Thyroid Cancer
( for residents and specialists)
Introduction
Thyroid cancer is the most common endocrine malignancy, accounting for more than 95%
of all endocrine cancers.The spectrum of thyroid cancer ranges from occult papillary thyroid
carcinoma, which has a relatively benign course, to aggressive anaplastic thyroid carcinoma.
Fortunately, more than 90% of all thyroid cancers are well differentiated, and individuals with
these tumors have a good long-term prognosis.
Clinical Presentation and Diagnosis
Most thyroid cancer patients present clinically with a palpable thyroid nodule. These are
usually asymptomatic. In rare cases, patients present with hoarseness, pain, dysphagia,
dyspnea, coughing, or choking spells. Pain associated with a malignant thyroid lesion should
raise the suspicion for medullary thyroid carcinoma, anaplastic carcinoma, or lymphoma.
In evaluating patients for thyroid cancers, clinical history and physical examination remain
the cornerstone of appropriate management. historical factors predicting malignancy include a
history of head and neck irradiation; total body irradiation for bone marrow transplantation; a
family history of thyroid cancer; and rapid growth or hoarseness. Children, men, and adults
older than 60 years have an increased risk of malignancy. Personal and family history of other
endocrine disorders, specifically hyperparathyroidism, pituitary adenomas, pancreatic islet
cell tumors, adrenal tumors, and breast cancer increase the risk of thyroid cancer. A family
history of papillary or medullary carcinoma (multiple endocrine neoplasia [MEN]
syndromes), familial polyposis also risk factors for thyroid cancer.
With the discovery of a thyroid nodule, a physical examination focusing on the thyroid
gland and adjacent cervical lymph nodes should be performed. physical findings suggesting
possible malignancy include a “hard texture” of the thyroid nodule, cervical
lymphadenopathy, vocal cord paralysis, and fixation of the nodule to surrounding tissue.
Patients presenting with hoarseness or patients planned for reoperation should have a direct
laryngoscopy before any surgical intervention to document the function of the vocal cords.
High-resolution thyroid ultrasonography has become an extension of the physical
examination in the evaluation of thyroid disease. Recent investigations have documented that
three sonographic features were significant independent risk factors for malignancy: irregular
margins, intranodular vascular pattern, and microcalcifications.
FNA biopsy (FNAB) is the most reliable and cost-efficient method for evaluating thyroid
nodules. These should now routinely be performed under ultrasound guidance for small or
difficult-to-palpate or complex nodules to reduce failure rates. FNAB is not as accurate in
radiation-induced thyroid cancer or in patients with a family history of thyroid cancer; these
patients should undergo surgical resection if there is clinical suspicion of malignancy.
Preoperatively, all patients should therefore undergo ultrasound examination of the thyroid
gland and cervical lymph nodes, as well as thyroid function tests, serum thyroglobulin, and
antithyroglobulin antibody levels and blood calcium levels. In the case of medullary thyroid
cancer, serum calcitonin, CEA, and calcium levels should be obtained. All patients with
medullary thyroid cancer should also be tested for the RET proto-oncogene and evaluated for
pheochromocytoma and hyperparathyroidism before surgery.
Well-Differentiated Thyroid Carcinoma
1) Papillary Thyroid Carcinoma
PapillaryThyroid Carcinoma accounts for approximatel 70% of all thyroid malignancies, it
is has best prognosis.Papillary thyroid cancer is twice as common in women as men and has a
peak age of presentation of 38 to 45 years. This tumor also accounts for 90% of radiationinduced thyroid cancer and is familial in 5% of patients.
Patients can be separated into low- and high-risk groups on the basis of patient age, grade of
tumor, and extent and size of tumor (AGES); age, metastases, extent, and size (AMES); .
