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Thyroid cancer – 2016

1. GENERAL INFORMATION

1.1 Incidence and mortality

Thyroid cancer is a rare disease, representing 1.4% among all malignant neoplasms in Europe (EU28) (Globocan). In 2014, there were almost 25,700 new cases of thyroid carcinomas and 1,230 new cases of thyroid endocrine tumours (RARECAREnet). The age standardized incidence rates were 7.2 per 100,000 per year in women and 2.4 in men.
There is a 10-fold difference in incidence among different parts of the world for women, but only a 3-fold difference for men (Globocan). The highest incidence rates in women (>10 per 100,000/year) were reported for North America, Australia, New Zeeland and Polynesia (Globocan).
Incidence rates increased with age. The annual rates per 100,000 can be found in children (11.0) and in adolescents (15-24 years). Rates increased up to 8.2 in the age group of 55-64 years and remain stable in the age group 65+ years (7.9) (RARECAREnet).
The annual incidence rates increased from 1995 to 2007 (from 2.9 to 4.4). Incidence of carcinoma of thyroid increased more than endocrine carcinoma of thyroid (RARECAREnet).
Many authors attributed the increasing incidence of thyroid cancer to improved diagnostic procedures to detect thyroid nodules. In Europe thyroid cancer mortality remained unchanged or slightly reduced in recent years (DepIarc). In the EU28 there are about 3,639 deaths/year from thyroid cancer (Globocan).

1.2 Survival

Survival was analysed for some 78,533 adults diagnosed with carcinoma of thyroid in Europe during the period 2000-2007 and followed up to the end of 2008 (RARECAREnet). Relative survival was 93% at one year and 90% at five years, slightly worse survival for the endocrine tumours; the corresponding figures were 93% and 84%. The latter figures are based on 3,793 cases.
Women had better survival than men: 92% vs. 85% for thyroid carcinoma and 88% and 76% at 5 years for endocrine tumours. Survival decreased with increasing age at diagnosis, and was worst for very elderly patients: 5-year survival was 99% in young patients (<45 years of age) and declined to 70% in older patients (65 or more year of age). The corresponding figures for endocrine tumours were 91% and 67% (RARECAREnet).
In England and Wales, survival from thyroid cancer has been lower in the most deprived patient group compared to the most affluent group since the early 1970s, both for men and women. The gap in survival, related to deprivation, diagnosed during the period 1981-1985 was about 10% one, five and ten years after diagnosis. On average, therefore, survival improved slightly more in the deprived groups than in the affluent groups during 1980s, but the deprivation gradient remained statistically significant (DepIarc).

1.3 Prevalence

In Europe (EU28), about 380,000 people are living with a diagnosis of thyroid tumours (RARECAREnet). They could be cured or under treatment or in clinical follow-up. Long survivors may be cured and can be estimated to be about 46% of the complete prevalence, that is those still alive 15 years or more from diagnosis. By contrast, patients in treatment or in clinical follow-up, that is 5-year prevalence, are 25% of complete prevalence (RARECAREnet).

1.4 Aetiological and risk factors

1.4.1 Ionizing radiation

The most well-established cause of thyroid cancer is exposure to ionizing radiation; an association that has been known since 1950 (Duffy 1950). The susceptibility to radiation-induced thyroid cancer is strongly and inversely related to age at exposure (being higher in infancy and early childhood), directly related to background iodine deficiency, and, to a lesser extent, to gender (being higher in women) (Dal Maso 2009). A pooled analysis of seven studies (Ron 1996) showed a significant dose-risk for exposure during childhood. Women had an approximately 2-fold higher risk than men. A latent period of 5-9 years emerged with highest risk 15-29 years after exposure. Risk continued to be elevated for 40 or more years after exposure. The relative risk (RR) also decreased significantly with increasing age at exposure, with still some excess risk after age 20 years.
Further confirmation emerged after the Chernobyl nuclear power plant accident of April 1986, where a large increase in the incidence of childhood thyroid cancer was reported in contaminated areas (Moysich 2002). The Chernobyl accident also showed that the adult thyroid is less radiosensitive than that of a child (Moysich 2002). The next analysis on the thyroid cancer incidence risk after the Chernobyl accident confirmed the results of the seven study polled analysis (Jacob 2006).
Cardis et al. investigated the role of radioactive iodine in children with a case-controlled study. An approximately 7-fold excess risk for thyroid cancer was estimated for a dose of 1 Gray and a linear dose–risk relationship was observed at least up to 2 Gray (Cardis 2005). The administration of potassium iodide as a dietary supplement reduced the risk of radiation-related thyroid cancer by a factor of 3 for consumption of potassium iodide versus no consumption (Cardis 2005). Another specific source of thyroid irradiation is radiotherapy for head and neck malignancies. Indeed, in a cohort of childhood cancer survivors, 7.5% of all secondary malignancies were thyroid cancers (Black 1998).

1.4.2 Genetic susceptibility

Around 20-25% of medullary carcinomas of thyroid can be attributed to genetic factors (Liska 2005). In particular, germ-line mutations in the RET gene are responsible for the hereditary tumour syndrome (i.e., multiple endocrine neoplasia type 2, MEN 2) which includes three subgroups, MEN 2A, MEN 2B, and familial medullary thyroid carcinoma, depending on the tissue involved.
Differentiated Thyroid carcinomas are present in several familial syndromes, including Cowden’s disease (hamartomas, multi-nodular goiters, and thyroid, breast, colon, and lung cancer); familial adenomatous polyposis; Gardner’s syndrome.
However, familial differentiated thyroid cancer in the context of these syndromes is very rare. The large majority of familial cancers (almost always papillary) occurs as isolated, non-syndromic, papillary thyroid cancer, in which no candidate predisposing oncogene has been detected. This form of familial cancer has been reported in 3-10% of patients in different series. In a study including all thyroid carcinomas diagnosed between 1958 and 2002 in Sweden, the familiar risk for papillary carcinoma was found to be 3 and 6 when thyroid cancers were diagnosed in a parent or a sibling, respectively (Hemminki 2005). The risk was approximately 5-fold higher in first-degree relatives of thyroid cancer patients compared with the general population (i.e., this represented one of the most elevated RRs among all cancer sites in the Swedish study). Recently, an epidemiological study has demonstrated that these pedigrees exhibit the phenomenon of “genetic anticipation”, consisting in the appearance of thyroid carcinoma at an earlier age and with increased aggressiveness in the second and subsequent generation 32. In the same families, a germline alteration has also been demonstrated, consisting of short telomeres and increased telomerase activity, leading to genomic instability and possibly predisposing the risk of thyroid carcinoma (Capezzone 2009).

1.4.3 Benign diseases of thyroid

Benign thyroid disease can influence the development of thyroid cancer with goitre and benign nodules being the strongest risk factors with relative risks of approximately 3 and 30, respectively. The prevalence of cancer in single thyroid nodules is about 5% (Hegedus 2004) and patients with multinodular goiter have the same risk of cancer. Moreover, patients with multinodular goiter have the same risk of thyroid cancer than patients with single nodules (ATA 2009). The role of hypothyroidism and hyperthyroidism remains unclear (Franceschi 1999).

1.4.4 Reproductive factors

Thyroid cancer occurs approximately three times more frequently in women than in men, therefore hormonal factors may play a role in its aetiology. The pooled analysis of case-control studies by Negri et al showed that the associations between thyroid cancer and menstrual or reproductive factors were generally weak, although they appeared to be stronger among women diagnosed with thyroid cancer at a young age (Negri 1999). Artificial menopause was positively associated with thyroid cancer as was the ever use of oral contraceptives; the association declined with increasing time since stopping oral contraception. A small increase in risk was also seen among women who took drugs for lactation suppression (La Vecchia 1999). Later studies confirmed that hormonal and reproductive factors were weakly associated with thyroid cancer (Dal Maso 2009).
From the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (345,157 women) followed for an average of 11 years, 508 differentiated thyroid cancer cases were identified. Significant associations were found with history of infertility problems (HR 1.70; 95%CI 1.12-2.60), a recent pregnancy (HR for ≤5 vs. >5 years before recruitment 3.87; 95%CI 1.43-10.46), menopause type (HR for surgical vs. natural menopause: 2.16; 95%CI 1.41-3.31), oral contraceptive (OC) use at recruitment (HR: 0.48; 95%CI 0.25-0.92) and duration of OC use (HR for ≥9 vs. ≤1 year: 0.66; 95%CI: 0.50-0.89). An increased risk was also found with hormone replacement therapy use at recruitment (HR: 1.30, 95%CI 1.02-1.67), but this was not significant after adjustment for type of menopause (HR: 1.22, 95%CI 0.95-1.57) (Zamora-Ros 2015).

1.4.5 Dietary risk factors and body mass

Iodine deficiency influences thyroid function directly, as well as indirectly, through a reduction in the level of thyroid hormones and a consequent rise in TSH secretion. Chronic iodine deficiency is firmly established as a risk factor for goiter and follicular thyroid cancer, while some aetiological studies suggested that iodine supplementation programmes could increase the incidence of papillary thyroid cancer by inducing iodine excess (Dal Maso 2009). Increased surveillance and improvement in the quality of diagnostic tools are, however, likely responsible for the increase. Recent findings are reassuring with respect to the concern that iodine supplementation may increase the risk of papillary thyroid cancer, associating the increased trend in this cancer to improved diagnostics rather than iodine supplementation which has benefits (Verkooijen 2003).
One pooled analysis of 13 case-control studies and 2 separate case-control studies investigated fish consumption (Rezzonico 2009; WCRF 2007). These were consistent in showing a significantly reduced incidence with increased consumption in areas of endemic iodine deficiency, but none in areas where iodine intakes are high. Fish is known to be an important natural source of iodine in the diets of different populations, and therefore an association between fish intake and thyroid cancer risk may be mediated by iodine.
A moderate favourable effect was found in a large pooled-analysis for the high intake of vegetables other than cruciferous. Vegetables contain many potentially protective substances, including several antioxidants, as well as phytochemicals with antiproliferative capabilities. They are also a rich source of folate, which plays an important role in the synthesis, repair, and methylation of DNA (WCRF 2007).
One pooled analysis of 12 case-control studies and 1 cohort study investigated BMI or obesity. Obesity was associated with a statistically significant increased incidence in women, with a clear dose-response relationship. Body size might affect iodine requirement and therefore, indirectly, influence thyroid cancer risk (WCRF 2007). A recent study supports the possibility that insulin resistance and hyperinsulinemia (a typical feature of obesity) rather than metabolic derangement may be a risk factor for thyroid cancer. Insulin regulates thyroid gene expression and stimulates thyrocyte proliferation, differentiation, and transformation. Insulin resistance was present in 50% of PTC patients versus 10% of matched controls (Rezzonico 2009).
One pooled analysis of 12 case-control studies investigated adult attained height. Greater height was associated with a statistically significant increased incidence of thyroid cancer in both women and men, with a clear dose-response relationship. The effect was greater in men than in women. Body size might affect iodine requirement and therefore, indirectly, influence thyroid cancer risk. The association with height in both men and women may indicate a potential influence of some growth factor or hormone during childhood or adolescence, but the potential role of growth factors on thyroid carcinogenesis is still poorly defined (WCRF 2007). The WCRF panel of expert concluded that both iodine deficiency (probably) and iodine excess (possibly) were causes of thyroid cancer, and also that vegetables and fruits were possibly protective.

1.5 Screening

There is insufficient evidence to support thyroid cancer screening based on the currently available tests for identifying asymptomatic or premalignant lesions. There are no clinical trials on-going for the evaluation of the efficacy of a screening programme (Hakama 2008).

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

Follicular cell proliferation and function is physiologically regulated by thyroid stimulating hormone (TSH or thyrotropine). Although activating point mutations of the TSH receptor have been discovered in 60-70% of benign toxic adenomas (Van Sande 1995; Tonacchera 1999), a pathogenetic role for these mutations in malignant transformation has been excluded or rarely reported (Cetani 1999). Several other genetic abnormalities, either determining activation of oncogenes or inactivation of tumour suppressor genes, have been described in different thyroid tumour histotypes. In particular, H-, N- and K-RAS gene activating point mutations have been reported both in follicular adenomas and carcinomas, while RET/PTC and TRK rearrangements, BRAF point mutations and MET overexpression have been detected in papillary thyroid cancer (PTC). RET gene activating point mutations are exclusively found in medullary thyroid carcinoma (MTC), both as somatic mutations in about 50% of sporadic cases and as germline point mutations in 99% of hereditary cases. It is of interest that RAS, RET, TRK, MET and BRAF genes are all involved in the activation of the intracellular MAP kinase cascade whose activation leads to cell proliferation. An abnormal activation of this cascade is one of the best-recognized mechanisms of thyroid tumorigenesis.
Other abnormalities have been sporadically reported to be involved in thyroid tumorigenesis such as DNA methylation (Matsuo 1993) and gene deletions in chromosomes 11q13 and 3p (Matsuo 1991; Grebe 1997a).
The next paragraphs are focused on the most important genetic alterations involved in thyroid tumorigenesis.

2.1.1 H-, K-, N-RAS oncogenes

RAS genes activation induces cell division and inhibits cell differentiation. The encoded p21 plays an important role in the intracellular signal transduction from the cell surface to the nucleus where it is able to activate intranuclear genes (Giehl 2005). The mechanisms through which mutated RAS proteins stimulate cell proliferation are poorly known. It has been hypothesized that activated p21 could interact with some thyroid-specific transcription factors such as TTF1 or PAX-8 (Gire 2000).
RAS oncogenes are activated by point mutations mainly found in 3 hot spots located in codons 12, 13 and 61. RAS oncogene point mutations have been found in nearly 40% of benign and malignant follicular thyroid tumours while they are much less frequent, although not completely absent, in the papillary histotype (Lemoine 1989; Suarez 1990; Wright 1989). Interestingly, RAS mutations are more frequent in thyroid tumours of subjects living in countries where iodine intake is inadequate (Shi 1991).

2.1.2 RET Oncogene

The RET proto-oncogene is located on chromosome 10q11-2. It encodes a tyrosine kinase transmembrane receptor involved in the activation of the MAP kinase cascade. The proto-oncogene is normally expressed in a variety of neural cell lineages including thyroid C cells and adrenal medulla but it is not expressed, or at very low levels, in normal thyroid follicular cells (Santoro 1995).
RET oncogene activation may be determined either by a rearrangement generating the fusion, at the chromosomal level, of the tyrosine kinase domain of RET gene and the 5’ domain of different genes (Grieco 1990) or by activating point mutations (Castellone 2008). While RET/PTC rearrangements have been reported only in PTC (Fusco 1987) and in some cases of benign follicular adenomas (Wirtschafter 1997), activating RET point mutations have been exclusively found in MTC (Castellone 2008).
Several RET/PTC rearrangements have been described but all of them are characterized by the fusion of the RET tyrosine kinase domain with a foreign gene which is constitutively expressed and its 5’ domain acts as promoter ensuring permanent expression of the RET gene in the follicular cell in which it is not normally expressed (Grieco 1994; Pierotti 1992; Santoro 1994).
RET/PTC rearrangements are related to ionizing radiation exposure which is a well-recognized risk factor for PTC. The evidence of an increased prevalence of RET/PTC rearrangements in childhood post-Chernobyl thyroid carcinomas (Nikiforov 1997) and the possibility of determining RET/PTC rearrangements in vitro in thyroid cells experimentally exposed to ionizing radiation (Caudill 2005) speak in favour of a causative connection between radiation exposure and these chromosomal alterations.
Despite this evidence, RET/PTC rearrangements have also been reported in sporadic PTC (Elisei 2001). The prevalence of RET/PTC rearrangements in thyroid tumours of patients who had no history of neck irradiation ranges from 2.5 to 35% among different series (Bongarzone 1989; Bounacer 1997; Grieco 1990; Nikiforov 1997; Santoro 1992; Viglietto 1995; Zou 1994). The prevalence is much higher, up to 75%, in post-Chernobyl childhood thyroid carcinoma (Nikiforov 2006).
The finding of RET/PTC rearrangements in microPTCs suggests that it is an early event in thyroid carcinogenesis (Viglietto 1995). On the other hand, RET/PTC positive tumours do not show signs of progression to poorly or undifferentiated tumour phenotype (Tallini 1998).
Activating RET point mutations are typically found in MTC which derives from C cells in which it is normally expressed. The point mutation determines a constitutive activation of the tyrosine kinase receptor and, as consequence, a continuous stimulus to cell proliferation. Germline RET point mutations are mainly localized in the tyrosine kinase domain and in the cysteine domain of the gene. Recently several other non-cysteine mutations have been described, usually correlated with less aggressive phenotypes (Niccoli-Sire 2001). A certain genotype-phenotype correlation has been recognized over the years and some RET mutations (e.g., Met918Thr) are almost exclusively found with a specific phenotype such as the MEN 2B syndrome. Somatic mutations have been found in the tumoral tissues of about 50% of sporadic cases. The somatic mutations are mainly localized at codon 918 and, if present, represent a negative prognostic factor in terms of survival (Elisei 2007).
RET genetic screening, i.e., the analysis of the constitutive DNA of a MTC patient from a venous blood sample, is fundamental to enable the early discovery of gene carriers who, once diagnosed, can be monitored and eventually treated with a prophylactic total thyroidectomy (Frank-Raue 2006).

