Thyroid cancer is the cancer affecting thyroid gland which is located in the neck near the oesophagus. It represents the most prevailing endocrine malignancy and it has growing tendency in the last decades in all the world. From the histological point of view thyroid gland basically consist of two types of cells, follicular cells and parafolicular cells. Both types of mentioned cells can be further classified giving rise to wide spectrum of thyroid tumours. The circumstances leading to development of thyroid cancers are not known yet.

Although the majority of them is derived from follicular cells. In thyroid cancer there is a dramatic difference in the incidence, aggressiveness, and death rate by gender, given that the thyroid cancer is 2-4 times more frequent in women than men. Actually it is the ninth most common malignancy found in women.

Cancer is usually described as differentiated or undifferentiated which is referring to the histological characteristic of given cancer. 

  • The cells forming differentiated cancerous structure have quite similar appearance to those cells from which they came from. Differentiated cancers tend to be less aggressive with better prognosis. Differentiated cancers of thyroid glands include papillary thyroid cancer (PTC; Pic. 1), follicular thyroid cancer (FTC; Pic. 2) and medullary thyroid cancer (MTC).
  • On the other hand, undifferentiated cancers or poorly differentiated cancers are formed by more or less undifferentiated cells of no resembling appearance to the cells which they came from. This type of cancers is usually more aggressive with poor prognosis. Undifferentiated cancers of thyroid gland are represented by anaplastic thyroid cancer (ATC). Other types of thyroid cancers are represented by thyroid lymphoma and squamous cell carcinoma.

The diagnosis of the type of thyroidal cancer is crucial for its successful treatment. There are several ways of diagnosing thyroid carcinoma. The diagnosis of thyroid cancer is most often made on the basis of a biopsy of a thyroid nodule or after the nodule removal by surgery. 

With the development of new techniques, less invasive and more precise methods have been developed to diagnose specific thyroidal tumours. In case of retrieval of tumorous tissue (biopsy) there is the fine-needle cytology (Pic. 3) and core needle cytology. The initial workup for suspected thyroid cancer often includes chemo-biological analysis. This analysis includes processes like complete blood count, serum analysis and thyroid function tests. The imagining techniques such as ultrasound also represent a useful tool to diagnose specific thyroidal cancers as well as computed tomography (CT), magnetic resonance imaging (MRI) and 18F-Flurodeoxygluoce positron emission tomography (FDG-PET). 

Nevertheless, most attention now days in the area of cancer diagnosis is put to so called molecular markers. As the many subtypes of thyroidal tumours can be characterized by different molecular markers, the analysis of such markers in combination with other diagnostic techniques seems to have a great potential. These molecular markers are specific chemical substances in the cell based on proteins and they are part of cell signalling pathways (signal molecules) that serve to the cell as way of its function modulation (growth) and communication with other. 

If a gene producing specific molecular marker is compromised (Pic. 4), it may cause detrimental effects to the cell just like in cancerous cell, which is characterized by continual growth. 

There are actually many signalling cellular molecules (RAS, BRAF, NTRK1, PTEN…) that can serve as molecular markers since their modification (and related gene damage) is characteristic for cancerous cells. Thanks to that fact, molecular markers can represent a very useful tool to exactly determinate the type of cancer and its aggressiveness. This is essential for choosing the right therapy and therefore it could improve the outcome of treatment. 

As thyroid cancers represent wide spectrum of cancers, many different approaches are possible depending also on the stage of development of cancer, its specific characteristics and other factors such as the successfulness of previous treatment. Obviously some thyroid cancer types are harder to treat not only given to increased aggressiveness and related high mortality rates but also given to the fact that they are relatively rare (anaplastic thyroidal cancer, squamous cell thyroidal cancer and others) and thus less investigated. As an example of the great differences of treatment of thyroid carcinomas squamous cell thyroid cancer and primary lymphoma thyroid cancer may serve well. While squamous thyroid cancer is a special case in the way that it cannot be treated by radiotherapy or chemotherapy, the primary thyroid lymphoma consisting of various histological subtypes, has no defined treatment therapy as the treatment therapy varies a lot depending on the subtype. In most cases of thyroid malignancies combined modality treatment is applied.

