Oncogenes (Fig. 18-11)

We now begin to understand oncogenesis in more details. More than 30 "oncogenes" have been recognized in the human genome. The most likely genetic events in thyroid cancer are reported in Fig. 18-11. These genes, normally silent, can be¬come activated by chromosomal translocations, deletions, or mutations, and then can "transform" normal cells into a condition of uncontrolled growth. Most onco¬genes appear to be closely related to normal growth factors, genes that control cell division, or to hormone receptors. In general, these genes, when turned on, promote cell growth and cell division and depress differentiation. Typically activation of one such gene may not be enough to produce malignancy, but if accompanied by ex¬pression of another oncogene, or if gene mutation or reduplication occurs, the cell may progress toward a malignant potential. Information on expression of oncogenes in human thyroid tissue is rapidly accumulating. Expression of c-myc is stimulated in normal thyroid cells by TSH, and the proto-oncogene is expressed in adenomas and carcinomas. Activating mutations of h-ras at codons 12, 13, and 61, and over expression of h-ras, are found in adenomas and carcinomas, but h-ras mutations are also found in nodular goiter tissue (118), suggesting that h-ras mutations could be an early event in oncogenesis (119). Other studies, it should be noted, find ras mutations uncommon (120).

Figure 18-11Possible role of oncogene activation, receptor or G-protein mutation, or tumor repressor gene alteration in the induction of thyroid carcinoma.

Santoro and co-workers (121) cloned an oncogene which is frequently and specifically expressed in papillary thyroid cancers. This oncogene is found on chromosome 10 and involves an intrachromosomal rearrangement of the tyrosine kinase domain of the ret oncogene so that it is attached to one of three different promoters, produc¬ing retPTC-1, retPTC-2, and retPTC-3. As a mean, one of these translocation products is found in about 20% of PTC, although in different series a large variation is observed (20-70%). This rearrangement leads to constitutive expression of the oncogene. It has been shown that intra-thyroidal expression of the ret/PTC1 oncogene can induce thyroid cancer (122). BRAF mutations, in the form of point mutations, are the most frequent alterations in papillary carcinoma, and undifferentiated cancers that have arisen from papillary tumors (123), approaching 40% of all PTCs (124).

Recently a mutational change has been associated with follicular cancers. In 5 of 8 follicular cancers, Kroll et al (125) found translocation of the DNA binding domain of PAX8 to domains A-F of the peroxisome proliferator-activater receptor (PPAR) gamma1 gene. The fusion oncogene is able to transform thyrocytes, so appears to be able to produce malignancies (126). Although initially thought to be exclusively present in follicular cancers, it is now known to be present in follicular adenomas as well (127).

Mutation or deletion of the p53 tumor suppressor gene is found in some differentiated thyroid cancers, and many undifferentiated cancers, suggesting that this genetic deletion may be one of the final steps leading to anaplastic cancer growth. A proliferation of studies in this field has provided many clues to thyroid tumorigenesis. Simian virus 40-like sequences are found in many thyroid cancers, as well as other cancers, and the Tag gene sequence found is known to be oncogenic in animal models (128). Mutated and non-functional thyroid hormone receptors are recognized in up to 90% of PTC by one author, suggesting a role in oncogenesis, but other workers find these mutations to be rare (129,130). The tumor suppressor gene TSG101 is over-expressed in most PTCs (131). Overexpression of many other genes -galectin-3, Thymosin beta-10,hTERT, CD97, CD26, VEGF-has been detected, but of course a question always is whether these changes represent the cause or the result of oncogenesis.

Mutations in the proteins involved in the normal TSH-receptor-G protein-adenyl¬cyclase-kinase signal transduction pathway also play a role in tumor formation. Activating TSH receptor mutations have been found by Parma and co-workers (132) to be the cause of most hyperfunctional nodules, and are now known to be common in "hot" nodules in patients with multi-nodular goiter.. These mutations involve the extracellular loops of the transmembrane domain and the transmembrane segments, and are proven to induce hyperfunction by transfection studies. However these mutations are not associated with cancer formation. Mutations of the stimulatory GTP binding protein subunit are also present in some patients with hyperfunctioning thyroid adenomas (133). TSH-R mutations are, however, unusual in thyroid cancer (134), (excepting hyperfunctional adenomas). TSH-R expression tends to be lost as cancers de-differentiate, and persistence of expression is associated with a better prognosis (135).

In addition to positive genetic factors, oncogenesis frequently involves loss of tumor suppressor genes. This has been proven in hereditary retinoblastoma. These genes are normally present on both sets (maternal and paternal) of chromosomes. In retinoblastoma the inherited lack of one suppressor (RB) gene does not cause disease, but if a genetic event (deletion, recombination, mutation, etc.) causes failure of expression of the second allele, cancer ensues. The presence of tumor-specific suppressor genes is often detected because of lack of heterozygosity of chromosomal markers associated with deletions of segments of genetic material. Evidence for characteristic chromosomal abnormalities within tumor cells may lead to recognition of a tumor suppressor gene. Deletions of the tumor suppressor genes, p53 and the RB gene, have been detected in differentiated and undifferentiated thyroid cancer (136). Many chromosomal rearrangements are found in Hurthle cell tumors, and correlate with tumor recurrence (137).

Ret oncogene and Medullary Thyroid Cancer

Studies on patients with MENI and MEN II indicated linkage to chromosomes 11 (138) and 10, respectively. Subsequent studies demonstrated that the ret oncogene is present at 10q11.2. Germline mutations have been detected in this oncogene in all patients with MEN II and MEN III (or IIB), and familial MTC (139). RET is a cell-membrane receptor of the growth factor family, with tyrosine kinase function. In up to 97% of patients with MenIIA, mutations are found in codons 609,611,618, 620, and 630 in exons 10 and 11. These all involve substitutions of other aminoacids for cysteine, and are thought to cause activation of the gene by aberrant disulphide bonding causing dimerization. Similar changes are seen in Familial MTC. In patients with the MENIIB syndrome, almost all,if not all, mutations involve an amino acid substitution of threonine for methionine at codon (918) in exon 16, and are thought to induce a change in substrate phosphorylation. Somatic mutations in ret are present in up to half of patients with sporadic MTC and are almost always in codon 918 (140,141). Gene mutations in this codon are thought to imply a poor prognosis.

Familial tumors

Apparent familial thyroid cancer development has been reported by several clinicians, including cases which seem to show a dominant pattern of inheritance (142,143). Thyroid carcinomas occur rarely as part of several familial syndromes, which may involve hereditable loss of tumor suppressor genes. Papillary cancer can occur as an independent familial syndrome in 5-10% of patienst in different series. Whether the recurrence of PTC represents a true familial aggregation or rather the fortuitous association of PTC in the same family, is still a matter of discussion. However, recent evidence seem to support the existence of a true familial PTC syndrome based on the demonstration that familial PTC display the features of “genetic anticipation” (the disease recurs at an earlier age and at an higher aggressiveness in the 2nd generation compared to the first one) typical of familial diseases (144). In addition, a germline alteration consisting in short telomeres has been demonstrated in familial cases of PTC (145,146), which may be responsible for genomic instability leading eventually to thyroid cancer.

