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Thyroid cancer management: from a suspicious nodule to targeted therapy

Perri, Francescoa; Giordano, Antonioe; Pisconti, Salvatorea; Ionna, Francob; Chiofalo, Maria, G.c; Longo, Francescob; Leopardo, Davided; Della Vittoria Scarpati, Giuseppinaa; Pezzullo, Lucianoc

doi: 10.1097/CAD.0000000000000617
Review Article

Thyroid nodules are very common, and their frequency is four to five times higher in women than in men. Most of them are benign, with only a very little percentage revealing a malignant neoplasm. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography and following fine-needle aspiration. Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. A standard diagnostic approach is represented by ‘first-level’ exams, consisting in neck ultrasonography and serum thyroid-stimulating hormone measurement, followed, only for nodules that are suspicious of malignancy, by ‘second-level’ exams, consisting of fine-needle aspiration and mutational test, which does detect particular DNA mutations present only in malignant cells. In this review, we will analyze the genetics of thyroid cancer and its heterogeneity, and we will briefly describe the current available diagnostic and therapeutic approaches.

aMedical Oncology Unit, POC SS Annunziata, Taranto

bDepartment of Head and Neck Surgery, Otolaryngology Unit

cOtolaryngology Unit, Department of Thyroid Surgery, National Tumor Institute of Naples, Foundation G Pascale, Naples

dMedical Oncology Unit, Hospital of Caserta, Caserta, Italy

eDepartment of Medicine, Division of Hematology & Oncology, Medical University of South Carolina, Charleston, South Carolina, USA

Correspondence to Francesco Perri, MD, Medical Oncology Unit, POC SS Annunziata, Taranto 74100, Italy Tel: +34 89 145 086; fax: +34 99 458 5813; e-mail:

Received November 23, 2017

Accepted February 20, 2018

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Thyroid nodules are a very common pathology, and their frequency is four to five times higher in women than in men. Most of them are benign, and a very little percentage of nodules are malignant thyroid neoplasms. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography (US) and subsequent fine-needle aspiration (FNA) 1,2.

Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. Usually, thyroid carcinoma is more frequent in women than in men, and often its onset is preceded by a history of benign thyroid disease. An acknowledged risk factor is the exposure of the gland to ionizing radiations, but also iodine deficiency and genetic diseases may be taken into account. Gardner, Cowden, and MEN-2B (multiple endocrine neoplasms) are genetic syndromes associated with thyroid cancer development 3.

Overall, considering both localized and advanced forms, the prognosis of thyroid carcinomas is fairly good, reaching a 5-year overall survival of about 70% 4. Nevertheless, thyroid cancers can present in either indolent or aggressive diseases. The aim of this review is to help clinicians to discover thyroid cancer early and then to face it adequately, addressing all therapeutic strategies that are currently available.

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Thyroid nodules

The first step in clinic is to appropriately manage the diagnosis of thyroid nodules. As mentioned above, thyroid nodules are very common and often they are diagnosed in asymptomatic young women (third to fourth decade of life). Usually, patients report the presence of a neck nodule detected by self-palpation. Equally common, thyroid nodules are casually discovered during a diagnostic computed tomography (CT) scan or a PET carried out for other reasons. The diagnostic workup should be aimed to exclude a diagnosis of malignancy. Once identified, a thyroid nodule should be investigated with ‘first-level’ exams, such as neck US and serum thyroid-stimulating hormone (TSH) measurement (tireotropin). Specifically, TSH level, neck US, and anamnesis are used to determine whether it is necessary to perform an FNA, which represents the ‘second-level’ diagnostic exam.

