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MINISTRY OF HEALTH OF UKRAINE
VINNITSA NATIONAL PIROGOV MEMORIAL MEDICAL
UNIVERSITY
"CONFIRM"
at the methodical meeting
Department of Ray diagnostics,
Ray therapy and Oncology
Head of the department
As. of Prof., M.S.D. Kostyuk A.G.
________________________
"______" ________ 2013 year
METHODICAL GUIDELINES
For self-study for students in preparing for the practical (seminary) lessons
Subject of Study
Oncology
Module No
1
Theme No
12
Topic of Lesson
Thyroid cancer.
Risk factors. Classification by TNM. Methods of
diagnostics. Clinics. Treatment: surgery, radiotherapy,
chemotherapy, combined.
Course
5
Faculty
General Medicine
2
Topicality. It was estimated that in 2002, more than 20,000 individuals would be
diagnosed with carcinoma of the thyroid gland and that approximately 1,300 patients
would die as a consequence of complications of these diseases or their treatments. Of
these patients, 80% and 14%, respectively, would have papillary and follicular
carcinomas, which are the differentiated carcinomas that derive from the thyroid
hormone producing follicular epithelial cells. Another 4% would have medullary
carcinoma, which is a neuroendocrine malignancy, and the remaining 2% would
have the highly aggressive anaplastic carcinoma. Rates of disease recurrence and
cancerspecific mortality are increased in patients with metastases, especially those
with extracervical spread. In the Surveillance, Epidemiology, and End Results
(SEER) report of 15,700 patients, the overall 10-year age- and gender-corrected
survival rates were 98% for papillary, 92% for follicular, 80% for medullary, and
13% for anaplastic carcinoma. Older age at diagnosis and wider spread of disease are
associated with a worse prognosis, independent of the type of cancer. Although
differentiated carcinomas have a 2:1 female predominance, gender does not appear to
affect prognosis.
Learning Objectives:
1. Epidemiology of Thyroid cancer.
2. Ethiology and Risk factors.
3. Differential diagnosis.
3. Morphology of Thyroid cancer.
4. Classification TNM Thyroid cancer.
5. Methods for obtaining of material for cytological and histological examination
6. Diagnostic of Thyroid cancer
7. Treatment of Thyroid cancer.
8. Types of surgical treatments.
9. Indications and contraindications for chemo- and radiotherapy.
10. Complication and adverse event of chemo- and radiotherapy
11. Survival and prognosis.
12. Follow-up.
13. Palliative care
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Cancers of the Thyroid Gland
The thyroid gland lies across the lower part of the neck with one lobe on either side
of the trachea on the lower part of the larynx. The thyroid gland uses iodine to make
the hormone thyroxine, which is essential for basic metabolism.
Causes and Presentation
Cancer of the thyroid gland is usually fi rst noticed as a single lump in the gland.
The lump is most often just to one or other side of the midline in the lower anterior
part of the neck but cancer may occasionally develop as one lump that enlarges and
becomes more obvious and harder in a multinodular goitre. Lumps in the thyroid
move up and down when the patient swallows due to movement of the tongue that
elevates the hyoid bone and the larynx, to which the thyroid gland is attached.
General enlargement of the thyroid gland is called a goitre, and multiple cysts and
other lumps may develop in some goitres. This process is usually due to a shortage of
iodine in the food. A lumpy goitre is known as a multinodular goitre. Occasionally
one of the lumps in a multinodular goitre will become malignant and develop into a
cancer although more often when a cancer develops in the thyroid gland it begins as
a single lump in an otherwise apparently normal thyroid gland. Most thyroid cancers,
especially those that occur in young people, are generally characterised by slow
growth with a relatively good long-term outlook compared to other cancers.
