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thyroid cancer
Thyroid cancer is cancer of the thyroid gland.
There are four forms: papillary, follicular, medullary and anaplastic.
The most common forms (papillary and follicular) are slow growing and
may recur, but these forms are rarely fatal in patients under age 45.
The medullary form also has a good prognosis if it is restricted to
the thyroid gland and a poorer prognosis if there has been spread;
anaplastic thyroid cancers are fast-growing and respond poorly to
therapy.
Thyroid nodule are diagnosed by ultrasound guided fine needle
aspiration (USG/FNA) or frequently by thyroidectomy (surgical removal
and subsequent pathological examination). As the thyroid cancer can
uptake iodine, radioactive iodine is a commonly used modality in
thyroid carcinomas. However, it is followed by TSH suppression by
thyroxine therapy.
Symptoms
Most often the first symptom of thyroid cancer is a nodule
in the thyroid region of the neck, but only few (up to 5%) of these
nodules are malignant. Sometimes the first sign is an enlarged lymph
node. Other symptoms that can be present are pain, changes in voice
and symptoms of hypo- or hyperthyroidism.
Diagnosis
After a nodule is found during a physical examination,a
referral to an endocrinologist, or a thyroidologist is the best
approach. They will begin an evaluation of the patient. They will do
or order an ultrasound to confirm the presence of a nodule, and assess
the status of the whole gland. TSH, and anti-thyroid antibodies will
help decide if there is a functional thyroid disease such as
Hashimoto's thyroiditis present that may cause nodular goiter. The
most cost-effective, sensitive and accurate test to determine whether
the nodule is malignant is the fine needle biopsy. This test, or the
ultrasound guided FNA usually yields sufficient cells to assess the
risk of malignancy, although in some cases, the suspected nodule is
removed surgically for pathological examination. Rarely, a biopsy is
done using a large cutting needle, so that the a piece of capsule can
be obtained. Blood or imaging tests may be done prior to or in lieu of
a biopsy. The possibility of a nodule which secretes thyroid hormone
(which is less likely to be cancer) or hypothyoidism is investigated
by measuring Thyroid Stimulating hormone (TSH), and the thyroid
hormones thyroxine (T4) and triiodothyronine (T3). Tests for serum
thyroid autoantibodies are sometimes done as these may indicate
autoimmune thyroid disease (which can mimic nodular disease). The
blood assays may be accompanied by ultrasound imaging of the nodule to
determine the position, size and texture, and to assess whether the
nodule may be cystic (fluid filled). Also suspicious findings in a
nodule are hypoechoicic, irregular borders, microcalcifications, 4
plus blood flow within the nodule. Less suspicious findings in benign
nodules include, hyperechoic, comet tail artifacts from colloid, no
blood flow in the nodule and a halo, or smooth border. Some clinicians
will also request technetium or radioactive iodine imaging of the
thyroid. An I/123 scan showing a hot nodule, accompanied by a lower
than normal TSH, is strong evidence that the nodule is not cancerous.
Classification
Thyroid cancers can be classified according to their
pathological characteristics. The following variants can be
distinguished (distribution over various subtypes may show regional
variation):
Papillary thyroid cancer (75%, incl. mixed papillary/follicular)
Follicular thyroid cancer (16%)
Medullary thyroid cancer (5-7%)
Anaplastic thyroid cancer (3%)
Lymphoma (1%)
Squamous cell carcinoma, sarcoma (0.5 - 2%)
Papillary thyroid cancer
This is the most common type of thyroid cancer. It occurs
more frequently in women and presents in the 30-40 year age group. It
is also the predominant cancer type in children with thyroid cancer,
and in patients with thyroid cancer who have had previous radiation to
the head and neck (in this group, the cancer tends to be multifocal
with early lymphatic spread, and portends a relatively poor
prognosis). Thyroglobulin can be used as a tumor marker for
well-differentiated papillary thyroid cancer.
Pathology
Characteristic Orphan Annie eye nuclear inclusions and
psammoma bodies on light microscopy
Lymphatic spread is more common than hematogenous spread
Multifocality is common
The so-called Lateral Aberrant Thyroid is actually a lymph node
metastasis from papillary thyroid carcinoma.
