Thyroid cancer
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Thyroid cancer refers to any of four kinds of tumors of the thyroid gland: papillary, follicular, medullary and anaplastic. Papillary and follicular tumors are the most common and usually are benign: they grow slowly, may recur, but are generally not fatal in patients under 45 years of age. Medullary and anaplastic tumors are malignant. Medullary tumors have a good prognosis if restricted to the thyroid gland and a poorer prognosis if metastasis occurs. Anaplastic tumors are fast-growing and respond poorly to therapy. Thyroid nodule are diagnosed by ultrasound guided fine needle aspiration (USG/FNA) or frequently by thyroidectomy (surgical removal and subsequent histological examination). As the thyroid cancer can uptake iodine, radioactive iodine is a commonly used modality in thyroid carcinomas. However, it is followed by TSH suppression by thyroxine therapy.
Symptoms
Most often the first symptom of thyroid cancer is a nodule in the thyroid region of the neck, but only few (up to 5%) of these nodules are malignant. Sometimes the first sign is an enlarged lymph node. Other symptoms that can be present are pain and changes in voice. Thyroid cancer is usually found in a euthyroid patient but hyperthyroidism may be a symptom of a large or metastatic well differentiated tumor.
Diagnosis
After a nodule is found during a physical examination, a referral to an endocrinologist, or a thyroidologist is the best approach. Most commonly an ultrasound is performed to confirm the presence of a nodule, and assess the status of the whole gland. Measurement of thyroid stimulating hormone and anti-thyroid antibodies will help decide if there is a functional thyroid disease such as Hashimoto's thyroiditis present, a known cause of a benign nodular goiter. The most cost-effective, sensitive and accurate test to determine whether the nodule is malignant is the fine needle biopsy (FNB). FNB or ultrasound-guided FNA usually yields sufficient thyroid cells to assess the risk of malignancy, although in some cases, the suspected nodule may need to be removed surgically for pathological examination. Rarely, a biopsy is done using a large cutting needle, so that the a piece of nodule capsule can be obtained. Blood or imaging tests may be done prior to or in lieu of a biopsy. The possibility of a nodule which secretes thyroid hormone (which is less likely to be cancer) or hypothyroidism is investigated by measuring thyroid stimulating hormone (TSH), and the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Tests for serum thyroid autoantibodies are sometimes done as these may indicate autoimmune thyroid disease (which can mimic nodular disease). The blood assays may be accompanied by ultrasound imaging of the nodule to determine the position, size and texture, and to assess whether the nodule may be cystic (fluid filled). Also suspicious findings in a nodule are hypoechoic, irregular borders, microcalcifications, or very high levels of blood flow within the nodule. Less suspicious findings in benign nodules include, hyperechoic, comet tail artifacts from colloid, no blood flow in the nodule and a halo, or smooth border. Some clinicians will also request technetium (Tc) or radioactive iodine (I) imaging of the thyroid. An I123 scan showing a hot nodule, accompanied by a lower than normal TSH, is strong evidence that the nodule is not cancerous.
Classification
Thyroid cancers can be classified according to their pathological characteristics. The following variants can be distinguished (distribution over various subtypes may show regional variation):
- Papillary thyroid cancer (75%, incl. mixed papillary/follicular)
- Follicular thyroid cancer (16%)
- Medullary thyroid cancer (5-7%)
- Anaplastic thyroid cancer (3%)
- Lymphoma (1%)
- Squamous cell carcinoma, sarcoma (0.5 - 2%)
Papillary thyroid cancer
This is the most common type of thyroid cancer. It occurs more frequently in women and presents in the 30-40 year age group. 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 (in this group, the cancer tends to be multifocal with early lymphatic spread, and portends a relatively poor prognosis). Thyroglobulin can be used as a tumor marker for well-differentiated papillary thyroid cancer.
Pathology
- Characteristic Orphan Annie eye nuclear inclusions and psammoma bodies on light microscopy
- Lymphatic spread is more common than hematogenous spread
- Multifocality is common
- The so-called Lateral Aberrant Thyroid is actually a lymph node metastasis from papillary thyroid carcinoma.
Prognostic indicators
There are at minimum 13 known scoring systems for prognosis; some of these outright conflicting. Among the more often used are:
- AGES - Age, Grade, Extent of disease, Size
- AMES - Age, Metastasis, Extent of disease, Size
- MACIS - Metastasis, Age at presentation, Completeness of surgical resection, Invasion (extrathyroidal), Size (this is a modification of the AGES system)
- TNM - Tumor, node, metastasis. Remarkable about the TNM grading for (differentiated) thyroid carcinoma is that the scoring is different according to age.
