*Correspondence address: Department of General Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097 Halle, Germany
Tel: +49-345-557-2314; Fax: +49-345-557-2551 E-mail: oliver.gimm@medizin.uni-halle.de

Key words: Papillary, Follicular, Undifferentiated, Medullary, ras, RET, TRK, PTEN, p53, Diagnosis, Management

Summary
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.

1. 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.

1.1. Types of thyroid carcinomas and histological appearance
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).

1.2. Epidemiology and aetiology
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 3 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 analysing 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 [5-7]. 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 endocrince 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 [18-20]. 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 [23-29]. Recently, two new fusion genes, ELKS and PCM-1, involving RET have been reported [30, 31]. Of note, RET rearrangements 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 9 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 [38-40]. Recently, a fusion oncogene involving PAX8 and PPARg 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, L790F, S891A). Future large scale analysis, most likely including the ligands (GDNF, NTN, Artemin, Persephin) and co-factors (GFRa-1, GFRa-2, GFRa-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 (Tab. 1, Tab. 2, and Fig. 1).

1.3. Prognosis, prognostic parameter and prognostic scoring systems
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 [54-59]. 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].

2. Clinic
2.1. 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 exclude the presence of thyroid cancer. In patients with PTC, LNM are often present at diagnosis (average about 50%, can be as high as 85-90% in some series). Haematogenous spread is rather a rare and late event. Of interest, distant metastases are very frequently found in children and adolescents with PTC. In patients with FTC distant metastases are more common than LNM and may be the initial symptom. In UTC, LNM have been reported to be present in up to 40%. However, their incidence is most likely underestimated due to the overall dominating appearance of the rapidly growing thyroid tumour. At diagnosis, distant metastases (most often found in lung, bone, brain) have been reported in 50% of patients. At autopsy, all patients have distant metastases. In sporadic MTC, LNM are found in 50-80% while distant metastases have only been reported in about 5–15% [61, 62]. However, metastases in MTC tend to be small in size. Hence, the real incidence is most likely higher since CT levels remain elevated in more than 50% of patients following primary surgery [63]. In summary, enlarged cervical lymph nodes as a sign of metastatic involvement may be the initial symptom of thyroid cancer, in particular in PTC and MTC.

A fine-needle aspiration cytology (FNAC) should be performed if thyroid nodules are clinically suspicious to be malignant (e.g. solid, rapidly growing) (Tab. 3) [64]. FNAC may also be helpful in the evaluation of suspicious lymph nodes. Recently, a RT-PCR-based method analysing thyroid specific transcripts of the TSH-receptor and thyroglobulin has been shown to facilitate preoperative diagnosis of DTC in small lymph nodes [65]. Cytologic features of PTC are diagnostic by FNAC. In FTC, however, the contribution of FNAC in making the diagnosis is limited since it often fails to distinguish between FTC and follicular adenoma. It remains to be shown whether the fusion oncogene involving PAX8 and PPARg can be used for preoperative diagnosis [41]. The data on telomerase activity and telomere length are not uniform and are therefore of little help. Also, the preoperative value of thyroglobulin measurements is low [66]. In contrast, CT is a very specific and sensitive tumour marker in MTC and should be measured (basally, if necessary after stimulation) if thyroid nodules are believed to be malignant. As provocative agent, either calcium (2mg/kg KG of 10% Ca2+ injected IV over 1 min) or, preferably, pentagastrin (0.5µg/kg KG, diluted in 5-10 ml sterile saline, injected IV over 5-15 s) or a combination of both can be used. CT should be measured immediately before, 1, 2, 5, and 10 min after injection. An increase of CT levels more than 2-3x compared to basal levels is considered pathologic [10]. Rarely, excessive CT secretion can produce symptoms (diarrhoea). For usual, these patients present with progressive disease and also have elevated CEA levels. The combination of diarrhoea and elevated CEA levels may misguide the clinician who may assume the presence of a malignant tumour of the gastrointestinal tract. Regarding hereditary MTC, the discovery of RET as the disease-causing gene enables identification of patients at risk theoretically immediately after birth. Patients at risk should undergo mutation analysis as soon as possible. Once the MEN 2-specific RET mutation is diagnosed, the search for accompanying disease (phaeochromocytoma, hyperparathyroidism) needs to be undertaken. RET mutation analysis should be performed in any patient with MTC to exclude hereditary MTC, even in patients 70 years or older with apparently sporadic MTC [67, 68]. Their own risk might be low but it is mandatory to determine whether their descendants are at risk. If no RET mutation was found and in the absence of other signs or symptoms suggestive for hereditary MTC, these patients and their family member can forego further screening for other MEN 2-specific diseases. Of note, the diagnosis of sporadic MTC should only be made in the absence of MEN 2-specific RET mutations. Similar to DTC, a RT-PCR-based method analysing transcripts of RET using RNA extracted from leftover cells after FNAC has been shown to facilitate preoperative diagnosis [69] but care is warranted. A negative result does not exclude the presence of MTC. Also, a positive result can not distinguish between sporadic and hereditary MTC. Of note, ultrasound-guided FNA can significantly improve the diagnostic accuracy of thyroid FNA specimens [70].

