TITLE: Thyroid Cancer
SOURCE: Grand Rounds Presentation, UTMB, Galveston, TX
DATE: October 6, 1998
PRESENTATION BY: Christopher Muller (MS 4)
Byron J. Bailey, M.D. and Anna M. Pou, M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.
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Thyroid disease has been recognized since earliest recorded history, but consistent techniques of thyroid surgery date back only100 years ago. At the turn of the century, Theodor Kocher, of Bern Switzerland, made major contributions to the understanding of thyroid disease and techniques of thyroid surgery. In 1872, he performed his first thyroidectomy and by 1901 he had performed 2,000 thyroid operations. The overall, mortality for thyroid surgery by this time had decreased from 50% to 4.5%. In 1909 Kocher won the Nobel Prize for his work (4).
Thyroid cancer is a relatively uncommon malignancy accounting for 1.0%-1.5% of all new cancer cases in the United States - ten fold less than that of lung, breast, or colorectal cancer (56,58). Approximately 8,000-14,000 new cases of thyroid cancer are diagnosed each year (56,19). These numbers probably underestimate the true prevalence of thyroid cancer. Occult thyroid cancers are found in 3% and microscopic cancers are found in at least 10% of patients who die from other causes (50). In other studies up to 35 percent of thyroid glands removed at autopsy (40) or surgically (46) contained clinically undetectable (<1.0cm) papillary carcinomas.
More than 90% of thyroid carcinomas, including papillary, follicular, and medullary carcinomas are well differentiated (19). Thyroid cancer is a slowly progressing disease and has an overall favorable outcome, with only 9% of patients dying from it (50). The relatively indolent nature of thyroid malignancy is generally ascribed to the inherent, innocuous biologic behavior that is characteristic of these neoplasms. Despite its overall good prognosis, approximately 1,000-1,200 patients in the United States die each year of thyroid cancer, and despite recent advances in diagnosis and treatment little decrease in mortality has been seen over the past several decades (19,21,47).
It is estimated that 4%-7% of adults in North America have palpable thyroid nodules with the frequency increasing throughout life (39,61). Single nodules are approximately four times more common in women than in men (39). The presence of a thyroid nodule raises the question of malignancy, although fewer than 5% of nodules are actually malignant (40). The key role of the physician evaluating thyroid nodularity is to determine which patients are at risk for malignancy.
A careful history should be the first step in the evaluation of a thyroid nodule to determine specific risk factors a patient has and the characteristics and progression of their symptoms. The most common presentation of a thyroid nodule, benign or malignant, is a painless mass in the area of the thyroid gland (21). Symptoms of pain, dysphagia, stridor, hemoptysis, and rapid enlargement of the mass are more consistent, but not pathognomonic for malignancy. These symptoms are rarely reported with well-differentiated thyroid carcinomas (20). A particularly disturbing symptom is hoarseness which is almost invariably associated with cancer. In rare cases, however, it may be due to a large benign thyroid adenoma (6).
Previous exposure to external irradiation, whether in low doses or high doses (40 to 50 Gy [4000 to 5000 rad]), especially in childhood, is extremely important. If there is a history of radiation exposure, the chance of malignancy increases in a solitary nodule up to 30%-50% (21). Thyroid exposure to radiation is the only factor that has been definitively shown to increase the incidence of thyroid cancer (57). This includes patients treated with low dose external beam radiation for conditions such as a large thymus, acne, enlarged tonsils, cervical adenitis, sinusitis, and malignancies. Schneider and co-workers (54) at the University of Chicago have extensively studied, with long-term follow-up, a population of over 3000 patients who underwent childhood irradiation at their institution. In this population 1145 of 3042 patients developed thyroid nodules; 318 have proved to be thyroid cancer, for an overall incidence of 10.5%. Any environmental radiation exposure such as atomic bombs, radioactive sands/soils, or nuclear plant accidents is also important and has been shown to increase the incidence of thyroid cancer. The lag time between exposure and occurrence of thyroid cancer ranges from 5-25 years with a peak incidence at 15-25 years (13,63). Fortunately, use of low dose external beam radiation has been recognized as carcinogenic and its use has been significantly decreased over the past three decades. This should lead to decreased numbers of radiation-induced thyroid cancers in the future.
