Management of patients with hypothyroidism,
Management of patients with thyroid nodules.
Hypothyroidism (myxedema)
It is the characteristic reaction to thyroid
hormone deficiency. The spectrum of hormone ranges from a few non – specific symptoms
to overt hormone, to myxedema coma. Hypothyroidism occurs in 3 to 6 for the
adult population, but is symptomatic only in a minor of them. It occurs 8 to 10
times more often in woman than in men and usually develops after the age of 30.
Classification
1.Congetial.
2.
Acquired: 1. Primary (thyroid
gland disturbances).
2. Secondary (due to pituitary
disease).
3.Tertiary
(due to hypothalamic disease).
4.Peripheral.
Etiology
A cause is
usually evident from the history and physical examination.
1.Primary (thyroidal) hypothyroidism.
1) environmental iodine deficiency is the
most common cause of hypothyroidism on a worldwide basis.
2) autoimmune
processes (hypothyroidism usually occurring as a sequel to Hashimoto’s
thyroiditis and results in shrunken fibroid thyroid gland with a little or no
function and infiltrative diseases (tuberculosis, actynomycosis). Chronic
autoimmune thyroiditis (Hashimoto’s thyroiditis) is the most common cause of
hypothyroidism in areas of iodine sufficiency. Autoimmune thyroid diseases
(AITDs) have been estimated to be 5-10 times more common in women than in men.
Distinct
genetic syndromes with multiple autoimmune endocrinopathies have been
described, with some overlapping clinical features. The presence of two of the
three major characteristics is required to diagnose the syndrome of multiple
autoimmune endocrinopathies (MAEs). The defining major characteristics for type
1 MAE and type 2 MAE are as follows:
o
Type 1 MAE:
Hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis caused by
mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE
protein (51). Autoimmune thyroiditis is present in about 10%-15%.
o
Type 2 MAE: Addison’s
disease, autoimmune thyroiditis, and type 1 diabetes known as Schmidt’s
syndrome;
3) surgical
removal, total thyroidectomy of thyroid carcinoma, subtotal thyroidectomy
(hypothyroidism occurs from 25 to 75 of patients in different series);
4) irradiation
(hypothyroidism results from external neck irradiation therapy in doses 2000 rads
or more such as are used in the treatment of malignant lymphoma and laryngeal
carcinoma); I131 therapy for hyperthyroidism (it results in hyperthyroidism in
20 % to 60 % of patients within the first year after therapy and in 1 % to2 %
each year after);
5) during
or after therapy with propylthyouracil, methimazole, iodides;
6) Medications
such as amiodarone, interferon alpha, thalidomide, lithium, and stavudine have
also been associated with primary hypothyroidism.
7) Trauma.
2.Secondary and tertiary hypothyroidism
It
occurs due to either deficient secretion of TSH from the pituitary or lack of
secretion of TRH from the hypothalamus. Secondary hypothyroidism accounts for
less than 5% or 10% of hypothyroidism cases. Tertiary hypothyroidism accounts
for less than 5% of hypothyroidism cases.
1. hypothalamic
tumors (including craniopharyngiomas)
2. inflammatory
(lymphocytic or granulomatous hypophysitis)
3. infiltrative
diseases
4. hemorrhagic
necrosis (Sheehan’s syndrome)
5.
surgical and radiation
treatment for pituitary or hypothalamic disease
6. drugs (reserpin, parlodel).
3. Peripheral
hypothyroidism:
-
peripheral tissue resistance to
thyroid hormones;
-
decreasing of T4 peripheral
transformation into T3 (in liver or in kidneys) ;
-
production
of antibodies to thyroid hormones.
Congenital:
-
Maldevelopment –hypoplasia or
aplasia;
-
Inborn deficiencies of biosynthesis
or action of thyroid hormone;
-
Atypical localization of thyroid
gland;
Classification. (cont.)
B. 1.
Laboratory (subclinical) hypothyroidism.
2. Clinical hypothyroidism, which can be divided
on stages of severity: mild, moderate, severe.
C. 1.
Compensation.
2. Subcompensation.
3. Decompensation.
D. 1.
Without complications.
2. With complications
(myopathy, polyneuroparhy, encephalopathy, coma).
Clinical features
The major symptoms and signs of hypothyroidism
reflect showing of physiologic function. Virtually every organ system can be
affected. The onset of symptoms may be rapid or gradual,
severity varies considerably and correlates poorly with biochemical changes.
Because many manifestations of hypothyroidism are non-specific, the diagnosis
is particularly likely to be overlooked in patients with other chronic
illnesses and elderly.
Nervous system
Most of hypothyroid patients complain of
fatigue, loss of energy, lethargy, forgetfulness, reduced memory. Their level
of physical activity decreases, and they may speak and move slowly. Mental
activity declines and there is inattentiveness, decreased intellectual
function, and sometimes may be depression.
Neurological
symptoms include also hearing loss, parasthesias, objective neuropathy,
particularly the carpal tunnel syndrome, ataxia.
Tendon
reflex shows slowed or hung-up relaxation.
Skin
and hair.
Hypothyroidism
results in dry, thick and silk skin, which is often cool and pale.
Glycosoamynoglicanes, mainly hyaluronic acid accumulate in skin and
subcutaneous tissues retaining sodium and water. So, there is nonpitting oedema
of the hands, feet and periorbital regions (myxedema). Pitting oedema also may
be present. The faces are puffy and features are coarse. Skin may be orange due
to accumulation of carotene. Hair may become course and brittle, hair growth
slows and hair loss may occur. Lateral eyebrows thin out and body hair is
scanty.
Cardiovascular
system.
There
may be bradycardia, reduced cardiac output, quiet heart sounds, a flabby
myocardium, pericardial effusion (see pict.), cardiac wall is thick, it is increased by interstitial oedema. (These findings,
along with peripheral edema, may simulate congestive heart failure). Increased
peripheral resistance may result in hypertension. The ECG may show low voltage
and/or non-specific ST segment and T wave changes. Hypercholesterolaemia is
common. Whether or not these is an increased prevalence
of ischemic heart disease is controversial. Angina symptoms, when present,
characteristically occur less often after the onset of hypothyroidism, probably
because of decreased activity.
Gastrointestinal
system.
Hypothyroidism
does not cause obesity, but modest weight gain from fluid retention and fat
deposition often occurs. Gastrointestinal motility is decreased loading to
constipation and abdominal distension. Abdominal distension may be caused by
ascities as well. Ascitic fluid, like other serous effusions in myxedema, has
high protein content. Achlorhydria occurs, often associated with pernicious
anemia.
Renal system.
Reduced excretion of a water load may be associated
with hyponatriemia. Renal blood flow and glomerular filtration rate are reduced,
but serum creatinine is normal. May be mild proteinuria and
infections of urinary tract.
Respiratory
system.
Dyspnea of effort is common. This complaint may be
caused by enlargement of the tongue and larynx, causing upper airway
obstruction, or by respiratory muscle weakness, interstitial edema of the
lungs, and for pleural effusions which have high protein content. Hoarseness
from vocal curt enlargement often occurs.
Musculoskeletal
system.
Muscle and joint aches, pains and stiffness are
common. Objective myopathy and joint swelling or effusions are less often
present. The relaxation phase of the tendon reflexes is prolonged. Serum
creatine phosphokinase and alanine aminotransferase activities are often
increased, probably as much to slowed enzyme degradation as to increased
release from muscle.
Hemopoetic
system.
Anemia, usually normocytic, caused by decreased red
blood cell production, may occur. It is probably from decreased need of
peripheral oxygen delivery rather than hematopoetic defect. Megaloblastic
anemia suggests coexistent pernicious anemia. Most patients have no evidence
iron, folic acid or cyancobalamin deficiency.
Endocrine
system.
There may be menorrhagia (from anovulatory cycles),
secondary amenorrhea, infertility and rarely galactorrhea. Hyperprolactinemia
occurs because of the absence of the inhibitory effect of thyroid hormone on
prolactine secretion (and causes galactorrhea and amenorrhea or Van – Vik –
Cheness – Ross’s syndrome).
Pituitary-adrenal function is usually normal. Pituitary
enlargement from hyperplasia of the thyrotropes occurs rarely in patients with
primary hypothyroidism –such enlargement also may be caused by a primary
pituitary tumor, which resulting TSH deficiency.
Enlargement of thyroid gland in young children with hypothyroidism
suggests a biosynthetic defect. Hypothyroidism in adults is caused by Hashimoto
thyroiditis.
Secretion of growth hormone is deficient because
thyroid hormone is necessary for synthesis of growth hormone. Growth and
development of children are retarded. Epiphyses remain open.
Metabolic
system.
Hypothermia is common. Hyperlipidemia with increase of
serum cholesterol and trigliceride occurs because of reduced lipoprotein lipase
activity.
Subclinical
(laboratory) hypothyroidism.
It is an asymptomatic state in which serum T4 and free
T4 are normal, but serum TSH is elevated. ). This designation is only
applicable when thyroid function has been stable for weeks or more, the
hypothalamic-pituitary-thyroid axis is normal, and there is no recent or
ongoing severe illness. It is a state in which we can’t find
clinical features of hypothyroidism and euthyroidism is reached by compensatory
increasing of TSH secretion and that’s why synthesis and secretion of such
level of thyroid hormone that will be enough for organism.
An elevated TSH, usually above 10
mIU/L, in combination with a subnormal free T4 characterizes
overt hypothyroidism. The presence of elevated TPOAb titers in patients with
subclinical hypothyroidism helps to predict progression to overt
hypothyroidism—4.3% per year with TPOAb vs. 2.6% per year without elevated
TPOAb titers. The higher risk of developing overt hypothyroidism in
TPOAb-positive patients is the reason that several professional societies and
many clinical endocrinologists endorse measurement of TPOAbs in those with
subclinical hypothyroidism.The therapy may provide the
patient with more energy, a feeling of well being, desirable weight reduction,
improved bowel function or other signs of better health even though the patient
is not aware of these symptoms before therapy.
Peculiarities
of congenital hypothyroidism
•
Children are born with increased
weight
•
Subcutaneous edema
•
Hypotermia
•
Prolonged jaundice
•
Physical (dwarfism) and mental
retardation (cretinism
Diagnostic of
hypothyroidism is based on:
1) history;
2) clinical
features;
3) blood
analysis: anemia; hypercholesterolemia;
4) levels
of thyroid hormone: both serum T4 and T3 are decreased (but in 25% of patients
with primary hypothyroidism may be normal circulating levels of T3);
5) ECG;
6) examination
of tendon reflexes;
7) ultrasonic
examination;
Measurement of serum TSH is
the primary screening test for thyroid dysfunction, for evaluation of thyroid
hormone replacement in patients with primary hypothyroidism, and for assessment
of suppressive therapy in patients with follicular cell-derived thyroid cancer.
TSH levels vary diurnally by up to approximately 50% of mean values. TSH
secretion is exquisitely sensitive to both minor increases and decreases in
serum free T4, and abnormal TSH levels
occur during developing hypothyroidism and hyperthyroidism before free T4 abnormalities
are detectable. According to NHANES III, a disease-free population, which
excludes those who self-reported thyroid disease or goiter or who were taking
thyroid medications, the upper normal of serum TSH levels is 4.5
mIU/L.
Recommendations of Six Organizations Regarding
Screening of
Asymptomatic Adults for Thyroid Dysfunction
|
Organization |
Screening
recommendations |
|
American
Thyroid Association |
Women and
men >35 years of age should be screened every 5 years. |
|
American
Association of Clinical Endocrinologists |
Older
patients, especially women, should be screened. |
|
|
Patients ≥60 years of age should be screened. |
|
|
Women ≥50
years of age with an incidental finding suggestive of
symptomatic thyroid disease should be evaluated. |
|
|
Insufficient
evidence for or against screening |
|
|
Screening
of the healthy adult population unjustified |
Differential
diagnosis of primary and secondary hypothyroidism:
1) clinical
features:
Secondary
hypothyroidism is not common, but it often involves other endocrine organs
affected by the hypothalamic – pituitary axis. The clue to secondary
hypothyroidism is a history of amenorrhea rather than menorrhagia in a woman
with known hypothyroidism.
