88 % of all thyroid carcinomas are DTC. Papillary tumors arise from thyroglobulin (Tg)-producing follicular cells (thyrocytes), and 85 % of DTC are PTC in developed countries where sufficient iodine is present in the diet [6, 7, 29]. PTC is the most well-differentiated histology. It usually presents as multifocal lesions, with a high incidence of regional lymph node metastases [30]. They vary in size from microscopic cancer to large tumor. They may invade the thyroid capsule and contiguous structures and lymphatics. But blood vessel invasion is rare. Cystic changes, calcifications, and even ossification may be identified. Psammoma bodies, calcified scarred remnants of tumor papillae, are commonly seen in about 50 % of PTC and pathognomonic for PTC [6, 7, 29, 30]. Pure PTC has very good prognosis. But the insular, tall cell, columnar cell, and diffuse sclerosing variants are more aggressive forms of PTC [28] (Table 21.1). PTC less than 1 cm are often referred to as microcarcinomas [6, 7, 29]. Papillary thyroid carcinoma seems closely related to the activation of trk and RET proto-oncogenes. The trk proto-oncogene codes for the tyrosine kinase receptor; the ret shows a paracentric inversion of chromosome 10 and 11 in 30–35 % of the cases. Activating RET mutations may be the result of ionizing radiation [31]. RET/PTC gene rearrangements or RAS, BRAF, or MEK–ERK pathway mutations are present in 70 % of PTCs, and the upregulation of vascular endothelial growth factor (VEGF) signaling is also common in metastatic disease [6, 7, 32]. RET/PTC genetic alterations are the most common mutation found in the Chernobyl radiation-induced thyroid carcinomas [33, 34]. The most common were RET/PTC1 and RET/PTC3, and the latter was associated with the more aggressive form of PTC. BRAF mutation is the most common genetic alteration in thyroid cancer, particularly in PTC. BRAF mutation is associated with poor clinicopathologic characteristics of PTC. Detection of BRAF mutation on FNA specimen before surgery is recommended as a useful diagnostic marker and prognostic indicator for PTC and thus influences the surgeon’s decision on the management of PTC [35]. The prevalence of genetic alterations in patients with various thyroid carcinomas is outlined in Table 21.2 [36].

FTC is 12 % of DTC. True FTC is an unusual tumor comprising approximately 5–10 % of thyroid malignancies in non-endemic goiter areas of the world [29]. Prior to the introduction of iodinated salt, follicular carcinoma was much more frequently diagnosed. Follicular tumors although frequently encapsulated, microscopically vascular and capsular invasion commonly present. This histologic finding distinguishes benign neoplasms from malignant follicular neoplasm. Cytology alone cannot be used to diagnose follicular carcinoma [6, 7]. FTC may be associated with RAS mutations and mutations on chromosome 3 (PAX8–PPAR) [6, 36] (Table 21.2).

HCC or oncocytic carcinoma is a histological variant of FTC often of more aggressive behavior and accounts for 3 % of DTCs [6, 7].

Many tumors have both papillary and follicular elements histologically, and they are called follicular variants of papillary carcinoma and classified as papillary carcinoma. Because the clinical behavior of these tumors are not different from pure PTC [7, 37]. DTCs most often secrete thyroglobulin, and it can be used as a tumor marker.

Poorly differentiated thyroid carcinoma (PDTC) was introduced and defined by Sakamoto et al. and Carcangiu et al. in the 1980s [38, 39]. PDTC has aggressive histologic behavior with necrosis, increased mitotic rate, and vascular invasion. They account for 4–7 % of all thyroid cancers [36]. RET/PTC genetic alterations are 0 %, and TP53 mutations are present in 20–30 % of cases [36] (Table 21.2). PDTC is more aggressive than DTC and less aggressive than ATC.

Other very rare forms of PTC and FTC are seen in Table 21.2.

MTCs are derived from parafollicular cells or calcitonin-secreting C cells. RET proto-oncogene mutations are characteristic, with germline activating RET mutations as seen in FMTC and MEN 2A predisposing factor. Calcitonin and carcinoembryonic antigen (CEA) can be used as tumor markers [6, 7, 36, 37] (Table 21.2).

ATC is the most aggressive form of thyroid carcinomas and typically the cause of death within 6 months. One-year survival is about 20 %. This type is less than 3 % of thyroid malignancies in the USA [6, 7, 37]. ATC can occur de novo or has arisen from more differentiated cancer that went undiagnosed for many years. In some cases there is a spectrum from papillary to anaplastic cancer [40]. ATC is distinguished from poorly differentiated (grade 3) thyroid carcinoma in part by loss of TTF-1 expression and abnormalities in p53 signaling pathway [6, 36] (Table 21.2). BRAF and RAS mutations are also shown in ATC [36] (Table 21.2).

Thyroid lymphoma (5 %), thyroid sarcoma (<1 %), and squamous carcinoma of the thyroid (<1 %) are the other very rare cancers of the thyroid gland [6, 7, 29, 30, 37]. Breast, lung, and kidney cancers are the most frequent cancers that metastasize to the thyroid.