Prognostic indicators
There are at minimum 13 known scoring systems for
prognosis; some of these outright conflicting. Among the more often
used are:
AGES - Age, Grade, Extent of disease, Size
AMES - Age, Metastasis, Extent of disease, Size
MACIS - Metastasis, Age at presentation, Completeness of surgical
resection, Invasion (extrathyroidal), Size (this is a modification of
the AGES system)
TNM - Tumor, node, metastasis. Remarkable about the TNM grading for
(differentiated) thyroid carcinoma is that the scoring is different
according to age.
Surgical treatment
Minimal disease (diameter up to 1.0 centimeters) -
hemithyroidectomy (or unilateral lobectomy) and isthmectomy is may be
sufficient. There is some discussion whether this is still preferable
over total thyroidectomy for this group of patients.
Gross disease (diameter over 1.0 centimeters)- total thyroidectomy,
and central compartment lymph node removal is the therapy of choice.
Additional lateral neck nodes can be removed at the same time if an
ultrasound guided FNA and thyrobulin TG cancer washing was positive on
the pre-operative neck node ultrasound evaluation.
Arguments for total thyroidectomy are:
Reduced risk of recurrence, if central compartment nodes are removed
at the original surgery.
Papillary carcinoma is a multifocal disease (hemithyroidectomy may
leave disease in the other lobe)
Ease of monitoring with thyroglobulin (sensitivity for picking up
recurrence is increased in presence of total thyroidectomy, and
ablation of remnant normal thyroid by low dose radioiodine 131 after
following a low iodine diet (LID).
Ease of detection of metastatic disease by thyroid and neck node
ultrasound.
Thyroid total body scans are less reliable at finding recurrence than
TG and ultrasound.
Follicular thyroid cancer
This occurs more commonly in women of over 50 years old.
Thyroglobulin can be used as a tumor marker for well-differentiated
follicular thyroid cancer.
Surgical Treatment
Unilateral hemithyroidectomy is uncommon due to the
aggressive nature of this form of thyroid cancer.
Total thyroidectomy is almost automatic with this diagnosis. This is
invariably followed by radioiodine treatment at levels from 50 to 200
millicuries following two weeks of a low iodine diet (LID).
Occasionally treatment must be repeated if annual scans indicate
remaining tissue. Some doctors favor administering the maximum safe
dose (calculated based on a number of factors), while others favor
administering smaller doses, which may still be effective in ablating
all thyroid tissue. I-131 is used for ablation of the thyroid tissue.
Some studies have shown that Thyroglobulin (Tg) testing combined with
neck ultrasound is more productive in finding disease recurrence than
whole body scans (WBS) using radioactive iodone. However, current
protocol (in the USA) suggests a small number of clean annual WBS are
required before relying on Tg testing plus neck ultrasound. When
needed, whole body scans consist of withdrawal from thyroxine
medication and/or injection of recombinant human Thyroid Stimulating
Hormone (TSH). In both cases, a low iodine diet regimen must also be
followed to optimize the takeup of the radioactive iodine dose. Low
dose radioiodine of a few millicuries is administered. Full body
nuclear medicine scan follows using a gamma camera. Scan doses of
radioactive iodine may be I-131 or I-123.
Recombinant human TSH, commercial name Thyrogen, is produced in cell
culture from genetically engineered hamster cells.
Hurthle cell variant
This type of thyroid cancer is a variant of follicular cell
carcinoma with some exceptions
They are more often bilateral and multifocal
They are more likely to metastasize to lymph nodes than follicular
carcinoma
Management - like follicular carcinoma, unilateral hemithyroidectomy
is performed for non-invasive disease, and total thyroidectomy for
invasive disease
Medullary thyroid cancer (MTC)
This form of thyroid carcinoma originates from the
parafollicular cells (C cells), which produce the hormone calcitonin.
While the increased calcitonin itself is probably not harmful, it is
useful as a marker which can be tested in blood. A second marker,
carcinoembryonic antigen (CEA), is also produced by medullary thyroid
carcinoma. It can also be measured as a serum or blood tumor marker
like calcitonin. In general measurment of CEA is less sensitive than
calcitonin, but has less minute to minute variability and is therefore
useful as an indicator of tumor mass.