In the presence of low level of serum TSH, the nodule is almost always an hyperfunctioning nodule, and then frequently a benign nodule. In this case, further test is not necessary. In contrast, a normal or high serum TSH value may be compatible with a malignant nodule, and, in this case, the workup should be continued with a neck US. When performed by an expert radiologist, neck US can provide a great deal of information. In fact, morphology of the nodule, other than its dimension, can help determine whether an FNA needs to be performed. Generally, nodules smaller than 1 cm in the greatest dimension have a very low probability to be malignant. However, important information could be taken analyzing the morphology of the nodules. Features associated with malignant nature are irregular margins, hypoechoic appearance, the presence of microcalcifications, mixed solid-cystic features, a tall rather than wide shape, an increased internal vascularity, and evidence of extrathyroidal invasion. In contrast, features typical of benign nodules are purely cystic in nature, with hyperanechoic appearance, well-defined margins, and a spongiform appearance, known as multicystic nature of the nodule. In Table 1, are described the US features typical of benign and malignant nodules 5,6. Moreover, patient clinical history can help guide the diagnosis of nodules. History of radiation therapy (RT) of the neck, one or more relatives with a diagnosis of thyroid carcinoma, or symptoms such as laryngeal paralysis are signs that FNA of suspected nodules should be performed 7. Finally, a thyroid nodule can be incidentally detected during other radiologic exams, such as CT and PET scan. A contrast-enhancing nodule on CT scan, as well as a lesion taking up fluorine-18-fluorodeoxyglucose on PET, should be further investigated by neck US. Nodules that are suspicious of carcinoma must be addressed by the ‘second-level’ test FNA. The recommended approach to thyroid nodule is described in Fig. 1.

Table 1

Table 1

Fig. 1

Fig. 1

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Thyroid carcinoma: overview of genetics and pathology

Thyroid carcinoma is a heterogeneous disease, being composed by a number of different histopathologic and clinical entities. Papillary thyroid carcinoma (PTC, about 87%) and follicular thyroid carcinoma (FTC, about 11%), which includes also a particular subgroup named ‘Hurthle cell’ carcinoma, account for the majority of cancer histotypes. With lower frequency, we found medullary thyroid carcinoma (MTC, 1%) and anaplastic carcinoma (ATC, <1%). PTC, FTC, and Hurthle cell carcinomas derive from follicular cells of the gland; those tumors are characterized by a very similar clinical behavior and show a good prognosis with low recurrence rate after primary therapy 8. MTC originates from the neuroendocrine parafollicular C-cells secreting calcitonin, and it cannot be treated with radioiodine (RAI) therapy because they are not derived from thyroid follicles. ATC is the rarest and the most lethal thyroid cancer affecting mainly the elderly patients and is characterized by poor grade of differentiation, high aggressiveness, and very poor prognosis 9,10.

Generally, PTC and FTC, especially if diagnosed at an early stage, have a good prognosis, and can be effectively cured with surgery followed by RAI plus suppressive endocrine therapy. Nevertheless, about 10% of patients will suffer from recurrent disease, which can be locoregional (thyroid bed or laterocervical lymph nodes) or systemic (lung, bone, liver, etc.). MTC often spreads to laterocervical lymph nodes and/or at distance sites, but its prognosis is overall good. ATC is a lethal disease, being characterized by a rapidly enlarging neck mass, provoking early hemorrhage and/or suffocation 11,12.

Lately, the biology and genetics of thyroid carcinomas have been better understood to help install a correct therapy. Several studies have been carried out with the aim to identify DNA mutations involved in the cancerogenesis of thyroid carcinomas. A wide number of data have been collected and, surprisingly, a low number of intracellular pathways has been found to be altered during the cancerogenesis process.

