TITLE: Thyroid Cancer
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
RESIDENT PHYSICIAN: Mai H. Nguyen, MD
FACULTY PHYSICIAN: Francis B. Quinn, Jr., MD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."
In 1812, Gay-Lussac discovered the element iodine as a factor caused goiter. By 1833, Boussingault prescribed iodized salt for prevention and treatment of goiter. In 1836, T.W. King, an English morphologist, presented descriptions of the thyroid follicle, its lymphatic and blood supply, and some predicted theories about the nature of colloid. In the 1870s, Fagge demonstrated the absence of thyroid function causes sporadic and congenital cretinism. William Gull and William Ord clarified the clinical and pathological role of the thyroid in myxedema.
The biggest contribution was from Theodor Kocher,
a skillful surgeon from
Thyroid cancer was first described by Halsted in his extensive compilation of documented thyroidectomies by the terms sarcomatous degeneration, thyroid tumor or thyroid cancer cells. He described thyroid cancers as the silent growths, even though these sleeping tumors can suddenly became more aggressive, metastasize, recur and transform into highly lethal or high mortality cancers.
The thyroid gland is the first endocrine gland to form in the human embryo. In the fourth week, it begins as a thickened median endodermis caudally to the later site the median tongue bud. It then migrates anteriorly and inferiorly onto the hyoid bone and laryngeal cartilages, through the thyroglossal duct. At the end of fifth week, the duct breaks down and the thyroid gland continues descending to its position, anterior to the trachea, by the seventh week. The thyroglossal duct then normally disappears by the tenth week.
gland locates deep to the sternohyoid muscle, from the level C5 to T1 vertebrae
or anterior to the 2nd and 3rd tracheal rings. It
consists of two lobes, connected in the middle by a narrow isthmus, which is
conical or pyramidal shape. In 50% of population, thyroid gland may stay as
high as the level of the hyoid bone. Each lateral lobe is attached to the
trachea by a consolidated connective tissue called the lateral
The thyroid gland was supplied by four main arteries:
(1) The superior thyroid arteries (paired) originate from the external carotid artery (the first or second branch) or the common carotid artery. When it approaches the thyroid gland, the superior thyroid artery divides into anterior and posterior branches, which will then distribute numerous small branches to the gland and join with their counterparts from the opposite side.
(2) The inferior thyroid arteries (paired) arise from the thyrocervical trunk and ascend into the neck on the medial aspect of the anterior scalene muscle, deep to the prevertebral fascia and cross vertically to the ascending recurrent laryngeal nerve. The inferior thyroid artery divides further into two branches: the upper branch supplies to the posterior aspect of the gland and the lower branch supplies to the lower pole of the gland.
In 1.5% to 12% of the cases, the thyroid ima artery, a variation of the inferior thyroid artery, may present usually in right side and ascend in front of the trachea. The superior and middle thyroid veins drain to the anterior facial vein and internal jugular vein. The inferior thyroid vein and thyroid ima vein form the innominate vein and drain into the branchiocephalic vein. The recurrent laryngeal nerves are close to the thyroid globes and the inferior thyroid arteries.
The lymphatic vessels of the thyroid gland drain into the internal jugular chain, the pericapsular region, the prelaryngeal, pretracheal and paratracheal lymph nodes. The lateral lymphatic vessels located along the superior thyroid vein pass to the inferior deep cervical lymph nodes such as retropharyngeal and retroesophageal areas. Nerve innervation of the thyroid gland is from the superior, middle, and inferior cervical sympathetic ganglia, which form the cardiac, and superior and inferior thyroid periarterial plexuses.
Three components participate in the euthyroidism control:
(1) Thyroid gland responsible for the synthesis, storage, and secretion of thyroxine (T4) and 3,5,3’-triodothyronine (T3: the most potent biologic agent).
(2) The peripheral control of the T3, T4 metabolism, after their release into the circulation.
(3) Thyroid stimulating hormone (TSH) and thyroid hormone-releasing hormone (TRH) mediate the thyroid hormone output in a classic negative feedback mechanism. TSH regulates (1) the synthesis of thyroglobulin (Tg), (2) the uptake and organization of iodine, (3) the iodication of Tg to form T4 and T3, (4) the storage of T3 & T4 in the gland as colloid, and (5) the hydrolysis of the stored Tg to release T4 and T3 into the circulation.