Its prognosis is poorer than that of follicular and papillary thyroid
cancer when it has metastasized (spread) beyond the thyroid gland. In
a proportion, approximately 25%, the cancer develops in families, both
in isolated form (termed familial medullary thyroid carcinoma) or as
part of the syndrome of multiple endocrine neoplasia, type 2 (MEN2),
that includes medullary thyroid carcinoma (>90%), hyperparathyroidism
(5-15%), and unilateral or bilateral pheochromocytoma (40-60%). MEN3
(also known as 2B) is characterized by MTC, pheochromocytoma, mucosal
neuromas, and a marfanoid appearance.
The causes of medullary thyroid cancer
Mutations (DNA changes) of the RET proto-oncogene, a
tyrosine kinase receptor involved in cell growth and development and
located on chromosome 10, initiate nearly all cases of hereditary or
familial medullary thyroid carcinoma and are also responsible for the
development of hyperparathyroidism and pheochromocytoma. Hereditary
medullary thyroid cancer is inherited as an autosomal dominant trait,
meaning that each child of an affected parent has a 50/50 probability
of inheriting the mutant RET proto-oncogene from the affected parent.
DNA analysis makes it possible to identify children who carry the
mutant gene; surgical removal of the thyroid in children who carry the
mutant gene is curative if the entire thyroid gland is removed at an
early age, before there is spread of the tumor. The parathyroid tumors
and pheochromocytomas are removed when they cause clinical
symptomatology. Hereditary medullary thyroid carcinoma or MEN2 account
for approximately 25% of all medullary thyroid carcinomas.
Seventy-five percent of medullary thyroid carcinoma occurs in
individuals without an identifiable family history and is assigned the
term "sporadic". Individuals who develop sporadic medullary thyroid
carcinoma tend to be older and have more extensive disease at the time
of initial presentation than those with a family history (screening is
likely to be initiated at an early age in the hereditary form).
Approximately 25% of sporadic medullary thyroid carcinomas have a
somatic mutation (one that occurs within a single "parafollicular"
cell) of the RET proto-oncogene. This mutation is presumed to be the
initiating event, although there could be other as yet unidentified
causes.
Clinical features of medullary thyroid
carcinoma
The major clinical symptom of medullary thyroid carcinoma
is diarrhea; occasionally a patient will have "flushing" episodes,
particularly with liver metastasis. This generally occurs in
individuals who have a sizeable amount of tumor, most commonly having
spread to the liver. Occasionally, diarrhea will be the initial
presenting complaint. Sites of spread of medullary thyroid carcinoma
include local lymph nodes in the neck, lymph nodes in the central
portion of the chest (mediastinum), liver, lung, and bone. It may also
spread to other locations, but such spread is uncommon.
Adjuvant therapy for medullary thyroid cancer
Unlike differentiated thyroid carcinoma, there is no role
for radioiodine treatment in medullary-type disease. External beam
radiotherapy should be considered for patients at high risk of
regional recurrence, even after optimum surgical treatment. Brierley
et al., conducted a retrospective study of the treatment given to
patients with microscopic residual disease, extraglandular invasion,
or lymph-node metastases and found the locoregional relapse-free rate
at 10 years was 86%, compared with 52% for those patients who did not
receive adjuvant therapy.[citation needed] Typically, 40 Gy is given
in 20 fractions to the cervical, supraclavicular, and upper
mediastinal lymph nodes for 4 weeks, with subsequent booster doses of
10 Gy in five fractions to the thyroid bed, especially in the setting
of gross residual disease.
After a long period during which surgery and radiation therapy formed
the major treatments for medullary thyroid carcinoma, clinical trials
of several new tyrosine kinase inhibitors (www.thyroidtrials.org) are
now being studied. Preliminary results show clear evidence of response
of a small percentage of patients, providing hope for future advances.
Medullary Thyroid Carcinoma Prognosis
Indicators
The prognostic value of measuring calcitonin and
carcinoembryonic antigen (CEA) concentrations in the blood has been
recently studied in a retrospective study of 65 MTC patients; see
Barbet, et al. The post-surgical times ranged from 2.9 years to 29.5
years; all 65 patients continued to have abnormal calcitonin levels
after total thyroidectomy and bilateral lymph node dissection. The
prognosis of surviving MTC appears to be correlated with the rate at
which a patient's postoperative calcitonin concentration doubles,
rather than the pre- or postoperative absolute calcitonin level.
