Benign Neoplasia

Most adenomas are follicular and have a histologic appearance characteristic of thyroid tissue. Adenomas usually exhibit a uniform orderly architecture and few mitoses and show no lymphatic or blood vessel invasion. They are characteristically enveloped by a discrete fibrous capsule or a thin zone of compressed surrounding thyroid tissue. Fetal and embryonal adenomas show a progressively reduced “adult” structure. Whether papillary adenoma is a real entity is debatable; most observers believe that all papillary tumors should be considered carcinomas. Others believe that some papillary tumors are benign adenomas. It is our impression that papillary tumors are best thought of as carcinomas, although the degree of invasive potential may be very slight in some instances. The same confusion extends to Hürthle cell adenomas. Many pathologists consider all these tumors low-grade carcinomas in view of their common late recurrence. For this reason, the nondefinitive term Hürthle cell tumor is commonly used. Hürthle cell tumors are found on electron microscopy to be packed with mitochondria, which accounts for their special eosinophilic staining quality.

On gross inspection, nearly half of all single nodules have a gelatinous appearance, are composed of large colloid-filled follicles, and are not completely surrounded by a well-defined fibrous capsule. In our classification, these nodules are listed as colloid variants of follicular adenomas. Many pathologists report them as colloid nodules and suggest that each is a focal process perhaps related to multinodular goiter rather than a true adenoma. These tumors are not usually surrounded by a capsule of compressed normal tissue and often show degeneration of parenchyma, hemosiderosis, and colloid phagocytosis. The histologic pattern of various benign tumors of the thyroid is shown in Fig. 18-1.

The first distinction to be made among benign nodules is between functioning (“hot” on thyroid scan) and nonfunctioning (“cold”) nodules. Whereas a “hot” nodule is almost synonymous with a benign nodule, a “cold” nodule is not synonymous with a malignant nodule, because only a minority will turn out to be thyroid carcinomas. Cold nodules can be solid or cystic (around 10% to 20% of the total). However, mixed, solid-cystic forms are also common and should be considered solid in terms of frequency of malignancy. As a general rule, thyroid carcinoma is more common among solid, single, cold nodules.

Thyroid adenomas are usually monoclonal “new growths”¹⁷ that are formed in response to the same sort of stimuli that produce carcinomas. Heredity does not appear to play a major role in their appearance. One clue to their origin is that they are four times more common in women than in men, although no definitive relationship of estrogen to cell growth has been demonstrated. Thyroid radiation, chronic thyroid-stimulating hormone (TSH) stimulation, and oncogenes (see following) are believed to be related to the origin of these lesions; these are discussed in the following section on thyroid cancer.¹⁸ Of specific interest in relation to benign nodules is the observation by Parma and colleagues that activating mutations of the TSH receptor are the specific cause of most hyperfunctioning adenomas¹⁹ and the common involvement of ras gene mutations found in follicular adenomas.¹⁹ In view of the frequent discovery of ras gene mutation in follicular (and also papillary) thyroid carcinomas, the question is whether a ras mutated follicular adenoma should be considered as a pre-neoplastic lesion that should always be treated surgically.

Non-Neoplastic Nodules

These lesions are not true nodules but represent focal areas of glandular hyperplasia that arise spontaneously or, more commonly, as a consequence of previous partial thyroidectomies. Also, thyroid hemiagenesis may rarely be manifested as hyperplasia of the existing lobe and mimic a thyroid nodule. Nodule(s) associated with Hashimoto’s thyroiditis are the expression of lymphocytic infiltration and fibrosis. Nodules seen during the initial phase of subacute thyroiditis are a result of the inflammatory process that gives origin to typical granulomas.

Micronodules

Micronodules are nodules 1 cm or less in diameter. With the routine use of neck ultrasound, the discovery of micronodules is increasing, and nearly 50% of women older than 60 years have such nodularities. One view is that micronodules in general are not clinically relevant and, in the absence of other clinically suspicious findings, do not require investigation or treatment. The usual advice is to repeat thyroid ultrasound at regular intervals and reconsider therapy if growth is seen. However, in light of evidence that the frequency of malignancy is the same in micronodules or macronodules,¹² an alternative view is that the former should be evaluated by FNAC under ultrasound guidance.

Personal History

The age of the patient is an important consideration because the ratio of malignant to benign nodules is higher in youth and lower in older age. In a study involving nonirradiated children with cold thyroid nodules, a twofold increased risk for thyroid cancer, regardless of sex,²⁸ was found when compared with the rate for similar adults.² In adult men, nodules are less common, and a greater proportion are malignant.

Rarely, the family history may be helpful in decision making regarding surgery. Patients with the heritable multiple endocrine neoplasia (MEN) syndrome, type 1, may have thyroid adenomas, parathyroid adenomas, islet cell tumors, and adrenal tumors, whereas patients with MEN type 2 may have pheochromocytomas, medullary thyroid carcinomas, hyperparathyroidism, and mucosal neuromas.29–31 Familial medullary cancer (without MEN) is also possible. Furthermore, we have noted that 6% to 12% of patients with differentiated thyroid carcinoma have one or (less frequently) more family members with a history of malignant (nonmedullary) thyroid neoplasm, most often papillary.³² Familial papillary thyroid tumors occur in Cowden’s disease, Gardner’s syndrome, and familial polyposis coli³³ but most of the time are not associated with other manifestations (nonsyndromic). Recently, it has been reported that isolated familial papillary thyroid cancer displays the feature of “genetic anticipation,” that is, the tendency for a familial cancer to present at an earlier age and with a more aggressive phenotype in subsequent generations compared with the first generation.³² As is discussed in the following sections, a history of prior irradiation to the head or neck during infancy or childhood is strongly associated with the subsequent occurrence of carcinoma.³⁴ A history of such radiation exposure and the presence of a palpable nodule or nodules must raise the possibility of thyroid cancer, which requires a cytologic diagnosis.

The epidemic of childhood papillary thyroid cancer observed in Belarus and Ukraine after the Chernobyl nuclear accident³⁵ is believed to be the result of contamination from radioactive fallout, mainly iodine isotopes, which were released in huge amounts into the atmosphere. Several studies have reported no increase in the risk for thyroid cancer after diagnostic or therapeutic exposure to ¹³¹I. However, the possibility that many naturally occurring thyroid carcinomas may be caused by fallout radiation after nuclear tests, other radiation sources, or natural background radiation must be seriously considered.

The history of the neck lump itself is important. Recent onset, growth, hoarseness, pain, regional nodes, symptoms of brachial plexus irritation, and local tenderness all suggest malignancy but of course do not prove it. The usual cause of sudden swelling and tenderness in a nodule is hemorrhage into a benign lesion. Although the presence of a nodule for many years suggests a benign process, some cancers grow slowly. In our series, the average time from recognition of a nodule to the diagnosis of cancer was 3 years.

Coexisting benign thyroid disease is important in the evaluation of cancer risk associated with a thyroid nodule. A history of residence in an endemic goiter zone during the first decades of life is relevant and must raise the possibility of multinodular goiter as the true diagnosis. Hashimoto’s thyroiditis is often associated with discrete nodules, which are an expression of the autoimmune process. The frequency of thyroid carcinoma is not increased in patients with Hashimoto’s thyroiditis; however, Hashimoto’s thyroiditis is a common preexisting condition in patients in whom thyroid lymphoma develops.³⁶ Higher risk for differentiated thyroid cancer has been noted in patients with Graves’ disease and cold thyroid nodules,^36–39 and increased aggressiveness of such Graves’ disease–associated thyroid cancer has been proposed.⁴⁰ In the experience of the authors and of other groups,^41,42 the response to traditional therapy and the final outcome of patients with thyroid cancer and Graves’ disease are not different with respect to thyroid cancer patients without Graves’ disease.

Physical Examination Findings

In the era of thyroid ultrasound, evaluation of the thyroid gland has been enormously facilitated; however, accurate palpation of the thyroid gland and the cervical node chains is still of paramount importance in the evaluation of thyroid nodular pathology. It gives an idea of the number and size of the nodule(s), their consistency and motility, and the status of the rest of the thyroid gland, as well as the presence and the importance of lymph node involvement.