In secondary hypothyroidism, the skin and hair
are dry but not as coarse; skin depigmentation is often noted; macroglossia is
not prominent; breasts are atrophic; the heart is small without accumulation of
the serous effusions in the pericardial sac; blood pressure is low, and
hypoglycemia is often found because of concomitant adrenal insufficiency or
growth hormone deficiency.
2) laboratory
evaluation:
shows
a low level of circulating TSH in secondary hypothyroidism, whereas in primary
hypothyroidism there is no feedback inhibition of the intact pituitary and
serum levels of TSH are very high. The serum TSH is the most simple and
sensitive test for the diagnosis of pituitary hypothyroidism.
Serum
cholesterol is generally low in secondary hypothyroidism, but high in pituitary
hypothyroidism.
Other
pituitary hormones and their corresponding target tissue hormones may be low in
secondary hypothyroidism.
The
TSH test is useful in distinguishing between secondary and tertiary
hypothyroidism in the former; TSH is not released in response to TRH; whereas
in the later, TSH is released.
Treatment of
hypothyroidism.
1. No
specific diets are required for hypothyroidism.
2. Regimen
is not restricted.
3.
1) replacement therapy:
-
desiccated animal thyroid (this is an
extract of pig and cattle thyroid glands, which standardized based on its
iodine content but they are too variable in potency to be reliable and should
be avoided);
-
synthetic preparations of :
T4
(l-thyroxine)
-
T4 is preparation of choice, because
it produces stable serum levels of both T4 and T3.
-
Absorption is fairly constant 90 to
95% of the dose. T3 is generated from T4 by the liver.
-
The initial dosage can be 1.6 mkg/kg
of ideal weight or 12.5-25 mkg in older patients and 25-50 mkg in young adult. Patients
who are athyreotic (after total thyroidectomy and/or radioiodine therapy) and
those with central hypothyroidism may require higher doses, while patients with
subclinical hypothyroidism or after treatment for Graves’ disease may require
less. However, patients with subclinical hypothyroidism do not require full
replacement doses. Doses of 25-75 μg daily are usually sufficient for
achieving euthyroid levels, with larger doses usually required for those
presenting with higher TSH values. Moreover, although elderly patients absorb
L-thyroxine less efficiently they often require 20-25% less per kilogram daily
than younger patients, due to decreased lean body mass
-
Young healthy adults may be
started on full replacement dosage, which is also preferred after planned (in
preparation for thyroid cancer imaging and therapy) or short-term inadvertent
lapses in therapy. Starting with full replacement versus low dosages leads to
more rapid normalization of serum TSH but similar time to symptom resolution.
-
The dosage can be increased in 25-50
mkg increments at 4 to 6 week intervals until clinical and biochemical
euthyroidism is achieved. In older patients more gradual increments are
indicated. Cautious replacement is particularly warranted in patients with ischemic
heart disease, because angina pectoris or cardiac arrhythmia may be
precipitated by T4 therapy.
Patients older than 50-60
years, without evidence of coronary heart disease (CHD) may be started on doses
of 50 μg daily. Among those with known CHD, the usual starting dose is
reduced to 12.5-25 μg/day. Clinical monitoring for the onset of anginal
symptoms is essential. Anginal symptoms may limit the attainment of
euthyroidism. However, optimal medical management of arteriosclerotic
cardiovascular disease (ASCVD) should generally allow for sufficient treatment
with L-thyroxine to both reduce the serum TSH and maintain the patient
angina-free.
-
The average maintenance dosage is 100
to 150 mkg/day orally, only rarely is a larger dosage required. In general, the
maintenance dose may decrease in the elderly and may increase in pregnancy.
-
The dosage should be minimum that
restores TSH levels to normal (though this criterion cannot be used in patients
with secondary hypothyroidism). The most reliable
therapeutic endpoint for the treatment of primary hypothyroidism is the serum
TSH value. Confirmatory total T4, free T4, and T3 levels do
not have sufficient specificity to serve as therapeutic endpoints by
themselves, nor do clinical criteria. Moreover, when serum TSH is within the
normal range, free T4 will also
be in the normal range. On the other hand, T3 levels
may be in the lower reference range and occasionally mildly subnormal.
-
Patients being treated for
established primary hypothyroidism should have serum TSH measurements done at
4-8 weeks after initiating treatment or after a change in dose. Once an
adequate replacement dose has been determined, periodic TSH measurements should
be done after 6 months and then at 12-month intervals, or more frequently if
the clinical situation dictates otherwise.
-
In patients with central
hypothyroidism, assessment of free T4 or free T4 index,
not TSH, should be done to diagnose and guide treatment of hypothyroidism.
-
Patient takes the whole dose of T4
once a day (in the morning), in the summer the dose may be decreased and in the
winter should be increased.
-
When a woman with
hypothyroidism becomes pregnant, the dosage of L-thyroxine should be increased
as soon as possible to ensure that serum TSH is <2.5 mIU/L and that serum
total T4 is in the normal reference
range for pregnancy. Moreover, when a patient with a positive TPOAb test
becomes pregnant, serum TSH should be measured as soon as possible and if
>2.5 mIU/L, T4 treatment
should be initiated. Serum TSH and total T4 measurements
should be monitored every 4 weeks during the first half of pregnancy and at
least once between 26 and 32 weeks gestation to ensure that the requirement for
L-thyroxine has not changed.
T3
(liothyronine sodium) should not be used alone for long-term
replacement because its rapid turnover requires that it be taken. T3 is
occasionally used mainly in starting therapy because the rapid excretion is
useful in the initial titration of a patient with longstanding hypothyroidism
in whom cardiac arrhythmia may occur early in replacement therapy. The risk of
jatrogenic hyperthyroidism is therefore greater in patients receiving these
preparations.
In addition, administering standard replacement
amounts of T3 (25 to 50 mkg/day) results in rapidly increasing serum T3 levels
to between 300 and 1000 mkg within 2 to 4 h, these levels return to normal by
24 h. Therefore, when assessing serum T3 levels in patients on this particular
regimen, it is important for the physician to be aware of the time of prior administration
of the hormone. Additionally, patients receiving T3 are chemically hyperthyroid
for at least several hours a day and thus are exposed to greater cardiac risks.
Similar patterns of serum T3
concentrations are seen when mixtures of T3 and T4 are taken orally, although the peak levels
of T3 are somewhat lower. Replacement
regimes with synthetic preparations of T4
reflect a different pattern of serum T3
response increases in serum T3 occur gradually over weeks, finally
reaching a normal value about 8 wk. after starting therapy.
Synthetic T3 and T4
combinations (liotrix, thyreocomb). These preparations were
developed before it was appreciated that T4 is converted to T3 outside of the
thyroid. These preparations should not be used.
2) Symptomatic therapy:
-
beta-blockers (should be used in
patients with tachycardia and hypertension);
-
hypolypidemic agents;
-
vitamins (A, B, E);
-
diuretics and others.
Subclinical hypothyroidism
However, there are virtually no clinical outcome data
to support treating patients with subclinical hypothyroidism with TSH levels
between 2.5 and 4.5 mIU/L. The possible exception to this statement is
pregnancy because the rate of pregnancy loss, including spontaneous miscarriage
before 20 weeks gestation and stillbirth after 20 weeks, have been reported to
be increased in anti-thyroid antibody-negative women with TSH values between
2.5 and 5.0
Many endocrinologists would treat such patients
with T4, especially if hypercholesterolemia were present. Even in the absence
of hyperlipidemia, a trial of therapy might be varianted to determine if the
patient experiences improvement presumably the normal serum T4 concentrations
before therapy did not reflect adequate tissue effects of thyroid hormones in
such patients. Unfortunately, it is also reasonable to follow these patients
without T4 therapy by surveying thyroid function at 4-to 6 months intervals to
determine whether thyroid failure has occurred, as indicated by the serum T4
falling to subnormal levels along with a greater increase in serum TSH and the
appearance of clear symptoms.
Reviews by the US Preventive Services Task Force
and an independent expert panel found inconclusive evidence to
recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L. The
Endocrine Society recommends thyroxine replacement in pregnant women with
subclinical hypothyroidism; the
Hashimoto thyroiditis (chronic lymphocytic
thyroiditis)
This
is the frequent reason of hypothyroidism worldwide.
Etiology
HT is an organ - specific autoimmune disorder, a
chronic inflammation of the thyroid with lymphocytic infiltration of the gland
generally thought to be caused by autoimmune factors.
It is more prevalent (8:1) in woman than men and is
most frequent between the ages of 30 and 50 . A family history of thyroid
disorders is common, and incidence is increased in patients with chromosomal
disorders, including Turners, Down and Klinefelters syndromes. Histologic
studies reveal extensive infiltration of lymphocytes in the thyroid.
The basic defect underlying this disease suggests an
abnormality in suppressor T lymphocytes that allows helper T lymphocytes to
interact with specific antigens directed against the thyroid cell. A genetic
predisposition is suggested because of the frequent occurrence of the HLA- DR5
histocompatibility antigen in patients with HT.
Pict.
Interstitial lymfoid infiltrate (HASH)
Pict. Low
power view of a case of Hashimoto’s thyroiditis.
Notice
lymphoid follicles
Pict. High
power view of a case of Hashimoto’s thyroiditis
showing
lymphoid follicles within thyroid tissue.
Clinical features
HT is characterized by a wide spectrum of clinical
features, ranging from no symptoms and the presence of small goiter to frank
myxedema.
Occasionally
patients complain of a vague sensation of tightness in the area of the anterior
neck or mild dysphagia. In general, however, thyroid enlargement is insidious
and asymptomatic. Symptoms of hypothyroidism may or may not be present,
depending on the presence or absence of biochemical hypothyroidism.
Physical examination
usually discloses a symmetrically enlarged, very firm goiter, a smooth or knobby
consistency is common. Occasionally patients present with a single thyroid
nodule.
A
small group of patients have a form of HT termed primary idiopathic
hypothyroidism, goiter is usually absent in this group.(atrophic form of HT).
Yet
a small subset of patients(probably 2-4%) present with hyperthyroidism and have
so-called hashitoxicosis (hypertrophy from of HT).
Laboratory findings
1) early
in the disease a normal T and high titers of antithyroid (antimicrosomal)
antibodies, peroxidase antibodies can be detected. Late in the disease, the
patient develops hypothyroidism with a decreased in T and antibodies in this
stage are usually no longer detectable;
2) the
thyroid scan typically shows a irregular pattern of iodine uptake;
3) fine-needle
biopsy of the nodule or enlarging area should be done to rule out a coexistent
neoplasm.
Treatment
1) treatment
of HT requires lifelong replacement with thyroid hormone to correct and prevent
hypothyroidism. The average oral replacement dose with l-thyroxine is 100 to
150 mkg/day;
2) glucocorticoids
have been reported to be effective in HT when true is a rapidly enlarging
goiter associating with pressure symptoms;
3) symptomatic
therapy
THYROID NODULES
Both benign and malignant disorders can cause thyroid
nodules. Hence, the clinical importance of newly diagnosed thyroid nodules is
primarily the exclusion of malignant thyroid lesions. In iodine-deficient
areas, however, local symptoms, functional autonomy, and hyperthyroidism are
common clinical problems.
