Cancer of the Thyroid: Papillary & Follicular
Table of Contents
Introduction
The diagnosis of cancer is terrifying for most patients because
it has become associated in our minds with pain and death. But,
in fact, the outlook for patients with thyroid cancer is usually
excellent because: 1) most thyroid cancer is easily curable with
surgery, 2) it causes little pain or disability, and 3) novel and
effective means of diagnosis and therapy are available for several
kinds of thyroid cancer.
Thyroid cancer usually presents itself as a lump or nodule in the
thyroid gland. However, it should be emphasized that most thyroid
nodules (95% or more) are benign. Unfortunately, it may be difficult
to distinguish a benign from a malignant nodule on the basis of
history and physical examination, even with the help of laboratory
tests including blood hormone levels and scans (images) of the thyroid
gland. Therefore, biopsy of thyroid nodules (generally Fine Needle
Aspiration, FNA) provides the most valuable information in helping
a physician to determine whether a surgical operation is necessary.
Occasionally, a thyroid cancer can present as a swollen lymph node
in the neck, as hoarseness due to pressure from the tumor on the
nerve to the voice box (recurrent laryngeal nerve), or as difficulty
in swallowing or breathing due to a tumor obstructing the esophagus
or windpipe. Rarely it presents as disease which has spread to another
part of the body (metastatic disease).
In this review, we will discuss the most common types of thyroid
malignancy.
What is Well-Differentiated Thyroid Cancer?
A cancer is a malignant tumor which grows in the body. A well-differentiated
cancer is one which superficially looks like the normal parent tissue,
in this case the thyroid gland. There are two types of well-differentiated
thyroid cancer, papillary and follicular, both derived from the
normal thyroid cell, the follicular cell.
Well-differentiated thyroid cancers account for about 90% of all
thyroid malignancies and most are associated with an excellent outlook.
Although we do not know exactly what causes these well-differentiated
cancers to grow, we do know that they are more likely to develop
in patients who have received x-ray treatments in childhood for
enlarged tonsils, enlarged thymus glands, acne, and occasionally
for other malignancies such as Hodgkin's disease. An important epidemic
of papillary carcinoma developed in the
region surrounding Chernobyl after the nuclear power plant melt-down.
Routine diagnostic x-rays (like chest x-rays, dental x-rays, or
thyroid scans) do not cause such thyroid cancer.
What is Papillary Thyroid Cancer?
A papilla is a nipple-like projection. Papillary cancers have multiple
projections giving them a fern or frond-like appearance under the
microscope. In addition the nuclei (central portion of the cells)
are changed compared to normal thyroid cell nuclei. Tiny, microscopic
areas of papillary cancer can be found in up to 10% of "normal"
thyroid glands, when thyroid tissue is carefully examined with a
microscope. The more carefully a pathologist looks for these tiny
cancers, the more commonly they are found. These microscopic cancers
seem to have no clinical importance and are more a curiosity than
a disease. In other words, there does not seem to be a tendency
for these small cancer-like growths to enlarge and become more serious
malignant tumors.
On the other hand, when papillary cancer grows large enough to
form a lump in the thyroid gland, we consider it clinically important,
for it is likely to continue to enlarge and may spread elsewhere
in the body. Papillary tumors make up about 70% to 80% of all thyroid
cancers, and can occur at any age. There are only about 12,000 new
cases of papillary cancer in the United States each year, but because
these patients have such a long life expectancy, we estimate that
one in a thousand people have or have had this form of cancer.
Papillary cancer tends to grow slowly and to spread by means of
the lymphatic system to lymph glands in the neck. In fact, in about
one third of the patients who undergo surgery for papillary cancer,
the tumor has already spread to surrounding lymph glands (lymph
node metastases). Fortunately, the generally excellent outlook is
usually not altered by lymph gland metastases. Some clinicians believe
that the presence of abnormal lymph nodes on both sides of the neck
or abnormal lymph nodes in the chest area does worsen the prognosis.
The outlook or prognosis for patients with papillary thyroid carcinoma
is determined by several features at the time of diagnosis. Many
different staging systems have been used, without consensus among
experts. Based on the Mayo Clinic system, the most favorable characteristic
is a primary tumor confined to the thyroid itself (intrathyroidal).