Differential Diagnosis of a Thyroid Nodule
Benign thyroid disease
Macrofollicular
Colloid adenoma
Adenomatoid hyperplasia
Microfollicular Follicular adenoma
Hürthle cell adenoma
Toxic adenoma
Hashimoto thyroiditis
Graves disease
Infection
Tuberculosis
Fungal
Pneumocystis
Abscess
Thyroid cyst
Infiltrative and granulomatous disease
Malignant thyroid disease
Differentiated thyroid carcinoma
Papillary thyroid carcinoma
Follicular thyroid carcinoma
Medullary thyroid carcinoma
Anaplastic thyroid carcinoma
Primary thyroid lymphoma
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Metastatic
Breast carcinoma
Renal cell carcinoma
Lung carcinoma
Melanoma
Colon carcinoma
Gastric carcinoma
Extrathyroidal disease
Parathyroid adenoma, cyst, or carcinoma
Esophageal diverticulum
Lipoma
Aberrant subclavian artery
Accidental Irradiation
Increased numbers of people with thyroid cancer have been one of the most serious
long-term consequences of atomic irradiation as seen in survivors of Hiroshima and
Nagasaki atomic bombs and again after the Chernobyl atomic energy plant disaster.
Investigations
An isotope scan is a useful investigation for thyroid cancer. In this procedure a scan
of the thyroid is taken after injection of a very small dose of radioactive iodine into a
vein. The cancer will usually show as a “cold nodule”, that is, part of the thyroid
gland that is replaced by cancer, does not concentrate the iodine and appears nonfunctional and clear on the scan. Most cold nodules are benign cysts or benign
adenomas but about 10% of solitary cold nodules are cancer. However as cysts and
some other lumps also show up as “cold nodules”, to make a diagnosis the lump
should be biopsied. This is usually done by needle aspiration of fl uid or cells from
the lump. Alternatively the diagnosis is more certain if the lump is surgically excised
and examined microscopically.
Frozen section examination may then allow the surgeon to proceed with further
surgery if the lump proves to be a cancer. Occasionally a “hot nodule”, that is a
functioning thyroid lump, may be found to be a cancer.
Types of Thyroid Cancer
There are four broad types of thyroid cancer.
Papillary Cancer
Papillary carcinoma constitutes about 60% of thyroid cancers and is three times
more common in women than men. It is more common in young adults, occasionally
in teenagers or even children but fortunately it is the least malignant of thyroid
cancers.
Papillary cancer may be present in different parts of the thyroid gland at the same
time and may spread to nearby draining lymph nodes, but usually does not spread
further until very late in the disease. For this reason, removal of the whole of the
thyroid gland together with any enlarged lymph nodes will usually cure the patient.
After total removal of the thyroid gland the patient thereafter must take thyroid or
thyroxine tablets by mouth because thyroxine is essential for normal body function.
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Follicular Cancer
The second most common type of thyroid cancer more commonly affects adults of
middle age and is called follicular carcinoma. It too, usually presents as a lump in the
thyroid gland and is usually not diagnosed with certainty until the lump has been
removed surgically and examined microscopically.
These cancers tend to be present in one lobe of the thyroid gland only and have a
greater tendency to spread by the bloodstream to bone, lungs or liver rather than by
lymphatics to lymph nodes. These cancers often more closely resemble normal
thyroid tissue than do the other thyroid cancers and although they usually appear as
“cold nodules” in radio-iodine scans, they may sometimes scan as normal thyroid
tissue or even rarely as hyperactive “hot nodules”.
Because of their tendency to involve one lobe of the thyroid gland only they are
usually treated by removal of the involved half of the thyroid gland, leaving the other
half to carry out normal thyroid function and production of thyroxine. Metastases
may be treated by surgical excision (if in lymph nodes) by radio-therapy or by radioactive iodine being injected intravenously so that it becomes concentrated in thyroid t
issue where it ir radiates and destroys cells, including the cancer cells wherever they
are. Again thyroxine tablets must be taken thereafter to maintain normal endocrine
body function. Chemotherapy is also sometimes effective in the treatment of
metastases.
Medullary Cancer
This type of thyroid cancer arises from the calcitonin-producing cells in the thyroid
gland. It may be familial and it may be associated with other endocrine disturbances
or with an adrenal gland tumour called pheochromocytoma. Calcitonin levels can
be elevated with this cancer and will fall to normal if treatment has been successful.
Total removal of the thyroid gland usually results in cure.