2.1.3 BRAF oncogene

Recently, an activating mutation of the B isoform of the Raf kinase gene, located on exon 15, which results in a valine to glutamic acid substitution at amino acid 600 (BRAFV600E mutation) has been found to be the most common mutation in PTC. The BRAFV600E mutation constitutively activates and promotes tumorigenesis through the MAP kinase pathway. Its prevalence is highly variable, ranging from 29 to 83%, in different published series (Xing 2005a; Xing 2005b; Fugazzola 2006).
The BRAFV600E mutation shows a high specificity for PTC and also for anaplastic thyroid carcinoma (ATC) especially when these evolve through dedifferentiation of PTC. By contrast, this mutation has never been described in other malignant thyroid histotypes or benign neoplasms (Nikiforova 2003). The relationship between the BRAFV600E mutation and the clinical and pathological features of PTC is still controversial. Some authors demonstrated that BRAFV600E mutations are more frequently present in PTC with an advanced tumour stage at diagnosis (Xing 2005a, Xing 2005b). However, in other studies this association has not been, or has only partially been confirmed (Puxeddu 2004). As matter of fact, the BRAFV600E mutation signals a worse prognosis with decreased survival for patients whose PTC harbours this somatic mutation (Xing 2005a; Xing 2005b; Kim 2006; Elisei 2008).

2.1.4 p53 tumour suppressor gene

p53 is a tumour suppressor gene involved in the control of the cell cycle and cell apoptosis. For its role of conserving stability by preventing genome mutations it has been described as “the guardian of the genome”. Its inactivation makes cells unable to repair DNA damage, and at the same time to go to apoptosis, thus allowing mutated cells to proliferate. Since p53 mutations have never been described in differentiated thyroid carcinoma it is generally recognized that they are specific to poorly differentiated and ATC (Fagin 1993; Donghi 1993). Although p53 immunohistochemical overexpression is frequent in ATC, gene mutations are not so frequent (Salvatore 1996), suggesting that its function can be abrogated by other mechanisms.

2.2 Histotypes and grading

According to the WHO histological classification (Sobin 2002), thyroid tumours are classified as follows:

  • Papillary thyroid tumours;
  • Follicular thyroid tumours;
  • Poorly differentiated thyroid tumours;
  • Undifferentiated or anaplastic thyroid carcinoma;
  • Medullary thyroid carcinoma;
  • Other rare thyroid tumours (i.e., lymphomas, sarcomas, hemangiosarcomas, mucoepidermoid, etc);
  • Secondary thyroid tumours.
2.2.1 Papillary and follicular thyroid cancer
2.2.1.1 Histology of papillary thyroid cancer

Papillary (PTC) and follicular (FTC) carcinomas are defined as “differentiated thyroid carcinomas” of the follicular epithelium. The diagnosis of PTC is based on the demonstration of cells with the typical nuclear features of the follicular cells organized in papillary and/or follicular structures. The diagnosis of FTC is based on evidence of follicular differentiation but in the absence of the typical nuclei and without papillary architecture (LiVolsi 1992; Rosai 1992).
PTC may be distinguished in micro- and macrocarcinomas, carcinomas limited to the thyroid gland and carcinomas extending beyond the thyroid capsule. According to the WHO classification, tumours less than 1 cm in diameter are microcarcinomas (Hedinger 1988). They may exhibit features of a classic, small papillary carcinoma, or may appear as nonencapsulated sclerotic nodules of a few millimetres in size, infiltrating the surrounding thyroid tissue and defined as “occult”. They are rare in childhood. The general improvement of diagnostic techniques, in particular neck ultrasound, has led to an increase in the number of microcarcinomas (Davies 2006). Microcarcinomas have usually a good prognosis and their clinical impact is debated, especially when considering the results of autopsy studies where they are found in up to 35% of subjects who died for reasons other than thyroid cancer (Mortensen 1955). However, this good behaviour is recognized only for microcarcinoma with no extrathyroidal and/or lymphnodal extension (Pellegriti 2004). Larger, clinically detectable tumours represent nearly 70% of all PTC. They appears as firm, nonencapsulated or partly encapsulated tumours (Carcangiu 1984; LiVolsi 1992). PTC may be partly necrotic and some are cystic (Hammer 1982).
About 50% of all PTC are multifocal in one lobe and 30% of all cases are bilateral (Rosai 1992).
Microscopically, PTCs contain papillary areas either with a focal distribution or with a diffuse pattern. Papillae contain a fibro-vascular structure covered by a single layer of neoplastic cells sometime associated with follicles filled with colloid, trabecular or lobular patterns, areas of sclerosis and squamous metaplasia. About 50% of PTCs are characterized by the presence of “psammoma bodies” which are typical deposits of calcium (Johannessen 1980). These features are not present in each PTC, and their absence does not exclude the diagnosis of PTC, which is indeed based on the peculiar features of follicular cells nuclei (Rosai 1992).
Nuclei of malignant cells in PTCs are larger than in normal cells. They are transparent at the centre and contain hypodense chromatin and, for this reason they are defined as “ground grass nuclei”. The nuclear limits are irregular and may reveal fissures thus being similar to “coffee beans”. Large, circular, well-delimited intra-nuclear inclusions, corresponding to cytoplasmic invagination, are also present (Chan 1986).
About 50% of PTC are associated with lymphocyte infiltrates resembling that of chronic lymphocytic thyroiditis which can surround the tumour foci or spread in the normal thyroid tissue (Holm 1985; Matsubayashi 1995). A higher prevalence of patients with thyroid antibodies has been reported in thyroid cancer patients relative to the general population (Pacini 1988).

2.2.1.2 Histological variants of PTC

The features described above are found in the majority of PTCs and make up the so-called “classical” variants of PTC. However, a subgroup of tumours accounting for 15-20% of all PTC display less common histological features and is classified as PTC based only on the specific and peculiar nuclear features described above.
The “follicular” variant is a grossly-encapsulated tumour (Rosai 1983; Tielens 1994), exhibiting a diffuse pattern of follicular growth with colloid-containing follicles. This tumour is classified as PTC because of the presence of typical nuclei. The biological behaviour is similar to that of the classic variant, although some are more aggressive. The follicular variant is more frequent in young patients and its prevalence was relatively high (more than 20%) in the post-Chernobyl childhood thyroid cancer. It is the most prevalent histotype in histopathology-confirmed thyroid tumours presenting as “follicular neoplasms” on cytological examination (LiVolsi 2004).
The “diffuse sclerosing” variant is rare and mostly found in children and young adults (Carcangiu 1989; Soares 1989). It is characterized by a diffuse thyroid enlargement with both lobes replaced by a very firm and quite often calcified multifocal tumour. Papillae are associated with squamous metaplasia, abundant psammoma bodies and extensive lymphocyte infiltration of the gland. The prognosis is less favourable compared to that of classic variant of PTC, although response to treatment is often excellent.
The “tall cell” and the “columnar cell” variants (Evans 1986; Mizukami 1994) are rare and more frequently found in elderly patients. Tumours are usually large and extend beyond the thyroid capsule. They have a papillary pattern, with elongated cell containing a granular and eosinophilic cytoplasm. Vascular invasion is frequently observed. A worse prognosis has been reported with these variants.

2.2.1.3 Histology of follicular thyroid cancer

FTC is usually unifocal and well encapsulated: the invasiveness of the capsule and the vascular invasion are the features that distinguish follicular carcinoma from follicular adenoma. For this reason the diagnosis of FTC cannot be made on the basis of cytological findings, requiring a tissue diagnosis. Even an intraoperative diagnosis using frozen sections can be incorrect. Depending on the degree of invasiveness, the tumour is classified as minimally invasive or widely invasive (Hedinger 1988; Rosai 1992), the latter having a worse prognosis. Although vascular invasion may represent an adverse prognostic factor, the threshold beyond which the prognosis becomes unfavourable has not been defined. On the contrary, the prognostic impact of capsular invasion alone is less important (Lang 1986; van Heerden 1992).
Minimally and widely invasive FTC are of variable degrees of differentiation ranging from well differentiated tumours with well-formed follicles containing colloid, to poorly differentiated tumours with a solid cellular growth pattern. The latter carries the least favourable prognosis (Rosai 1992). For prognostic purpose, it is important to take into account both the degree of invasion and differentiation because there is no close correlation between these factors.
While aggressive PTC invades lymphatics most of the time, FTC commonly invades blood vessels and spread to lung, bones, and, less frequently, to the brain and liver.

2.2.1.4 Histological variants of FTC

FTC with “clear cells” is a rare variant (Fisher 1977; Schroder 1986). Its architectural and clinical features are similar to those of classical FTC. Cells are clear because of the formation of intra-cytoplasmic vesicles, with glycogen or fat accumulation. These tumours must be distinguished from clear cell adenoma, parathyroid adenoma or carcinoma, and particularly from metastatic clear cell renal carcinoma. Immunohistochemistry with anti Tg antibodies, if positive, confirms the follicular cell origin of the tumour (de Micco 1987).
The “oncocytic or oxyphilic” cells type (or Huerthle cells type) is composed of cells derived from the follicular epithelium, typically large with an abundant granular, eosinophilic cytoplasm, large nuclei and a prominent nucleolus. The granular appearance of the cytoplasm is conferred by the large number of mitochondria (Feldman 1972; Nesland 1985). Macroscopically, the oncocytic variant presents as a solitary thyroid tumour with complete or partial encapsulation.
It is noteworthy that Huerthle cells can be found in a number of benign conditions, including nodular goiter, hyperthyroidism and Hashimoto’s thyroiditis. To qualify a nodule as an oncocytic tumour, all or a high percentage (>75%) of cells must exhibit oncocytic features (Hedinger 1988; Rosai 1992). The same criteria of malignancy for follicular tumours (i.e., vascular and capsular invasion) also apply to oncocytic cell tumours. Huerthle cell carcinomas with papillary structures and without the specific nuclear features of PTC have been reported in a significant proportion of patients (Herrera 1992). Oncocytic carcinomas are associated with extrathyroid extension and with both distant and lymph-node metastases more frequently than typical follicular carcinomas. In several series, the prognosis of Huerthle cell carcinoma was less favourable than that of the follicular cell type (Herrera 1992; Watson 1984).

2.2.2 Poorly differentiated thyroid cancer

Poorly-differentiated thyroid cancers are considered as a distinct histological type. The malignant cells have lost the typical features of the follicular cells although the cells are still positive for Tg expression using immunohistochemistry. They represent only 5-10% of all thyroid tumours and are more frequent in older patients even though young patients may be affected as well. The prognosis is unfavourable for both their aggressiveness and limited ability to enrich iodine.
Insular carcinoma is also a rare variant (Carcangiu 1984). It is a poorly differentiated, invasive follicular carcinoma, with solid components and small follicles with scant colloid. Cells are regular in shape, smaller and denser than in typical follicular cancer. The general picture may resemble carcinoid tumours. Metastases frequently arise in lymph nodes and in distant organs. The prognosis usually is poor.

2.2.3 Undifferentiated or anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers (Ain 1998). The mean mortality rate is 50% at 6 months from the time of diagnosis and 100% at 2 years.

In most cases it represents the terminal stage of the dedifferentiation process of a PTC or a FTC. However, in many cases it appears as ATC from the beginning. Fortunately ATC is a rare cancer (1-2% of all thyroid tumours) and more frequent in areas of endemic goiter. The tumoral cells are usually polygonal, spindle or giant. Keratin is the most significant epithelial marker and is present in 50% to 100% of cases. Thyroglobulin is usually not expressed immunohistochemically. Although areas of PTC may additionally be present, these tumours are still considered as ATC (Carcangiu 1985).

2.2.4 Medullary thyroid cancer

Medullary thyroid cancer (MTC) derives from the parafollicular C cells of the thyroid and accounts for 5-10% of all thyroid tumours. It is a neuroendocrine tumour and can be either sporadic (75%) or hereditary (25%). Nowadays, genetic analysis of RET germline mutations, which are responsible for RET oncogene activation, can easily identify those individuals at risk of developing hereditary MTC. All first-degree relatives of an identified RET carrier should be analysed for the trait so that identified RET carriers can undergo thyroidectomy as soon as possible (Elisei 2007).
Histologically, MTC consists of sheets of spindle, round and polygonal cells separated by fibrous stroma: Because these cells are present also in ATC these two histological types may be confused with each other, especially on cytology. The nuclei are usually uniform in shape and with rare mitotic figures. Deposits of amyloid are usually present and diagnostic of MTC. A positive immunohistochemistry for calcitonin (CT), a polypeptide almost exclusively produced by C cells, is diagnostic of MTC.
MTC may be accompanied by C cell hyperplasia (95-100% of hereditary case and 30% of sporadic cases) which is controversially defined as the presence of more than 50 parafollicular C cells in at least three different fields at a 100-fold magnification (LiVolsi 1997).
Mixed MTCs are rare although reported by several authors. They include one component with C cell features (staining for CT) and one component with follicular features (staining for Tg). They may derive from a “collision” of two different tumours or as a unique tumour from a common ancestral cell capable of both follicular and parafollicular differentiation (Caillou 1991; Elisei 1994).

2.2.5 Other rare thyroid tumors

This group includes primary thyroid lymphoma or tumours arising from other cell types. Primary lymphomas of the thyroid are rare (less than 2% of all extranodal lymphomas) and are usually non-Hodgkin’s lymphomas. They generally affect older patients (Matsuzuka 1993; Salhany 1993). The majority of primary thyroid lymphomas arise in patients who also have chronic autoimmune thyroiditis. Because cytology cannot always distinguish between these two pathologies, a biopsy may be required. The majority of thyroid lymphomas can be considered as “mucosa associated lymphoid tissue lymphomas” (MALT-L) (Zucca 1996). Usually immunohistochemistry is positive for bcl2. Monoclonality for light chain immunoglobulin is considered as a strong indicator of malignant lymphoma.
Mesenchymal thyroid tumours are absolutely rare but have been reported. Primary fibrosarcoma and angiosarcoma are rarely described (Ruchti 1984). Two different types of thyroid teratomas have been described in exceptional cases (Buckley 1986; Fisher 1982).
Microscopic metastases to the thyroid are a quite common autopsy finding in patients who died from other causes (Leboulleux 1999; Nakhjavani 1997). Negative immunostaining with anti-Tg and anti-CT is strong evidence for the metastatic origin of these thyroid tumours.

3. DIAGNOSIS

3.1 Signs and symptoms

Thyroid carcinoma is rare among human malignancies, but is the most frequent endocrine cancer, accounting for about 5% of thyroid nodules. Thyroid nodules are a common clinical problem. Since most nodules are benign, extensive work-up or surgical excision of each thyroid nodule usually is not practical, necessary, or cost-effective. Thyroid nodules may be solitary or multiple. Among multinodular goiters, one nodule may become clinically dominant (Belfiore 1992). The aim of the diagnostic work-up of thyroid nodules is the differential diagnosis between benign and malignant nodules. A complete history of the patient and physical examination of the neck are important after the discovery of a thyroid nodule. A history of familial thyroid cancer and/or exposure to radiation during childhood signify a risk for malignancy. The accurate palpation of the thyroid gives an idea of the location and the size of the nodules, of their consistency and motility during swallowing and of any extra-nodular thyroid tissue. Neck examination can also clarify the presence and the extent of lymph-node involvement, which is frequently found in papillary carcinomas (Angelos 2002).
The appearance of the following signs are suggestive of malignancy:

  • nodules that are firm in consistency and irregular, or fixed to local tissues;
  • palpable neck lymph nodes;
  • rapid increase in size of the nodules over weeks or months;
  • dysphagia or hoarseness.

