Etiology and Epidemiology

The annual incidence of thyroid cancer is 0.5 to 10 per 100,000 people in the general population in most countries; a global estimate suggested 87,000 new cases worldwide each year.²² Clinical thyroid malignancy is relatively uncommon, accounting for only about 2% of human malignancies.^2,23 Nonetheless, it was estimated that thyroid cancers would account for 95% of endocrine malignancies in the United States in 2010.² It was estimated by the American Cancer Society that 1690 patients with thyroid cancer would die during 2010, accounting for 66% of deaths from endocrine malignancies.²

Most thyroid cancers are derived from follicular epithelium. In most countries, incidence rates for papillary thyroid carcinoma (PTC) generally exceed the incidence rates for follicular thyroid carcinoma (FTC), and either PTC or FTC is far more common than the usually lethal anaplastic (undifferentiated) thyroid carcinoma.^24,25 Very similar data on the frequency of the various histologic types are contained in three large series of more than 97,000 cases of thyroid cancer reported from the United States and Japan.^26–28 These data are summarized in Table 36-1.

Anaplastic carcinomas and FTCs tend to be relatively more common in areas endemic for goiter, and numerous case-control studies have strongly suggested that dietary iodine content is responsible for the increased incidence rates in these areas.²⁹ This hypothesis is supported by the fact that dietary iodine supplementation has been shown to increase the relative proportion of PTC and to decrease the frequency of FTC.³⁰

PTC and FTC are more than twice as common in women as men and tend to occur much more commonly in middle age and later, although patients with PTC are younger than patients with FTC.^24,25 The preponderance of women with FCDC has led to speculation about the role of estrogens as a risk factor. Other putatively estrogen-dependent tumors, particularly breast cancer, and thyroid cancer occur more frequently in the same individual than expected by chance.³¹ Case-control studies have suggested a correlation between pregnancy, a high estrogen state, and the onset of thyroid cancer.³² Other studies have suggested that pregnancy per se, rather than the associated estrogen levels, may be associated with increased thyroid cancer risk.³³ The role of female sex hormones as a risk factor for thyroid cancer development must still be considered unresolved.

The most firmly established risk factor for development of thyroid cancer is prior exposure to ionizing radiation, particularly to the head and neck region during childhood, which used to be a common problem in some exposed populations in Japan and the Pacific during the 1960s and 1970s in the aftermath of atomic bomb use at the end of World War II and in areas exposed to atmospheric nuclear bomb tests during the 1950s and 1960s.^34,35 In most other countries, radiation treatments for benign medical conditions, such as acne vulgaris, thymic enlargement, tinea capitis, or inflammatory connective tissue disorders, contributed to increasing numbers of patients with thyroid cancer.^36,37 These practices have largely been abandoned, and radiation exposure as a risk factor for the most part has ceased to be of significant importance.³⁷ Exceptions are areas of high natural background radiation; radiotherapy used for malignant conditions³⁸; and areas where radioactive contamination of the environment from military or civilian sources is a notable problem, particularly in many countries in the southern part of the former Soviet Union that were heavily contaminated in the wake of the Chernobyl nuclear reactor accident.³⁹ The contamination in parts of Belarus and Ukraine was significant and prolonged, and there is mounting clinical evidence that this contamination has led to increased rates of thyroid malignancies, often of an unexpectedly aggressive nature.^40–42 In the United States, it has been disclosed that a significant segment of the U.S. population was exposed to radioiodine during a series of nuclear bomb explosions at the Nevada test site in the 1950s.⁴³ Predictions of excess relative risk of thyroid cancer vary but may prove to be significant. However, it is impossible to determine whether individual thyroid cancers arose as a result of radiation exposure or as sporadic events.⁴³

Although most cases of thyroid cancer are sporadic occurrences, a small proportion of thyroid cancers may be familial, and in the case of C cell–derived malignancy, medullary thyroid carcinoma (MTC) may be associated with multiple endocrine neoplasia (MEN) type II (MEN-II) syndrome and its associated adrenal medullary tumors (pheochromocytomas). In patients with the MEN-II syndrome, a strong and typical family history can often be obtained. PTC may also be associated with other nonthyroid malignancies and with premalignant conditions such as Cowden’s syndrome and familial adenomatous polyposis coli (i.e., Gardner’s syndrome).⁴⁴ Several cases of familial PTC have been described.⁴⁵ No such distinct associations exist for FTC, but aggregation of FTC cases in families with dyshormonogenesis has been described.⁴⁶

Prevention and Early Detection

Most thyroid cancers are sporadic and not caused by an avoidable environmental agent. Prevention of thyroid malignancy usually is impossible.