The majority of patients with thyroid cancer present with a clinically or ultrasonographically (USG) detectable solitary nodule. All thyroid nodules in the general population have a 5–8 % chance of malignancy [6, 7, 29, 41, 42]. History, physical examination, USG, and FNA are the four most important diagnostic methods. History is very important: history of dyspnea, dysphagia, and persistent dysphonia and male sex, age <14 years or >70 years, personal thyroid cancer history with lobectomy, radiation exposure in childhood or adolescent period, first-degree relative with thyroid cancer or MEN2, personal history of familial adenomatous polyposis, Carney complex, Cowden syndrome, FDG avid on PET scan are the high risk clinical features for malignancy. Firm and hard fixed nodule/s or rapidly growing nodules on physical examination and cervical lymph node/nodes palpation are important findings for malignancy [6, 7, 29, 30, 37, 42, 43].

Neck and thyroid USG and fine needle aspiration (FNA) are very important in the differential diagnosis of thyroid nodules: sonographic features and thresholds for FNA, according to the National Cancer Center Network (NCCN) guideline, are outlined in Table 21.3 [42]. The rate of carcinoma of a suspicious nodule is about 20 %. The false-positive and false-negative FNA cytology rates for all nodules are less than 5 % [7, 29, 37]. The Bethesda system suggests a six-category classification system to report thyroid FNA biopsy (FNAB) results [44]. In one of the last studies, the authors reviewed eight published studies including 25,445 thyroid FNABs [45]. Twenty-five percent of the patients (6,362 pts) subsequently underwent thyroidectomy. The final pathology results were compared to the FNAB results.

As a result, in patients with benign or inadequate FNAB results, other factors, such as USG findings (Table 21.3), personal history, and nodule size, should be considered for the decision to do surgery. The author researchers recommend to repeat FNAB when the diagnosis is indeterminate [45]. In this group, molecular markers (BRAF, RET/PTC, RAS, PAX8/PPAR mutations) (Table 21.2) may help to find out in which patients surgery is necessary [35, 46, 47]. Gene mutations are very rare in benign FNABs (approximately ≤5 %).

All patients suspicious for cancer category should undergo surgery because of the very high (75 %) possibility of cancer [41, 45].

Papillary, medullary, and anaplastic carcinomas can be easily diagnosed with FNA cytology, but it is difficult to distinguish benign from malignant follicular lesions. Histologic examination showing capsular and vascular invasion is necessary to classify a lesion as malignant for follicular and Hürtle cell neoplasia [7, 29, 37]. Molecular diagnostics may be useful to allow reclassification of follicular lesions, such as follicular neoplasm or follicular lesions with undetermined significance [48]. In the diagnosis of follicular lesion with undetermined significance (other terms are atypia of undetermined significance, rule out neoplasm, atypical follicular lesion, and cellular follicular lesion, and the estimated risk of malignancy is 5–10 %), FNA can be repeated or surgery can be considered according to the clinical and USG findings [42].

Another diagnostic method is radionuclide scan: In the last years, it is not used in the initial evaluation of thyroid nodule, except for suppressed TSH levels. In this situation, radionuclide scan is done to assess for a functioning (hot) adenoma. Malignant lesions usually are documented as hypofunctioning or cold lesions. The overall incidence of cancer in a cold nodule is 12–15 %, but it is higher in people younger than 40 years and in people with calcifications present on preoperative USG [49, 50].

Serum calcitonin measurement may be helpful for the diagnosis of MTC [51]. According to the American Association of Clinical Endocrinologist/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA) guideline, assessment of serum thyroglobulin is not recommended in the differential diagnosis of thyroid nodules. In patients undergoing surgery for malignancy, serum thyroglobulin (Tg) measurement may be useful to detect potential false-negative results. Measurement of basal serum calcitonin level may be a useful test in the initial evaluation of thyroid nodules [43].

There are many prognostic factors for DTC. Age, sex, histologic type, tumor size, tumor grade, multicentricity, extrathyroidal extension, type of surgery, ploidy, lymph node metastases, vascular invasion, and ¹³¹I RAI ablation therapy are important prognostic factors [6, 7, 29, 30, 37, 52–55]. Also there are multiple prognostic scoring systems for DTC. These are AGES (age, grade, extent, size), AMES (age, metastases, extent, size), DAMES (ploidy + AMES), MACIS (metastases, age, completeness of resection, invasion, size), and the AJCC-TNM staging system 2010 7th edition (age, stage) (Tables 21.4 and 21.5) [52, 56–59]. Prognoses according to the type of cancer and stage are outlined in Table 21.6 [59, 60]. Age, size, and extent of the tumor are present in all prognostic scoring systems. Adverse prognostic factors included age older than 45 years, follicular histology, primary tumor size larger than 4 cm, extrathyroidal extension, and distant metastases.