Unfortunately, all the classification systems are based on postoperative findings. These
classifications help predict tumor behavior, and the risk of death from thyroid cancer ( 5% in
the low-risk group, versus 40% in the high-risk group )
Table :Classification of Low-versus High-Risk Patients Using the AGES System
Variable
Low Risk
High Risk
Age
Women <50 years
Women > 50 years
Men <40 years
Men > 40 years
Poorly differentiated
Grade
Well differentiated
Fibrous struma
Insular, mucoid, columnar, and tall-cell variant
Extent
Confined to the thyroid
Invasive to adjacent tissues or distant
metastases
Tumor with maximal diameter <4
Tumor with maximal diameter >4 cm
cm
AGES, Patient age and grade, extent, and size of tumor.
Size
Treatment :
The recommendations is total or near total thyroidectomy when postoperative treatment
with iodine-131 (I-131) is considered. Low-risk patients, who have papillary thyroid cancer of
less than 1 cm, can be treated by thyroid lobectomy and isthmectomy; However, the benefits
of total thyroidectomy include (1) the thyroid tissue is removed so that postoperative
radioiodine scanning and ablative therapy can be effective, (2) serum thyroglobulin levels are
more sensitive for detecting recurrent or persistent disease, (3) intrathyroidal cancer that is
present in more than 50% of patients is removed, and (4) the small risk of a differentiated
thyroid cancer becoming an undifferentiated cancer is decreased.
Functional neck dissection ( lymph node dissection ) should generally be performed only in
patients has clinical or sonographic evidence of lymph node involvement. Intraoperative
enlarged lymph nodes in the central and lateral neck should be removed and submitted for
frozen section. If positive, a formal lymph node dissection should be undertaken.Recurrence
of papillary thyroid cancer can occur anytime during the patients' lifetime, thus lifelong
surveillance is required. Unfortunately approximately one third of patients who develop
recurrent thyroid cancer eventually die from it.
2) Follicular Thyroid Carcinoma
Follicular cancer accounts for approximately 10% of all thyroid malignancies. Although
follicular thyroid cancer can occur in any age group, these patients are typically older than are
patients with papillary thyroid cancer group, usually in the sixth decade of life. As with
papillary thyroid cancer, the female-to-male ratio is between 2:1 and 5:1.
Follicular thyroid cancer usually presents as a slowly growing solitary thyroid nodule.
Occasionally it has local symptoms. Rarely patients with follicular cancer present with
symptoms of distant metastasis to the bone, lung, brain, and liver because these tumors, unlike
papillary cancers, have a tendency to spread hematogenously. Less than 6% of follicular
thyroid cancers metastasize to the cervical lymph nodes.
The prognosis of follicular cancer is slightly worse than that for papillary cancer. Depending
on the stage of the patient at presentation, overall survival ranges from 43% to 95% at 10
years. However, unlike patients with papillary thyroid cancers, those with follicular thyroid
cancer who have not experienced recurrence within 12 years of their initial operation are
usually cured. Therefore lifelong surveillance is not necessary. The important prognostic
factors include the following: (1) presence of metastatic disease (2) older age (usually >40
years), (3) degree of invasion (microcapsular vs. angioinvasion with or without capsular and
widely invasive), and (4) degree of tumor differentiation.
FNAB is unable to distinguish benign from malignant follicular neoplasms because this
technique evaluates cellular features. To distinguish benign from malignant follicular
neoplasm, the whole specimen must be evaluated for vascular and capsular invasion.
Because the diagnosis of follicular cancer cannot be made on FNAB, the recommendation
isinitial operation is lobectomy and isthmectomy. Frozen sections are usually of limited utility
in determination of malignancy. If the tumor has evidence of vascular invasion or is widely
invasive on final pathology, the patient should undergo a completion thyroidectomy. some
centers will and others will not perform a completion thyroidectomy if the patient has
minimal capsular invasion.
3) Hurthle Cell Carcinoma
Hurthle cell cancer accounts for approximately 3% of all thyroid cancers. As with follicular
cancer, it has a peak incidence in the fifth and sixth decades. The female-to-male ratios range
from 2:1 to 10:1. Radiation exposure, age, and familial Hurthle cell tumors are associated
with an increased risk of these neoplasms. The 10-year survival of Hurthle cell carcinoma is
70%. Prognosis generally depends on extent of disease at the initial diagnosis and the extent
of resection.