The mitogen activated protein kinase (MAPK) pathway was found to be disrupted or upregulated in about 80% of PTC and a large percentage of ATC. The MAPK pathway is regulated by several upstream proteins, such as RET (rearranged during transcription). RET is a tyrosine kinase receptor that is able to influence cell survival by MAPK cascade activation. The aforementioned pathway is activated by the interaction between an extracellular ligand (which is often a growth factor) and a transmembrane receptor that is able, once activated, to exert a tyrosine kinase function. RET is one of the many tyrosine kinase receptors (RTK) that are capable of stimulating the MAPK pathway 13,14. A chimeric form of RET enzyme (resulting from RET-PTC gene fusion) is responsible for the hyperactivation of RET without ligand stimulation. In addition, distinct point mutations of RET are responsible for the same behavior. Regardless of the mechanism at the base of RET kinase activation, it results in uncontrolled cell proliferation. Mutations of RET proto-oncogene are responsible for all inherited, almost all sporadic, MTC and a good percentage of PTC 14–16. The BRAF mutation (V600E) is a common somatic mutation in thyroid cancer occurring in 45% of PTCs and about 25% of ATC, whereas it is never found in FTC and MTC. RAF is an intracellular tyrosine kinase participating and strongly activating the MAPK pathway stimulating cell growth and angiogenesis. BRAF mutations are often associated with more aggressive neoplastic phenotype and worse survival when compared with the wild-type counterpart. Some diagnostic tests, during the assessment of thyroid cancer, take into account BRAF mutations 14. PAX-8-PPARg (peroxisome proliferator activated receptor) is a fusion protein that is able to alter the apoptosis and to stimulate cell proliferation. PAX-8-PPARg in normal conditions upregulates a protein that is able to block the cell cycle (phosphatase and tensin homolog), and thus a reduction in PAX-8-PPARg function leads to cell cycle progression and angiogenesis stimulation. PAX-8-PPARg, as well as BRAF, mutations are often found in FTC, and they are often checked in the diagnostic workup of thyroid carcinomas 17.

In summary, thyroid carcinoma is not a single entity, but it is composed of several histopathologies, each one carrying a different natural history and response to therapy. Moreover, not only the histology but also the genetic landscape of thyroid carcinoma should be taken into account, both in the diagnostic workup and in the therapeutic setting.

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Fine-needle aspiration: the standard procedure for diagnosis of thyroid carcinoma

FNA is the procedure of choice when evaluating suspicious thyroid nodules. Cytologic examination of an FNA specimen can identify the following diagnostic categories: (i) carcinoma, (ii) follicular or Hurthle cell neoplasms, (iii) atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS), (iv) thyroid lymphoma, (v) benign, and (vi) insufficient biopsy.

The finding of a ‘benign nodule’ does not necessitate further examinations, with only a periodic follow-up with neck US every 6–12 months. AUS/FLUS represents indeterminate diagnostic categories and necessitates further evaluations. In the presence of atypical thyroid cells that are not indicative of malignancy (AUS/FLUS), a molecular diagnostic test, which is aimed to identify specific DNA mutations, can be taken into account. As specific DNA mutations are typical of carcinoma and not found in benign lesions, the discovery of these mutations in tissue samples can help identify the malignant nature of a nodule. One of the most useful molecular tests is the ‘seven genes test’, which is able to assess the contemporary presence of crucial mutations such as BRAF, RAS, PAX-8-PPARg, and RET/PTC. In the presence of AUS/FLUS and a positive result on the ‘seven genes molecular test’, thyroidectomy might be considered. However, this indication is not shared by all experts, and repeating an FNA after 6 months represents the alternative 18,19.

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Staging of thyroid carcinoma

Staging can be defined as the evaluation of disease extension in the body, and it should be performed once thyroid carcinoma has been diagnosed. Nevertheless, staging can be avoided in the presence of early-stage carcinoma and/or tumors with low grade of aggressiveness. FNA is the procedure of choice for obtaining diagnosis of thyroid carcinoma, and in some cases it is followed by thyroidectomy or hemithyroidectomy, if the FNA results are not sufficient or doubtful. For early-stage differentiated cancers (PTC and FTC stage I–II), staging is not necessary, and the patient can directly undergo surgery. After surgery, the staging should be performed with RAI whole-body scan and serum thyroglobulin (Tg) level measurement.

