Cancer Letters

Cancer Letters

Volume 163, Issue 2, 26 February 2001, Pages 143-156
Cancer Letters

Mini-review
Thyroid cancer

https://doi.org/10.1016/S0304-3835(00)00697-2Get rights and content

Abstract

Four types of thyroid cancer comprise more than 98% of all thyroid malignancies. Papillary thyroid carcinoma (PTC) may have a very benign course while undifferentiated thyroid carcinoma (UTC) belongs to the most aggressive human malignancies. A variety of genes have been identified to be involved in the pathogenesis of thyroid carcinoma. Somatic Ras mutations seem to be an early event and are frequently found in follicular thyroid carcinomas. Somatic rearrangements of RET and TRK are almost exclusively found in PTC and may be found in early stages. Germline RET missense mutations lead to hereditary medullary thyroid carcinoma (MTC). In contrast, the significance of somatic RET mutations in sporadic MTC is unknown. p53 seems to play a crucial role in the dedifferentiation process of thyroid carcinoma. The precise role of PTEN remains to be elucidated. The only clearly identified exogenous factor that may lead to thyroid carcinoma (mainly PTC) is radiation. Of interest, radiation is capable to induce RET rearrangements. In general, early diagnosis is mandatory to enable the chance of cure. Surgery is the treatment of choice. Depending on the tumour type, surgery in combination with either radioiodine, external radiation or chemotherapy often enables the control of local tumour burden. In MTC and UTC, once thyroid cancer is spread to distant organs, efficacious therapeutic agents are almost non-existing. However, our growing knowledge of genes involved in thyroidal oncogenesis may contribute to the development of more effective treatment modalities. Some preliminary data on gene therapy are quite promising.

Introduction

According to the WHO, thyroid malignancies are classified as carcinomas, which are by far the most common thyroid malignancies, sarcomas, lymphomas and even less frequent tumours including metastases to the thyroid. This review will focus on thyroid carcinomas, their aetiology, genes that seem to play a role in their pathogenesis, and clinical aspects, diagnostic and therapeutic ones as well.

Four types of thyroid cancer comprise more than 98% of all thyroid malignancies: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), both of which may be summarised as differentiated thyroid carcinoma (DTC), undifferentiated (anaplastic) thyroid carcinoma (UTC) and medullary thyroid carcinoma (MTC). PTC, FTC and UTC derive from the thyroid follicular epithelial cells while MTC derives from the parafollicular C-cells. The diagnosis PTC is based on a constellation of features such as papillary architecture, the presence of psammoma bodies, and characteristic nuclear features (e.g. nuclear chromatin, nuclear orientation, nuclear grooving), not all of which may be present in a single tumour [1]. FTC is defined as a thyroid follicular epithelial cell neoplasm, not belonging to papillary thyroid carcinoma, with evidence of capsular and/or vascular invasion. UTC is defined as a highly aggressive, poorly differentiated thyroid neoplasm with evidence of epithelial differentiation (keratin immunoreactivity). MTC is a malignant thyroid tumour with C-cell differentiation. Almost all MTC express to a greater or lesser extent calcitonin (CT) which can be used both for diagnosis and follow-up. A variety of subtypes exist in PTC (e.g. occult, encapsulated, follicular, oxyphilic, clear cell, tall cell, columnar cell), FTC (e.g. minimally invasive, widely invasive, oxyphilic type), UTC (e.g. giant cell, spindle cell, epitheloid cell) and MTC (e.g. classic, encapsulated, papillary, follicular type).

It is estimated that thyroid carcinoma comprises approximately 1% of all malignancies. Reliable epidemiological studies, however, do not exist. In Europe and the US, about three out of 100 000 people develop a thyroid malignancy but considerable regional differences exist. Generally, thyroid cancer is more common in women than in men (2–3:1) [2], [3]. PTC is the most common malignant thyroid neoplasm in countries with sufficient iodine diets and comprises up to 80% of all thyroid malignancies. It occurs in all age groups but is most common in the 3rd to 5th decades. FTC is more common in regions with insufficient iodine diets and represents approximately 10–20% of all thyroid malignancies. It occurs over a wide age range but is most common in the 5th and 6th decades. UTC, accounting for up to 10%, typically occurs in patients beyond the 6th decade. The incidence of MTC is not well known. Epidemiologic studies are rare and most of them were published shortly after MTC had been identified as an own entity [4]. The incidence of MTC was reported as less than 4%. Most likely, MTC was often misdiagnosed as UTC, dedifferentiated carcinoma or lymphoma. In recent studies analyzing the importance of routine preoperative CT measurement in any patient with a thyroid nodule suspected to be malignant, 16–40% of all malignant tumours turned out to be MTC [5], [6], [7]. Generally, it is believed that MTC comprises for about 5–10% of all thyroid malignancies. About 25% of patients with MTC are hereditary [8] and subclassified as familial MTC (FMTC), multiple endocrine neoplasia type 2A (MEN 2A) or type 2B (MEN 2B). About half of the patients with MEN 2A and MEN 2B develop a phaeochromocytoma [9], [10]. They are almost always benign but in 50–80% bilateral (synchronously or metachronously). In addition, 10–30% of patients with MEN 2A may develop primary hyperparathyroidism. Patients with MEN 2B may present with a marfanoid habitus or ganglioneuromatosis. Patients with FMTC develop MTC only. The remaining 75% of all MTCs are sporadic. From the clinical point of view, these patients neither have a family history of MTC nor do they have any other MEN 2-specific disease.