At primary operation, extensive imaging techniques are often not required unless invasion of the trachea or oesophagus or distant metastases are suspected. Ultrasound, however, should be performed to identify the extent and localisation of the primary and coexisting thyroid nodules and to diagnose enlarged cervical lymph nodes [71, 72]. Radioiodine can not be used as a diagnostic tool unless the thyroid gland has been removed and is generally of no use in MTC. Prior to extensive operation, distant macrometastases (in DTC most often found in the lung and bones, in MTC commonly seen in lung, liver and bones) should be ruled out. In DTC, their presence may already be shown on a plain chest x-ray. If infiltration of the oesophagus or trachea is suspected, computed tomography or, preferably, nuclear magnetic resonance imaging and endoscopy (tracheoscopy, oesophagoscopy) should be performed. In recurrent disease, a variety of imaging and non-imaging techniques have been shown to be helpful in localising the tumour (e.g. Technetium-99m, Thallium-201, and FDG-PET in non-MTC and octreoscan, MIBG, MIBI, anti-CEA scintigraphy, FDG-PET, selective venous catheterisation sampling, and laparoscopy in MTC). FDG-PET seems to be one of the most promising techniques in both non-MTC and MTC. The different techniques have distinct advantages regarding the detection of metastases in different organs. Their sensitivity in detecting micrometastases is generally low.

2.2. Surgical treatment
Even though surgery is accepted as the treatment of choice in thyroid carcinoma neither the extent of thyroidectomy nor the extent of lymph node dissection is uncontroversial. The goal of surgery is to eliminate the locoregional tumour burden while keeping the morbidity at a reasonable level.

In PTC, the most common type of thyroid cancer, much controversy exist regarding the extent of thyroid gland resection. In general, total thyroidectomy is more commonly recommended in Europe while less than total thyroidectomy is advocated in the US [73]. The pros and the cons for total thyroidectomy are shown in Tab. 4. The prognostic significance of LNM is controversial and, hence, recommendation regarding the extend of lymph node dissection not uniform. Generally, it is accepted that LNM are associated with an increased rate of tumour recurrence. Only a few studies showed a significant influence on survival [74]. However, the mean follow-up time in those studies showing a prognostic significance was usually longer than 10-15 years. Thus, the clinical significance of LNM in PTC might not be obvious after short-term follow-up. In this regard, it is of note that PTC as recurrent disease in regional lymph nodes may undergo anaplastic transformation [75]. Surgery is the treatment of choice if LNM are present. LNM in PTC are often macrometastases but can be very small in size. Of note, radioiodine might fail to ablate especially these micrometastases [76]. Hence, lymph node dissection should therefore not only include obviously enlarged lymph nodes but also the whole adipose and connective tissue in order to dissect also the very small, possibly metastastic lymph nodes within this compartment. The prognostic significance of these micrometastases, however, is unknown. Despite high frequencies of microscopic LNM (60-90%) only 5–15% of patients with PTC in whom no prophylactic dissection was performed develop clinically significant LNM at a later time.

In FTC, total thyroidectomy is widely accepted as the treatment of choice. Haematogenous metastases are more common and can not be treated adequately with radioiodine if a thyroid remnant exists.

In UTC, total thyroidectomy is desirable but can often not be achieved. The goal must be to control the local tumour burden, i.e. preventing obstruction of the trachea and oesophagus. In general, this can only be achieved by a multimodal therapeutic strategy consisting of surgery, external radiation and chemotherapy [77]. Resection of the trachea and oesophagus should be avoided since they are associated with a shortened survival due to increased morbidity.

Surgery is the treatment of choice for both sporadic and hereditary MTC. The success is monitored measuring postoperative serum CT levels [60, 61, 78]. In several situations, e.g. the presence of distant metastases, more than 10 LNM, LNM in more than two lymph node compartments, or if the primary tumour is not limited to the thyroid gland, no normalisation of CT can be expected [63, 78]. However, the indication to operate may still be given since MTC is generally a slowly progressing tumour. The general recommendation to perform total thyroidectomy seems to be justified since MTC is often multifocal (hereditary MTC 80-90%, sporadic MTC 10-20%) and not susceptible to radioiodine ablation. In addition, the prognostic significance of LNM is widely accepted. Since 50-80% of non-screening patients harbour LNM, the routine dissection of the cervicocentral compartment is mandatory. It is further generally accepted to dissect compartments obviously involved with LNM. Different algorithms have been reported to determine the extent of lymphadenectomy beyond the cervicocentral compartment if no obvious involvement is present (Tab. 5). LNM of MTC can be very small in size and neither diagnosable pre- nor intraoperatively. Thus, if lymphadenectomy is performed it should include not only obviously enlarged lymph nodes but the whole adipose and connective tissue within a compartment in order to dissect also the very small single lymph node within this compartment that may be involved too [79].