Nodular thyroid disease generally can be detected early by careful neck palpation in the course of routine physical examinations. High-resolution ultrasound can readily detect impalpable thyroid nodules 2 to 3 mm in diameter. There is no evidence, however, that population screening for nodular thyroid disease using ultrasound is warranted because 70% to 90% of diagnosed thyroid malignancies are of the papillary histologic type. In such incidentally discovered papillary tumors, 85% to 90% are deemed low risk and are associated with mortality rates close to rates predicted by actuarial curves and comparable to rates for nonmelanoma skin cancer.

In contrast, early detection of the often more aggressive, familial MTC is possible when there is evidence within the family of an inherited mutation of the RET proto-oncogene in the pericentromeric region of the short arm of chromosome 10. Such mutations have been found in more than 90% of familial MTC cases, and since the successful cloning and sequencing of the RET gene, asymptomatic members of affected families can be tested for the presence of a mutation at this locus.⁴⁷ A positive test result obviates the need for any further testing. The present recommendation for persons shown to harbor the mutation is to undergo prophylactic total thyroidectomy, which completely prevents the development of the invariably multicentric MTC associated with these conditions.^11,48 If such a mutation is found in infancy, the current practice is to perform a total thyroidectomy when the child is 3 to 5 years old.^11,49

Pathology and Pathways of Spread

Most thyroid cancers are well-differentiated tumors derived from follicular cells. PTC accounts for 40% to 90% of cases, and 15% to 40% are classified as FTC, which includes the so-called oxyphilic or Hürthle cell variant. Anaplastic thyroid cancer (ATC), also derived from the follicular cell, is the least common FCDC, typically constituting 1% to 5% of most series. The frequency of C cell–derived MTC depends on the diligence with which reporting centers pursue the early diagnosis of patients with familial MTC and MEN-II, but it may account for 2% to 8% of thyroid cancers. Nonepithelial thyroid tumors include sarcomas, malignant hemangioendotheliomas, and malignant lymphomas. Lymphomas may involve the thyroid as the only manifestation of the disease or as part of a systemic disease; such tumors may rarely complicate Hashimoto’s (autoimmune) chronic lymphocytic thyroiditis, which in the United States is the most common cause of goiter and noniatrogenic hypothyroidism. Blood-borne metastases to the thyroid are common at autopsy in patients with widespread malignancy, but they rarely cause clinically detectable thyroid enlargement.

PTC most often occurs in patients 30 to 50 years old; the mean age at diagnosis is about 45 years. Most primary tumors are 1 to 4 cm in diameter; the average is about 2 to 3 cm in the greatest dimension. Of tumors, 95% are classified on the basis of degree of differentiation as histologic grade 1 (of 4); 80% of primary PTC tumors are assessed to be DNA diploid by flow cytometry.⁵⁰ Extrathyroidal invasion of adjacent soft tissues is present in about 15% (range 5% to 34%) at primary surgery, and about one-third of PTC patients have clinically evident lymphadenopathy at presentation.⁵¹ About 35% to 50% of excised neck nodes have histologic evidence of involvement, and in patients 17 years old or younger, nodal involvement may be present in up to 90%.⁵² The primary disease is confined to the neck in 93% to 99% of PTC patients at diagnosis.^50,51 Spread to superior mediastinal nodes is usually associated with extensive neck nodal involvement. Distant metastases are diagnosed in only 1% to 7% of patients with PTC before or within 30 days of primary treatment.^50,53