The result of the 65 patient study can be summarized with respect to
the calcitonin doubling time (CDT):
CDT < 6 months: 3 patients out of 12 (25%) survived 5 years. 1 patient
out of 12 (8%) survived 10 years
CDT between 6 months and 2 years: 11 patients out of 12 (92%) survived
5 years. 3 patients out of 8 (37%) survived 10 years
CDT > 2 years: 41 patients out of 41 (100%) were alive at the end of
the study
The 65 patients had a median age of 51 (range was 6 to 75), with 24
age 45 years or younger and 41 older than 45 years. The gender
representation was 31 males and 34 females.
The same study noted that calcitonin doubling time is a statistically
better predictor of MTC survival, compared with CEA.
Anaplastic thyroid cancer
This form of thyroid cancer has a very poor prognosis (near
100% mortality) due to its aggressive behavior and resistance to
cancer treatments. It rapidly invades surrounding tissues (such as the
trachea).
Treatment
Unlike its differentiated counterparts, anaplastic thyroid
cancer is not curable neither by surgery nor by any other treatment
modality, and is in fact usually unresectable due to its high
propensity for invading surrounding tissues. Palliative treatment
consists of radiation therapy usually combined with chemotherapy.
Post-operative radiotherapy for differentiated thyroid carcinoma: when and
how much
The role of external beam radiotherapy (EBRT) in thyroid cancer
remains controversial and there is no level I evidence to recommend
it. No published randomised controlled trials have examined the
addition of EBRT to standard treatment, namely surgery, radioactive
iodine and medical suppression of thyroid stimulating hormone.
Imbalances in age, sex, completeness of surgical excision,
histological type and stage, between patients receiving and not
receiving EBRT, confound retrospective studies. Variability also
exists between treatment and non-treatment groups in the use of
radio-iodine and post-treatment thyroid stimulating hormone (TSH)
suppression and treatment techniques between and within retrospective
studies.
Farahati et al. and Philips et al. have reported statistically
significant advantages for post operative EBRT, however, in both
studies many confounding factors have been reported. For example,
patients receiving EBRT were more likely to have node-positive
disease, extracapsular extension and incomplete macroscopic excision.
The differences in patient groups among these studies, and the
difficulties with confounding factors, make evidence-based
recommendations for the use of EBRT difficult to formulate. Tsang et
al. have suggested a role for EBRT in patients with papillary cancer,
with microscopic residual disease based on sub-group analysis showing
a statistically significant advantage in terms of cause-specific
survival (100% vs 95%; P=0.038) and local recurrence (93% vs 78%;
P=0.01). Farahati et al. recommend the use of EBRT in node-positive
patients over 40 years of age with papillary histology on the basis of
an increase in time to local or distant failure (P=0.0009). Other
indications for EBRT include high-grade tumours that do not
concentrate iodine and tumours with gross local invasion where there
is a high suspicion of microscopic or macroscopic residual disease.
The use of EBRT is controversial for those patients with microscopic
residual disease. All reports on the use of EBRT have been
retrospective, with varying criteria for patient selection, resulting
in contradictory conclusions. Several studies have described either no
or deleterious effects for EBRT, but many others have described
benefit. In a study from Toronto, Brierley et al. found superior local
control and improved survival in patients who received EBRT for
microscopic residual disease (10-year local relapse-free rate 93%
compared with 83% for patients not receiving EBRT, P = 0.01; and
cause-specific survival 99% compared with 93%; P = 0.04). “Total
thyroidectomy with adjuvant 131I, followed by TSH suppression is
considered standard therapy for differentiated thyroid carcinoma”. In
the absence of randomised data, there is credible evidence from
retrospective studies (Level II-III) to recommend EBRT in addition to
standard therapy in high-risk patients.