In the presence of advanced (stage III–IV) cancers or more aggressive histologies, such as ATC, Hurthle cell carcinoma, and poorly differentiated FTC/PTC, a CT scan of neck and chest should be performed. CT of neck or neck-MRI is more accurate than neck US for the assessment of trachea and deep tissues, and must precede surgery.

PET/CT is preferred in the presence of not iodine avid thyroid carcinoma, such as the majority of ATC and all MTC 9,20. Calcitonin and carcinoembryonic antigen measurements should be performed in the presence of MTC.

TNM (tumor, node, metastasis) staging of thyroid cancer is detailed in Fig. 2.

Fig. 2

Fig. 2

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Surgical treatment of thyroid carcinoma

Surgery represents the cornerstone of thyroid cancer treatment, and carries additional diagnostic and staging purposes. The most performed surgical procedure is the total thyroidectomy, namely the removal of all the thyroid parenchyma. Regional thyroid lymph nodes are divided in central compartment lymph nodes (level IV, according to Robbins classification) and lateral compartments lymph nodes (levels II and III). The current guidelines do not recommend prophylactic lymph node removal at the same time as thyroidectomy, and lymph nodes (both central and lateral compartments) should be removed only if they are clinically positive (N1) 20. Figure 3 shows the different laterocervical lymph node levels according to Robbins classification.

Fig. 3

Fig. 3

Controversies exist with regard to the extent of thyroidectomy, with many experts recommending hemithyroidectomy in the site of total gland removal, in the presence of small tumors. Current guidelines strongly recommend total thyroidectomy and reserve hemithyroidectomy only in the presence of unifocal, very small cancer, such as less than 1 cm tumor. In fact, when hemithyroidectomy is performed as a diagnostic procedure and the diagnosis is a well-differentiated tumor, PTC or FTC less than 1 cm (T1a stage), and with no vascular invasion, a total thyroidectomy is not necessary 21,22.

Total thyroidectomy is recommended also for other reasons, such as interference with the ability to perform adjuvant RAI therapy and a reliable follow-up with iodine whole-body scan and Tg periodic measurement. The presence of remaining thyroid tissue can interfere with both therapeutic adjuvant RAI and diagnostic RAI whole-body scan, being the remaining thyrocytes able to pick up most administered radiolabelled iodine. Moreover, the detection of high values of serum Tg is not specific in patients with remnant thyroid tissue 23,24.

In addition to the aforementioned caveats of partial thyroidectomy, many patients prefer to undergo total thyroidectomy to avoid a second hospitalization and repeat surgery.

Laterocervical lymph nodes should be removed only if presurgical procedures, such as neck US and/or FNA of suspect lymph nodes with contestual Tg level in the aspiration liquid, demonstrated an N+ disease 20.

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Adjuvant radioiodine therapy

Most thyroid carcinomas are differentiated diseases, composed by thyrocytes that are able to pick up iodine. This feature represents the rationale behind RAI and diagnostic iodine whole-body scan. For a long time, adjuvant RAI used to be administered in all patients in the post-thyroidectomy setting, regardless of pathologic staging. Lately, adjuvant RAI indication has been accurately revised because several clinical trials did not show survival improvement in unselected patients 25,26.

In the postoperative setting, it is necessary to stratify patients based on their recurrence risk. In 2009, American Thyroid Association released new guidelines to define the risk of recurrence after thyroidectomy. They put into account the following characteristics: primitive tumor extent, serum level of postsurgical Tg, histology of tumor (aggressive vs. nonaggressive), postoperative tumoral residue, and the presence of intravascular neoplastic emboli. On the basis of this classification (Fig. 2), risk of recurrence can be categorized as low, intermediate, and high. Decision to perform or not perform adjuvant RAI must take into account this classification 9 (Table 2).