The rationale to operate patients harbouring a MEN 2-specific germline mutation derives from a study that showed an incidence of clinically symptomatic cases in up to 70% of patients harbouring an MEN 2 mutation by the age of 70 years [80]. Despite some obvious differences between sporadic and hereditary MTC, recommendations regarding surgical treatment do not differ significantly. Of interest, CT levels are not unlikely to be within normal limits in young children with MEN 2 despite the presence of MTC [10, 81, 82]. The necessity to remove the entire thyroid gland in patients with hereditary MTC is given due to the fact that every single C-cell harbours a malignant potencial. In addition, LNM are often present at diagnosis, especially beyond age 10 years. Hence, total thyroidectomy and cervicocentral lymphadenectomy are generally accepted to be the minimal treatment [10, 81, 82]. Of interest, lymph node involvement seems to be extremely rare if stimulated CT is within normal limits or if patients are younger than 10 years. In addition, patients harbouring some RET mutations (e.g. E768D, L790F, Y791F, V804L, V804M) seem to grow slower and may develop LNM at higher age. Therefore, routine inclusion of the cervicocentral compartment might not be necessary in these patients. However, a high variable disease course exists [68, 83]. Further large-scale analyses will be necessary to provide general recommendations.

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 radioiodine. Another therapeutic option might be retinoic acid that may be capable to induce redifferentiation of less-differentiated thyroid carcinoma [84, 85]. Routine use of external radiation must be avoided. Whether general application of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4) is cabable to improve recurrence-free survival remains to be shown [86]. However, external radiation can very well be indicated in the treatment of in the presence of non-resectable tumour and bone metastases. The use of chemotherapy is limited, remission could only be achieved in single patients.

In UTC, radioiodine seems to be of no value. In contrast, external radiation may be helpful in controlling the local tumour burden. Hyperfractionated radiotherapy is reputed to be more effective than conventional radiotherapy with less toxicity. However, in some studies a higher toxicity was reported [77]. Similarly, unacceptable toxicity has been observed after accelerated radiotherapy [87]. Chemotherapeutic agents may improve the response of radiation therapy [88]. Chemotherapy is also the only available treatment in the case of disseminated distant metastases. A variety of agents have been analysed (e.g. doxorubicin, cisplatin, vincristin). The most promising single agent seems to be paclitaxel [89]. Reexpression of p53 in thyroid cancer cell lines has been shown to inhibit proliferation and restores differentiation (e.g. reexpression of thyroid peroxidase) [90]. The effect of exogenous p53 transduction was only seen in cells carrying an altered p53, whereas it is ineffective in cells expressing wild-type p53 activity [91]. Another study suggested that p53-defective thyroid carcinomas may benefit from a combination of p53 gene therapy and radiotherapy [92]. Hence, the results of clinical studies are anxiously awaited.

Generally, radioiodine therapy in MTC is not indicated since C-cells do not uptake iodine. However, radioimmunotherapy with iodine-131-labelled anti-CEA antibodies might prove useful in non-resectable locoregional tumour or the therapy of distant metastases [93, 94]. Routine use of external radiation should be avoided. However, in non-resectable cases and in the treatment of bone metastases external radiation can very well be indicated. The use of chemotherapy is limited. Remission could only be achieved in single patients. Octreotide which may be useful in imaging lymph node and lung metastases, could not improve the outcome of patients with MTC. In patients who suffer from symptoms due to excessive CT secretion, octreotide with or without recombinant Interferon a-2b may be used to alleviate the symptoms [95, 96]. It has been shown that the calcitonin promoter is highly specific for C-cells and the high specificity could even be improved by modification of the promoter [97]. First reports on gene therapy in animal models are promising yet clearly show the difficulties of such an approach [98, 99]. Clinical trials have been started.

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 to consist of a combination of surgery, radioiodine and external radiation as well as chemotherapy.

Table 1: Overview of genes implicated in the pathogenesis of thyroid carcinoma

Histological	Type Gene	Comment
Papillary (PTC)	RET/PTC	Rearrangements are found in up to 40% (regional differences exist). At least 8 rearrangements. RET/PTC1 most common in non-irradiated PTC and late post-Chernobyl PTC, RET/PTC3 most common in early post-Chernobyl PTC.
	TRK	Rearrangements may also be quite common. At least 3 rearrangements.
	p53	Involved in the dedifferentiation process.
	PTEN	Underexpressed (cytoplasmic rather than nuclear expression), almost never mutations.
	ras	Mutations may be early event in oncogenesis.
	MET	May be overexpressed without mutations.
	p16	May be mutated, methylation found in 33%.
	c-erbB-2	Expressed in about 50% (cytoplasmic and nuclear expression)
	"mtDNA"	Somatic mitochondrial DNA mutations identified.
Follicular (FTC)	p53	Involved in the dedifferentiation process.
	ras	Mutations early event in oncogenesis and seemingly more common in tumours with metastases.
	PPARg	Seemingly only rearranged in cancers, not in adenomas.
	PTEN	Underexpressed, almost never mutations.
Undifferentiated (UTC)	p53	Overexpressed, often mutated.
	b-Catenin	Mutations found in 61%, nuclear localisation.
	PTEN	Very low levels of expression, high frequency of LOH.
Medullary (MTC)	RET	Germline missense mutations in >95% of hereditary cases. Somatic missense mutations in about 30-50% in sporadic cases.
	c-erbB-2	Expressed in seemingly 100% (restricted to cytoplasm).