The aetiology of most thyroid cancers is unknown. DTC is generally sporadic but familial occurrence has been described. Familial DTC probably constitutes 3–7% of all thyroid cancer cases. An association between PTC and colorectal disease as well as FTC and breast disease has been described in at least two hereditary cancer syndromes: familial adenomatous polyposis (FAP) [11] including its subtype Gardner's syndrome and Cowden disease, a hereditary hamartoma syndrome [12]. The genes for both syndromes have been identified: APC (5q21) [13], [14] and PTEN (10q23.3) [15], respectively. Familial forms of DTC have also been reported without the association of either FAP or Cowden disease. While a gene for familial non-toxic multinodular goitre has been localised to a region of 14q, linkage studies suggest that no etiologic gene of familial DTC is present in this region [16]. Recently, a gene predisposing to familial non-medullary thyroid cancer with cell oxyphilia was mapped to 19p13.2 [17]. However, no gene has been identified yet.

The aetiology of the more common sporadic form of DTC remains speculative. External radiation is the only exogenous factor that has clearly been identified as being able to cause thyroid carcinoma (almost exclusively PTC). Iodine excess and deficiency are also discussed. Interestingly, somatic mutations of PTEN or APC have rarely, if ever, been reported in sporadic DTC [18], [19], [20]. However, LOH analysis and immunohistochemistry suggest that PTEN may very well play a role in the pathogenesis of follicular thyroid tumours [21]. Infection of thyroid cancer cell lines with PTEN wildtype leads to cell cycle arrest and/or apoptosis depending on the cell type (unpublished data). Whether the gene yet to be identified located on 19p13.2 plays a role needs to be shown. Interestingly, loss of heterozygosity (LOH) on 19p has been found in up to 36% of UTC [22]. Rearrangements involving the proto-oncogene RET (10q11.2) are the most common (10–40%) somatic genetic changes found in PTC. At least eight types of RET rearrangements (inversions and translocations, named RET/PTC1-8) have been described yet [23], [24], [25], [26], [27], [28], [29]. Recently, two new fusion genes, ELKS and PCM-1, involving RET have been reported [30], [31]. Of note, RET re-arrangements have never been reported in UTC. Irradiation has been shown to be capable to induce these rearrangements [32], maybe due to the proximity of chromosomal loci that participate in the rearrangement process [33].

Thyroid cancer is considered to be a rare event in children and adolescents but its real incidence is not known. Actually, about 10% of all thyroid cancers are diagnosed in this age group. The Chernobyl disaster from 1986 has demonstrated the impact of nuclear fallout on the incidence of thyroid cancer, in particular PTC in children. Between 1976 and 1985, there were only nine cases of thyroid cancer in the cancer registry of Belarus [34]. In contrast, at least 101 cases of cancer in children younger than 15 years of age were reported between 1986 and 1991. Extrathyroidal invasion (pT4-tumour), LNM and distant metastases (in particular lung metastases) were frequently found. RET/PTC1 is most often found in patients who underwent external radiation [35]. In contrast, RET/PTC3 is most often found in the first decade in patients affected by the Chernobyl disaster and often associated with solid variants of PTC while RET/PTC1 is not [36]. Seemingly, at longer intervals after exposure to ionising radiation there seems to be a shift from RET/PTC3 to RET/PTC1 [37]. NTRK1 (also known as TrkA; located on 1q22) is another gene often activated in PTC. Like RET, the activation of NTRK1 is caused by rearrangements, at least three genes are involved [38], [39], [40]. Recently, a fusion oncogene involving PAX8and PPARγ has been found in FTC but neither in follicular adenoma nor PTC [41].

Another gene of importance is the tumour suppressor gene p53. Seemingly, p53 plays an important role in the dedifferentiation process of thyroid carcinoma. Mutations are frequently found in UTC but rarely in primary DTC [42]. In addition, LOH is more often found in poorly DTC and UTC when compared with DTC [43]. Overexpression of p53, probably due to decreased protein degradation, is found in 11% of PTC, 14% of FTC, 25–41% of poorly DTC, and 64–71% of UTC [44], [45]. The contrary observation was made regarding PTEN. LOH on 10q23 (the PTEN locus) has been found in 5–21% of PTC, 7–30% of FTC, and 35–59% of UTC which negatively correlated with PTEN protein expression [21]. Very recently, it could be shown that the highly malignant phenotype of the UTC is recessive, i.e. UTC seems to be achieved by the impairment of recessive tumour suppressor genes rather than by the activation of dominant oncogenes [46].