The adenoma typically is felt as a discrete lump in an otherwise normal gland, and it moves with the thyroid. Enlarged lymph nodes should be carefully sought, particularly in the area above the isthmus, in the cervical chains, and in the supraclavicular areas. Their presence suggests malignant disease unless a good alternative diagnosis (e.g., recent oropharyngeal sepsis, viral infection) is apparent. Fixation of the nodule to strap muscles or to the trachea is alarming. Characteristically, a benign thyroid adenoma is part of the thyroid and moves with deglutition, but it can be moved in relation to the strap muscles and within the gland substance to some extent. Pain, tenderness, or sudden swelling of the nodule usually indicates hemorrhage into the nodule but can also indicate invasive malignancy. Hoarseness may arise from pressure or from infiltration of a recurrent laryngeal nerve by a neoplasm. Obviously, the presence of a firm, fixed lesion associated with pain, hoarseness, or any one of these features should signal some degree of alarm. It is worth noting that these signs are not specific for the diagnosis of malignancy. In a study that correlated suspicious clinical features with the histologic diagnosis, the authors reported benign disease in 29% of patients with palpable cervical adenopathy, in 50% of patients with hard nodules, in 29% of patients with apparent nodule fixation, and in 17% of patients with true vocal cord paralysis.⁴³ The converse situation, the absence of such characteristics, suggests but does not prove benignity. Fluctuance within the lesion suggests the presence of a cyst that is usually benign.

The presence of a diffusely multinodular gland, ascertained on the basis of palpation, ultrasound, or scanning, generally is interpreted as a sign of safety. Multinodular goiters coming to surgery have a significant prevalence of carcinoma (4% to 17%), but this finding is believed to be caused largely by selection of patients for surgery, and is not believed to be typical of multinodular goiter in the general population.⁴⁴ If one area within a multinodular goiter seems different from the remainder of the gland on the basis of palpation or function, or has demonstrated rapid growth, or if two discrete nodules are found in a gland that is otherwise normal, one should consider malignant change rather than a benign multinodular goiter.

Occasionally, in addition to a nodule, the gland exhibits the diffuse enlargement and firm consistency of chronic thyroiditis, a palpable pyramidal lobe, and antibody test results that may be positive. These findings strongly suggest thyroiditis but do not disclose the nature of the nodule, which must be evaluated independently. It should be remembered that 14% to 20%^45,46 of thyroid cancer specimens contain diffuse or focal thyroiditis.

Thyroid Function Tests

Unless a toxic adenoma is present, the patient is usually euthyroid, and this impression is supported by normal values for serum-free thyroxine (FT₄), free triiodothyronine (FT₃), and TSH. Low thyroid hormones or elevated TSH results should raise the question of thyroiditis. Several centers advocate measurement of serum antithyroid autoantibodies (antithyroglobulin [anti-Tg] and antithyroperoxidase [anti-TPO]) in every new patient in search of an underlying autoimmune thyroid disease. The serum Tg concentration may be elevated, as in all other goitrous conditions. Its increase is related mainly to the size of the nodule, rather than to its nature and to the size of the thyroid gland.⁴⁷ Thus, serum Tg measurement is not a valuable tool in the differential diagnosis. On the contrary, elevation of circulating calcitonin levels in a patient with a thyroid nodule is almost always diagnostic of medullary thyroid cancer. Several prospective studies have shown that routine measurement of circulating calcitonin in thyroid nodules allows the preoperative diagnosis of medullary thyroid carcinoma with better accuracy than is seen with FNAC^48–51 (Table 18-4). A large retrospective study involving more than 10,000 patients seen at a single institution has recently confirmed that on calcitonin screening, the incidence of medullary thyroid carcinoma (MTC) is 1 in 250 unselected thyroid nodules—higher than was previously believed. In addition, the study demonstrated that such screening offers the possibility of finding MTCs before they have metastasized, thus increasing the chance for definitive cure. Comparison with an historical group of patients with MTC diagnosed before the screening showed a significantly better long-term outcome for MTC detected by calcitonin screening.⁵² According to these authors, measurement of serum calcitonin should be included in the diagnostic evaluation of thyroid nodules at the first visit of the patient; this has been incorporated into the European Thyroid Association guidelines,⁵³ but not the American Thyroid Association guidelines.^54a Cost-effectiveness, one of the major issues in screening for thyroid nodules, has been calculated recently, and the result favored calcitonin screening.⁵⁵ Calcitonin assay is, of course, mandatory in the presence of a suggestive family history or coincident features of the MEN2 syndromes.

Routine measurement of serum calcium is advocated by several centers. The aim is not directly related to the diagnosis of thyroid nodules, but rather to detection of undiagnosed parathyroid adenomas.

Imaging

Diagnostic Protocol

A possible practical diagnostic approach to patients with thyroid nodules is schematically represented in Fig. 18-5.

Serum thyroid hormone and TSH measurement and thyroid ultrasound are performed as first-line exploration. Determination of antithyroid antibodies is calcitonin are also helpful.

If TSH is suppressed or low, a thyroid scan is performed to confirm the presence of an autonomously functioning nodule; the subsequent approach will depend on the presence of clinical or subclinical thyrotoxicosis and on the size of the nodule. If the nodule is cold and cystic, FNAC will be performed both as a therapeutic technique (evacuation) and as a diagnostic tool to detect the small percentage of cystic adenocarcinomas. If the nodule is cold and totally or partially solid, the therapeutic decision will depend on the results of FNAC.

Surgical Therapy

We favor selecting the malignant nodules for surgery, and we suggest medical therapy or follow-up for the others. However, surgical treatment should also be suggested for some benign lesions, either single or associated with multinodular goiter, when they are large enough to produce symptoms and signs of discomfort or aesthetic concern. Another surgical indication is for questionable nodules, including those characterized by follicular proliferation on FNAC.

If surgery is selected, we believe that it is crucial to work in conjunction with a surgeon who has frequent and continuous experience in thyroid surgery to obtain good results. This is not to say that resection of a thyroid lobe for a nodule is a difficult procedure; however, if more extensive surgery is required, and especially if total or near-total thyroidectomy and lymph node resection are indicated, it is imperative that the surgeon have the proper knowledge and experience to reduce the possibility of damage to recurrent laryngeal nerves and parathyroid glands.

Medical Therapy

Papillary Thyroid Carcinoma: Classic Type

According to their size and extension, papillary carcinomas may be classified as microcarcinomas, carcinomas limited to the thyroid gland, and carcinomas extending outside the thyroid.

Microcarcinomas are tumors smaller than 1 cm in diameter; they are also called “occult.” They may have the features of a classic small papillary carcinoma, or they may appear as unencapsulated sclerotic nodules of a few millimeters, infiltrating the surrounding thyroid. Microcarcinomas are found in 5% to 35% at autopsy, depending on the geographic area and the method used,^5,124 but they are very rare in childhood. As a result of general improvements in diagnostic techniques, the number of microcarcinomas selected for surgery is increasing. Their prognosis is very good.^125,126

Larger, clinically detectable tumors represent nearly 70% of all papillary cancers. They appear as firm nonencapsulated or partly encapsulated tumors.^123,127 A few papillary cancers may be partly necrotic or cystic. Papillary cancer is often multicentric in one lobe and bilateral, with a frequency varying between 20% and 80% in different series.^128–130

Microscopically, papillary carcinomas contain papillary areas with a focal distribution or with a diffuse pattern. The papillae consist of a stromal-vascular axis lined by characteristic cells. The presence of true papillae is a peculiar feature of papillary thyroid cancer, and these papillae must be differentiated from the pseudopapillae and the macropapillae seen in Graves’ disease, in benign nodules, or in goiter with hypothyroidism.

Other aspects may be associated with the papillae. Follicles filled with colloid or a trabecular or lobular aspect, squamous metaplasia, and psammoma bodies are other distinguishing features present in 40% to 50% of tumors. Also typical of papillary lesions are areas of sclerosis found in the central portion of the tumor or at the periphery.