Other, more rare forms of familial thyroid tumors are those associated with complex hereditable diseases. Cowden’s disease is a familial syndrome which includes a variety of hamartomas, multinodular goiter, and carcinomas of several tissues including breast, colon, lung, and thyroid, especially in women (147). Thyroid carcinoma also co-occurs in patients with familial adenomatous polyposis of the colon (148), and can occur in the absence of bi-allelic inactivation of the APC gene. Differentiated thyroid carcinoma is reported to co-occur with chemodactomas of the carotid body, which can be inherited in a familial autosomal dominant form (149). Thyroid carcinoma is also associated with Gardner’s syndrome (150) and Carney’s Syndrome (151). Papillary thyroid carcinoma has been associated with papillary renal neoplasia in a distinct hereditable tumor syndrome. Some patients in the families also have nodular thyroid disease. The predisposing gene has been chromosome 1q21 (152). These syndromes are listed in table 18.5.

Experimental Thyroid Tumor Formation

Thyroid tumors have been induced experimentally in rodents by several procedures having as their common denominator a prolonged increase in pituitary thyrotropin production and thyroid stimulation. Goitrogenic drugs, if administered to animals for a prolonged period, can induce tumors, as numerous investigators (153) have demonstrated. These tumors are typically papillary adeno-carcinomas, and are associated with a diffuse hyperplasia of the thyroid gland. Old rats of some strains appear to develop thyroid cancers spontaneously

Roentgen irradiation of the thyroid and administration of 131I have both induced carcinomas in the experimental animal (154). A combination of 131I injury to the thyroid cell and prolonged administration of a goitrogen is especially likely to produce carcinomas, as shown by Doniach (155). Cell metabolism is altered by 131I, even when small amounts are administered. In the rat, 5 µCi prevents subsequent response to a goitrogenic drug (156). With larger doses the colloid is sparse, the follicles are variable in size, and large eosinophilic acinar cells appear. Very large doses of 131I (producing several thousand rads) to the rat thyroid radically alter cell metabolism, liberate TG within 1 or 2 weeks, and subsequently reduce the efficiency of hormone synthesis. 131I iodine irradiation in rats in doses so low as not to alter hormone biosynthesis immediately inhibits DNA synthesis and cell replication, as shown by a failure to respond to subsequent goitrogenic challenge. The cells also have a shortened life span. Similar inhibition of hyperplasia follows x-irradiation to the thyroid.

Therapeutic doses of 131I to patients also induce atypical nuclei, which may remain for many years (157). The doses of RAI needed to produce neoplastic change in the thyroid glands of animals closely parallel those given in the treatment of thyrotoxicosis in humans. The morphologic changes are intensified by a goitrogenic stimulus and reduced by thyroid hormone treatment.

The effects of radiation may be twofold. The nuclear morphologic changes may derive from an abnormality in cell division or replication of nucleic acids, which may predispose to carcinomatous change. Also, the damaged cell produces less thyroid hormone, and thereby ultimately comes under intense TSH stimulation, as in experiments with goitrogens. Thus, it seems certain that chronic TSH stimulation in animals is associated with the evolution of a neoplasm, especially if it is combined with radiation damage to the cell nuclei. Experimental thyroid tumors induced by 131I are initially TSH dependent. At first, they can be transplanted successfully only into thyroidectomized animals that are producing much TSH. After serial passages through several generations, the tumors may become autonomous and will then grow in a normal host. Partial or complete dependence on TSH is also observed in some human papillary and follicular tumors.

External Radiation and Thyroid Cancer

Duffy and Fitzgerald (158) first made the important observation that a high proportion of children with thyroid carcinoma had received therapeutic x-irradiation to the upper mediastinum or neck during childhood for control of benign lesions such as enlarged thymus, tonsils, or adenoids. Their finding has been amply confirmed (159-166). Winship and Rosvoll (167) studied 562 children with thyroid carcinoma from all parts of the world. Among those for whom adequate historical data were available, 80% had a history of prior x-ray treatment. This relationship is not so obvious for carcinomas developing after age 35. Significant x-irradiation to the head, neck, and chest in childhood increases the frequency of thyroid cancer by 100-fold (168), and the incidence is proportional to the dose, reaching at least 1.7% at 500 rads, or 5.5 cases per million exposed persons per rad each year (Fig. 18-6). Our own data dislose a 7% incidence by 30 years after irradiation (163). The latent period averages 10 -20 years, but tumors occur even after 20-40 years (Fig. 18-7). There appears to be no true threshold, since even doses as low as 9 rads increase the incidence of cancer (160). It is in fact probable that “natural” background radiation may produce many of the spontaneous tumors (169). There is a direct dose-response relationship through 1,000 rads (168). Higher doses of irradiation also induce tumors, and the true dose-response curve in the range 1,000 -5,000 rads in humans is not known. Benign nodules occur with nearly 10 times the frequency of cancers. Interestingly, the type of tumor induced is not different from those occurring spontaneously, and there is no relation between dose and latent period. For some reason, women are more prone to develop radiation-induced tumors than men, and both ethnic and familial factors may influence tumor development (170).

Figure 18-6

Estimated dose response for thyroid cancer in humans from external irradiation. The incidence of carcinomas each year is plotted against the original thyroid irradiation dose. (From Maxon H, Thomas SR, Saenger EL, Buncher ER, and Kereiakes JG. American J Med, 63:967, 1977)

Figure 18-7

Distribution of patients with a history of irradiation to the head and neck, according to the time after irradiation at which they were examined. The majority of patients were seen 20 - 35 years after irradiation, but the incidence of tumors peaked 5 - 10 years earlier. Tumors continued to occur through 40 years after irradiation, and it is not clear that there is a finite latency period.

Probably any x-ray exposure of the thyroid has some carcinogenic potential, although the risk may decrease with age. Adults were extensively treated by x-irradiation for Graves’disease from 1930 to 1950. An increased incidence of carcinoma has been reported in these patients (171). A significant incidence of thyroid neoplasia was observed in patients who received x-ray therapy for thyroid disease (172). These patients were treated at ages up to 34, received 500-1,500 rads, and developed tumors 10-27 years after treatment. In a study of survivors of the atomic blasts at Nagasaki and Hiroshima, an increased incidence of thyroid cancer was found among persons who had received large amounts of radiation (173). Thus, the thyroid of the adult is sensitive to the carcinogenic action of x-rays, although not so sensitive as that of the child.

