyroiditis may also result in nondiagnostic specimens. A repeated biopsy with ultrasound guidance is recommended for the unsatisfactory specimens. The risk of malignancy in this category is from 1 to 4%.

**2.3. Molecular testing**

**carcinoma (DTC) patients**

overtime risk evaluation [16, 52].

esophagus. or recurrent laryngeal nerve

superior mediastinal region (level VII)

NO No metastatic lymph nodes (LNs)

MO No distant metastases Ml Distant metastases

TO No evidence of primary tumor

Bethesda indeterminate categories 3 and 4 comprise the so-called "gray zone" in thyroid cytopathology. Further stratification of malignancy risk and, respectively, the decision for surgery could be made by some ancillary techniques as molecular testing. The largest studies of preoperative molecular markers in patients with indeterminate FNA cytology have, respectively, evaluated a seven-gene panel of genetic mutations and rearrangements (BRAF, RAS, RET/PTC, PAX8/PPRAγ) [49], a gene expression classifier (167 GEC, mRNA expression of 167 genes) [50] and galectin-3 immunohistochemistry (cell blocks) [51]. Due to the lack of a single optimal molecular test to exclude malignancy and the high cost of these ancillary techniques, they are still not routinely recommended. In the absence of molecular diagnosis, surgical removal of all undetermined lesions and follicular neoplasms is recommended [5].

Thyroid Cancer: Diagnosis, Treatment and Follow-Up http://dx.doi.org/10.5772/intechopen.77163 57

**3. Role of staging and risk stratification in differentiated thyroid** 

T1a Tumor < 1 cm in greatest dimension. limited to the thyroid. without extrathyroidal extension

T1b Tumor between 1 cm and 2 cm, without extrathyroidal extension T2 Tumor between 2 cm and 4 cm, without extrathyroidal extension T3 Tumor > 4 cm in its greatest dimension. limited to the thyroid gland or

Disease staging is recommended for all patients with DTC not only as a requirement of the cancer registries but also as a factor determining the following treatment, risk assessment, and prediction of disease recurrence or persistence as well as disease mortality. Moreover, in the last years, risk stratification for thyroid cancer patients has changed from a single-point assessment at the time of the diagnosis and initial treatment to a more dynamic and changing

Any tumor with minimal extrathyroidal spread (e.g., extension into sternothyroid muscle or perithyroid soft tissues)

T4a Any tumor. with extension beyond the thyroid capsule and invasion of subcutaneous tissue. larynx. trachea.

N1b Metastases to unilateral, bilateral, or contralateral cervical LNs (levels I, II, III, IV, or V) or retropharyngeal or

**Table 2.** AJCC 7th edition of TNM classification system for differentiated thyroid carcinoma (adapted from the AJCC

T4b Tumor of any size, with invasion of prevertebral fascia or encasing carotid artery or mediastinal vessels

N1a Metastases to LNs in level VI (pretracheal, paratracheal, and prelaryngeal LNs)

cancer staging manual. Seventh edition (adapted from edge et al. [53]).


Most guidelines recommend surgical removal of nodules with cytology corresponding to Bethesda categories 3, 4, 5, and 6 [5, 13]. Preoperatively, clinical staging is performed through US and/or CT for neck cervical lymph nodes engagement [5, 12]. A CT/MRI is also indicated in selected cases to determine the local invasion of trachea and surrounding structures. In cases of suspicious neck lymphadenopathy, an FNAB of the lymph node with cytological assessment can be combined with a measurement of thyroglobulin/calcitonin in the wash out of the needle [48].

#### **2.3. Molecular testing**

representing cystic thyroid nodules, richly vascularized nodules and pronounced fibrosis in Hashimoto thyroiditis may also result in nondiagnostic specimens. A repeated biopsy with ultrasound guidance is recommended for the unsatisfactory specimens. The risk of

**2. Benign cytology** comprises benign follicular nodules (adenomatoid nodules, colloid nodules, etc), lymphocytic (Hashimoto) thyroditis and granulomatous (subacute) thyroiditis. A "benign" or "negative for malignancy" result is obtained from 60 to 70% of all thyroid FNABs, thus avoiding unnecessary surgery in the majority of the patients. Surgery is indicated for very big nodules (usually over 4 cm) causing compression or cosmetic concerns. The benign category carries very low risk of malignancy (0–3%) and if during the US follow-up the nodule shows more than 50% increase in volume or "suspicious" sonographic

**3. Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS)** refers to cytological specimens with follicular arrangement and scant colloid that do not fulfill the criteria for the other categories (4, 5, rarely 6). The estimated risk of malignancy varies between 5% and 15%. The recommended management is clinical correlation and a repeated FNA which may lead to a more definitive interpretation. However, the physician may choose not to repeat the FNA but observe the nodule clinically or, alternatively, refer the patient to operation due to clinical and/or sonographic concerns [44, 46].

**4. Follicular neoplasm (FN) or suspicious for a follicular neoplasm** (SFN)—the specimens typically have high cellularity, and colloid is scant or absent. Since the differentiation between follicular carcinoma and adenoma is made on the basis of capsular and/or vascular invasion, that are visible only on histology, FNAB reports them by this summary term "follicular neoplasm," requiring a definitive diagnostic histology procedure, usually lobectomy. The risk of malignancy in the category of FN/SFN amounts to 15–30% [44, 47].

**5. Suspicious for malignancy** is a cytology suggestive of malignancy without meeting all criteria for the definitive diagnosis of papillary or medullary carcinoma or very rarely lymphoma. The likelihood of definitively confirmed malignancy is approximately 70% and a

**6. Malignant cytology** indicates that the cytomorphologic features of the cells are conclusive for malignancy—usually papillary thyroid carcinoma (PTC), more rarely anaplastic, medullary cancer, lymphoma or a metastatic lesion of another origin. Thyroidectomy is indicated for this category. The positive predictive value of a malignant FNA interpreta-

Most guidelines recommend surgical removal of nodules with cytology corresponding to Bethesda categories 3, 4, 5, and 6 [5, 13]. Preoperatively, clinical staging is performed through US and/or CT for neck cervical lymph nodes engagement [5, 12]. A CT/MRI is also indicated in selected cases to determine the local invasion of trachea and surrounding structures. In cases of suspicious neck lymphadenopathy, an FNAB of the lymph node with cytological assessment can be combined with a measurement of thyroglobulin/calcitonin in the wash out

malignancy in this category is from 1 to 4%.

56 Thyroid Disorders

changes, a repeated FNAB is indicated [44].

surgery is recommended [44, 46].

tion is from 97–99% [44].

of the needle [48].

Bethesda indeterminate categories 3 and 4 comprise the so-called "gray zone" in thyroid cytopathology. Further stratification of malignancy risk and, respectively, the decision for surgery could be made by some ancillary techniques as molecular testing. The largest studies of preoperative molecular markers in patients with indeterminate FNA cytology have, respectively, evaluated a seven-gene panel of genetic mutations and rearrangements (BRAF, RAS, RET/PTC, PAX8/PPRAγ) [49], a gene expression classifier (167 GEC, mRNA expression of 167 genes) [50] and galectin-3 immunohistochemistry (cell blocks) [51]. Due to the lack of a single optimal molecular test to exclude malignancy and the high cost of these ancillary techniques, they are still not routinely recommended. In the absence of molecular diagnosis, surgical removal of all undetermined lesions and follicular neoplasms is recommended [5].