Age and sex are extremely important aspects of the history when evaluating a patient with a potential thyroid malignancy. Benign nodules occur most frequently in women in the 20 to 40 year age bracket. In this group of patients the risk of cancer is 5%-10% (6). Nodules occurring in the extremes of age, particularly in men, are more likely to be cancerous. Belfiore et. al. found that the odds of cancer in men quadrupled by the age of 64 years, reaching a frequency of more than 50 percent by 70 years. In general a high index of suspicion for malignancy should be maintained for women greater than 50 years, men greater than 40 years, and both men and women younger than 20 years with a thyroid nodule regardless of signs or symptoms.
Family history is also important. If a family member has a history of medullary or papillary thyroid cancer or of familial polyposis (Gardner’s syndrome), this increases the likelihood that a thyroid nodule is cancerous.
A full head and neck exam is imperative in any patient with a new or changing thyroid nodule. Certain aspects of the physical exam may indicate whether or not a thyroid nodule may be malignant. A benign nodule is characteristically soft, well circumscribed, nontender and moves with swallowing. Cancer is more suggestive with masses greater than 4 cm in diameter and those with a hard consistency that are fixed to the underlying tissue. Although the physical characteristics of a nodule may increase the likelihood that it is cancerous, a hard nodule may be caused by certain benign conditions such as chronic thyroiditis or a calcified adenoma, whereas a soft nodule may be a cystic papillary cancer (26). Solitary nodules have a higher risk of being malignant. A single nodule has a 5%-12% malignancy rate whereas multiple nodules have a 3% malignancy rate (21). Examination of the tongue is important to rule out any ectopic thyroid tissue (20). Indirect or fiberoptic laryngoscopy should always be done to rule out involvement of the airway or recurrent laryngeal nerve by tumor. The preoperative appearance and function of the larynx should be documented. Systematic palpation of the neck should be done to detect any adenopathy. Palpable metastatic adenopathy is most commonly found along the middle and lower portions of the jugular vein and the anterior compartment (region III, IV, and VI), but it is also not unusual to find nodal disease lateral to the sternocleidomastoid muscle in the lower portion of the posterior triangle overlying the scalene muscles (region V) (20). It is important to attempt to elicit Chvostek’s sign in every patient prior to surgery. It is estimated that 10% of the normal population have a positive sign, and therefore, preoperative assessment is imperative (20)
Laboratory evaluation should include thyroid function tests [thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH)] to help rule out other disorders such as unsuspected thyrotoxicosis (39). Elevated thyroxine (T4) or triiodothyronine (T3) levels in the patient with a solitary thyroid nodule may indicate the presence of a hyperfunctioning adenoma that has a very low incidence of malignancy. Serum calcium levels should also be measured to evaluate parathyroid function (56). This is important because the incidence of parathyroid adenoma and other hyperfunctioning anomalies of the parathyroid gland are more frequent in the presence of a thyroid nodule or carcinoma (20). If well-differentiated cancer is suspected, some authors suggest that serum thyroglobulin (TG) levels be obtained (18). Others disagree, however (20). TG has been shown to correlate well with histologic tumor type (2). For example, papillary tumors have lower serum TG levels than mixed papillary-follicular tumors, which have lower levels than pure follicular tumors. Although TG does not fluctuate in adults, it may increase after an FNA, and therefore, should be obtained prior to needle aspiration (35). It is also important to note that TG levels may also be elevated with subacute thyroiditis but usually return to normal after treatment with corticosteroids. Serum TG is most useful in following patients postoperatively for tumor recurrence (see postoperative management). Measurement of serum calcitonin is a very useful test in diagnosis and screening of patients who have medullary thyroid carcinoma (MTC) and members of their family. It is not measured routinely, however, in patients who present with thyroid nodules who have no family history of MTC or inheritable conditions associated with MTC.