Radiation-associated tumors of the thyroid continue to occur, although x-ray treatment of thymic enlargement and tonsillar or adenoid hypertrophy has been discontinued since 1959. A recent analysis of 1787 patients treated with X-ray for Hodgkin’s disease found 1.7% to have thyroid cancer (174). The most dramatic and terrifying data emerged from the area around Chernobyl, where thousands of people of all ages received large doses of radiation from external fallout and ingested isotopes, especially short-lived isotopes of iodine. In this epidemic the risk of thyroid cancer is highest among children who were under 9 years and especially under 5 years old at the time of the Chernobyl explosion, and presumably ingested iodide via milk from cows grazing on contaminated forage. The latent period in these children is amazingly short (6 to 7 years), the tumors tend to be relatively aggressive, and are frequently associated with thyroid autoimmunity (175).

Radiation-associated tumors are generally found among younger patients. They are rarely undifferentiated, but some have been fatal. In a review of x-ray associated thyroid tumors at the University of Chicago Thyroid Clinic (163), the latent period among children treated predominantly in adolescence for tonsillar enlargement or acne averaged 20 years. It appears that the peak incidence of lesions is at 10 -25 years after exposure (Fig. 18-7, above), and it is probable that the occurrence of new cancers decreases over time. Among 100 consecutive patients seen in 1973 and 1974, only because they knew of prior radiation exposure, 15% had lesions suggestive of tumor and 7% had cancer proven at operation (162). Favus et al. (176) found a similar incidence of cancer (60/1056) in irradiated patients called back for evaluation. Although one case-controlled study suggests a lack of effect of radiation, the evidence, reviewed by Maxon et al (168), clearly confirms the importance of this problem.

Fig 18-8The size of radiation associated and non-radiation associated tumors was statistically non-different.

Based on these facts, it has been accepted by most physicians in the field that patients with a history of thyroid irradiation (over 20 rads, and certainly 50 rads) should be located and advised to have an assessment. This evaluation should consist at least of a physical examination and thyroid ultrasound. If one or more clear-cut nodules is found, then FNAC should be performed followed by surgical intervention in case of malignant result. Benign nodules are also found in these glands, with an incidence much higher than that of cancers. Serum TG levels tend to be elevated in irradiated patients, and antithyroid antibodies are more commonly present, but these tests are not of diagnostic value. When excised these glands often show multiple benign as well as malignant nodules as well as areas of fibrosis and hyperplasia (177).

M.P., 52-Year-Old-Woman: Thyroid Radiation and Multiple Gland Abnormalities

This patient was first seen with a history of irradiation for acne during her teens. She subsequently developed telangiectasia of the skin of her face. The month before the examination, she had observed a lump on the right side of the neck. Examination disclosed a 1-cm nodule in the right lobe of the thyroid and some irregularity of the left lobe. Thyroid scintiscan showed a cold nodule of the lower pole of the right lobe. Ultrasound examination of the right lobe identified a partially cystic nodule and a small cystic structure of the left. The FTI was slightly elevated at 10.9. RAIU was above normal. Thyroid antibodies were not present. Thyroid needle aspiration showed cells indicative of malignancy.

Routine blood tests disclosed alkaline phosphatase of 107 units (normal, 25-100 units), calcium 10.9 and 11.5 mg/dl (normal, 8.5-10.2 mg/dl), and phosphate 2.7 ng/dl. Repeated assay of FTI again demonstrated an elevated value of 15 (normal = 6-10.5). The level of parathyroid hormone was 0.65 ng/ml (with a coincident calcium level of 11.5 mg/dl), values indicative of primary hyperparathyroidism.

The patient was treated with potassium iodide for 1 week and admitted for ex¬ploratory surgery. A right upper para-thyroid adenoma weighing 908 mg was found. The adenoma showed areas of cystic degeneration and fibrosis. The thyroid gland was multinodular and was suspicious on frozen section for follicular carcinoma. There was extensive fibrosis around and adherent to the thyroid gland.A near-total thyroidectomy was performed. The gland weighed 17 g. Multiple nodules in the gland measured 1-18 mm in diameter. An 18-mm nodule in the right lobe was iden¬tified as follicular carcinoma. There were, in addition, multiple follicular adenomas and multiple Hurthle cell tumors, focal hyperplasia, and colloid nodules in the right and left lobe.

Postoperatively the patient received thyroid hormone. When seen 1 month after surgery, her calcium level was 9.4 mg/dl, phosphorus 3.5 mg/dl, and parathyroid hormone 0.28 ng/ml (normal). The FTI was 9.2 while taking 0.15 mg L-T4.

This patient developed a cystic parathyroid adenoma with hyperparathyroidism, multiple adenomas of the thyroid, follicular carcinoma, and multiple functioning adenomas that produced thyrotoxicosis. All of these tumors occurred concurrently in a gland showing changes typical of prior radiation exposure.

D.C., 19-Year-Old-Girl: Development of Thyroid Carcinoma, After X-Ray Therapy, While Receiving Thyroid Hormone

At age 10 the patient had respiratory distress and was found to have a superior-anterior mediastinal mass. There was left cervical lymphadenopathy and bilateral supraclavicular lymphadenopathy. Biopsy revealed Hodgkin’s disease of the nodular sclerosing variety. The result of staging laparotomy was negative. She was treated with 4,000 rads to a neck mantle field.

One year later the results of thyroid function tests were normal, but two years after x-ray treatment the FTI was 4.1 and the TSH level was 24 µU/ml. Thyroid hormone replacement therapy was begun, and the patient was carefully monitored over sub¬sequent years with periodic FTI and TSH determinations. Six years after irradiation a2-cm nodule was noted in the left lobe of the thyroid. This nodule was found to be cold on 123-I scan. Fine needle aspiration revealed cells suggestive of malignancy.

At surgery a papillary adenocarcinoma with capsular and vascular invasion was found, and a near-total thyroidectomy was performed. Postoperatively residual thy¬roid tissue was ablated by administration of 30mCi131I.The skeletal survey findings were negative; chest x-ray films and bone films were normal. She has remained free of evidence of thyroid carcinoma or Hodgkin’s disease in the subsequent three years.

This history demonstrates the occurrence of thyroid carcinoma, in a gland heavily irradiated during therapy for Hodgkin’s disease, while the patient was taking ade¬quate replacement doses of thyroid hormone. Possibly the period of X-ray induced hypothyroidism played a role in tumor induction. The tumor developed within six years of the radiation therapy. Fortunately, the tumor was not metastatic and has presumably been eradicated by surgery and RAI ablation of residual tissue.

In our series, postradiation carcinomas averaged 1.7 cm in size (Fig. 18-8), and 14% were below 0.5 cm.

The size distribution was similar to that of non-X-ray-associated tumors. They were more frequently multicentric than those in non irradiated glands and as aggressive, or more so, in behavior than tumors arising without known irradiation (178). The tumors are mainly papillary or follicular, but an occasional anaplastic cancer is also found.In examining patients, it should be remembered that benign and malignant salivary gland neoplasms, neuromas, parathyroid adenomas (179), laryngeal cancer, skin malignancies, and breast cancer also occur with undue frequency in this group of patients.

