Thyroid Cancer

WHAT IS THYROID CANCER?

The thyroid gland is at the base of the throat. It has two lobes, one on the right side and one on the left. The thyroid gland makes important hormones that help the body function normally. Thyroid cancer is a disease in which cancer (malignant) cells are found in the tissues of the thyroid gland.



Carcinoma of the thyroid gland is an uncommon cancer but is the most common malignancy of the endocrine system. Differentiated tumors (papillary or follicular) are highly treatable and usually curable. Poorly-differentiated tumors (medullary or anaplastic) are much less common, are aggressive, metastasize early, and have a much poorer prognosis. Thyroid cancer affects women more often than men, and usually occurs in people between the ages of 25 and 65 years. The incidence of this malignancy has been increasing over the last decade. Thyroid cancer commonly presents as a cold nodule. The overall incidence of cancer in a cold nodule is 12% to 15%, but it is higher in people younger than 40 years and in people with calcifications present on preoperative ultrasonography.

There are four main types of thyroid cancer (based on how the cancer cells look under a microscope):

papillary and follicular
medullary
anaplastic

WHAT ARE THE RISK FACTORS OF THYROID CANCER?

Patients with a history of radiation administered in infancy and childhood for benign conditions of the head and neck, such as enlarged thymus, acne, or tonsillar or adenoidal enlargement, have an increased risk of cancer as well as other abnormalities of the thyroid gland. In this group of patients, malignancies of the thyroid gland first appear beginning as early as 5 years following radiation and may appear 20 or more years later.
Radiation exposure as a consequence of nuclear fall-out has also been associated with a high risk of thyroid cancer, especially in children.
Other risk factors for the development of thyroid cancer include a history of goiter, family history of thyroid disease, female gender, and Asian race.
The thyroid gland may occasionally be the site of other primary tumors, including sarcomas, lymphomas, epidermoid carcinomas, and teratoma, and may be the site of metastasis from other cancers, particularly of the lung, breast, and kidney.



WHAT IS STAGE OF THYROID CANCER?

TNM definitions

Primary tumor (T)

[Note: All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor (the largest determines the classification).]

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 2 cm or less in greatest dimension, limited to the thyroid
T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid
T3: Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
All anaplastic carcinomas are considered T4 tumors.

T4a: Intrathyroidal anaplastic carcinoma—surgically resectable
T4b: Extrathyroidal anaplastic carcinoma—surgically unresectable.
Regional lymph nodes (N)

Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes
Distant metastases (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
AJCC stage groupings

Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic (undifferentiated) carcinoma.

Papillary or follicular thyroid cancer

Younger than 45 years

Stage I
Any T, any N, M0
Stage II
Any T, any N, M1
Age 45 years and older

Stage I
T1, N0, M0
Stage II
T2, N0, M0
Stage III
T3, N0, M0
T1, N1a, M0
T2, N1a, M0
T3, N1a, M0
Stage IVA
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, M0
T4a, N1b, M0
Stage IVB
T4b, any N, M0
Stage IVC
Any T, any N, M1
Medullary thyroid cancer

Stage I

T1, N0, M0
Stage II
T2, N0, M0
Stage III

T3, N0, M0
T1, N1a, M0
T2, N1a, M0
T3, N1a, M0
Stage IVA

T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, M0
T4a, N1b, M0
Stage IVB

T4b, any N, M0
Stage IVC

Any T, any N, M1
Anaplastic thyroid cancer

All anaplastic carcinomas are considered stage IV.

Stage IVA

T4a, any N, M0
Stage IVB

T4b, any N, M0
Stage IVC

Any T, any N, M1
Papillary and follicular thyroid cancer

Stage I papillary thyroid cancer

Stage I papillary carcinoma is localized to the thyroid gland. In as many as 50% of cases there are multifocal sites of papillary adenocarcinomas throughout the gland. Most papillary cancers have some follicular elements, and these may sometimes be more numerous than the papillary formations, but this does not change the prognosis. The 10-year survival rate is slightly better for patients younger than 40 years than for patients older than 40 years.

Stage II papillary thyroid cancer

Stage II papillary carcinoma is defined as either (1) tumor that has spread distantly in patients younger than 45 years or (2) tumor that is larger than 2 cm but not more than 4 cm and is limited to the thyroid gland in patients older than 45 years. In as many as 50% to 80% of cases there are multifocal sites of papillary adenocarcinomas throughout the gland. Most papillary cancers have some follicular elements, and these may sometimes be more numerous than the papillary formations, but this does not appear to change the prognosis.

Stage III papillary thyroid cancer

Stage III is papillary carcinoma in patients older than 45 years that is larger than 4 cm and is limited to the thyroid or with minimal extrathyroid extension, or positive lymph nodes limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes. Papillary carcinoma that has invaded adjacent cervical tissue has a worse prognosis than tumors confined to the thyroid.