Surgical treatment
- Minimal disease (diameter up to 1.0 centimeters) - hemithyroidectomy (or unilateral lobectomy) and isthmectomy may be sufficient. There is some discussion whether this is still preferable over total thyroidectomy for this group of patients.
- Gross disease (diameter over 1.0 centimeters) - total thyroidectomy, and central compartment lymph node removal is the therapy of choice. Additional lateral neck nodes can be removed at the same time if an ultrasound guided FNA and thyrobulin TG cancer washing was positive on the pre-operative neck node ultrasound evaluation.
Arguments for total thyroidectomy are:
- Reduced risk of recurrence, if central compartment nodes are removed at the original surgery.
- Papillary carcinoma is a multifocal disease (hemithyroidectomy may leave disease in the other lobe)
- Ease of monitoring with thyroglobulin (sensitivity for picking up recurrence is increased in presence of total thyroidectomy, and ablation of remnant normal thyroid by low dose radioiodine 131 after following a low iodine diet (LID).
- Ease of detection of metastatic disease by thyroid and neck node ultrasound.
Thyroid total body scans are less reliable at finding recurrence than TG and ultrasound.
Follicular thyroid cancer
This occurs more commonly in women of over 50 years old. Thyroglobulin (Tg) can be used as a tumor marker for well-differentiated follicular thyroid cancer.
It is not possible to distinguish between follicular adenoma and carcinoma on cytological grounds. If fine needle aspiration cytology (FNAC) suggests follicular neoplasm, thyroid lobectomy should be performed to establish the histopathological diagnosis. Follicular carcinoma tends to metastasize to lung and bone via the bloodstream, while papillary thyroid carcinoma commonly metastasizes to cervical lymph nodes.
Surgical Treatment
- Unilateral hemithyroidectomy (removal of one entire lobe of the thyroid) is uncommon due to the aggressive nature of this form of thyroid cancer.
- Total thyroidectomy is almost automatic with this diagnosis. This is invariably followed by radioiodine treatment at levels from 50 to 200 millicuries following two weeks of a low iodine diet (LID). Occasionally treatment must be repeated if annual scans indicate remaining cancerous tissue. Some physicians favor administering the maximum safe dose (calculated based on a number of factors), while others favor administering smaller doses, which may still be effective in ablating all thyroid tissue. I-131 is used for ablation of the thyroid tissue.
- Some studies have shown that thyroglobulin (Tg) testing combined with neck ultrasound is more productive in finding disease recurrence than full- or whole-body scans (WBS) using radioactive iodine. However, current protocol (in the USA) suggests a small number of clean annual WBS are required before relying on Tg testing plus neck ultrasound. When needed, whole body scans consist of withdrawal from thyroxine medication and/or injection of recombinant human Thyroid Stimulating Hormone (TSH). In both cases, a low iodine diet regimen must also be followed to optimize the takeup of the radioactive iodine dose. Low dose radioiodine of a few millicuries is administered. Full body nuclear medicine scan follows using a gamma camera. Scan doses of radioactive iodine may be I131 or I123.
- Recombinant human TSH, commercial name Thyrogen, is produced in cell culture from genetically engineered hamster cells.
Hurthle cell variant
Hurthle cell thyroid cancer is a variant of follicular cell carcinoma. Hurthle cell forms are more likely than follicular carcinomas to be bilateral and multifocal and to metastasize to lymph nodes. Like follicular carcinoma, unilateral hemithyroidectomy is performed for non-invasive disease, and total thyroidectomy for invasive disease
Medullary thyroid cancer (MTC)
This form of thyroid carcinoma originates from the parafollicular cells (C cells), which produce the hormone calcitonin. While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in blood. A second marker, carcinoembryonic antigen (CEA), also produced by medullary thyroid carcinoma, is released into the blood and it is useful as a serum or blood tumor marker. In general measurement of serum CEA is less sensitive than serum calcitonin for detecting the presence of a tumor, but has less minute to minute variability and is therefore useful as an indicator of tumor mass.
The prognosis of MTC is poorer than that of follicular and papillary thyroid cancer when it has metastasized (spread) beyond the thyroid gland. Approximately 25% the cancer develops in families. When MTC occurs by itself it is termed familial MTC; when it coexists with tumors of the parathyroid gland and medullary component of the adrenal glands (pheochromocytoma) it is called multiple endocrine neoplasia type 2 (MEN2).