Causes
of Thyroid Nodules
|
Benign nodular goiter |
|
Chronic lymphocytic thyroiditis |
|
Simple or hemorrhagic cysts |
|
Follicular adenomas |
|
Subacute thyroiditis |
|
Papillary carcinoma |
|
Follicular carcinoma |
|
Hürthle cell carcinoma |
|
Poorly differentiated carcinoma |
|
Medullary carcinoma |
|
Anaplastic carcinoma |
|
Primary thyroid lymphoma |
|
Sarcoma, teratoma, and miscellaneous tumors |
|
Metastatic tumors |
|
|
Clinical
feature
Most patients with thyroid nodules have few or to
symptoms, and usually no clear relationship exists between nodule histologic
features and the reported symptoms. Thyroid nodules are often discovered
incidentally on physical examination, color Doppler evaluation of the carotid
artery, or imaging studies performed for unrelated. In symptomatic patients, a
detailed history and a complete physical examination may guide the selection of
appropriate clinical and laboratory investigations.
·
Slow
but progressive growth of the nodule (during weeks or months) is suggestive of
malignant involvement.
·
Sudden
pain is commonly due to hemorrhage in a cystic nodule.
·
In
patients with progressive and painful enlargement of a thyroid nodule, however,
anaplastic carcinoma or primary lymphoma of the thyroid should be considered.
·
Symptoms
such as a choking sensation, cervical tenderness or pain, dysphagia, or
hoarseness may be perceived as attributable to thyroid disease, but in most
patients, these symptoms are caused by nonthyroid disorders.
·
Slow-onset
cervical symptoms and signs caused by the compression of vital structures of
the neck or upper thoracic cavity usually occur if thyroid nodules are embedded
within large goiters. When observed in the absence of a multinodular goiter
(MNG), the symptoms of tracheal compression (cough and dysphonia) suggest an
underlying malignant lesion. Differentiated
thyroid carcinomas rarely cause airway obstruction, vocal cord paralysis, or
esophageal symptoms at their clinical presentation. Hence, the absence of local
symptoms does not rule out a malignant tumor.
Physical evaluation
Small
differentiated thyroid cancers are frequently devoid of alarming
characteristics on physical evaluation. However, a firm or hard, solitary or
dominant thyroid nodule that clearly differs from the rest of the gland
suggests an increased risk of malignant involvemen. Therefore, despite the low
predictive value of palpation, a careful inspection and palpation of the
thyroid gland and the anterior and lateral nodal compartments of the neck
should always be done. Available to detect thyroid lesions, measure their
dimensions, identify their structure, and evaluate diffuse changes in the
thyroid gland. If results of palpation are normal, US should be performed when
a thyroid disorder is suspected on clinical grounds or if risk factors have
been recognized. The physical finding of suspicious neck adenopathy warrants US
examination of both lymph nodes and thyroid gland because of the risk of a metastatic
lesion from an otherwise unrecognized papillary microcarcinoma.
Standardized
Indications for US of thyroid gland:
·
Patients
at risk for thyroid malignancy
·
Patients
with palpable thyroid nodules or MNGs
·
Patients
with lymphadenopathy suggestive of a malignant lesion
AACE/AME/ETA Thyroid Nodule Guidelines, Endocr
Pract. 2010;16(Suppl 1)
Indications for FNA
FNA
biopsy is recommended for nodule(s):
-
Of
diameter larger than
-
Of
any size with US findings suggestive of extracapsular growth or metastatic
cervical lymph nodes
-
Of
any size with patient history of neck irradiation in childhood or adolescence;
PTC, MTC, or MEN
-
Of
any size with patient history of previous thyroid surgery for cancer;
-
Of
any size with patient history of
increased calcitonin levels in the absence of interfering factors;
-
Of
diameter smaller than
-
the
coexistence of 2 or more risk of thyroid cancer
- Nodules that are hot on scintigraphy
should be excluded from FNA biopsy
US
Criteria for FNA Biopsy of Palpable Nodules.
The risk of cancer is not significantly
higher for palpable solitary thyroid nodules than for multinodular glands or
nodules embedded in diffuse goiters. Moreover, in 50% of thyroid glands with a
“solitary” nodule on the basis of palpation, other small nodules are discovered
by US.
For MNGs, the cytologic sampling should be
focused on lesions with suspicious
Large neoplastic lesions may be
characterized by degenerative changes and multiple fluid-filled areas, findings
rarely noted in microcarcinomas. Although most complex thyroid nodules with a
dominant fluid component are benign, UGFNA biopsy should always be performed
because papillary thyroid carcinoma (PTC) can be partially cystic. Extension of
irregular hypoechoic lesions beyond the thyroid capsule, invasion of prethyroid
muscles, and infiltration of the recurrent laryngeal nerve are infrequent but
threatening
US Criteria for FNA Biopsy of Impalpable Nodules and
Nodular Goiters
Clinically inapparent thyroid lesions were
detected by US in about half of the women in several studies. The prevalence of
cancer reported for nonpalpable thyroid lesions ranges from 5.4% to 7.7% and
appears to be similar to that reported for palpable lesions (5.0%- 6.5%).
Clinical criteria for a malignant nodule are lacking for most nonpalpable
lesions. Hence, it is essential to determine which thyroid lesions have a high
malignant potential on the basis of their
FNA
Biopsy of Multinodular Glands
It is rarely necessary to biopsy more than 2 nodules
when they are selected on the basis of previously described criteria
If a radioisotope scan is available, do not biopsy hot
areas
In the presence of suspicious cervical
lymphadenopathy, FNA biopsy of both the lymph node and suspicious nodule(s) is
essential
FNA
Biopsy of Complex (Solid-Cystic) Thyroid Nodule(s)
Always sample the solid component of the lesion by
UGFNA biopsy
Submit both the FNA biopsy specimen and the drained
fluid for cytologic examination
FNA
Biopsy of Thyroid Incidentalomas
Thyroid incidentalomas should be managed according to
previously described criteria for nodule diagnosis. Incidentalomas detected by
CT or MRI should undergo
LABORATORY
EVALUATION
I. Assessment
of Thyroid Function:
ü
TSH Assay The high sensitivity of the TSH assay for
detecting even subtle thyroid dysfunction makes it the most useful laboratory
test in the initial evaluation of thyroid nodules. Third-generation TSH
chemiluminometric assays, with detection limits of about 0.01 microunits/mL,
should be used in current clinical practice. They can detect decreased TSH
levels even in mild cases of hyperthyroidism and allow a reliable diagnosis of
mild (subclinical) thyroid hyperfunction.
Measuring serum levels of free thyroid hormones and TPOAb or
anti–TSH-receptor antibody (TRAb) should be the second diagnostic step, which
is necessary for confirmation and the subsequent definition of thyroid dysfunction
if the TSH concentration is outside the reference range
ü Serum Free Thyroxine and Free
Triiodothyronine
If the serum TSH level is within the reference range, the
measurement of free thyroid hormones adds no further relevant information.
If TSH levels are low, however, measurement of free thyroxine and
free triiodothyronine levels is necessary to confirm the presence of
hyperthyroidism or consider central hypothyroidism, in which TSH can be normal
or low and free thyroxine levels may be low.
To limit unnecessary laboratory testing, the following strategy
should be followed for most patients with thyroid nodules:
• Serum
TSH level within normal limits:
no further testing (unless suspicion of central hypothyroidism)
• Increased
serum TSH: test free thyroxine and TPOAb to evaluate for hypothyroidism
• Decreased
serum TSH: test free thyroxine and triiodothyronine to evaluate for
hyperthyroidism
ü
Antibody Assays
TPOAb
Assay TPOAb should be measured in
patients with high levels of serum TSH. High serum TPOAb values and a firm,
diffusely enlarged, or small thyroid are very suggestive of autoimmune or
Hashimoto thyroiditis. Occasionally, a nodular goiter may represent Hashimoto
thyroiditis. Antithyroglobulin antibody testing should be reserved for patients
with US and clinical findings suggestive of chronic lymphocytic thyroiditis in
conjunction with normal serum TPOAb levels.
TRAb determination should be performed in patients with
hyperthyroidism for more complete etiologic clarification, because 17% of
patients in iodine-deficient areas with scintigraphic criteria for toxic MNG
are positive for TRAb.
Thyroglobulin
Assay Assessment of serum thyroglobulin is not recommended in the
diagnosis of thyroid nodules. In patients undergoing surgery for malignancy,
testing of serum thyroglobulin may be considered so as not to overlook a
false-negative serum thyroglobulin value due to decreased thyroglobulin
immunoreactivity or heterophilic antibodies.
Calcitonin
Assay Calcitonin is a serum marker for MTC and correlates with tumor
burden. Calcitonin testing is imperative in patients with a history or a
clinical suspicion of familial MTC or MEN 2. Calcitonin measurement is
recommended if FNA biopsy results are suggestive of MTC and in patients with
nodular goiters undergoing thyroid surgery to avoid the risk of inadequate
surgical treatment. Routine testing of serum calcitonin for MTC in all patients
with unselected thyroid nodules is still debated. Studies of nodular thyroid
disease have reported a prevalence of MTC ranging from 0.4% to 1.4% of all
patients. Calcitonin levels can be increased in patients with pulmonary or
pancreatic endocrine tumors, kidney failure, autoimmune thyroid disease, or
hypergastrinemia (resulting from proton-pump inhibitor therapy); other factors
that increase calcitonin are alcohol consumption, smoking, sepsis, and
heterophilic anticalcitonin antibodies. In addition, sex, age, weight,
increased calcium levels, and the assay itself also affect the calcitonin
level. Cutoff values, such as 10 or 20 pg/mL, have been effectively used for
the screening of unselected nodules. The false-positive rate decreases with
increasing cutoff levels. Therefore, a single nonstimulated calcitonin
measurement can be used in the routine workup of thyroid nodules. If the
calcitonin value is increased, the test should be repeated and, if confirmed in
the absence of the above modifiers, pentagastrin-stimulation testing will
increase the diagnostic accuracy. The availability of pentagastrin is limited
outside Europe; in the United States, calcitonin stimulation may be performed
with calcium. The diagnostic value of calcium-stimulation test results has not
been completely assessed, but a cutoff for the response in healthy subjects is
under investigation. Screening of at-risk family members should be done by
testing for germline mutations in the RET proto-oncogene. Screening for RET proto-oncogene
germline mutations in apparently sporadic MTC may detect MEN
II.
RADIONUCLIDE SCANNING
Thyroid
Scintigraphy Thyroid scintigraphy is the only technique
that allows for assessment of thyroid regional function and detection of areas
of AFTN.
Diagnostic
Accuracy On the basis of the pattern of radionuclide uptake, nodules may be
classified as hyperfunctioning (“hot”), hypofunctioning (“cold”), or
indeterminate. Hot nodules almost never represent clinically significant
malignant lesions, whereas cold or indeterminate nodules have a reported
malignancy risk of 3% to 15%. Because most thyroid lesions are cold or
indeterminate and only a small minority of them are malignant, the predictive
value of hypofunctioning or indeterminate nodules for the presence of malignant
involvement is low.
Pic. Multinodular
goiter Pic.
Autonomous hot nodule
The diagnostic specificity is further decreased in small lesions (<
The early recognition of autonomous nodules, before they induce the
suppression of TSH, enables early treatment to avoid thyroid growth and
progression toward manifest hyperthyroidis. Furthermore, in iodine-deficient
euthyroid goiters, microscopic areas of hot thyroid tissue contain
constitutively activating TSH receptor mutations, which increase the risk of
iodine-induced hyperthyroidism. Quantitative pertechnetate scintigraphy
(calculation of technetium thyroid uptake under suppression) is a sensitive and
specific technique for the diagnosis and quantitation of thyroid autonomy and
is a reliable predictor of hyperthyroidism in the setting of euthyroid
autonomy.
Thyroid scintigraphy is a procedure producing one or
more planar images of the thyroid obtained within 15–30 min after intravenous
injection of Tc- 99m pertechnetate or 3–24 hr after the oral ingestion of
radioactive iodine (I-131).