Thyroid nodularity and cancer also occur as a sequela of nuclear fallout. In the accident at Rongelap in the Marshall Islands (180), individuals received 200-1,400 rads. The incidence of nodularity was 40%, and nearly 6% proved to have cancer. Children in Utah exposed to small amounts of fallout from atomic bomb testing have been proven to develope nodules and possibly carcinomas.

Lack of Association of 131I Treatment and Thyroid Carcinoma

Iodine-131 treatment induces abnormalities in the thyroid gland that persist for many years (181). Giant nuclei, increased mitotic activity, hyperchromatic nuclei, and other abnormalities appear. It seems reasonable that these nuclear changes could lead to carcinomatous degeneration. Chromosomal damage in circulating lymphocytes has also been reported after 131I administration (182). Patients have developed thyroid nodules or tumors after 131I therapy for Graves’ disease; it has been suggested, but not proved, that the highest incidence has been among those treated during childhood. Some of the lesions found in 131I-treated children may actually have been carcinomas, but there has been debate (183) among the various pathologists who examined the specimens. Several reports of isolated instances of cancer after 131I treat¬ment of adults for Graves’ disease have appeared, but the large United States Public Health Service cooperative study failed to show an increased risk in this group (184-186). Studies by Holm et al (186) also failed to show an increase in cancer incidence among persons given 131-I either for diagnosis or for therapy for thyrotoxicosis. These patients were adults, and usually in the 40-60-year age group. Also, very large radiation doses may be less carcinogenic than small ones, and in half or more of these patients, the thyroid has been totally destroyed. Lastly, the follow-up time averages 8-13 years, which may be too soon to see radiation-induced neoplasia. Thus the evidence is reassuring but the question cannot be considered closed.

Thyroid Hyperplasia and Cancer

Chronic stimulation of the thyroid with TSH probably can lead to carcinogenesis in humans, as it can in animals. There are several reports of intensely hyperplastic congenital goiters, untreated for long periods, in which carcinomas have finally developed (187-191). Fortunately, most patients with congenital goiter are recognized and treated with replacement thyroid hormone at sometime during early childhood, so that chronic TSH stimulation does not occur. Interestingly, activating mutations of the TSH-R, which are metabolically like chronic TSH stimulation, lead to benign and not malignant change, as described above.

Relation of Cancer To Other Thyroid Disease

The relationship of thyroid tumors to other thyroid disease is still debated. In the preceding section we discussed whether carcinomas arise from adenomas, occurring either singly or as a component of a multinodular gland. While this must happen rarely, it is not the ordinary course of events. In support of this view one may note, for example, that, whereas adenomas are rarely if ever papillary, approximately 80% of all thyroid carcinomas are papillary. If carcinomas arise from adenomas, one might expect that the majority would be follicular rather than papillary, and this is not the case. Also, although carcinomas, largely of the papillary type, occur in nontoxic nodular goiters with a reported frequency of 4-17% of cases, the age of diagnosis of papillary carcinomas does not follow that for nontoxic goiter (192). Papillary carcinomas occur in children and adolescents, and reach their highest frequency during the middle decades of life. Multinodular goiter, by contrast, is infrequent in childhood, but increases with each decade. The high frequency of carcinomas detected in nodular goiter appears to reflect the efficiency of selection of patients for operation on the basis of suspicious clinical findings in the gland. Although it remains unproven, it is likely that in many or most thyroid adenomas and carcinomas, one specific mutational event leads directly to the development of the specific neoplasm.

Parathyroid adenomas occur in a small percentage of patients with thyroid cancer. The converse relationship may also exist; 2-11% of patients with parathyroid adenomas also have thyroid cancer (193-195). An important reason for this association is the induction of both tumors by X-ray exposure.

Neoplasia and Autoimmune thyroid diseases

An increased incidence of cancer in Hashimoto’s thyroiditis has been reported, Further, focal thyroiditis may occur as an immunologic response to thyroid cancer. In most series in the past the coexistence of Hashimoto’s thyroiditis among thyroid cancer patients was between 2-4%, but the real association, particularly with microcarcinomas, is difficult to be assessed because Hashimoto’s thyroiditis is rarely operated upon. Recently this issue has gained new attention in the era of FNAC, and several reports have found that when a thyroid nodule is associated with autoimmune thyroiditis, the chance of malignancy is significantly higher (9-40%) than in nodules not associated with thyroid autoimmunity (196,197). One possible explanation for this finding might be that patients with autoimmune thyroiditis tend to have higher levels of serum TSH (potential thyroid carcinogen) compared with non-autoimmune patients.

Many reports on Graves’ disease stress a normal or low coincidence of cancer, but several series have reported a significant association between Graves’ disease and thyroid cancer, ranging from 3 to 10% (198-200). However, most of these series were surgical, and the patients were selected for surgery on the basis of suspicious nodules or large goiters. In Graves’ patients treated by radioiodine, no subsequent increase in the discovery of thyroid cancer has been reported.In our review, 4 of 50 patients with thyroid cancer had coincident Graves’ disease (201). Belfiore et al found the risk of thyroid cancer in Graves’ disease to be increased 2-3 fold (198). TSAb can stimulate thyroid cancers when Graves disease coexists, so the idea that TSAb might induce malignant change is tenable, but not proven. It also is possible, but unproven, that continued stimulation of a tumor may make it behave in a more aggressive manner (198,202). Patients with Graves disease and thyroid cancer who underwent total thyroidectomy and 131I ablation fared as well in follow-up as did patients without Graves’ disease.

Micro-carcinomas

The term micro-carcinoma refers to tiny carcinomas (<1 cm), usually papillary and often sclerotic. Such tumors were frequently found in autopsy studies when the thyroids were sectioned completely at 1-2 mm intervals and every abnormality was studied, or during histology of glands operated for large multinodular goiters (203,204). Nowadays, with the extensive use of thyroid ultrasound, micronodules (<1 cm) are frequently discovered in the general population, and proven malignant in a significant percentage. These tumors are probably synonymous with the "occult" tumors described at autopsy, but since they are discovered during life can no longer be considered occult. The term microcarcinomas is now preferred to occult.