However, these signs are not specific for malignancy.

3.2 Diagnosis

Serum TSH, FT3, and FT4 levels are measured to exclude thyroid dysfunction, but these parameters are not helpful for the differential diagnosis between benign and malignant nodules.
Measurement of thyroglobulin, which is usually elevated, is not informative as to the nature of the nodule.
Controversy still exists with regard to the use of routine calcitonin measurement in patients with nodular thyroid disease between the American Thyroid Association (ATA) (Haugen 2016) 2 and European Thyroid Association (ETA) consensus (2006). This practice is standard of care in selected centres in European countries, but there has been controversy regarding its acceptance in the US. The current American Task Force suggests that physicians should decide whether or not calcitonin measurement is useful in the management of their patients. Once the diagnosis of MTC is confirmed, the following additional investigations should be performed in all cases: at least one 24-hour urine sample assayed for catecholamines and nor / metanephrines or plasma nor / metanephrines (required to exclude phaeochromocytoma), and a serum calcium dosage (to exclude hyperparathyroidism). These tests must be carried out in all MTC patients prior to neck surgery even in the absence of a positive family history or symptoms to exclude a MEN.
Thyroid ultrasonography is the most accurate imaging technique for the detection of thyroid nodules and it is mandatory when a palpable nodule is discovered.
Ultrasonography is an accurate means of determining the volume of the gland, defining size, number and structure (cystic, solid or mixed) of thyroid nodules, distinguishing thyroidal from extrathyroidal masses, evaluating lymph-node metastasis, and guiding FNA biopsy. Hypoechoic nodules are more frequently malignant than hyperechoic nodules. In particular the absence of a peripheral halo, irregular borders, microcalcifications, and hypervascularization in colour Doppler ultrasonography are indicators of malignancy (Hegedus 2001; Papini 2002).
Thyroid scintigraphy is able to distinguish nodules which are hot, functioning, and usually benign, from those nodules which are cold and non-functioning, without being able to clarify the benign or malignant nature of cold nodules. In general, thyroid scans have low diagnostic specificity and sensitivity and are used as adjunctive rather than first-line diagnostic tests. A thyroid scan is helpful when a hyperfunctioning nodule is considered in the differential diagnosis because of a suppressed TSH level (Cooper 2006).
X-ray of the neck is useful to disclose a deviation of the trachea or lumen restriction, in large nodules and in multinodular goiter.
Computed tomography (CT) or magnetic resonance imaging (MRI) may be useful in identifying the extent and location of advanced thyroid tumours. These imaging studies are generally reserved for mediastinal thyroid masses, and identification of regional or distant metastasis (Pacini 2006a).
Although all these diagnostic procedures provide useful details regarding the stage of the disease, only fine-needle aspiration (FNA) cytology can determine the nature of a thyroid nodule with certainty (Randolph 2007). The ultrasound-guided FNA is currently considered the most effective test for the differential diagnosis of thyroid nodules. FNA biopsy is a rapid, accurate, and inexpensive means of evaluating thyroid nodules; its sensitivity is up to 95 % and specificity up to 96%, with an accuracy of 98 %. (Giuffrida 1995). Any solitary thyroid nodule (>1 cm) should be subjected to FNAB. Micronodules, less than 1 cm, should be subjected to FNAB only in the event of a suspicious finding on ultrasonography. In case of suspicious MTC calcitonin should be measured in washout fluid from Fnab and in addition immunohistochemistry staining of the Fnab sample should be carried out to detect the presence of markers such as Calcitonin, chromogranin, and CEA.
Molecular analysis (e.g., BRAF V600E mutation for PTC, alone or part of a panel) is an emerging field and may enhance the prediction of both benignity and malignancy in thyroid cytology samples, increasing the total accuracy from 60%, in cases where cytology is used alone, to 90%, when cytology is combined with molecular testing for BRAF, RAS, RET, TRK, and PPARγ mutations (Cantara 2010). Furthermore, molecular analysis is now formally advised for indeterminate cytology in the 2009 Revised American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer.

4. STAGING

4.1    Work-up for locoregional and distant disease

Derived from follicular thyroid cells (papillary, follicular, and anaplastic carcinoma) or parafollicular C cells (C cell or medullary carcinoma), almost all carcinomas arise from within the thyroid gland. Rare exceptions include carcinomas originating from ectopic follicular thyroid tissue of the thyroglossic duct (Plaza 2006) or branchiogenic cleft cysts (papillary carcinoma) (Matsumoto 1999), which often are diagnosed incidentally. High-resolution ultrasonography, coupled with fine needle aspiration cytology, will detect and confirm most of these tumours from a size of 5 millimetres, as well as many cervical lymph-node metastases (Stulak 2006). This is to be considered as a standard option, on a type 3 level of evidence.
Depending on the type and location of the tumour near, or far away from, the thyroid capsule, carcinomas may, or may not, breach the thyroid capsule and invade neighbouring structures: laterally the recurrent laryngeal nerve and internal jugular vein; medially the larynx, trachea and cervical oesophagus; and inferiorly the mediastinum. When laryngeotracheal, oesophageal or mediastinal invasion including involvement of mediastinal lymph nodes is suspected clinically or ultrasonographically, additional imaging will be required to delineate the extent of the locoregional disease and to determine tumour resectability, as a standard option on a type C basis. In terms of resolution, magnetic resonance imaging (MRI) often is superior to computed tomography (CT) in the neck and mediastinum, also because the former does not require the use of an iodine-containing contrast enhancing agent. This is critical for patients with iodine-enriching papillary and follicular carcinomas who postoperatively have to undergo radioiodine therapy for ablation, as a standard option on a type C basis. In some instances, tracheobronchoscopy and oesophagoscopy, including biopsies of suspect lesions, are necessary to confirm or rule out mucosal involvement by the tumour. Preoperative confirmation of such invasion is of paramount importance, as a standard option on a type C basis, since it can render the tumour technically unresectable (e.g., involvement of the mediastinal trachea), may not be advisable on oncological grounds (progressive distant disease; e.g., anaplastic carcinoma), or because of patient-related factors (e.g., old age or pre-existent major morbidity).
For localization of persistent or recurrent disease, more sophisticated imaging techniques are available: radioiodine diagnostic scan for iodine-enriching papillary and follicular carcinomas (Durante 2006; Hindié 2007); 18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) for carcinomas without radioiodine uptake (Robbins 2006; Giraudet 2007; Esteva 2009); and 18-fluorodihydrooxyphenylalanine positron emission tomography (18F-DOPA PET) for medullary carcinoma (Hoegerle 2001; Koopmans 2008). Digital fusion images of Iodine 131 (131-I) single-photon emission computed tomography (SPECT) (Chen 2008; Wong 2008; Aide 2009; Kohlfuerst 2009; Schmidt 2009; Spanu 2009; Wang 2009; Wong 2009), 18F-FDG PET (Palmedo 2006; Oudoux 2007; Seiboth 2008; Leboulleux 2009; Dong 2009) and 18F-DOPA PET (Beheshti 2009) with CT or MRI coregistration often enable one to pinpoint more precisely residual tumour deposits, as a standard option on a type 3-level of evidence. For diagnosis of bone metastases, MRI (axial skeleton including skull, vertebrae and long bones) and Tc-bone scintigraphy (peripheral bones including clavicles and ribs) may be complementary (Giraudet 2007). In some instances, more than one imaging modality is needed for clarification, which is suitable for individual clinical use on a type C basis.

4.2  Staging Systems

Several staging systems have been developed by authorising centres. Each of these staging systems provides good risk stratification based on data available shortly after initial therapy. The most popular of these is the American Joint Committee Cancer/International Union against Cancer TNM staging system based mainly on the extent of tumour and age (Edge 2010).

4.2.1 The TNM system (7th edition)
Table 1. Classification according to tumour, nodes, and metastases.
Primary tumour (T)
Tx Primary tumours cannot be assessed
T0 No evidence of primary tumours
T1 Tumours ≤2 cm in greatest dimension limited to the thyroid
T1a Tumour ≤1 cm, limited to the thyroid
T1b Tumour >1cm but ≤2 cm in greatest dimension, limited to the thyroid
T2 Tumour >2 cm but ≤4 cm in greatest dimension, limited to the thyroid
T3 Tumour >4cm in greatest dimension limited to the thyroid or any tumour with m inimal extra thyroidal extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
T4a* Tumour of any size extending beyond the thyroid capsule to invade subcutaneous soft tissue, larynx, trachea, oesophagus, or recurrent laryngeal nerve
T4b* Tumour invades prevertebral fascia or encases carotid artery or mediastinal vesselsAll anaplastic carcinomas are considered pT4 tumours
pT4a Anaplastic carcinoma limited to thyroid
pT4b Anaplastic carcinoma extends beyond t ds beyond thyroid capsule.
Multifocal tumours (≥ 2 foci) of all histological types should be designated (m), the largest focus determining the classification, e.g., pT2(m)
Regional lymph nodes (N) (cervical or upper mediastinal)
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph-nodes metastasis
N1 Regional lymph-node metastasis
N1a Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
N1b Metastas to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII)
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Residual tumours (R)
Rx The presence of residual primary tumour cannot be assessed
R0 No residual primary tumour
R1 Microscopic residual primary tumour
R2 Macroscopic residual primary tumour
Table 2. Papillary or follicular carcinoma staging.
Papillary or follicular thyroid tumours, in a person younger than 45 years
Stage I a tumour (any T) with or without spread to lymph nodes (any N) and no distant metastasis (M0)
Stage II a tumour (any T) with any metastasis (M1) regardless of whether it has spread to the lymph nodes (any N)
Papillary or follicular thyroid tumours, in a person of 45 years or older
Stage I any small tumour (T1) with no spread to lymph nodes (N0) and no metastasis (M0)
Stage II a larger, non-invasive tumour (T2) with no spread to lymph nodes (N0) and no metastasis (M0)
Stage III a tumour larger than 4 cm but contained in the thyroid (T3) with no spread to lymph nodes (N0) and no metastasis (M0).orany localized tumour (T1-3) with spread to the central compartment of lymph nodes (N1a), but no distant spread (M0)
Stage IVa a tumour that has spread to nearby structures (T4a), regardless of whether it has spread to the lymph nodes (any N), but it has not spread to distant places (M0)ora localized tumour (T1-3), with lymph node spread beyond the central compartment (N1b), but no distant spread (M0)
Stage IVb a tumour that has spread beyond nearby structures (T4b), regardless of spread to lymph nodes (any N), but no distant spread (M0)
Stage IVc all tumours (any T, any N) when there is evidence of metastasis (M1)

5. PROGNOSIS

5.1 Papillary and follicular thyroid  carcinomas (E)

About 80% of patients with well differentiated thyroid carcinoma (DTC) can be cured with initial treatment, while 95-97% of them are still alive after 30 years of follow up (DeGroot 1990). Despite this good prognosis, some patients are at high risk of recurrence and even death; these patients should be identified at the time of diagnosis by using well established prognostic factors which can be subdivided into personal, histopathological, biological, molecular and treatment-related factors.

5.1.1 Personal prognostic factors
5.1.1.1. Age

Age at diagnosis is one of the most important independent prognostic factors for both PTC and FTC. Advanced age at diagnosis represents a negative prognostic factor both for recurrence and death. The prognostic significance of age persists when the total death rate is corrected for the overall mortality of a control population of the same sex, age, and year of birth when only cancer-related deaths are considered. The risk of recurrence and death increases linearly with age, particularly after 40 (Carcangiu 1985), 45 (Simpson 1987; Tubiana 1985a), 50 (Hay 1990), or 60 years (Mazzaferri 1994).
Although it is still unclear why they have a worse prognosis the elderly tend to have more often locally invasive tumours at presentation, a higher incidence of distant metastases at diagnosis and more frequently aggressive histological variants. All these factors may signal a worse prognosis. Thyroid tumours tend to have shorter doubling times in older patients and, at same time, are less well differentiated with a 131-I uptake much lower than in younger patients and thus a reduced effectiveness of 131-I therapy.
By contrast, children and adolescents, despite frequently displaying locally extensive disease at diagnosis, have an excellent long-term prognosis (Ceccarelli 1988; Schlumberger 1987).

5.1.1.2. Gender

Male gender has been reported to be a risk factor in some series (Akslen 1991; Cady 1988; Loh 1997; Mazzaferri 1994; Tubiana 1985a), but not in others. While it is usually a negative prognostic factor on univariate analysis, it loses its prognostic value on multivariate analysis. The question of whether male sex truly is a negative prognostic factor is still not answered.

5.1.2 Histopathological factors
5.1.2.1 Histologic types and variants

The prognosis of PTC is better than that of follicular thyroid cancer (FTC). The less favourable prognosis of FTC is more likely related to the patient’s older age and to the extent of the tumour at the time of diagnosis than to histology alone. Survival rates for patients with PTC and FTC are similar among patients of comparable age and disease stage (Brennan 1991; Mazzaferri 1994; Tubiana 1985a). Furthermore, within these two histological entities the prognosis may differ for their respective variants (Rosai 1992).
In PTC, the tall cell variant (Johnson 1988; Taylor 1998), the columnar cell variant (Evans 1986), and the oxyphilic variant (Herrera 1992) have been shown to have a worse prognosis. By contrast, a good prognosis is observed when the cancer is well encapsulated (Evans 1987; Schroder 1984) and in cases of follicular variants, although some of them are more aggressive (Carcangiu 1985; Rosai 1983; Tielens 1994). An intermediate prognosis has been reported with the diffuse sclerosing variant (Carcangiu 1989; Soares 1989).
While the minimally invasive FTC shows a good prognosis the widely invasive FTC has a less favourable prognosis (Rosai 1992). An advanced vascular invasion represents a negative prognostic factor (Lang 1986) while the degree of capsular invasion is of limited prognostic relevance (Brennan 1991). Some FTC variants, such as Huerthle cell carcinoma, poorly differentiated and insular histotypes, have been frequently associated with an unfavourable prognosis (Akslen 1991; DeGroot 1995; Sakamoto 1983; Tubiana 1985a). It is of interest that the degree of invasion and the degree of differentiation are not related to each other so that both parameters must be taken into account from a prognostic viewpoint.
When microscopic foci of undifferentiated cells are found within a differentiated thyroid cancer, the tumour must be regarded and treated as anaplastic cancer.

5.1.2.2 Tumour Grade and DNA Ploidy

The degree of cellular differentiation is of considerable prognostic significance in both papillary and follicular cancers. However, there is no general consensus on the definition of well, moderate and poor differentiation within the group of differentiated thyroid carcinomas. Tumour grade, according to Broder’s classification, which is based on nuclei and cytoplasmic features and the number of mitotic figures, was a significant prognostic factor both in univariate and multivariate analyses in papillary thyroid carcinoma (Hay 1990; Hay 1987).
Nuclear DNA content is considered one of the best prognostic indicators of malignancy in a wide variety of human tumours. In DTC, one study reported that DNA aneuploidy was an adverse factor on univariate analysis, but was not an independent prognostic factor in a multivariate analysis (Joensuu 1986). In the Mayo Clinic’s series abnormal DNA content was associated with higher cancer mortality, at least in high-risk papillary tumours (Hay 1990). The importance of this parameter is not well established for follicular cancer.

5.1.2.3 Tumour size

The size of the primary tumour may vary from less than 1 cm in diameter (very frequent nowadays) to a huge tumour. When they are unifocal and node-negative, tumours less than 1 cm, the so-called “microcarcinomas” have an excellent prognosis both in terms of survival and of relapse-free survival (Baudin 1998; Hay 1992).
There is a gradual increase in the risk of recurrence and tumour-specific mortality as primary tumours increase in size (Akslen 1991; Cady 1988; DeGroot 1995; Hay 1990; Hay 1987; Mazzaferri 1994). Tumour size is a significant risk factor in multivariate analysis. It seems to be more predictive in papillary than in follicular tumours, in which the degree of differentiation and the magnitude of invasion prevail over tumour size. (Brennan 1991; Emerick 1993; Lang 1986; Rosai 1992; Sakamoto 1983; Shaha 1995; Tubiana 1985a).