Nuclei are characteristic. They are larger than those found in normal follicular cells when superimposed on one another, are pale and transparent at the center, and contain hypodense chromatin and prominent nuclear membranes. The shape is irregular and may be “fissured” like “coffee grains.” Large, circular, well-delimited intranuclear inclusions, an expression of cytoplasmic invagination, are present.¹³¹ In the absence of other features of the tumor, the diagnosis of papillary cancer is based on typical features of the nuclei.¹²³

Scattered lymphocytes are often found at the invasive periphery of the tumor. More rarely, a true lymphocyte infiltrate resembling chronic lymphocytic thyroiditis is seen within the tumor; this is associated with a favorable prognosis.¹³²

Commonly and early in the disease, papillary carcinoma invades lymphatic vessels. Invasion progresses from the perithyroid chains to more distant chains. Nodes along the recurrent nerve most often are involved. Lymphatic spread within the thyroid is probably the reason for the high frequency of multifocality of the tumor.^128,129 Venous invasion and distant metastases (most often to the lung and bone) are rare and account for 5% to 7% of cases.¹³³

Variants of Papillary Thyroid Carcinoma

The more frequent variant of papillary thyroid cancer is the follicular variant. It is grossly encapsulated^134,135 and shows a diffuse pattern of follicular growth with colloid-containing follicles. The papillary nature of this tumor can be recognized by the findings of clear nuclei, psammoma bodies, desmoplastic reaction, and lymphocytic infiltration. Lung metastases are common and respond well to conventional treatment. The prognosis is similar to that of the classic variants. They often are found in young subjects, and 21% of the post-Chernobyl childhood thyroid cancers in Belarus were classified as follicular variants.¹³⁶

The rare diffuse sclerosing variant is found most often in children and young adults.¹³⁷ Its characteristics are those of diffuse thyroid enlargement as seen in goiter, but with both lobes replaced by a very firm and calcified tumor. At microscopy, this form is almost always multicentric. Tumor papillae are associated with squamous metaplasia without keratinization and abundant psammoma bodies. Extensive lymphocytic infiltration of the gland is often found, and lymph node metastases are present in 100% of cases. Also, distant metastases are common. The prognosis is less favorable than for classic papillary cancer, although the response to treatment may be excellent.

In the tall cell variant¹³⁸ and the columnar cell variant,¹³⁹ the tumor is usually large and extends outside the thyroid gland. These tumors have a papillary pattern, and the cells are tall and have a granular, eosinophilic cytoplasm. Vascular invasion is commonly seen, and the tumors are typical of older patients. A poor prognosis has been reported with this variant.

The encapsulated variant is characterized by a capsule similar to an adenoma but focally invaded. Microscopically, the typical cytologic and nuclear features of papillary tumor and psammoma bodies are found. This variant represents 8% to 13% of cases.¹⁴⁰

In subjects affected by polyposis coli, papillary thyroid cancer has typical features: common multifocality with classic papillary aspects associated with solid areas and elongated cells.

Follicular Thyroid Carcinoma

At variance with the papillary histotype, follicular carcinoma usually is seen as a solitary, more or less encapsulated nodule in the thyroid. Depending on the degree of invasiveness, the tumor is classified as minimally invasive (encapsulated) or widely invasive.¹²³ The distinction has great prognostic impact because the prognosis is more severe when more extensive vascular invasion is present.¹⁴¹

Minimally invasive carcinomas represent more than 50% of cases. The diagnosis of malignancy is based totally on the demonstration of unequivocal vascular invasion and/or invasion of the full thickness of the capsule. Examination of multiple blocks, including the periphery of the nodule, is often necessary to exclude or confirm the presence of invasion. Cytologically, they cannot be distinguished from benign adenomas. Thus, FNAC is of no help in the differential diagnosis between benign and malignant lesions. Frozen section can lead to misdiagnosis and is not recommended by some experts in the field.

Widely invasive tumors present few diagnostic problems. They show widespread infiltration of blood vessels and surrounding thyroid tissue. The capsule, when present, is infiltrated in several areas and is grossly disrupted.

In minimally and widely invasive follicular carcinoma, the morphology is variable and ranges from well differentiated with well-formed follicles full of colloid to poorly differentiated with a solid, cellular growth pattern.

Follicular cancer invades blood vessels but rarely invades lymphatics. Metastases are spread hematogenously to the lungs, bones, and, less commonly, the brain and liver.¹³³ Metastases are very common with the widely invasive variant, less common with the minimally invasive variant.

Variants of Follicular Carcinoma

Clear cell tumor is a rare variant, with architectural and clinical features similar to those of the usual follicular carcinomas. The cells are clear because of the formation of intracytoplasmic vesicles, glycogen or fat accumulation, or intracellular Tg deposition. These tumors must be distinguished from clear cell adenoma, from parathyroid adenoma or carcinoma, and particularly from metastatic clear cell renal carcinoma.

The oxyphilic cell type (or Hürthle cell type) is composed of cells derived from the follicular epithelium and characterized by large size with abundant granular, eosinophilic cytoplasm; large nuclei; and prominent nucleoli. The granular appearance of the cytoplasm is conferred by the large number of mitochondria inside the cell. Hürthle cell tumors can also be of papillary lineage, as shown by the presence of RET/PTC mutations.

Because Hürthle cells can be found in papillary carcinomas and in a number of benign conditions (e.g., nodular goiter, hyperthyroidism, Hashimoto’s thyroiditis, benign nodules), the same criteria for malignancy mentioned for follicular tumors (i.e., invasion) apply to oxyphilic cell tumors. As with follicular carcinoma, macroscopically the oxyphilic variant is seen as a solitary thyroid nodule with complete or partial encapsulation. In several series, the prognosis for this variant has been reported as less favorable than for the follicular cell type.¹⁴²

Insular carcinoma is also a rare variant.¹⁴³ It is a poorly differentiated, invasive follicular cancer with a solid aspect and follicular differentiation represented by small vesicles with very little colloid. The cells are very homogeneous in shape and smaller and more dense than in typical follicular cancer. The general picture may resemble that of carcinoid tumors. Metastases, very common, are found in lymph nodes and in distant organs. The prognosis is poor.

Other Tumors

Anaplastic cancer originates from the follicular epithelium, but its high degree of undifferentiation does not allow the recognition of any feature of the thyroid gland. It represents 5% to 15% of all thyroid cancers and is one of the most aggressive human cancers. Local extension at diagnosis and distant metastases are almost the rule.

Medullary tumors derive from the calcitonin-secreting parafollicular C cells of the thyroid. They occur as solid masses of spindle or rounded cells with large nuclei, much fibrosis, and deposits of amyloid. In the familial syndromes MEN2A and MEN2B, C cell hyperplasia precedes the cancer and typically is present in the gland. Immunochemical staining for calcitonin is useful for differentiating medullary thyroid tumors from other histologic types, especially when the origin of metastatic adenocarcinoma is being considered.

Other rare tumors include primary thyroid lymphoma or tumor arising from other cell types.

Oncogenes

The most interesting new concept in tumor causes relates to the role played by oncogenes and tumor suppressor genes. Recent advances in molecular biology have resulted in significant improvement in our understanding of the pathogenesis of thyroid carcinoma.¹⁴⁴ Gene rearrangements involving the RET and TRK proto-oncogenes have been demonstrated as causative events specific for a subset of the papillary histotype. Oncogenic activation of these genes is accomplished by fusion of their tyrosine kinase domain with the N-terminal promoter sequences of other genes in the same or other chromosomes. TRK oncogenes are created by rearrangement of the NTK1 gene, which encodes a receptor for nerve growth factor and is linked to at least three different activating genes.¹⁴² In the case of RET rearrangements, the resulting chimeric oncogenes have been called PTC, an acronym for papillary thyroid carcinoma.^145,146 Several chimeric forms have been identified, the most common being RET/PTC 1, 2, and 3. Although strictly associated with papillary thyroid carcinoma, RET/PTC is found in less than half of cases unassociated with irradiation.^146–149 In papillary thyroid carcinomas occurring after irradiation, the frequency of RET/PTC activation is between 60% and 80%, either in Belarus children heavily exposed to radiation after the Chernobyl nuclear disaster^150–153 or in patients who received external radiation treatment during childhood.¹⁵⁴ Worthy of note, these radiation-induced tumors are often of the solid variant of papillary cancer, and the oncogene involved is mainly RET/PTC 3, particularly in the youngest subjects. In spontaneous tumors or in classic papillary variants of radiation-induced cancers, RET/PTC 1 is the predominant rearrangement.¹⁵⁵ Based on this finding, one can speculate that RET/PTC 3 is linked specifically to radiation and to solid papillary tumors arising in young patients (most Belarus cancers were diagnosed in children) with or without the cooperation of radiation. This second hypothesis is supported by data showing a significant correlation between high rates of RET/PTC activation and lower age at diagnosis in Italian patients not exposed to radiation.¹⁵⁶

Recently, another oncogene, BRAF, has been associated specifically with PTC with a frequency even higher (around 40%) than that of RET/PTC rearrangements.¹⁵⁷ Apparently, the activation of BRAF and RET/PTC does not occur in the same tumor. Mutated forms of the H-ras, K-ras, and N-ras oncogenes are found in differentiated thyroid cancer; however, in this case, the mutations are not restricted specifically to malignant lesions, because the same mutations have been found in benign thyroid nodules.¹⁵⁸ It is conceivable that mutations of the ras gene family may represent early events in thyroid tumorigenesis. Activating mutations of the genes encoding the thyrotropin receptor and the α subunit of the G_s protein, similar to those found in toxic adenomas and probably of irrelevant pathogenic importance, have been reported in a few hyperfunctioning follicular carcinomas.¹⁵⁹ Inactivating mutations of the p53 tumor suppressor gene are rare in patients with differentiated thyroid carcinoma but common in those with undifferentiated thyroid carcinoma.^150,160