As already mentioned above, there are several types of thyroid cancer, each type with its specific characteristics:

Papillary thyroid cancer (PTC)

PTC develops as the aberration of follicular cells of thyroid gland. It is the most common type of thyroid cancer, representing approximately 80 % of all thyroid cancer cases. As all thyroid cancers, it occurs more frequently in women that are usually between 20 – 55 years of age. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. It belongs to the group of well differentiated cancers characterized by slow growth and lower chance of metastasis.

Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels. Moreover, papillary carcinomas have an indolent growth, and 40 percent of cases spread out of the capsule.

Follicular thyroid cancer (FTC)

Follicular thyroid carcinoma accounts for 10–20 % of differentiated thyroid carcinomas, and it is the second malignant tumour originating from the follicular cells of the thyroid. It is affecting mostly women over 50 years of age. FTC is more likely to metastasize to distant organs rather than to regional lymph nodes because of its tendency to invade blood vessels thus resulting in haematogenous dissemination. 

Medullary thyroid cancer (MTC) 

Medullary thyroid cancer (MTC) occurs in less than 1% of thyroid nodules and accounts for 5-10% of thyroid malignancies. It is a differentiated neuroendocrine carcinoma arising from parafollicular calcitonin-producing cells (C-cells) of the thyroid gland and is associated with elevated serum calcitonin levels. Among differentiated thyroid carcinomas, MTC is the most aggressive (after the anaplastic thyroid cancer it is the most aggressive thyroid malignancy with high morbidity and mortality), with survival rates of 40-50% at 10 years (American Thyroid Association). 

Anaplastic thyroid cancer (ATC)

ATC is known to be one of the most aggressive tumour types. Anaplastic thyroid carcinoma (ATC) is a rare and accounts for about 1%–2% of all thyroid cancer diagnoses. ATC comprises undifferentiated tumours that arise as such or by dedifferentiated progression from PTC or FTC. Most of the ATC tumours are inoperable at the time of diagnosis and prove to be fatal. The average survival rate is 5%–15% at 3 years. The mean survival time from diagnosis to death is 6 months, even with aggressive, multimodal therapy involving surgery, radiotherapy, and chemotherapy, probably due to synchronous lung metastases in 20%–50% of cases.

Thyroid lymphoma

Primary thyroid lymphoma is an uncommon malignancy that constitutes 2 % of all thyroid malignancies. Histologic subtypes include diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphomas, follicular lymphomas, and rarely Hodgkin lymphomas. The rarity of this disease precludes optimizing diagnostic and management modalities. Diagnostic tools — such as fine-needle cytology and axial imaging yield higher predictive values, so surgical management is rarely required. Primary thyroid lymphoma is more prevalent in women, with a male:female ratio of 1:1.3 to 1:7.6. It usually affects women of 65 – 75 years of age and has highest prevalence in white populations. Many epidemiologic studies of primary thyroid lymphoma have found an association with Hashimoto thyroiditis. 

Hashimoto thyroiditis is autoimmune destruction of thyroidal glands with symptoms of thyroidal enlargement or/and hypothyroidism. The detection of Hashimoto thyroiditis is actually associated with up to 80% of thyroid lymphomas. Hashimoto thyroiditis is the most important risk factor for development of thyroidal lymphoma. 

Squamous cell carcinoma (SCTC)

Squamous-cell thyroid carcinoma is rare malignant neoplasm of thyroid gland which shows tumour cells with distinct squamous differentiation (diversification of squamous cells characteristic for epidermis). The incidence of SCTC is less than 1% out of thyroid malignancies. The SCTC is biologically aggressive malignant neoplasm which is associated with rapid growth of neck mass followed by infiltration of thyroid-adjacent structures leading to difficulties in its management. Primary squamous cell carcinoma (PSCC) of the thyroid represents less than 1% of all primary thyroid malignancies and only a few cases have been reported in the world literature. It is chemo- and radio-resistant thyroid cancer. The median survival after diagnosing case as a PSCC of thyroid is less than six months. Death is mainly due to persistent progression and local invasion (often due to airway infiltration) by the tumour. 