Table 2. Mutation frequency, LOH frequency, and expression levels of genes mainly implicated in the pathogenesis of thyroid carcinoma

Table 3: Cytological aspects of different types of thyroid carcinomas

Histological	Cytological Appearance
Normal Follicular Cell	arranged in follicles or monolayer sheets with a honeycomb pattern; well-defined borders; polarized nuclei
Papillary (PTC)	little colloid; hypercellular; monolayer sheets; cells with enlarged, irregular, crowded nuclei with loss of polarity; psammoma bodies may be found
Follicular (FTC)	little or no colloid; hypercellular; most often microfollicles or syncytial groups; poorly defined borders; slightly enlarged round nuclei
Undifferentiated (UTC)	cell sheets, clusters or isolated cells; large pleomorphic cells; hyperchromatic nuclei; mitoses and necrotic background present
Medullary (MTC)	abundant cells; loose groups; poorly defined borders; often multi- or binucleation; nuclei eccentrically (plasmacytoid); amyloid may be found

Table 4: The pros and the cons for total thyroidectomy in papillary thyroid carcinoma (PTC)

The reasons to advocate total thyroidectomy in PTC are:

1. PTC is often multifocal (> 25%).

2. Completion thyroidectomy of thyroid remnants may be associated with a higher morbidity.

3. Small lesions may grow aggressively with the potential of dedifferentiation.


4. Rate of local recurrences is increased after less than total thyroidectomy.

5. An experienced surgeon can perform a total thyroidectomy with minimal or no long-term complications.

6. Ablation of gross thyroid thyroid remnants with radioiodine can be associated with pain.

7. Radioiodine can be used for diagnostic and therapeutic purposes of metastatic disease.

8. Measurement of thyreoglobulin can be used during follow-up.

Less than total thyroidectomy has been recommended for the following reasons:

1. Development of a recurrent thyroid cancer in the remnant thyroid lobe is considerably less common then the reported incidence of microscopic disease.

2. Low risk (<1%) of conversion of PTC to undifferentiated (anaplastic) thyroid carcinoma.

3. Local recurrences can be managed by reoperation.

4. No difference in survival as compared to total thyroidectomy.

5. Decreased morbidity after lobar or subtotal thyroidectomy as compared to total thyroidectomy.

6. If necessary, ablation of the thyroid remnant with radioiodine can be accomplished with no morbidity.

7. Scoring systems enable to identify low-risk patients who have a 20-year survival rate of >99% and a 20-year disease-free survival of >90%.

Obviously, different investigators get different results when analysing their data. It has been assumed that this can be explained by a different genetic background [100].

Table 5: Different algorithms to determine extent of lymphadenectomy in medullary thyroid carcinoma (MTC)

Lymph node dissection of the cervicolateral compartment(s):

1. Lymph node dissection ipsilateral (regarding the site of the primary tumour) and/or bilateral cervicolateral in the presence of cervicocentral LNM.

2. Inclusion of the ipsilateral cervicolateral compartment if primary tumour >2 cm in diameter.

3. General inclusion of the ipsilateral cervicolateral compartment.

4. Bilateral cervicolateral lymphadenectomy in any patient with clinical evidence of disease.

Lymph node dissection of the mediastinal compartment:

1. More than 3 LNM in the cervicocentral compartment (C1).

2. LNM in one of the cervicolateral compartments (C2 or C3).

3. Proved LNM within the upper mediastinum or cervicomediastinal transition.


In MTC, ipsilateral (regarding the primary tumour) cervicolateral LNM are common (50-70%). Since hereditary MTC is often bilateral (80-90%), a routine bilateral cervicolateral extension of the lymphadenectomy seems to be justified. In patients younger than 15 years, however, cervicolateral LNM are extremely rare [82]. In these instances, a routine lymph node dissection of the cervicolateral compartment might not be indicated.

Figure Legend

Figure 1: Multistep oncogenesis in follicular thyroid neoplasms. The diagram simplifies the real interconnection of genes involved. It is neither specific nor comprehensive. It is not known whether follicular thyroid carcinoma develops through pre-existing adenoma or not. For additional information see Tab. 1 and Tab. 2.