Most patients with Hurthle cell neoplasms present with a solitary nodule. FNAB can
reliably diagnose these neoplasms, but similar to follicular neoplasms, it cannot determine
malignancy, which occurs in 35% of patients. Malignancy is determined by capsular or
vascular invasion. In patients presenting with malignant lesions, 70% to 80% are confined to
the gland, 10% to 20% have lymph node metastasis, and 15% have distant metastasis, most
commonly to bone or lung.
Careful surgical exploration should always be undertaken to detect the presence of obvious
malignant disease. In patients with obvious malignant disease or contralateral nodular disease,
or in patients with a history of childhood head and neck radiation, a one-stage total
thyroidectomy is the preferred approach. For the routine patient with a solitary nodule,
surgical management should consist of lobectomy and isthmectomy. Frozen section is
unreliable in Hurthle cell neoplasm, similar to follicular neoplasm, and should be used
judiciously. Lymph node dissection is indicated only for clinically or sonographically evident
disease.
4) Medullary Thyroid Carcinoma
Medullary thyroid cancer (MTC) accounts for 7% of thyroid cancers . Approximately 75%
of the cases are sporadic, and 25% are hereditary. These tumors originate from c cells or
parafollicular cells and may be associated with c-cell hyperplasia. Because of the location of
the parafollicular cells, these tumors are almost always located laterally at the junction of the
upper two thirds of the thyroid gland at approximately the level of the cricoid cartilage. In the
sporadic form, there is usually a single focus of malignancy and unilateral disease in 85% of
cases, compared with the hereditary form, in which the disease is multifocal and bilateral in
90% of cases and there is c-cell hyperplasia.
MTC is associated with the RET proto-oncogene mutation. The hereditary forms of MTC
are MEN 2A, MEN 2B, and familial MTC (FMTC). These causes of MTC all have point
mutations in the RET proto-oncogene. A diagnosis of isolated FMTC is made when three or
more cases are identified in a family without other associated endocrinopathies. Thus all
patients with MTC should be RET proto-oncogene tested. Genetic testing and surgical
treatment should begin no later than 5 years of age in MEN 2A and soon after birth in MEN
2B.
The diagnosis is usually suspected on the basis of characteristic cytological features and the
presence of immunostaining for calcitonin on FNAB specimen. Blood testing for calcitonin
and CEA may also be informative. After the diagnosis of MTC is made, it is important to
screen the patients for pheochromocytoma and hyperparathyroidism because 20% of patients
have these associated conditions.
Lymph node metastases are positive in 70% of patients with palpable disease.
Serum markers for calcitonin support the diagnosis and correlate with tumor bulk, nodal,
and distant metastasis. A calcitonin level greater than 1000 pg/ml after total thyroidectomy
with no evidence of recurrence in the neck invariably indicates the presence of distant
metastases (usually micrometastases in the liver). MTC can also metastasize to the lung and
bone. High CEA levels correlate with a poorer prognosis.
Prevention and cure of MTC is by surgery, Therefore surgeries for MTC should be
performed in RET-positive patients with familial disease before age 6. A prophylactic central
neck dissection is not necessary.
Children with MEN 2B is classified as high risk and should have their thyroidectomy and
central node dissection before 1 year of age or at diagnosis in those with an increased
calcitonin. Children with MEN 2A and familial MTC without other endocrinopathies should
have a total thyroidectomy and central node dissection by age 5. In sporadic MTC, a routine
ipsilateral central and lateral functional lymph node dissection should be performed.
MTC is not sensitive to radioiodine therapy.