Squamous epithelial cells are not found in normal thyroid, thus the origin of SCTC is not clear. However, it might be a derived from the embryonic remnants such as thyroglossal duct or branchial clefts. Primary STCT is usually diagnosed in both lobes of thyroid gland. 

Associated diseases 

  • breast cancer
  • Graves' disease (autoimmune disorder of thyroid gland)
  • Hashimoto thyroiditis (Hashimoto thyroiditis is autoimmune destruction of thyroidal glands)
  • Thyroid nodules
  • Cowden’s disease (inherited cancerous disorder of skin)
  • Carney’s complex (cancerous disease of connective tissue affecting heart and skin)
  • Familial polyposis of colon (genetically predisposed disease of malignant polyp formation within the colon) 

Complications 

Metastasis of thyroid cancers represent the main complication. In case of differentiated types of thyroid cancers, it is less probable to happen, as they are less aggressive. Due to alteration of hormonal balance within the bade, fertility potential is usually also reduced.

Risk factors 

Known risk factors include family history with thyroidal cancers and other genetically predisposed cancerous diseases such as Cowden’s disease and Carney’s complex and familial polyposis of colon.
Exposure to radiation is another risk factor especially in case of children. Other risk factors are not known yet as the cause of thyroid cancer development remains unrevealed.

Thyroid cancers are connected with modulation of thyroid gland function (especially in case of differentiated thyroid cancers) and may lead to hyper/hypothyroidism. This means that the secretion of thyroid hormones is increased or decreased, respectively. As thyroid hormones, with primary function of metabolic regulation which can also affect hormonal regulation of reproduction system. In other words, thyroid hormones basically affect function of whole body through hormonal cascade so the imbalance in their production may be also connected with some fertility related problems.

In women thyroid cancers may be connected with impaired function of the ovaries and disturbances of the menstrual cycle. Abnormal function of thyroid gland also deteriorates pregnancy outcomes and increase chances of miscarriage. Corrupted function of thyroid gland in man may affect sperm production and sperm quality. Cancerous diseases of thyroid gland are also connected with psychological changes and may induce even depressions. There is well documented correlation between state of mind and fertility. Under stressful conditions, the quality of produced gametes (sperm cells/oocytes) is reduced. Obviously in both gender it may be connected with lower conception rates.

Since the causes of development of thyroidal cancers are not yet clarified, the prevention of thyroid cancer is almost impossible. 

On the other hand, if there is and incidence of thyroid cancer in family history it is reasonable to seek out a genetic specialist who can analyse the genetic predisposition for development of thyroid cancer. If positive result after genetic analysis is obtained, the surgical removal of thyroid gland should be considered. 

Although there is a quiet extensive discussion about the relation of thyroid cancers and obesity (which often related with functional complications of thyroid gland), one never makes a mistake by practicing exercise and active life style. In combination with healthy alimentation including sufficient amounts of iodine, it may help prevent the development of the cancer (as the incidence tends to be higher in iodine deficient areas).

  • nodule in the thyroid area of the neck 
  • hypothyroidism
  • hyperthyroidism
  • dysphonia (hoarseness)
  • dysphagia (difficulty in swallowing)
  • dyspnoea (shotness of breath)
  • facial and hand swelling 
  • clavicular and cervical adenopathy 
  • night sweating
  • fever >38°C
  • loss of weight (10 % of weight in six months or less)
  • itching
  • headache

There’s no self-therapy or any other alternative therapy that would be verified valid and useful by scientific examination.

Depending on the type of thyroid cancer being diagnosed different treatment methods are applied. As in case of any other cancerous disease, a team of collaborating medical experts is required to increase the chances of success and decrease negative impact of the treatment on the rest of the body.    

Pharmacotherapy 

To stabilise the metabolism of body and to prevent the growth of cancerous cells that remain after cancer therapy, thyroid hormone may be used. The main hormones produced by thyroid gland are thyroxin and triiodothyronine (T4 and T3) and they are also used in hormonal therapy. 

Surgical therapy 

Thyroidectomy

Thyroidectomy and dissection of central neck compartment is initial step in treatment of thyroid cancer in majority of cases.