FTC occurs in older patients, and the mean age in most studies is more than 50 years, about 10 years older than for typical PTC.^25,54 Women affected by FTC outnumber men by more than 2 : 1. FTC patients rarely (4% to 6%) have clinically evident lymphadenopathy at presentation.⁵⁵ In most series, the average tumor size in FTC is larger than in PTC.⁵⁴ When tumor grading is performed, higher grade tumors are more common than with PTC.⁵⁴ DNA aneuploidy is present in about 60% of FTC tumors and in up to 90% of patients with oxyphilic or Hürthle cell variant tumors.^25,56 Direct extrathyroidal extension into adjacent soft tissues does not occur in the common “minimally invasive” FTC, but it is not unusual in the rare patient with “widely invasive” FTC. Of patients with FTC, 5% to 20% may have distant metastases at presentation, and the most common sites of distant spread are lung and bone.^25,57

MTC arises from the C cells of the thyroid rather than the follicular epithelium; secretes a characteristic hormone, calcitonin; is frequently associated with one or more paraendocrine manifestations; and provides an early biochemical signal (i.e., hypersecretion of calcitonin) that permits its early detection, treatment, and cure.11,58 The tumor occurs in sporadic and familial forms, with the latter constituting about 20% of the total. The familial variety usually appears at a younger age, is almost invariably bilateral, is less likely to have associated cervical metastases at presentation, and has a better prognosis.^11,58 Most importantly, the familial variety is preceded by a premalignant C cell hyperplasia that can be cured by total thyroidectomy.⁵⁹

ATC is the least common FCDC and typically constitutes less than 5% of most reported series.⁶⁰ It usually occurs after age 60 years, and it is only slightly more common in women than men (1.3 : 1 to 1.5 : 1). It is highly malignant, rapidly invading adjacent structures and metastasizing throughout the body. Pathologic examination of tumor biopsy specimens may reveal evidence of PTC or FTC, which may represent a precursor of ATC. Thorough biopsy sampling may be necessary to detect residual well-differentiated thyroid tissue. On histologic examination, the tumor is usually composed of atypical cells that exhibit numerous mitoses and form a variety of patterns. Spindle-shaped cells and multinucleated giant cells usually predominate, but in a third histologic pattern described as squamoid, the cells are undifferentiated but retain an epithelial appearance. It was formerly thought that there was a small cell ATC, but most of these tumors have been classified as malignant thyroid lymphomas.

Biologic Characteristics, Prognostic Factors, and Staging

It has long been recognized that prognosis in thyroid cancer largely depends on the age of the patient, the histology of the tumor, and the anatomic extent of disease at presentation. Although head and neck cancer is staged entirely on the basis of anatomic extent, thyroid cancer staging is unique in that the histologic diagnosis and the age of the patient are included because of their prognostic importance.

The seventh edition of the TNM (primary tumor, regional nodes, metastases) staging scheme for thyroid carcinoma, approved in 2009 by the International Union Against Cancer⁶¹ and in 2010 by the American Joint Committee on Cancer (AJCC),⁶² is presented in Table 36-2. The primary tumor status is defined in this scheme on the basis of the size of the primary lesion (diameter in centimeters) and the presence of extrathyroidal extension. A T1 tumor is 2 cm or smaller and limited to the thyroid. T1a refers to tumors of 1 cm or less, and T1b refers to a tumor more than 1 cm but not more than 2 cm in greatest dimension. A T2 tumor is 2.1 to 4.0 cm in diameter and limited to the thyroid. A T3 tumor is larger than 4 cm and limited to the thyroid or any tumor with minimal extrathyroidal extension (i.e., to sternothyroid muscles or perithyroid soft tissues). A T4a tumor represents moderately advanced disease, which extends beyond the thyroid capsule and invades subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve, and a T4b tumor represents very locally advanced disease, typically invading prevertebral fascia or encasing carotid artery or mediastinal vessels.

When tumor spreads to lymph nodes, it is classified as N1. N1a refers to metastasis in level VI (i.e., pretracheal and paratracheal nodes, including prelaryngeal and delphian nodes), and N1b describes metastasis to other unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes. M1 refers to the presence of distant metastasis involving nonregional lymph nodes, internal organs, or bones.

To make this TNM information clearer, several of these TNM descriptions can be grouped together into stages I through IV. For the seventh edition of the TNM/AJCC staging system, the grouping for MTC is the same as for PTC or FTC in patients older than 45 years with one exception. A T3 N0 M0 MTC patient is considered stage II, whereas such a patient with papillary and follicular cancers is considered stage III. All patients with ATC are considered stage IV, reflecting the poor prognosis of this type of cancer.