The genetics of medullary thyroid cancer
Mutations (DNA changes) in the RET proto-oncogene, located on chromosome 10, lead to the expression of a mutated receptor tyrosine kinase protein, termed RET. RET is involved in the regulation of cell growth and development and its mutation is responsible for nearly all cases of hereditary or familial medullary thyroid carcinoma. Its mutation may also be responsible for the development of hyperparathyroidism and pheochromocytoma. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50/50 probability of inheriting the mutant RET proto-oncogene from the affected parent. DNA analysis makes it possible to identify children who carry the mutant gene; surgical removal of the thyroid in children who carry the mutant gene is curative if the entire thyroid gland is removed at an early age, before there is spread of the tumor. The parathyroid tumors and pheochromocytomas are removed when they cause clinical symptomatology. Hereditary medullary thyroid carcinoma or multiple endocrine neoplasia (MEN2) accounts for approximately 25% of all medullary thyroid carcinomas.
Seventy-five percent of medullary thyroid carcinoma occurs in individuals without an identifiable family history and is assigned the term "sporadic". Individuals who develop sporadic medullary thyroid carcinoma tend to be older and have more extensive disease at the time of initial presentation than those with a family history (screening is likely to be initiated at an early age in the hereditary form). Approximately 25% of sporadic medullary thyroid carcinomas have a somatic mutation (one that occurs within a single "parafollicular" cell) of the RET proto-oncogene. This mutation is presumed to be the initiating event, although there could be other as yet unidentified causes.
Clinical features of medullary thyroid carcinoma
The major clinical symptom of medullary thyroid carcinoma is diarrhea; occasionally a patient will have flushing episodes. Both occur particularly with liver metastasis. Occasionally, diarrhea or flushing will be the initial presenting complaint. The flushing that occurs in medullary thyroid carcinoma is indistinguishable from that associated with carcinoid syndrome. The presumed cause of flushing and diarrhea is the excessive production of calcitonin gene products (calcitonin or calcitonin gene-related peptide) and differs from the causation of flushing and diarrhea in carcinoid syndrome. Sites of spread of medullary thyroid carcinoma include local lymph nodes in the neck, lymph nodes in the central portion of the chest (mediastinum), liver, lung, and bone. Spread to other sites such as skin or brain occurs but is uncommon.
Adjuvant therapy for medullary thyroid cancer
Unlike differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease. External beam radiotherapy should be considered for patients at high risk of regional recurrence, even after optimum surgical treatment. Brierley et al., conducted a retrospective study of the treatment given to patients with microscopic residual disease, extraglandular invasion, or lymph-node metastases and found the locoregional relapse-free rate at 10 years was 86%, compared with 52% for those patients who did not receive adjuvant therapy. Typically, 40 Gy is given in 20 fractions to the cervical, supraclavicular, and upper mediastinal lymph nodes for 4 weeks, with subsequent booster doses of 10 Gy in five fractions to the thyroid bed, especially in the setting of gross residual disease.
After a long period during which surgery and radiation therapy formed the major treatments for medullary thyroid carcinoma, clinical trials of several new tyrosine kinase inhibitors [3] are now being studied. Preliminary results show clear evidence of response of a small percentage of patients, providing hope for future advances.
Medullary Thyroid Carcinoma Prognostic Indicators
The prognostic value of measuring calcitonin and carcinoembryonic antigen (CEA) concentrations in the blood has been recently studied in a retrospective study of 65 MTC patients; see Barbet, et al. The post-surgical times ranged from 2.9 years to 29.5 years; all 65 patients continued to have abnormal calcitonin levels after total thyroidectomy and bilateral lymph node dissection. The prognosis of surviving MTC appears to be correlated with the rate at which a patient's postoperative calcitonin concentration doubles, rather than the pre- or postoperative absolute calcitonin level.
The result of the 65 patient study can be summarized with respect to the calcitonin doubling time (CDT):
CDT < 6 months: 3 patients out of 12 (25%) survived 5 years. 1 patient out of 12 (8%) survived 10 years. All died within 6 months to 13.3 years.
CDT between 6 months and 2 years: 11 patients out of 12 (92%) survived 5 years. 3 patients out of 8 (37%) survived 10 years. 4 patients out of 12 (25%) survived to the end of the study.
CDT > 2 years: 41 patients out of 41 (100%) were alive at the end of the study. These included 1 patient whose calcitonin was stable, and 11 patients who had decreasing calcitonin levels.
The 65 patients had a median age of 51 (range was 6 to 75), with 24 age 45 years or younger and 41 older than 45 years. The gender representation was 31 males and 34 females. All patients shared the following characteristics: 1) had total thyroidectomy and lymph node dissection; 2) had non-zero calcitonin levels after surgery; 3) had at least 4 serum calcitonin measurements after surgery; 4) had a status that could be confirmed at the conclusion of the study.