5.1.2.4 Multifocality

Papillary thyroid cancer is multifocal in about 50% of cases (from 20 to 80% depending on the number of pathological slices examined) (DeGroot 1990; Hay 1990; Mazzaferri 1994; Mortensen 1955). At variance, FTC is usually unifocal.
Multifocal PTCs are more frequently accompanied by lymph-node metastases (Baudin 1998; Katoh 1992) and have more frequently evidence of local disease persistence, regional recurrences, and distant metastases. Controversial data have been reported about the relationship between multifocality and mortality (Carcangiu 1985; Mazzaferri 1994; Pacini 1994). In this regard it is worthwhile noting that multifocality in one lobe is associated with a higher probability of having involvement of the other lobe. This finding can, at least in part, explain why recurrences and cancer-related deaths are less frequent with total thyroidectomy than with less radical surgical procedures (Baudin 1998).

5.1.3 Biological prognostic  factors
5.1.3.1 Extra-thyroidal Invasion

Tumour extension beyond the thyroid capsule is an independent predictor of a worse prognosis in both PTC and FTC. It is observed in 5-10% of PTC and in 3-5% of FTC, and is associated with higher rates of local recurrence, distant metastases, and tumour-related death (DeGroot 1990; Hay 1990; Hay 1993; Mazzaferri 1994; Simpson 1987; Yamashita 1997). However, the distinction between microscopic invasion of the thyroid capsule and macroscopic invasion with involvement of other neck organs should be made. In the latter event the prognosis is bleaker, especially because of the difficulty of clearing the disease locally (Hu 2007).

5.1.3.2 Lymph-node Metastases

Lymph-node metastases are frequent in PTC (30%-60%) but not so frequent in FTC (15-20%) (Grebe 1996). They are more common in children, occurring in up to 80% with PTC. Local nodes may be involved, even in the event of papillary microcarcinoma (Baudin 1998).
Many authors have shown that regional lymph-node metastases are associated with higher rates of tumour recurrence and cancer-specific mortality (Akslen 1991; DeGroot 1990; Mazzaferri 1994; Tubiana 1985a), while others found no significant difference in survival (Hay 1990; Hay 1993). Lymph-node involvement is associated with a significantly poorer outcome even in patients without extrathyroid invasion. In the series from the Ohio State University, bilateral cervical and mediastinal lymph-node metastases were an independent prognostic factor predictive of tumour recurrence and cancer-related mortality (Mazzaferri 1994). At the Institute Gustave-Roussy, palpable node metastases represented an independent risk factor for cancer-related death (Tubiana 1985a). We experienced a 3.6% mortality in patients with lymph-node metastases which is extremely high for a disease widely considered to carry an excellent prognosis (Pacini 1994).
Other than the presence or absence of node metastases, the site, size, number and extension of lymph nodes beyond the thyroid capsule (Yamashita 1997) probably also impact on the prognosis even though they were not taken into account in most series.

5.1.3.3 Distant Metastases

Distant metastases at the time of diagnosis is the poorest prognostic factor in patients with both papillary and follicular thyroid carcinoma. Tumour-specific mortality in patients with distant metastases varies from 36% to 47% at 5 years; it depends on the duration of follow-up and increases to approximately 70% at 15 years (Hoie 1988; Pacini 1994; Schlumberger 1996).
Univariate analysis has shown that in the event of distant metastases, younger age, well-differentiated histological type, localization in the lung rather than in the bone, the presence of small lesions and 131-I uptake are factors associated with a better prognosis. However, multivariate analysis has shown that extensive metastatic disease has a greater prognostic impact than anatomic location (lung or bone).
The best outcome is seen in younger patients with micronodular metastases responsive to radioiodine therapy that are not visible on standard X-rays.

5.1.4 Molecular Prognostic Factors

A bleak outcome is associated with loss of expression of thyroid-specific differentiation genes, such as the TSH receptor, Na+/I- symporter, thyroglobulin (Tg) and thyroperoxidase genes, as demonstrated by the low expression of these genes in poorly differentiated tumours and their absence in undifferentiated tumours (Arturi 1998; Elisei 1994). Among oncogenes involved in the pathogenesis of PTC, only BRAF V600E has been demonstrated to have a negative impact on outcome (Xing 2007; Elisei 2008) while this was not the case for RET/PTC rearrangements (Basolo 2001; Adeniran 2006). Somatic mutations of the p53 tumour suppressor gene or the overexpression of its encoded protein carry a worse prognosis inside the group of ATC which are per se highly lethal tumours (Pollina 1996). Similarly overexpression of the p21 protein, which is encoded by the RAS oncogene, has been associated with more aggressive thyroid carcinomas (Romano 1993).
The above findings are only the beginning of a new approach to tumour biology and indicate that oncogenes and oncogene products may reveal the prognosis of thyroid tumours.

5.1.5 Treatment-related Prognostic Factors
5.1.5.1 Extent of Primary Surgery

A delayed diagnosis and/or an aggressive tumour behaviour may contribute to recurrent local thyroid disease or development of distant metastases (Mazzaferri 1994). However, an inadequate initial operation also needs to be taken into consideration. Several studies have shown that incomplete surgical removal of neoplastic foci in the neck is associated with unfavourable prognosis. For clinically detectable cancers, near-total and total thyroidectomy significantly reduces the risk of recurrence (in all patients) and improves survival unlike more limited thyroid resections. Total thyroidectomy when performed in experienced hands does not increase the rate of surgical complications. These more definitive procedures are advocated by most authors for any differentiated thyroid cancer other than intrathyroidal, unifocal microcarcinomas (Samaan 1992; Mazzaferri 1994).
The influence of lymph-node dissection upon regional and distant recurrence and total survival remains to be established.

5.2 Medullary carcinoma

Sporadic and hereditary medullary carcinomas do not differ in prognosis, provided that tumours with equal risk factors are compared with each other. Under this premise, the same basic principles apply to both tumour entities.
As long as the tumour has not spread beyond the thyroid capsule, total thyroidectomy is curative and is standard option on a type 3 level of evidence. In node-positive tumours, cure is much more difficult to accomplish, requiring systematic cervical lymph-node dissection, as a standard option on a type 3 level of evidence). Surgical cure is exceptional with:

  1. more than 10 involved lymph nodes (Machens 2000; Weber 2001; Scollo 2003);
  2. involvement of both left and right lateral cervical or mediastinal lymph nodes (Machens 2006);
  3. invasion of neighbouring organs, such as trachea or oesophagus (Chen 1998);
  4. extrathyroidal extension;
  5. extranodal tumour growth (Machens 1999; Moley 1997);
  6. distant metastases (Machens 2007a; Moley 1999).

The risks of locoregional recurrence and distant metastases are reflected by the number of lymph-node metastases: the fewer lymph nodes involved, the smaller the risk of locoregional recurrence (Machens 2007a), distant metastases (Machens 2000), and cancer-specific death (Machens 2007a; Oskam 2008). Unlike localized disease, systemic dissemination is not amenable to surgical intervention in the neck. In face of distant metastases, the disease can take a chronic rather than a rapid fatal course, with some patients surviving for many years and occasionally decades.
In the absence of surgical intervention and histopathologic analysis, most of these risk factors will not be apparent. In lieu of histopathologic data, determination of serum basal calcitonin (Cohen 2000; Machens 2005) and carcinoembryonic antigen (CEA) levels (Machens 2007b), which are produced and released by the tumour cells, afford a preliminary risk stratification, as a standard option on a type 3 level of evidence. The higher the levels of these biomarkers, the higher the risk of locoregional spread and systemic dissemination and the lower the prospects of cure. For instance, patients with node-positive medullary carcinoma and basal calcitonin levels above 3,000 pg/mL cannot be cured surgically (Machens 2005). Likewise, CEA levels greater than 30 ng/mL indicate central and ipsilateral lateral lymph-node metastases whereas CEA levels greater 100 ng/mL signify contralateral lateral lymph-node metastases and distant metastases (Machens 2007b).
Owing to the importance of early tumour detection and surgical intervention, the European Thyroid Association (Pacini 2006a), but not the American Thyroid Association (Wells 2015), guidelines favour calcitonin screening in patients with nodular thyroid disease, despite some concerns about the cost-effectiveness of these screening programs from a public health perspective (Borget 2007), as a standard option on a type C basis. Stored in secretory granules, from which it is released by stimulation with pentagastrin, calcitonin is a more sensitive tumour marker than CEA, which is predominantly bound to the cell membrane and less susceptive to stimulation (standard option on a type 3 evidence level). Both biomarkers are believed to reflect overall tumour cell mass (Cohen 2000; Machens 2000; Machens 2007b). Total thyroidectomy is generally advocated for suspected medullary thyroid carcinoma, when basal calcitonin levels exceed 1. the upper normal limit of the respective assay and 2. a minimum level of 100 pg/mL after intravenous injection of 0.5 μg pentagastrin per kg body weight (Costante 2007). Because basal and stimulated calcitonin levels represent a biological continuum, no sharp line of division exists between benign and malignant C cell disease. As a consequence, there is room for both overtreatment (“unnecessary” operation for benign thyroid disease although stimulated calcitonin levels are greater than 100 pg/mL) and undertreatment (no operation for medullary carcinoma because stimulated calcitonin levels are lower than 100 pg/mL). This trade-off must be discussed with the patient, enabling him to make an informed decision based on his personal preferences and values, as a standard option on a type 3 level of evidence for patients with very high stimulated calcitonin levels; this option is suitable for individual clinical use on a type 3 level of evidence with moderately elevated stimulated calcitonin levels.

5.3 Anaplastic carcinoma

Anaplastic thyroid carcinoma (ATC) accounts for 5%-15% of primary malignant thyroid neoplasms.
The pronounced differences in the biological behaviour of the various histological types of thyroid carcinoma are well known. In contrast to papillary and follicular thyroid carcinoma, ATC is one of the most aggressive neoplasms in humans. Generally, it is rapidly fatal; the mortality rate is over 90% with a mean survival of 6 months after diagnosis (Giuffrida 2000). Because ATC is rare, it has been difficult to study a sufficient number of patients to obtain a better understanding of the natural history of the tumour and the factors that may influence treatment and survival (Ordonez 2004).
ATC occurs mainly in the elderly. The median age of 84 consecutive patients evaluated at the Mayo Clinic from 1971 to 1993 was 70 years (range 43-87 years) (McIver 2001). Females were affected more frequently than males (F:M = 1.3:1; 57% vs. 43%). Advanced ATC has typical clinical manifestations. The most common is a rapidly enlarging thyroid mass. Haemorrhage into the thyroid mass may be manifested as rapid enlargement and accompanied by pain and severe dysphagia or hoarseness.
The most frequent and important signs and symptoms of the patients in the Mayo Clinic series were hoarseness (77%), followed by dysphagia (56%), vocal cord paralysis (49%), cervical pain (29%), and dyspnoea (19%). In the same series, the following features were found on initial examination: single nodule (58%), multiple nodules (36%), bilateral involvement (24%), and a hard and fixed lesion (75%).
The tumour was larger than 10cm in 6% of the patients and ranged from 5 to 10cm in 58%. Also, surrounding structures were invaded in 70% of the patients: muscles (65%), trachea (46%), oesophagus (44%), laryngeal nerve (27%), and larynx (13%). Lymph-node metastases were observed in 43% of the patients.
Distant metastases are observed in 20%-50% of cases at the time of diagnosis.
The most frequent site of distant metastasis is the lung, followed by bone, skin, and brain. Cardiac metastases have also been described (Giuffrida 2001).
In the Mayo Clinic series, lung metastases were diagnosed in 45% of the patients and bone metastases in 12% at the time of diagnosis.
Accurate staging with laryngoscopy, neck ultrasonography, bone scan, and computed tomography (CT) of head, neck, mediastinum, thorax, and abdomen is important for determining the extent of infiltration by the tumour.
ATC is rapidly growing neoplasm and one of the most aggressive tumours in humans. The prognosis is dismal. The mean overall survival is about six months. The most important prognostic factors are age and extent of disease at presentation. Usually, patients younger than 60 years have less extensive disease at the time of diagnosis. In a series of 82 patients evaluated at the Mayo Clinic, Cox multiple regression indicated that the following were potential predictors of worse survival: histological type of cell (giant cell carcinoma), size of lesion (6 cm or larger), surgical treatment (biopsy only), invasion of adjacent structures, and extent of disease with distant metastases. Also, the anaplastic component needs to be assessed to determine whether it is a small or the predominant component. Treatment of ATC has not been standardized.
Most patients die within a few months after diagnosis, primarily of airway obstruction caused by local tumour invasion. Although cure is rare, every effort should be made to control the disease locally to improve the patient’s quality of life. Surgery, radiotherapy, or chemotherapy alone is seldom adequate for controlling the disease, but a combination of these treatments may improve local control (Kebebew 2005).

6. TREATMENT

6.1 Papillary and follicular carcinomas

6.1.1 Surgery for locoregional disease
6.1.1.1 Rationale

Papillary and follicular carcinomas differ greatly in terms of their biological behaviour and disease progression. While papillary carcinomas are notorious for their propensity to spread early to cervical lymph nodes, follicular carcinomas rarely develop lymph-node metastases – usually starting from a size of 20 mm (Machens 2005). Lymph-node metastases from follicular carcinomas are limited to the central neck most of the time and indicative of more advanced disease (Machens 2003a). Unlike follicular carcinomas, which are solitary most of the time, papillary carcinomas frequently exhibit multifocal growth. This multifocal growth more often is polyclonal, indicating independent origins of the thyroid tumours rather than monoclonal, which would signify lymphatic spread from one thyroid tumour within the thyroid gland (Shattuck 2005). For papillary carcinoma, total thyroidectomy is associated with lower recurrence rates than subtotal thyroidectomy and lobectomy (Bilimoria 2007; Pelizzo 2007).
More aggressive varieties of differentiated carcinoma include the diffuse sclerosing, columnar cell, and tall cell variants (TCV) of papillary carcinoma and the insular variant of follicular carcinoma, or insular carcinoma, for which the same basic principles apply (Sywak 2004; Volante 2004).

6.1.1.2 Extent of surgery

Ideally, all tumour deposits should be removed along with all normal thyroid tissue during the initial operation so that serum thyroglobulin can be used as a tumour biomarker for postoperative monitoring of disease, as a standard option on a type R basis (Bachelot 2002; Toubeau 2004; Sywak 2006; Heemstra 2007; Kebebew 2007). For this reason, and because of the frequent multifocal growth of papillary carcinoma and higher recurrence rates in the absence of total thyroidectomy, total thyroidectomy is widely considered the standard procedure on a type 3 level of evidence (Bilimoria 2007; Pelizzo 2007). The only exceptions from this rule are small solitary papillary cancers measuring 10 mm or less since these tumours rarely spread beyond the thyroid capsule (Lin 2005; Passler 2005). In the absence of evidence for locoregional disease, there does not seem to be much room for routine central neck lymph-node dissection in patients with follicular carcinoma. Conversely, central lymph-node dissection is increasingly recommended as a standard option on a type C basis for papillary carcinoma, even on a routine basis because of its ability to abrogate serum thyroglobulin levels in node-positive papillary carcinoma (Sywak 2006). There is less agreement regarding the need for additional lateral lymph-node dissection, which remains suitable for individual clinical use, on a type C basis. Owing to the concurrence of central and lateral neck involvement (Machens 2002), lateral lymph-node dissection may be beneficial in the presence of central lymph-node metastases (Roh 2008), certainly when there are more than five central lymph-node metastases (Pereira 2005; Machens 2009). As mediastinal involvement is exceptional in patients with papillary and follicular carcinoma (Machens 2009), mediastinal lymph-node dissection should only be performed for confirmed mediastinal disease, as a standard option on a type C basis.
“For completion”, essentially the same principles apply to patients with recurrent or persistent cancer without systematic lymph-node dissection at the initial operation. Selective excision of confirmed lymph-node metastases (“cherry picking” or “node plucking”) is suitable for individual clinical use, on a type C basis, and may be warranted only in those patients with thyroid cancer who have already had systematic dissections of the respective neck area(s) during the previous operations.
Total thyroidectomy and systematic lymph-node dissection in the central and lateral neck have been linked to higher surgical morbidity; recurrent laryngeal nerve palsy (total thyroidectomy); hypoparathyroidism (central lymph-node dissection); lymphatic leakage, bleeding and haematoma; accessory and hypoglossic nerve palsy; brachial plexus injury; or Horner’s syndrome (lateral lymph-node dissection) (Shaha 2008). On reoperation, and with more extensive procedures, such as segmental tracheal resection or cervical evisceration (Brauckhoff 2006), these rates commonly are higher than at the initial operation. To minimize any morbidity from extensive procedures, these patients should be referred to specialist surgical centres dedicated to thyroid cancer, as a standard option on a type C basis.

