In up to 3-7% of adults, a thyroid nodule can be detected on physical examination, but the vast majority of them are benign and posess no harm for the individual [6]. In absence of other accompanying symptoms and no associated risks (family history or prior neck irradiation), thyroid cancer is highly unlikely, but an asymptomatic course may be frequently observed in initial stages. In fact, papillary carcinomas often present as an asymptomatic, painless mass in the neck, due to the fact that it is a nonfunctional tumor [4]. Findings such as cervical lymphadenopathy, sudden onset of pain in the neck, unexplained voice changes or hoarseness and a rapidly growing mass are potential signs of malignant disease, in which case a detailed workup is mandatory [6].

• Cervical Lymphadenopathy

  However, symptoms such as cervical lymphadenopathy, hoarseness, voice changes, and sudden onset of pain in the neck may be present, particularly in advanced stages of the disease. [symptoma.com]

  Most, but not all, stain with thyroglobulin or thyroid transcription factor 1; those that do not represent particular diagnostic challenges. 1 3 We describe a 60-year-old man who presented with bilateral cervical lymphadenopathy and an enlarged thyroid [nejm.org]

  Palpable cervical lymphadenopathy. Insidious or persistent pain lasting for several weeks. Investigations[2] TFTs should be performed for any patient with a thyroid nodule. [patient.info]

  lymphadenopathy. ( SR-M ) A) Completion thyroidectomy should be offered to those patients for whom a bilateral thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. [guidelinecentral.com]

  Since it metastasizes frequently, neck lymphadenopathy is usually the first manifestation. Most (70%) of the patients with palpable MTC have evidence of cervical node involvement at the time of surgery [106]. [intechopen.com]

• Thyroid Nodule

  As people age, they are more likely to develop a thyroid nodule. By the time we are 80 years of age, 90% of us will have at least one thyroid nodule. Fewer than 1% of all thyroid nodules are malignant (cancerous). [endocrineweb.com]

  Unlike papillary thyroid cancer, follicular thyroid cancer (FTC) is usually found as a solitary thyroid nodule. [chop.edu]

  nodules McGill Thyroid Nodule Score TIRADS Ultrasound (U) classification of thyroid nodules postoperative assessment after thyroid cancer surgery ultrasound-guided fine needle aspiration of the thyroid Ultrasound - neck and thyroid ultrasound (introduction [radiopaedia.org]

  Thyroid nodules Lumps or bumps in the thyroid gland are called thyroid nodules. Most thyroid nodules are benign, but about 2 or 3 in 20 are cancerous. Sometimes these nodules make too much thyroid hormone and cause hyperthyroidism. [cancer.org]

• Pain

  However, symptoms such as cervical lymphadenopathy, hoarseness, voice changes, and sudden onset of pain in the neck may be present, particularly in advanced stages of the disease. [symptoma.com]

  But as it grows, it can cause pain and swelling in your neck. Several types of thyroid cancer exist. Some grow very slowly and others can be very aggressive. Most cases of thyroid cancer can be cured with treatment. [mayoclinic.org]

  The below MRI study was obtained for a patient complaining of neck pain following a motor vehicle accident. [endocrineweb.com]

  Other symptoms include bone pain and fractures, pain from kidney stones, depression, and constipation. Larger parathyroid cancers may also be found as a nodule near the thyroid. [cancer.org]

  This may include clearing the airway via tracheostomy, placing a feeding tube, or giving pain medication. Palliative care is given in addition to treating the cancer and does not necessarily mean the cancer treatment will not be effective. [thyroid.org]

• Hoarseness

  However, symptoms such as cervical lymphadenopathy, hoarseness, voice changes, and sudden onset of pain in the neck may be present, particularly in advanced stages of the disease. [symptoma.com]

  Late symptoms Dysphagia Hoarseness (vocal cord paresis) Horner syndrome Possible obstruction of the superior vena cava Only 25% of thyroid carcinomas detected by ultrasound exhibit clinical signs or symptoms ! [amboss.com]