Stage IV papillary thyroid cancer

Stage IV is papillary carcinoma in patients older than 45 years with extension beyond the thyroid capsule to the soft tissues of the neck, cervical lymph node metastases, or distant metastases. The lungs and bone are the most frequent distant sites of spread, although such distant spread is rare in this type of thyroid cancer. Papillary carcinoma more frequently metastasizes to regional lymph nodes than to distant sites. The prognosis for patients with distant metastases is poor.

Stage I follicular thyroid cancer

Stage I follicular carcinoma is localized to the thyroid gland. Follicular thyroid carcinoma must be distinguished from follicular adenomas, which are characterized by their lack of invasion through the capsule into the surrounding thyroid tissue. While follicular cancer has a good prognosis, it is less favorable than that of papillary carcinoma. The 10-year survival is better for patients with follicular carcinoma without vascular invasion than for patients with vascular invasion.

Stage II follicular thyroid cancer

Stage II follicular carcinoma is defined as either tumor that has spread distantly in patients younger than 45 years, or tumor that is larger than 2 cm but not more than 4 cm and is limited to the thyroid gland in patients older than 45 years. The presence of lymph node metastases does not worsen the prognosis among patients younger than 45 years. Follicular thyroid carcinoma must be distinguished from follicular adenomas, which are characterized by their lack of invasion through the capsule into the surrounding thyroid tissue. While follicular cancer has a good prognosis, it is less favorable than that of papillary carcinoma; the 10-year survival is better for patients with follicular carcinoma without vascular invasion than for patients with vascular invasion.

Stage III follicular thyroid cancer

Stage III is follicular carcinoma in patients older than 45 years, larger than 4 cm and limited to the thyroid or with minimal extrathyroid extension, or positive lymph nodes limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes. Follicular carcinoma invading cervical tissue has a worse prognosis than tumors confined to the thyroid gland. The presence of vascular invasion is an additional poor prognostic factor. Metastases to lymph nodes do not worsen the prognosis in patients younger than 45 years.

Stage IV follicular thyroid cancer

Stage IV is follicular carcinoma in patients older than 45 years with extension beyond the thyroid capsule to the soft tissues of the neck, cervical lymph node metastases, or distant metastases. The lungs and bone are the most frequent sites of spread. Follicular carcinomas more commonly have blood vessel invasion and tend to metastasize hematogenously to the lungs and to the bone rather than through the lymphatic system. The prognosis for patients with distant metastases is poor.

Medullary thyroid cancer

Stage 0 medullary thyroid cancer

Clinically occult disease detected by provocative biochemical screening.

Stage I medullary thyroid cancer

Tumor less than 2 cm.

Stage II medullary thyroid cancer

Tumor larger than 2 cm but not more than 4 cm.

Stage III medullary thyroid cancer

Tumor larger than 4 cm with minimal extrathyroid extension or any primary tumor less than 4 cm with metastases limited to the pretracheal, paratracheal, or prelaryngeal/Delphian lymph nodes.

Stage IV medullary thyroid cancer

Stage IV medullary thyroid cancer is divided into:

Stage IVA (potentially resectable with or without lymph node metastases [for T4a] but without distant metastases).
Stage IVB (locally unresectable with or without lymph node metastases but no distant metastases).
Stage IVC (distant metastases).
Medullary carcinoma usually presents as a hard mass, and is often accompanied by blood vessel invasion. Medullary thyroid cancer occurs in 2 forms, sporadic and familial. In the sporadic form the tumor is usually unilateral. In the familial form, the tumor is almost always bilateral. In addition, the familial form may be associated with benign or malignant tumors of other endocrine organs, commonly referred to as the multiple endocrine neoplasia syndromes (MEN 2A or MEN 2B).

Family members should be screened for calcitonin elevation to identify individuals who are at risk of developing familial medullary thyroid cancer. MEN 2A gene carrier status can be more accurately determined by analysis of mutations in the RET gene. Whereas modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the RET mutation is the optimal approach in evaluating MEN 2A. All patients with medullary carcinoma of the thyroid (whether familial or sporadic) should be tested for RET mutations, and, if they are positive, family members should also be tested. Family members who are gene carriers should undergo prophylactic thyroidectomy at an early age.

Anaplastic thyroid cancer

There is no generally accepted staging system for anaplastic thyroid cancer. All patients are considered to have stage IV disease.