Indications for Thyroid Scintigraphy:
1.
With a single thyroid nodule and
suppressed TSH level; FNA biopsy is not necessary for hot nodules
2.
For MNGs, even without suppressed TSH, to
identify cold or indeterminate areas for FNA biopsy and hot areas that do not
need cytologic evaluation
3.
For large MNGs, especially with substernal
extension
4.
In the diagnosis of ectopic thyroid tissue
5.
In subclinical hyperthyroidism to identify
occult hyperfunctioning tissue
6.
In follicular lesions to identify a
functioning cellular adenoma that may be benign; however, most such nodules are
cold on scintigraphy
7.
To determine eligibility for radioiodine
therapy
8.
To distinguish low-uptake from high-uptake
thyrotoxicosis
It
is important to ensure that the patient is not pregnant or lactating. The
concentration of radioiodine in the thyroid is affected by many factors:
a. Medications, such as thyroid hormones and antithyroid agents which affect
the pituitary- thyroid axis
b.
Iodine-containing food (e.g. kelp) and medications (e.g. iodinated contrast,
amiodarone, betadine)
Except
under very specific circumstances (e.g. to determine if a nodule is
autonomous), thyroid scintigraphy should be delayed for a period long enough to
eliminate the effects of these interfering factors.
Patient
will be positioned on an examination table. If necessary, a nurse or
technologist will insert an intravenous (IV) line into a
vein in his hand or arm. Depending on the type of nuclear medicine exam, the
dose of radiotracer is then injected intravenously, swallowed or inhaled as a
gas.
When radiotracer is taken by mouth,
in either liquid or capsule form, it is typically swallowed up to 24 hours
before the scan. The radiotracer given by intravenous injection is usually
given 30 minutes prior to the test.
When it is time for the imaging to
begin, patient will lie down on a moveable examination table with his head tipped backward and neck
extended. The gamma camera
will then take a series of images, capturing images of the thyroid gland from
three different angles. Patient will need to remain still for brief periods of
time while the camera is taking pictures.
Thyroid scintigraphy can be performed with 123I or 99mTcO4 –
(sodium pertechnetate). Each of these imaging agents has advantages and disadvantages.
99mTcO4
• Advantages: less
expensive; more readily available; more rapid examination
• Disadvantages: technetium
is trapped but not organified (risk of false-positive images); activity in
esophagus or vascular structures can be misleading; poor image quality when
uptake is low
123I
• Advantages: better
visualization of retrosternal thyroid tissue; better images when thyroid uptake
is low; real iodine clearance of the thyroid may be measured instead of Tc
uptake as a surrogate parameter
• Disadvantages: higher cost; less
comfortable for the patient (delayed imaging at 24 hours is often used); less
readily available; imaging times usually longer
Thyroid Nodules During
Pregnancy
Most cases of thyroid nodules during
pregnancy are in patients with preexisting nodules who then become pregnant;
occasionally, however, a thyroid nodule is detected for the first time during
pregnancy. A thyroid nodule in a pregnant woman should be managed in the same
way as in nonpregnant women, except for avoiding the use of radioactive agents
for both diagnostic and therapeutic purposes. Thyroid nodule diagnosis during
pregnancy necessitates FNA biopsy if findings are suspicious, regardless of the
gestational age of the fetus. Sharing of findings among the endocrinologist,
obstetrician, thyroid surgeon, pathologist, and anesthesiologist is
recommended. Furthermore, the patient’s preferences should also be
appropriately considered.
Effects
of Pregnancy on Nodular Thyroid Disease Several datas indicate that pregnancy is associated
with an increase in the size of preexisting nodules and with the appearance of
newly developed thyroid nodules, possibly because of the negative iodine
balance that frequently occurs during pregnancy.
Management
and Therapy
Benign
Thyroid Nodule Although
pregnancy is a risk factor fo arresting the growth of thyroid nodules during
pregnancy. Hence, levothyroxine suppressive therapy for thyroid nodules is not
advisable during pregnancy.
Follicular or Suspicious Thyroid Nodule Suspicious cytologic findings pose a
difficult problem during pregnancy. Although pregnancy may cause a misleading
diagnosis of follicular neoplasm because of a physiologic increase in
follicular epithelium, the malignancy rate of follicular neoplasm in pregnant
women is similar to that in nonpregnant women—about 14%. Therefore, deferring
surgical treatment to the postpartum period seems reasonable.
Malignant Thyroid Nodule Thyroid cancer is rarely diagnosed during
pregnancy. If cancer is diagnosed during the first or second trimester, the
patient may undergo surgical treatment during the second trimester, when
anesthesia risks are minimal. However, women with no evidence of aggressive
thyroid cancer may be reassured that surgical treatment performed soon after
delivery is unlikely to adversely affect prognosis. If the cytologic diagnosis
is made during the third trimester, the surgical procedure can be postponed
until the immediate postpartum period.
Toxic nodular goiter
A toxic nodular goiter (TNG) is a thyroid
gland that contains autonomously functioning thyroid nodules, with resulting
hyperthyroidism. TNG, or Plummer's disease, was first described by Henry
Plummer in 1913. TNG is the second most common cause of hyperthyroidism in the
Western world, after Graves disease. In elderly individuals and in areas of
endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.
Toxic nodular goiter (TNG) represents
a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma)
within a multinodular thyroid to a gland with multiple areas of hyperfunction.
The natural history of a multinodular goiter involves variable growth of
individual nodules; this may progress to hemorrhage and degeneration, followed
by healing and fibrosis. Calcification may be found in areas of previous
hemorrhage. Some nodules may develop autonomous function. Autonomous
hyperactivity is conferred by somatic mutations of the thyrotropin, or
thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and
some nodules of multinodular goiters.Autonomously functioning nodules may
become toxic in 10% of patients. Hyperthyroidism predominantly occurs when
single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG
are similar to those of other types of hyperthyroidism.
Toxic nodular goiter occurs more
commonly in women than in men. In women and men older than 40 years, the
prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.
Most patients with toxic nodular
goiter (TNG) are older than 50 years.
Clinical
features
1.
Thyrotoxic
symptoms - Most patients with toxic nodular goiter (TNG)
present with symptoms typical of hyperthyroidism, including heat intolerance,
palpitations, tremor, weight loss, hunger, and frequent bowel movements.
Elderly patients may have more atypical symptoms,
including the following:
§
Weight loss is the most common
complaint in elderly patients with hyperthyroidism.
§
Anorexia and constipation may occur,
in contrast to frequent bowel movements often reported by younger patients.
§
Dyspnea or palpitations may be a
common occurrence.
§
Tremor also occurs but can be
confused with essential senile tremor.
§
Cardiovascular complications occur
commonly in elderly patients, and a history of atrial fibrillation, congestive
heart failure, or angina may be present.
F. Lahey, MD, first described apathetic
hyperthyroidism in 1931; this is characterized by blunted affect, lack of
hyperkinetic motor activity, and slowed mentation in a patient who is
thyrotoxic.
2.
Obstructive
symptoms - A significantly enlarged goiter can cause symptoms
related to mechanical obstruction.
o
A large substernal goiter may cause
dysphagia, dyspnea, or frank stridor. Rarely, this goiter results in a
surgical emergency.
o
Involvement of the recurrent or
superior laryngeal nerve may result in complaints of hoarseness or voice
change.
3.
Asymptomatic -
Many patients are asymptomatic or have minimal symptoms and are incidentally
found to have hyperthyroidism during routine screening. The most common
laboratory finding is a suppressed TSH with normal free thyroxine (T4) levels.
Diagnostic
1.
Thyroid function tests - evidence of
hyperthyroidism must be present in order to consider a diagnosis of toxic
nodular goiter (TNG).
o
Third-generation TSH assays are
generally the best initial screening tool for hyperthyroidism. Patients with
TNG will have suppressed TSH levels.
o
Free T4 levels or surrogates of free
T4 levels (ie, free T4 index) may be elevated or within the reference range. An
isolated increase in T4 is observed in iodine-induced hyperthyroidism or in the
presence of agents that reduce peripheral conversion of T4 to triiodothyronine
(T3) (eg, propranolol, corticosteroids, radiocontrast agents, amiodarone).
o
Some patients may have normal free T4
levels (or free T4 index) with an elevated T3 level (T3 toxicosis); this may
occur in 5-46% of patients with toxic nodules. Note that the total T3 and T4
levels may often be within the reference range but may be higher than the
normal range for a particular individual; this is especially true in patients
with nonthyroidal illness in which T3 levels are decreased.
o
Some patients may have subclinical
hyperthyroidism (suppressed TSH levels with normal free T4 and total T3
levels).
2.
Patchy uptake of iodine (123I) in a
toxic multinodular goiter.
3.
Nuclear scintigraphy - nuclear scans
should be performed on patients with biochemical hyperthyroidism. Nuclear
medicine scans can be performed with radioactive iodine-123 (123 I)
or with technetium-99m (99m Tc). These isotopes are chosen for their
shorter half-life and because they provide lower radiation exposure to the
patient when compared with sodium iodide-131 (Na131 I).
4.
Ultrasonography - ultrasonography is
a highly sensitive procedure for delineating discrete nodules that are not
palpable during thyroid examination. Ultrasonography is helpful when correlated
with nuclear scans to determine the functionality of nodules. Dominant cold
nodules should be considered for fine-needle aspiration biopsy prior to definitive
treatment of a TNG.
5.
Fine-needle aspiration is not usually
indicated in an autonomously functioning (ie, hot) thyroid nodule. The risk of
malignancy is quite low. Interpretation of the cytology specimen is difficult,
because it is likely to demonstrate a follicular neoplasm (ie, sheets of
follicular cells with little or no colloid), and distinguishing between a
benign lesion and a malignant lesion is not possible without histologic
sectioning to examine for the presence of vascular or capsular invasion.Perform
a fine-needle aspiration biopsy if a dominant cold nodule is present in a
multinodular goiter. A clinically significant nodule is larger than 1 cm in
maximum diameter, based on either palpation or ultrasonographic images, unless
there is an increased risk of malignancy. Nonpalpable nodules may be biopsied
with the assistance of ultrasonography.
Surgical Care
Surgical
therapy is usually reserved for young individuals, patients with 1 or more
large nodules or with obstructive symptoms, patients with dominant
nonfunctioning or suspicious nodules, patients who are pregnant, patients in
whom radioiodine therapy has failed, or patients who require a rapid resolution
of the thyrotoxic state.
·
Subtotal thyroidectomy results in
rapid cure of hyperthyroidism in 90% of patients and allows for rapid relief of
compressive symptoms.
·
Restoring euthyroidism prior to
surgery is preferable.
·
Complications of surgery include the
following:
o
In patients who are treated surgically,
the frequency of hypothyroidism is similar to that found in patients treated
with radioiodine (15-25%).
o
Complications include permanent vocal
cord paralysis (2.3%), permanent hypoparathyroidism (0.5%), temporary
hypoparathyroidism (2.5%), and significant postoperative bleeding (1.4%).
o
Other postoperative complications
include tracheostomy, wound infection, wound hematoma, myocardial infarction,
atrial fibrillation, and stroke.
o
The mortality rate is almost zero.
THYROID
CANCER
The thyroid consists predominantly of follicular epithelial cells, which
incorporate iodine into thyroid hormone to be stored in follicles, and of
smaller numbers of parafollicular cells, which produce calcitonin (CT).
Malignant transformation of either type of cell may occur, but the
parafollicular malignancy (medullary carcinoma of the thyroid [MCT]) is
much less common than cancers derived from follicular epithelial cells.