6.1.2 Adjuvant therapy
6.1.2.1 Rationale and modality

Surgery is usually followed by the administration of 131-I activities aimed at ablating any remnants of thyroid tissue and potential microscopic residual tumour. This procedure decreases the risk of locoregional recurrence and facilitates the long-term surveillance based on serum Tg measurement and diagnostic radioiodine WBS. In addition, the high activity of 131-I makes it possible to obtain a highly sensitive post-therapeutic WBS.
From a clinical perspective, the aim is to adapt the treatment to the individual in order to reduce the risk of recurrence and not expose patients with good prognosis to aggressive treatments with side effects, which may have an impact on quality of life. The American Thyroid Association (ATA) and the European Thyroid Association (ETA) have recently published practical guidelines in which the risk of recurrence has been graded into three categories of increasing risk on the basis of tumour-related parameters (pTNM and histological variant) integrated with other clinical features. These guidelines are useful in deciding whether patients should undergo radioiodine remnant ablation, intensity, and method of follow-up in the post-operative period.

Table 3. Guideline for remnant ablation, intensity, and method of follow-up in the post-operative period.
Risk level Characteristics
Post-operative risk stratification for risk of recurrence of DTC
Low-risk patients
  • no local or distant metastases;
  • all macroscopic tumours have been resected, i.e., R0 or R1 resection (pathological definition);
  • no tumour invasion of loco regional tissues or structures;
  • the tumour does not have aggressive histology (tall cell, or columnar cell PTC, diffuse sclerosing PTC, poorly differentiated elements), or angioinvasion;
  • if 131I given, no 131I uptake outside the thyroid bed on the post-therapeutic WBS.

No benefits, no indication for postoperative 131I administration.

Intermediate-risk patients
  • microscopic invasion of tumour into the perithyroidal soft tissues (T3) at initial surgery;
  • cervical lymph node metastases (N1a or N1b);
  • tumour with aggressive histology (tall cell, or columnar cell PTC, diffuse sclerosing PTC, poorly differentiated elements) or angioinvasion.

Benefits of postoperative 131I are controversial and as a result RAI ablation is recommended for selected patients.

High-risk patients
  • Extra thyroidal invasion;
  • Incomplete macroscopic tumour resection (R2);
  • Distant metastases (M1)

Postoperative 131I administration reduces the recurrence rate and possibly prolongs survival.

Very-low risk patients
  • complete surgery;
  • patients with no extension beyond the thyroid capsule and without lymph node metastases.

No benefits, no indication for postoperative 131I administration

Low-risk patients
  • no local or distant metastases;
  • no tumor invasion of locoregional tissues or structures;
  • no aggressive histology or vascular invasion.

Benefits of postoperative 131I are controversial and there are still uncertainties as to whether it should be administered to all patients or only to selected patients.

High-risk patients
  • Less than total thyroidectomy;
  • tumor invasion of locoregional tissues or structures;
  • cervical lymph node metastases;
  • distant metastases;
  • aggressive histology or vascular invasion.

Postoperative 131I administration reduces the recurrence rate and possibly prolongs survival

Radioiodine ablation therapy is usually administered 4-6 weeks after surgery, until thyroid hormone replacement is withheld and iodine contamination is avoided. 131-I ablation consists in administering an activity of 1.1 GBq (30 mCi) or 3.7 GBq (100 mCi). In recent years, it has become increasingly apparent that successful thyroid ablation may be achieved using low activities of 131-I (1110-1850 MBq) (Pilli 2007; Chianelli 2009).
131-I thyroid remnant ablation must be performed under TSH stimulation to increase the uptake of radioiodine by follicular thyroid cells. After the recent recognition of the effectiveness and safety of human recombinant TSH (rhTSH) (Haugen 1999a) (Level of evidence 2), thyroid remnant ablation can be performed by administering 131-I 24 hours after the intramuscular injection of 0.9 mg of rhTSH for 2 consecutive days (Pacini 2006b) (Level of evidence 2). If rhTSH is not available, a 40-45 day period of thyroxine (LT4) withdrawal is required: serum TSH should be >30 μU/ml before 131-I treatment is given, otherwise the withdrawal period is prolonged for another 1-2 weeks (Level of evidence 4). The absence of iodine contamination should be always verified by measuring urinary iodine content (Regalbuto 1994). Pregnancy must be excluded in women of childbearing age.
As previous exposure to 131-I may “stun” the thyroid cells, i.e., decrease the efficiency of subsequent treatment with 131-I, a WBS with a diagnostic dose of 131-I before ablation is not usually recommended (Muratet 1997; Park 1994).
A total body scan is performed 3 to 5 days after 131-I treatment to determine the distribution and the sites of 131-I uptake. The discovery of foci of radioiodine uptake outside the thyroid bed calls for more effective treatment, notably surgical reintervention. Treatment with LT4 should be initiated immediately after 131-I administration.
In patients with no uptake outside the thyroid bed, the result of total ablation is checked 12 months later with a serum Tg test under rhTSH stimulation: if stimulated Tg is undetectable or very low (i.e., <1-2 ng/ml) in the absence of serum Tg antibodies, the patient can be regarded as disease free. Conversely, if the serum Tg is increased after stimulation, a second course of 131-I treatment should be considered (Pacini 2001) (Level of evidence 3-4).

6.1.2.2. Benefits

Controversial data are currently available demonstrating apparent benefits of 131-I ablation in terms of recurrence and mortality rates (Grebe 1997b; Wartofsky 1998). Iodine ablation is clearly not beneficial for patients with small intrathyroid tumours (1.5 cm), and multifocal tumour extension beyond the thyroid capsule or lymph-node metastases, the benefits of 131-I continue to be debated (Grebe 1997b; Mazzaferri 1994; Simpson 1988; Tenenbaum 1993; Tubiana 1985b). In patients with high-risk differentiated thyroid cancer, there is a clear need for 131-I treatment to prolong disease-free and overall survival (Level of evidence 3-4).
Since both normal or neoplastic thyroid tissue may be responsible for Tg production in patients with thyroid remnants, Tg measurement will be more useful for the detection of persistent or recurrent disease after all alternative sources of Tg secretion, i.e., thyroid remnants, have been eliminated. Any detectable Tg level after total thyroid remnant ablation should signify the presence of residual tumour. On the other hand, 131-I WBS is more sensitive after 131-I ablation of normal thyroid remnants, because thyroid remnants with high uptake preclude the visualization of neoplastic foci in which radioiodine uptake is lower.
A number of studies have shown that the sensitivity of 131-I-WBS for detecting thyroid cancer is also improved after thyroid remnant ablation (Level of evidence 3-4).

6.1.2.3. Side effects

Side effects of 131-I thyroid remnant ablation are usually minimal and transient (Alexander 1998; Allweiss 1984; Burmeister 1991; DiRusso 1994). Nausea and gastric pain occur frequently after 131-I treatment and last a few days. Sialoadenitis is also frequent, with pain and enlargement of the salivary glands but rarely lead to xerostomia. For prophylaxis, patients are advised to drink large quantities of fluids and lemon juice. Loss of taste is a regular side effect but usually lasts only a few days. When large thyroid remnants are present and completion thyroidectomy is not feasible, steroids should be given to prevent swelling in the neck (Level of evidence 4).

6.1.2.4 Radiation safety

The main rule of radiation safety is that radiation exposure, be it internally or externally, remains as low as possible. When a radiometabolic therapy is administered (i.e., 131-I) every effort should be made to avoid contamination of the skin with radioactive material, and even greater care should be taken to prevent internal contamination by swallowing and breathing.
Written and oral information should be given to the patient before 131-I treatment is started. Hospital personnel should be regularly updated, and written treatment procedures should be at hand.
Regulations vary widely between countries. In some countries such as the United States, France and Italy, patients are hospitalised in special units where doses of more than 0.7 to 1 GBq (20 to 30 mCi) are administered. It is recommended that the patients can be discharged from the unit when the dose rate is below 40 μSv/h at a distance of 1 meter, which corresponds to an activity ranging from 0.7 to 1 GBq. Exposed patients are instructed to avoid contact with children and pregnant women and debarred from using public transportation for a few days. In other countries such as Germany, regulations are even stricter.
Although initially high, the risk of external radiation, according to the activity administered, is short-lived in thyroid cancer patients: uptake is low in the thyroid tissues (typically < 2%) and the biologic and resulting effective half-life in thyroid tumours and the total body is short (typically < 1 day). Within 24 hours of treatment, the risk of external radiation arising from these patients is lower than the risk coming from hyperthyroid patients after 131-I treatment.
Simple measures such as abundant oral hydration for 24hours after 131-I administration, administering lemon juice and laxative treatment reduce the accumulation of radioiodine in the body (Level of evidence 4).

6.1.3 Thyroxine therapy
6.1.3.1 General considerations

The hormones produced by the thyroid gland are tetraiodothyronine or thyroxine (T4), which contains 4 atoms of iodide, and triiodothyronine (T3) which contains three atoms of iodide. These hormones have two isomers, which can be levo- (L) or dextrorotatory (D): the levorotatory isoform is the biologically active variant. Since levo-thyroxine (L-T4), which is converted to T3 in the periphery, is the main hormone produced by the thyroid, the drug of choice for long-term treatment of thyroid carcinoma is L-T4. The oral administration of L-T4 mimics physiological conditions and stabilizes serum T3 levels (Bartalena 1987; Busnardo 1983; Marcocci 1994; Demeester-Mirkine 1992).
The main objectives of LT4 treatment in papillary and follicular thyroid cancer patients after thyroidectomy are twofold:

  • to correct postoperative hypothyroidism; and
  • to suppress TSH secretion which is responsible for the growth and function of persistent or recurrent neoplastic disease.

In contrast, undifferentiated thyroid carcinomas, and medullary thyroid carcinomas which derive from parafollicular C cells, reveal no TSH-dependency, do not benefit from TSH suppression and only require LT4 replacement therapy to correct postoperative hypothyroidism.

6.1.3.2 Thyroxine administration: drug, dose and modality

The purity of T4 preparations is close to 100%, with a margin of 3%. However, the bioavailability of the drug may vary between different preparations. For this reason it is preferable that patients do not change the usual thyroxine daily dosage and, in particular do not change brands too frequently since this may change blood hormone level because of differences in bioavailability (Demeester-Mirkine 1992).
The LT4 dose ranges between 1.6 and 2.8 μg/kg/day. However, it is recognized that it must be tailored on an individual base since it roughly correlates with body weight and age. Younger patients, especially children, and patients with a high lean body mass, usually require higher doses per kg of body weight (Santini 2005). By contrast, older patients require lower L-T4 daily doses and further reductions are needed for subjects with concurrent heart disease (Sawin 1983; Sawin 1994) (levels of evidence 4).
Since L-T4 has a blood half-life of 6-8 days, a single daily dose is usually sufficient. After oral administration, up to 80% of L-T4 is absorbed in the gut with inter-individual variability (Hays 1991; Demeester-Mirkine 1992). Food intake is an important factor which reduces L-T4 absorption. Patients should be advised to take their L-T4 dose on an empty stomach, preferably early in the morning, 20 to 30 minutes before breakfast. Several substances are known to interfere with L-T4 absorption in the gut (Hays 1991; Uzzan 1996; Demeester-Mirkine 1992). In addition, several chronic diseases, such as regional enteritis, pancreatic disease, and cirrhosis may be associated with decreased L-T4 absorption (Checchi 2008; Centanni 2006).
The effectiveness of LT4 therapy is monitored by measuring serum TSH with an ultra-sensitive assay, approximately 3 months from initiation of therapy (Bartalena 1987): the parameters to be monitored are serum TSH, which should be suppressed (i.e., less than 0.1 μU/ml), and serum free T3 (FT3), which should be in the normal range to avoid iatrogenic thyrotoxicosis (Bartalena 1987; Marcocci 1994). A major concern for patients and physicians is the possibility that – despite the normal FT3 levels – normal to high levels of LT4 may have negative effects on target organs during long-term suppressive therapy (Jennings 1984; Ross 1991). The bone and heart are considered organs at major risk. However, when patients are monitored as described above, L-T4 suppressive therapy is safe and free of long-term adverse effects. It is important to underline that L-T4 suppressive therapy in children has no adverse effect on bone maturation, final height, and pubertal development.
Since a 25% increase of FT4 is usually observed when the blood is drawn 3-4 hours after ingestion of L-T4 patients should be instructed not to take their medication the morning before blood testing.
An important issue is for how long the L-T4 therapy must be continued on a TSH suppressive dose. There is no doubt that patients with evidence of persistent or recurrent disease or at a high risk of recurrence should be kept on suppressive therapy, which is believed to decrease the risk of recurrence (Cooper 1998). However, in patients with favourable prognostic factors and evidence of complete cure (i.e., a negative 131-I total body scan and undetectable serum thyroglobulin off L-T4), the dose of L-T4 may be decreased with the aim of maintaining serum TSH levels between 0.1 and 0.5 μU/ml, on a type 3 level of evidence. Nowadays, low risk patients who are cured with initial treatment represent more than 80% of the cases. Long- term suppressive therapy is thus maintained only in patients with persistent disease or, less commonly, in those at high risk of recurrence.

6.1.4 Delayed Risk Stratification

Recent reports have developed the new concept of delayed risk stratification for patients who have undergone total thyroidectomy. This concept is based on the continuous integration of the initial risk stratification (at the time of diagnosis) as clinical, radiologic, and laboratory data become available during the time of follow-up. A combination of clinical-pathological factors with treatment response criteria allows a more personalized approach to treatment, follow-up and prognosis. This should facilitate follow-up in the majority of patients, predicting the risk of recurrence and persistent disease.

6.1.4.1 Dynamic risk assessment of response to initial therapy for differentiated Thyroid cancer
  • Excellent response → Low risk, presenting any of the following characteristics:
    • suppressed and stimulated Tg;
    • neck US without evidence of disease;
    • cross-sectional and/or nuclear medicine imaging negative (if performed).
  • Indeterminate response → Intermediate risk, presenting any of the following aspects:
    • suppressed Tg • Neck US with nonspecific changes or stable sub centimetre lymph nodes;
    • cross-sectional and/or nuclear medicine imaging with nonspecific changes, although not completely normal.
  • Incomplete response → High risk, presenting any of the following characteristics:
    • suppressed Tg≥1 µg/L or stimulated Tg≥10 µg/L;
    • rising Tg values;
    • persistent or newly identified disease on cross-sectional and/or nuclear medicine imaging.
6.1.5 Management of metastatic disease
6.1.5.1 Introduction

Distant metastases occur in 10% to 15% of patients with differentiated thyroid carcinomas (Hoie 1988). They are the major cause of thyroid cancer related deaths, but, unlike metastases from other primary cancers, are compatible with long-term survival in a significant proportion of patients, on a type 3 level of evidence (Akslen 1991; Smith 1988).
Distant metastases are present at diagnosis in 50% of cases while in the remainder they can be discovered from 2-3 to more than 10 years after the initial treatment. This observation indicates that follow-up must continue throughout the patient’s life (Schlumberger 1996). The early discovery of distant metastases is based on the combined use of serum thyroglobulin (Tg) measurement and radioiodine (131-I) whole body scanning (WBS).
Most distant metastases from differentiated thyroid cancer are located in the lung (50-60%) or bones (20-30%). Liver, brain, and skin metastases, which are much more rare, are found in about 3% of patients at the time of the identification of a diffuse metastatic disease, or may occur later with respect to the initial diagnosis of lung metastasis during the course of distant dissemination and may be prognostic of a rapid evolution of the disease. Ten percent of cases show metastases at multiple sites (Ozata 1994; Schlumberger 1996). Skin metastases signify a dismal survival, on a type 3 level of evidence.
The site of metastatic disease depends on a number of factors. Metastases in the lungs are more frequently observed in patients with papillary carcinoma and in younger patients: they are practically the only site of distant metastases in children (Ceccarelli 1988; Schlumberger 1987; Vassilopoulou-Sellin 1993). Bone metastases, in contrast, are more frequently observed in patients with follicular carcinoma and in older patients, on a type 3 level of evidence (Schlumberger 1996).
Patients with metastatic disease need a complete work-up. A WBS performed after the administration of 3.7GBq (100mCi) of 131-I may clarify the extent and location of metastatic disease. In particular WBS often reveals lung metastases not visible on plain chest X-rays or CT scan. In half of the patients with normal chest X-rays, who have diffuse uptake of 131-I in the lungs, CT shows peripheral micronodular lung metastases (Schlumberger 1988; Schlumberger 1996).
X-rays are required for patients with bone metastases that are painful and enrich radioiodine. CT scan or MRI will help to delineate the extent of these metastases. MRI is particularly useful in the work up of metastases of the spine and base of skull. Because most bone metastases are hypervascularized arterial embolization may be helpful to facilitate subsequent surgical removal.