For patients younger than 45 years with a diagnosis of PTC or FTC, the TNM stage is I (any T, any N, M0) if there is no distant spread and stage II (any T, any N, M1) if there are distant metastases beyond the neck or upper mediastinal lymph nodes. For patients with MTC or who are 45 years or older with PTC or FTC, the seventh edition of the TNM/AJCC staging system is more complicated than before.

In patients with PTC or FTC who are 45 years of age or older, stage I (T1 N0 M0) cancers are 2 cm or smaller and have not spread to lymph nodes or distant sites. Stage II (T2 N0 M0) cancers are more than 2 cm in diameter but not bigger than 4 cm, and they are localized to the thyroid. Stage III (T3 N0 M0 or T1-3 N1a M0) encompasses tumors larger than 4 cm or with minimal extrathyroidal extension and tumors of any size that have spread to central neck nodes.

In former TNM/AJCC classifications, stage IV referred only to patients who had distant spread, but the later editions (since 2002) define these patients as IVC (any T, any N, M1), and the designations IVA and IVB define more aggressive tumors that have not spread to distant sites. Stage IVB (T4b, any N, M0) refers to the unusual situation of a tumor that has grown back to the spine (i.e., prevertebral fascia) or into nearby large blood vessels (i.e., carotid artery or mediastinal vessels). The new stage IVA (T1-4a, N0-1b, M0) was formerly considered to be stage III, and it encompasses locally invasive T4a tumors (i.e., with or without nodal involvement [any N]) and node-positive N1b tumors (with primary tumors of any size but localized or showing only minimal extrathyroidal extension [T1-3]).

Because of significant differences in the tumor biology displayed by the four principal types of thyroid carcinomas, the remainder of this discussion of tumors is divided according to histologic type.

Papillary Thyroid Carcinoma

Most patients with PTC present with localized, node-negative disease.28,50,65 Patients 45 years old or older with nodal metastases or extrathyroidal extension account for less than 20% of cases.⁵⁰ Only about 1% to 3% of older PTC patients present with distant metastases. Figure 36-1 shows cause-specific survival according to pathologic TNM (pTNM) stage in a cohort of 1851 patients who underwent surgical treatment at Mayo Clinic during the period 1940-1990.⁶³

Figure 36-1 Cause-specific survival according to pathologic TNM (primary tumor, regional nodes, metastases) stage for a cohort of 1851 patients with papillary thyroid carcinoma treated at the Mayo Clinic during the period 1940-1990. Numbers in parentheses are the percentages of patients in each pathologic TNM stage grouping.

From Larsen PR, Davies TF, Hay ID: The thyroid gland. In Wilson JD, Foster DW, Kronenberg HM, et al, editors: Williams Textbook of Endocrinology, 9th ed, Philadelphia, 1998, WB Saunders, pp 389-515.

Three types of tumor relapse may occur with PTC: postoperative regional nodal metastasis, local recurrences, and postoperative distant metastases. Local recurrence has been defined as “histologically confirmed tumor occurring in the resected thyroid bed, thyroid remnant, or other adjacent tissues of the neck (excluding lymph nodes)” after complete surgical removal of the primary tumor.⁶⁴ Nodal or distant spread is considered postoperative if the metastases are discovered within 180 days or 30 days, respectively. In a cohort of 2370 patients with PTC who did not have initial distant metastases and had complete surgical resection of their primary tumors during treatment at Mayo Clinic from 1945-2000, relapse rates at nodal, local, and distant sites were 9.8%, 5.5%, and 4.6% after 25 years of follow-up.⁶⁵ In a larger cohort of 2512 PTC patients treated during the period 1940-1990 at Mayo Clinic, the cause-specific survival rates at 5, 10, and 20 postoperative years were 98%, 96%, and 95%.⁶⁵ Of patients with lethal PTC, 20% of deaths occurred within the first year after diagnosis, and 80% of the deaths occurred within 10 postoperative years.^50,51,65