Follicle, the functional unit of thyroid gland, is separated from the interstitium by a complete basement membrane. Lobule is a group of 20-30 follicles, separated to each other by a thin fibrous connective tissue layer. Follicular cells contain T4, T3, and other low molecular weight such as cytokeratins, vimentin, and epithelial membrane antigen. Follicular cells with rich esinophilic cytoplasm are referred to as oncocytes, oxyphil cell, Askanazy cells or Hurthle cells. C cells or parafollicular cells are most abundant in a zone at the junction of the upper and middle thirds of the lateral lobes. They secrete calcitonin and other peptides (e.g. somatostatin, gastrin-releasing peptide, and thyrotropin-releasing hormone.)
biosynthesis requires 0.100 mg to 0.150 mg of inorganic iodide per day. The
source of iodine is diet. Average, daily intake is from 0.3 to 0.7 mg per day
The goal of peripheral thyroid hormone metabolism is to maintain the circulating and tissue T3 level, which appropriates for the thyroid hormone requirements. The unbound or free T3 crosses the cell membrane, by passive diffusion, through T3 receptors, which mediates the physiologic actions of thyroid hormone including growth, differentiation, calorigenesis, and TSH suppression.
About 4% to 7% of the population has nodular thyroid disease. Approximately, 4% of these nodules are malignant and account for about 1% of all cancers. The incidence of thyroid nodules in female to male is 6.5% to 1.5%. However, the risk of being malignant thyroid nodules is twice as high in males as compare to females. Thyroid cancer develops most commonly between the ages 40 through 60.
Thyroid cancers are classified by their predominant histologic cell types, as follow: (1) well-differentiated malignant neoplasm (WDTC) accounts for 85% of thyroid cancers, including papillary, follicular, and Hurthle cell carcinomas, and (2) more aggressive variants include medullary carcinoma and anaplastic carcinoma (3) other tumors including lymphomas and metastatic tumors.
(1) Papillary Thyroid Carcinoma (PTC): is the most common, accounting for 75% to
80% of thyroid cancer and 80% to 90% of radiation induced thyroid carcinomas.
Female to male ratio is 3 to 1. Peak incidence is in the 30s to 40s year of
age, with prolonged course and rarely caused death (1% - 10%). The 10-year
survival rate is from 84% to 90%. Tumors are usually composed of mixed
papillary fronds or follicular component. According to the size and location of
the tumors, there are three subclasses of papillary carcinomas (1) occult or
less than 1.5 cm, (2) intrathyroidal, (3) extrathyroidal. The majority of
papillary tumors are nonencapsulated, usually invade lymphatics and replace
normal thyroid tissue. Grossly, these tumors often show central necrosis with
fibrosis or hemorrhage; large tumors may have cystic degeneration and may
resemble a benign thyroid cyst. Multicentricity develops in 75% of tumors,
especially in patients with prior exposure to ionizing radiation. Papillary
carcinomas have increased incidence in familial adenomatous polyposis syndromes
such as Gardber’s and Cowden’s. Histologic findings of papillary tumors consist
of columnar thyroidal epithelium set in papillary projection with well-formed
fibrovascular cores or “psammoma bodies”. Nuclei are vesicular and
house-glass or “Orphan Annie” appearance. Factors affect surgical treatment
including extrathyroidal extension, vascular and adjacent structural invasion
or lymph node metastasis. There is a high rate of local regional lymph nodes
(50%) but low risk of hematogenous dissemination. Spires et al. at MD Anderson
Cancer Center determined that the most important prognostic factors for
papillary carcinoma of thyroid are (1) age, (2) sex, (3) histology
of the cancer, and (4) presence of distant metastatic diseases.
(2) Follicular Thyroid Carcinoma (FTC) accounts for 5% of all
thyroid cancers and 15% of primary epithelial malignant tumors of the thyroid,
(3) Hurthle (oxyphilic) cell Carcinoma is the most aggressive
well-differentiated neoplasm and accounts for about 5% of WDTC or 2% to 3% of
all thyroid cancers. There is high incidence of bilateral thyroid lobe
involvement and long-term lethal potential for local recurrence and mortality
if the tumors were treated less aggressively. Female to male ratio is 2 to 1.
Hurthle cell carcinomas have poor prognosis with five-year survival rate in
about 50% to 60%.
(4) Medullary Carcinoma (MTC) accounts for 5% to 10% of thyroid cancer. The tumor originates from calcitonin-producing parafollicular C-cell. Grossly, medullary tumors are gray to yellow, firm, well-circumscribed or invasive with bilateral multicentric involvement. Medullary carcinomas are classified as two groups:
(1) Sporadic (80%): have a poorer prognosis, usually unifocal, not associated with other endocrine tumors, occur in middle age to elderly patients, equal in both sexes; single nodule is common in sporadic form with clusters of cells and stromal amyloid in 85% to 90% cases,
(2) Family trait (20%): autosomal dominant inheritance, tumors associated with C-cell hyperplasia or the calcitonin-producing lesions; these tumors usually have early high calcitonin screening and better prognosis. The familial form of medullary cancers usually develop in the third decade of life with the female to male rate is 1.5 to 1. The familial medullary carcinomas are associated with other endocrine tumors such as:
· (1) Sipple’s syndrome or multiple endocrine neoplasm type II (MEN IIa), including (a) medullary thyroid carcinoma or C-cell hyperplasia, (b) adrenal medullary carcinoma and (c) hyperparathyroidism.