AnaplasticCancer
The fourth broad type of thyroid cancer is anaplastic cancer. This is the most
dangerous form of thyroid cancer and is usually rapidly growing. It is fortunate that it
is also the least common. It tends to affect older people and may grow rapidly
presenting as an enlarging lump or enlarging swelling of the whole of the thyroid
gland. It may press on the trachea and make breathing diffi cult. This cancer is
virtually incurable by surgery and is best palliated by radiotherapy or sometimes by
chemotherapy.
Other Types
The thyroid gland is occasionally the site of other primary malignant tumours such
as lymphoma, sarcoma or even secondary cancers from a primary cancer elsewhere,
but these are uncommon.
TNM (Tumor, Node,Metastases): The AJCC (American Joint Committee on Cancer)
Staging Scheme for Thyroid Carcinomas (Fifth Edition)
T: Tumor status
T1 < 1 cm
T2 1–4 cm
T3 > 4 cm
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T4 extension beyond thyroid capsule
Tx tumor status known
N: Regional node status
N0 no nodes involved
N1a unilateral cervical nodes positive
N1b bilateral cervical or mediastinal nodes positive
Nx nodes status unknown
M: Distant metastases
M0 no distant metastases
M1 distant metastases
Mx metastases status unknown
Stage Assignments
Differentiated carcinoma
< 45 years > 45 years
Stage I Any T, any N, M0 T1, N0, M0
Stage II Any T, any N, M1 T2, N0, M0
T3, N0, M0
Stage III T4, N0, M0 Any T, N1, M0
Stage IV Any T, any N, M1
Medullary carcinoma
Stage I T1, N0, M0
Stage II Any T, N0, M0
Stage III Any T, N1, M0
Stage IV Any T, any N, M1
Anaplastic carcinomas
All are classified as stage IV
PRIMARY SURGICAL MANAGEMENT Total thyroidectomy is the preferred
initial surgical procedure for most patients with differentiated thyroid carcinoma, as
supported by these arguments: the foci of papillary carcinoma are found in both
thyroid lobes in 60% to 85% of patients; 5% to 10% of recurrences of papillary
carcinoma after unilateral surgery occur in the contralateral lobe, with subsequent
high risk of disease related death; and the efficacy of therapy with radioiodine and
the specificity of serum thyroglobulin levels as a tumor marker are maximized by
resection of as much thyroid tissue apossible. In a retrospective analysis of the
outcomes of 1,685 low-risk patients, the 20-year recurrence rate after lobectomy was
22%, compared with 8% for patients treated with total thyroidectomy. Other
retrospective studies reported similar results of reduced recurrence, although the
degree of improvement in survival has varied. In contrast, the arguments put forth to
support a unilateral procedure include lack of a major survival benefit with more
extensive surgery and fewer complications following unilateral surgery, including
hypoparathyroidism and recurrent laryngeal nerve paralysis. In one study of low risk,
there was no significant difference after a median 20 year follow-up in local
recurrence rates (4% vs 1%) or overall failure rates (13% vs 8%) for the 276 patients
treated with unilateral lobectomy as compared to the 90 treated with total
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thyroidectomy. Resolution of the controversy concerning the extent of thyroidectomy
might be achieved through a randomized trial comparing total thyroidectomy with
ipsilateral lobectomy. However, using data from published series, 3,100 patients and
at least 6 years of follow-up would be necessary to detect an improvement in causespecific mortality rates from 1.5% to 0.4%; four times as many patients would be
required for a comparison of complication rates. In the absence of prospective trials,
several consensus groups have recommended that a total thyroidectomy should be
performed by an experienced thyroid surgeon if the primary papillary carcinoma is at
least 1 cm in diameter, if there is extrathyroidal extension of tumor, or if there are
metastases. This operation should also be performed in patients with a history of
exposure to ionizing radiation of the head and neck, given the high rate of tumor
recurrence with lesser operations. In selected patients whose papillary tumor is < 1
cm in diameter and confined to one lobe of the gland, a unilateral lobectomy may be
sufficient. For patients with a cytologically suspicious follicular neoplasm, unilateral
lobectomy and isthmusectomy should be performed; a complete thyroidectomy is
done if there is a diagnosis of malignancy. Although microscopic regional nodal
metastasis of papillary carcinoma occurs in up to 80% of patients, only about 35%
have cervical or mediastinal node metastasis grossly detectable at the time of
surgery. Unlike most other malignancies, the presence of lymph node metastasis is
only a minor risk factor for mortality. A metaanalysis of nine studies demonstrated
no relationship between the lymph node status at presentation and survival, although
several studies did show an increased risk of tumor recurrence. As a surrogate
outcome measure, however, disease recurrence after nodal metastasis of papillary
carcinoma portends a markedly increased risk for mortality. Two of five studies that
examined follicular carcinoma demonstrated decreased survival rates in patients with
initial nodal disease, although this is an uncommon presentation. Given that the
presence of regional nodal metastasis influences recurrence rates, neck dissection
should be performed at the time of thyroidectomy if node involvement is identified.