Only a fraction (≈15%) of PTC patients have relapse of disease, and even fewer (≈5%) have a lethal outcome.50–52,65 The exceptional patient who experiences an aggressive course tends to relapse early, and the rare fatalities usually occur within 5 to 10 years of initial diagnoses.^50,51,65

Multivariate analyses have been used to identify variables predictive of cause-specific mortality.66,67,68,69 Increasing patient age and presence of extrathyroidal invasion are independent prognostic factors in all such studies.^66,67,68,69 The presence of initial distant metastases and large size of the primary tumor are also significant variables in most studies,^66,68 and some groups^{26,28,50,66,67} have reported that histopathologic grade (i.e., degree of differentiation) is an independent variable. The completeness of initial tumor resection (i.e., postoperative status) is also a predictor of mortality.^50,69 The presence of initial neck nodal metastasis, although relevant to future nodal relapse, does not apparently influence cause-specific mortality.^50,51,69

From a multivariate analysis of more than 14,200 patient-years of experience, a prognostic scoring system was devised and named the AGES system after five independent variables: patient’s age, tumor grade, tumor extent (e.g., local invasion, distant metastasis), and tumor size.^50,66 With the use of such a scoring system, 86% of PTC patients were in the minimal-risk group (AGES score <4), and they had a cause-specific mortality rate of only 1%.⁵⁰ In contrast, patients with AGES scores of 4 or greater (i.e., high-risk group is 14% of the total) had a 20-year cause-specific mortality rate of 40%. Based on the description of the Mayo Clinic–derived AGES system,⁶⁶ Cady and Rossi,⁷⁰ working at the Lahey Clinic, devised a simplified version of the AGES system, which they called the AMES multifactorial system. The AMES system disregarded tumor grade because this information was not readily available to the authors, but they took advantage of the other four variables: age, metastasis, extent, and size. The details of the AMES system are presented in Table 36-3. Of the 1961-1980 cohort of patients studied by Cady and Rossi, 89% were deemed low risk and had a death rate of 1.8%—outcome results virtually identical to results defined by the AGES prognostic scores.^50,66

TABLE 36-3 Classification of Risk Group Categories According to the AMES System

Low Risk

1 Younger patients (men <41 yr; women <51 yr), no distant metastasis 2 Older patients with (a) minor tumor capsule involvement and (b) primary cancers <5 cm in diameter and (c) no distant metastasis

High Risk

1 All patients with distant metastasis

2 All older patients with (a) major tumor capsule involvement or (b) primary cancers ≥5 cm in diameter

AMES, age, metastasis, extent, and size.

Data from Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947-953, 1988.

Although the AGES scheme had the potential for universal application, some academic centers could not include the differentiation variable (tumor grade [G]) because their surgical pathologists did not recognize higher grade PTC tumors.⁷¹ Another prognostic scoring system for predicting PTC mortality rates was devised with the use of candidate variables that included completeness of primary tumor resection but excluded histologic grade.⁶⁹ Cox model analysis and stepwise variable selection led to a final prognostic model that included five variables: metastasis, age, completeness of resection, invasion, and size (MACIS). The final score was defined as MACIS = 3.1 (if age is ≤39 years) or 0.08 × age (if age is ≥40 years), +0.3 × tumor size (in centimeters), +1 (if tumor not completely resected), +1 (if locally invasive), +3 (if distant metastases are present). As illustrated by Figure 36-2, the MACIS scoring system permitted identification of patient groups with a broad range of risk of death from PTC. Twenty-year cause-specific survival rates for patients with MACIS scores of less than 6, 6 to 6.99, 7 to 7.99, and 8 or more were 99%, 84%, 56%, and 24%. When cumulative mortality from all causes of death was considered, approximately 85% of PTC patients (who had AGES scores <4 or MACIS scores <6) experienced no excess mortality over rates predicted for control subjects.^50,65,66,69

Figure 36-2 Cause-specific survival according to MACIS (metastasis, age, completeness of resection, invasion, and size) scores of <6, 6-6.99, 7-7.99, and ≥8 for a cohort of 1851 consecutive patients with papillary thyroid carcinoma (PTC) undergoing initial treatment at the Mayo Clinic during the period 1940-1990. Numbers in parentheses are the numbers and percentages of patients with PTC in each of the four risk groups.