Radiographs provide limited information in the evaluation of thyroid masses and are not routinely used. A chest radiograph may show tracheal deviation or incidental calcifications in the thyroid which may occur in the presence of MTC. Calcifications, however, are not uncommon in other carcinomas and even benign lesions of the thyroid. Metastatic disease to the lung may also be picked up by a chest radiograph. Computed tomography or magnetic resonance imaging is not necessary in the initial work-up of a thyroid nodule. If a patient is found to have cancer or a recurrence, either of these studies should be obtained before surgery to evaluate for nodal involvement or extension of the lesion to other structures such as the trachea, larynx, and mediastinum or to evaluate for metastatic disease.
Ultrasound is the most sensitive procedure for identifying lesions in the thyroid. It is capable of finding masses as small as 2-3mm. It is also able to categorized nodules as solid, cystic, or mixed with more than 90% accuracy and is the best method of determining the volume of a nodule (51). In addition it can detect the presence of lymph node enlargement and calcifications. Unfortunately it is unable to reliably diagnose true cystic lesions and therefore, cannot accurately distinguish benign from malignant nodules. Ultrasound is very useful in certain situations, however. For example, with its ability to measure nodule dimensions, it can provide longitudinal follow-up after needle aspiration of cystic lesion, evaluate the involution of a multinodular gland under medical treatment, and follow thyroid nodules during pregnancy. It is also used to help localize a lesion and direct a needle biopsy when a nodule is difficult to palpate or is in a deep-seated location (20).
Up until the widespread use of fine-needle aspiration (FNA), isotope scintigraphy had been the mainstay diagnostic procedure in the evaluation of thyroid nodules. Thyroid scanning is performed with technetium 99m pertechnetate or radioactive iodine (I-131, I-125, or I-123). Technetium 99m is popular because of its low cost, readily availability, and short half-life, but it is only trapped by the thyroid and not organified. This means that it cannot be used to determine whether or not a nodule is functional (18). Radioactive iodine is the only agent that is trapped and organified and therefore is able to determine function. The major value in scanning is in differentiating cold (nonfunctional) nodules from hot (functional) nodules, diffusely enlarged glands from a nodular enlargement, and a true single nodule from a multinodular goiter.
There are limitations to the thyroid scan. It is estimated that approximately 90 to 95 percent of thyroid nodules are hypofunctioning, with only 10 to 20 percent being malignant (20,56). Campbell and Pillsbury (6) performed a meta-analysis of 10 studies correlating the results of radionuclide scans in patients with solitary thyroid nodules with the pathology reports following surgery. They found that 17% of cold nodules, 13% of warm or cool nodules, and 4% of hot nodules are malignant. These results bring into question the ability of thyroid isotope scanning to accurately distinguish benign from malignant thyroid nodules. To operate on a nodule simply because it is cold would be to subject many patients to surgery unnecessarily. In addition, a small but significant number of patients with hot nodules would actually have cancer but would not be operated on.
Thyroid scanning is necessary to detect residual thyroid tissue after a patient has undergone thyroid surgery. It will also pick up small foci of disease or occult distant metastasis that can then be adequately treated with therapeutic doses of radioactive iodine. Others have suggested the use of thyroid scanning for specific situations such as patients with benign nodules (by FNA) that are solid (by U/S) or in a patients with nonoxyphilic follicular neoplasm (19).
Currently, fine-needle aspiration is considered to be the best first-line diagnostic procedure in evaluation of the thyroid nodule because it is safe, cost-effective, minimally invasive and leads to a better selection of patients for surgery than any other test (51). The accuracy of FNA biopsy in making a diagnosis of thyroid cancer is greater than 90% (19). Studies (25,29,51,40) have shown that the percentage of patients undergoing thyroidectomy has decreased by 25%-50%, and the yield of carcinoma in patients who undergo surgery has increased from 15% to up to 50%.
The pathologic result of an aspirate is usually categorized into three groups: positive, negative, or indeterminate cytologic results (39). Others (29) use four cytologic diagnostic categories. Hossein and Goellner (29) pooled data from seven series and came up with the following rates for these categories: Benign, 69%; suspicious, 10%; malignant, 4%; and nondiagnostic, 17%. Limitations of FNA are related to the skill of the aspirator, the expertise of the cytologist, and the difficulty in distinguishing some benign cellular adenomas from their malignant counterparts. The false negative rate of results from FNA ranges from 1 to 6 percent (39). Sampling error usually occurs when one is aspirating very small (<1 cm) or very large (>4 cm) nodules, hemorrhagic nodules, or multinodular glands (39). In these instances, an inadequate number of cells is obtained for diagnosis. These problems can be minimized by taking multiple specimens and by using ultrasound to guide the needle biopsy. The false positive rate of FNA results ranges from 3 to 6 percent (51,39,24) and is often a result of Hashimoto’s thyroiditis (39).