In a retrospective analysis of 141 papillary carcinoma patients, 51% who were treated
with thyroidectomy alone developed regional recurrence, as compared to 18% who
also had lateral and central neck dissection. These results suggest that neck
dissections at the time of initial thyroidectomy may decrease the incidence of
regional recurrence and support the practice of routine preoperative ultrasonography
to evaluate regional lymphatics. In the presence of invasion of aerodigestive tract
structures, similar survival rates are achieved from either complete surgical resection
or shave excision leaving only microscopic residual disease. In the presence of frank
cartilage destruction or intraluminal involvement of the aerodigestive tract structures,
a shave excision cannot be performed without leaving gross tumor behind, leading to
a 50% death rate within 4 years. Surgery in patients with extensively invasive thyroid
carcinoma should, therefore, aim to remove all gross tumor, attempting to retain as
much airway, vocal, and digestive function as possible. However, only if the tumor is
unresectable or the patient does not agree to a radical resection should gross tumor
be left behind in the neck.
POSTOPERATIVE ADJUVANT THERAPY Radioiodine Adjuvant ablation of
residual thyroid tissue following primary surgery has two rationales: to destroy any
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residual microscopic foci of disease, and to increase the specificity and negative
predictive value of subsequent 131I scanning and serum thyroglobulin measurements
for detection of recurrent or metastatic disease by eliminating residual normal tissue.
Combining retrospective data from multiple studies, radioiodine ablation is
associated with a 50% reduction in locoregional relapse, and long-term diseasespecific mortality may be reduced in patients with primary tumors that are at least 1
cm in diameter, are multicentric, or have soft-tissue invasion at presentation. For
patients with residual disease following optimal surgery, including extracervical
metastases, radioiodine therapy is also recommended. In contrast, ablation is
generally not recommended for solitary primary tumors less than 1 cm without
evidence of extrathyroidal invasion or metastasis. The efficacy of radioiodine
depends on patient preparation, tumor-specific characteristics, sites of disease, and
administered radioiodine activity. Iodide uptake by thyroid tissue is stimulated by
TSH and is suppressed by increased endogenous iodide stores. Following
thyroidectomy, the patient’s thyroid hormone levels must decline sufficiently to
allow the TSH concentration to rise to above 25 to 30 mU/L. This period of hormone
withdrawal typically lasts 4 to 5 weeks. To minimize the resulting symptoms of
hypothyroidism, the shorter-acting hormone liothyronine (T3) is often administered
at doses of 25 µg two times per day. Lower doses are administered to elderly patients
and those with ischemic heart disease. Liothyronine is stopped at least 2 weeks prior
to dosing for a radioiodine scan. Patients should avoid foods with high iodine content
for at least 2 weeks prior to the scanning. For similar reasons, radioiodine uptake can
be iatrogenically suppressed for 1 to 3 months after administration of iodinated
intravenous contrast for radiographic procedures. Urinary iodine content can be
measured to confirm excessive iodine intake if suspected. Whole-body radioiodine
scans for localization of uptake prior to ablation or therapy are frequently performed
24 to 72 h after administration of a diagnostic activity of 2 to 5 mCi of 131I. Most
patients demonstrate significant uptake of radioiodine within the thyroid bed
following thyroidectomy, presumably from normal residual thyroid. Greater
sensitivity for the detection of residual or metastatic tumor can be attained with the
use of higher amounts of 131I. But larger radioisotope activities can lead to
“stunning,” in which reduced uptake of the subsequent ablative or therapeutic dose
occurs as a consequence of radiation delivered by the diagnostic dose.