From Larsen PR, Davies TF, Hay ID: The thyroid gland. In Wilson JD, Foster DW, Kronenberg HM, et al, editors: Williams Textbook of Endocrinology, 9th ed, Philadelphia, 1998, WB Saunders, pp 389-515.

Follicular Thyroid Carcinoma

When more than 75% of cells in an FTC exhibit Hürthle cell or oncocytic features, the tumor is classified as a Hürthle cell carcinoma (HCC), oncocytic carcinoma, or oxyphilic variant FTC.²⁵ Most patients with FTC or HCC present with tumors 2 cm or larger and confined to the neck. Patients 45 years old or older with nodal metastases or extrathyroidal extension account for only about 4% to 7% of FTCs and 8% to 10% of HCCs.^28,63 In contrast to PTC patients, among whom only 1% to 3% present with distant metastases, about 4% to 6% of HCC patients and 7% to 15% of non–oxyphilic variant FTC patients have distant metastases at the time of initial diagnosis.^25,28,63 Figure 36-3 shows cause-specific survival according to pTNM stage in a cohort of 153 patients with nonoxyphilic FTC surgically treated at Mayo Clinic during the period 1940-1990.⁶³

Figure 36-3 Cause-specific survival according to pathologic TNM (primary tumor, regional nodes, metastases) stages for a cohort of 153 patients with nonoxyphilic follicular thyroid carcinoma treated at the Mayo Clinic during the period 1940-1990. Numbers in parentheses are the percentages of patients in each pathologic TNM stage grouping.

From Larsen PR, Davies TF, Hay ID: The thyroid gland. In Wilson JD, Foster DW, Kronenberg HM, et al, editors: Williams Textbook of Endocrinology, 9th ed, Philadelphia, 1998, WB Saunders, pp 389-515.

Nodal metastases are rare in typical FTC, and nodal relapse rates at 10 and 20 postoperative years are 1% and 2%. About 6% of patients with HCC have nodal involvement at presentation,⁵⁵ but at 20 and 30 years after primary surgery, 18% and 24% of these patients have nodal relapse.²⁵ When relapse at neck or distant sites is considered, patients with HCC have the highest rates of tumor relapse after 10 or 20 years. Local recurrences account for most of these postoperative events because the numbers of distant metastases in patients with HCC are comparable with the numbers of metastases found in nonoxyphilic FTC (i.e., about 20% after 20 postoperative years).²⁵

Cause-specific mortality rates vary with the presenting TNM stage for patients with FTC or HCC. The death rates tend to parallel the curves for development of distant metastases. In 5 decades of Mayo Clinic experience, the mortality rate for FTC initially exceeded that of HCC, but by 20 and 30 postoperative years, there were no significant differences in cause-specific survival (CSS) rates between FTC and HCC,²⁵ with both survival rates about 80% at 20 postoperative years and 70% at 30 postoperative years.

The risk factors that predict outcome of patients with FTC are largely the same as for patients with PTC: distant metastases at presentation, increased patient age, large tumor size, and presence of local (extrathyroidal) invasion.²⁵ To a lesser degree, increased mortality is associated with male sex and higher grade tumors. Vascular invasiveness, lymphatic involvement at presentation, DNA aneuploidy, and oxyphilic histology are potential prognostic variables unique to FTC.²⁵ The importance of vascular invasion is underscored by a study showing that FTC patients with minimal capsular invasion and no evidence of vascular invasion had 0% cause-specific mortality after 10 years of postoperative follow-up.⁷²

Prognostic scoring systems for FTC allow stratification of patients into high-risk and low-risk categories.25,73 A multivariate analysis at the Mayo Clinic found that distant metastases, patient age older than 50 years, and marked vascular invasion predicted a poor outcome.⁵⁴ As illustrated by Figure 36-4, if two or more of these factors are present, the 5-year survival rate is 47%, and the 20-year survival rate is 8%. If only one of these factors is present, the 5-year survival rate is 94%, and the 20-year survival rate is 86%.⁵⁴

Figure 36-4 Cause-specific survival among 100 patients with nonoxyphilic follicular thyroid carcinoma treated at the Mayo Clinic during the period 1946-1970 and plotted by high-risk and low-risk categories. High risk is characterized by two or more of the following factors: age older than 50 years, marked vascular invasion, and metastatic disease at the time of initial diagnosis.

