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Cancer of the Thyroid: Medullary and Anaplastic

Anaplastic Thyroid Carcinoma

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Anaplastic or undifferentiated thyroid carcinoma makes up about 7% of all thyroid cancer. This tumor occurs in older patients, usually over sixty years of age. The tumor often originates in benign or low grade malignant tumors of the thyroid, even though the actual percentage of benign and low grade malignant tumors that progress to anaplastic carcinoma is extremely low. The change from a relatively slow growing to a rapidly growing tumor is usually caused by a mutation or change in a tumor suppressor gene known as p53. When present in its usual form, the p53 gene helps the body destroy newly formed abnormal tumor cells by inducing the cells to "commit suicide." When p53 is abnormal, tumor growth may proceed unchecked.

Anaplastic carcinoma usually starts as a rapidly enlarging lump in the neck, and is likely to cause local symptoms such as hoarseness, difficulty breathing or swallowing, or blockage of the large veins in the neck and chest. In contrast with papillary carcinoma, which is one of the slowest growing tumors in the body, anaplastic carcinoma is one of the most rapidly growing cancers. The diagnosis is usually suspected from the clinical situation and confirmed with a fine needle aspiration biopsy (FNA) or open biopsy. The role of surgery is controversial. We generally recommend radiation and chemotherapy, sometimes followed by surgery if the disease has not spread to distant sites. Others recommend surgery followed by radiation and/or chemotherapy. We recommend consultation with a medical oncologist (cancer specialist) to help plan therapy. The prognosis is generally but not invariably poor, as the tumor quickly spreads to distant sites.

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Therapy and Follow-up

Surgery is the mainstay of therapy for medullary thyroid carcinoma. A bilateral near total thyroidectomy with dissection (removal) of surrounding lymph glands is mandatory. Because this tumor often starts on both sides of the thyroid gland, removal of only half of the thyroid is not recommended. Remember, when MTC is known or suspected, a pheochromocytoma should be excluded before surgery is performed to avoid sudden increases in blood pressure during the operation. The persistence of high serum calcitonin values after apparently successful surgery suggests that tumor is still present, but does not necessarily imply a poor prognosis. Obviously, a low or undetectable calcitonin value is a more favorable indicator.

Two additional tests may be helpful assessing the prognosis. Carcinoembryonal antigen (CEA) is a protein which is produced by many cancers including MTC. When post-operative CEA concentrations are very high, the prognosis is worse. Some institutions examine the DNA (genetic material) or calcitonin content of cells in the pathological specimen. The more abnormal the DNA content or the less calcitonin present, the worse the prognosis.

When calcitonin does not return to normal after surgery, residual tumor or metastatic tumor must be sought. A neck ultrasound is often helpful in localizing small abnormal lymph nodes which may harbor MTC. Some clinicians recommend extensive neck dissection to remove all possible abnormal nodes in the neck even when localization testing is negative. This lengthy operation may lower calcitonin to normal in a minority of patients. The ability to scan the body for residual MTC with the radioactively labelled chemical pentreotide is a major advance. However, in our experience when calcitonin values are only moderately elevated (< 1000 pg/ml) this scan is usually negative. In some patients, scanning with radioactively labelled anti-CEA antibodies or with PET scanning helps localize distant disease. When disease activity is not discovered, other tests including CT or MRI of the chest, abdomen and head, and a bone survey may be indicated. Whenever possible, surgery should be performed when new areas of MTC are discovered.

External radiation is recommended when the surgeon is unable to remove all the tumor in the neck and when painful bony metastases are present. The role of external radiation to the neck in selected patients with persistent calcitonin elevation is unresolved. Newer chemotherapy regimens are effective in a minority of patients. Aggressive radiotherapy using high dose radioisotope labelled anti-CEA antibodies may be effective but often requires bone marrow transplantation.