Undifferentiated (anaplastic) carcinomas are highly malignant cancers of the thyroid. They may be subclassified as small cell or large cell carcinomas. Both grow rapidly and extend to structures beyond the thyroid. Both small cell and large cell carcinomas present as hard, ill-defined masses, often with extension into the structures surrounding the thyroid. Small cell anaplastic thyroid carcinoma must be carefully distinguished from lymphoma. This tumor usually occurs in an older age group and is characterized by extensive local invasion and rapid progression. Five-year survival with this tumor is poor. Death is usually from uncontrolled local cancer in the neck, usually within months of diagnosis.



HOW TO TREAT THYROID CANCER?

Papillary and Follicular Thyroid Cancer

Stage I and II

Surgery is the therapy of choice for all primary lesions. Surgical options include total thyroidectomy or lobectomy. The choice of procedure is influenced mainly by the age of the patient and the size of the nodule. Survival results may be similar; the difference between them lies in the rates of surgical complications and local recurrences.

Total thyroidectomy: This procedure is advocated because of the high incidence of multicentric involvement of both lobes of the gland and the possibility of dedifferentiation of any residual tumor to the anaplastic cell type. The procedure is associated with a higher incidence of hypoparathyroidism, but this complication may be reduced when a small amount of tissue remains on the contralateral side. This approach facilitates follow-up thyroid scanning.
I131:A postoperative course of therapeutic (ablative) doses of I131 results in a decreased recurrence rate among high-risk patients with papillary and follicular carcinomas. It may be given in addition to exogenous thyroid hormone, but is not considered routine. Patients presenting with papillary thyroid microcarcinomas (tumors <10 mm) have an excellent prognosis when treated surgically, and additional therapy with I131 would not be expected to improve the prognosis.

Lobectomy: This procedure is associated with a lower incidence of complications, but approximately 5% to 10% of patients will have a recurrence in the thyroid following lobectomy. Patients younger than 45 years will have the longest follow-up period and the greatest opportunity for recurrence. Follicular thyroid cancer commonly metastasizes to lungs and bone; with a remnant lobe in place, use of I131 as ablative therapy is compromised. Abnormal regional lymph nodes should be biopsied at the time of surgery. Recognized nodal involvement should be removed at initial surgery but selective node removal can be performed and radical neck dissection is usually not required. This results in a decreased recurrence rate, but has not been shown to improve survival.
Following the surgical procedure, patients should receive postoperative treatment with exogenous thyroid hormone in doses sufficient to suppress thyroid-stimulating hormone (TSH); studies have shown a decreased incidence of recurrence when TSH is suppressed.

I131: Studies have shown that a postoperative course of therapeutic (ablative) doses of I131 results in a decreased recurrence rate among high-risk patients with papillary and follicular carcinomas. It may be given in addition to exogenous thyroid hormone, but is not considered routine. Patients presenting with papillary thyroid microcarcinomas (tumors <10 mm) have an excellent prognosis when treated surgically, and additional therapy with I131 would not be expected to improve the prognosis.

Stage III



Total thyroidectomy plus removal of involved lymph nodes or other sites of extrathyroid disease.

I131 ablation following total thyroidectomy if the tumor demonstrates uptake of this isotope.
External-beam irradiation if I131 uptake is minimal.
Stage IV

The most common sites of metastases are lymph nodes, lung, and bone. Treatment of lymph node metastases alone is often curative. Treatment of distant metastases is usually not curative but may produce significant palliation.

I131: Metastases that demonstrate uptake of this isotope may be ablated by therapeutic doses of I131.
External-beam irradiation for patients with localized lesions that are unresponsive to I131.
Resection of limited metastases, especially symptomatic metastases, should be considered when the tumor has no uptake of I131.
Thyroid-stimulating hormone suppression with thyroxine is also effective in many lesions not sensitive to I131.
Patients unresponsive to I131 should also be considered candidates for clinical trials testing new approaches to this disease.

Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. These tumors usually present as a mass in the neck or thyroid, often associated with lymphadenopathy, or they may be diagnosed through screening family members. MTC can also be diagnosed by fine-needle aspiration biopsy. Cytology typically reveals hypercellular tumors with spindle-shaped cells and poor adhesion.

The overall survival of patients with MTC is 86% at 5 years and 65% at 10 years. Poor prognostic factors include advanced age, advanced stage, prior neck surgery, and associated-multiple endocrine neoplasia (MEN) 2B.

Family members should be screened for calcitonin elevation and/or for the RET proto-oncogene mutation to identify other individuals at risk for developing familial MTC. All patients with MTC (whether familial or sporadic) should be tested for RET mutations, and if they are positive, family members should also be tested. Whereas modest elevation of calcitonin may lead to a false-positive diagnosis of medullary carcinoma, DNA testing for the RET mutation is the optimal approach. Family members who are gene carriers should undergo prophylactic thyroidectomy at an early age.