The same study noted that calcitonin doubling time is a statistically better predictor of MTC survival, compared with CEA.
Anaplastic thyroid cancer
This form of thyroid cancer has a very poor prognosis (near 100% mortality) due to its aggressive behavior and resistance to cancer treatments. It rapidly invades surrounding tissues (such as the trachea). The presence of regional lymphadenopathy in older patients in whom FNA reveals characteristic vesicular appearance of the nuclei would support a diagnosis of anaplastic carcinoma.
Treatment
Unlike its differentiated counterparts, anaplastic thyroid cancer is highly unlikely to be curable either by surgery or by any other treatment modality, and is in fact usually unresectable due to its high propensity for invading surrounding tissues. Palliative treatment consists of radiation therapy usually combined with chemotherapy. However, with today's technology, new drugs, such as Bortezomib and TNF-Related Apoptosis Induced Ligand (TRAIL), are being introduced and trialed in clinical labs. Recent studies in Italy, have shown positive results against ATC, but more tests, outside the lab, are needed to confirm this, before it can be used in Chemotherapy. There has been some case studies where patients with aggressive Thyroid Cancer have survived outside the mean expected survival time. But the best treatment recommended at this stage is early detection and complete surgery, followed by Chemotherapy alongside Radiotherapy, for any chance of survival of ATC.
Post-operative radiotherapy for differentiated thyroid carcinoma: when and how much
The role of external beam radiotherapy (EBRT) in thyroid cancer remains controversial and there is no level I evidence to recommend it. No published randomised controlled trials have examined the addition of EBRT to standard treatment, namely surgery, radioactive iodine and medical suppression of thyroid stimulating hormones.
Imbalances in age, sex, completeness of surgical excision, histological type and stage, between patients receiving and not receiving EBRT, confound retrospective studies. Variability also exists between treatment and non-treatment groups in the use of radio-iodine and post-treatment thyroid stimulating hormone (TSH) suppression and treatment techniques between and within retrospective studies.
Farahati et al. and Philips et al. have reported statistically significant advantages for post operative EBRT, however, in both studies many confounding factors have been reported. For example, patients receiving EBRT were more likely to have node-positive disease, extracapsular extension and incomplete macroscopic excision. The differences in patient groups among these studies, and the difficulties with confounding factors, make evidence-based recommendations for the use of EBRT difficult to formulate. Tsang et al. have suggested a role for EBRT in patients with papillary cancer, with microscopic residual disease based on sub-group analysis showing a statistically significant advantage in terms of cause-specific survival (100% vs 95%; P=0.038) and local recurrence (93% vs 78%; P=0.01). Farahati et al. recommend the use of EBRT in node-positive patients over 40 years of age with papillary histology on the basis of an increase in time to local or distant failure (P=0.0009). Other indications for EBRT include high-grade tumours that do not concentrate iodine and tumours with gross local invasion where there is a high suspicion of microscopic or macroscopic residual disease.
The use of EBRT is controversial for those patients with microscopic residual disease. All reports on the use of EBRT have been retrospective, with varying criteria for patient selection, resulting in contradictory conclusions. Several studies have described either no or deleterious effects for EBRT, but many others have described benefit. In a study from Toronto, Brierley et al. found superior local control and improved survival in patients who received EBRT for microscopic residual disease (10-year local relapse-free rate 93% compared with 83% for patients not receiving EBRT, P = 0.01; and cause-specific survival 99% compared with 93%; P = 0.04). “Total thyroidectomy with adjuvant 131I, followed by TSH suppression is considered standard therapy for differentiated thyroid carcinoma”. In the absence of randomised data, there is credible evidence from retrospective studies (Level II-III) to recommend EBRT in addition to standard therapy in high-risk patients.
The apparent difference in outcomes related to the dose of radiotherapy is subject to the confounding factors in all retrospective studies of EBRT as outlined above. However, there are few published data that define the dose to be used. In one retrospective study, 114 patients with macroscopically resected, well-differentiated thyroid cancer were treated with EBRT and an ‘adequate’ total dose was defined as >45 Gy. Patients receiving an ‘adequate’ dose had a significantly improved local regional relapse-free survival (P<0.001). However, only three of the 114 patients in this study also received radio-iodine, and therefore the role of EBRT in addition to standard management was not examined. A total dose of 50–60 Gy was used in the two studies, which showed a reduction in local failure where EBRT was used in addition to radio-iodine (Farahatti et al., and Phillip et al.). Others have treated patients with gross residual disease with 50 Gy in 20 fractions or its equivalent and 40 Gy in 15 fractions or its equivalent in the presence of microscopic residual disease. If the decision is made to treat a large volume, including the cervical nodes for instance, or if there is extracapsular extension and local invasion of cervical nodes, fractionation is changed to 2 Gy fractions. Currently, recommended doses are 50 to 60 Gy in 25 to 30 fractions over 5 to 6 weeks.