Germline mutations (almost exclusively point mutations) of the proto-oncogene RET are found in more than 95% of patients with hereditary MTC (FMTC, MEN 2A or MEN 2B) [47]. In mice, these mutations were clearly able to induce MTC [48], [49]. While all mutations found in patients with MEN 2A are also found in families having only FMTC, some mutations have so far only been found in patients with FMTC but not MEN 2A (e.g. E768D, Y791F, S891A). Future large scale analysis, most likely including the ligands (GDNF, NTN, Artemin, Persephin) and co-factors (GFRα-1, GFRα-2, GFRα-3) of RET, will be necessary to determine whether any stringent genotype-phenotype correlation exist and, subsequently, whether some patients can forego phaeochromocytoma and hyperparathyroidism surveillance. The current available data do not justify such an approach.

In contrast to hereditary MTC, little is known regarding the aetiology of sporadic MTC. Somatic RET mutations are found in up to 70% (mean 30–50%) of DNA from sporadic tumours [50]. These somatic mutations are often heterogeneously present in tumour DNA, indicating that they occur more likely during clonal evolution rather than presenting the initial step of carcinogenesis. Deletions of several chromosome arms (1p, 3p, 3q, 11p, 13q, and 22q) have been reported in up to 38% [51]. No tumour suppressor gene has been identified, yet.

An overview of genes implicated in the pathogenesis of thyroid carcinoma is shown in (Table 1, Table 2, and Fig. 1).

The overall 5-year-survival-rate of patients with PTC is about 90–95%, the 10-year survival rate is about 80–95%. The survival rate of patients with FTC is slightly lower compared to PTC with 10-year survival rates between 70–95%. In some subtypes, e.g. widely invasive FTC, survival data rival those of poorly DTCs, with 25–45% 10-year survival rates. Of note, DTC may become less differentiated and even undifferentiated in time. Most patients with UTC die within 1 year after diagnosis. The 5-year survival rate is 1–5%. The 5-year survival rate of sporadic MTC is 80–90%, the 10-year survival rate is about 60–70%. Most likely, more than 50% of patients with sporadic MTC will die of their disease. Some studies reported a better prognosis for patients with hereditary MTC as opposed to patients with sporadic MTC. However, there has been no study analysing only index cases of hereditary MTC with sporadic cases. Due to earlier diagnosis in hereditary cases, these patients are generally diagnosed at an earlier stage resulting in a better prognosis.

A variety of factors have been shown to affect the prognosis of DTC. These factors include histological type and subtype, tumour stage, age, gender, histology type and differentiation, DNA euploidy, microvessel count, CD97, E-cadherin, telomerase activity, capsular and vascular invasion. The value of most of these prognosis factors, however, is not uniform in all studies. Primary tumour size, extrathyroidal extension and distant metastases, however, are among those factors generally correlated with outcome. In contrast, the prognostic significance of lymph node metastases (LNM) remains controversial. While it has been repeatedly shown that their initial presence is correlated with tumour recurrence [52], [53], most studies could not prove a significant influence on survival. A variety of prognostic scoring systems have been published, e.g. AGES, AMES, DAMES, MACIS, pTNM, age-related pTNM, EORTC prognostic index [54], [55], [56], [57], [58], [59]. Unfortunately, none of them is widely used, thus making comparison of studies extremely difficult if not impossible. In MTC, early postoperative stimulated CT levels have been repeatedly shown to be a powerful prognostic factor besides tumour stage [60], [61].

Section snippets

Diagnosis

Generally, surgery is the treatment of choice in thyroid cancer. In order to plan the adequate therapeutic strategy, the diagnosis of thyroid carcinoma should be made preoperatively. In a certain proportion of patients, however, the diagnosis will be made postoperatively.

A thyroid nodule is the most common symptom of patients with thyroid cancer. Most of these nodules are scintigraphically cold. Anyhow, most cold thyroid nodules are benign and a scintigraphically normal or hot nodule does not

Non-surgical treatment modalities

In Europe, patients with DTC are postoperatively often treated with radioiodine. This approach is less common in the US [2], [73]. The different frequency regarding the use of postoperative radioiodine is mainly since total thyroidectomy, which is a prerequisite for successful radioiodine ablation, is rarely performed routinely in the US. Radioiodine has been shown to be effective in ablation of small thyroid remnants and pulmonal metastases. Bone metastases are less likely to respond to

Conclusions

Thyroid cancer is a rare malignancy. A variety of genes have been identified as being implicated in the process of oncogenesis. Interestingly, one gene (RET) has been shown to play a role in both PTC and MTC while it obviously plays no role in FTC and UTC. Unfortunately, our increasing knowledge has not lead to the development of new therapies with clinical implications yet. However, some preliminary data on gene therapy are promising. Until their efficacy has been proved, therapy will continue

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