Table 2

Table 2

In summary, experts do not routinely recommend RAI for patients with all the following factors: (i) either unifocal or multifocal classic papillary microcarcinomas (<1 cm) confined to the thyroid; (ii) no detectable anti-Tg antibodies; or (iii) postoperative unstimulated Tg less than 1 ng/ml. This category of patients may be considered at very low risk to develop recurrence, and a iodine whole-body diagnostic scan, to exclude metastatic or persistent disease, is the only procedure to perform after thyroidectomy. In case of normal findings, follow-up alone is indicated.

If the primary tumor size is between 1 and 4 cm, conflicting data exist. Experts recommend adjuvant RAI therapy in the presence of intravascular tumor invasion (evaluated by pathology), or in the presence of aggressive histology, such as ‘tall cell’, ‘hobnail variant’ and ‘columnar variant’ of PTC.

Before RAI therapy is persued, a iodine whole-body diagnostic scan should be performed with the objective to exclude/identify both residual tumor and distant metastasis. In case of normal findings, RAI should be administered at an empiric dose of 30 mCi. When post-thyroidectomy serum Tg level is elevated (>1 ng/ml), a dose of 150 mCi is preferred 9.

Physicians must be aware of RAI toxicity profile, as salivary glands injury and pancytopenia could occur, directly proportional to the prescribed dose.

Patients affected by PTC, FTC, and Hurthle cell carcinoma considered at intermediate or high risk of recurrence, concomitant with RAI, should receive levothyroxine to suppress TSH levels 9.

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The role of external beam radiotherapy and adjuvant chemotherapy

At present, there is no role in the adjuvant setting for external beam radiotherapy and chemotherapy, with the only exception of ATC, often unresectable at the time of diagnosis and addressed with palliative tracheostomy, RT, and/or chemotherapy 27,28.

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Follow-up of upfront treatments

Periodic clinical exam after thyroidectomy, followed or not by adjuvant RAI, represents a very important tool, as about 10% of PTC and 20% of FTC may recur after primary treatment. An early diagnosis of recurrence allows installing an effective treatment and possibly cure the patient. Therefore, in patients considered at low risk of recurrence (according to American Thyroid Association guidelines), neck US and Tg level should be performed every 12 months. RAI whole-body diagnostic scan, in this category of patients, should not be performed after a first negative result. In patients considered at intermediate/high risk of recurrence, neck US and Tg level should be performed every 6 months, whereas iodine whole-body scan can be done every 12 months.

CT scan or PET/CT should be prescribed in the presence of high level of Tg and a negative iodine whole-body scan. In this case, disease may have become RAI resistant 29,30.

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Unresectable disease

Thyroidectomy should be always performed even for metastatic disease. Nevertheless, some tumors are not resectable ‘ab initio’ because of massive extrathyroidal extension involving thrachea and major neck arteries. These features are often observed in case of ATC. ATC is the most aggressive thyroid cancer, being often unresectable at diagnosis. In the presence of PTC and FTC (included Hurthle cells carcinoma), thyroidectomy should be performed even in the presence of distant metastasis; eventual RAI could be very difficult in the presence of thyroid gland, which would capture most of the RAI and prevent metastasis from being treated. Unresectable PTC and FTC are treated upfront with external beam RT. RAI should be administered after external beam RT, even if its efficacy is not optimal, with the thyroid gland still in place. Unresectable MTC and ATC, known to be not iodine avid diseases, should be managed with exclusive external beam RT, followed or not by systemic therapies, and not RAI 31,32.

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Recurrent/metastatic disease