6.1.5.2 Treatment of metastases

Conventional therapeutic strategies, such as surgery, radioiodine, external radiotherapy and chemotherapy, can be used for the treatment of metastatic thyroid cancer disease. The therapeutic strategy must be aligned with the number and size of metastases and involved distant sites.
Surgery should be considered with curative intent in patients with a single or a few brain metastases. Lung metastases are often multiple and surgical extirpation or pulmonary resection are rarely curative. Surgical intervention can prevent or delay the onset of clinical symptoms. Palliative surgery is required for bone metastases ideally before orthopaedic or neurological complications arise, especially when the risk of complications, such as vertebral collapse, is high (Marcocci 1989).
In two thirds of patients, metastases concentrate radioiodine (131-I), facilitating their detection and treatment. Since radioactive concentrations may be higher in small metastases with a relatively low uptake than in bulky metastases with a far greater uptake radioiodine can ablate small foci of neoplastic tissue, but seldom large tumour deposits (Schlumberger 1996). A radiation dose higher than 80 Gy should be delivered to obtain cure; if radiation doses are less than 35 Gy the chance of success is remote (Maxon 1992; Maxon 1983). The corresponding treatment activity is 3.7 to 5.5 GBq (100 to 50 mCi) in adults and approximately 37 MBq (1 mCi)/Kg of body weight in young children. As the outcome of 131-I therapy is related to the radiation dose, higher activities of 131-I (7.4 GBq [200 mCi] or more) have been recommended in patients with bone metastases.
Successive treatments with 131-I are given 6 months later for 1 to 2 years and then annually until there is no more evidence of residual radioiodine uptake on post-therapeutic WBS. There is no limit to the cumulative 131-I activity that can be given to patients with distant metastases, on a type 3 level of evidence. The risk of cancer and leukaemia rises slightly when the cumulative dose is higher than 18.5 GBq (500mCi). Higher cumulative activities are of little benefit, on a type 3 level of evidence (Schlumberger 1996). Radioiodine treatments must be performed under TSH stimulation reaching a minimum TSH level of 30 mU/L). These high TSH levels are obtained either through the withdrawal of L-thyroxine replacement or in patients who cannot tolerate the resulting severe hypothyroidism, with the use of recombinant TSH, on a type 3 level of evidence (Jarzab 2003; Lippi 2001; Luster 2005).
Diagnostic 131-I-WBS is useless in patients with known metastases because it will not alter the therapeutic strategy and may interfere with the uptake of therapeutic doses of 131-I (Park 1994). At variance, a WBS performed 4 to 7 days after therapeutic dose of 131-I may clarify both the distribution and metabolic activity of metastases. When radioiodine uptake is no longer demonstrable on post-therapeutic WBS radioiodine treatment must be discontinued (Pacini 1987).
Between two treatment courses, L-T4 suppressive therapy is continued in order to reduce TSH levels, which are thought to stimulate tumour growth. External beam radiotherapy may be indicated when complete surgical excision is not possible or when there is no significant radioiodine uptake in the tumour (ATA 2009; Pacini 2006b).
Recently the Knowledge of molecular basis of Thyroid cancer and genetic critical pathways involved in the development of specific histologic subtypes has led to the development of new drugs which target these pathways. Targeted therapy refers to a new generation of cancer drugs able to interfere with a specific molecular target, typically proteins that have a critical role in tumour growth or progression, these news drugs recently irrupted in the management of advanced thyroid carcinomas refractory to conventional therapy. Tyrosine kinase inhibitor (TKIs) being tested against differentiated thyroid cancer in clinical trials includes motesanib diphosphate, axitinib, sorafenib, sunitinib, and pazopanib. None of these is specific to one oncogene protein, but they target several TK receptors and proangiogenic growth TKIs are generally quite well tolerated; the most common adverse events are fatigue, weight loss, diarrhea and nausea, hypertension mucositis and hand foot skin reaction. Another common side effect with some TKIs is the increase of serum Thyroid Stimulating Hormone (TSH), probably due to interference in thyroid hormone metabolism that often requires an adjustment of L-tyroxine therapy. Sorafenib and lenvatinib are the most active agents and also provide the most clinical benefits to date. Both agents have been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.
Sorafenib was approved (on November 22, 2013) for the treatment of progressive DTC based on the results from a multicentre international randomized, double-blind, placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive DTC refractory to radioactive iodine treatment. Patients had papillary (57%), follicular (25%), and poorly differentiated carcinomas (10%). A total of 417 patients were randomized (207 to sorafenib and 210 to placebo). Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Ninety-six percent of patients had metastatic disease; the most common target lesions were lungs (71%), lymph nodes (40%), and bones (14%). The primary objective of this study was to compare PFS between placebo and sorafenib patients. The median PFS was significantly longer in the sorafenib group than in the placebo group (10.8 vs. 5.8 months; p<0.0001); PR was 12% vs. 0.5 (p<0.0001), and SD ≥6 months 42% vs. 33%. There was no statistically significant difference in the overall survival between the treatment arms (p = 0.138), a secondary endpoint of the trial (Brose 2014).
On February 13, 2015, the US FDA approved lenvatinib (Lenvima) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. The approval of lenvatinib was based on the demonstration of improved progression free survival (PFS) in a multicentre, double-blind, placebo-controlled trial (E7080-G00-303). The trial enrolled 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization. Patients were randomized (2:1) to receive either lenvatinib 24 mg orally per day (No. 261) or a matching placebo (No. 131). A statistically significant prolongation of PFS determined by independent radiology review was demonstrated (HR: 0.21; 95%CI 0.16-0.28; p<0.001, stratified log-rank test). Median PFS was 18.3 months in the lenvatinib arm and 3.6 months in the placebo arm. Objective response rates were 65% and 2% in the lenvatinib and placebo arms, respectively. No statistically significant difference in the overall survival between the two arms was demonstrated.

6.2 Medullary carcinoma

6.2.1 Surgery for locoregional disease
6.2.1.1 Rationale

All patients with suspicious MTC should undergo a staging work-up before surgery. The goal of a preoperative evaluation is to determine the extent of disease and to identify the comorbid conditions of hyperparathyroidism and/or pheochromocytoma in the case of hereditary forms. The preoperative biochemical evaluation should include basal serum CT, CEA, genetic testing for RET germline mutation and calcium and plasma metanephrines and normetanephrines, or 24-h urine collection for metanephrines and normetanephrines. Preoperative instrumental imaging includes: neck US in all patients, whereas preoperative chest CT, neck CT and three-phase contrast enhanced multidetector liver CT or contrast-enhanced MRI, and bone scintygraphy should be performed in patients with extensive neck disease and signs and symptoms of distant metastases as well as in all patients with serum CT >500 pg/ml (ATA 2009).
Early lymph-node metastasis to the central and lateral neck on the side of the thyroid tumour is a hallmark of medullary thyroid carcinoma. As long as the lymph-node metastases are confined to just one side of the neck and have not crossed the midline, surgical cure can often be achieved through systematic lymph-node dissection (Machens 2006). Indicative of systemic disease, lateral lymph-node metastases contralateral to the thyroid primary, and mediastinal lymph-node metastases reflect distant lymph-node metastases (Machens 2006). Despite a small risk of subsequent biochemical conversion (Modigliani 1998; Franc 2001), postoperative normalization of serum calcitonin (the most sensitive biomarker of C cell disease) constitutes the most powerful indicator of surgical cure.
Owing to the recognized link between lower postoperative calcitonin levels and longer survival, reoperations for persistent or recurrent disease in the neck and mediastinum may have a distinct, though difficult to quantify, impact on cancer-specific mortality.

6.2.1.2 Extent of surgery

Total thyroidectomy is considered standard option on a type 3 level of evidence, as it is a prerequisite for the postoperative monitoring of serum calcitonin, the level of which is believed to reflect overall C cell mass (Cohen 2000; Machens 2000). In the absence of tumour deposits outside the thyroid gland, the thyroid contains the entirety of C cells, representing the sole source of calcitonin in the body. Removal of all parafollicular C cells is even more critical in hereditary C cell disease since each parafollicular C cell can be subject to malignant transformation (Machens 2003b). Central neck lymph-node dissection is generally advocated together with total thyroidectomy, as a standard option on a type 3 level of evidence, with the possible exception of very young gene carriers who still have normal or only slightly elevated basal or stimulated calcitonin levels (Machens 2009). When central lymph-node metastases are present, systematic lymph-node dissection in the lateral neck, both ipsilateral and contralateral to the primary tumour, is normally required, as a standard option on a type 3 level of evidence (Fleming 1999; Moley 1999; Dralle 2002), certainly in the presence of more than 3 and 10 central lymph-node metastases, respectively (Machens 2008). Mediastinal lymph-node dissection is only advised as a palliative procedure for confirmed mediastinal involvement since this condition is incompatible with surgical cure, as a standard option on a type 3 level of evidence (Machens 2004).
Patients with recurrent or persistent C cell disease require systematic lymph-node dissection “for completion” if not yet performed elsewhere, as some of these patients may still be curable surgically; this is a standard option on a type 3 level of evidence. After adequate previous surgery, selective dissection of gross lymph-node metastases is sufficient in most instances, and is suitable for individual clinical use, on a type C basis.
To keep to a minimum any morbidity attendant to total thyroidectomy and systematic lymph-node dissection (see paragraph 6.1.1 «Surgery for locoregional disease»), patients should be referred to specialist surgical centres with expertise in reoperations and more extensive procedures for persistent, recurrent and locally invasive thyroid cancer, as a standard option on a type C basis.

6.2.2  Adjuvant Therapy

Postoperatively, levothyroxine (T4) replacement therapy is generally required, but without the need for TSH suppression, because medullary carcinoma cells, unlike follicular cell-derived tumours, do not express the TSH receptor in relevant quantities and hence are not under TSH control. For symptomatic postoperative hypoparathyroidism, calcium, with or without vitamin D, preparations should be used sparingly and only to relieve symptoms. Symptoms permitting, these replacements should be tapered off as soon as the residual parathyroid tissue begins to function. For severe symptoms of hypoparathyroidism in the absence of measurable serum levels of free parathyroid hormone, higher doses may be required for longer periods of time, as a standard option on a type C basis.
Balancing the benefits of resection against surgical morbidity, reoperations in the neck and mediastinum may not be warranted in a few patients, not even in experienced hands. Such rare exceptions include elderly patients who:

  • are in poor general health;
  • require segmental tracheal resection or oesophagectomy;
  • have progressive systemic disease; or
  • have multiple distant metastases.

Radiotherapy induces massive scarring in the irradiated area complicating subsequent neck operations. External radiation therefore is not generally recommended for locally invasive medullary carcinoma, except for inoperable tumours in the neck and inoperable symptomatic bone metastases, but it is suitable for individual clinical use on a type C basis. In the absence of a control group, the issue surrounding the effectiveness of radiotherapy in medullary carcinoma is difficult to settle.
Not expressing the sodium/iodine symporter, medullary carcinoma cells do not respond well to radioiodine therapy. Likewise, chemotherapy has only been moderately effective in some patients with advanced disease, and it is, therefore, to be considered as investigational on a type 3 level of evidence (Schlumberger 1995; Matuszczyk 2008), perhaps because medullary carcinoma cells divide at too slow a rate. Similar results have been obtained for the somatostatin analog 111-In-octreotide, which showed no appreciable impact on tumour progression but may provide some relief from medullary carcinoma-induced diarrhoea, and it is considered (Vainas 2004) suitable for individual clinical use on a type 3 level of evidence.
More promising are the first results of radioligand therapy using a bispecific anti-CEA antibody for advanced medullary carcinoma (Chatal 2006). Randomized clinical trials will be needed to determine the efficacy of this novel therapeutic agent, which is investigational on a type 3 level of evidence.
Also in MTC, new compounds (e.g., TKIs) targeting signalling pathways essential for tumour cell survival, proliferation and metastases have been tested. Preliminary evidence indicates that they may have important clinical benefits.

6.2.3 Management of distant metastasis
6.2.3.1 Rationale

Medullary carcinoma is notorious for early systemic metastasis. Systemic disease is generally suspected when the preoperative hypercalcitoninemia persists postoperatively in spite of adequate systematic clearance of the central and lateral lymph nodes. This condition normally requires the involvement of 10 and more lymph nodes (Machens 2000; Weber 2002; Scollo 2003; Machens 2007b; Oskam 2008). Distant metastases, the main determinant of cancer-specific mortality, have been found in patients whose preoperative calcitonin levels were as low as 150-400 pg/mL with an upper normal limit of <10 pg/mL. The lower the elevated calcitonin levels the more likely are these commonly miliary, distant metastases to escape imaging by even the most sophisticated technology. For suspected distant metastases, expectant observation with continual imaging of lung, liver, and bone is standard option on a type C basis.

6.2.3.2 Interventions

Visualization of distant metastases is the prerequisite for any targeted surgical intervention in patients with symptomatic systemic disease. Because distant metastases rarely occur in isolation, these operations are usually undertaken with palliative intent, normally to pre-empt local complications such as invasion of adjoining tissues or vertebral collapse standard option on a type C basis. As an alternative to hepatic resection, arterial chemoembolization of dominant liver metastases may provide symptomatic relief, at least in the short term, although its effectiveness is difficult to determine in the absence of a control group. This option is suitable for individual clinical use on a type 3 level of evidence (Lorenz 2005; Fromigué 2006).
In patients with significant tumour burden and symptomatic or progressive metastatic disease according to RECIST treatment with TKIs targeting both RET and VEGFR tyrosine kinases should be considered as systemic therapy.
In view of the fact that all patients with FMTC have the germline mutation of RET and that half of sporadic MTC patients have a somatic mutation of RET many agents that target RET kinase have been evaluated in several studies. Also, vascular endothelialgrowth factor (VEGF) receptors (VEGFR-1 and VEGFR-2) are often overexpressed in MTC, both in tumour cells and in the supporting vascular endothelium (339). Many agents that target VEGFR-2 kinase also target RET kinase. The most promising TKIs, being tested against MTC in clinical trials, include motesanib diphosphate, vandetanib, sorafenib and sunitinib, resulting in partial responses from 2% to 35% and in disease stabilization ratesfrom 27% to 87% with tolerable and manageable side effect, as those found in DTC patients.
On the basis of recent phase III studies, the FDA and EMA have approved vantetanib (2011) and cabozantinib (2012) for the treatment of advanced progressive MTC. In fact, these news drugs have shown the potential to provide high rates of disease control with durable responses and significant improvement of progression free survival.
Safety and effectiveness of vandetanib were established in a single, randomized, double-blind international phase III study. In this trial, 331 patients with unresectable locally advanced or metastatic, hereditary or sporadic medullary thyroid cancer were randomly assigned in a 2:1 ratio to receive vandetanib (300 mg/d) or placebo. The primary objective was to determine whether vandetanib, compared to the placebo, prolonged PFS. Secondary end-point included objective response rate, disease control rate at 24 weeks, duration of the response, overall survival, decreases in serum levels of calcitonin and CEA. At data cut-off a significant prolongation of PFS (p<0.001), disease control rate (p<0.001), and biochemical response (p<0.001), were observed in patients that received the drug compared with the placebo. Furthermore, the RET mutational status of these patients was studied, unfortunately, a large number of patients were classified under the RET mutation status «unknown» (45.3%) due to insufficient tumour DNA to perform complete analysis. In sporadic MTC with somatic RET mutations, a subgroup analysis of PFS by M918T mutation, suggested that patients testing positive to an M918T mutation have a higher response rate to vandetanib compared to M918T mutation negative patients.
cabozantinib was evaluated in an international, multicentre, randomized, controlled trial known as EXAM, which included 330 patients with progressive, metastatic MTC. Patients were randomized (2:1) in order to receive either cabozantinib 140 mg or a placebo once daily until disease progression or intolerable toxicity.
Approximately 50% of patients were found to be RET mutation-positive, with M918T being the predominant RET mutation isolated.
A statistically significant prolongation in progression-free survival was seen with cabozantinib compared to placebo (11.2 vs. 4.0 months; p<0.0001). Partial responses were observed only among patients in the active treatment arm (27% vs. 0%; p<0.0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs. 7.2%). Median duration of response was 14.7 months.