5) Anaplastic Thyroid Carcinoma
Fortunately anaplastic thyroid cancer (ATC) is a rare tumor, accounting for 1% to 2% of
thyroid malignancies. Unlike well-differentiated thyroid cancer, ATC is invariably lethal and
Survival is measured in months. ATC occurs most commonly within well-differentiated
thyroid cancer; this transformation occurs in approximately 1% of patients with differentiated
cancers. ATC occurs most commonly in patients older than 60 years and usually presents as a
rapidly expanding thyroid mass that is firm to hard and frequently fixed. The tumor may
compress the trachea and infiltrate the skin, causing overlying necrosis. Lymph node
enlargement is frequent (84%) and early. Local tumor extension can cause fixation of the
larynx, esophagus, and carotid vessels. Patients can present with hoarseness because of vocal
cord paralysis resulting from direct extension. Symptoms such as dysphagia, dysphonia, and
dyspnea are common. Systemic metastases occur in 75% of patients, usually involving the
lungs, bone, brain, and adrenal glands.
The diagnosis of ATC can be established by FNAB. The diagnosis of ATC must be
differentiated from that of lymphoma and poorly differentiated medullary carcinoma.
The standard form of treatment of thyroid cancer has been complete tumor removal, but in
ATC, this maneuver is usually not curative because many patients present with distant
metastases. Multimodality treatment consisting of radiation, chemotherapy, and then surgery,
followed by further radiation and chemotherapy, provides the best results. Besides tumor
resection, tracheostomy may be indicated for advanced disease.
Unfortunately, the current treatments still have a limited role in the management of ATC
because the majority of patients die within months of their diagnosis from local invasion or
distant metastases.
6) Lymphoma
Primary lymphomas of the thyroid are rare, accounting for only 1% to 2% of thyroid
malignancies and less than 2% of extranodal lymphomas. Most thyroid lymphomas are non–
Hodgkin's B-cell lymphomas. Thyroid lymphomas are predominantly associated with
Hashimoto's thyroiditis and may be histologically difficult to distinguish from this chronic
lymphocytic disease. The relative risk of lymphoma in these patients is 70 to 80 times higher
than general population control individuals.
Most patients present with a several-week history of a rapidly enlarging goiter and
respiratory difficulty. Typically the patients are female in their seventh decade of life with a
long-standing history of Hashimoto's thyroiditis. It is usually painless and often associated
with hoarseness and dysphagia. Less commonly patients may present with tracheal
compression. On physical examination, patients usually have a firm thyroid either unilateral
or bilateral with possible fixation to adjacent structures. Lymphadenopathy is common.
Clinically primary lymphoma poses a diagnostic and therapeutic challenge because it can
present in a fashion similar to ATC. As a result, it is essential to distinguish these two entities
because they have different therapeutic and prognostic implications. FNAB has helped
distinguish these two conditions preoperatively and has decreased the need for open biopsy.
Up to 88% of thyroid lymphomas are diagnosed on FNA alone, although core needle biopsy
or open surgical biopsy may be warranted.
Table : Staging for Thyroid Lymphoma
Stage IE Localized disease within the thyroid
Stage IIE Disease confined to thyroid and regional lymph nodes
Stage
IIIE
Disease on both sides of diaphragm
Stage
IVE
Disseminated disease
Surgery plays a limited role in thyroid lymphoma unless the diagnosis is not established.
Thyroid lymphomas have been shown to be both radiosensitive and chemosensitive; therefore
most current recommendations are to treat these tumors with a combined modality therapy.
Doxorubicin-based combination chemotherapy deceases the chance of distant metastasis. In
B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) of the thyroid, radiation
alone has resulted in a 96% complete response, with only a 30% relapse rate.
Advanced stage of the tumor, size greater than 10 cm, mediastinal involvement, and the
presence of dysphagia are poor prognostic factors. Most recurrences occur within the first 4
years. The overall survival for primary thyroid lymphoma is 50% to 70%, ranging from 80%
in stage IE to less than 36% in stage IIE and IVE
source
Current Surgical Therapy , J. L. Cameron, 9 th eddition, 2008
DR. S. ALDAQAL