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Thyroid malignancies account for approximately 1 to 1.5% of all malignancies in humans. It is also the most common among all endocrine malignancies and accounts for 90% of cases. Of these, differentiated thyroid carcinomas (DTCs) alone constitute approximately 95% of the disease bulk. There are three major types of DTCs: papillary thyroid carcinoma (PTC; Fig. 3.1), follicular thyroid carcinoma (FTC; Fig. 3.2), and Hürthle cell tumors. These three variants collectively account for approximately 90% of all DTC cases. The most commonly encountered DTC is papillary thyroid cancer (constitutes 80 to 85% of all cases), followed by follicular thyroid cancer (10 to 20% of all cases) and Hürthle cell cancer (2 to 5% of all DTC cases). The disease is more commonly encountered in women than in men, with a woman to man ratio of 3:1 in most of the studies. Production and secretion of thyroglobulin is the characteristic feature of all types of DTCs. The serum level of this hormone supports correct diagnosis, helps in surgical radicality assessment, and serves as an early biochemical recurrence marker. More than 80% of the patients diagnosed with DTC have good or even excellent prognosis, with approximately 99% 20-year survival rates. However, the remaining 20% of the patients have a less favorable course of disease, with 10-year rates ranging between 20 and 50%.¹

Epidemiology and Risk Factors

In the United States, approximately 20,000 new cases of thyroid carcinoma are diagnosed each year. Some 200,000 patients with thyroid carcinoma are followed-up each year in the United States, and nearly 1500 die from this disease annually.

The age at diagnosis ranges between 45 and 50 years. Less than 10% of all DTCs are found in patients younger than 21 years. The clinical course of DTC in children younger than 10 years is less favorable than in older individuals, as is in patients older than 65 years. This fact is not reflected in the current AJCC/TNM (American Joint Committee on Cancer/Tumor-Node-Metastasis) classification, and it also results in poorer outcomes for the whole stage I and II groups (all patients younger than 45 years and independent of extension of the disease are classified as stage I or II; see below for details).²

Various environmental, hormonal, and genetic factors play a role in the development of DTC. The risk of developing DTC is associated with radiation exposure: therapeutic irradiation (e.g., treatment for Hodgkin lymphoma in childhood/adolescence), accidental irradiation (e.g., after explosion in Chernobyl in 1986, 100-fold higher DTC incidence has been noted in several contaminated regions of Belarus and Ukraine), and occupational and geological irradiation. The peak risk of developing DTC is seen 20 to 30 years after irradiation. It is estimated that about 10% of the DTCs may be radiation induced.³ The risk of developing thyroid carcinoma rises linearly with increasing radiation doses. At doses higher than 20 Gy, complete ablation of the thyroid tissue supervenes.

One of the factors that cause the development of a DTC is iodine intake. Interestingly, PTC is more common in regions with high iodine intake, while FTC is common in iodine-deficient regions.⁴ Other environmental factors that possibly play a role in thyroid carcinoma development are retinol, vitamin C, and vitamin E.

Approximately 3 to 5% of PTC are inherited as an autosomal dominant trait and are supposed to be more clinically aggressive than the sporadic ones. Familial FTC is extremely rare. In general, familial DTC may be associated with familial adenomatous polyposis, Gardner syndrome, Cowden syndrome, Carney syndrome, or multiple endocrine neoplasia type I.

Among genetic mutations that are linked to the pathogenesis of DTC are RAS, RET/PTC, BRAF, PAX8/PPARg, TRK, MET. RAS oncogens are most commonly identified in DTC (up to 80% of FTC, 50% of PTC, and 12% of Hürthle cell carcinoma).⁴ BRAF proteins are found exclusively in PTC (up to 70% of the cases). Tyrosine kinase oncogenes (RET, TRK, MET) are also typical for PTC (RET in 50%, TRK in 20%, MET in up to 80% of the cases). The only tyrosine kinase oncogene found in FTC (10% of the cases) is MET. FTC is also associated with PAX8/PPARg.5

According to the Bethesda System for Reporting Thyroid Cytopathology, each thyroid fine-needle aspiration biopsy (FNAB) report should begin with a general diagnostic category. The diagnostic categories are given in Table 3.1.