6.3 Anaplastic carcinoma

6.3.1 Surgery for locoregional disease
6.3.1.1 Rationale

Anaplastic, or undifferentiated, carcinoma is a heterogeneous variety of neoplasms ranking among the most lethal human malignancies. At first diagnosis, some 95% of tumours have already breached the thyroid capsule and invaded the juxtathyroidal soft tissues, sometimes involving adjacent organs; ≥50% of tumours have developed lymph-node metastases; and some 40%-60% of tumours have spread to distant organs, most commonly the lung, and less often bone, liver and brain (Machens 2001; Are 2006). Although tracheal invasion in some patients may result in suffocation, many patients eventually die from systemic disease. As with all thyroid cancers, systemic dissemination at the time of the initial operation is the main determinant of survival. Most patients with anaplastic carcinoma have a median survival of just 3-6 months, and no more than one-third of patients survive more than one year even despite extensive resection in the neck (Machens 2001; Kebebew 2005).

6.3.1.2 Extent of surgery

Because of its aggressive biological behaviour, anaplastic carcinoma can rarely be cured unless the primary thyroid tumour contains only a minor anaplastic component. Even extensive surgical procedures in the neck, including tracheal resections, have failed to produce measurable survival benefits in patients with anaplastic carcinoma (Haigh 2001; Machens 2001; McIver 2001; De Crevoisier 2004). For this reason, surgical interventions are directed more towards providing a tissue diagnosis and reducing compression of the trachea through removal of the bulk of the tumour from the neck, together with the thyroid gland and lymph-node metastases, as a standard option on a type 3 level of evidence. As they entail significant surgical morbidity, extensive surgical procedures, such as tracheal or oesophageal resections, normally are not warranted in view of the bleak overall survival of these patients regardless of the type of intervention. Care must be taken to maintain the patency of the airway, which may require tracheal stenting. Construction of a tracheostomy should be exceptional because of the attendant poor quality of life, and it is suitable for individual clinical use on a type C basis.
Reoperations for anaplastic carcinoma are unusual, owing to its rapid clinical course and may be only clinically useful in select patients with clearly inadequate previous operations, as a standard option on a type C basis.
Because of the need for an interdisciplinary approach, patients with anaplastic carcinoma should be treated in comprehensive cancer centres offering the whole range of required interventions as a standard option on a type C basis.

6.3.2 Adjuvant Therapy

Because ATC usually is locally advanced with systemic dissemination, it cannot be cured surgically most of the time. Apart from providing a tissue diagnosis, the prime objective of any surgical procedure is to prevent, or at least delay, airway obstruction, a frequent cause of death in the past. Total thyroidectomy and radical neck dissection may have no advantage over a less aggressive surgical approach. Local control of disease is an important component of clinical management. Postoperatively levothyroxine replacement therapy is generally required.

6.3.2.1 Radiotherapy

External beam radiotherapy has been helpful in delaying local recurrence and in preventing thoracic outlet obstruction. It has not been shown to alter the mortality rate but to improve local control of the disease. External beam radiotherapy can provide substantial benefit in local control of disease, although ATC is considered a radio-resistant tumour. Simpson first reported treating ATC with a small number of large radiation fractions (350-800 cGy).
This protocol failed to eradicate local disease, and all patients died within nine months after diagnosis. Hyperfractionated local radiotherapy seems to be more effective than conventional treatment, but toxicity is higher. Wong et al. subsequently treated 14 patients with hyperfractionation (100 cGy for times daily) and achieved complete tumour regression in 43% and partial regression in 50%. However, after three treatment-related deaths, the protocol was discontinued. A twice-daily fractionation regimen is well tolerated and has a trend to longer survival (Wang 2006).
Junor and colleagues reported on 91 patients who had radiotherapy after surgery and noted that patients who had total or partial thyroidectomy had significantly better survival than those who had biopsy only (Junor 1992).
Most of the patients received between 30 and 60 Gy given in 2 Gy fractions (median survival: 21 weeks; 6-month survival: 45%; and 9-month survival: 32%).
Levendag et al. (Levendag 1993) reported on 51 patients who received external beam radiotherapy and surgery and concluded that local control is indispensable for achieving better short-term survival.
Patients with distant metastases who were locally free of disease had a median survival of 7.5 months compared with 1.6 months for those with residual local disease. In the study of Demeter et al. (Demeter 1991), 12 patients received radiotherapy and 42% had a documented response. Mitchell et al. reported that 10 of 17 patients who received high-dose accelerated radiotherapy had a partial or complete response, however, the toxicity was unacceptable.

6.3.2.2 Radiotherapy and chemotherapy

Wong et al. (Wong 1991) treated ATC with radiotherapy in combination with doxorubicin (40 mg/m²) as a radiosensitizing agent, but the results were disappointing, with a median survival less than six months and unacceptable toxicity. Radiotherapy in conjunction with a chemotherapeutic agent as a radiosensitizer has been attempted by others. Kim and Leeper (Kim 1987) treated 19 patients with hyperfractionated radiation (160 cGy per treatment twice daily for 3 days per week, to a total dose of 5.760 cGy in 40 days) and weekly doxorubicin (10 mg/m²,1.5 hours before radiotherapy); 84% had complete remission and 16% had local control of the disease. The median survival was 12 months. Tennvall et al. (Tennvall 1994) gave a combination of radiotherapy and chemotherapy preoperatively and postoperatively after attempted surgical resection of local disease. Two regimens of hyperfractionated radiotherapy were used: preoperative radiotherapy was given to total dose of 30 Gy and an additional 16 Gy was given postoperatively. The daily fraction was 1.0 or 1.3 Gy x 2, five days a week. Doxorubicin, 20mg, was administered one to two hours before the first radiotherapy each week. Debulking surgery was possible in 23 of the 33 (70%) patients. No sign of local recurrence was detected in 48% of patients, and 24% of patients died of local failure. Overall survival was similar for the 1.0 and 1.3 Gy regimens, with a median of 3.5 and 4.5 months, respectively. Four (12%) patients survived longer than two years.

6.3.2.3 Chemotherapy

Despite various approaches with single agents and various combinations of doxorubicin, etoposide, cisplastin, bleomycin, and vincristine, chemotherapy has not provided adequate control of ATC, and there is no consensus about which chemotherapeutic agents should be used.
In vitro chemosensitivity testing has been proposed to minimize the risk of exposing patients to ineffective chemotherapy. Doxorubicin has been used most commonly, but the results have been disappointing. In a randomized controlled study (Eastern Cooperative Oncology Group), Shimaoka (Shimaoka 1985) observed only 1 response among 21 patients treated with doxorubicin (60 mg/m²) monotherapy. However, the result of combination chemotherapy with doxorubicin (60 mg/m²) and cisplatin (40 mg/m²) were encouraging, and 6 of 18 patients had a response. This study showed that the response achieved with a combination of drugs is superior to that of single-agent chemotherapy.
In a review of the literature on the treatment of ATC, Ahuja and Ernst (Ahuja 1987) reported that the response rate with doxorubicin monotherapy was 22.1% (17 of 77 patients).
In a pilot study by the Japanese Society of Thyroid Surgery using a combination of doxorubicin (60 mg/m²), etoposide (100 mg/m² 3 days), peplomycin (5 mg), and granulocyte colony-stimulating factor ( to prevent bone marrow depression), 11 patients died of disease within 7 month after treatment and 4 survived from 3 to 11 months.
In the study of Auersperg et al. (Auersperg 1990) 15% of 89 patients with ATC who received vinblastine, cisplastin, doxorubicin, and mitoxantrone as primary treatment preoperatively died before undergoing surgery. Of the patients who completed the treatment, only 9% survived longer than one year. Demeter (Demeter 1991) reported a response rate of 55% with postoperative chemotherapy.
Recently, therapeutic strategies have been investigated to study the ability of the proteasome inhibitor bortezomib to induce apoptosis in ATC cell lines. Bortezomib was used as a single agent or in combination with TNF-related apoptosis-induced ligand (TRAIL). The combination induces the destruction of chemoresistant neoplastic thyrocytes and may represent a promising therapeutic strategy for the treatment of ATC (Conticello 2007).

6.3.2.4 Multimodality treatment (G)

ATC is highly malignant and survival is not affected by either radiotherapy or chemotherapy alone. In fact, tumours often grow despite ongoing therapy. The cause of death for most patients is local tumour invasion. A combination of surgery, chemotherapy and radiotherapy has been effective in some patients (Kurukahvecioglu 2007), both for survival and local disease control, and has prevented suffocation caused by tracheal invasion (Haigh 2001; De Crevoisier 2004).
In the report of Venkatesh (Venkatesh 1990), 11% of patients receiving both radiotherapy and chemotherapy survived for an average of 13 months. Tallroth divided 47 patients into 4 treatment groups. The first group received methotrexate and radiotherapy (30-40 Gy), and had a median overall survival of 9 months. The second group received bleomycin, cyclophosphamide, fluorouracil and radiotherapy, and had a median survival of four months. The third group received the same therapy as the second group with the addition of surgical resection; the median survival was also four months. The fourth group received doxorubicin, radiotherapy, and surgical resection and also had a median survival of four months.
Of the 34 patients treated with bleomycin, cyclophosphamide, fluorouracil and radiotherapy, only 11 died of local growth. Werner et al had similar results with a combination of chemotherapy and external beam radiotherapy. Most patients with anaplastic giant cell thyroid carcinoma should no longer die of airway obstruction caused by local tumour growth.
Schlumberger et al (Schlumberger 2004) used two different prospective protocols to treat 20 patients. Patients younger than 65 years received a combination of doxorubicin (60 mg/m²) and cisplatin (90 mg/m²), and those older received mitoxantrone (14 mg/m²). Radiotherapy (17.5 Gy in seven fractions to the neck and the superior mediastinum) was administered between days 10 and 20 of the first four cycles of chemotherapy.
Three patients survived longer than twenty months, and five patients had a complete response. No response was seen in patients with distant metastases. The treatment was effective for survival and local control, preventing death from local invasion. After making the diagnosis of ATC with fine needle biopsy or open biopsy, Tezelman and Clark administered bleomycin one to two hours before each dose of radiotherapy and fluorouracil before every second treatment. Three weeks after this combination therapy, thyroidectomy was performed to remove as much tumour as possible, and then two to three weeks later, radiotherapy and chemotherapy were again administered. This method of treatment prevented recurrence of tumour in the neck and fatal airway obstruction. Patient care requires close attention to pain control, maintenance of the airway, and other quality-of-life issues. Variable results have been reported with several chemotherapeutic agents, including paclitaxel, fluorouracil and hydroxyurea plus radiotherapy. Paclitaxel was added to fluorouracil and hydroxyurea because of its activity in head and neck cancer and its ability to enhance the efficacy of radiation. Clinical studies have shown a beneficial effect of paclitaxel with a 53% response rate (Ain 2000). Aggressive multimodality treatment regimens show promise in improving local control in patients with ATC. Survival rates for patients with anaplastic carcinoma of the thyroid, however, remain low.

6.4 Chemotherapy, radiotherapy, and new therapies

6.4.1 Chemotherapy

Poorly differentiated thyroid carcinomas are rarely able to take up iodine at the time of diagnosis. About 15% of differentiated thyroid carcinoma lose this property after several courses of 131-I treatment because of tumour dedifferentiation, on a type 3 level of evidence. When these tumours are metastatic and rapidly growing external radiotherapy and/or chemotherapy may be attempted despite the evidence of their low efficacy. Of the drugs administered to patients with metastatic differentiated thyroid carcinomas, the only agent that appeared effective was doxorubicin (Samaan 1992). A 33% response rate has been demonstrated when doxorubicin was given as a single agent, at a dose of 60 mg/m2 every 3 to 4 weeks. This was not confirmed by subsequent studies in which response rates ranged from 0% to 22% with all responses being partial and only of a few months’ duration without any benefit in terms of survival. In two reports, doxorubicin was combined with cisplatin, and the response rates yielded were similar to those of doxorubicin alone but at the expense of major toxicit (Shimaoka 1985; Williams 1986) (Level of evidence 2). Although these findings should be confirmed in larger series, an increased response rate has been observed in patients treated with cisplatin plus epirubicin after TSH stimulation relative to unstimulated patients treated with the same drugs (Santini 2002) (Level of evidence 2-3).
A few trials with other cytotoxic agents have been reported. These trials involved only limited numbers of patients (Dulgeroff 1994); mitoxantrone and etoposide (VP16) appeared to be ineffective.
Treatment with interferon-a or interleukin-2, either alone or in combination with doxorubicin, failed to yield any tumour response, similar to treatment with somatostatin analogues, which was ineffective as well (Zlock 1994). Retinoic acids decrease the tumour growth rate in “in vitro” studies and increase the expression of the sodium-iodine symporter (Elisei 2005; Haugen 2004; Miasaki 2008) but their clinical efficacy remains to be demonstrated (Grunwald 1998).
Taking into consideration the low efficacy and severe side effects of chemotherapeutic drugs, chemotherapy should only be given to patients with progressive metastatic disease refractory to radioiodine treatment. Even in these patients, the indication for chemotherapy should always be weighed against the natural course of the disease.

6.4.2 External Radiotherapy

The role of external radiotherapy (RT) to the neck for treatment of thyroid cancer remains controversial (O’Connell 1994). There are no prospective randomised controlled trials to confirm its value suggested by retrospective analyses. In these retrospective studies, patients treated with RT were older, revealed large tumours of mainly poor differentiation, tumour extension beyond the thyroid capsule, large lymph-node metastases, and limited iodine uptake.
The outcome of these patients was poor indeed, as attested by the low survival rates and the frequent occurrence of distant metastases. Several authors therefore concluded that RT was ineffective (Mazzaferri 1994; Samaan 1992; Taylor 1998). However, some data support the view that RT may improve local control in selected patients.
RT is clearly not indicated nor in patients with good prognostic features and complete tumour removal or in young patients (age <40 years) with residual disease and satisfactory 131-I uptake. RT may be warranted in patients older than 40 years of age with papillary thyroid carcinoma and extrathyroidal invasion who fail to demonstrate significant 131-I uptake in the neck. In these patients, RT may destroy neoplastic cells unresponsive to radioiodine therapy. Indeed, the analysis of patients with recurrent papillary carcinoma showed that locally invasive carcinoma, in contrast to lymph-node recurrence, often did not concentrate iodine (Samaan 1992). Patients with follicular carcinomas have a poorer survival due to frequent haematogenous spread to distant organs. Progression of distant metastases may compromise the benefits of local tumour control with regard to survival. Patients with inoperable gross residual disease after surgery also appear to benefit from RT, which can be combined with 131-I therapy if poorly differentiated tumour components should be present as well. In these patients, a combination of external radiotherapy with low-dose doxorubicin (10 mg/m2/week) may improve tumour response.
The most common acute complications of RT are oesophagitis and tracheitis. Long-term complications are neck fibrosis, decreased salivary flow and resulting dental injury. Arterial thrombosis, brachial plexus neuropathy, laryngeal necrosis, and radiation-induced tumours (soft tissue sarcomas) are observed in about 5% of patients. These severe complications clearly demonstrate that RT should be offered only to those patients who are technically inoperable or too ill to tolerate major resections and meet the above criteria.