  When symptoms do occur, they may include: a painless lump in the neck or throat swollen glands in the neck a hoarse voice or cough that doesn’t go away difficulty breathing or swallowing These symptoms can be caused by other problems, so if you notice [healthdirect.gov.au]

  Primary lymphoma of the thyroid typically presents as a rapidly-growing thyroid mass and can cause symptoms of hoarseness, difficulty swallowing, and cough or shortness of breath. [ent.uci.edu]

  Rare but worrisome presentations include hoarseness due to vocal cord paralysis and obstruction of the airway or esophagus. DTC grows slowly, and distant metastases are rare at the time of presentation. [orpha.net]

• Cough

  When symptoms do occur, they may include: a painless lump in the neck or throat swollen glands in the neck a hoarse voice or cough that doesn’t go away difficulty breathing or swallowing These symptoms can be caused by other problems, so if you notice [healthdirect.gov.au]

  As thyroid cancer progresses, the following symptoms may occur: a lump in the throat a cough hoarseness pain in the throat and neck difficulty swallowing swollen lymph nodes in the neck Talk to your doctor if you have any of these symptoms. [healthline.com]

  Primary lymphoma of the thyroid typically presents as a rapidly-growing thyroid mass and can cause symptoms of hoarseness, difficulty swallowing, and cough or shortness of breath. [ent.uci.edu]

  Tracheal compression or invasion by thyroid cancer can result in hoarseness of voice, dyspnea or cough, especially with exertion or in the recumbent position, or hemoptysis. [endocrinologyadvisor.com]

• Dyspnea

  After only seven days of treatment, the dyspnea symptoms improved and the patient was able to sleep in a semi-supine position. The dyspnea completely disappeared one month later. [spandidos-publications.com]

  Case 4 This is a 51 year old African American female who presented to our ER with stridor, dyspnea, odynophagia, and dysphonia. [peertechz.com]

  Tracheal compression or invasion by thyroid cancer can result in hoarseness of voice, dyspnea or cough, especially with exertion or in the recumbent position, or hemoptysis. [endocrinologyadvisor.com]

  Initially, nearby lymph nodes are struck early.[9] The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.[9] In lymph nodes metastasis, a common symptom is lymphadenopathy Lung metastasis: cough, hemoptysis and dyspnea [en.wikipedia.org]

• Hemoptysis

  Without specific symptoms, such as bone pain or hemoptysis, additional imaging (e.g., bone scans and PET scans) are not necessary in the pre-operative evaluation of DTC. [endocrinologyadvisor.com]

  Pre-operative Factors Which May Be Associated With Laryngeal Nerve Dysfunction History Voice abnormality, dysphagia, airway symptoms, hemoptysis, pain, rapid progression, prior operation in neck or upper chest. [guidelinecentral.com]

  Case 2 This is a 55 year African American female who presented with complaints of intermittent hemoptysis for over a year. [peertechz.com]

  […] symptoms[edit] Initially, nearby lymph nodes are struck early.[9] The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.[9] In lymph nodes metastasis, a common symptom is lymphadenopathy Lung metastasis: cough, hemoptysis [en.wikipedia.org]

• Stridor

  Any patient with a thyroid lump and associated stridor should be referred for same day review by a secondary care specialist, as this may be due to recurrent laryngeal nerve involvement secondary to a thyroid carcinoma. [patient.info]

  Case 4 This is a 51 year old African American female who presented to our ER with stridor, dyspnea, odynophagia, and dysphonia. [peertechz.com]

• Dysphagia

  Late symptoms Dysphagia Hoarseness (vocal cord paresis) Horner syndrome Possible obstruction of the superior vena cava Only 25% of thyroid carcinomas detected by ultrasound exhibit clinical signs or symptoms ! [amboss.com]

  Our otolaryngology service was consulted for a 4 week history of dysphagia, dysphonia, dyspnea, and 2 palpable neck masses. Her past medical history was negative for radiation exposure. [peertechz.com]

  Initially, esophageal compression or invasion by thyroid cancer will cause dysphagia at the level of the lower neck to solids and pills, but not to liquids. [endocrinologyadvisor.com]

  Patients usually present with a rapidly growing mass in the neck, which may cause symptoms of obstruction such as dyspnoea and dysphagia. [patient.info]