Malignancies originating from follicular epithelial cells are designated
according to their microscopic appearance and include papillary, follicular,
and anaplastic carcinomas
Papillary carcinoma and its variants comprise approximately 60-80% of
thyroid cancers, whereas follicular carcinoma makes up approximately 15-30% of
primary thyroid malignancies. These two forms are frequently referred to as the
differentiated thyroid carcinomas (DTCs). MCT accounts for 2-10% of
thyroid carcinomas, whereas anaplastic forms of thyroid carcinoma account for
1-10%.
Papillary and follicular carcinomas are histologically distinct.
Papillary carcinoma is generally an unencapsulated tumor marked by enlarged
cells with dense cytoplasm and overlapping nuclei that have granular, powdery
chromatin, nucleoli, and pseudonuclear inclusion bodies (often called
"Orphan Annie eyes"), all arranged in papillary fronds. Follicular
carcinoma is generally characterized by atypical-appearing thyroid cells with
dense, uniform, overlapping nuclei, and a disorganized microfollicular
architecture.
Papillary and follicular carcinomas behave as clinically distinct
entities. Most endocrinologists consider follicular carcinoma to be the more
aggressive of the differentiated cancers, with a higher rate of metastases,
more frequent recurrence after therapy, and an exaggerated mortality rate
compared with the relatively indolent papillary carcinoma. This view is not
universal. Some authors believe that the sharp dichotomy between the clinical
courses of papillary and follicular carcinomas is artificial and attribute the
apparent aggressiveness of follicular carcinoma to its occurrence in an older
population; they argue that when cases are controlled for age, outcomes of
patients with either form of DTC are comparable,
Follicular carcinoma usually presents as an asymptomatic nodule within
the thyroid, but unlike papillary carcinoma, it may present as an isolated
metastatic pulmonary or osseous focus without a palpable thyroid lesion. Very
rarely metastatic foci of follicular carcinoma retain hormonal synthetic
capability and overproduce thyroid hormones, causing thyrotoxicosis. The tumor
is nearly always encapsulated, and the degree of vascular or capsular
invasiveness (minimal to extensive) is indicative of malignant potential.
Follicular carcinoma is usually unifocal (< 10% multifocal). Death due to
follicular carcinoma occurs in 13-59% of patients followed for 20 years.
Prognostic factors at the time of initial therapy that portend a poor outcome
include age greater than 50 years, male sex (in some settings), marked degree
of vascular invasion, and distant metastases.
TNM CLASSIFICATION SYSTEM FOR DIFFERENTIATED THYROID
CARCINOMA
|
|
Definition |
|
|
T1 |
Tumor diameter |
|
|
T2 |
Primary tumor diameter >2 to |
|
|
T3 |
Primary tumor diameter > |
|
|
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 |
|
|
TX |
Primary tumor size unknown, but without
extrathyroidal invasion |
|
|
N0 |
No
metastatic nodes |
|
|
N1a |
Metastases to level VI (pretracheal, paratracheal,
and prelaryngeal/Delphian lymph nodes) |
|
|
N1b |
Metastasis to unilateral, bilateral, contralateral
cervical or superior mediastinal nodes |
|
|
NX |
Nodes not assessed at surgery |
|
|
M0 |
No distant
metastases |
|
|
M1 |
Distant
metastases |
|
|
MX |
Distant
metastases not assessed |
|
|
Stages |
|
|
|
|
Patient
age <45 years |
Patient age 45 years or older |
|
Stage I |
Any T, any
N, M0 |
T1, N0, M0 |
|
Stage II |
Any T, any
N, M1 |
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,
N0 |
|
|
|
T4a, N1b,
M0 |
|
Stage IVB |
|
T4b,
Any N, M0 |
|
Stage IVC |
|
Any T, Any
N, M1 |
The original source for this material is the AJCC
Cancer Staging Manual, Sixth Edition
Treatment of
DTCs
Simply stated, therapy for DTC is based on
surgical removal of the primary tumor and eradication of all metastatic disease
with radioactive iodine (131I). Lifelong suppression of
thyroid-stimulating hormone (TSH) with exogenous thyroid hormone subsequently
reduces the risk of recurrence.
Opinions about the extent of initial surgical resection have been
tempered by the possible complications of
thyroid surgery; recurrent laryngeal nerve damage with resultant hoarseness and/or
iatrogenic hypoparathyroidism may occur in 1-5% of thyroid resections. Fear of
complications, coupled with the relatively low mortality rate associated with
DTC, has prompted some surgeons to remove only the thyroid lobe in which cancer
is apparent at the time of exploration.
Patients with large or aggressive tumors, metastatic disease evident
during surgery, or extrathyroidal lesions visible on postsurgical whole-body
scans usually receive 100-200 mCi of 131I in an attempt to eradicate
the malignancy. These "large" doses of radioiodine have traditionally
been administered only in an approved inpatient facility under the auspices of
the Nuclear Regulatory Commission (NRC). Patients remain isolated until ambient
levels of radioactivity fall to acceptable levels. Radionuclide is excreted
renally, but significant amounts are also present in saliva and sweat. Such
wastes must be disposed of appropriately. Recently, the NRC has lifted the
absolute requirement for inpatient administration of high-dose 131I,
and it is now performed in some centers on an outpatient basis.
The early complications of 131I
therapy.
Radioiodine is absorbed by the salivary glands,
gastric mucosa, and thyroid tissue. Within 72 hours of oral administration of 131I,
patients may experience radiation sialadenitis and transient nausea. Such
symptoms are self-limited. Thyroid tissue may become edematous and tender but
rarely requires corticosteroid therapy. Radioiodine, borne in the blood, causes
transient, clinically insignificant suppression of the bone marrow. In some
centers, dosimetry is used to determine the maximum dose of 131I
that can be safely administered at one time to patients with invasive or
metastatic disease.
Late complications
of high-dose radioiodine therapy may include gonadal dysfunction and
predisposition to nonthyroidal malignancies. Some studies have demonstrated
reduced sperm counts in male patients proportional to the administered dose of 131I.
Older women may experience temporary amenorrhea and reduced fertility. Two
deaths from bladder cancer and three deaths from leukemia have been reported
among patients treated with lifetime cumulative doses of radioiodine exceeding
1000 mCi. Most studies suggest that cumulative doses of 131I less
than 700-800 mCi, given in increments of 100-200 mCi separated by 6-12 months,
are not leukemogenic.
Following surgery and radioiodine therapy, all
patients are placed on a large enough dose of exogenous thyroid hormone to
render serum TSH levels low or undetectable. Most endocrinologists recommend
detecting recurrent disease in the asymptomatic patient by annual neck
palpation and serum thyroglobulin measurement. This protein, manufactured only
by normal or malignant thyroid cells, should be undetectable in the serum of a
patient who has undergone complete surgical and radioiodine ablation.
Sensitivity of thyroglobulin measurement is enhanced if the patient is
withdrawn from exogenous thyroid hormone or stimulated with recombinant TSH
Anaplastic carcinoma occurs more commonly in the
elderly (peak age: 65-70 years) and affects equal numbers of males and females.
These cancers may arise in preexisting DTCs (dedifferentiation), in benign
nodules, or, most commonly, de novo. The minuscule number of anaplastic
malignancies within large series of patients followed for decades with DTC may
discredit the theory of dedifferentiation of established cancers.
1.
Papillary and follicular carcinomas
comprise the DTCs. Mortality rates are low.
2.
DTC is diagnosed by fine needle
aspiration (FNA) of a thyroid nodule.
3.
Therapy of DTC is based on surgical
resection of the primary tumor and removal of all remaining thyroid tissue
(bed).
4.
Orally administered radioactive
iodine is accumulated by thyroid tissue, ablating the thyroid bed and
metastatic foci.
5.
Thyroglobulin is the most sensitive
tumor marker for DTC.
6.
Elimination of TSH, a DTC growth
factor, by suppressive doses of levothyroxine is the most important therapeutic
intervention
The
type of histologic variant does not appear to affect outcome; prognosis is
dismal in most cases. Surgical extirpation has been combined with external beam
irradiation (4500-6000 cGy) or chemotherapy (usually doxorubicin or paclitaxel)
in an attempt to eradicate the malignancy. Despite vigorous therapy, average
survival is approximately 6-8 months.
Revised American Thyroid Association
Management Guidelines for Patients with Thyroid Nodules and Differentiated
Thyroid Cancer, November 2009
DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT GUIDELINES
Differentiated
thyroid cancer, arising from thyroid follicular epithelial cells, accounts for
the vast majority of thyroid cancers. Of the differentiated cancers, papillary
cancer comprises about 85% of cases compared to about 10% that have follicular
histology, and 3% that are Hürthle cell or oxyphil tumors (110).
In general, stage for stage, the prognoses of PTC and follicular cancer are
similar (107,110).
Certain histologic subtypes of PTC have a worse prognosis (tall cell variant,
columnar cell variant, diffuse sclerosing variant), as do more highly invasive
variants of follicular cancer. These are characterized by extensive vascular
invasion and invasion into extrathyroidal tissues or extensive tumor necrosis
and/or mitoses. Other poorly differentiated aggressive tumor histologies
include trabecular, insular, and solid subtypes (111).
In contrast, minimally invasive follicular thyroid cancer, is characterized
histologically by microscopic penetration of the tumor capsule without vascular
invasion, and carries no excess mortality (112–115).
[B2]
Goals of initial therapy of DTC
The goals of
initial therapy of DTC are follows:
1.
To remove the primary tumor, disease
that has extended beyond the thyroid capsule, and involved cervical lymph
nodes. Completeness of surgical resection is an important determinant of
outcome, while residual metastatic lymph nodes represent the most common site
of disease persistence/recurrence (116–118).
2.
To minimize treatment-related
morbidity. The extent of surgery and the experience of the surgeon both play
important roles in determining the risk of surgical complications (119,120)
3.
To permit accurate staging of the
disease. Because disease staging can assist with initial prognostication,
disease management, and follow-up strategies, accurate postoperative staging is
a crucial element in the management of patients with DTC (121,122).
4.
To facilitate postoperative treatment
with radioactive iodine, where appropriate. For patients undergoing RAI remnant
ablation, or RAI treatment of residual or metastatic disease, removal of all normal
thyroid tissue is an important element of initial surgery (123).
Near total or total thyroidectomy also may reduce the risk for recurrence
within the contralateral lobe (124).
5.
To permit accurate long-term
surveillance for disease recurrence. Both RAI whole-body scanning (WBS) and
measurement of serum Tg are affected by residual normal thyroid tissue. Where
these approaches are utilized for long-term monitoring, near-total or
total-thyroidectomy is required (125).
6.
To minimize the risk of disease
recurrence and metastatic spread. Adequate surgery is the most important
treatment variable influencing prognosis, while radioactive iodine treatment,
TSH suppression, and external beam irradiation each play adjunctive roles in at
least some patients (125–128).
[B3] What is
the role of preoperative staging with diagnostic imaging and laboratory tests?
[B4]
Neck imaging. Differentiated thyroid carcinoma
(particularly papillary carcinoma) involves cervical lymph nodes in 20–50% of
patients in most series using standard pathologic techniques (45,129–132),
and may be present even when the primary tumor is small and intrathyroidal (133).
The frequency of micrometastases may approach 90%, depending on the sensitivity
of the detection method (134,135).
However, the clinical implications of micrometastases are likely less
significant compared to macrometastases. Preoperative US identifies suspicious cervical
adenopathy in 20–31% of cases, potentially altering the surgical approach (136,137)
in as many as 20% of patients (138,139).
However, preoperative US identifies only half of the
lymph nodes found at surgery, due to the presence of the overlying thyroid
gland (140).
Sonographic
features suggestive of abnormal metastatic lymph nodes include loss of the
fatty hilus, a rounded rather than oval shape, hypoechogenicity, cystic change,
calcifications, and peripheral vascularity. No single sonographic feature is
adequately sensitive for detection of lymph nodes with metastatic thyroid
cancer. A recent study correlated the sonographic features acquired 4 days
preoperatively directly with the histology of 56 cervical lymph nodes. Some of
the most specific criteria were short axis >
|
|
||
|
|
FIG.