6.4.3 New Therapies

Conventional chemotherapies for anaplastic or medullary thyroid cancers and advanced metastatic thyroid carcinoma unresponsive to radioiodine, showed limited efficacy with response rates of about 20-25% (Haugen 1999b) (Level of evidence 3-4).
Following the discovery of oncogenic mutations involved in the pathogenesis of papillary and medullary thyroid carcinoma, a series of novel targeted drugs have been developed. These biological agents, which inhibit tumour growth by blocking physiological processes such as angiogenesis (i.e., antivascular agents) and intracellular signalling, are currently undergoing evaluation in clinical trials.
A common feature of thyroid cancers is their markedly increased vascularisation, with an elevated expression of the vascular endothelial growth factor (VEGF) by immunohistochemistry, compared with normal thyroid tissue. VEGF levels are correlated with tumour aggressiveness. Fosbretabulin (Combretastatin A4 phosphate – CA4P – is a tubulin-binding vascular disrupting agent that inhibits tumour blood flow, in particular stall blood flow through already existing vessels, with the result of depriving tumour cells of oxygen and nutrients (Chaplin 1996; Tozer 2002).
In a phase II trial by Cooney et al (Cooney 2006), CA4P alone was tested in 18 patients with metastatic ATC who had progressed with other standard therapies. Therapy was well tolerated at the dose selected. No objective responses were reported. Six patients had stable disease and 25% of patients survived longer than 3 months.
Based on a possible synergism between CA4P and cytotoxic drugs, A phase II study studied the safety and activity of triple combination of CA4P-paclitaxel-carboplatin in 26 patients with advanced ATC. There were no objective responses and a median survival of 4.7 months was observed. Therapy was well tolerated, with only 4% experiencing side effects with G4 toxicity (Mooney 2009).
Other anti-angiogenetic compounds have been evaluated in the preclinical setting. In particular, bevacizumab (a monoclonal antibody anti VEGF) was tested alone and in combination with cetuximab in an in vivo model compared with doxorubicin. This study demonstrated that both drugs, either alone or in combination, inhibited tumour growth and angiogenesis better than doxorubicin (Prichard 2007).
Sorafenib has also been assessed in a small number of ATC patients in two recent phase II clinical trials, with no RECIST responses observed in six treated patients (Gupta-Abramson 2008; Kloos 2009). Likewise, in a trial regarding all thyroid cancer histotypes, the tyrosine kinase inhibitor axitinib also yielded no responses in two treated ATC patients (196). Gefitinib, an epidermal growth factor receptor–targeted kinase inhibitor, similarly produced no responses in five treated ATC patients, although one had stable disease for 12 months (Pennell 2008). However, in a trial of the kinase inhibitor imatinib, two out of eight evaluable patients obtained a partial response, with stable disease reported in an additional four patients; 6 month progression-free survival was 36% and with somewhat encouraging 6-month overall survival at 45% (Ha 2010).
The recent proliferation of clinical trials with these novel drugs in patients with thyroid carcinomas who are beyond the reach of conventional therapies is substantial and encouraging. Preliminary results of these studies already indicate that a rational combination of therapeutic targets will need to be identified to maximize synergistic effectiveness while minimizing toxicity.
These results from several clinical trials on ATC could expand the limited strategies against Anaplastic thyroid cancer.

7. LATE SEQUELAE

The overall relative risk of a second primary carcinoma is increased only in patients treated with high cumulative dose of 131-I. A significantly greater risk of leukaemia and second primary carcinoma has been reported for patients treated with a cumulative dose of 600 mCi (22 GBq) of radioiodine (De Vathaire 1997). The risk of leukaemia appeared to be significantly increased in patients treated with high cumulative doses of 131-I, or in association with external radiotherapy. Only the risk of colon cancer was increased after radioiodine treatments. Radiation fibrosis may develop in patients with diffuse lung metastases who received repeated excessive doses (>150 mCi) of radioiodine at short intervals (Rubino 2003).

8. FOLLOW-UP

8.1 Papillary and Follicular carcinomas

The aims of following-up patients treated for PTC or FTC are twofold:

  • to maintain adequate L-thyroxine therapy;
  • to discover the persistence or recurrence of thyroid carcinoma early on.

FolIow-up will need to be lifelong because recurrences have occurred even 10-20 years after the initial treatment (Mazzaferri 1995; Schlumberger 1992; Tubiana 1985b).
The major tools used for the follow up of DTC patients are serum thyroglobulin (Tg) measurement, 131-I whole body scan (WBS) and neck ultrasound. The combination of these 3 diagnostic elements allow the clinicians to assess the clinical status of the patient (Mazzaferri 2003) (Level of evidence 3-4).

8.1.1 Serum Thyroglobulin Measurement

Thyroglobulin (Tg) is a glycoprotein that is produced exclusively by normal or neoplastic thyroid follicular cells. It is an excellent tumour marker after removal of the thyroid gland. Serum Tg should be undetectable after total thyroidectomy and thyroid remnant ablation. At variance, detection of increased Tg levels in such patients is diagnostic of the presence of persistent or recurrent disease (Van Herle 1973). Tg, is produced by practically all papillary and follicular cancer tissues, as demonstrated by immunohistochemistry using anti-Tg antibodies and more recently by RT-PCR (Watanabe 1993; Elisei 1994).
There are two limitations with regard to the measurement of serum Tg: first, the presence of circulating Tg autoantibodies (TgAb) may interfere with the measurement of serum Tg. According to the method used for the determination of serum Tg, serum TgAb may cause false positive results with an RIA assay, or false negative results with an IRMA assay (Spencer 2008). In patients with circulating TgAb, which account for about 20-25% of all patients with DTC (Pacini 1988), serum Tg measurement alone cannot be relied upon if not complemented by the measurement of serum TgAb. Second, the serum Tg production and secretion is kept to a minimum under L-thyroxine suppressive therapy so that TSH stimulation will be required for the confirmation of undetectable serum Tg levels indicative of cure. The TSH stimulation can be performed either through L-T4 withdrawal or stimulation with recombinant TSH (Haugen 1999b): a head-to-head comparison of both methods demonstrated their equivalence. Ideally, Tg stimulation should be performed with the use of rhTSH instead of inducing hypothyroidism, which is an extremely uncomfortable condition (Pacini 2001) (levels of evidence 1-2).

8.1.2 Iodine 131 total body scan

Diagnostic whole body scans, usually performed after the administration of a tracer dose of 4 mCi of 131-I are no longer recommended because of the inferior sensitivity relative to serum Tg measurements. Usually detectable levels of stimulated serum Tg indicate a need for therapeutic 131-I treatment (Pineda 1995). On the other hand, if stimulated Tg is undetectable in the absence of serum TgAb, the patient can be considered as cured (Pacini 2002).

8.1.3  Neck ultrasound

Neck ultrasound should be performed in all patients, and certainly in those at high risk for recurrent disease and those with suspicious clinical findings (Mazzaferri 2003). Lymph nodes can be easily detected with neck ultrasound in the lateral and, to a lesser degree, in the central neck. Ultrasound features are clearly different in patients with benign nodes, which are usually small, thin or oval and have a conspicuous hilum, and those with involved nodes, which are round in shape, display microcalcification, are hypoechoic and do not have a visible hilum (Leboulleux 2007). However, if a lymph-node metastasis is suspected, a fine-needle aspiration should be performed and the aspirate should be sent for cytology and Tg measurements (Pacini 1992).

8.1.4 Other Diagnostic Procedures

Other imaging modalities are available for use in patients with evidence of elevated serum Tg but negative post-therapeutic WBS and neck ultrasound. These include CT scan or MRI of the chest and neck, bone scintigraphy, nonspecific isotopic scan and PET scan – a recently introduced technique.
CT scan and MRI can localize very small nodes (2-5 mm) in the neck, chest and bones. However, it can be difficult to interpret findings in an area distorted by scars from previous operations. Both imaging techniques provide superior resolution and anatomic localization of lesions lighting up on isotopic scans.
Nonspecific isotopic tracers include Thallium-201 (Hoefnagel 1986), technetium 99m tetrofosmin (Lind 1997), technetium 99m sestamibi (Grunwald 1997), and indium 111 pentetreotide (Baudin 1996). They can be used while the patient is on thyroxine treatment. In some reports, the sensitivity of these techniques appeared to be high, without being able to replace 131-I -WBS. None of these imaging methods are recommended for routine use.
The PET scan holds more promise (Dietlein 1997; Feine 1996; Grunwald 1997). Enhanced glucose metabolism is a nonspecific feature of many tumour cells. Positron emission tomography (PET), using 18-fluorodeoxyglucose (FDG) can be performed while the patient is on thyroxine treatment. However, FDG uptake was found to be higher when thyroxine treatment was withdrawn (Sisson 1993). FDG uptake was seen more frequently in patients with poorly differentiated thyroid carcinoma in whom no 131-I uptake was demonstrable. Even involved lymph nodes smaller than 1 cm appear on PET scans, illustrating the great sensitivity of this imaging technique. However, PET scan failed to detect small lung metastases that were present on spiral CT scan. Although highly useful in certain clinical settings, the FDG PET scan cannot replace WBS. FDG PET scans should be performed preferentially in patients with a negative high-dose 131-I-WBS and a high likelihood of persistent or recurrent disease. All in all, PET positive thyroid cancers have a worse prognosis than PET-negative tumours (Wang 2000; Robbins 2006).

8.1.5 Recombinant human TSH

Both normal and malignant follicular thyroid cells depend on TSH stimulation for Tg secretion and iodine uptake. For endogenous stimulation, L-T4 must be withdrawn to render patients severely hypothyroid. The availability of large quantities of rhTSH prompted clinical trials in patients with differentiated thyroid cancer to investigate safety and efficacy of the agent in enhancing radioiodine uptake and Tg secretion (Duntas 2008). To date, rhTSH has been introduced into clinical practice for stimulation of serum Tg. The classical scheme of Tg stimulation involves two 0.9 mg intramuscular injections on two consecutive days and daily collection of venous blood samples. The serum peak Tg is usually reached 48-72 hours after the second injection. The diagnostic value of the rhTSH-stimulated Tg is comparable to the value of endogenous Tg stimulated by L-T4 withdrawal (Pacini 2001) (level of evidence 1-2).
Qualìty of life was maintained and in general much better during rhTSH stimulation than during hypothyroidism by thyroid hormone withdrawal. Side effects were minimal, mainly consisting in mild and transient nausea or headache (Schroeder 2006). To date, no patient developed detectable anti-rhTSH antibodies.
Many clinical trials have shown that rhTSH is an effective and safe alternative to thyroid hormone withdrawal suitable for the follow-up of differentiated thyroid cancer after total thyroidectomy (Haugen 1999b; Pacini 2006b) (Levels of evidence 1-2).

8.2. Follow-up strategy

8.2.1.Patients Treated by Total Thyroidectomy and Iodine 131 Ablation

Follow-up assessments of DTC patients start with the administration of 131-I for thyroid remnant ablation (Sherman 1994; Tenenbaum 1996). This ablation is highly recommended in high-risk patients, suggested in intermediate risk patients, and not advocated for low risk patients for lack of benefit (Pacini 2006b; Cooper 2006).
If the post-therapeutic whole body scan (WBS) reveals uptake outside the thyroid bed, additional 131-I treatments are warranted depending on the site of the uptake: distant metastases are treated again with 131-I 6-8 months after initial treatment until the uptake disappears; lymph-node metastases are treated with extra doses of 131-I but usually not more often than 2-3 times. If they should still concentrate radioiodine after that time, these lymph nodes will need to be cleared surgically. Therapeutic doses of 131-I should be always followed by a WBS check-up 3 to 4 days later. If no uptake is seen outside the thyroid bed on the post-therapeutic 131-I-WBS, a clinical evaluation is scheduled 6-12 months later, at which time serum Tg is measured together with thyroid hormones and TgAb. On this occasion, a physical examination and a neck ultrasound should be performed. If serum Tg is undetectable, an rhTSH stimulation test is needed 12-18 months after thyroid remnant ablation. If stimulated Tg is undetectable and there is no evidence of residual disease the patient can be considered as cured. L-thyroxine therapy can then be switched from a suppressive to a maintenance dose regimen (Level of evidence 4).
In particular, in low-risk cured patients the thyroxine dose should be decreased to maintain a low but detectable serum TSH level (0.1 to 0.5 uU/mL). The risk of recurrence is so remote in these patients that a higher thyroxine dose is unjustified (Pujol 1996; Cooper 1998). This subgroup, of usually middle-aged patients who represent more than 80% of all thyroid cancer patients, must be continued on life-long L-T4 therapy. Care must be exercised to avoid side effects resulting from a too high LT-dose (Fazio 2004; Morris 2007).
In high-risk patients, even when those are considered as cured, higher doses of thyroxine should be continued, with the objective of obtaining a serum TSH level of 0.1 μU/mL or less (Cooper 1998); the free triiodothyronine level should be maintained within the normal range to avoid any significant overdose. Clinical and biochemical evaluations should be performed annually; any other testing is unnecessary as long as the serum Tg level is undetectable.
If follow-up serum Tg levels become detectable, disease recurrence must be suspected and thyroxin therapy should be discontinued to enable treatment with 3.7 GBq (100 mCi) of 131-I, without performing a prior diagnostic WBS (4-5 mCi 131-I). If uptake is detected after 131-I therapy, patients are in an active phase of the disease and managed as previously described. In the absence of 131-I uptake, further administration of 131-I is unnecessary. In these patients, computed tomography or MRI of the neck, and lung and bone scintigraphy may be useful. PET scan is frequently positive in patients with thyroid cancer unable to concentrate 131-I, even when these lesions are minute (<1 cm in diameter). Unfortunately, there is no specific therapy for metastatic lesions refractory to radioiodine therapy. However, new targeted drugs are under development and several clinical trials have already started, some of which yielded encouraging preliminary results (Sherman 2008; Gupta-Abramson 2008).

8.3 Medullary carcinoma

8.3.1 Normalization of postoperative calcitonin levels

After the removal of all parafollicular C cells together with the thyroid gland, medullary carcinoma cells remain the sole source of calcitonin secretion in the body. In patients with residual disease after resection, intravenous stimulation with pentagastrin causes serum calcitonin levels to rise significantly within 2-5 minutes, preventing the misclassification of calcitonin levels as normal (Costante 2007; Scheuba 2007; Scheuba 2009). Postoperative normalization of hypercalcitoninemia, sometimes referred to as «biochemical cure», is the ultimate goal of any surgical intervention for localized thyroid tumours (standard option on a type 3 evidence level). In 3.3% of patients, the postoperative serum calcitonin levels may convert from normal to abnormal within 0.7 to 7.5 years after the initial operation. This conversion has been termed «biochemical recurrence» (Modigliani 1998; Franc 2001). Of note, not all these patients underwent stimulation with pentagastrin, which might have suggested residual occult tumour immediately after the initial operation. In patients with systemic disease, sustained locoregional control in the neck and mediastinum is the prime objective of any operation (standard option on a type C basis).

8.3.2 Persistence and recurrence of postoperative hypercalcitoninemia

Persistent or recurrent hypercalcitoninemia is indicative of residual medullary carcinoma. Serum calcitonin and CEA doubling times are believed to reflect tumour progression (Giraudet 2008). Persistence of hypercalcitoninemia after surgical intervention necessitates a thorough clinical work-up with the use of additional imaging studies (standard option on a type C basis). Barring rare exceptions, tumour deposit will not visualize in patients with postoperative basal calcitonin levels below 250 pg/mL, even with the use of the most sophisticated imaging technology (Yen 2003). In this setting, selective venous catheterization may help to localize occult tumour deposits. After previous ligation or resection of neck veins, changes in venous drainage patterns may occur, giving rise to misinterpretations regarding the position of the calcitonin-producing source. The higher the central to peripheral calcitonin gradient the more likely the presence of residual tumour deposits in the drained region (Abdelmoumene 1994). Systemic disease, including occult distant metastasis, is generally assumed when postoperative basal calcitonin levels are higher than 500 pg/mL after systematic clearance of the central and lateral neck lymph nodes (Ong 2007). Thoracoscopy and laparoscopy may be useful in diagnosing miliary metastatic disease to the lung and liver, which should be biopsied for histopathologic confirmation (Tung 1995). Alternatively, arterial angiography may visualize small hepatic metastases in up to 89% of medullary carcinoma patients with persistent hypercalcitoninemia (Esik 2001) (individualized options on a type C basis).

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Prof. Ruggero De Maria (Editor and Author)
Istituto Superiore di sanità – Rome, Italy
e-mail: demaria@iss.it

Prof. Henning Dralle (Reviewer)
Martin Luther University – Halle-Wittenberg, Germany
e-mail: henning.dralle@medizin.uni-halle.de

Prof. Rossella Elisei (Author)
University of Pisa – Pisa, Italy
e-mail: relisei@endoc.med.unipi.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gemma.gatta@istitutotumoti.mi.it

Dr. Dario Giuffrida (Author)
Istituto Oncologico del Mediterraneo – Viagrande, Italy
e-mail: dariogiuffrida@netscape.ne

Dr. Andreas Machens (Author)
Martin Luther University – Halle-Wittenberg, Germany
e-mail: andreasmachens@aol.com