The totality of ATCs, 35% of Hurthle cells carcinoma and MTCs, 20% of FTCs, and about 5–10% of PTCs recur after primary treatment 33. Recurrence can occur as locoregional disease, spreading to laterocervical lymph nodes and/or thyroid surgical bed, or as systemic disease, spreading to distance sites such as lung, bone, liver, and brain. Overall, surgery is the preferred therapy for locoregional recurrent disease, if tumor is resectable. Central or lateral neck lymphadenectomy represents the best surgical option, and it could be completed with resection of recurrent mass in the thyroid postsurgical bed (if present). However, surgery is the preferred option for olygometastatic disease, in the presence of resectable, small number of metastases (<3), especially for lung metastasis. Adjuvant RAI should follow surgical resection of metastasis in the presence of RAI avid disease (detected before surgery with whole-body RAI scan), and a dose of 150 mCi should be used. In case of unresectable disease, and many metastatic lesions, RAI is the preferred option if disease is iodine avid, and a total dose of 200 mCi should be used. External beam RT should be chosen to treat locoregional unresectable disease and/or symptomatic bone metastasis. Whole-brain RT is the mainstay of treatment in the presence of multiple brain metastases. Electrochemotherapy, a technique that combines chemotherapy with the electroporation of cancerous tissues, is often performed in the presence of cutaneous metastasis; thermoablation is often chosen in case of liver or lung metastasis not suitable for RT 34,35.

The presence of biochemical recurrence alone, for example, elevated serum Tg for PTC, FTC, and Hurthle cells carcinoma, or elevated serum carcinoembryonic antigen and/or calcitonin for MTC, does not represent an indication for therapy. Close surveillance until appearance of macroscopic disease is indicated in those cases.

Systemic therapy for thyroid carcinoma represents an option only in the presence of recurrent/metastatic disease, not iodine avid, not more suitable for palliative surgery, RT, electrochemotherapy, or thermoablation. Chemotherapy is usually not effective in thyroid carcinomas, with drugs showing very poor response rate in several clinical trials (overall response rate of 10–15%) 36,37. Small-molecule kinase inhibitors, such as lenvatinib, sorafenib, cabozantinib, and vandetanib, have completely replaced chemotherapy as the systemic approach in specific subgroups of patients. Sorafenib and lenvatinib have demonstrated a significant improvement in progression-free survival (the time elapsed by therapy start and the first progression of disease) in PTC and FTC. Instead, vandetanib and cabozantinib have demonstrated good results in patients affected by MTC.

Sorafenib is a BRAF inhibitor other than angiogenesis; lenvatinib and cabozantinib interfere with RTKs activated downstream effectors, blocking the MAPK pathway; vandetanib is able to block RET/PCR function, arresting the tumor angiogenesis. Even though they work with different mechanisms of action, all the above molecules interfere with the MAPK pathway, which, as we have shown before, is strongly disregulated in thyroid cancer (all histotypes) 38,39.

The major concern of using TKIs is toxicity, mainly consisting of diarrhea, cutaneous rash, hypertension, and, rarely, gastrointestinal bleeding. Clinicians should ponderate efficacy and side effects before using TKIs. Kinase inhibitor therapy is expected to cause side effects that may have a significant effect on quality of life.

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Thyroid carcinoma is a rare disease, representing 1% of all malignancies, in contrast to the high prevalence of benign thyroid nodules, particularly in women. Diagnosis of thyroid carcinoma is essentially made by FNA, which represents the cornerstone of the diagnostic workup. Thyroid carcinomas are very heterogeneous based on histology and genetic mutations. ATC is the rarest and most lethal histotype, whereas PTC carries the best prognosis. When feasible, surgery represents the mainstay of treatment, and it is often followed by adjuvant RAI and TSH suppression in patients considered at intermediate/high risk of recurrence. External beam RT is commonly used in ATCs because they are often not suitable for surgery. Recurrent/metastatic disease is primarily managed by surgery of resectable disease and RAI, when indicated. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Palliative external beam RT, other locoregional techniques such as thermoablation and electrochemotherapy, are available. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now Food and Drug Administration-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Figure 4 shows a flowchart illustrating the management of thyroid carcinoma.

Fig. 4

Fig. 4

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Antonio Giordano is supported by the Hollings Cancer Center’s K12 Paul Calebresi Clinical and Translational Oncology Training Program K12 CA157688.

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Conflicts of interest

There are no conflicts of interest.

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anaplastic; follicular; medullary; papillary; radioiodine therapy; targeted therapy; thyroid carcinoma; thyroid nodule

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