To treat the thyroid bed, a clinical target volume from the hyoid to suprasternal notch is determined. A simple technique is to use two antero-lateral oblique wedged fields, or direct electron beams. When using oblique fields the posterior border is placed to exclude the spinal cord. If it is determined that the clinical target volume should include the cervical and superior mediastinal lymph nodes, as well as the thyroid bed, a two-phase technique is commonly used. The initial volume (phase I) includes the regional lymph nodes from the mastoid tip to the carina, including the thyroid bed. The phase I volume may consist of parallel opposing antero-posterior/postero-anterior fields to 40–46 Gy. The phase II volume should include the tissues considered at highest risk of relapse, aiming to boost the high-risk area to a total dose of 14 Gy (cumulative total dose of 60 Gy). For the boost to the thyroid bed alone, several techniques can used, such as, a direct anterior electron beam, antero-lateral oblique wedge fields, or a lateral pair of angled-down oblique fields, achieved with a couch rotation of 10–20 degrees, aiming inferiorly to avoid the shoulders, off the spinal cord. Since the thyroid bed target volume is wrapped around many critical structures in the neck and it is often necessary to include regional lymph nodes, treatment planning of this difficult volume is ideal for conformal radiotherapy, or intensity-modulated radiation therapy. A conformal plan may be used either to treat the thyroid bed alone or to include the cervical nodes.
Recommended indications for the use of EBRT are:
- High Grade tumors that do not concentrate radio-iodine.
- Recommendations for EBRT after 131I therapy include high-risk patients defined as; older (>45 years) with potential microscopic residual disease, after resection of gross extrathyroid extension (i.e. UICC 6th edition category T4a or T4b but not T3), or multiple lymph-node involvement.
- Bulky tumors with superior mediastinal / retro-sternal extension.
- Gross evidence of local invasion at surgery and presumed to have significant macro or microscopic residual disease, particularly if there is residual tumour that fails to concentrate 131I and is apparent only by raised thyroglobulin.
- For locally advanced tumors which are inoperable for a variety of lesions it can be used for palliation along with TSH suppression.
- For recurrent disease in the neck which is not amenable to radio-iodine therapy or further surgery.
- For palliation of recurrent disease or metastatic disease in bone, cerebrum, spine and other areas.
Adjuvant therapy for anaplastic thyroid cancer
Treatment of anaplastic-type carcinoma is generally palliative in its intent for a disease that is rarely cured and almost always fatal. The median survival from diagnosis ranges from 3 to 7 months, with worse prognosis associated with large tumours, distant metastases, acute obstructive symptoms, and leucocytosis. Death is attributable to upper airway obstruction and suffocation in half of patients, and to a combination of complications of local and distant disease, or therapy, or both in the remainder. In the absence of extracervical or unresectable disease, surgical excision should be followed by adjuvant radiotherapy. In the 18–24% of patients whose tumour seems both confined to the neck and grossly resectable, complete surgical resection followed by adjuvant radiotherapy and chemotherapy could yield a 75–80% survival at 2 years.
There are a number of clinical trials for anaplastic thyroid carcinoma[4] underway or being planned.
References
- Bennedbæk F.N.; Perrild H.; Hegedüs L. (1999). "Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey". Clinical Endocrinology. 50 (3): 357–363.
- Carlo Ravetto, Luigia Colombo, Massimo E. Dottorini (2000). "Usefulness of fine-needle aspiration in the diagnosis of thyroid carcinoma". Cancer Cytopathology. 90 (6): 357–363.
- Jacques Barbet, Loïc Campion, Françoise Kraeber-Bodéré, Jean-François Chatal, and the GTE Study Group (2005). "Prognostic Impact of Serum Calcitonin and Carcinoembryonic Antigen Doubling-Times in Patients with Medullary Thyroid Carcinoma". The Journal of Clinical Endocrinology & Metabolism. 90 (11): 6077–6084.
See also
- Chernobyl disaster (radioactive contamination is a cause of thyroid cancer)
External links
- Template:Dmoz
- Thyroid Cancer Clinical Trials Page of the American Thyroid Association
- Nuclear Medicine Information =– Thyroid Diseases
- Thyroid Cancer- National Cancer Institute
- [5] - Thyroid Cancer Survivors' Association
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