As noted above, the presence or absence of lymph gland involvement
usually does not affect the prognosis. The 85% of patients with
intrathyroidal papillary carcinoma have a 25-year mortality rate
of 1%. This means that only 1 out of every 100 such patients will
be dead of thyroid cancer 25 years later.
Since the outlook in patients with intrathyroidal primary tumors
is so favorable, it is important that therapy not be more hazardous
than the disease. Radical surgery is rarely indicated for this mild
type of papillary cancer. Ten percent or more of patients with intrathyroidal
papillary cancer will have a subsequent recurrence. Fortunately
recurrences generally occur as enlarged lymph glands in the neck
and are not life-threatening. Such recurrences are usually removed
surgically.
The prognosis is not as good in patients where the cancer has grown
through the thyroid into surrounding tissues (extrathyroidal). Specifically,
this means spread through the fibrous capsule that surrounds the
thyroid gland into the tissues of the neck. Lymph node involvement
is not considered extrathyroidal spread. In a very small percentage
of patients (about 5%), the cancer eventually spreads through the
blood stream to distant sites, particularly the lungs and bones.
These distant tumor sites (metastases) can often be treated with
radioactive iodine but they are difficult to cure (see below).
Young patients who have papillary thyroid cancer generally have
an excellent prognosis (outlook). However, patients under the age
of 20 have a higher risk of spread to the lungs and of local recurrence.
The prognosis is also not as good in those
older than age 50 and those with larger tumors (particularly greater
than 3.5 to 4 cm. [around 1.5 inches in diameter]).
What is Follicular Thyroid Cancer?
The normal thyroid gland is made up of sphere-shaped structures
called follicles, which are lined by thyroid follicular cells. When
a thyroid cancer resembles these normal structures, the cancer is
called a follicular cancer. Follicular cancer makes up about 10%
of all thyroid cancers in the United States, and tends to occur
in somewhat older patients than papillary carcinoma.
Although follicular cancer of the thyroid is generally considered
to be more aggressive than papillary cancer, this is not always
true. Approximately one third of these patients have a minimally
invasive follicular thyroid carcinoma. Since the follicular cells
look just like normal thyroid cells, the diagnosis of cancer depends
on finding these cells where they do not belong. Follicular carcinoma
is considered minimally invasive when the cells grow through the
lining (capsule) of the nodule or at most into a few blood vessels.
The outcome is excellent in minimally invasive follicular carcinoma,
particularly those diagnosed with capsular invasion alone. On the
other hand, when the follicular cancer extensively
invades blood vessels, the prognosis is worse and spread to distant
sites including the lungs and bones is common. In general, the prognosis
is better in younger patients than in those over 50 years of age.
What is the Treatment of Well-Differentiated Thyroid Cancer?
The primary therapy for well differentiated thyroid cancer is surgical
removal of the tumor, which also allows preliminary staging of the
disease. When a skilled thyroid surgeon is available, a bilateral
near total removal of the thyroid (thyroidectomy) should be performed
for most patients with known papillary or follicular carcinoma.
However, there are many patients, previously treated with removal
of half of the thyroid gland (hemithyroidectomy) who continue to
thrive without disease recurrence. A particular dilemma occurs when
the diagnosis of a minimally invasive follicular carcinoma is made
after final pathology review, usually days after surgery is completed.
Preliminary pathological analysis (frozen section) generally cannot
distinguish benign from malignant follicular tumors at the time
of surgery. Therefore removal of only half of the thyroid is generally
performed. When the final diagnosis is minimally invasive follicular
carcinoma options include: additional surgery to remove the remaining
half of the thyroid gland (completion thyroidectomy), radioactive
iodine destruction (ablation) of the remaining half of the thyroid)
or thyroid hormone therapy alone, if the diagnosis is made by capsular
invasion alone. The advantages of each approach are still debated.
When thyroid cancer extensively invades local neck structures,
aggressive surgery, including removal of part of the trachea (air
passageway) or esophagus (food passageway) should be considered.
These patients require radioactive iodine therapy and often external
beam radiation as well.
It may trouble some patients to realize
that there are no absolute rules for the management of these cancers.