Tiny carcinomas, usually papillary and often sclerotic, have been found in 5.7% of thyroids of adults coming to autopsy in the United States (203). This prevalence is noted only when the thyroid is sectioned completely at 1-2 mm intervals and every abnormality is studied. The tumors have a mean diameter of 2 mm, and almost all are under 5 mm. The prevalence is best known in adults (204) and may be lower in young people. Since, in some glands, collections of psammoma bodies also exist in tiny scarred areas, it is hypothesized that such lesions may spontaneously regress. Because of their small size, they are detectable only at surgical or pathologic examination of the gland. These observations, now widely accepted, have provoked much discussion. Certainly most of these tiny tumors cannot be biologically significant, considering the low incidence of clinically recognized cancer. Most of the lesions are probably missed during routine surgical or autopsy pathologic studies. Their cause is unknown. They may be a variant of the occult sclerosing carcinomas described by Hazard, but the latter tumors are usually larger, have a predominant sclerotic component, and clearly do metastasize. It has been suggested that such lesions are in fact the cancers found after thyroid irradiation, but most likely they can explain only a small proportion of radiation-associated tumors. Most of these lesions would go undetected in a standard surgical pathologic examination, and the great majority of radiation-associated lesions are larger. In our own series, the radiation-associated le¬sions were on average 1.7 cm in diameter and only 14% were under 0.5 cm. Whether such "minimal" cancers are in fact the occasional precursors of clinically evident cancers is a moot point. It is clear that they are at present an important pathologic -but not clinical --entity.

Clinical signs

Most frequently the tumor is discovered accidentally by the patient or physician as a lump in the neck or may be a fortuitous finding at ultrasound of the neck. Less and less frequently, nowadays, it may appear as a gradually enlarging, painful mass with associated symptoms of hoarseness, dysphagia or dysphonia, or there may be difficulty in breathing. Occasionally a arrives with metastatic nodules in the neck, pulmonary symptoms from metastases, or a pathologic fracture of the spine or hip. Usually there are no symptoms of hyper-or hypothyroidism, but in very rare instances the tumor, usually metastatic follicular carcinoma, can produce enough hormone to cause hyperthyroidism (215,216). (See also Chapter 13)

Upon examination of the neck, carcinoma of the thyroid characteristically appears as an asymmetrical lump in the gland. If it is still within the confines of the gland, it will move with the gland when the patient swallows and may be moveable within the gland. If it has invaded the trachea or neighboring structures, it may be fixed; this is a useful sign. Lymph nodes containing metastases may be found in the supr-aclavicular triangles, in the carotid chain, along the thyroid isthmus, and rarely in the axillary nodes. A sentinel or "Delphic" node above the isthmus may be present. Although carcinoma of the thyroid is typically firm or hard, rapidly growing lesions may sometimes be soft or even fluctuant. When the tumor is poorly differentiated or anaplastic, the lesions may undergo necrosis and discharge through sinuses that developed in the skin of the neck. Patients with thyroid cancer are also prone to develop other cancers, the risk being about double the average. Among these cancers is an excess incidence of leukemia, perhaps related to 131I therapy (217-219).

Age at diagnosis has an important bearing on the patient’s subsequent course. The adverse effect of age on the prognosis increases gradually with each decade (220). For practical assessment purposes, it is clear that patients diagnosed before age 45 have a much better prognosis than those detected later (221). Age is also directly related to the incidence of undifferentiated tumors and to overall mortality. Pregnancy does not seem to worsen the course of established or previously treated thyroid can¬cer (222). Overall, women have a better prognosis than men with cancer (223). Other characteristics of the tumor, including (as would be expected) extraglandular extension, gross invasion of the tumor capsule, and increasing size also carry a worsened prognosis (223).

MEDULLARY CARCINOMA

Hazard et al. (205) first described a unique tumor in the thyroid characterized by sheets of cells with large nuclei, amyloid deposits, fibrosis, multicentricity, and an unexpectedly benign course in view of the solid tumor appearance. Over 50% may have local or distant metastases at diagnosis. The tumors may metastasize locally, or to bones and soft tissues. The thyroid primary tumor and the metastases may show dense calcification on x-ray film. The course tends to be progressive, and 10-year survivorship varies from 50 to 70%. These tumors, which constitute 2-8% of all thyroid cancers, are derived from the "light," or "C," or "parafollicular" cells. These are calcitonin (CT)-secreting cells, distinct from thyroid acinar cells, and are of ultimo-branchial origin.

The tumors may occur sporadically (about 70% of the total) or as part of the MENII syndromes, which constitute about 10-20% of the cases, and are transmitted in families as dominant traits due to activating germline point mutations of the RET proto-oncogene (254,255). In contrast with thyroid epithelial cell tumors, the female to male ratio is near unity. MEN-II (or IIA) includes patients with medullary thyroid cancers, pheochromocytomas, and parathyroid hyperplasia or adenomas. MEN-III (or MEN-IIB) includes medullary thyroid carcinoma, mucosal neuromas, pheochromocytomas, which are usually bilateral and often malignant, occasionally cafe-au-lait spots, and possibly Gardner’s syndrome (mucocutaneous pigmented nevi and small intestinal polyps) (133,256-259). An occasional variant of medullary thyroid cancer appears to contain both CT and TG, suggesting the cells, surprisingly, have features of both medullary thyroid cancer and follicular cancer (260).

Gastrointestinal symptoms including diarrhea, constipation, and rarely megacolon occur in these patients and may occur before the thyroid tumor is detected. Hyperplasia of C cells often precedes the development of familial cancers (261). Medullary tumors derived from the C cells not only secrete CT, but in addition may produce serotonin (with a carcinoid syndrome), prostaglandins, corticotropin releasing factor, and adrenocorticotropic hormone (causing Cushing’s syndrome), histaminase, and somatostatin. Some of these substances, rather than calcitonin, may be the cause of the severe diarrea syndrome associated with metastatic medullary thyroid cancer. Interestingly, expression of somatostatin appears to correlate with improved prognosis (262). Medullary thyroid carcinoma cells in tissue culture have been found to produce Ghrelin, which is an endogenous ligand for the GH secretagogue receptor. MTC is known to produce several gastrointestinal hormones and neuroendocrine peptides, in addition to calcitonin, and including CGRP, ACTH, serotonin, chromogranin A, and vasoactive intestinal peptide, and to this we now add Ghrelin (263). Alcohol ingestion is reported to induce attacks of flushing and diarrhea and to stimulate CT secretion by the tumors (264). The CT secreted by these tumors rarely causes hypocalcemia (265).

Medullary tumors have an ominous histologic pattern, with solid masses of cells with large vesicular nuclei (212). There may be considerable associated fibrosis, and deposits of amyloid are a helpful diagnostic point. At the time of initial histologic examination the pathologist should recognize these tumors as entities distinct from the undifferentiated cancers, for the medullary carcinomas have a much better progno¬sis.

BIOLOGICAL FUNCTION OF THYROID TUMORS

Interesting abnormalities in iodide metabolism are typical of thyroid adenomas (described above) and in thyroid carcinomas. In general, the tumors are cold at 131I scintiscan, because they tend to lose the ability to accumulate iodide from the plasma, to bind iodide to TG, or to synthesize thyroid hormone (287). The pattern is one of dedifferentiation, the loss of those functions peculiar to the thyroid gland. Follicular carcinomas tend to retain iodide metabolism more completely than other tumors, and therefore may be susceptible to treatment with RAI. Localization of 131I in tumors, if present at all, is spotty rather than homogeneous.