References
1. B.M. Wenig, C.S. Heffess, C.F. Adair. Atlas of endocrine pathology. Philadelphia London Toronto Montreal Sydney Tokyo: W.B. Saunders Company; 1997.
2. S.A. Hundahl, B. Cady, M.P. Cunningham, E. Mazzaferri, R.F. McKee, J. Rosai, et al. 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. 89 (2000) 202-217.
3. S. Holzer, J. Dudeck. [Patient care evaluation studies--a comprehensive concept for evaluation of oncologic patient management]. Z Arztl Fortbild Qualitatssich. 94 (2000) 121-126.
4. J.B. Hazard, W.A. Hawk, G. Crile. Medullary (solid) carcinoma of the thyroid - a clinicopathologic entity. J Clin Endocrinol Metab. 19 (1959) 152-161.
5. F. Pacini, M. Fontanelli, L. Fugazzola, R. Elisei, C. Romei, G. Di Coscio, et al. 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. 78 (1994) 826-829.
6. M. Rieu, M.C. Lame, A. Richard, B. Lissak, B. Sambort, P. Vuong-Ngoc, et al. 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). 42 (1995) 453-460.
7. H. Vierhapper, W. Raber, C. Bieglmayer, K. Kaserer, A. Weinhausl, B. Niederle. Routine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab. 82 (1997) 1589-1593.
8. F. Raue, J. Kotzerke, D. Reinwein, S. Schroder, H.D. Roher, H. Deckart, et al. Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register. Clin Investig. 71 (1993) 7-12.
9. R.J. Gorlin, R.A. Vickers. 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. 7 (1971) 69-72.
10. C.J.M. Lips, R.M. Landsvater, J.W.M. Hoppener, R.A. Geerdink, G. Blijham, J.M. Jansen-Schillhorn van Veen, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 331 (1994) 828-835.
11. B. Bell, E.L. Mazzaferri. Familial adenomatous polyposis (Gardner's syndrome) and thyroid carcinoma. A case report and review of the literature. Dig Dis Sci. 38 (1993) 185-190.
12. A.R. Hover, T. Cawthern, W. McDanial. Cowden disease. A hereditary polyposis syndrome diagnosable by mucocutaneous inspection. J Clin Gastroenterol. 8 (1986) 576-579.
13. K.W. Kinzler, M.C. Nilbert, L.K. Su, B. Vogelstein, T.M. Bryan, D.B. Levy, et al. Identification of FAP locus genes from chromosome 5q21. Science. 253 (1991) 661-665.
14. I. Nishisho, Y. Nakamura, Y. Miyoshi, Y. Miki, H. Ando, A. Horii, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 253 (1991) 665-669.
15. D. Liaw, D.J. Marsh, J. Li, P.L. Dahia, S.I. Wang, Z. Zheng, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 16 (1997) 64-67.
16. G.R. Bignell, F. Canzian, M. Shayeghi, M. Stark, Y.Y. Shugart, P. Biggs, 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. 61 (1997) 1123-1130.
17. F. Canzian, P. Amati, H.R. Harach, J.L. Kraimps, F. Lesueur, J. Barbier, et al. A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2. Am J Hum Genet. 63 (1998) 1743-1748.
18. P.L. Dahia, D.J. Marsh, Z. Zheng, J. Zedenius, P. Komminoth, T. Frisk, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 57 (1997) 4710-4713.
19. T. Iwama, M. Konishi, T. Iijima, K. Yoshinaga, T. Tominaga, M. Koike, et al. Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis. Jpn J Cancer Res. 90 (1999) 372-376.
20. L. Curtis, A.H. Wyllie, J.J. Shaw, G.T. Williams, A. Radulescu, C. DeMicco, et al. Evidence against involvement of APC mutation in papillary thyroid carcinoma. Eur J Cancer. 30A (1994) 984-987.
21. O. Gimm, A. Perren, L.P. Weng, D.J. Marsh, J.J. Yeh, U. Ziebold, et al. Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors. Am J Pathol. 156 (2000) 1693-1700.
22. Y. Kitamura, K. Shimizu, S. Tanaka, K. Ito, M. Emi. Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer. 27 (2000) 244-251.
23. M. Grieco, M. Santoro, M.T. Berlingieri, R.M. Melillo, R. Donghi, I. Bongarzone, 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. 60 (1990) 557-563.
24. G. Sozzi, I. Bongarzone, M. Miozzo, M.G. Borrello, M.G. Blutti, S. Pilotti, et al. A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. Genes Chromosomes Cancer. 9 (1994) 244-250.
25. M. Santoro, N.A. Dathan, M.T. Berlingieri, I. Bongarzone, C. Paulin, M. Grieco, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 9 (1994) 509-516.
26. L. Fugazzola, M.A. Pierotti, E. Vigano, F. Pacini, T.V. Vorontsova, I. Bongarzone. Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene. 13 (1996) 1093-1097.
27. S. Klugbauer, E.P. Demidchik, E. Lengfelder, H.M. Rabes. 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. 58 (1998) 198-203.