Although the general characteristics of tumor behavior are understood,
in any particular patient the choice of treatment is best made by
physicians skilled in the management of patients with thyroid cancer.
Radioiodine Therapy
Once papillary or follicular cancer has spread through the blood
stream into the surrounding tissues or to distant sites (especially
lungs and bones), the usual therapy is to administer a radioactive
form of iodine (131I) to try to destroy the tumor. To understand
this treatment, it is important to know the relationship between
iodine and the thyroid gland.
The thyroid gland normally concentrates iodine from the bloodstream,
and this process is stimulated by TSH (thyroid stimulating hormone)
from the pituitary gland. The iodine is subsequently used to produce
thyroid hormone (thyroxine, T4). Thyroid cancers or metastases from
thyroid cancer concentrate only tiny amounts of iodine (or radioactive
iodine) under normal conditions. However, when stimulated by high
concentrations of TSH, papillary and follicular carcinoma and their
metastases may be stimulated to concentrate significant amounts
of iodine. This permits the delivery of a large radiation dose directly
to the cancer, without damage to surrounding tissues. However, when
the normal thyroid gland is present and producing normal amounts
of thyroid hormone, the production of TSH by the pituitary remains
relatively low. But if the entire thyroid gland is removed or destroyed,
and the level of thyroid hormone is allowed to fall, the pituitary
gland will increase TSH secretion dramatically. In turn, this will
stimulate the thyroid cancer to concentrate radioactive iodine.
To prepare for radioactive iodine therapy, patients must be off
their thyroid hormone. We generally change patients from levothyroxine
(Levothroid, Levoxyl, Synthroid, Unithroid and others) (T4) to Cytomel
(T3) for four weeks and then discontinue the Cytomel for two weeks
prior to administering the scanning dose of radioiodine. Patients
are generally asked to adhere to a low iodine diet for several weeks
prior to such therapy.
For radioactive iodine therapy to successfully treat metastatic
thyroid cancer serum TSH must be elevated, which generally requires
removal or destruction of the entire thyroid gland. Once that has
been accomplished patients with residual tumor in the neck or known
distant metastases are scanned after receiving a small amount (scanning
dose) of radioactive iodine (131I, 2-10 millicuries or 123I, 1-2
millicuries), assuming the serum TSH concentration is greater than
25 uU/ml.
Patients then receive a therapeutic dose of 131I, usually 150 millicuries
or more in an attempt to destroy the tumor, provided a significant
amount of iodine is concentrated in the areas of the cancer. A repeat
scan is often performed after the therapeutic dose; post-therapy
scans identify additional sites of disease in approximately ten
percent of patients.
In most states, treatment with large doses of radioactive iodine
requires a one to several day hospitalization, until the amount
of radioactivity in the body falls to levels which will not be hazardous
to other people. However, this treatment has proved to be safe and
well-tolerated, and may be curative in patients with well-differentiated
thyroid cancer even after the tumor has spread to the lungs. The
treatment is generally well tolerated, however, nausea, vomiting
and pain in the salivary glands may occur. Salivary gland damage
after this treatment may leave patients with a dry mouth.
Because of the safety and effectiveness of radioactive iodine in
patients with more aggressive thyroid cancer, many physicians also
use it routinely in patients with less aggressive papillary and
follicular cancers. In this situation, radioactive iodine is used
to destroy tiny remnants of thyroid tissue still present after surgery.
This may improve the prognosis and makes it easier to monitor patients
for tumor recurrence using a blood test for thyroglobulin (see below).
Whether radioactive iodine ablation improves the survival or recurrence
rates in patients with favorable papillary carcinoma of the thyroid
gland is still debated.
When surgery and radioactive iodine cannot check the growth of
well-differentiated thyroid cancer, external radiation therapy to
local tumor sites is often helpful. We continue to search for specific
therapies when the tumor has spread widely
and continues to grow. Current chemotherapy is rarely effective
in this situation. Because lung metastases are often asymptomatic
for years, when radioiodine is no longer effective, cautious observation
is often recommended.
How are Thyroid Cancer Patients Followed?
Periodic follow-up examinations are essential for patients who
have had surgery for papillary or follicular thyroid cancer, because
recurrences sometimes occur many years after apparently successful
surgery. These follow-up visits should include a careful history
and physical examination with particular attention to the neck area.