· (2) Wermer’s syndrome (MEN IIb), including (a) medullary thyroid carcinoma, (b) pheochromocytoma, (c) mucosal neuromas (of the tongue, lips, conjuctivae), ganglioneuromas of the intestines, characterized by special facial appearance, and marfanoid habitus.
Overall prognosis of MTC is poor due to early metastases to lymph nodes and distant metastases. The five-year survival rate is in the range of 60% to 70% and 10 year-survival rate is 40% to 50%. About 50% of medullary cancers have regional metastases to local lymph nodes at the time of diagnosis. Distant metastases include lung, liver, adrenal glands, and bones (osteoblastic, opposed to other cancers, e.g. prostate cancer, osteolysis).
(5) Anaplastic Thyroid Carcinoma (ATC) or undifferentiated carcinoma accounts for 3% of all thyroid cancers, more common in elderly patients usually in their seventh decade. Females are more affected than males. Tumors have higher incidence in patients with pre-existing multinodular goiter (30%). The anaplastic thyroid cancer is the most aggressive thyroid cancer, is unencapsulated, and is associated with extended invasion outside the gland. Grossly, the neoplasm has fleshy, tan-white appearance, with hemorrhagic and necrotic areas. Histological cells with spindle or giant-cell variants. Patients with the anaplastic thyroid carcinomas have poor prognosis. Patients usually die within several months, dues to airway obstruction, vascular invasion, distant metastases to lung and bone and resistant to the therapy.
(6) Malignant Lymphoma accounts for 1% to 2% of thyroid cancers, increasing incidence in endemic goiter areas, most common in patients over 50 years of age. The female to male ratio is 3 to 1. It may develop from the pre-existing Hashimoto’s thyroiditis and present as a rapidly growing mass in history of multinodular goiter. Rapid enlarging tumors can result in tracheal or esophageal compression. Grossly, tumors are large, yellow-tan, and scaly with hemorrhagic and necrosis areas. The most common variant of thyroid lymphomas are small-cell noncleaved type (or poorly differentiated malignant lymphoma) and the large-cell noncleaved folicular cell-type. The cell types and stages are the critical factors in prognosis, e.g. small cell, Hogkin’s, and immunoblastic lymphomas have a favorable prognosis in early stage (stage I: 86% 5-year survival rate with lymphoma limited in the gland, 38% with lymph node involvement or invaded capsule, and rare with disseminated thyroid lymphoma).
(7) Metastatic Carcinoma found in 2% to 4% of patients who die of cancers. Metastatic thyroid carcinomas are most common from malignant melanoma, lung, kidney, breast, and colon cancer. Malignant cells metastasize by lymphatic or vascular deposits of tumor emboli. To identify the metastatic lesions is important because when they exist surgical excision is not beneficial.
*Histology: the cell type is one of the most predominant prognostic factor and influences other risk factors.
*Age: at the time of diagnosis is a significant effected risk factor, e.g. well-differentiated thyroid carcinoma has a greater tendency to invade the surrounding structures in patients older than 40. Mortality rate increases significantly in patients older than 60.
*Sex: females are at a higher risk of developing thyroid nodules, however, males have a higher risk of thyroid cancer. Tumors are more aggressive and the prognoses are poorer in males than those in females.
*Size of primary lesions: the larger the size of the tumor the greater the risk of vascular invasion or metastatic spread. Tumors greater than 1.5 cm carry a higher risk of recurrence and mortality.
* Extracapsular or vascular invasion and metastatic disease are poor prognosis factors. Regional metastasis in papillary carcinoma correlates positively with the incidence of local recurrence. Well-differentiated thyroid cancer, which invades and paralyzes the recurrent laryngeal nerve requires a wider resection. Distant metastases are rare in papillary cancers, but more often seen in follicular tumors, and are associated with poorer prognosis.
*History of radiation is associated with higher risk of papillary carcinomas requiring more extensive resection to eradicate disease.
The Mayo clinic
uses the “AGES” system incorporating age, grade, extracapsular
tumor, and size. The Lahey clinic uses the “
The most common diagnostic measures include needle biopsy or aspiration, thyroid blood study, radiology imaging. Needle biopsy, a superior diagnostic technique, which provides accurate cytologic finding with no morbidity, has become the first step in thyroid nodule workup.