• Neck Pain

  The below MRI study was obtained for a patient complaining of neck pain following a motor vehicle accident. [endocrineweb.com]

  In most of the cases, ATC usually presents with a rapidly enlarging neck mass and local symptoms such as neck pain, dysphagia, dyspnea, and hoarseness [97]. [intechopen.com]

Ultrasonography of the thyroid gland is a fast and effective initial method to differentiate and detect possible thyroid disease and nodular features such as hypoechogenicity, irregular borders, the presence of intranodular flow and absence of peripheral halo are suggestive of thyroid malignancy [7]. To confirm the diagnosis, however, fine-needle aspiration biopsy and subsequent histologic examination are necessary [7]. Biopsy should be performed in all patients in whom a nodule of > 1 cm is detected or in patients with nodules of < 1 cm with the previous history of head and neck radiation or family history of thyroid malignancy [7]. A characteristic feature on histology in the case of papillary form is the appearance of concentrically calcified structured called "psammoma bodies", while dispersed chromatin in the nucleus that is designated as ground glass or "Orphan Annie Eye" nuclei is also a characteristic feature [4] [5]. The main distinguishing characteristic of follicular carcinoma is the propensity to invade capsular tissue, while various degrees of differentiation may be seen [4]. In patients with suspected nodal metastatic spread, a thorough diagnostic workup should be performed, with a particular emphasis on the lungs and the skeletal system, the two most common sites of distant metastasis [9] [13]. A combination of ultrasonography and computed tomography (CT) or magnetic resonance imaging (MRI) should be used pre-operatively to assess local structures and tissues [6]. In terms of laboratory markers, serum levels of calcitonin may be useful to exclude the potential presence of medullary thyroid carcinoma [7].

Depending on the stage of the tumor, different therapeutic approaches exist. Prior to initiating therapy, it is essential to determine the exact stage of the tumor and determine potential involvement of local lymph nodes and other organs. In the majority of patients, however, total thyroidectomy is recommended, especially in the setting of tumor diameter of > 4 cm, multifocal disease, extra-thyroidal involvement or positive family history [6]. Partial or localized surgical procedures may be performed when tumors are very small [7], whereas dissection of lymph nodes is indicated in patients with more advanced stages (III or IV) [7]. Hypoparathyroidism and laryngeal nerve palsy are rare but important complications of surgery, occurring in < 2% [7]. In addition to surgical therapy, adjuvant administration of radioactive iodine (I 131), known as radioiodine ablation, is equally important in the long-term care of patients, with the idea of destroying any remnant thyroid tissue and residual tumor [6] [7]. To facilitate this procedure, the use of recombinant human TSH and levothyroxine is recommended [6]. In the setting of thyroid malignancy refractory to iodine therapy, the use of lenvatinib, a multitarget tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs) and platelet-derived growth factor alpha (PDGFR α), has substantially prolonged the disease-free period [14].

Factors that influence outcome are age (older patients have a much poorer prognosis), tumor size, histological subtype and presence of metastases, which has shown to be a major prognostic marker [1] [8]. Patients who possess several or all of these factors are classified into a high-risk group with a long-term survival rate of around 56%, whereas a 97% survival rate is seen in individuals with little or no harmful factors (low-risk group) [5]. In general, the TNM classification system proposes the following staging of papillary and follicular thyroid cancer [3] [6]:

• Stage I - In patients < 45 years, the absence of metastatic spread determines this stage regardless of nodal involvement or tumor size, whereas older patients are classified if the primary tumor is < 1 cm in diameter (T1), without nodal or metastatic spread (N0 and M0, respectively).
• Stage II - Metastatic spread is sufficient for patients < 45 years (M1), while tumor size of 1 - 4 cm or more (T2 and T3, respectively) without spread to proximal lymph nodes (N0) are hallmarks in older individuals.
• Stage III - Protrusion of the tumor through the thyroid capsule (T4) or extension of the tumor into regional lymph nodes (N1).
• Stage IV - Distant metastases (M1).