Expression of C-myc and C-fos is stimulated in normal thyroid tissue by TSH and occurs in adenomas and carcinomas,¹⁶¹ perhaps as a consequence of the neoplastic phenotype. The tumor suppressor gene at the 11q13 locus is lost in some follicular adenomas and carcinomas.¹⁶² Farid and coworkers found that the RB tumor suppressor gene is also mutated or deleted in a high proportion of thyroid tumors.¹⁶³

As far as follicular neoplasms are concerned, a specific oncogene originating by mutation of a gene with tumor suppressor function, PAX8/PPARγ, has been associated with the malignant phenotype with high frequency.¹⁶⁴ Recently activating mutations of the epidermal growth factor receptor (EGFR) gene have been identified in a subset of patients with papillary thyroid cancer. This observation suggests that EGFR-tyrosine-kinase inhibitors may be used in the treatment of a subset of patients with PTC.¹⁶⁵

Based on the gene defects discovered in the different types of thyroid carcinoma, a hypothetical model of the sequential changes involved in tumorigenesis of follicular thyroid cells is offered in Fig. 18-6.

Regarding differentiated thyroid cancer, it is known that cancer tissues often lose their ability to concentrate and to organify iodide; this is why neoplastic tissue often is cold on scintiscan. At the molecular level, a possible explanation for this finding comes from experiments that suggest that the NIS gene (coding for a basolateral membrane protein that actively transports the iodide into the thyroid follicular cells) is less expressed in tumor than in normal thyroid tissue.¹⁶⁶ It is agreed that NIS protein expression correlates with radioactive iodine (¹³¹I) uptaking activity, suggesting that NIS protein levels may predict the therapeutic efficacy of radioiodide therapy for thyroid cancer. However, to be effective, the NIS protein must maintain its physiologic polarization on the plasma membrane. In a recent study, loss of polarization with cytoplasmic localization of NIS has been reported in tumor tissues lacking radioiodine uptake. Posttranscriptional events may cause this defect in membrane targeting localization of the NIS protein. Such alterations might explain reduced iodide uptake in cases of thyroid cancer with normal NIS mRNA expression levels.

Ionizing Radiation

External irradiation of the neck during childhood increases the risk for papillary thyroid carcinoma.^{34,45,167–170} The latency period between exposure and diagnosis is usually 5 years, is maximal at about 20 years, remains high for about 20 years, and then decreases gradually. A linear dose response relationship is found between external irradiation and thyroid cancer, starting with radiation doses as low as 10 cGy and up to 1500 cGy. Beyond this point, the risk for thyroid cancer decreases, probably because of thyroid cell killing. A major risk factor is young age at the time of irradiation; after the age of 15 or 20 years, the risk is much reduced. In children exposed to a dose of 1 Gy (100 rad) to the thyroid, excess risk for thyroid cancer is 7.7-fold.¹⁶⁷

Diagnostic or therapeutic administration of ¹³¹I to adults does not seem to be associated with an increased risk for thyroid cancer.168–170 However, the increased incidence of papillary thyroid cancer in children in the Marshall Islands after atomic bomb testing and, more recently, in Belarus and Ukraine after the Chernobyl nuclear reactor accident^35,171–174 indicates a direct carcinogenic effect of radioactive isotopes, both ¹³¹I and/or short-lived isotopes, on the thyroid gland. At variance with the cancers observed after external irradiation, the post-Chernobyl cancers diagnosed in Belarus and Ukrainian children and young adults (Table 18-6) developed after a very short mean latency period (6.5 years on average) from exposure to diagnosis.¹⁷¹ Whether these discrepancies are caused by different radiation doses to the thyroid; by the very young age of the patients, when the growing thyroid is particularly sensitive to radiation; or by a combination of these and other environmental factors(iodine deficiency) is still a matter of discussion.

Other Factors

In countries where iodine intake is adequate, differentiated thyroid cancers account for more than 80% of all thyroid carcinomas, with the papillary histotype being the more common form (60% to 80%). In areas with nutritional iodine deficiency, a relative increase in follicular and anaplastic cancer with respect to papillary tumors is the rule, but no definitive demonstration of an increased prevalence of thyroid cancer has been made in such countries.^168,170 Chronic stimulation by slightly elevated TSH levels may be the underlying mechanism for thyroid hyperplasia and, possibly, carcinomatous degeneration in iodine-deficient countries. In thyroid hyperplasia in humans, whether induced by congenital metabolic defects or by other causes, the resultant elevation in TSH levels can lead to carcinomatous degeneration if the hypothyroidism is unrecognized and remains untreated for decades.¹⁷⁵

Abnormalities in TSH receptors have been sought in tumor cells. It appears that differentiated tumors have normal receptors, presumably explaining their TSH-dependent growth, whereas anaplastic cancers lack high-affinity receptors and thus respond poorly to TSH.¹⁷⁶ The thyroid-stimulating immunoglobulins present in the sera of patients who have coincident autoimmune thyroid disease may cause tumor growth, and they occasionally appear to make tumors behave more aggressively, but usually concurrence of Graves’ disease does not worsen the prognosis.³³ Although no evidence indicates that thyroid-stimulating immunoglobulins cause malignancy, it is of interest that up to 6% of thyroid glands removed because of Graves’ disease harbor a carcinoma.^38,177 It has been reported that positive associations exist between Hashimoto’s thyroiditis (or multinodular goiter) and thyroid cancer.

Genetic factors influencing the development of thyroid cancer have been reported, including chromosome instability in patients with medullary thyroid carcinoma.¹⁷⁸ An increased incidence of HLA-DR1 in differentiated thyroid carcinoma was reported by one group¹⁷⁹ but was not found by others.¹⁸⁰ We recently detected an association of HLA-DR7 with differentiated follicular thyroid cancer in patients without a previous history of head and neck irradiation, but not in those with radiation-associated thyroid cancer.¹⁸¹

Thyroid carcinomas are present in several familial syndromes, including Cowden’s disease (hamartomas, multinodular goiters, and thyroid, breast, colon, and lung cancer),¹⁸² familial adenomatous polyposis,^183,184 Gardner’s syndrome,¹⁸⁵ and familial chemodectomas.¹⁸⁶ The incidence of thyroid cancer is estimated to be increased 100-fold above baseline in patients with intestinal polyposis.^183,184 However, familial differentiated thyroid cancer in the context of these syndromes is very rare. A large majority of familial cancers (almost always papillary) occur as isolated, nonsyndromic, papillary thyroid cancer, in which no candidate predisposing oncogene has been detected. This form of familial cancer has been reported in 3% to 10% of patients in different series.^33,187 Recently, an epidemiologic study demonstrated that these pedigrees exhibit the phenomenon of “genetic anticipation,” consisting of the appearance of thyroid carcinoma at an earlier age with increased aggressiveness in the second and subsequent generations.³² In the same families, a germline alteration has been demonstrated, consisting of short telomeres and increased telomerase activity, leading to genomic instability and possibly predisposing to the risk for thyroid carcinoma.¹⁸⁸

Age and Sex

In the papillary and follicular histotypes, the risk for recurrence and cancer-related death increases linearly with age at diagnosis.^{42,125,127,209–216} In older patients, clinical relapse occurs more rapidly after initial treatment, and the interval between detection of recurrence and death is shorter.²¹¹ Older patients tend to have more locally aggressive tumors and a higher incidence of distant metastases at diagnosis and more aggressive histologic variants. Their metastases often lack ¹³¹I uptake. On the other hand, children and adolescents have an excellent long-term prognosis and a very low mortality rate, even when affected by metastatic disease.^{196,217–219} Male sex has been reported as an independent risk factor in some series^{42,211,215,220} but not in others. Its importance as a prognostic factor is always less than that of age.