From Brennan MD, Bergstralh EJ, van Heerden JA, et al: Follicular thyroid cancer treated at Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 66:11-19, 1991.

Systems developed to predict outcomes for PTC or FTC have been applied to patients with FTC. Specifically, the AMES risk-group categorization by Cady and Rossi has proved useful in FTC.28,70 From a multivariate analysis of 228 patients with FTC treated at Memorial Sloan-Kettering Cancer Center, the independent adverse prognostic factors were identified as age older than 45 years, Hürthle cell histologic type, extrathyroidal extension, tumor size exceeding 4 cm, and presence of distant metastasis.⁷⁴ The prognostic importance in FTC of histologic grade has also been confirmed^74,75 by the Memorial Sloan-Kettering group, who have included this factor in their assignment of risk groups to low-risk, intermediate-risk, and high-risk categories, with 20-year survival rates of 97%, 87%, and 49%.⁷⁴ The AGES and MACIS prognostic scoring systems, originally developed for PTC, have also been successfully applied to FTC.^76,77 It seems that scoring systems used in PTC can be cautiously applied in FTC as long as some of the unique features of this tumor, such as vascular invasiveness and the remarkable significance of DNA aneuploidy in HCC, are considered.²⁵

Medullary Thyroid Carcinoma

In reported studies of treated MTC, the proportion of patients with intrathyroidal node-negative tumors of 2 cm in diameter or smaller (TNM stage I) varies, depending on the number of familial cases detected by biochemical testing or DNA screening. The number of patients who present with TNM stage I MTC ranges from 5% to 25%, with the lower numbers representing the older series. Of patients, 25% to 50% present with positive neck nodes; the proportion of patients presenting with distant metastases usually exceeds the proportion with PTC but is typically less than the proportion with FTC. Stage IV cases constitute 3% to 10% of most MTC series. Figure 36-5 illustrates CSS according to pTNM stage in a cohort of 181 patients with MTC surgically treated at Mayo Clinic during the period 1940-1990.⁶³

Figure 36-5 Cause-specific survival according to pathologic TNM (primary tumor, regional nodes, metastases) stage for a cohort of 181 patients with medullary thyroid carcinoma treated at the Mayo Clinic during the period 1940-1990. Numbers in parentheses are the percentages of patients in each pathologic TNM stage grouping.

From Larsen PR, Davies TF, Hay ID: The thyroid gland. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors: Williams Textbook of Endocrinology, 9th ed, Philadelphia, 1998, WB Saunders, pp 389-515.

Other prognostic factors relevant to outcome in MTC include age at diagnosis, male gender, vascular invasion, calcitonin immunoreactivity, amyloid staining, presence or absence of postoperative gross residual disease, and abnormal postoperative plasma calcitonin levels.11,78–80 In a multivariate analysis from Toronto, only the presence of extrathyroidal invasion and postoperative gross residual disease were significant in the prediction of CSS.⁸⁰ In another multivariate study from Mayo Clinic, however, the only factors remaining in the final Cox model were pTNM stage III or IV disease, negative Congo red staining for amyloid, and postoperative gross residual disease.⁷⁹ Based on these three independent prognostic variables, a scoring system was devised to define four risk groups with 10-year mortality rates ranging from 5% to 100%.⁷⁹

Anaplastic Carcinoma

Patients with ATC have a very poor prognosis, and survival beyond 1 year is rare. There is no real use for an elaborate staging system for these patients, although distant and lymphatic spread at presentation, advanced age, and extremely poor differentiation have been identified as factors that make an already grim picture worse.60,81 Figure 36-6 shows survival curves for 82 patients with ATC, stratified by extent of disease at presentation.⁶⁰

Figure 36-6 Survival to death from anaplastic thyroid cancer is plotted by extent of disease at presentation. Notice the logarithmic scale of the ordinate.

From Nel CJ, van Heerden JA, Goellner JR, et al: Anaplastic carcinoma of the thyroid: a clinicopathological study of 82 cases. Mayo Clin Proc 60:51-58, 1985.