The risk of metastatic spread is highest for papillary carcinoma, but when looking at 5-year and 20-year survival rates are 94% and 87%, respectively, this subtype carries a good prognosis even if diagnosed in later stages of the disease [10] [11]. A somewhat lower expectancy was observed for follicular carcinoma (87% and 81% for 5 and 20-year survival rates) [10]. Studies have also shown that patients with thyroid cancer are at a higher risk for developing another malignancy, presumably due to exposure to radioactive isotopes [12].

The exact cause of differentiated thyroid malignancies remains unknown, but several genetic mutations have been identified up to now. Namely, abnormalities in the MAP kinase pathway have been confirmed in 30-50% of papillary thyroid cancers, whereas the PI-3K/AKT pathway is shown to be upregulated in follicular thyroid cancer in many patients [2] [4]. Various additional mutations within these pathways have also been determined, but their triggers, as well as their clear association with thyroid malignancy, is still undisclosed.

Thyroid cancer comprises about 1% of all malignant diseases, affecting about 3 per 100,000 individuals in Europe and the United States [2]. In the United Kingdom, annual incidence rates have shown that thyroid malignancies occur much more commonly in males (5.1 per 100 000) than in females (1.9 per 100 000) [6], suggesting that male gender is considered to be a risk factor. When looking into differentiated forms of thyroid malignancy, however, both follicular and papillary thyroid carcinoma have a significant predilection toward female gender, ranging from 2-4:1 in certain reports [4] [5]. Reduced dietary intake of iodine has shown to be strongly associated with follicular thyroid carcinoma [2], but previous exposure to radiation is considered to be the most important risk factor for both forms [5].

When it comes to papillary thyroid carcinoma, the pathogenesis starts with mutations that alter the MAP kinase intracellular signaling pathway [3]. Namely, point mutations of BRAF, RAS and RET genes involved in the signaling cascade lead to their overexpression and consequent upregulation of this pathway, eventually causing carcinogenic changes in thyroid cells [4]. In approximately 20-40% of cases, the fusion of RET and papillary thyroid carcinoma (PTC) protein on the epithelium occurs and is considered to be a key step in tumor proliferation [4]. On the other hand, dysregulation of the PI-3K/AKT signaling pathway is the principal mechanism of disease in follicular thyroid carcinoma. Specifically, gain-of-function mutation of RAS, PIK3CA, and inhibition of PTEN, a tumor suppressor gene, are most frequently encountered, whereas a translocation of PAX8 and peroxisome-proliferator-activated receptor gene (PPARG) has been described in almost 50% of cases [4]. These genes are critical for normal thyroid cell development and terminal differentiation of various thyroid subsets, respectively. Mutations in TSH receptors, p16 (tumor suppressor gene) and c-MYC have been described in the literature [3].

The focus of prevention should be turned to an early diagnosis and prompt evaluation of nodular masses for possible malignancy, primarily because of substantially higher survival rates in early stages, but also because current preventive strategies for papillary variant does not exist. Individuals with a positive family history for thyroid disease may be screened through occasional ultrasonography, as 5% of cases were attributed to familial forms [2]. Also, complete body irradiation and head & neck radiation in children should be avoided.

Although thyroid malignancy comprises only 1% of all cancers, it is considered to be the most common endocrine neoplasm encountered in clinical practice [1], affecting approximately 3 per 100,000 individuals in Europe and the United States [2]. Differentiated thyroid gland carcinoma is a term that encompasses two subtypes [2] [3]:

• Papillary thyroid carcinoma - Comprising between 70-80% of all thyroid malignancies, this tumor is most frequently seen in patients between 3rd and 5th decades and the pathogenesis presumably involves activation of the MAP kinase pathway, either by changes in RET or neurotrophic tyrosine kinase receptor 1 (NTRK1) [4]. Mutations in BRAF, RAS and several other genes involved in the MAP kinase cascade have also been discovered [4].
• Follicular thyroid carcinoma, on the other hand, comprises 5-15% of all thyroid cancers and is associated with inadequate dietary intake of iodine in certain geographical areas [4]. Older age is somewhat more characteristic for this subtype, as the majority of patients are in their 5th and 6th decades at the time of diagnosis. In these tumors, the phosphatidylinositol-3-kinase (PI-3K)/AKT pathway, usually playing an important role in signal transduction, is dysregulated through gain-of-function mutations, leading to permanent activation in the absence of a specific signal, thus predisposing to malignant alteration [4].

