Mini-reviewThyroid cancer
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
References (100)
- et al.
Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer
Am. J. Hum. Genet.
(1997) - et al.
A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2
Am. J. Hum. Genet.
(1998) - et al.
Evidence against involvement of APC mutation in papillary thyroid carcinoma
Eur. J. Cancer
(1994) - et al.
Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors
Am. J. Pathol.
(2000) - et al.
PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas
Cell
(1990) - et al.
Serum thyroglobulin measurements in differentiated thyroid cancer
Biomed. Pharmacother.
(2000) - et al.
Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG–>ATG) mutation
Surgery
(2000) Lymph node metastases: CT and MRI
Eur. J. Radiol.
(2000)- et al.
Risk estimation and screening in families of patients with medullary thyroid carcinoma
Lancet
(1988) - et al.
Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma
Radiother. Oncol.
(1999)
High level, tissue-specific expression of a modified calcitonin/calcitonin gene-related peptide promoter in a human medullary thyroid carcinoma cell line
Mol. Cell. Endocrinol.
Atlas of endocrine pathology
Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study
Cancer
Patient care evaluation studies – a comprehensive concept for evaluation of oncologic patient management
Z Arztl Fortbild Qualitatssich
Medullary (solid) carcinoma of the thyroid - a clinicopathologic entity
J. Clin. Endocrinol. Metab.
Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma [see comments]
J. Clin. Endocrinol. Metab.
Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules [see comments]
Clin. Endocrinol. (Oxf)
Routine measurement of plasma calcitonin in nodular thyroid diseases
J. Clin. Endocrinol. Metab.
Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register
Clin. Invest.
Multiple mucosal neuromas, pheochromocytoma, medullary carcinoma of the thyroid and marfanoid body build with muscle wasting: reexamination of a syndrome of neural crest malmigration
Birth Defects Orig. Artic. Ser.
Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A
N. Engl. J. Med.
Familial adenomatous polyposis (Gardner's syndrome) and thyroid carcinoma. A case report and review of the literature
Dig. Dis. Sci.
Cowden disease. A hereditary polyposis syndrome diagnosable by mucocutaneous inspection
J. Clin. Gastroenterol.
Identification of FAP locus genes from chromosome 5q21
Science
Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients
Science
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Nat. Genet.
Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors
Cancer Res.
Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis
Jpn. J. Cancer Res.
Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q
Genes Chromosomes Cancer
A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma
Genes Chromosomes Cancer
Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma
Oncogene
Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer
Oncogene
Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5
Cancer Res.
The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas
Oncogene
Translocation t(10;14) (q11.2:q22.1) fusing the kinetin to the RET gene creates a novel rearranged form (PTC8) of the RET proto-oncogene in radiation-induced childhood papillary thyroid carcinoma
Cancer Res.
Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma
Genes Chromosomes Cancer
RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma
Oncogene
In vitro irradiation is able to cause RET oncogene rearrangement
Cancer Res.
Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells
Science
Epidemiologic and clinical evaluation of thyroid cancer in children from the Gomel region (Belarus)
World J. Surg.
Preferential induction of RET/PTC1 rearrangement by X-ray irradiation
Oncogene
Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children
Cancer Res.
Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus
Int. J. Cancer
Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas
Genes Chromosomes Cancer
TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas
Oncogene
The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain
Mol. Cell. Biol.
PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]
Science
High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas
J. Clin. Invest.
Genetic alterations in thyroid tumor progression: association with p53 gene mutations
Jpn. J. Cancer Res.
Overexpression of p53 as a possible prognostic factor in human thyroid carcinoma
Am. J. Surg. Pathol.
Cited by (187)
Thyroid autoimmune disorders and cancer
2020, Seminars in Cancer BiologyCitation Excerpt :Basal thyroglobulin (Tg), and Tg after recombinant thyroid-stimulating hormone (TSH) determination, and neck ultrasound are the key elements for the subsequent evaluation of DTC patients, previously been submitted to surgery [12,17,18], however the presence of circulating anti-thyroglobulin antibodies (AbTg) might reduce the value of Tg determination. Papillary thyroid cancer (about 85% of TCs), FTC (about 10% of TCs), and medullary thyroid carcinoma (MTC) (<5% of TCs) represent almost the entirety of TC cases [19,20]. Anaplastic thyroid cancer (ATC) is rarer (<2% of TCs) but it is one of the most lethal human cancers, and it causes around 15–40% of death for TC [21–25].
EphB3 stimulates cell migration and metastasis in a kinase-dependent manner through Vav2-Rho GTPase axis in papillary thyroid cancer
2017, Journal of Biological ChemistryCitation Excerpt :Thyroid cancer (TC)3 is the most common endocrine malignancy, and its incidence is rising rapidly. The main type of TC is papillary thyroid cancer (PTC), which accounts for >81% of the new TC cases (1, 2). The treatment for PTC generally benefits the majority of the patients with well differentiated PTC; however, up to 10% of patients eventually die of the disease, and many more patients have the risk of recurrences (3–5).
ApolipoproteinL1 is expressed in papillary thyroid carcinomas
2016, Pathology Research and PracticeCitation Excerpt :Carcinomas (FTC, PTC and ATC) all originate from thyroid follicular cells. PTC, the most frequent well-differentiated thyroid cancer is associated with features that are not necessary present all together in the same lesion: they include distinguishable neoplastic papillae lined by one or several layers of cells with the presence of psammoma bodies and distinctive nuclear signatures such as nuclei overlapping, ground glass appearance, longitudinal nuclear groove or cytoplasmic invagination in the nucleus [4,5]. Oncogenic mutations most commonly associated with PTCs involve BRAFV600E mutation with enhanced serine-threonine kinase activity (45% of cases) or RET-PTC rearrangement (30% of cases), as well as activating mutations of RAS.