2. Lymph node compartments separated into levels and sublevels.
Level VI contains the thyroid gland, and the adjacent nodes bordered
superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic)
artery, and laterally on each side by the carotid sheaths. The level II, III,
and IV nodes are arrayed along the jugular veins on each side, bordered
anteromedially by level VI and laterally by the posterior border of the
sternocleidomastoid muscle. The level III nodes are bounded superiorly by the
level of the hyoid bone, and inferiorly by the cricoid cartilage; levels II
and IV are above and below level III, respectively. The level I node
compartment includes the submental and submandibular nodes, above the hyoid
bone, and anterior to the posterior edge of the submandibular gland. Finally,
the level V nodes are in the posterior triangle, lateral to the lateral edge
of the sternocleidomastoid muscle. Levels I, II, and V can be further
subdivided as noted in the figure. The inferior extent of level VI is defined
as the suprasternal notch. Many authors also include the pretracheal and
paratracheal superior mediastinal lymph nodes above the level of the
innominate artery (sometimes referred to as level VII) in central neck
dissection (166). |
|
Confirmation
of malignancy in lymph nodes with a suspicious sonographic appearance is
achieved by US-guided FNA aspiration for cytology and/or measurement of Tg in
the needle washout. This FNA measurement of Tg is valid even in patients with circulating
Tg autoantibodies (143,144).
Accurate
staging is important in determining the prognosis and tailoring treatment for
patients with DTC. However, unlike many tumor types, the presence of metastatic
disease does not obviate the need for surgical excision of the primary tumor in
DTC (145).
Because metastatic disease may respond to RAI therapy, removal of the thyroid
as well as the primary tumor and accessible locoregional disease remains an
important component of initial treatment even in metastatic disease.
As US
evaluation is uniquely operator dependent, alternative imaging procedures may
be preferable in some clinical settings, though the sensitivities of CT, MRI,
and PET for the detection of cervical lymph node metastases are all relatively
low (30–40%) (146).
These alternative imaging modalities, as well as laryngoscopy and endoscopy,
may also be useful in the assessment of large, rapidly growing, or retrosternal
or invasive tumors to assess the involvement of extrathyroidal tissues (147,148).
- RECOMMENDATION 21
Preoperative neck US for the contralateral lobe and cervical (central and especially lateral neck compartments) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic findings on biopsy. US-guided FNA of sonographically suspicious lymph nodes should be performed to confirm malignancy if this would change management. Recommendation rating: B
- RECOMMENDATION 22
Routine preoperative use of other imaging studies (CT, MRI, PET) is not recommended. Recommendation rating: E
[B5]
Measurement of serum Tg. There is limited
evidence that high preoperative concentrations of serum Tg
may predict a higher sensitivity for postoperative surveillance with serum Tg (149).
Evidence that this impacts patient management or outcomes is not yet available.
- RECOMMENDATION 23
Routine preoperative measurement of serum Tg is not recommended. Recommendation rating: E
[B6] What is
the appropriate operation for indeterminate thyroid nodules and
DTC? The goals of thyroid surgery can include provision of a
diagnosis after a nondiagnostic or indeterminate biopsy, removal of the thyroid
cancer, staging, and preparation for radioactive ablation and serum Tg
monitoring. Surgical options to address the primary tumor should be limited to
hemithyroidectomy with or without isthmusectomy, near-total thyroidectomy
(removal of all grossly visible thyroid tissue, leaving only a small amount
[<1 g] of tissue adjacent to the recurrent laryngeal nerve near the ligament
of Berry), and total thyroidectomy (removal of all grossly visible thyroid
tissue). Subtotal thyroidectomy, leaving >
[B7]
Surgery for a nondiagnostic biopsy, a biopsy suspicious for papillary cancer or
suggestive of “follicular neoplasm” (including special consideration for
patients with other risk factors).
Amongst solitary thyroid nodules with an indeterminate (“follicular neoplasm”
or Hürthle cell neoplasm) biopsy, the risk of malignancy is approximately
20% (151–153).
The risk is higher with large tumors (>
- RECOMMENDATION 24
For patients with an isolated indeterminate solitary nodule who prefer a more limited surgical procedure, thyroid lobectomy is the recommended initial surgical approach. Recommendation rating: C
- RECOMMENDATION 25
a.
Because of an increased risk for
malignancy, total thyroidectomy is indicated in patients with indeterminate
nodules who have large tumors (>4 cm), when marked atypia is seen on biopsy,
when the biopsy reading is “suspicious for papillary carcinoma,” in patients with
a family history of thyroid carcinoma, and in patients with a history of
radiation exposure. Recommendation rating: A
b.
Patients with indeterminate nodules
who have bilateral nodular disease, or those who prefer to undergo bilateral
thyroidectomy to avoid the possibility of requiring a future surgery on the
contralateral lobe, should also undergo total or near-total thyroidectomy. Recommendation
rating: C
[B8]
Surgery for a biopsy diagnostic for malignancy. Near-total
or total thyroidectomy is recommended if the primary thyroid carcinoma is >
- RECOMMENDATION 26
For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases. Recommendation rating: A
[B9]
Lymph node dissection. Regional
lymph node metastases are present at the time of diagnosis in 20–90% of
patients with papillary carcinoma and a lesser proportion of patients with
other histotypes (129,139).
Although PTC lymph node metastases are reported by some to have no clinically
important effect on outcome in low risk patients, a study of the Surveillance,
Epidemiology, and End Results (SEER) database found, among 9904 patients with
PTC, that lymph node metastases, age >45 years, distant metastasis, and
large tumor size significantly predicted poor outcome on multivariate analysis
(163).
All-cause survival at 14 years was 82% for PTC without lymph node and 79% with
lymph node metastases (p < 0.05). Another recent SEER registry study
concluded that cervical lymph node metastases conferred an independent risk of
decreased survival, but only in patients with follicular cancer and patients
with papillary cancer over age 45 years (164).
Also, the risk of regional recurrence is higher in patients with lymph node
metastases, especially in those patients with multiple metastases and/or
extracapsular nodal extension (165).
In many
patients, lymph node metastases in the central compartment (166)
do not appear abnormal preoperatively with imaging (138)
or by inspection at the time of surgery. Central compartment dissection
(therapeutic or prophylactic) can be achieved with low morbidity in experienced
hands (167–171),
and may convert some patients from clinical N0 to pathologic N1a, upstaging
patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to
III (172).
A recent consensus conference statement discusses the relevant anatomy of the
central neck compartment, delineates the nodal subgroups within the central
compartment commonly involved with thyroid cancer, and defines the terminology
relevant to central compartment neck dissection (173).
Comprehensive
bilateral central compartment node dissection may improve survival compared to
historic controls and reduce risk for nodal recurrence (174).
In addition, selective unilateral paratracheal central compartment node
dissection increases the proportion of patients who appear disease free with
unmeasureable Tg levels 6 months after surgery (175).
Other studies of central compartment dissection have demonstrated higher
morbidity, primarily recurrent laryngeal nerve injury and transient
hypoparathyroidism, with no reduction in recurrence (176,177).
In another study, comprehensive (bilateral) central compartment dissection
demonstrated higher rates of transient hypoparathyroidism compared to selective
(unilateral) dissection with no reduction in rates of undetectable or low Tg levels (178).
Although some lymph node metastases may be treated with radioactive iodine,
several treatments may be necessary, depending upon the histology, size, and
number of metastases (179).
- RECOMMENDATION 27*
a.
Therapeutic central-compartment
(level VI) neck dissection for patients with clinically involved central or
lateral neck lymph nodes should accompany total thyroidectomy to provide
clearance of disease from the central neck. Recommendation
rating: B
b.
Prophylactic central-compartment neck
dissection (ipsilateral or bilateral) may be performed in patients with
papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes,
especially for advanced primary tumors (T3 or T4). Recommendation
rating: C
c.
Near-total or total thyroidectomy
without prophylactic central neck dissection may be appropriate for small (T1
or T2), noninvasive, clinically node-negative PTCs and most follicular cancer. Recommendation
rating: C
These
recommendations (R27a–c) should be interpreted in light of available surgical
expertise. For patients with small, noninvasive, apparently node-negative
tumors, the balance of risk and benefit may favor simple near-total
thyroidectomy with close intraoperative inspection of the central compartment
with compartmental dissection only in the presence of obviously involved lymph
nodes. This approach may increase the chance of future locoregional recurrence,
but overall this approach may be safer in less experienced surgical hands.
Lymph nodes
in the lateral neck (compartments II–V), level VII (anterior mediastinum), and
rarely in Level I may also be involved by thyroid cancer (129,180).
For those patients in whom nodal disease is evident clinically, on preoperative
US and nodal FNA or Tg measurement, or at the time of surgery, surgical
resection may reduce the risk of recurrence and possibly mortality (56,139,181).
Functional compartmental en-bloc neck dissection is favored over isolated
lymphadenectomy (“berry picking”) with limited data suggesting improved
mortality (118,182–184).
- RECOMMENDATION 28*
Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. Recommendation rating: B
[B10]
Completion thyroidectomy. Completion
thyroidectomy may be necessary when the diagnosis of malignancy is made
following lobectomy for an indeterminate or nondiagnostic biopsy. Some patients
with malignancy may require completion thyroidectomy to provide complete
resection of multicentric disease (185),
and to allow RAI therapy. Most (186,187)
but not all (185)
studies of papillary cancer have observed a higher rate of cancer in the
opposite lobe when multifocal (two or more foci), as opposed to unifocal,
disease is present in the ipsilateral lobe. The surgical risks of two-stage
thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to
those of a near-total or total thyroidectomy (188).
- RECOMMENDATION 29
Completion thyroidectomy should be offered to those patients for whom a near-total or total thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. This includes all patients with thyroid cancer except those with small (<1 cm), unifocal, intrathyroidal, node-negative, low-risk tumors. Therapeutic central neck lymph node dissection should be included if the lymph nodes are clinically involved. Recommendation rating: B
- RECOMMENDATION 30
Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (189). It is unknown whether this approach results in similar long-term outcomes. Consequently, routine radioactive iodine ablation in lieu of completion thyroidectomy is not recommended. Recommendation rating: D
[B11]
What is the role of postoperative staging systems and which should be used?
[B12]
The role of postoperative staging.
Postoperative staging for thyroid cancer, as for other cancer types, is used:
1) to permit prognostication for an individual patient with DTC; 2) to tailor
decisions regarding postoperative adjunctive therapy, including RAI therapy and
TSH suppression, to assess the patient’s risk for disease recurrence and
mortality; 3) to make decisions regarding the frequency and intensity of
follow-up, directing more intensive follow-up towards patients at highest risk;
and 4) to enable accurate communication regarding a patient among health care
professionals. Staging systems also allow evaluation of differing therapeutic
strategies applied to comparable groups of patients in clinical studies.
[B13]
AJCC/UICC TNM staging. Application of the
AJCC/International Union against Cancer (AJCC/UICC) classification system based
on pTNM parameters and age is recommended for tumors of all types, including
thyroid cancer (121,190),
because it provides a useful shorthand method to describe the extent of the
tumor (191)
(Table 4).
This classification is also used for hospital cancer registries and
epidemiologic studies. In thyroid cancer, the AJCC/UICC stage does not take
account of several additional independent prognostic variables and may risk
misclassification of some patients. Numerous other schemes have been developed
in an effort to achieve more accurate risk factor stratification, including
CAEORTC, AGES, AMES, U of C, MACIS, OSU, MSKCC, and NTCTCS systems. (107,116,122,159,192–195).