Use of 123I, with a lower radiation dose to thyroid tissue, may prevent stunning of
therapeutic uptake after a diagnostic scan without loss of diagnostic accuracy.
However, the exact utility of scanning before therapy when metastatic disease is not
likely is undefined, and therefore scanning before ablation may be considered
optional.
With postoperative radioiodine uptake in the thyroid bed, an empirically selected
activity of 131I is administered for adjuvant ablation, typically 75 to 150 mCi. Lower
activities of radioiodine have also been used, permitting treatment that does not
require hospitalization for radiation safety precautions. Assuming that the 24-h
radioiodine uptake is less than 5%, this lower activity has a similar efficacy of
successful ablation and could be considered for patients with disease entirely
confined to the thyroid gland.
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Nonetheless, there is scant information about long-term outcomes, and considerably
more study is required before such low doses can be generally recommended.
lternatively, quantitative dosimetry can be applied to estimate the radioiodine activity
necessary to deliver an effective radiation dose to the tissue of at least 30,000 cGy.
When substantial yet unsuspected locoregional disease or excessive thyroid remnants
are detected, strong consideration is given to additional surgery before radioiodine
administration. A posttreatment scan is performed several days after administration
of the radioiodine dose, although the diagnostic utility of such scans immediately
after ablative treatments is maximal in patients whose thyroid bed activity was previously ablated.
Chemotherapy. Although 10% to 15% of patients with differentiated thyroid cancer
die from their disease, and an even higher proportion suffer morbidity from
recurrence, two recent authoritative texts devoted to thyroid cancer apportioned only
1% of their content to discussion of chemotherapy for these diseases. This reflects
the dearth of substantial research in this area. Little progress has been made since the
original reports of partial responses to doxorubicin in approximately one-third of
patients. The best responses occur in patients with pulmonary metastases and high
performance status. Combining the results of 10 published reports, doxorubicin
yields a nearly 40% response rate for progressive differentiated cancers unresponsive
to radioiodine, including Hürthle cell carcinoma. The recommended dose is 60 to 75
mg/m2 every 3 weeks, administered as a continuous intravenous infusion for 48 to 72
h to minimize the risk of cardiac toxicity. Cumulative doses of up to 600 mg/m2 can
be administered in responsive patients. Other single chemotherapeutic agents that
have been attempted include bleomycin, cisplatin, carboplatin, methotrexate,
melphalan, mitoxantrone, etoposide, and aclarubicin, without suggestion of improved
response rates. In one comparative trial, the combination of doxorubicin, 60 mg/m2,
and cisplatin, 40 mg/m2, induced complete or partial response in 16%, whereas
doxorubicin alone yielded a 31% response rate. Of another 11 patients treated with
the combination of doxorubicin, bleomycin, vincristine, and melphalan, 36% had
partial or complete response, with 1 patient experiencing a complete remission
lasting at least 5 years.
Toxicities, including pancytopenia and gastrointestinal side effects, are markedly
more common and severe, however, during these combination therapies, without
clear evidence of greater benefit.
Long-Term Follow-Up: Diagnostic Imaging After initial ablation, radioiodine
scanning should be performed 6 to 12 months later. The predictive value for 10-year
relapse-free survival of one negative radioiodine scan is approximately 90%, whereas
two consecutive negative scans have a predictive value greater than 95%.