Occasionally follicular thyroid cancers express high levels of Type2 iodothyronine deiodinase, and cause "consumptive hypothyroidism" (288). This surprising phenomenon has also been observed in patients who have highly vascular tumors which express the deiodinase (289).

In rare cases follicular tumors or their metastases produce significant amounts of thyroid hormone. In many instances the thyroid gland has been completely removed or destroyed, but the metastases have been sufficiently active to maintain the patient in a thyrotoxic state. More frequently, the metastases produce enough hormone to maintain the patient in a euthyroid condition, but not enough to produce thyrotoxicosis. This action indicates that the tumor may be responsive to thyrotrophic hormone, like the observation that thyrotropic hormone can induce growth of the tumors.

Carcinomas usually are associated with elevated serum TG levels. Growing differentiated tumors may cause levels of TG of > 2000 ng/ml. In Hurthle cell tumors and anaplastic cancers, TG levels are usually minimally elevated.

Differentiated thyroid cancers tend to retain a normal affinity and capacity for binding of TSH to their membrane receptors (290), and TSH stimulates cAMP production normally in tumor tissue. Perhaps in keeping with the clinically recognized unresponsiveness to TSH, undifferentiated tumors lack high-affinity TSH receptors. Genetic studies show that in these tumors the expression of the TSH receptor gene, and other thyroid differentiation genes is usually lost (291). In autonomous thyroid nodules, TSH stimulates cAMP accumulation normally; hypersensitivity to the hormone has sometimes been found (292,293).

DIAGNOSIS

Most patients with thyroid carcinoma are recognized because of a positive or suspicious FNA done for the clinical or sonographical discovery of a thyroid nodule, either single or in "multinodular" goiter (304). Anaplastic cancers and lymphomas commonly present as a smooth goiter. Stony hardness, fixation to the trachea, and damage to recurrent laryngeal or cervical sympathetic nerves are other important clinical signs. The problems of differentiating carcinoma from other lesions of the thyroid have been reviewed in the preceding discussion of thyroid nodules. A few additional comments are given here. FNA and US studies, constitute the basic and most useful laboratory studies. TSH and fT4 are usually measured to verify metabolic status, and anti-TPO and TG antibodies may be useful in helping differentiate thyroiditis. Isotope scans have a limited role in initial diagnosis.

CHOICE OF OPERATIVE PROCEDURE

Which operative procedure is indicated when FNA is suspicious or indicative of cancer? (Table 18-6)

Suspicious FNA lesions have a nearly 70-80% chance to be malignant, while an FNA indicative of papillary thyroid cancer is almost always true positive at final histology. Thus, we recommend total (or near-total) thyroidectomy as the initial surgical procedure in these categories, regardless of the size of the nodule. "Near-total" thyroidectomy refers to a procedure which intentionally leaves small portions of thyroid tissue near parathyroid glands or at the entry of the recurrent nerve into the larynx, and is associated with a marked reduction in possibility of hypoparathyroidism and nerve damage. It is frequently used with intended 131I ablation of residual thyroid tissue.

Some authors prefer lobectomy with frozen section examination in case of suspicious FNA. .It must be noted that frozen section carries a high rate of false negative diagnosis, compared to final histology. For this reason, some authors prefer to do total (or near-total) thyroidectomy without performing frozen section. In addition, in many follicular lesions the diagnosis of malignancy can be made only from paraffin sections.

* STT = Subtotal thyroidectomy ** NTT = Near-total thyroidectomy *** MND = Modified neck dissection

Among patients with papillary cancer within the gland, some will have cervical lymph node involvement and others will have no obvious spread. The utility of prophylactic neck dissection is controversial. Sone authoritative centers are in favour but other, including the authors of this chapter, prefer to perform central neck dissection only when there is a preoperative evidence of lymph node metastases at US or intraoperative evidence, The same attitude seems indicated for lymph node dissection of other node chains. Whenever a patient treated with lobectomy is found to have cancer at final histology, the question arise whether to perform completion thyroidectomy. The indication of several guidelines (39) are in favour of completion thyroidectomy, with the exception of patients with unifocal, small, intrathyroidal, papillary thyroid cancers without evidence of lymph node metastases and favourable histology.

The approach proposed here, is based on several observations. Multicentric involvement is reported to range from 25 to 90%. The wide variation of multicentricity (or intraglandular dissemination) can be explained in part by the finding that the incidence of multicentricity is doubled if one does whole gland histologic sections. There is little or no relationship between the size of a solitary nodule and the incidence of intraglandular dissemination, but an increasing degree of histologic malignancy is associated with the frequency of dissemination.

Mazzaferri et al., in their review of 576 cases of papillary carcinoma, found that total thyroidectomy significantly reduced the incidence of recurrences, and recurrences will presumably be correlated with deaths from disease (234). Samaan et al (311) also supported this procedure. Hay et al. evaluated the efficacy of different surgical approaches to treatment of patients with low risk papillary carcinoma at the Mayo Clinic and concluded that more extensive surgery was not associated with lower case specific mortality rates, but was associated with a lower risk of local regional recurrence. Their data supports the use of bilateral resection as the preferable initial surgical approach (312).

Total thyroidectomy carries an increased risk of hypoparathyroidism, recurrent nerve damage, and the necessity for tracheostomy (313). Accidental unilateral nerve damage may reach 5%, but fortunately bilateral injury is rare (314). All surgeons attempt to preserve those parathyroid glands that can be observed and spared, and an attempt is often made to transplant resected glands into the sternocleidomastoid muscles. Reports range from a 1 to a 25% incidence of hypoparathyroidism after total thyroidectomy (234,315).

TUMOR STAGING AFTER SURGERY

Tumor staging is intended to identify the risk of death or recurrence after initial treatment. The most used staging system is the TNM Staging system which combines simplicity with rather good predictive power.

Several other staging systems have been developed. One is the Clinical Class system developed at the University of Chicago and is based simply on the extent of disease (316). Other systems are designed to predict outcome. The EORTC classification pro¬posed by the European Thyroid Association is based on age, sex, histology, invasion, and metastases (317). The Dames classification includes data on age, extent and size of primary, distant metastases, and DNA ploidy (318). MACIS includes data on age, invasion, metastases, size, and completeness of surgery (319). All of the systems appear to be effective in categorizing patients into largely similar low and high risk groups.