28. S. Klugbauer, H.M. Rabes. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene. 18 (1999) 4388-4393.
29. K. Salassidis, J. Bruch, H. Zitzelsberger, E. Lengfelder, A.M. Kellerer, M. Bauchinger. 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. 60 (2000) 2786-2789.
30. T. Nakata, Y. Kitamura, K. Shimizu, S. Tanaka, M. Fujimori, S. Yokoyama, et al. Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma. Genes Chromosomes Cancer. 25 (1999) 97-103.
31. R. Corvi, N. Berger, R. Balczon, G. Romeo. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene. 19 (2000) 4236-4242.
32. T. Ito, T. Seyama, K.S. Iwamoto, T. Hayashi, T. Mizuno, N. Tsuyama, et al. In vitro irradiation is able to cause RET oncogene rearrangement. Cancer Res. 53 (1993) 2940-2943.
33. M.N. Nikiforova, J.R. Stringer, R. Blough, M. Medvedovic, J.A. Fagin, Y.E. Nikiforov. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells [In Process Citation]. Science. 290 (2000) 138-141.
34. A. Antonelli, P. Miccoli, V.E. Derzhitski, G. Panasiuk, N. Solovieva, L. Baschieri. Epidemiologic and clinical evaluation of thyroid cancer in children from the Gomel region (Belarus). World J Surg. 20 (1996) 867-871.
35. T. Mizuno, K.S. Iwamoto, S. Kyoizumi, H. Nagamura, T. Shinohara, K. Koyama, et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene. 19 (2000) 438-443.
36. Y.E. Nikiforov, J.M. Rowland, K.E. Bove, H. Monforte-Munoz, J.A. Fagin. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 57 (1997) 1690-1694.
37. J. Smida, K. Salassidis, L. Hieber, H. Zitzelsberger, A.M. Kellerer, E.P. Demidchik, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer. 80 (1999) 32-38.
38. G. Sozzi, I. Bongarzone, M. Miozzo, C.T. Cariani, P. Mondellini, C. Calderone, et al. Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas. Genes Chromosomes Cancer. 5 (1992) 212-218.
39. A. Greco, M.A. Pierotti, I. Bongarzone, S. Pagliardini, C. Lanzi, G. Della Porta. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene. 7 (1992) 237-242.
40. A. Greco, C. Mariani, C. Miranda, A. Lupas, S. Pagliardini, M. Pomati, et al. 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. 15 (1995) 6118-6127.
41. T.G. Kroll, P. Sarraf, L. Pecciarini, C.J. Chen, E. Mueller, B.M. Spiegelman, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected] [published erratum appears in Science 2000 Sep 1;289(5484):1474]. Science. 289 (2000) 1357-1360.
42. J.A. Fagin, K. Matsuo, A. Karmakar, D.L. Chen, S.H. Tang, H.P. Koeffler. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest. 91 (1993) 179-184.
43. T. Ito, T. Seyama, T. Mizuno, N. Tsuyama, Y. Hayashi, K. Dohi, et al. Genetic alterations in thyroid tumor progression: association with p53 gene mutations. Jpn J Cancer Res. 84 (1993) 526-531.
44. Y. Dobashi, A. Sakamoto, H. Sugimura, M. Mernyei, M. Mori, T. Oyama, et al. Overexpression of p53 as a possible prognostic factor in human thyroid carcinoma. Am J Surg Pathol. 17 (1993) 375-381.
45. R. Donghi, A. Longoni, S. Pilotti, P. Michieli, G. Della Porta, M.A. Pierotti. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Invest. 91 (1993) 1753-1760.
46. M.L. Martelli, M.G. Miano, C. Battaglia, F. Trapasso, A. Stella, R. Iuliano, et al. The highly malignant phenotype of anaplastic thyroid carcinoma cell lines is recessive [In Process Citation]. Eur J Endocrinol. 143 (2000) 515-521.
47. C. Eng, D. Clayton, I. Schuffenecker, G. Lenoir, G. Cote, R.F. Gagel, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 276 (1996) 1575-1579.
48. F.M. Michiels, S. Chappuis, B. Caillou, A. Pasini, M. Talbot, R. Monier, et al. Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation. Proc Natl Acad Sci U S A. 94 (1997) 3330-3335.
49. C.L. Smith-Hicks, K.C. Sizer, J.F. Powers, A.S. Tischler, F. Costantini. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. Embo J. 19 (2000) 612-622.
50. C. Eng, L.M. Mulligan. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum Mutat. 9 (1997) 97-109.
51. L.M. Mulligan, E. Gardner, B.A. Smith, C.G. Mathew, B.A. Ponder. Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2. Genes Chromosomes Cancer. 6 (1993) 166-177.
52. L.J. DeGroot, E.L. Kaplan, M. McCormick, F.H. Straus. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 71 (1990) 414-424.
53. C.J. Hughes, A.R. Shaha, J.P. Shah, T.R. Loree. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck. 18 (1996) 127-132.