Complementary testing procedures likely improve the predictive value of relapse-free
survival. Ultrasonography of the thyroid bed and cervical node compartments can
accurately identify locoregional metastases and recurrence measuring several
millimeters in diameter and facilitate FNA of such lesions. Ultrasonography should
be considered in the routine follow-up of patients with extrathyroidal invasion or
locorgional nodal metastases. As many as half the patients with locoregional disease
diagnosed by high-resolution ultrasonography may have falsenegative radioiodine
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scans or undetectable serum thyroglobulin. CT is not as sensitive for detecting such
small lesions, but the technique is more readily standardized and less operatordependent. Routine chest radiographs are of limited sensitivity, particularly in the
setting of micronodular metastases but may identify macronodular metastases that do
not concentrate radioiodine.
ANAPLASTIC THYROID CARCINOMA
Anaplastic thyroid carcinomas are aggressive undifferentiated tumors, with a
disease-specific mortality approaching 100%. Patients with anaplastic carcinoma are
older than those with differentiated carcinomas, with a mean age at diagnosis of
about 65 years. Fewer than 10% of patients are younger than 50 years, and 60% to
70% are women. Approximately 50% of patients with anaplastic cancer have either a
prior or coexistent differentiated carcinoma. Anaplastic carcinoma develops from
more differentiated tumors as a result of one or more dedifferentiating steps,
particularly loss of the p53 tumor-suppressor protein. No precipitating events have
been identified, and the mechanisms leading to anaplastic transformation of
differentiated carcinomas are uncertain. Patients with anaplastic carcinoma present
with extensive local invasion, and distant metastases are found at initial disease
presentation in 15 to 50% of patients. The lungs and pleura are the most common
sites of distant metastases, being seen in up to 90% of patients with distant disease.
Approximately 5% to 15% of patients have bone metastases, 5% have brain
metastases, and a few have metastases to the skin, liver, kidneys, pancreas, heart, and
adrenal glands. The diagnosis of anaplastic carcinoma is usually established by FNA
or surgical biopsy. CT of the neck and mediastinum can accurately determine the
extent of the thyroid tumor and identify tumor invasion of the great vessels and upper
aerodigestive tract structures. Most pulmonary metastases are nodules that can be
detected by routine chest radiography. Bone lesions are usually lytic.
TREATMENTAND PROGNOSIS There is no effective therapy for anaplastic
carcinoma, and the disease is uniformly fatal. The median survival from diagnosis
ranges from 3 to 7 months, and the 1- and 5-year survival rates are approximately
25% and 5%, respectively. Death is attributable to upper airway obstruction and
suffocation (often despite tracheostomy) in half the patients and to a combination of
complications of local and distant disease and/or therapy in the remainder. Patients
with disease confined to the neck at diagnosis have a mean survival of 8 months, as
compared to 3 months if the disease has extended beyond the neck. Other variables
that may predict worse prognosis include older age at diagnosis, male gender, and
dyspnea as a presenting symptom. Except for patients whose tumors are small and
confined entirely to the thyroid, total thyroidectomy with complete tumor resection
does not prolong survival. EBRT, administered in conventional doses, also does not
prolong survival.
Although up to 40% of patients may respond initially to radiation therapy, most
have local recurrence. Treatment with single-drug chemotherapy also does not
improve survival or control of disease in the neck, although perhaps 20% of patients
have some response in distant metastases. The introduction of hyperfractionated
radiotherapy, combined with radiosensitizing doses of doxorubicin, may increase the
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local response rate to about 80%, with subsequent median survival of 1 year; distant
metastases then become the leading cause of death. Similar improvement in local
disease control has been reported with the combination of hyperfractionated
radiotherapy and doxorubicin, followed by debulking surgery in responsive patients.
However, the addition of larger doses of other chemotherapeutic drugs has not been
associated with improved control of distant disease or improved survival. Paclitaxel
has recently been tested in newly diagnosed patients and may provide some palliative
benefit.
Suggested Reading:
1. Manual Of Clinical Oncology, - Dennis A. Casciato, Barry B. Lowitz, 2000
2. Oxford Handbook of Oncology, - Oxford University Press, 2002
3. Basics of Oncology, - Frederick O. Stephens · Karl R. Aigner, 2009
4. HARRISON’S Manual of Oncology, - Bruce A. Chabner, Thomas J. Lynch,
Jr., Dan L. Longo, 2008