These schemes take into account a number of factors identified as prognostic
for outcome in multivariate analysis of retrospective studies, with the most
predictive factors generally being regarded as the presence of distant
metastases, the age of the patient, and the extent of the tumor. These and
other risk factors are weighted differently among these systems according to
their importance in predicting outcome, but no scheme has demonstrated clear
superiority (195).
Each of the schemes allows accurate identification of the majority (70–85%) of
patients at low-risk of mortality (T1–3, M0 patients), allowing the follow-up
and management of these patients to be less intensive than the higher-risk
minority (T4 and M1 patients), who may benefit from a more aggressive management
strategy (195).
Nonetheless, none of the examined staging classifications is able to account
for more than a small proportion of the uncertainty in either short-term,
disease-specific mortality or the likelihood of remaining disease free (121,195,196).
AJCC/IUCC staging was developed to predict risk for death, not recurrence. For
assessment of risk of recurrence, a three-level stratification can be used:
- Low-risk patients have the following
characteristics: 1) no local or distant metastases; 2) all macroscopic
tumor has been resected; 3) there is no tumor invasion of locoregional
tissues or structures; 4) the tumor does not have aggressive histology
(e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion;
5) and, if 131Iis given, there is no 131I uptake
outside the thyroid bed on the first posttreatment whole-body RAI scan
(RxWBS) (197–199).
- Intermediate-risk patients have any of the
following: 1) microscopic invasion of tumor into the perithyroidal soft
tissues at initial surgery; 2) cervical lymph node metastases or 131I
uptake outside the thyroid bed on the RxWBS done after thyroid remnant
ablation (200,201); or 3) tumor with aggressive histology or vascular invasion (202–204).
- High-risk patients have 1) macroscopic tumor
invasion, 2) incomplete tumor resection, 3) distant metastases, and
possibly 4) thyroglobulinemia out of proportion to what is seen on the
posttreatment scan (205).
Since initial
staging is based on clinico-pathologic factors that are available shortly after
diagnosis and initial therapy, the AJCC stage of the patient does not change
over time. However, depending on the clinical course of the disease and
response to therapy, the risk of recurrence and the risk of death may change
over time. Appropriate management requires an ongoing reassessment of the risk
of recurrence and the risk of disease-specific mortality as new data are
obtained during follow-up (206).
TABLE
4. TNM CLASSIFICATION SYSTEM FOR DIFFERENTIATED THYROID CARCINOMA
|
|
Definition |
|
|
T1 |
Tumor
diameter 2 cm or smaller |
|
|
T2 |
Primary
tumor diameter >2 to 4 cm |
|
|
T3 |
Primary
tumor diameter >4 cm limited to the thyroid or with minimal
extrathyroidal extension |
|
|
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 |
|
|
TX |
Primary
tumor size unknown, but without extrathyroidal invasion |
|
|
N0 |
No metastatic nodes |
|
|
N1a |
Metastases
to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph
nodes) |
|
|
N1b |
Metastasis
to unilateral, bilateral, contralateral cervical or superior mediastinal
nodes |
|
|
NX |
Nodes not
assessed at surgery |
|
|
M0 |
No distant metastases |
|
|
M1 |
Distant metastases |
|
|
MX |
Distant metastases not assessed |
|
|
Stages |
|
|
|
|
Patient age <45 years |
Patient age
45 years or older |
|
Stage I |
Any T, any N, M0 |
T1, N0, M0 |
|
Stage II |
Any T, any N, M1 |
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, N0 |
|
|
|
T4a, N1b, M0 |
|
Stage IVB |
|
T4b, Any N, M0 |
|
Stage IVC |
|
Any T, Any N, M1 |
Used with the
permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, Sixth
Edition (435).
RECOMMENDATION 31
Because of its utility in predicting disease mortality, and its requirement for
cancer registries, AJCC/UICC staging is recommended for all patients with DTC.
The use of postoperative clinico-pathologic staging systems is also recommended
to improve prognostication and to plan follow-up for patients with DTC.
Recommendation rating: B
[B14]
What is the role of postoperative RAI remnant ablation?
Postoperative RAI remnant ablation is increasingly being used to eliminate the
postsurgical thyroid remnant (122).
Ablation of the small amount of residual normal thyroid remaining after total
thyroidectomy may facilitate the early detection of recurrence based on serum
Tg measurement and/or RAI WBS. Additionally, the posttherapy scan obtained at
the time of remnant ablation may facilitate initial staging by identifying
previously undiagnosed disease, especially in the lateral neck. Furthermore,
from a theoretical point of view, this first dose of RAI may also be considered
adjuvant therapy because of the potential tumoricidal effect on
persistent thyroid cancer cells remaining after appropriate surgery in patients
at risk for recurrence or disease specific mortality. Depending on the risk
stratification of the individual patient, the primary goal of the first dose of
RAI after total thyroidectomy may be 1) remnant ablation (to
facilitate detection of recurrent disease and initial staging), 2) adjuvant
therapy (to decrease risk of recurrence and disease specific mortality by
destroying suspected, but unproven metastatic disease), or 3) RAI therapy
(to treat known persistent disease). While these three goals are closely
interrelated, a clearer understanding of the specific indications for treatment
will improve our ability to select patients most likely to benefit from RAI
after total thyroidectomy, and will also influence our recommendations
regarding choice of administered activity for individual patients. Supporting
the use of RAI as adjuvant therapy, a number of large, retrospective studies
show a significant reduction in the rates of disease recurrence (107,159,160,207)
and cause-specific mortality (159,160,207–209).
However, other similar studies show no such benefit, at least among the
majority of patients with PTC, who are at the lowest risk for mortality (110,122,162,209–212).
In those studies that show benefit, the advantage appears to be restricted to
patients with tumors >
TABLE 5.
MAJOR FACTORS IMPACTING DECISION MAKING IN RADIOIODINE REMNANT ABLATION
|
|
|
Expected benefit |
|
|
||
|
Factors |
Description |
Decreased risk of death |
Decreased risk of recurrence |
May
facilitate initial staging and follow-up |
RAI ablation usually recommended |
Strength of evidence |
|
T1 |
1 cm
or less, intrathyroidal or microscopic multifocal |
No |
No |
Yes |
No |
E |
|
|
1–2 cm, intrathyroidal |
No |
Conflicting dataa |
Yes |
Selective usea |
I |
|
T2 |
>2–4 cm, intrathyroidal |
No |
Conflicting dataa |
Yes |
Selective usea |
C |
|
T3 |
>4 cm |
|
|
|
|
|
|
|
<45 years old |
No |
Conflicting dataa |
Yes |
Yes |
B |
|
|
≥45 years old |
Yes |
Yes |
Yes |
Yes |
B |
|
|
Any size,
any age, minimal extrathyroidal extension |
No |
Inadequate dataa |
Yes |
Selective usea |
I |
|
T4 |
Any size
with gross extrathyroidal extension |
Yes |
Yes |
Yes |
Yes |
B |
|
Nx,N0 |
No metastatic nodes documented |
No |
No |
Yes |
No |
I |
|
N1 |
<45 years old |
No |
Conflicting dataa |
Yes |
Selective usea |
C |
|
|
>45 years old |
Conflicting data |
Conflicting dataa |
Yes |
Selective usea |
C |
|
M1 |
Distant metastasis present |
Yes |
Yes |
Yes |
Yes |
A |
aBecause
of either conflicting or inadequate data, we cannot recommend either for or
against RAI ablation for this entire subgroup. However, selected patients
within this subgroup with higher risk features may benefit from RAI ablation
(see modifying factors in the text).
In addition
to the major factors listed in Table 5,
several other histological features may place the patient at higher risk of
local recurrence or metastases than would have been predicted by the AJCC
staging system. These include worrisome histologic subtypes (such as tall cell,
columnar, insular, and solid variants, as well as poorly differentiated thyroid
cancer), the presence of intrathyroidal vascular invasion, or the finding of
gross or microscopic multifocal disease. While many of these features have been
associated with increased risk, there are inadequate data to determine whether
RAI ablation has a benefit based on specific histologic findings, independent
of tumor size, lymph node status, and the age of the patient. Therefore, while
RAI ablation is not recommended for all patients with these higher risk
histologic features, the presence of these features in combination with size of
the tumor, lymph node status, and patient age may increase the risk of
recurrence or metastatic spread to a degree that is high enough to warrant RAI
ablation in selected patients. However, in the absence of data for most of
these factors, clinical judgment must prevail in the decision-making process.
For microscopic multifocal papillary cancer, when all foci are <
Nonpapillary
histologies (such as follicular thyroid cancer and Hürthle cell cancer)
are generally regarded as higher risk tumors. Expert opinion supports the use
of RAI in almost all of these cases. However, because of the excellent
prognosis associated with surgical resection alone in small follicular thyroid
cancers manifesting only capsular invasion (without vascular invasion
(so-called “minimally invasive follicular cancer”), RAI ablation may not be
required for all patients with this histological diagnosis (112).
- RECOMMENDATION 32
a.
RAI ablation is recommended for all
patients with known distant metastases, gross extrathyroidal extension of the
tumor regardless of tumor size, or primary tumor size >
b.
RAI ablation is recommended for
selected patients with 1–4 cm thyroid cancers confined to the thyroid, who have
documented lymph node metastases, or other higher risk features (see preceding
paragraphs) when the combination of age, tumor size, lymph node status, and
individual histology predicts an intermediate to high risk of recurrence or
death from thyroid cancer (see Table 5
for strength of evidence for individual features). Recommendation rating: C
(for selective use in higher risk patients)
c.
RAI ablation is not recommended for
patients with unifocal cancer <1 cm without other higher risk features (see
preceding paragraphs). Recommendation rating: E
d.
RAI ablation is not recommended for
patients with multifocal cancer when all foci are <1 cm in the absence other
higher risk features (see preceding paragraphs). Recommendation
rating: E
[B15]
How should patients be prepared for RAI ablation? (see Fig. 3)
Remnant ablation requires TSH stimulation. No controlled studies have been
performed to assess adequate levels of endogenous TSH for optimal ablation
therapy or follow-up testing. Noncontrolled studies suggest that a TSH of
>30 mU/L is associated with increased RAI uptake in tumors (218),
while studies using single dose exogenous TSH suggest maximal thyrocyte
stimulation at TSH levels between 51 and 82 mU/L (219, 220).
However, the total area under the TSH curve, and not simply the peak serum TSH
concentration, is also potentially important for optimal RAI uptake by thyroid
follicular cells. Endogenous TSH elevation can be achieved by two basic
approaches to thyroid hormone withdrawal, stopping LT4 and switching
to LT3 for 2–4 weeks followed by withdrawal of LT3 for 2
weeks, or discontinuation of LT4 for 3 weeks without use of LT3.
Both methods of preparation can achieve serum TSH levels >30 mU/Lin >90%
of patients (220–229).
These two approaches have not been directly compared for efficiency of patient
preparation (efficacy of ablation, iodine uptake, Tg
levels, disease detection), although a recent prospective study showed no
difference in hypothyroid symptoms between these two approaches (230).
Other preparative methods have been proposed, but have not been validated by
other investigators (231,232).
Children with thyroid cancer achieve adequate TSH elevation within 14 days of
LT4 withdrawal (233).
A low serum Tg level at the time of ablation has excellent negative predictive
value for absence of residual disease, and the risk of persistent disease
increases with higher stimulated Tg levels (198,205,234).