54. J. Tennvall, A. Biorklund, T. Moller, J. Ranstam, M. Akerman. Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer. 57 (1986) 1405-1414.
55. I.D. Hay, C.S. Grant, W.F. Taylor, W.M. McConahey. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery. 102 (1987) 1088-1095.
56. S.T. Kukkonen, R.K. Haapiainen, K.O. Franssila, A.H. Sivula. Papillary thyroid carcinoma: the new, age-related TNM classification system in a retrospective analysis of 199 patients. World J Surg. 14 (1990) 837-841; discussion 841-832.
57. B. Cady. Papillary carcinoma of the thyroid. Semin Surg Oncol. 7 (1991) 81-86.
58. J.L. Pasieka, J. Zedenius, G. Auer, L. Grimelius, A. Hoog, G. Lundell, et al. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Surgery. 112 (1992) 1154-1159; discussion 1159-1160.
59. I.D. Hay, E.J. Bergstralh, J.R. Goellner, J.R. Ebersold, C.S. Grant. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 114 (1993) 1050-1057; discussion 1057-1058.
60. M.E. Girelli, S. Dotto, D. Nacamulli, M. Piccolo, D. De Vido, T. Russo, et al. Prognostic value of early postoperative calcitonin level in medullary thyroid carcinoma. Tumori. 80 (1994) 113-117.
61. M.E. Dottorini, A. Assi, M. Sironi, G. Sangalli, G. Spreafico, L. Colombo. Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer. 77 (1996) 1556-1565.
62. L. Scopsi, G. Sampietro, P. Boracchi, R. Del Bo, M. Gullo, M. Placucci, et al. Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer. 78 (1996) 2173-2183.
63. O. Gimm, J. Ukkat, H. Dralle. Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma. World J Surg. 22 (1998) 562-567; discussion 567-568.
64. P. Werga, G. Wallin, L. Skoog, B. Hamberger. Expanding role of fine-needle aspiration cytology in thyroid diagnosis and management. World J Surg. 24 (2000) 907-912.
65. F. Arturi, D. Russo, D. Giuffrida, A. Ippolito, N. Perrotti, R. Vigneri, et al. Early diagnosis by genetic analysis of differentiated thyroid cancer metastases in small lymph nodes. J Clin Endocrinol Metab. 82 (1997) 1638-1641.
66. M.E. Girelli, D. De Vido. Serum thyroglobulin measurements in differentiated thyroid cancer [In Process Citation]. Biomed Pharmacother. 54 (2000) 330-333.
67. K.E. Shannon, O. Gimm, R. Hinze, H. Dralle, C. Eng. Germline V804M mutation in th RET proto-oncogene in two apparently sporadic cases of TMC presenting in the seventh decade of life. J. Endocr. Genet. 1 (1999) 39-45.
68. G.L. Feldman, M.W. Edmonds, P.J. Ainsworth, I. Schuffenecker, G.M. Lenoir, A.W. Saxe, et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 128 (2000) 93-98.
69. T. Takano, A. Miyauchi, F. Matsuzuka, G. Liu, T. Higashiyama, T. Yokozawa, et al. Preoperative diagnosis of medullary thyroid carcinoma by RT-PCR using RNA extracted from leftover cells within a needle used for fine needle aspiration biopsy. J Clin Endocrinol Metab. 84 (1999) 951-955.
70. Z.W. Baloch, D. Tam, J. Langer, S. Mandel, V.A. LiVolsi, P.K. Gupta. Ultrasound-guided fine-needle aspiration biopsy of the thyroid: role of on-site assessment and multiple cytologic preparations [In Process Citation]. Diagn Cytopathol. 23 (2000) 425-429.
71. B.M. Barraclough, B.H. Barraclough. Ultrasound of the thyroid and parathyroid glands. World J Surg. 24 (2000) 158-165.
72. M.W. van den Brekel. Lymph node metastases: CT and MRI. Eur J Radiol. 33 (2000) 230-238.
73. S. Holzer, C. Reiners, K. Mann, M. Bamberg, M. Rothmund, J. Dudeck, et al. Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U.S. and German Thyroid Cancer Group. Cancer. 89 (2000) 192-201.
74. G.F. Scheumann, O. Gimm, G. Wegener, H. Hundeshagen, H. Dralle. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg. 18 (1994) 559-567; discussion 567-558.
75. D. Wynford-Thomas. Origin and progression of thyroid epithelial tumours: cellular and molecular mechanisms. Horm Res. 47 (1997) 145-157.
76. M.L. Sautter-Bihl, G. Herbold, H.G. Heinze, H. Bihl. Late cervical lymph node recurrence in differentiated thyroid carcinoma. An inherent problem of 131I beta dose distribution in small tumor deposits? Nuklearmedizin. 31 (1992) 137-141.
77. K.B. Ain. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin Surg Oncol. 16 (1999) 64-69.
78. A. Machens, O. Gimm, J. Ukkat, R. Hinze, U. Schneyer, H. Dralle. Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer. 88 (2000) 1909-1915.
79. H. Dralle, I. Damm, G.F. Scheumann, J. Kotzerke, E. Kupsch, H. Geerlings, et al. Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Surg Today. 24 (1994) 112-121.