Associated Autoimmune Phenomena

With the exception of one report,⁴⁰ no major differences have been found in several series of patients with differentiated thyroid cancer with or without Graves’ disease with regard to clinical features and response to therapy^{37,39,41,177,221–223} or tumor-related mortality.²²⁴ On the contrary, the association of Hashimoto’s thyroiditis²²⁵ or lymphocytic infiltration¹³² with papillary thyroid cancer seems to confer a better prognosis. In a series from Italy,²²⁶ circulating thyroid autoantibodies were found in 23% of patients with differentiated thyroid cancer. No difference in final outcome was found between antibody-positive and antibody-negative patients. The disappearance of circulating antibodies was correlated with effective treatment of the disease, whereas their persistence was associated with stable or progressive disease (Fig. 18-9), suggesting that complete removal of thyroid autoantigens after effective treatment is followed by disappearance of the corresponding autoantibodies.²²⁷

Histopathologic Factors

A poor prognosis has been reported with the tall cell variant,^138,228 the columnar cell variant,²²⁹ and the oxyphilic variant^230,231 of papillary thyroid cancer. A good prognosis is found with the encapsulated^140,232,233 and follicular variants.^127,134,139 An intermediate prognosis has been reported for the diffuse sclerosing variant.^137,234

Widely invasive follicular cancers have a less favorable prognosis than do minimally invasive tumors. Other follicular variants (e.g., the Hürthle cell, insular, and trabecular variants) are often associated with a poor prognosis.^211,235,236

Tumor Grade and DNA Ploidy

Tumor grade was a significant prognostic factor both by univariate analysis and by multivariate analysis in papillary thyroid carcinoma studied at the Mayo Clinic²²⁵ and in three European series.^210,237,238

In the report by Joensuu and colleagues, DNA aneuploidy was an adverse factor in univariate analysis but was not an independent prognostic factor.²³⁹ In the Mayo Clinic series, abnormal DNA content was associated with higher cancer mortality in high-risk tumors.⁴²

Size of the Primary Tumor and Multicentricity

Microcarcinomas (or minimal or occult) have an excellent prognosis in terms of survival and relapse-free survival, whatever the extent of the primary surgical treatment. Several series have reported a progressive increase in risk for recurrence and tumor-specific mortality with increasing size of the primary tumor.* Tumor size seems to be more predictive in papillary than in follicular tumors.

Multicentricity, whether an expression of intrathyroidal metastases or of multiple primary tumoral foci,²³² has been associated with significantly higher rates of lymph node metastasis,^232,242,243 locally persistent disease and distant metastases,²³² and 30-year mortality.²⁴⁰

Extrathyroidal Invasion

Extrathyroidal invasion is present in 5% to 10% of papillary tumors and in 3% to 5% of follicular tumors; it exposes the patient to higher rates of local recurrence and distant metastases, as well as to a higher percentage of tumor-related death.^† Invasion limited to the thyroid capsule, without infiltration of soft tissues, carries the same adverse prognosis that is seen with overt extrathyroidal invasion.²²¹

Lymph Node Metastases

Lymph node metastases are present in 37% to 65% in different series of papillary carcinoma^‡ and much less often (nearly 17%) in the follicular histotype.²⁴⁸ Local node involvement is found with microcarcinomas and with large tumors and may be bilateral in cases of bilateral tumor. Some authors have shown that regional lymph node metastases are associated with higher rates of tumor recurrence and cancer-specific mortality,* whereas others have found that cumulative survival is not significantly affected.^{42,133,229,252} In the series of Ohio State University,²⁴⁰ the presence of lymph node metastases was an important independent prognostic factor that predicted cancer death. Bilateral cervical and mediastinal nodes were particularly likely to be associated with cancer death. In the series of the Department of Endocrinology in Pisa, of 304 patients with lymph node metastases, 253 (83.2%) were cured after surgery and ¹³¹I therapy, 37 (12.1%) had persistent progressive disease, and 14 (4.6%) died of their disease during a mean follow-up period of 12 years. Taken together, these data indicate that lymph node metastases are a potential cause of death and underscore the importance of early and thorough treatment.

Distant Metastases

Distant metastases at diagnosis confer the poorest prognosis in patients with papillary, follicular, or medullary thyroid carcinoma. Tumor-specific mortality of patients with distant metastases ranges from 36% to 47% at 5 years and reaches approximately 70% at 15 years.^{42,236,253–255} Univariate analysis has shown the following factors to be associated with better prognosis in the case of distant metastases: young age, well-differentiated histotype, localization in the lung rather than in bone, small size, and the presence of ¹³¹I uptake. However, multivariate analysis has shown that the extent of metastatic involvement rather than the site (lung or bone) has prognostic value.^236,256,257 The best outcome is found with micronodular metastases visible with radioiodine whole body scanning (WBS) but not visible with standard radiographs.^{133,196,236,253,256–259}

Oncogenes, Antioncogenes, and Oncogene-Encoded Proteins

The presence of gene alterations or of oncogene-encoded proteins has been correlated with prognosis. Loss of expression of thyroid-specific differentiation genes (e.g., the TSH receptor, Tg, and TPO genes) is associated with poor outcomes of poorly differentiated or undifferentiated tumors.²⁶⁰ Somatic mutations of the p53 oncogene or hyperexpression of its encoded protein is found exclusively in poorly differentiated and anaplastic tumors.^160,261 Point mutations of the ras gene and overexpression of p21 protein have been found in papillary thyroid carcinoma and have been correlated with poor survival rates.²⁶² Likewise, c-myc expression has been correlated with more aggressive thyroid carcinomas.²⁶³

In a retrospective study comparing patients with papillary thyroid cancer with or without RET/PTC rearrangements, no difference was noted in their outcomes.²⁶⁴ On the contrary, point mutations of BRAF have been associated with an adverse prognosis and more aggressive behavior, including frequent loss of iodine uptake.²⁰⁸ Somatic RET proto-oncogene mutations, found in 50% of cases of sporadic medullary thyroid carcinoma, have been associated with metastatic progression and worse outcomes than those of tumors not carrying the mutation.^265,266

The above findings represent only the beginning of a new way to look into tumor biology and indicate that exploration of oncogenes and oncogene products may yield new insights with regard to the prognosis for thyroid tumors.

Extent of Primary Surgery

Total (or near-total) thyroidectomy is associated with fewer cancer recurrences and tumor-related deaths.267–270 In the Mayo Clinic series, the extent of surgery significantly affected the risk for local recurrence.¹²⁵ Data from the University of Chicago revealed that when compared with lobectomy or bilateral subtotal resection, near-total thyroidectomy decreased the risk for death in papillary tumors larger than 1 cm and decreased the risk for recurrence among all patients.¹⁹³ A much higher frequency of recurrent cancer in the form of lung metastasis has been reported with subtotal thyroidectomy.²⁷¹ In another series, patients with tumors 1.5 cm or larger, multicentric tumors, local invasion, or cervical metastases had significantly fewer recurrences after total (11.3%) than after subtotal (22.0%) thyroidectomy.²⁷² Similar results have been observed in the series of the Institute of Endocrinology in Pisa.

¹³¹I Ablation of Thyroid Residue

Postsurgical radioiodine ablation of the thyroid residue may destroy microscopic neoplastic foci and may reduce the risk for relapse. Whereas some authors have found no significant effect of ¹³¹I ablation on the rate of recurrence or tumor-related death,^42,210 others have shown beneficial effects in terms of both recurrence and long-term survival,^193,235 at least in patients with tumors larger than 1.5 cm. However, no randomized study is available, and retrospective studies suffer from the comparison of groups of patients (ablated vs. not ablated) not always accurately matched with regard to other important clinicopathologic factors. Ablation increases the sensitivity of subsequent ¹³¹I WBS and the specificity of serum Tg determination, and it provides reassurance to the patient when these tests are negative on subsequent examination.

Serum Thyroglobulin Measurement

Serum Tg measured after initial treatment gives valuable predictive information on subsequent disease evolution. After surgical treatment has been provided, and when ¹³¹I imaging is negative, the finding of undetectable serum Tg in the absence of thyroid hormone administration is an excellent indicator of definitive cure.273–275 On the contrary, persistence of elevated serum Tg concentrations requires extensive clinical evaluation, including WBS after the administration of therapeutic doses of ¹³¹I and imaging studies, to detect the site of Tg production and to plan the most appropriate treatment.^236,276

Prognostic Scoring Systems

Prognostic scoring systems based on multiple regression analysis of prognostic factors are intended to distinguish between low-risk patients to be treated with less aggressive protocols and high-risk patients to be treated with the most aggressive therapy.