PTC has characteristic cytological features, which can be easily recognized in aspirates from FNAB. Typically, there is a large number of cells that may be grouped into clusters and monolayers or formed papillary arrangements (Fig. 3.1). Other important features that help distinguish PTC from follicular cells are crowding, overlapping, and molding. The defining and diagnostic features of PTC are seen in the nuclei of cancer cells—enlarged nuclei containing dusty (powderlike) chromatin (ground glass nuclei).

Contrary to PTC, cytological diagnosis of FTC is often impossible because of microscopic similarity to adenoma. Smears contain numerous clusters of glandular cells, usually arranged in ringlike (follicular) or rossette-like acinar structures (Fig. 3.2). The presence of nuclear atypia does not necessarily imply malignant behavior of tumor. Therefore, the diagnosis of malignancy has to be based on histological and not cytological evaluation. The cytological diagnosis of follicular neoplasm implies obligatory surgical excision and microscopic examination of specimen.

The World Health Organization (WHO) classification of thyroid tumors specifies 16 histological types of PTCs (including conventional variant). The histological division is based on the growth patterns, cytological features of tumor cells, and the type of tumor stroma. All papillary carcinomas present the typical nuclear features that are required for the diagnosis of PTC (see section on Cytology). Histological variants of PTC and their respective clinical behavior are listed in Table 3.2.

Table 3.1 Bethesda System for Reporting Thyroid Cytopathology with Risk of Malignancy

By definition, it is a malignant epithelial tumor that shows a follicular differentiation (follicle formation) and a lack of characteristic nuclear features of papillary carcinoma (see section on Cytology). FTC accounts for 10 to 15% of the thyroid malignancies. FTC is more common in women and usually occurs later in life compared with PTC. It has much lower frequency of lymph-node metastasis compared with PTC (less than 5%), but distant metastasis (mainly to lung and bone) are more frequent at presentation (20 to 33%).6

Follicular carcinomas usually present as encapsulated solid tumors of larger than 1 cm diameter. The color varies from gray-tan to brown. The capsule can be noticed in some cases. Minimally invasive carcinomas are practically identical on gross examination with follicular adenomas.

Morphology of FTC is variable and includes tumors with follicles filled with colloid and neoplasms, which have solid and trabecular growth patterns. Diagnosis of malignant growth is based on the presence of vascular and/or capsular invasion. Architecture and cytological atypia are not essential for the diagnosis. Generally, FTC is divided into two main groups according to the extent of tumor invasiveness: minimally invasive (with limited infiltration of the tumor capsule or extension through the tumor capsule and/or vascular invasion) and widely invasive follicular carcinoma. The latter category includes carcinomas with distinct and wide infiltration of the thyroid tissue and/or blood vessels. “Capsular invasion” should be recognized with the penetration of tumor cells only through the capsule (not in the site of previous FNAB). “Vascular invasion” means the presence of intravascular tumor cells covered by endothelium or associated with thrombus; it refers to the vessels only within or beyond the capsule. Some authors also use the term “grossly encapsulated angioinvasive follicular carcinoma” to describe tumor in which both capsular invasion and vascular invasion are present (as opposed to minimally invasive carcinoma with only capsular invasion). Histological variants of FTC and their respective clinical behavior are presented in Table 3.2.

Survival rates for FTC vary from 70 to 95% and are little lower than for PTC. Prognostic factors that are related to unfavorable prognosis include age greater than 45 years, oncocytic variant of FTC, malignant infiltration beyond the thyroid, tumor size greater than 4 cm, and the presence of distant metastases.

Hürthle Cell Carcinoma

The WHO classification lists Hürthle cell carcinoma as a variant of FTC (“oncocytic variant of FTC”; see Table 3.2); however, it is frequently considered a separate pathologic entity characterized by distinct microscopic appearance and clinical behavior. Hürthle cell carcinoma or oncocytic variant of FTC comprises approximately 5% of the malignant thyroid tumors, and in contrast to FTC, the frequency of nodal metastases in this neoplasm is approximately 30%.