Thyroid-stimulating hormone (TSH) suppression has been used as a diagnostic measure to differentiate benign from malignant nodules but is rarely used for this purpose today. Exogenous thyroid hormone causes a negative feedback to the pituitary which decreases its production of TSH and thereby, reduces the stimulus for thyroid growth. The usefulness of this test lies in the thought that thyroid cancer is autonomous and does not require TSH for growth whereas benign processes do. Therefore, administration of exogenous thyroid hormone will cause benign disease to shrink, but malignancies will continue to grow. Unfortunately up to 16% of malignant nodules and only 21% of benign nodules are suppressible. Most authorities agree today that thyroid suppression for nodules has little or no use as a first line diagnostic procedure. Geopfert (19) recommends using thyroid suppression in the following situations:
Treatment involves administering Levothyroxine (synthetic T4) with maintenance of TSH levels at less than 0.1 mIU/L. A patient with a benign nodule that decreases in size during suppression may be followed up without therapy, with adjustment of hormone dose to keep the TSH concentration near the lower limit of normal. Any lesions that continue to grow should be excised.
Well-differentiated thyroid carcinomas (WDTC) - Papillary, Follicular, and Hurthle cell
Papillary, follicular, and Hurthle carcinomas are classified as well-differentiated
malignancies. Papillary and follicular carcinomas are the two most common malignancies
found in the thyroid gland. All three of these cancers arise from the thyroid
hormone producing follicular cells, however, their pathogenesis is largely unknown
(20). Unlike medullary carcinoma, they do not have a definite genetic inheritance
pattern. Only a small number are thought to occur in rare familial syndromes
(20). Recent research has lead to the identification of a few cancer-causing
genes that may be responsible for the benign or malignant transformation of
follicular cells. Specifically, RET proto-oncogene mutations have been implicated
in papillary and medullary carcinoma but a definitive link has yet to be proven
(19). Despite the uncertainty of these molecular events, certain clinical factors,
such as exposure to radiation, increases the likelihood for developing thyroid
cancer, especially papillary carcinoma. In areas with endemic goiter, in populations
that are iodine deficient and therefore have high level of TSH stimulation,
the incidence of follicular carcinoma is high. Although this relationship has
been confirmed in the laboratory where follicular carcinoma can be induced by
exposure to TSH after exposure to a mutagen, the exact mechanism for this is
not known (21). This relationship has not been consistent with papillary or
Hurthle cell carcinoma (21).
Papillary carcinoma is the most common cancer of the thyroid gland accounting for 60%-80% of all thyroid malignancies (19,43). These tumors can be divided histologically into various subgroups, however, no studies have been done to show any differences in tumor behavior among these subgroups (36). They will therefore, be discussed as one entity. Of all the thyroid malignancies, papillary carcinoma has the best prognosis (21) with 80% of patients surviving after 10 years (19). It occurs more often in young females with a mean age of presentation at 35 years (41).
Lymph node involvement is relatively common in papillary carcinoma, with lymphatic spread being the major route of metastasis. At the time of diagnosis, it is estimated that 46%-50% have metastases to the regional lymph nodes (53,19). Other investigators (16,19) report lymph node metastatses as high as 75%-90%, occurring most commonly in the central compartment. Clinically evident lymphatic involvement worsens the prognosis in patients with papillary carcinoma. When lymph node involvement is microscopic, however, the long-term survival is no different than if there is no involvement.