Several scoring systems are available (Table 18-9). The EORTC (European Organization for the Research and Treatment of Cancer) system considers age at diagnosis, sex, principal histotype, extrathyroidal invasion, and distant metastases.^277,278 The Institut Gustave-Roussy system is based on age at diagnosis and histotype.²¹¹ The TNM system (by the International Union Against Cancer) is based on the extent of the primary tumor (T), lymph node status (N), the presence of distant metastases (M), and, since the last version, age (younger or older than 45 years) and capsule (encapsulated or nonencapsulated).^279,280 AMES, an acronym for age, distant metastases, and extent and size of the primary tumor,²⁸¹ was subsequently modified to DAMES by adding DNA ploidy.²⁸² AGES includes age, grade (by Broders’ classification), tumor extent (local invasion and distant metastases), and size of the primary tumor.⁴² In 1993, AGES was revised to MACIS, which includes distant metastases, age, completeness of surgery, invasion of extrathyroidal tissues, and size.²²⁴ The Ohio State University system considers tumor size, the presence or absence of cervical metastases, multiple tumors, local tumor invasion, and distant metastases.²⁴⁰ Clinical Class, a very simple and effective staging system developed at the University of Chicago,¹⁹³ consists of four classes that depend on the extent of tumor tissue: Class I includes patients with single or multiple intrathyroidal foci; class II patients have lymph node metastases; in class III are patients whose tumors (or unresectable lymph nodes) have invaded outside the thyroid gland; and class IV patients have distant metastases. This classification is primarily anatomic but correlates well with prognosis.

Class I Differentiated (Papillary and Follicular) Carcinoma

The minimal surgical procedure for thyroid carcinoma should be total (or near-total) thyroidectomy, whenever the diagnosis has been made before surgery at FNAC. Less extended procedures (lobectomy and subtotal thyroidectomy) may be considered in cases of papillary thyroid cancer discovered accidentally at final histology after surgery for benign disorders, provided that the tumor was small (<1 to 1.5 cm), unifocal, and intrathyroidal, and had favorable histology. The value of total or near-total thyroidectomy for low-risk patients has been confirmed by the results of second “completion” thyroidectomy performed in the centers of the two authors of this chapter. The percentage of patients with detectable tumor in the reoperative specimens was 31% at the University of Chicago¹⁰³ and 44% at the University of Pisa.¹³⁰ In the last series, no difference in the rate of second tumors was found between patients defined as low risk or high risk at the time of the first operation (Fig. 18-10). In any surgical procedure, recurrent laryngeal nerves and parathyroid glands should be identified carefully, and portions of the thyroid (especially the posterior capsule on the contralateral side) may be left behind, if necessary, to prevent damage.

In lesions that are found to be multicentric on the basis of observations by the surgeon or the pathologist, greater effort is made to perform total thyroidectomy, as long as it can be done without compromise of the parathyroid glands. After surgery, residual thyroid tissue is ablated by ¹³¹I administration in most cases, especially in patients who have multicentric foci or a history of irradiation. All patients are given suppressive therapy with thyroid hormone.

Our own experience¹⁹³ and long-term follow-up of 576 cases of papillary thyroid cancer by Mazzaferri and Young^268,285 appear to support this approach. Patients with near-total thyroidectomy and postoperative ablation had a significantly improved prognosis, especially when follow-up extended over 10 to 15 years. Massin and coworkers found that “complete thyroidectomy” and ¹³¹I ablation gave the lowest incidence of late metastatic recurrence,²⁷¹ as did Samaan and colleagues,¹²⁶ who found that ¹³¹I treatment was the most important influence on recurrence and survival.

Most series reporting on the results of total or near-total thyroidectomy indicate that hypoparathyroidism occurs in 1% to 15% of patients, and recurrent unilateral nerve damage occurs in 2% to 5%, but fortunately, bilateral nerve injury is rare.²⁸⁷ It is because of these complications and the apparently satisfactory results attained with lobectomy that some investigators prefer the simpler procedure. On the other hand, 20% to 80% of stage I thyroid cancers are multicentric.^128,288 It is clear that not all these foci are of clinical importance, but the recurrence rate of cancer in the contralateral lobe after unilateral lobectomy is at least 6%, and some patients with recurrence eventually die of their lesion.^271,289,290 Because of known multicentricity, the ability of our collaborating surgeons to avoid hypoparathyroidism, and the associated improved prognosis,¹⁹³ we prefer the more extensive resection. Surgeons who are especially skilled in performing thyroidectomies can hold the incidence of hypoparathyroidism to about 1% and have an equally low incidence of recurrent nerve damage.

In past years, more radical procedures, including prophylactic radical neck dissection, were advocated for thyroid carcinomas. Forty-six percent of patients with presumed stage I disease were found, in fact, to have lymph node involvement when specimens were studied thoroughly after prophylactic neck dissection.²⁹¹ Apparently, however, these lymph node metastases, when not clinically detectable, in some way are controlled by the body’s defense mechanisms and rarely lead to death of the patient. Thus, recent opinion is controversial regarding prophylactic central node dissection but is definitively in agreement against radical or en bloc neck dissection.

Because follicular lesions tend to be more directly invasive and lethal than papillary lesions,¹⁴¹ many surgeons pursue a more aggressive operative approach with stage I follicular cancer than with papillary cancer and perform routine near-total thyroidectomy in patients with the former lesion.²⁹² Postoperative ¹³¹I thyroid ablation and continuous thyroid hormone administration are considered essential.²⁹³

Up to 20% of low-grade follicular neoplasms are misdiagnosed on operative frozen section as benign, with the diagnosis achieved 1 to 3 days later after review of permanent sections. If the lesion is smaller than 1 cm, unicentric, and intrathyroidal, and the patient is younger than 45 years, no further surgery is required, and, as indicated before, some physicians accept lobectomy as a definitive procedure. In general, in patients with lesions larger than 1 cm who are older than 45 years or with multifocality, we prefer reoperation to achieve near-total thyroidectomy, along with subsequent ¹³¹I therapy. As was already mentioned, in an analysis of patients who have undergone a second operation, we found that in 31% of operations at the University of Chicago¹⁰³ and in 44% of those performed at the University of Pisa,¹³⁰ residual cancer was recovered on the remaining lobe.⁶⁷ This problem is best avoided by performing at least a lobectomy plus contralateral subtotal thyroidectomy if any question about the benignity of the “adenoma” is still unanswered at the time of surgery.

The use of radioactive iodide, as described above, can be questioned, because the ablative dosage exposes these patients, who often are young, to 10 to 15 rad of whole body radiation. Although the genetic and carcinogenic risks of this radiation dosage cannot be ignored completely, they are minimally different from the average background whole body radiation exposure that individuals normally receive by age 30 years, and most likely do not represent a significant hazard. In addition, the recent introduction of thyroid ablation aided by a recombinant human TSH (rhTSH) preparation may result in lower radiation doses to the whole body, thereby preserving the quality of life.^294,295

Class II Differentiated Carcinoma

Less disagreement surrounds the management of class II disease. The usual procedure is a near-total or total thyroidectomy.^271,296 Small portions of the gland may be left in situ (for later radioiodide ablation), if necessary, to preserve recurrent laryngeal nerves or viability of the parathyroid glands. A modified neck dissection is performed to remove involved nodes. An attempt is made to retain the jugular vein and sternocleidomastoid muscles, and an en bloc resection is not attempted, except occasionally in patients with metastatic follicular cancer. If both sides of the neck are involved, resections usually are staged, because otherwise the incidence of tracheal edema requiring tracheotomy is significant. Radical neck dissection with removal of the jugular vein and sternocleidomastoid muscle is not favored, because the disease usually can be managed by the less mutilating procedure, and uninvolved nodes that become apparent at a later date generally can be resected successfully. Patients are given ¹³¹I to ablate residual thyroid tissue after surgery and for treatment of functioning metastases found on scanning.

Class III Differentiated Carcinoma

Patients with class III disease should receive a near-total or total thyroidectomy, appropriate lymph node dissection, and resection of all possibly invading neoplasm. The tendency at present is to avoid mutilating surgery in patients younger than 45 years in an effort to resect all cancerous tissue, because less extensive surgery,¹³¹I treatment, and suppressive thyroid hormone therapy usually lead to prolonged survival or cure, even if complete excision of the tumor is impossible.^{297 131}I therapy is given as discussed in the following section. External irradiation may be useful in preventing recurrence.²⁹⁸ However, because most cases appear to be controlled by surgery and ¹³¹I, and because definitive experience with supplemental prophylactic irradiation is not always available, the usual course is to withhold irradiation until recurrence is seen in younger patients, but to advise prophylactic treatment in patients older than 45 to 50 years who have known residual disease after surgery and radioactive iodine (RAI) treatment.