80. B.A. Ponder, M.A. Ponder, R. Coffey, M.E. Pembrey, R.F. Gagel, M. Telenius-Berg, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet. 1 (1988) 397-401.
81. S.A. Wells, Jr., D.D. Chi, K. Toshima, L.P. Dehner, C.M. Coffin, S.B. Dowton, et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg. 220 (1994) 237-247; discussion 247-250.
82. H. Dralle, O. Gimm, D. Simon, K. Frank-Raue, G. Gortz, B. Niederle, et al. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg. 22 (1998) 744-750; discussion 750-741.
83. H.S. Hansen, H. Torring, C. Godballe, A.C. Jager, F.C. Nielsen. Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome? Cancer. 89 (2000) 863-867.
84. D. Simon, J. Koehrle, C. Reiners, A.R. Boerner, C. Schmutzler, K. Mainz, et al. Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg. 22 (1998) 569-574.
85. C. Schmutzler, J. Koehrle. Innovative strategies for the treatment of thyroid cancer. Eur J Endocrinol. 143 (2000) 15-24.
86. J. Farahati, C. Reiners, M. Stuschke, S.P. Muller, G. Stuben, W. Sauerwein, et al. Differentiated thyroid cancer. Impact of adjuvant external radiotherapy in patients with perithyroidal tumor infiltration (stage pT4). Cancer. 77 (1996) 172-180.
87. G. Mitchell, R. Huddart, C. Harmer. Phase II evaluation of high dose accelerated radiotherapy for anaplastic thyroid carcinoma. Radiother Oncol. 50 (1999) 33-38.
88. J. Tennvall, G. Lundell, A. Hallquist, P. Wahlberg, G. Wallin, S. Tibblin. Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Report on two protocols. The Swedish Anaplastic Thyroid Cancer Group. Cancer. 74 (1994) 1348-1354.
89. K.B. Ain, M.J. Egorin, P.A. DeSimone. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group [In Process Citation]. Thyroid. 10 (2000) 587-594.
90. F. Moretti, A. Farsetti, S. Soddu, S. Misiti, M. Crescenzi, S. Filetti, et al. p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells. Oncogene. 14 (1997) 729-740.
91. F. Moretti, S. Nanni, A. Farsetti, M. Narducci, M. Crescenzi, S. Giuliacci, et al. Effects of exogenous p53 transduction in thyroid tumor cells with different p53 status. J Clin Endocrinol Metab. 85 (2000) 302-308.
92. M. Narimatsu, Y. Nagayama, K. Akino, M. Yasuda, T. Yamamoto, T.T. Yang, et al. Therapeutic usefulness of wild-type p53 gene introduction in a p53-null anaplastic thyroid carcinoma cell line. J Clin Endocrinol Metab. 83 (1998) 3668-3672.
93. M. Juweid, R.M. Sharkey, T. Behr, L.C. Swayne, T. Herskovic, M. Pereira, et al. Radioimmunotherapy of medullary thyroid cancer with iodine-131-labeled anti-CEA antibodies. J Nucl Med. 37 (1996) 905-911.
94. T.M. Behr, E. Wulst, S. Radetzky, R.D. Blumenthal, R.M. Dunn, S. Gratz, et al. Improved treatment of medullary thyroid cancer in a nude mouse model by combined radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of radiolabeled antibodies in a radioresistant tumor type. Cancer Res. 57 (1997) 5309-5319.
95. C. Mahler, J. Verhelst, M. de Longueville, A. Harris. Long-term treatment of metastatic medullary thyroid carcinoma with the somatostatin analogue octreotide. Clin Endocrinol (Oxf). 33 (1990) 261-269.
96. G. Lupoli, E. Cascone, F. Arlotta, G. Vitale, L. Celentano, M. Salvatore, et al. Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha-2b and octreotide. Cancer. 78 (1996) 1114-1118.
97. M. Messina, D.M. Yu, D.L. Learoyd, G.W. Both, P.L. Molloy, B.G. Robinson. High level, tissue-specific expression of a modified calcitonin/calcitonin gene-related peptide promoter in a human medullary thyroid carcinoma cell line [In Process Citation]. Mol Cell Endocrinol. 164 (2000) 219-224.
98. R. Zhang, D. Baunoch, L.J. DeGroot. Genetic immunotherapy for medullary thyroid carcinoma: destruction of tumors in mice by in vivo delivery of adenoviral vector transducing the murine interleukin-2 gene. Thyroid. 8 (1998) 1137-1146.
99. R. Zhang, L.J. DeGroot. Gene therapy of established medullary thyroid carcinoma with herpes simplex viral thymidine kinase in a rat tumor model: relationship of bystander effect and antitumor efficacy. Thyroid. 10 (2000) 313-319.
100. P.E. Goretzki, J. Lyons, S. Stacy-Phipps, W. Rosenau, M. Demeure, O.H. Clark, et al. Mutational activation of RAS and GSP oncogenes in differentiated thyroid cancer and their biological implications. World J Surg. 16 (1992) 576-581; discussion 581-572.

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