The apparent difference in outcomes related to the dose of
radiotherapy is subject to the confounding factors in all
retrospective studies of EBRT as outlined above. However, there are
few published data that define the dose to be used. In one
retrospective study, 114 patients with macroscopically resected,
well-differentiated thyroid cancer were treated with EBRT and an
‘adequate’ total dose was defined as >45 Gy. Patients receiving an
‘adequate’ dose had a significantly improved local regional
relapse-free survival (P<0.001). However, only three of the 114
patients in this study also received radio-iodine, and therefore the
role of EBRT in addition to standard management was not examined. A
total dose of 50–60 Gy was used in the two studies, which showed a
reduction in local failure where EBRT was used in addition to
radio-iodine (Farahatti et al., and Phillip et al.). Others have
treated patients with gross residual disease with 50 Gy in 20
fractions or its equivalent and 40 Gy in 15 fractions or its
equivalent in the presence of microscopic residual disease. If the
decision is made to treat a large volume, including the cervical nodes
for instance, or if there is extracapsular extension and local
invasion of cervical nodes, fractionation is changed to 2 Gy
fractions. Currently, recommended doses are 50 to 60 Gy in 25 to 30
fractions over 5 to 6 weeks.
To treat the thyroid bed, a clinical target volume from the hyoid to
suprasternal notch is determined. A simple technique is to use two
antero-lateral oblique wedged fields, or direct electron beams. When
using oblique fields the posterior border is placed to exclude the
spinal cord. If it is determined that the clinical target volume
should include the cervical and superior mediastinal lymph nodes, as
well as the thyroid bed, a two-phase technique is commonly used. The
initial volume (phase I) includes the regional lymph nodes from the
mastoid tip to the carina, including the thyroid bed. The phase I
volume may consist of parallel opposing antero-posterior/postero-anterior
fields to 40–46 Gy. The phase II volume should include the tissues
considered at highest risk of relapse, aiming to boost the high-risk
area to a total dose of 14 Gy (cumulative total dose of 60 Gy). For
the boost to the thyroid bed alone, several techniques can used, such
as, a direct anterior electron beam, antero-lateral oblique wedge
fields, or a lateral pair of angled-down oblique fields, achieved with
a couch rotation of 10–20 degrees, aiming inferiorly to avoid the
shoulders, off the spinal cord. Since the thyroid bed target volume is
wrapped around many critical structures in the neck and it is often
necessary to include regional lymph nodes, treatment planning of this
difficult volume is ideal for conformal radiotherapy, or
intensity-modulated radiation therapy. A conformal plan may be used
either to treat the thyroid bed alone or to include the cervical
nodes.
Recommended indications for the use of EBRT are:
High Grade tumors that do not concentrate radio-iodine.
Recommendations for EBRT after 131I therapy include high-risk patients
defined as; older (>45 years) with potential microscopic residual
disease, after resection of gross extrathyroid extension (i.e. UICC
6th edition category T4a or T4b but not T3), or multiple lymph-node
involvement.
Bulky tumors with superior mediastinal / retro-sternal extension.
Gross evidence of local invasion at surgery and presumed to have
significant macro or microscopic residual disease, particularly if
there is residual tumour that fails to concentrate 131I and is
apparent only by raised thyroglobulin.
For locally advanced tumors which are inoperable for a variety of
lesions it can be used for palliation along with TSH suppression.
For recurrent disease in the neck which is not amenable to
radio-iodine therapy or further surgery.
For palliation of recurrent disease or metastatic disease in bone,
cerebrum, spine and other areas.
Adjuvant therapy for anaplastic thyroid cancer
Treatment of anaplastic-type carcinoma is generally
palliative in its intent for a disease that is rarely cured and almost
always fatal. The median survival from diagnosis ranges from 3 to 7
months, with worse prognosis associated with large tumours, distant
metastases, acute obstructive symptoms, and leucocytosis. Death is
attributable to upper airway obstruction and suffocation in half of
patients, and to a combination of complications of local and distant
disease, or therapy, or both in the remainder. In the absence of
extracervical or unresectable disease, surgical excision should be
followed by adjuvant radiotherapy. In the 18–24% of patients whose
tumour seems both confined to the neck and grossly resectable,
complete surgical resection followed by adjuvant radiotherapy and
chemotherapy could yield a 75–80% survival at 2 years.
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