Class IV Differentiated Disease

Patients with a thyroid mass and solitary metastasis to the lung or bone probably should have thyroidectomy and excision of the single metastasis, because cure or prolonged survival may be obtained. If multiple metastases are present, thyroidectomy is probably the quickest way to achieve hypothyroidism, so that uptake of radioactive iodide in the metastases and possible therapies can be evaluated.

Hürthle Cell Carcinoma

It is clear that Hürthle cell tumors range in invasiveness from zero to an aggressively locally invading lesion or a tumor with rapidly growing pulmonary metastases. These variations result in a wide range of opinion on therapy. We advocate treatment as described for follicular cancer, of which these are a subgroup. Postoperative ¹³¹I ablation is carried out, although its value may be restricted because many Hürthle cell tumors fail to accumulate ¹³¹I. Invasive tumors (class III) should be treated with mantle irradiation. ¹³¹I treatment is attempted for class III or IV tumors, but it usually is not possible despite the presence of functioning metastases as proved by elevated Tg levels.

Lymphoma

Staging should include neck, chest, and abdominal CT scans and bone marrow biopsy. If the disease appears to be limited to the thyroid gland and contiguous lymph nodes, thyroidectomy is advised, although occasionally only biopsy is possible. Patients with intrathyroidal lymphoma or disease limited to the neck and upper part of the mediastinum have been treated conventionally by mantle irradiation to about 45 Gy over a 3 to 4 week period.²⁹⁹ Because the overall survival rate at 5 years has been about 50%,^299–301 patients increasingly are being treated primarily by chemotherapy followed by radiotherapy. Patients with more extensive disease and those who relapse are given chemotherapy.

Undifferentiated Thyroid Carcinoma

Undifferentiated thyroid carcinoma is among the most aggressive malignant tumors in humans. Management of this type of cancer is cause for major concern because its poor prognosis is not ameliorated by surgery, chemotherapy, or radiotherapy. As soon as a diagnosis of undifferentiated thyroid cancer has been made, total thyroidectomy should be attempted. Unfortunately, infiltration of the soft tissues of the neck, almost invariably present at surgery, makes radical surgery impossible. External radiotherapy is used after surgery to control local disease, but this treatment is generally unsatisfactory.³⁰² Several chemotherapeutic protocols, including single (doxorubicin) and combination (doxorubicin plus cisplatin) drugs, have been totally disappointing.^303,304 The combination of radiotherapy and chemotherapy has been used with very modest advantage.^305–307 With any form of treatment, mean survival ranges between 3 and 12 months after diagnosis,^305–308 although individual survival exceeding 2 to 3 years has been reported.³⁰⁹

Because radical surgery, as mentioned earlier, is rarely feasible, a novel approach is to use hyperfractionated radiotherapy in combination with chemotherapy as initial treatment, with surgery left as a second step.³¹⁰ The idea is to control and reduce the primary tumor with medical therapy, thus giving the surgeon a better chance to perform a radical thyroidectomy. Further radiotherapy and chemotherapy may be added after surgery to stabilize the results of treatment. With this integrated therapeutic approach, complete local control has been obtained in 5 of 16 patients, and 3 patients survived longer than 20 months in one study.³¹¹ Other schemes based on the same combination of radiotherapy and chemotherapy have been used with similar results.^312,313

The discovery of point mutations of the p53 tumor suppressor gene specifically associated with undifferentiated thyroid carcinoma^160,314 has opened a new field of research aimed at the development of more effective treatment strategies at the molecular level. Recent studies using tyrosine kinase inhibitors are discussed in the following sections.

Diagnostic Procedures

Local and Regional Recurrences

After primary surgery, recurrences in the neck may develop in the thyroid bed and in surrounding soft tissues or in the regional lymph nodes. They carry an unfavorable prognosis, and most patients dying of differentiated thyroid cancer are included in this group.^252,358,359 The prognosis is better when recurrent cancer is diagnosed by ¹³¹I scintigraphy rather than clinically, and when the tumor is able to concentrate iodine.^133,358,360 Any clinically detectable local recurrence should be treated by surgery if possible, although radical reoperation involving central dissection is difficult and risks complications to the parathyroid glands and recurrent laryngeal nerve.

Recurrent disease in the lateral cervical nodes is easier to treat surgically because the operative field has not been dissected previously. The preferred surgical procedure is a modified radical neck dissection. When lymph nodes concentrate iodine, treatment with ¹³¹I is a partially effective adjunct to reoperation. Two or three therapeutic courses of ¹³¹I are effective in treating more than 60% of patients.¹³³ If nodal disease persists after ¹³¹I, reoperation with the use of an intraoperative isotope probe³⁶¹ may be considered.

Local recurrences that cannot be excised completely and that do not take up ¹³¹I can benefit from external radiotherapy.³⁶²

Treatment for Distant Metastases

Effective treatment for distant metastases depends largely on the size, location, and number of metastatic lesions, and their ability to take up radioiodine. Micronodular diffuse lung metastases and, to a lesser extent, small metastatic bone foci revealed by WBS in the absence of radiographic changes have the greatest chance of cure. This observation is particularly true in children, who often have a diffuse pattern of metastatic pulmonary spread and do exceptionally well with radioiodine therapy.^133,196,217 Macronodules in the lung and large bone metastases carry a poor prognosis. Loss of radioiodine uptake is also a prognostic indicator of poor outcome. Taken together, these findings emphasize the concept that early recognition and early treatment of distant metastases are of paramount importance to the final outcome.

Surgical Treatment

The decision to treat distant metastases by surgery depends on their location, spread, ability to concentrate radioiodine, and radiologic pattern.

Lung metastases are typically treatable by radioiodine therapy, with the choice of surgical therapy left to a minority of selected cases. Patients eligible for surgery are those with a single macronodular lesion or more than one in the same lobe, with or without mediastinal lymph node involvement, particularly when they are devoid of radioiodine uptake. Too few patients have undergone surgery for lung metastases to allow a statistical conclusion to be made on their outcomes. However, some appear to achieve long-term remission and, in less advanced cases (one single pulmonary nodule), even definitive cure.³⁶³

The surgical approach to bone metastases is gaining support because of their relative insensitivity to radioiodine therapy.^{323,344,363,364} The intent of bone surgery may be palliative or curative. Palliation is required for pathologic fractures or to ameliorate neurologic symptoms resulting from spinal cord compression by vertebral metastases. Curative surgery is possible in single, localized metastases. For large metastases not radically resectable, surgery may be of help in reducing tumor mass to allow more effective action of radioiodine therapy.

Brain metastases are extremely rare and range from 0.15% to 1.3% in different series364–368; they carry a very poor prognosis. Although brain metastases usually demonstrate ¹³¹I uptake, the therapy of choice, whenever feasible, is surgery, because of severe neurologic symptoms.

Radioiodine Treatment

The role and the indications for ¹³¹I therapy in the management of distant metastases from differentiated thyroid carcinoma are well established. Results are reproducible in large series of patients and indicate complete response in 35% to 45% of patients.^{133,318–321} Lung metastases, particularly when micronodular, respond better than do bone metastases. The poor prognosis of patients with bone metastases usually is linked to the bulkiness of the lesions and the presence of tumor cells that do not concentrate ¹³¹I.^323,360 In adult patients, the treatment dose is usually 100 to 200 mCi, repeated every 6 to 8 months. Lower doses (empirically 1 mCi/kg body weight) should be used in children with lung metastases, particularly of the diffuse type, to avoid the risk for radiation-induced pulmonary fibrosis.^217,369

An alternative method is to adjust the dosage of ¹³¹I to a maximally tolerable level based on dosimetric analysis of a tracer dose. With this method, doses of 200 to 500 mCi sometimes are given. Because it is cumbersome, expensive, and of unproven benefit, the protocol currently is used in only a few institutions.