The ability to follow MTC by measuring the tumor marker calcitonin is both a boon and a curse. Persistent calcitonin elevations are often frustrating and frightening for patients. The calcitonin elevation suggests the presence of persistent tumor, but often the residual tumor cannot be located, or, if located, cannot be eradicated with our currently available therapies. It is extremely important to realize that calcitonin is a tumor marker (indicator), not a lethal substance. Some patients can lead perfectly normal lives for decades with markedly elevated calcitonin concentrations. In some patients with metastatic disease calcitonin and tumor mass change slowly or not at all. Unfortunately medullary carcinoma advances rapidly in some patients.

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Medullary Thyroid Carcinoma (MTC)

Medullary thyroid carcinoma (MTC) is relatively rare (about 3-5% of all thyroid cancer) and has several unique characteristics. Unlike other types of thyroid cancer, medullary carcinoma originates in the parafollicular cells of the thyroid gland. Parafollicular cells are not involved in making thyroid hormone. They are also known as C cells, because they produce calcitonin, a hormone which has poorly characterized effects on the skeleton. Almost all medullary cancers produce calcitonin. Thus, the presence of medullary carcinoma can be suspected on the basis of an elevated blood calcitonin level. The skill which a well-trained physician has is knowing to check a calcitonin blood level in a particular patient. Calcitonin is not routinely measured, even in patients with thyroid nodules, since the yield of such measurements is quite low. However the role of calcitonin measurements in patients with thyroid nodules is still debated.

Medullary carcinoma usually presents as a thyroid nodule or mass in the neck. Fine Needle Aspiration (FNA) biopsy may be difficult to interpret, but when the diagnosis of medullary thyroid carcinoma is considered, staining the biopsy material for calcitonin or measuring serum calcitonin is generally diagnostic. MTC is often misdiagnosed when a frozen section (preliminary pathological diagnosis) is analyzed at the time of surgery for a thyroid nodule. It is occasionally misdiagnosed as a very aggressive undifferentiated cancer and is sometimes confused with a typical follicular thyroid cancer. Positive tissue staining for calcitonin is diagnostic.

About twenty percent of patients with MTC have an inherited form of the disease. This means that once a patient is diagnosed as having MTC, it is essential that members of the patient’s family be screened for MTC. All patients with thyroid nodules should be questioned about family members with thyroid cancer, particularly MTC.

The presence of MTC in both lobes of the thyroid gland may be an important clue pointing to the familial form of the disease. Although the cancer may appear to be confined to one lobe of the thyroid gland, it is important for the pathologist to examine the other lobe for increased numbers of C cells to be sure that the tumor is not present there as well.

There are three different types of hereditary MTC, two of which are associated with other endocrine gland tumors. The first kind is a condition called Multiple Endocrine Neoplasia (or MEN) II a. Characteristics of MEN II a include: MTC, usually bilateral, pheochromocytomas (tumors of the adrenal gland which produce adrenaline and cause high blood pressure), and hyperparathyroidism (overactivity or tumors of the parathyroid glands which cause elevated serum calcium). Although MEN II a is relatively rare, its recognition is extremely important because it can be dangerous or even lethal to perform thyroid surgery when an unsuspected pheochromocytoma is present. When MTC is diagnosed on FNA, a twenty four hour urine collection for adrenaline and its metabolites or an appropriate blood test should be analyzed before surgery.

A rarer form of hereditary MTC is called Multiple Endocrine Neoplasia II b (MEN II b) and includes MTC, pheochromocytomas, and a peculiar body shape, with long, thin legs, as well as multiple neuromas or nerve tumors on the lips, tongue, eyes, and in the intestinal tract.

The third variety of hereditary MTC is called familial MTC without other associated tumors. It is likely much more common than we realized.

All three of these diseases or syndromes are inherited in a dominant fashion. This means that on average, half of the children of a patient with this disease will also develop the disease.