Clinical Manifestations and Patient Evaluation

At initial assessment, most patients with thyroid cancer have a palpable neck mass, which may represent the primary intrathyroidal tumor or metastatic regional lymphadenopathy. In some patients, the tumor may be clinically occult, and the impalpable lesion may first be recognized on high-resolution neck imaging³ or during the course of a neck exploration for presumed benign thyroid disease. In patients with a family history of MTC or MEN-II syndrome, the finding of a RET oncogene mutation (identical to the proband) or abnormal calcitonin (or stimulated calcitonin) levels, or both, may necessitate elective prophylactic thyroidectomy in a patient who may prove to have early MTC visible only under the surgical pathologist’s microscope.^48,49

Features of the history and physical examination rarely provide convincing evidence for a diagnosis of thyroid malignancy.^8,9 The diagnosis of thyroid cancer necessitates pathologic confirmation from cytologic or histologic material. It is generally recognized that fine-needle aspiration (FNA) biopsy is the most effective method available of preoperatively distinguishing between benign and malignant thyroid nodules.^8,9 All cancer diagnoses should be verified, however, by careful examination of histologic material after surgical excision of affected tissues. This approach is particularly relevant to the problem of the cellular follicular lesions described by cytologists as “suspicious” for follicular or Hürthle cell neoplasm. The diagnosis of FTC or HCC depends on the demonstration of invasion of the thyroid capsule or the adjacent blood vessels (i.e., angioinvasion), a process that typically necessitates careful evaluation of serial sections from the excised specimen for the presence or absence of such microinvasion. Even if FTC or HCC is apparently excluded at intraoperative frozen section, the resected specimen must be carefully reviewed in multiple sections from paraffin-embedded material.²⁵

FNA biopsy can usually allow a confident diagnosis of PTC, which typically represents more than 75% of clinically recognized thyroid cancers in most contemporary series.^12,26,28,50 Some authorities claim that the characteristic nuclear abnormalities diagnostic for PTC may be best seen in cytologic preparations from an FNA biopsy specimen, rather than in frozen sections or in paraffin-embedded histologic material. MTC may be readily diagnosed by FNA biopsy, but in equivocal cases, amyloid stained by Congo red or immunoperoxidase labeling of intracytoplasmic calcitonin may allow a definitive preoperative diagnosis.^11,58 ATC may often be diagnosed by FNA biopsy, but it sometimes may be difficult to distinguish from carcinoma metastatic to the thyroid.⁶⁰ When the biopsy specimen is found to be suspicious for ATC, immunostaining for thyroglobulin can help confirm the diagnosis of ATC. FNA diagnosis of thyroid lymphoma is difficult to make, and verification may necessitate examination of open biopsy material and specific immunostaining for clonal B-cell and T-cell populations.⁸²

The evaluation of a patient with thyroid cancer requires obtaining a thorough history and performing physical examination with particular attention to signs and symptoms associated with local (extrathyroidal) invasion, involvement of regional (neck) nodes, and distant spread. Historical features suggesting a possible thyroid cancer include growth of a thyroid nodule over weeks or months; changes in speaking, breathing, or swallowing; and systemic symptoms of malignancy, such as weight loss, fatigue, and night sweats. On thyroid palpation, typical signs may include firm consistency of the dominant nodule, irregular shape, and fixation to underlying or overlying tissues. Evidence of suspicious regional lymphadenopathy may be present in up to one-third of patients with PTC and MTC, but it is absent in most patients with FTC.

Patients with thyroid cancer are typically euthyroid, and when measured, the serum thyroid-stimulating hormone (TSH) level is usually normal. FNA biopsy can provide a confident diagnosis of PTC, MTC, and usually ATC. Diagnosing follicular cancer preoperatively remains a problem because capsule or vascular invasion cannot be shown in cytologic material. When FCDC is suspected and the decision is made for surgical exploration, it is often advisable to draw blood for a baseline serum thyroglobulin. This thyroid-specific protein can be used as a tumor marker to assess the efficacy of future therapies. Similarly, for patients with MTC, baseline measurements of calcitonin and carcinoembryonic antigen may permit a more accurate subsequent assessment of tumor control.