In a review of 118 patients with distant metastases treated with ¹³¹I therapy,¹³³ 43 patients (36.4%) were cured (defined as negative WBS and undetectable serum Tg while not receiving levothyroxine), 28 (23.7%) died of their disease, and the others had persistent disease. Metastases from papillary tumors exhibited better response than did those from follicular tumors. The risk for dying was higher if lung metastases were macronodular and detectable by chest radiography, if bone metastases were multiple, and if both lung and bone metastases were present. The mean cumulative dose of ¹³¹I used in cured patients was 233 mCi, delivered in 2.2 treatment courses over a 3.4 year period. Loss of radioiodine uptake was seen in 5.2% of patients after a mean cumulative dose of 161 mCi. Six patients with single bone metastases and one with a macronodular lung metastasis were given surgical therapy. In the series of the Institut Gustave Roussy in Paris, the authors followed more than 400 patients with distant metastases and found that overall survival after treatment was associated with the size of the metastases, their location, and their ability to take up radioiodine. Better response was observed in radioiodine avid, micronodular lung metastases, and the worst outcome was found with large bone metastases.³⁷⁰

As was previously mentioned, some patients (15% to 20%) have elevated serum Tg levels and no uptake detectable by diagnostic WBS.^336,337 The site of metastatic involvement in such patients, usually the lung or mediastinal lymph nodes, may be detected by WBS performed 5 to 7 days after the administration of high doses of ¹³¹I (100 mCi).^234,296,297 This procedure is also of possible therapeutic value. A few days after administration of ¹³¹I therapy, a transient increase in serum Tg concentration occurs and can be explained by release into the circulation of stored Tg by radiation-damaged tumor cells. Furthermore, progressive normalization of WBS and serum Tg levels over years^276,338,339 and normalization of chest CT scans in patients with radiographic evidence of micronodular lung metastases³³⁸ have been observed in patients periodically treated with this treatment modality. This treatment does expose patients to significant radiation, and as of this time, there is no proof that it alters outcome or prolongs life.

Side effects after the administration of therapeutic ¹³¹I doses usually are very mild, and most are reversible in a few days. They consist mainly of gastrointestinal symptoms, nausea and occasionally vomiting, and acute sialoadenitis. In patients given more than 100 mCi, dry mouth often develops, and salivary obstruction or loss of saliva leading to dental problems may occur. More serious complications affect the blood and bone marrow. An increased risk for leukemia on the order of 5 cases per 1000 treated patients has been documented by several published series, especially in patients who received more than 600 mCi total dosage.³¹⁸ The risk increases with increasing cumulative doses, with reduction of the interval between treatments, and with administration of total whole body radiation doses per treatment greater than 2 Gy.³⁷¹ Pancytopenia has been reported in 4.4% of patients treated with mean ¹³¹I doses of 536 mCi.³⁷² In the same study, anemia was found in about 25% of patients, and thrombocytopenia was found in one third.

Another rare complication of radioiodine therapy is radiation-induced pulmonary fibrosis, which may develop in patients repeatedly treated for lung metastases, particularly of the diffuse type. Children seem to be particularly prone to this complication. In adults, generally no more than 60 to 70 mCi should be deposited in the lungs during treatment.

Finally, transient and permanent testicular damage limited to the germinal epithelium has been reported in men, as has transient ovarian failure in women, after treatment with high levels of ¹³¹I.^{373,374 131}I-induced genetic damage in the offspring of patients treated with ¹³¹I has not been documented in recent series addressing this issue.^375,376 The only anomaly reported was an increased frequency of miscarriage in women treated with ¹³¹I during the year before conception.

Levothyroxine Suppressive Therapy

Both the function and the growth of metastatic thyroid cells are under TSH control. It is a common observation that bone or lung metastases increase in size and take up radioiodine during a period of levothyroxine withdrawal, whereas reduction in size and depressed uptake are observed with levothyroxine administration. Serum Tg, a marker of cell function, increases dramatically during hypothyroidism, whereas it returns to low levels during hormone therapy. Suppression of endogenous TSH to low or undetectable levels is a true antineoplastic therapy and should never be omitted in patients with active disease.

The drug of choice is levothyroxine, and the effective dosage is between 1.6 and 2.2 µg/kg body weight. A higher dosage is usually required in children. In every patient, an attempt should be made to use the smallest dose necessary to suppress TSH secretion. Adequacy of therapy is monitored by measurement of serum TSH. Serum TSH theoretically should be undetectable with an ultrasensitive assay, but levels less than 0.1 µU/mL are probably acceptable. FT₃ should be in the normal range to avoid iatrogenic thyrotoxicosis. When these guidelines are followed, levothyroxine suppressive therapy is safe and largely devoid of long-term side effects on the heart or bone.¹⁰⁷

A shift from suppressive therapy to replacement therapy is appropriate in patients who have well-documented stable and complete remission, as assessed by a negative ¹³¹I WBS and undetectable stimulated serum Tg in the absence of anti-Tg antibodies and negative neck ultrasound.

Radiation Therapy

Radiation therapy is appropriate for any class III differentiated tumor not responding to ¹³¹I therapy or hormone suppression, for class III Hürthle cell tumors and follicular cancers in older patients, for any expanding class IV lesion, for painful osseous metastases, and for lymphomas and undifferentiated tumors.³⁷⁷ Unfortunately, no adequate studies are available to assess the value of prophylactic radiation after resection of class III tumors. Prophylactic mantle radiotherapy may be useful in patients with medullary thyroid cancer who have residual hypercalcitoninemia after surgery in the absence of detectable lesions (Table 18-10), but the value of this treatment is debated.³⁷⁸

Chemotherapy

A variety of traditional chemotherapeutic approaches have been attempted with minimal success. The overall response rate of thyroid cancer to various chemotherapeutic agents, including the alkylating agents 5-fluorouracil and methotrexate, is estimated to be 10% to 15%, which is comparable with that for other solid tumors.³⁷⁹ Bleomycin and especially doxorubicin (Adriamycin) have been reported to provide a higher percentage of remission (20% to 33%).^{313,379–384} However, response to these chemotherapeutic agents is partial and of short duration, with limitation imposed by toxicity of the medication. Chemotherapeutic agents given in combination appear to be slightly more effective than doxorubicin alone.^{313,379–384} Chemotherapy in differentiated thyroid carcinoma, preferably doxorubicin, is warranted in class III and IV lesions after other modalities of therapy have been exhausted and tumor growth is certain (Table 18-11). Recently, an Italian study reported an improvement in the rate of success when an administered chemotherapy scheme was based on the use of epirubicin and cis-platinum, administered while the patient was under endogenous or exogenous TSH stimulation.³⁸⁵ The rationale for this protocol is based on the assumption that tumor cells may be more prone to be killed if they are in a state of active replication, as can be obtained by stimulating them with TSH, rather than in a quiescent state, as may be observed during suppression of circulating TSH. As was already mentioned, chemotherapy may be used in combination with external irradiation for the treatment of anaplastic thyroid carcinoma after surgery.

Novel Therapeutic Strategies for Poorly Differentiated Thyroid Cancer

A small but significant proportion of patients with thyroid cancer do not respond to any of the above mentioned treatment modalities and eventually die of thyroid cancer. New therapeutic strategies are needed for these patients. Several research strategies are being implemented, and some new therapeutic approaches have already been entered into clinical trials.

One idea has been to reinduce a pattern of well differentiation in poorly differentiated or undifferentiated tumors, the so-called “redifferentiation therapy.” Poorly differentiated tumors are characterized by loss of expression of differentiation genes specific for the thyroid gland, such as the TSH receptor gene, the thyroglobulin gene, or the NIS gene. The last is the gene responsible for iodine uptake, and its expression is often lower in thyroid cancer cells as compared with normal follicular cells³⁸⁶; it is completely abolished in tumors no longer responsive to radioiodine therapy. Reinducing expression of the NIS gene would again render the tumors sensitive to the effects of radioiodine. Retinoids are biologically active metabolites of vitamin A, with growth-inhibiting and differentiation-inducing properties. They have been used for treatment and chemoprevention of several human cancers (e.g., acute promyelocytic leukemia) and recently were proposed as a potential agent of redifferentiation in thyroid cancer. In vitro, treatment for follicular thyroid carcinoma cell lines with retinoic acid (RA) exerted significant antiproliferative effects,³⁸⁷ elicited an increase in NIS mRNA expression and iodine uptake,^388,389 and, by decreasing extracellular matrix degradation, had beneficial effects on metastatic behavior.³⁹⁰ In vivo, 13-cis-retinoic acid (Roacutan) has been used in several limited series of poorly differentiated thyroid cancer with the aim of reinducing iodine uptake, at doses of 1.0 to 1.5 mg/kg body weight for 2 to 6 weeks. Reinduction of ¹³¹I uptake was observed in 5 of 12, 8 of 20, and 4 of 10 patients in three different series.^391–393 Taken together, results of the in vitro and in vivo studies may be interpreted as evidence of redifferentiation deserving of continued clinical evaluation.

Another futuristic approach is gene therapy, whose essence is the introduction of DNA into target cells. Although cancer is a multigenic disease, with more than one gene being dysfunctional, several oncogenes have been unequivocally associated with thyroid carcinoma and may become the target for gene therapy. Several approaches to thyroid cancer have been specifically proposed.³⁹⁴