Periodic measurement of the blood level of the protein thyroglobulin
is also important.
This substance is produced and released by normal thyroid cells
and also by well-differentiated thyroid cancer cells. The blood
level of thyroglobulin is very low after total thyroid gland removal,
and in most patients who are taking thyroid hormone after thyroid
surgery. An elevated or rising level of thyroglobulin is a "tumor
marker" which generally implies persistent or growing thyroid
cancer, but does not necessarily imply a poor prognosis. A high
thyroglobulin level found in a follow-up examination alerts the
physician to the possibility that other tests may be needed to be
sure the tumor is not recurring. Approximately 20 to 30% of thyroid
cancer patients have interfering antibodies in their blood which
prevent accurate thyroglobulin measurement. Thyroglobulin production
is stimulated by TSH; the blood thyroglobulin concentration rises
when TSH increases. Therefore a low serum thyroglobulin at the time
of an elevated TSH is particularly reassuring.
How often should imaging and scanning be done? Many different protocols
have been suggested to follow patients with well-differentiated
thyroid cancer. I generally modify the testing based on the tumor
stage. Patients with favorable papillary carcinomas with undetectable
serum thyroglobulin concentrations need the fewest imaging tests.
After radioactive iodine ablation of residual thyroid tissue, many
endocrinologists and patients want the reassurance of a subsequent
negative scan. Fortunately, a new method of radioiodine scanning
is available for select patients, which does not require withdrawal
of thyroid hormone. Patients receive injections of human TSH (made
by genetic engineering) known as Thyrogen (recombinant human TSH,
rhTSH) to raise their TSH concentrations. Radioiodine scanning and
thyroglobulin measurements are performed. A negative post-Thyrogen
scan and a serum thyroglobulin concentration less than 2 ng/ml after
Thyrogen injections is very reassuring. I generally restrict this
scanning approach to patients who are expected to have a negative
scan and who have a low serum thyroglobulin while on thyroid hormone
therapy. In exceptional circumstances, radioactive iodine therapy
can be performed after Thyrogen injections rather than after withdrawal
of thyroid hormone.
Patients with persistent cancer need periodic rescanning and treatment
with radioactive iodine. Currently, this is best done after withdrawing
thyroid hormone. In some patients the radioiodine scan is negative
but serum thyroglobulin is still high. Several approaches have been
suggested. I generally start with a thyroid ultrasound. If abnormal
tissue or lymph nodes are found, additional surgery is generally
indicated, sometimes after an ultrasound guided biopsy. If the ultrasound
is negative, administration of larger doses of radioiodine with
subsequent scanning may help localize the sites of disease. If these
tests are negative, other scans and/or x-rays are necessary to localize
the disease sites. These may include but are not limited to PET
scanning, chest x-ray, CT or MRI, head CT or MRI, bone survey, CT
or MRI of the spine, sestimibi, thallium or octreotide scanning.
Whether serial neck ultrasounds should be performed in all patients
with well-differentiated thyroid carcinoma is an unanswered question.
However, I recommend ultrasound in all patients with a history of
locally invasive papillary thyroid
carcinoma and in those with positive thyroglobulin antibodies where
that tumor marker cannot be followed. You should feel comfortable
asking the physician who is treating your tumor to discuss his or
her choice of tests and treatments for your situation.
What about Thyroid Hormone Treatment?
If the thyroid gland has been mostly or completely removed, thyroid
hormone must be taken for the body to remain normal (euthyroid).
Even if part of the thyroid remains, levothyroxine (Levothroid,
Levoxyl, Synthroid, Unithroid and others) (T4) administration is
an important therapy which lowers blood TSH concentration and seems
to prevent tumor recurrence. Thyroid hormone should be administered
in sufficient quantities to suppress TSH levels to subnormal values,
except when medically contraindicated. Sensitive TSH measurements
are necessary for monitoring TSH concentrations to confirm that
the serum TSH is below normal or at the lower limits of normal in
patients at low risk of cancer recurrence. Patients with more aggressive
forms of papillary or follicular cancer should take larger doses
of thyroxine in order to suppress TSH to undetectable levels.
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