Lobectomy

If differentiated thyroid cancer is diagnosed and is located in a small area, the lobectomy may be considered. It is the partial removal of thyroid gland or better said the removal of just one lobe if thyroid gland.

Other therapy

Thyroid-preserving operation may be applied in cases, when thyroid cancer exhibits low biological aggressiveness (e.g. well-differentiated cancer with no evidence of lymph node metastases) in patients younger than 45 years. 

Chemotherapy

Chemotherapy is used after surgery to treat any residual disease, if appropriate. In some cases, there may be reason to perform chemotherapy first, followed by surgery. This is called "neoadjuvant chemotherapy", and is common when a tumor cannot be completely removed or optimally debulked via surgery. Chemoterapeutics are substances with anti-cancerous effect such as cyclophosphamide, vincristine, prednisone, adriamycin and bleomycin.

Radiation therapy 

Radioactive Iodine-131 is used in patients with papillary or follicular thyroid cancer for ablation of residual thyroid tissue after surgery and for the treatment of thyroid cancer. External irradiation may be used when the cancer is unresectable (cannot be removed by surgical intercession), when it recurs after resection, or to relieve pain from bone metastasis.

Immunotherapy

An alternative approach for the treatment of cancers may represent the use of cell vaccines aiming to activate the immune system. 


As in case of any other cancers, thyroid cancers are also connected with (lower or higher) chances of metastasis plus the cancer treatment is most often detrimental for the function of gonads making the conception impossible. 

Therefore, a cryopreservation of generative cells (sperm cells and oocytes) should be considered to preserve the fertility. Cryopreservation involves the storage of reproductive cells (oocytes and sperm cells) within carbon dioxide ensuring extremely low temperatures to prevent cell ageing. 

After the treatment of ovarian cancer, genetic testing (PGS) is recommended. Preimplantation genetic screening allows studying the DNA of eggs/sperm cells or embryos to select those that do not carry certain damaging characteristics. In case, that generative cells are genetically compromised and cannot be used, the use of donated sperm/oocyte can be contemplated. 

The usage of donor sperm/oocytes involve the IVF (in vitro fertilization) or ICSI (intracytoplasmic sperm injection) procedure. IVF is common method used to fertilize an oocyte under laboratory conditions and usually requires up to 100 000 sperm cells. On the other hand, ICSI is an advanced method which requires usage of only one sperm cell to fertilize and oocyte. 

An embryo gained during IVF/ICSI cycle is later implemented into the uterus. To prepare the uterus for implementation, hormonal therapy involving administration of sex hormones (oestrogen) is necessary, especially in case that the function of female sex glands (ovaries) has been compromised.

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Sources

Thyroid cancer ―sourced from Wikipedia licensed under CC BY-SA 3.0
Graves' disease ―sourced from Wikipedia licensed under CC BY-SA 3.0
Linfoma tiroideo, un dilema diagnóstico ―by Finozzi et al licensed under CC BY-NC 4.0
Molecular Markers in Thyroid Cancer ―by Andrade et al. licensed under CC BY-NC 4.0
Association between breast and thyroid cancers ―by Lehrer et al. licensed under CC BY-NC 3.0
Papillary thyroid cancer ―sourced from Wikipedia licensed under CC BY-SA 3.0
Linfoma primario tiroideo y tiroiditis de Hashimoto ―by Crespo Valadés licensed under CC BY-NC 3.0
Thyroid lymphoma ―sourced from Wikipedia licensed under CC BY-SA 3.0
Squamous cell carcinoma ―sourced from Wikipedia licensed under CC BY-SA 3.0
Squamous-cell thyroid carcinoma ―sourced from Wikipedia licensed under CC BY-SA 3.0
Thyroid nodule ―sourced from Wikipedia licensed under CC BY-SA 3.0
Follicular thyroid cancer ―sourced from Wikipedia licensed under CC BY-SA 3.0
Cowden syndrome ―sourced from Wikipedia licensed under CC BY-SA 3.0
Carney complex ―sourced from Wikipedia licensed under CC BY-SA 3.0
Thyroid papillary carcinoma histopatholgy ―sourced from Wikipedia licensed under CC BY-SA 3.0
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