There is no evidence that pathogenesis of Hürthle cell carcinoma is different from that of conventional FTC, although H-Ras mutations are more often found in this type of tumor than in FTC.

Table 3.2 Histological Variants of PTC and FTC and Their Respective Prognosis

Patients with Hürthle cell carcinoma are considered to have a poorer prognosis compared with patients with FTC and PTC. The frequency of lymph-node metastases as well as of distant metastases is higher than in non-Hürthle DTC. A lower uptake of radioactive iodine also makes the treatment of these tumors more challenging.

Because the autopsy series suggests that up to 50% of the general population can have thyroid nodules, it is of utmost importance to identify those lesions that are potentially harmful. Furthermore, a vast majority of thyroid nodules that are being seen and investigated by clinicians are incidental, asymptomatic findings. It is therefore crucial to not overdiagnose and overtreat otherwise healthy individuals who happen to have a completely benign thyroid nodule. The algorithm presented in Fig. 3.3 should help in correctly addressing these issues.

Laboratory Tests and Imaging Studies

The screening test for the evaluation of thyroid function is a must when evaluating any thyroid nodule. It is sufficient to start with the estimation of serum thyroid-stimulating hormone (TSH) level. In the case of subnormal TSH serum levels (i.e., < 0.5 mIU/L), one should proceed to T3 and T4 serum levels evaluation and a radionuclide scan should be obtained. The serum TSH level serves as a screening test for thyroid function. The evaluation of T3 and T4 can confirm the diagnosis of hyperthyroidism, and radionuclide scan will identify hyperfunctioning nodules. The evaluation of thyroid nodules with radionuclide scan (it has been estimated that 16% of the nonfunctioning nodules and 9% of the normal-functioning nodules on radionuclide scan are malignant, while hyperfunctioning nodules only occasionally harbor a malignancy) is no longer used as a first-line diagnostic tool in thyroid cancer.

Obtaining a thyroid ultrasound is an essential step for the exact characterization of the mass, and best results are achieved when it is performed by a dedicated neck ultrasonologist. The decision whether ultrasound-guided FNAB should follow is based on several factors, as shown in Fig. 3.3. If the decision on FNAB is taken, the laboratory tests for hemostatic function become mandatory.

Until recently, it was presumed that the size of thyroid nodule as seen on ultrasound should be a threshold for biopsy. This approach has changed, and currently the decision concerning the biopsy is based on features other than the tumor size. The ultrasonic features of a thyroid nodule that warrant an FNAB are calcification, irregularity (irregular halo), solid lesion, and hypervascularity.

The possible general categories of FNAB of a thyroid mass are as follows:

• Benign.

• Malignant (PTC, medullary thyroid carcinoma, anaplastic thyroid carcinoma).

• Indeterminant (follicular neoplasm; this can mean FTC and follicular adenoma). and

• Insufficient/nondiagnostic specimen (15 to 25% of all FNABs).

The FNAB result should be reported by using Bethesda System for Reporting Thyroid cytopathology (see Table 3.1). The diagnostic accuracy of FNAB is estimated at greater than 95%, and its false-negative rates are around –5%. FNAB is more accurate for lesions measuring 1 to 4 cm in diameter. Smaller lesions are difficult to sample accurately, while larger lesions have greater sampling error. As mentioned before, the FNAB is able to provide definitive diagnosis of PTC due to characteristic nuclear changes. It is unfortunately unable to distinguish between FTC and follicular adenoma, and therefore the diagnosis of FTC requires a histological proof of capsular invasion and/or vascular invasion. If the FNAB result suggests follicular neoplasm, thyroid lobectomy should be performed to permit full histological evaluation of the tumor. In approximately 20% of the lobectomy specimens in patients operated on because of FNAB suggesting follicular neoplasm, the final diagnosis confirms FTC. Undetermined or insufficient FNAB requires repetition of FNAB (see algorithm in Fig. 3.3).