(1) Core needle biopsy provides adequate tissue for diagnosis in 90% of cases. Biopsy is guided by palpation. It is significantly more difficult, more traumatic and has more complication than fine needle biopsy
(2) Fine needle aspiration (FNA) is
more prefer because of less morbidity. Technique is performed on a palpable
nodule or under ultrasonography guidance. Fine needle biopsy is an accurate
diagnostic procedure in papillary, medullary, metastatic, anaplastic cancers,
and malignant lymphomas. Differentiation between follicular and Hurthle cell
neoplasms is based on capsular or vascular invasion. Ashcraft and Van Herle, in
a comprehensive review compared the accuracy of fine needle aspiration and core
biopsy, concluded that neither biopsy technique is superior, but fine needle
aspiration has a lower yield of tissue and almost free of complication. In a
recent report, fine needle aspiration has false negative rate of 0.3 to 10%,
and a false positive rate of 0 to 2.5%. Therefore, a malignant specimen on fine
needle aspiration is a strong indication for surgery; however, a negative
result cannot rule out cancer. There are some limitations of fine needle
aspiration to differentiate (1) adenomatoid nodule vs. follicular neoplasm,
(2) papillary carcinoma with cystic change and benign cystic nodules, (3) large
multinodular goiters and present malignancy, (4) Hashimoto’s thyroiditis vs.
oxyphilic cell (Hurthle) neoplasm, (5) multinodular goiter vs. Hurthle cell neoplasm,
(6) Hashimoto’s vs. malignant lymphoma, (7) malignant melanoma.
Staging of thyroid cancer
Staging is determined by physical exam, thyroid imaging, and endoscopic examination:
N1a: ipsilateral lymph node metastasis
N1b: bilateral, midline, or contralateral cervical or mediastinal lymph node metastasis
Note: undifferentiated (anaplastic carcinoma) is considered by definition as stage IV tumors.
Clinical staging of papillary or follicular carcinoma:
. Stage I: any T, any N, M0
. Stage II: any T, any N, M1
. Stage I: T1, N0, M0
. Stage II: T2 or T3, N0, M0
. Stage III: T4, N0, M0, or any T, N1, M0
. Stage IV: any T, any N, M1
Clinical staging of medullary carcinoma:
A. Well-differentiated Thyroid Carcinoma: (Papillary, Follicular, and Hurthle cell)
analysis should be done before the surgery regarding to the factors such as
age, gender, extranodular invasion, distant metastasis, nodule size and
involvement. A study at
All thyroid nodules should be approached as potential malignancies. Typically, total thyroidectomy is indicated for malignant lesions within one or the other lobe of the gland. Lobectomy is an option if frozen section (and subsequent permanent) histology returns a benign diagnosis.
According to Cannon, recurrent laryngeal nerve (RLN) is the key to thyroid operations. When the nerve cannot be found in the usual location, surgeons should dissect very carefully to identify the nerve near the superior pole of the thyroid gland. In the lateral aspect of the gland, the branches of the inferior thyroid artery and the parathyroid glands are dissected free of the thyroid globe, without interrupting their blood supply. Parathyroid autotransplantation is recommended when the glands or their blood supply are injured.
B. Undifferentiated Carcinoma:
These tumors are usually unresectable. Tracheotomy is considered when airway is compressed. Diagnosis is made by FNA and usually by open biopsy for completed cell study. A combination treatment of surgery, radiation or chemotherapy may help to control the tumors.
C. Medullary Thyroid Cancer:
Cervical metastasis at the time of diagnosis is observed in 50% of cases. Surgical resection includes the anterior compartment node dissection, which removes the lymphatics and adipose tissue from the hyoid bone to the sternal notch and laterally to the internal jugular vein. The lymph node groups removed are pre-tracheal, paratracheal, pre-cricoid, Delphian and perithyroidal nodes. With N(+) cervical lymph nodes, a selective lateral neck dissection of zones II, III, IV can be included.
Recurrent MTC is resistant to chemotherapy and radiation. Moley reported that chemotherapy cured 28% and controlled 69% of patients. At the MD Anderson hospital, radiation is used as an adjuvant therapy in patients with soft tissue invasion, multiple positive nodes and metastatic MTC. When diagnose early and treat appropriately, the expected 10-year survival rate of MTC is about 90%. The most effective treatment is primary total thyroidectomy. Indications include the following reasons: (1) the C-cells have diffuse and bilateral anatomic distribution resulting in multifocal and bilobular tumors, (2) in the sporadic form, 30% of patients have bilateral involvement, (3) in the family cases, bilateral involvement is 100%.
D. Hurthle (oxyphilic) Cell Carcinoma:
The treatment of choice is total thyroidectomy because the tumor is aggressive and relatively unresponsive to radiation therapy. Another option is partial thyroidectomy. If the frozen section is negative for malignancy, the procedure is adequate. If it comes back positive, complete thyroidectomy should be done within 2 weeks. Patients have N(+) cervical lymph nodes need a routine modified neck dissection. Post-op thyroid suppression is helpful because Hurthle cell tumors have TSH receptors. Postoperative radioactive iodine is not indicated because these tumors take up 131-I poorly.
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