Papillary thyroid microcarcinomas, another manifestation of papillary thyroid carcinoma, are defined as carcinomas smaller than 1.0 cm (36). It is believed, based on autopsy report and at resection for other disease processes, that papillary thyroid microcarcinomas are much more prevalent than we imagine. Because they are usually clinically silent, however, they are rarely diagnosed based on any symptomatology. Most authors agree that the morbidity and mortality from microcarcinoma is minimal, with tumor behavior being quiet benign. Some studies have found the mortality rate from these tumors to be 1% and there have been reports of distant metastases and lymph node involvement, but the overall consensus is that they have little effect on mortality or quality of life.
On gross examination, papillary carcinomas vary considerably in size, are often
multi-focal, and are unencapsulated but may have a pseudocapsule. Histologically,
it consists of closely packed papillae with little colloid within follicles.
The stromal cores sometimes contain small calcified laminated bodies known as
psammoma bodies. The nuclei are characteristically pale staining and
empty looking with a ground glass appearance. They are also elongated or oval
and enlarged as compared to the normal round shape. Nucleoli are usually prominent
and pushed to the edge of the nucleus. Occasional mitotic figures are also not
Follicular carcinoma occurs in approximately 20% of patients with thyroid cancer. Like papillary carcinoma, it is more frequently found in women with reported ratios ranging from 2:1 to 4:1.2 (12,15). It tends to occurs at an older age than papillary, however, with a mean age of 39 years (41). Overall approximately 60% will survive to 10 years but this varies for particular subgroups (20).
In contrast to papillary carcinoma, follicular carcinoma tends to metastasize via angioinvasion and hematogenous spread and has a higher frequency of distant metastasis. Frequency of regional lymph node involvement has been reported to be less than 13% (21). When nodes are involved, however, outcome is usually poor. This probably relates to the fact that patients with lymph node involvement at the time of diagnosis are also likely to have significant local disease and visceral invasion (56). Bone is the most common site of distant metastasis with lung coming in second.
Follicular carcinoma is an encapsulated lesion and is not multi-focal, but
solitary (21). Histologically these lesions are usually very well-differentiated
making distinction between follicular adenoma and follicular carcinoma difficult.
The definitive diagnosis is made by the demonstration of capsular invasion at
the interface of the tumor and the thyroid gland (56). Fine needle aspiration
as well as frozen section are usually unable to demonstrate this finding and
are therefore, not the method of choice for making an accurate diagnosis. These
cancers are characterized as having a well-structured follicular pattern. Epithelial
cells are cuboidal with relatively large nuclei. Although the nuclei of the
epithelial cells show no pleomorphism, scattered mitoses and pyknotic nuclei
are usually present throughout the tumor (11).
One of the most controversial and confusing neoplasms of the thyroid gland is the Hurthle cell carcinoma (HCC). This WDTC comprises approximately 4%-10% of thyroid malignancies (56). It was first discovered in 1907 by Askanazy who described large polygonal thyroid follicular cells with abundant granular cytoplasm and numerous mitochondria (21). These cells are believed to be a derived from follicular cells and together form a variant of a follicular neoplasm(56). A Hurthle cell neoplasm is defined as an encapsulated group of follicular cells with at least a 75% Hurthle cell component. Like follicular carcinoma, HCC requires histologic proof of vascular and capsular invasion to distinguish it from an adenoma. This makes diagnosis with either FNA or frozen section almost impossible, requiring permanent sections. Although classified as a WDTC carcinoma, HCC is more aggressive than follicular carcinoma. It also has a greater propensity for malignant transformation to anaplastic carcinoma than any other WDTC.
Hurthle cell neoplasms are more common in women and tend to occur in the elderly. Patients usually present with a painless nodule, just like other WDTCs. Lymphatic spread is seen in approximately 30% of patients and 15% present with distant metastasis to bone and lung (21).