Both subtypes exhibit a significant predilection toward female gender, while the single most important risk factor is prior exposure to radiation, which was shown in many reports across the world [5]. Apart from the presence of a nodular mass in the neck region, the clinical course of differentiated thyroid gland carcinoma may be asymptomatic. However, symptoms such as cervical lymphadenopathy, hoarseness, voice changes, and sudden onset of pain in the neck may be present, particularly in advanced stages of the disease [6]. To make the diagnosis, it is necessary to perform an ultrasound of the neck, followed by fine-needle aspiration and confirmation of malignant etiology by histologic examination [6]. Treatment principles somewhat vary depending on the stage, but generally, involve surgery (either partial or total thyroidectomy), use of recombinant thyroid-stimulating hormone (rhTSH) and levothyroxine, but also the administration of radioactive iodine (I131) as adjuvant therapy [7]. Depending on the presence of factors that influence the prognosis (late diagnosis, large tumor size, metastatic spread), long-term survival rates range from 97% in the low-risk group to 56% in the high-risk group, showing that an early recognition of the disease is the key to achieving good patient outcomes [8]. Unfortunately, isolated reports suggest that almost 50% of cases already have skeletal metastases at initial diagnosis, with a markedly reduced 10-year survival under such circumstances (13%) [9], implying that more effort in general practice is needed to identify this condition in its initial stages.

Tumors of the thyroid gland represent approximately 1% of all malignant diseases in clinical practice and several forms are recognized. Differentiated thyroid gland carcinoma is a term that comprises two most common tumors of the thyroid gland - papillary and follicular thyroid carcinoma. Both tumors are thought to develop as a result of genetic mutations that interfere with normal signal transduction in cells of the thyroid gland, but the cause of these mutations remains to be discovered. Papillary thyroid cancer comprises almost 80% of all tumors of the thyroid gland and most commonly develops in individuals between 3rd and 5th decades, whereas follicular carcinoma is encountered in patients older than 40 years. Previous exposure to radiation is considered to be the most important risk factor for both tumors, whereas inadequate dietary intake of iodine has been associated with follicular thyroid carcinoma. Many patients initially present with an asymptomatic, painless mass in the neck, as this tumor has an indolent course and rarely give symptoms in the initial stages of the disease. Later on, enlargement of lymph nodes in the neck, voice changes, hoarseness (due to mechanical pressure of the tumor and the thyroid on the larynx) and pain associated with the mass may be reported, in which case immediate diagnostic measures should be taken. Initial examination with ultrasonography should be performed to make a presumptive diagnosis, whereas biopsy of the mass should be performed through a procedure called fine-needle aspiration. If suspicion of disseminated disease exists, imaging techniques such as computed tomography (CT scan) and magnetic resonance imaging (MRI) should be performed to determine the exact stage of the tumor, ranging from 1 (small tumor confined to the thyroid gland) to 4 (presence of metastatic disease). On the basis of tumor staging, different therapeutic principles may be implemented, but in most cases, either partial or total removal of the thyroid gland (thyroidectomy) is recommended. The use of radioactive iodine after surgery is considered to be vital in the treatment of thyroid malignancies, as this substance kills any residual thyroid and potentially remnant malignant tissue in the body, thus limiting the chances of recurrence. In a small percentage of patients, however, tumors can recur and cause significant harm, which is why drugs such as lenvatinib (inhibitor of various growth factors used by the tumor) and several other are becoming highly useful in practice. With early recognition of the disease, the prognosis is excellent, with 10-year survival rates of 94%, but if the diagnosis is made in advanced stages of the disease, survival rates fall significantly lower. Having in mind the fact that almost 3-7% of all adults in the general population have a detectable nodule in the thyroid gland, a high index of clinical suspicion may surely reduce the number of deaths from this condition.

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