Family screening is very important in patients with MTC. A major advance in this area occurred when the genetic basis was discovered for most patients with hereditary MTC. Mutations (changes) in a gene called RET have been identified in almost all patients with MEN II a and MEN II b and in about 85% of patients with familial MTC. It is likely that unrecognized mutations in this gene cause the disease in the remaining patients. Analysis of RET mutations is now available through several commercial laboratories. When a patient is found to have MTC, a RET analysis should be performed by analyzing the genetic material in blood cells after a simple bloodletting. If a RET mutation is found, all first degree relatives (parents, siblings, and children) should be screened by looking for the same mutation. When that RET mutation is discovered in a family member, surgery is generally recommended even when the thyroid gland appears normal. MTC or its precursor called C-cell hyperplasia will be found in 96% of patients who undergo preventative removal of the thyroid gland. Although the absence of a RET mutation in a patient with MTC is reassuring, a familial form of the disease is not completely excluded. In that situation the first degree blood relatives should have their calcitonin blood level tested. An elevated calcitonin level generally means that MTC or a premalignant precursor (C-cell hyperplasia) exists. When a member of a known hereditary but RET negative MTC family has a normal baseline calcitonin, further tests should be done to stimulate the release of calcitonin. While the calcitonin level of normal individuals will rise slightly after an intravenous injection of calcium or a chemical called pentagastrin, the calcitonin level of patients harboring MTC or C-cell hyperplasia will rise much higher. Pentagastrin is currently unavailable. Most patients with familial forms of MTC will have abnormal calcitonin blood measurements by age 35.

Most patients with MTC are diagnosed (1) because a lump in the neck is discovered, or (2) as a result of a family screening program. Rarely, MTC can cause symptoms due to production of a variety of chemicals. Such patients may develop severe diarrhea or symptoms of excess cortisone production. Remarkably, many individuals with distant spread of MTC have no symptoms at all.

The prognosis of MTC is extremely variable. In many patients, the tumor behaves in a very indolent manner, while in others, the tumor is much more aggressive. The prognosis is usually excellent in patients with familial medullary carcinoma without other tumors and in MEN II a. The outlook is generally not as good in patients with MEN II b, while that for non-familial MTC falls somewhere in between.

The initial tumor stage influences the course of the disease. If the primary tumor is confined to the thyroid gland (intrathyroidal) the prognosis is usually excellent. When lymph nodes are positive the prognosis is not quite as good. When the tumor has grown through the wall of the thyroid into surrounding tissues (extrathyroidal), or spread through the blood to distant sites, the outlook is guarded.

Thyroid Lymphoma

A lymphoma is a cancer of the lymph glands or white blood cells called lymphocytes. Some lymphomas originate in the thyroid gland rather than in a lymph gland. Although thyroid lymphoma makes up only about 4% of all thyroid cancers, it has been increasing in frequency in recent decades. Most patients are middle-aged or older, but the disease can afflict younger people as well. The majority of patients with thyroid lymphoma have an underlying inflammation in the thyroid gland called Hashimoto’s thyroiditis. In Hashimoto's thyroiditis the thyroid gland is filled with lymphocytes and the lymphoma presumably originates in those cells. It is worth emphasizing that while Hashimoto’s thyroiditis is very common, thyroid lymphoma is rare. The risk of a patient with Hashimoto’s developing a lymphoma is extremely low.

Thyroid lymphoma commonly presents as a rapidly enlarging neck mass. Hoarseness, difficulty swallowing, difficulty breathing and fever may be present. Lymphoma should be suspected in patients with known Hashimoto’s thyroiditis who develop an enlarging mass or goiter. Fine needle aspiration may be diagnostic of lymphoma, but when the diagnosis is uncertain a core needle or open surgical biopsy may be necessary.

The prognosis of thyroid lymphoma depends upon whether it is confined to the thyroid or has spread to other areas. Tumor staging with various scans is recommended to evaluate its spread to other parts of the body. This is usually done under the guidance of a medical oncologist. Therapy consists of external radiation, chemotherapy, or most commonly a combination of the two. Although surgery is usually performed for diagnostic purposes only, some physicians still recommend surgical excision for lymphoma confined to the thyroid gland. The prognosis is variable but frequently quite favorable.

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