Several groups have recently established new criteria for risk assessment based on pathological features combined with clinical features and with the response to initial therapy. The idea is to delay the risk assignement to a time when the response to initial therapy may be evaluated. The first proposal (called “Ongoing Risk Stratification”) came from the Memorial Center in New York (320), where patients were assigned to low or high risk category based on the results of follow-up after initial treatment. Patients in apparent complete remission at that time were defined as low risk, regardless of the initial risk stratification obtained soon after surgery. A second proposal came from an Italian study (321). These authors assigned patients to low or high risk group at the moment of the first evaluation done 8-12 months after surgery and radioiodine ablation (if performed). Patients free of disease (negative neck US, undetectable basal and stimulated serum Tg and no other evidence of disease) were classified at low risk. Patients with any evidence of ersistent disease (including detectable TG) were considered at high risk of recurrence. The authors demonstrated that nearly half of the patients could be shifted from the high risk category (at the time of surgery) to the low risk category. The system was named Delayed Risk Stratification (DRS). One advantage of these delayed risk stratification systems is that gives an idea of the risk of recurrence which is not considered in the TNM classification.

TSH SUPPRESSIVE/REPLACEMENT THERAPY

After operation all patients are kept on TSH-suppressive thyroid hormone therapy with l-thyroxine . At the time or the first post-surgical evaluation, individuals with current active cancer (other than medullary or lymphoma) should continue with TSH-suppressive therapy aimed to a TSH around 0.1 µU/ml. Pushing TSH below this level has not been associated with better outcome, while has been associated with more frequent side effects from clinical or subclinical hyperthyroidism. Patients who are considered free of disease, should have their replacement lowered to provide a TSH in the low-normal range, and ultimately as safety is assured, in the normal range.

CHILDHOOD THYROID CANCER

Some special features of thyroid cancer occurring in children deserve comment. It is, of course, an uncommon disease. The tumors are usually papillary or mixed histologically, and tend to grow slowly, with a high frequency (50 -80%) of neck metastases, but with a relatively favorable prognosis. Very young patients (under age 12) often have relatively aggressive disease. The association with x-ray exposure has already been discussed. As in adults, the incidence in girls is double that in boys. Multicen¬tricity of tumors is found in 30 -80%. Metastases to lungs, usually microscopic, are common (perhaps 20%), but tumor is rarely found in the bones. Lung metastases usually accumulate 131-I and can often be eradicated with this isotope, particularly those not visible with X-rays.

As with adult tumors there is no universally accepted surgical approach, but it is certain that sentiment has swung away from prophylactic and radical neck dissections to a more conservative position (322,323). The operations employed are as described above, and near-total thyroidectomy, done by an experienced surgeon, is favored. Thyroid remnants are destroyed with 131-I in patients with multicentric lesions and in all Clinical Stage II, III, and IV. Detection of metastases is attempted by131-I scanning, as described elsewhere in this chapter. Most childhood metastatic thyroid cancers are found to accumulate sufficient 131-I to allow useful and sometimes curative therapy, often with doses of 75-150 mCi. Presumably children are more likely to suffer side-effects of 131-I therapy, as described below.

Reproductive potential is diminished by large doses of 131-I (324), but an increased incidence of birth defects has to date not been encountered among the relatively few progeny studied (325-327). Thyroid hormone is given to suppress TSH to the 0.1uU/ml area in patients who have known residual or probable residual disease, even though this is known to cause some loss of bone mineral. Although the 10-year survival is from 90 to 95%, long term follow-up demonstrates an eight fold greater than normal mortality (230) and emphasizes the need for comprehensive therapy and long term follow-up.

RAI 131-I ABLATION

Most patients who have had a "total" thyroidectomy, and all patients who have had a subtotal resection, will have some functioning thyroid tissue remaining in the normal position after surgery, and will thus be candidates for 131I ablation. This is done to remove any possible residual tumor in the thyroid bed (thyroid ablation), to make subsequent scans and TG assays more interpretable, and (hopefully) to kill tumor cells elsewhere (adjuvant therapy). There is no unanimity regarding the use of postoperative 131I ablation in Stage I tumors, since absolutely convincing evidence of its value is lacking (234,328). But for all patients with papillary and follicular cancers as a group, 131I ablation correlates with improved survival (232). Our data demonstrate that postoperative 131I ablation correlated with decreased recurrences for all patients with papillary cancers over 1 cm in size. Samaan et al (311), in a review of 1599 patients, observed that 131I treat¬ment was the most powerful indicator for disease-free survival.

Ablation can be accomplished in most instances by one dose of 30 mCi 131I, giving the patients about 10 whole body rads (329). In our practice 80% of patients are ablated successfully with one dose of 30mCi, and the remainder require repeat therapy at the time of their second scan. Other clinicians find this dose insufficient, and give 50-150 mCi as an inpatient treatment. In part this difference may depend upon the surgeon, since small remnants of residual thyroid are more easily ablated than large amounts of residual tissue. Low dose (30 mCi) ablation of thyroid tissue after near-total thyroidectomy was recently reviewed by Roos et al. Surveying many studies, they concluded that 30 mCi was as effective as larger doses in inducing ablation, and since it could be administered without hospitalizing the patient, was an appropriate treatment (330). Doses of 100 mCi may provide more certain ablation with one dose (although at the expense of greater patient radiation) but there is little difference between ablation rates with does of 30-75 mCi. There is no data proving that one method or the other provides superior results in terms of survival. We do not routinely use ablation in patients under age 21 with tumors under 1 cm. Patients with tumors above this size, older patients, or those with multicentricity or a history of neck irradiation are advised to take 131I. This practice is followed in most clinics.

The indications for thyroid ablation, based on levels of evidence have been detailed in recent ATA guidelines (39). Three groups of patients are identified, one (at very low risk of recurrence) in which thyroid ablation is not indicated due to the lack of evidence of any benefit; a second group where the benefit, if any, are not evidence based. In this group, ablation should be offered in selected cases according to the judgement of the treating physician. Finally, a third group, including high risk patients, in which ablation has a strong indication based on good evidence that it may reduce cancer recurrence and possibly deaths.

Irrespective of the protocol and the dose used for ablation, there is always a subgroup of about 20% of patients that will not be successfully ablated with the first RAI course. The factors associated with ablation failure are not fully understood. Ablation failure does not correlate precisely with the dose, with the levels of TSH stimulation, the amount of thyroid residue or the level of urinary iodine excretion (331). In particular, it is not certain whether the use of doses higher than 3.70 GBq would result in any addi¬tional benefit, or whether there is a ’stunning’ effect of the diagnostic dose of 131I on the subsequent ablation rate, although likely to occur. A retrospective analysis was performed of all patients (n=389) with well-differentiated thyroid cancer treated at our institution between 1992 and 2001. The therapeutic dose was the only variable found to be associated with success (odds ratio, 1.96 per 1.85 GBq increment). Our results confirm the presence of a significant percentage of ablation failures (24.4%) despite the use of high ablative doses (3.70-7.40 GBq). Higher therapeutic doses are associated with higher rates of successful ablation, even when administered to patients with more advanced stages. Higher diagnostic doses were not associated with higher rates of ablation failure. (332).

