Cancer of the Thyroid: Medullary and Anaplastic
Anaplastic Thyroid Carcinoma
Table of Contents
Introduction
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.
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.
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.
|
Top
of Page