The factors that determine prognosis in patients with well-differentiated carcinomas of the thyroid have been well delineated and are based on age, sex, and findings at the time of surgery (19). Several prognostic schemes, represented by acronyms, have been established by different groups and are as follows: AMES (Lahey Clinic, Burlington, MA), GAMES (Memorial Sloan-Kettering Cancer Center, New York, NY), and AGES (Mayo Clinic, Rochester, MN). The letters stand for A - age, S - sex, E - extent of primary tumor, M - metastasis to distant sites, and G - histologic grade of the tumor. Depending on variables present, patients can be categorized into one of three groups: high, intermediate, or low risk which are defined as follows (5):
Low risk group
Intermediate risk group
High risk group
Medullary thyroid carcinoma accounts for approximately 10% of all thyroid cancers and has an incidence of approximately 1000 new cases, in the United States, each year (1). It arises from the parafollicular cells or C-cells of the thyroid gland that differentiate from neural crest cells during embryologic development. These cells migrate from the pharyngeal arches into the fourth pair of pharyngeal pouches. The ventral portion of these pouches develop into the ultimobranchial body which eventually fuses with the superior poles of the thyroid gland (45). The parafollicular cells disseminate within the thyroid parenchyma with the majority (two thirds) concentrating in the superior poles (10). They function by secreting calcitonin which plays a role in calcium metabolism.
Medullary thyroid cancer develops in four unique clinical settings: sporadic, familial MTC, and in association with multiple endocrine neoplasia IIa (MEN IIa) and multiple endocrine neoplasia IIb (MEN IIb). Overall, MTC tends to be a more aggressive cancer than the WDTCs. It usually spreads early by lymphatic dissemination to peritracheal and mediastinal lymph nodes has an over all incidence of lymph node metastases >50% (38).
Sporadic MTC accounts for approximately 70%-80% of all MTCs (10,38). The mean age at presentation is 50 years (48) and the 15 year survival is 75% (1). This form of MTC tends to occur unilaterally and unifocally and usually presents as an enlarging thyroid nodule. It is slightly more aggressive than MTC associated with MEN IIa and familial MTC, with 74% of patients having extrathyroid involvement at the time of presentation (48).
Familial MTC was first described by Farndon et. al. in 1986 (17). It is characterized by having an autosomal dominant inheritance pattern and is not associated with any endocrinopathies (10). Patients present with this malignancy at a mean age of 43 years (17). Like the other forms of inherited MTC, familial MTC often occurs bilaterally and multifocally. This form of MTC is the least aggressive and has the best prognosis with a 15 year survival of 100% (17).
Multiple endocrine neoplasia IIa, also known as Sipple syndrome, is characterized clinically by MTC, pheochromocytoma, and parathyroid hyperplasia (10). Like familial MTC it is also transmitted via autosomal dominant inheritance. One hundred percent of patients with MEN IIa develop MTC and present at a mean age of 27 (7).
MTC in patients with MEN IIa tends to behave less aggressively than in patients with MEN IIb or sporadic MTC, with a 15 year survival of 85%-90% (1,3)
Patients with multiple endocrine neoplasia IIb, also referred by some as MEN III, mucosal syndrome or Wermer’s syndrome, develop MTC, pheochromocytoma multiple mucosal neuromas, and have a marfanoid body habitus (10). By the second decade of life, approximately 90% of patients have developed MTC (8). This form of MTC presents at the youngest age [mean age of 19 (8)] and is the most aggressive of all types of MTC. Fifteen year survival is estimated to be <40%-50% (8). Fortunately, because of the characteristic phenotype of these patients, their disease can be diagnosed early and can be treated before they develop cancer.
The most common clinical presentation of sporadic and inherited MTC is a mass in the neck (44). MEN IIb can be diagnosed by physical exam alone but patients with MEN IIa and familial MTC have normal phenotypes. Occasionally, patients with MEN IIa or IIb will present with signs of other endocrine neoplasias such as hypertension, episodic sweating, and palpitations associated with pheochromocytoma, but this is rare. If MTC is suspected in a patient, family history of thyroid, adrenal, or parathyroid tumors should be elicited. Laboratory work-up of all patients suspected of having MTC involves measurement of basal and pentagastrin stimulated calcitonin levels (>300pg/ml is suggestive), serum calcium, and 24 hour urinary catecholamines, vanyllmandelic acid, and metanephrines in those with a family history of MEN to rule out pheochromocytoma (33). Some authors advocate measuring preoperative carcinoembryonic antigen (CEA) which can then be followed postoperatively for detecting tumor recurrence. It is estimated that 50% of MTCs secrete CEA (33).