FIG. 3. Algorithm for initial
follow-up of patients with differentiated thyroid carcinoma.
aEBRT, external beam radiotherapy. The usual indication for EBRT is
macroscopic unresectable tumor in a patient older than 45 years; it is not
usually recommended for children and adults less than age 45.
bNeck ultrasonography of operated cervical compartments is often
compromised for several months after surgery.
cTg, thyroglobulin with anti-thyroglobulin antibody measurement;
serum Tg is usually measured by immunometric assay and may be falsely elevated
for several weeks by injury from surgery or by heterophile antibodies, although
a very high serum Tg level after surgery usually indicates residual disease.
dSome clinicians suspect residual disease when malignant lymph
nodes, or tumors with aggressive histologies (as defined in the text) have been
resected, or when there is a microscopically positive margin of resection.
erhTSH is recombinant human TSH and is administered as follows:
0.9mg rhTSH i.m. on two consecutive days, followed by 131I therapy on the third
day.
fTHW is levothyroxine and=or triiodothyronine withdrawal.
gSee text for exceptions regarding remnant ablation. The smallest
amount of 131I necessary to ablate normal thyroid remnant tissue
should be used. DxWBS (diagnostic whole-body scintigraphy) is not usually
necessary at this point, but may be performed if the outcome will change the
decision to treat with radioiodine and=or the amount of administered activity.
hRxWBS is posttreatment whole-body scan done 5 to 8 days after
therapeutic 131I administration.
iUptake in the thyroid bed may indicate
normal remnant tissue or residual central neck nodal metastases.
- RECOMMENDATION 33
Patients undergoing RAI therapy or diagnostic testing can be prepared by LT4 withdrawal for at least 2–3 weeks or LT3 treatment for 2–4 weeks and LT3 withdrawal for 2 weeks with measurement of serum TSH to determine timing of testing or therapy (TSH >30 mU/L). Thyroxine therapy (with or without LT3 for 7–10 days) may be resumed on the second or third day after RAI administration. Recommendation rating: B
[B16]
Can rhTSH (Thyrogen™) be used in lieu of thyroxine withdrawal for remnant
ablation? For most patients, including those unable
to tolerate hypothyroidism or unable to generate an elevated TSH, remnant
ablation can be achieved with rhTSH (235,236).
A prospective randomized study found that thyroid hormone withdrawal and rhTSH
stimulation were equally effective in preparing patients for 131I
remnant ablation with 100 mCi with significantly improved quality of life (237).
Another randomized study using rhTSH showed that ablation rates were comparable
with 50 mCi compared to 100 mCi with a significant decrease (33%) in whole-body
irradiation (238).
Finally, a recent study has shown that ablation rates were similar with either
withdrawal or preparation with rhTSH using 50 mCi of 131I (239).
In addition, short-term recurrence rates have been found to be similar in
patients prepared with thyroid hormone withdrawal or rhTSH (240).
Recombinant human TSH is approved for remnant ablation in the United States,
Europe, and many other countries around the world.
- RECOMMENDATION 34
Remnant ablation can be performed following thyroxine withdrawal or rhTSH stimulation. Recommendation rating: A
[B17]
Should RAI scanning be performed before RAI ablation? RAI
WBS provides information on the presence of io-dine-avid thyroid tissue, which
may represent the normal thyroid remnant or the presence of residual disease in
the postoperative setting. In the presence of a large thyroid remnant, the scan
is dominated by uptake within the remnant, potentially masking the presence of
extrathyroidal disease within locoregional lymph nodes, the upper mediastinum,
or even at distant sites, reducing the sensitivity of disease detection (241).
Furthermore, there is an increasing trend to avoid pretherapy RAI scans
altogether because of its low impact on the decision to ablate, and because of
concerns over 131Iinduced stunning of normal thyroid remnants (242)
and distant metastases from thyroid cancer (243).
Stunning is defined as a reduction in uptake of the 131I therapy
dose induced by a pretreatment diagnostic activity. Stunning occurs most
prominently with higher activities (5–10 mCi) of 131I (244),
with increasing time between the diagnostic dose and therapy (245),
and does not occur if the treatment dose is given within 72 hours of the
scanning dose (246).
However, the accuracy of low-activity 131I scans has been
questioned, and some research has reported quantitatively the presence of
stunning below the threshold of visual detection (247).
Although comparison studies show excellent concordance between 123I
and 131I for tumor detection, optimal 123I activity and
time to scan after 123I administration are not known (248).
Furthermore, 123I is expensive, is not universally available, its
short half life (t½ = 13 hours) makes handling this isotope
logistically more difficult (249),
and stunning may also occur though to a lesser degree than with 131I
(245).
Furthermore, a recent study showed no difference in ablation rates between
patients that had pre-therapy scans with 123I (81%) compared to
those who had received diagnostic scans using 2 mCi of 131I (74%, p
> 0.05) (250).
Alternatively, determination of the thyroid bed uptake, without scanning, can
be achieved using 10–100 µCi 131I.
- RECOMMENDATION 35
Pretherapy scans and/or measurement of thyroid bed uptake may be useful when the extent of the thyroid remnant cannot be accurately ascertained from the surgical report or neck ultrasonography, or when the results would alter either the decision to treat or the activity of RAI that is administered. If performed, pretherapy scans should utilize 123I (1.5–3 mCi) or low-activity 131I (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity. Recommendation rating: C
[B18]
What activity of 131I should be used for remnant ablation?
Successful remnant ablation is usually defined as an
absence of visible RAI uptake on a subsequent diagnostic RAI scan or an
undetectable stimulated serum Tg. Activities between 30 and 100 mCi of 131I
generally show similar rates of successful remnant ablation (251–254)
and recurrence rates (213).
Although there is a trend toward higher ablation rates with higher activities (255,256),
a recent prospective randomized study found no significant
difference in the remnant ablation rate using 30 or 100 mCi of 131I
(257).
Furthermore, there are data showing that 30 mCi is effective in ablating the
remnant with rhTSH preparation (258).
In pediatric patients, it is preferable to adjust the ablation activity
according to the patient’s body weight (259)
or surface area (260).
- RECOMMENDATION 36
The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B
- RECOMMENDATION 37
If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma), then higher activities (100–200 mCi) may be appropriate. Recommendation rating: C
[B19]
Is a low-iodine diet necessary before remnant ablation? The
efficacy of radioactive iodine depends on the radiation
dose delivered to the thyroid tissue (261).
Low-iodine diets (<50 µg/d of dietary iodine) and simple recommendations to
avoid iodine contamination have been recommended prior to RAI therapy (261–263)
to increase the effective radiation dose. A history of possible iodine exposure
(e.g., intravenous contrast, amiodarone use) should be sought. Measurement of iodine
excretion with a spot urinary iodine determination may be a useful way to
identify patients whose iodine intake could interfere with RAI remnant ablation
(263).
Information about low-iodine diets can be obtained at the Thyroid Cancer
Survivors Association website (www. thyca.org).
- RECOMMENDATION 38
A low-iodine diet for 1–2 weeks is recommended for patients undergoing RAI remnant ablation, particularly for those patients with high iodine intake. Recommendation rating: B
[B20]
Should a posttherapy scan be performed following remnant ablation?
Posttherapy whole-body iodine scanning is typically conducted approximately 1
week after RAI therapy to visualize metastases. Additional metastatic foci have
been reported in 10–26% of patients scanned following high-dose RAI treatment
compared with the diagnostic scan (264,265).
The new abnormal uptake was found most often in the neck, lungs, and mediastinum, and the newly discovered disease altered the
disease stage in approximately 10% of the patients, affecting clinical
management in 9–15% (264–266).
Iodine 131 single photon emission computed tomography (SPECT)/CT fusion imaging
may provide superior lesion localization after remnant ablation, but it is
still a relatively new imaging modality (267).
- RECOMMENDATION 39
A posttherapy scan is recommended following RAI remnant ablation. This is typically done 2–10 days after the therapeutic dose is administered, although published data supporting this time interval are lacking. Recommendation rating: B
[B21]
Postsurgery and RAI therapy early management of DTC
[B22]
What is the role of TSH suppression therapy? DTC expresses the TSH
receptor on the cell membrane and responds to TSH stimulation by increasing the
expression of several thyroid specific proteins (Tg, sodium-iodide symporter) and by increasing the rates of
cell growth (268).
Suppression of TSH, using supra-physiologic doses of LT4, is used commonly to
treat patients with thyroid cancer in an effort to decrease the risk of
recurrence (127,214,269).
A meta-analysis supported the efficacy of TSH
suppression therapy in preventing major adverse clinical events (RR = 0.73; CI
= 0.60–0.88; p < 0.05) (269).
[B23]
What is the appropriate degree of initial TSH suppression?
Retrospective and prospective studies have demonstrated that TSH suppression to
below 0.1 mU/Lmay improve outcomes in high-risk thyroid cancer patients (127,270),
though no such evidence of benefit has been
documented in low-risk patients. A prospective cohort study (214)
of 2936 patients found that overall survival improved significantly
when the TSH was suppressed to undetectable levels in patients with NTCTCSG
stage III or IV disease and suppressed to the subnormal to undetectable range
in patients with NTCTCSG stage II disease; however, in the latter group there
was no incremental benefit from suppressing TSH to
undetectable levels. Suppression of TSH was not beneficial
in patients with stage I disease. In another study, there was a positive
association between serum TSH levels and the risk for recurrent disease and
cancer-related mortality (271).
Adverse effects of TSH suppression may include the known consequences of
subclinical thyrotoxicosis, including exacerbation of angina in patients with
ischemic heart disease, increased risk for atrial fibrillation
in older patients (272),
and increased risk of osteoporosis in postmenopausal women (273).
- RECOMMENDATION 40
Initial TSH suppression to below 0.1 mU/L is recommended for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal (0.1–0.5 mU/L) is appropriate for low-risk patients. Similar recommendations apply to low-risk patients who have not undergone remnant ablation, i.e., serum TSH 0.1–0.5 mU/L. Recommendation rating: B
[B24]
Is there a role for adjunctive external beam irradiation or chemotherapy?
[B25]
External beam irradiation. External beam irradiation is used
infrequently in the management of thyroid cancer except as a palliative
treatment for locally advanced, otherwise unresectable disease (274).
There are reports of responses among patients with locally advanced disease (275,276)
and improved relapse-free and cause-specific survival in
patients over age 60 with extrathyroidal extension but no gross residual
disease (277).
It remains unknown whether external beam radiation might reduce the risk for
recurrence in the neck following adequate primary surgery and/or RAI treatment
in patients with aggressive histologic subtypes (278).
- RECOMMENDATION 41
The use of external beam irradiation to treat the primary tumor should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective. The sequence of external beam irradiation and RAI therapy depends on the volume of gross residual disease and the likelihood of the tumor being RAI responsive. Recommendation rating: B
[B26]
Chemotherapy. There are no data to support the use
of adjunctive chemotherapy in the management of DTC. Doxorubicin may act as a
radiation sensitizer in some tumors of thyroid origin (279),
and could be considered for patients with locally advanced disease undergoing
external beam radiation.
- RECOMMENDATION 42
There is no role for the routine adjunctive use of chemotherapy in patients with DTC. Recommendation rating: F
References for Guidelines: http://thyroidguidelines.net/revised/references
References.
А.
1.
Davidson's Principles and Practice of
Medicine / Edited by Nicki R. Colledge, Brian R. Walker,Stuart H.
Ralston, 1st Edition. - - Philadelphia
2.
Harrison’s Principles of Internal
Medicine (18th edition) / D.
Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson,
J.Loscalzo. – New
York : McGraw-Hill Education - Europe, 2011.–4012 p.
3.
Kumar and Clark's Clinical Medicine (8th
Revised edition) (With STUDENTCONSULT Online Access)
/ P.
KumarM.L. Clark . –
B. Additional
1.
Greenspan's Basic and Clinical Endocrinology ( 9th Revised edition) / David G.
Gardner, Dolores M. Shoback. –
2. Oxford
Textbook of Endocrinology and Diabetes2nd Revised edition)
/ John
A. H. WassP.StewartS. A. AmielM. J. Davies. –
3.
Web-sites:
a) http://emedicine.medscape.com/endocrinology
b) http://www.endo-society.org/
ATA/AACE Guidelines CLINICAL PRACTICE
GUIDELINES FOR HYPOTHYROIDISM IN ADULTS