Thyroidectomy: Patients with medullary thyroid cancer should be treated with a total thyroidectomy, unless there is evidence of distant metastasis. In patients with clinically palpable medullary carcinoma of the thyroid, the incidence of microscopically positive nodes is more than 75%; routine central and bilateral modified neck dissections have been recommended. When cancer is confined to the thyroid gland, the prognosis is excellent.
External radiation therapy: External radiation therapy has been used for palliation of locally-recurrent tumors, without evidence that it provides any survival advantage. Radioactive iodine has no place in the treatment of patients with MTC.
Palliative chemotherapy: Palliative chemotherapy has been reported to produce occasional responses in patients with metastatic disease. No single drug regimen can be considered standard. Some patients with distant metastases will experience prolonged survival, and can be managed expectantly until they become symptomatic.
Anaplastic Thyroid Cancer

Surgery: Tracheostomy is frequently necessary. If the disease is confined to the local area, which is rare, total thyroidectomy is warranted to reduce symptoms caused by the tumor mass.
Radiation therapy: External beam radiation therapy may be used in patients who are not surgical candidates or whose tumor cannot be surgically excised.
Chemotherapy: Anaplastic thyroid cancer is not responsive to I131 therapy; treatment with individual anticancer drugs has been reported to produce partial remissions in some patients. Approximately 30% of patients achieve a partial remission with doxorubicin. The combination of doxorubicin plus cisplatin appears to be more active than doxorubicin alone and has been reported to produce more complete responses.
The combination of chemotherapy plus irradiation in patients following complete resection may provide prolonged survival, but has not been compared to any one modality alone.[5] Clinical trials evaluating new treatment approaches for this disease should also be considered.
Recurrent Thyroid Cancer

Patients treated for differentiated thyroid cancer should be followed carefully with physical examinations, serum quantitative thyroglobulin levels, and radiologic studies based on individual risk for recurrent disease. Approximately 10% to 30% of patients thought to be disease-free after initial treatment will develop recurrence and/or metastases. Of patients who recur, approximately 80% recur with disease in the neck alone and 20% with distant metastases. The most common site of distant metastasis is the lung.

The prognosis for patients with clinically detectable recurrences is generally poor, regardless of cell type. However, those patients who recur with local or regional tumor detected only by I131 scan have a better prognosis. The selection of further treatment depends on many factors, including cell type, uptake of I131, prior treatment, site of recurrence, and individual patient considerations. Surgery with or without I131 ablation can be useful in controlling local recurrences, regional node metastases, or, occasionally, metastases at other localized sites. Approximately half of the patients operated on for recurrent tumors can be rendered free of disease with a second operation. Local and regional recurrences detected by I131 scan and not clinically apparent can be treated with I131 ablation and have an excellent prognosis.

Up to 25% of recurrences and metastases from well-differentiated thyroid cancer may not show I131 uptake. For these patients, other imaging techniques shown to be of value include imaging with thallium-201, magnetic resonance imaging, and pentavalent dimercaptosuccinic acid. When recurrent disease does not concentrate I131, external-beam or intraoperative radiation therapy can be useful in controlling symptoms related to local tumor recurrences. Systemic chemotherapy can be considered. Chemotherapy has been reported to produce occasional objective responses, usually of short duration.



WHAT ARE THE PROGNOSTIC FACTORS OF THYROID CANCER?

Age appears to be the single most important prognostic factor. The prognosis for differentiated carcinoma is better for patients younger than 40 years without extracapsular extension or vascular invasion. Female gender, multifocality, and regional node involvement are favorable prognostic factors. Adverse factors included age older than 45 years, follicular histology, primary tumor larger than 4 cm (T2-3), extrathyroid extension (T4), and distant metastases.

Other studies, however, have shown that regional lymph node involvement had no effect or even an adverse effect on survival.

Diffuse, intense immunostaining for vascular endothelial growth factor in patients with papillary cancer has been associated with a high rate of local recurrence and distant metastases.

An elevated serum thyroglobulin level correlates strongly with recurrent tumor when found in patients with differentiated thyroid cancer during postoperative evaluations. Serum thyroglobulin levels are most sensitive when patients are hypothyroid and have elevated serum thyroid-stimulating hormone levels.

Expression of the tumor suppressor gene p53 has also been associated with an adverse prognosis for patients with thyroid cancer.

Patients considered to be low risk by the age, metastases, extent, and size (AMES) risk criteria include women younger than 50 years and men younger than 40 years without evidence of distant metastases. Also included in the low-risk group are older patients with primary tumors less than 5 cm and papillary cancer without evidence of gross extrathyroid invasion or follicular cancer without either major capsular invasion or blood vessel invasion.