In recent years it was discovered that defects in the RET proto-oncogene were responsible for the hereditary forms of MTC (22). Now, with the identification of these germline RET gene mutations in individuals affected by MEN IIa and familial MTC, it is possible to test persons at risk who are gene carriers before they develop overt neoplasms. Any first degree relative of a patient with MTC should be evaluated. The test involves only the drawing of blood for extraction of lymphocyte DNA. Polymerase chain reaction is done followed by direct sequencing of the gene. It only needs to be performed once in an at risk individual’s lifetime. If a family member is negative for the mutation they will not develop MTC and the need for repeated provocative testing for calcitonin is precluded. If the test is positive, they are candidates for thyroidectomy regardless of their stimulated calcitonin levels (44).
Anaplastic carcinoma of the thyroid is a rare but highly lethal form of cancer with a median survival in most series of less than 8 months (30,31,32,34). It comprises 1%-10% of all thyroid tumors and up to 30% of thyroid malignancies in patients older than 70 years (33,37,59). ATC usually occurs in the elderly with a mean age of presentation of 60 years and has a slight female predominance (31). The most common clinical symptom is a rapidly enlarging mass (60) and because of its aggressiveness, symptoms of invasion such as hoarseness, dysphagia, dyspnea, and superior vena cava syndrome are not uncommon.
Although the topic is controversial, many believe that anaplastic carcinoma of the thyroid may represent the dedifferentiation of WDTC. In one series (14), it was found that 47% of patients had a previous or recurrent WDTC before they developed anaplastic carcinoma. In addition, ATC has a predilection for occurring in patients with a history of benign thyroid disease: primarily goiter and occasionally hyperthyroidism (30). 53% of patients in Demeter’s (14) series had benign thyroid disease. Radiation exposure also has a well known association with anaplastic carcinoma (28).
Anaplastic carcinoma of the thyroid is classified as either larger or small cell types. Large cell ATC is by far the most common. They are characterized histologically by sheets of small, very poorly differentiated cells with little cytoplasm. Numerous mitoses are also seen along with necrosis and invasiveness in both the thyroid gland and the surrounding tissues (63).
Surgery is the definitive and accepted management for the majority of thyroid cancers with the exclusion of most cases of anaplastic carcinoma of the thyroid and lymphoma (21). The minimal operation necessary for a potentially malignant thyroid nodule is an ipsilateral thyroid lobectomy with isthmusectomy (59). Total thyroidectomy consists of removal of the entire thyroid gland with preservation of at least the parathyroid glands on the contralateral side and if possible, bilaterally (21). A subtotal thyroidectomy is anything less than a total thyroidectomy and may vary from a lobectomy to removal of most of the gland, leaving only a small rim of thyroid tissue around the parathyroid glands to decrease the risk of hypoparathyroidism and injury to the recurrent laryngeal nerve.
There is considerable debate as to whether patients with unilateral papillary or follicular carcinoma should undergo ipsilateral resection with isthmusectomy or total thyroidectomy. Proponents of total thyroidectomy cite the following reasons justifying this procedure:
Those who support less aggressive surgery (subtotal thyroidectomy) feel that the frequency of complications is significantly less than that associated with total thyroidectomy. Permanent hypoparathyoidism after total thyroidectomy is reported to range from 1% to 29% (55). Recurrent laryngeal nerve injury occurs in 1%-2% and damage to the superior laryngeal nerve occurs even less often (55). Probably the most compelling argument for less aggressive surgery is that, although local recurrence occurs more frequently after subtotal thyroidectomy compared to total thyroidectomy, the overall survival rate is the same for both (23)
Soh (59) suggests that patients with papillary or follicular carcinoma that are smaller than 1cm should undergo lobectomy as the initial operation if the frozen section is benign. If permanent section then shows malignancy, a completion thyroidectomy should be performed. Others stratify patients, recommending that a total thyroidectomy be performed in any patient with papillary or follicular carcinoma who is older than 40 years, patients at any age with invasive follicular carcinoma that demonstrates obvious angioinvasion, anyone with a thyroid nodule with a history of irradiation, or those with large or extrathyroidal infiltrating primary tumors.
In all patients undergoing thyroidectomy for malignancy, the pericapsular and tracheoesophageal nodes need to be carefully dissected out and routinely removed. If there is any overt nodal involvement, exploration of the mediastinal and lateral neck nodes should be done. If lymph node involvement is detected in these areas, nodal dissection should be performed (18). Goldman (21) recommends neck dissection for positive cervical lymph nodes, either clinically palpable or identified by CT or MR imaging. Prophylactic neck dissections are not done for papillary and follicular carcinoma without clinical or intraoperative evidence of nodal metastasis (18).
Four to six weeks after surgery, patients should have a diagnostic radioiodine scan to detect any residual thyroid tissue or any metastases. Leeper (33) recommends that the following subgroups receive radioiodine ablation therapy:
Repeat scans are done 6-12 months after ablation, at 1 year, and then every 2 years after that. Serum thyroglobulin should be measured every 6 months (18). Levels greater than 30 ng/ml are abnormal and indicate some thyroid pathology but are not diagnostic because there is a large overlap of abnormal levels among other benign thyroid conditions (21). Thyroid hormone suppression should be done in all patients who have had total thyroidectomies or have had radioactive ablation of any remaining thyroid tissue to control any residual. It is controversial whether or not this should be done in patients who had subtotal thyroidectomies. It is important to note that the sensitivity of thyroglobulin testing and radioiodine scans is considerably higher when a patient is off TSH suppression (21).
Total thyroidectomy is recommended for patients with Hurthle cell carcinoma because of their multifocal nature, more aggressive course, and because they are relatively unresponsive to ablation with radioactive iodine. All patients who are found to have a neoplasm containing Hurthle cells by FNA should undergo a total lobectomy with isthmusectomy. If the frozen section is negative for malignancy, the procedure is complete. If permanent section comes back positive for cancer, then a completion thyroidectomy should be done within 2 weeks (59). Patients with clinically palpable neck nodes should all undergo a routine modified neck dissection.
Postoperative therapy should include thyroid suppression because Hurthle cell neoplasms have been shown to have TSH receptors. In addition they usually produce thyroglobulin which should be followed every 6 months (59). Postoperative scanning with radioactive iodine is not helpful because only 10% of these tumors take up enough radioactive iodine for this treatment to be effective (9).
For patients with MTC, who have palpable disease and a clinically negative neck, a total thyroidectomy with parathyroid autotransplantation should be done along with central lymph node dissection and lateral jugular node sampling (48). All patients diagnosed with MEN IIb should undergo these procedures even if they have no evidence of MTC, including normal stimulated calcitonin levels. Patients with MEN IIa and FMTC may elect to undergo surgery when they have develop elevated serum calcitonin levels (48) but most authorities recommend prophylactic removal of the thyroid. The recommended age for thyroidectomy is > 5 years. If any nodes feel suspicious, an ipsilateral modified neck dissection should be done. Any patients with one of the MEN syndromes who are found to have a pheochromocytoma should have these removed prior to thyroid surgery to avoid an acute intraoperative adreneric crisis (10).
Management of patients after total thyroidectomy for MTC involves thyroid hormone replacement with L-thyroxine, two weeks of calcium and vitamin D supplementation, and disease surveillance with serial measurements of calcitonin (44) and CEA (52). Two weeks after surgery, serum calcium levels and basal and stimulated calcitonin level should be tested. Calcitonin testing should be continued 3 times monthly for a year and then biannually after that (18). If a patient continues to have elevated calcitonin after surgery, residual or recurrent disease is present and should be localized with radiographic imaging (including a chest X-ray, bone scan, and CT or MRI of the neck, chest , and abdomen) and removed surgically.
At the time of diagnosis, the majority of anaplastic thyroid cancers have extensive extrathyroidal involvement and are surgically unresectable. Surgery, chemotherapy, radioiodine administration, and external radiotherapy have been used to treat this cancer, however, little improvement is seen among any of the treatment protocols in long term survival. The standard of care presently is maximum surgical debulking of tumor, when possible, plus aggressive adjuvant treatment with radiotherapy and concomitant chemotherapy. Doxorubicin appears to be the single most effective chemotherapeutic agent, especially when used with radiotherapy, with combination chemotherapy using doxorubicin and cisplatin also demonstrating some efficacy when given with irradiation (30,60).
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