The utility of radioactive iodide treatment of patients with papillary and follicular cancer was recently reviewed in a series of articles by Wartofsky, Sherman, and Schlumberger and their associates. Schlumberger concludes that routine radioactive iodide ablation is not indicated in patients with differentiated thyroid carcinomas of less than 1.5 cm in diameter, and advocates restricting RAI ablation to patients with poor prognostic indicators for relapse or death (333). Wartofsky points out a secondary benefit of postoperative low dose 131I ablation in that, for many patients, it provides a high degree of certainty and peace of mind when subsequent scans are negative and TG is undetectable. Another argument for radioactive iodide ablation and early detection of any recurrence is the data presented by several groups, including Schlumberger and colleagues, that there is a reciprocal relationship between the success of cancer therapy and the size and duration of the lesions.

In patients with Stage II to IV disease, we proceed to destroy all residual thyroid and to treat demonstrable metastases if they can be induced to take up enough 131I. Use of 131I therapy is investigated in these patients, regardless of the histologic characteristics of the resected lesion, although significant uptake rarely is found in Hurthle tumors (243,334) or in patients with anaplastic lesions.

FOLLOW -UP TREATMENT BASED ON TG ASSAYS

As assays for thyroglobulin (TG) have become more sensitive and reliable, measurement of TG assumes more and more importance in determining the management of patients followed after thyroidectomy and radioactive iodide ablation treatment for thyroid cancer. Serum TG levels, in the absence of antibodies interfering in the assay, correlate well with tumor burden, although detectable tumor may well be present even in the presence of negative TG assays in individuals who are on replacement thyroid hormone (346). Pacini et al (347) reported that in a retrospective study of 315 patients who had undetectable serum TG in the hypothyroid state at the time of the first control body scan after thyroid ablation, no useful information was provided by the body scan. Thus they propose that diagnostic 131I whole body scans can be avoided in patients with undetectable levels of stimulated TG after initial ablation, and that the patients can be monitored with clinical examination, ultrasound, and serial TG measurements on thyroxin treatment during the subsequent follow-up.

However, some concerns may be noted. The TG assay used in their study recognized a value of <3ng/ml as "undetectable". Also, of the 90 patients in the study with thyroid bed RAIU, 54 received a second course of treatment, and seven received two additional courses. This seems to question the recommended approach (347). In a second study (348) they found that an undetectable TG, when hypothyroid at the time of the first control scan after ablation, predicted complete and permanent remission. They propose that subsequent 131-I scanning is unneeded, and follow-up clinically and by TG assays while on thyroxin, would be sufficient. Mazzaferri and Kloos (349) studied retrospectively 107 patients who were “clinically free of disease” and had undetectable or very low serum TG levels during thyroid hormone therapy. The Tg levels on treatment were all 1 ng/ml or less, and 95% were under 0.5 ng/ml in their assay, which was a commercial (Nichols Institute) chemoluminescent antibody assay. In response to the administration of two doses of recombinant TSH and assay of TG on samples taken on the fifth day, 20% were found to have a value above 2, with values ranging from above 2 up to 18 ng/ml. Twenty percent of the patients who had low or undetectable Tg had elevation above 2 ng/ml after rhTSH stimulation, and many of these patients ended up with therapy. However, the authors found that radioactive iodide whole body scans often failed to localize the source of the elevated TG, which was found after post-therapy scans or by other imaging methods. This study suggests that even with a TG level below 1 while on replacement therapy, persistent disease may sometimes be present and be detected by stimulation using recombinant TSH or thyroid hormone withdrawal.

Wartofsky (350,351) comments on these studies and supports the idea that TG testing, both on suppression and after TSH stimulation, can help in determining therapy. He suggests that, in patients with a serum TG<0.5ng/ml on suppression, and in a low risk category, that stimulation by recombinant TSH and measurement of TG, rather than scanning, is satisfactory. If the TG remains <1, the patients can be evaluated annually with such a stimulation test. In patients with slightly higher TGs, up to 2, he suggests measuring a recombinant TSH stimulated TG, and scanning. In patients with higher TGs, he suggests that thyroid hormone withdrawal and radioactive iodide treatment, without initial scanning, may be appropriate. In a study done by the rhTSH-Stimulated Thyroglobulin Study Group (352) and published in 2002, a cut off level of 1 ng/ml for stimulated TG was taken as the safe level for patients with low risk. This group would presumably be monitored by repeat rTSH stimlated TG assays rather than scans. It is of interest that in this study 14 of the patients with stimulated TG <2ng/ml underwent isotope scanning and 9 were positive. These "could be interpreted as false negative" tests. Five had uptake outside the thyroid bed. This group suggests that patients with stimulated TG above 2 would have subsequent thyroid hormone withdrawal and possible 131-I therapy without scanning. A recent “consensus” statement by a group of thyroidologists also supports the categorization of patients into high and low risk groups, and use of TG as described above for following low risk patients (353).

Whether this approach, with omission of whole body scans, has any adverse effect on long term outcome is not yet known.

STUNNING FROM "TRACER" RAI-

The amount of 131I used for scanning varies from 2-10 mCi, in various clinics, or even larger amounts. Clearly the larger doses detect more lesions, but this rarely alters treatment plans. More importantly, doses of 5-10 mCi have been shown to decrease tumor uptake of the subsequent treatment dose due to "stuning" of the tumor (354). The exact importance of this phenomena is uncertain, but use of a 2mCi dose has seemed to be a reasonable compromise. A study by Lassmann et al (355) call this assumption into question, since they found that even a 2mCi scan dose reduced RAIU by up to 50% in a second procedure done 6 weeks later.This study was carefully performed on a few patients, but it is possible that prolonged stimulation of the thyroid by elevated TSH may have adversely altered iodide kinetics in the remnants during the second RAIU procedure.

Although a reduction of uptake after prior low dose scans has been reported, it is uncertain that this limits the effectiveness of treatment. It was found that ablation rates were equal in individuals who had, or had not, received scans prior to their treatment dose of 131-I (356).

Ingestion of large amounts of iodide, or exposure to contrast dye within 6 (or more) weeks, can prevent RAIU. Uptake can be enhanced by prescribing a low iodine diet for at least two weeks before scanning and therapy, although also this assumption has been questioned by a recent study (331). It is useful to give magnesium citrate to induce bowel emptying prior to the scan. As discussed above, the value of routine follow-up diagnostic scans has been challenged by two European study, who suggest that such scans rarely give information of value in patients who have TG <1 after thyroid ablation (357,358). They suggest testing TG after thyroid hormone withdrawal or rhTSH, and directly treating those with TG above 10 by administration of 100mCi 131-I. This concept is of interest and awaits further examination, but has obvious problems as noted.

HIGH DOSE RAI THERAPY FOR INVASIVE OR METASTATIC DISEASE

Efficacy and morbidity of high activity of 131-I therapy was assessed in 38 patients with locally advanced or metastatic differentiated thyroid cancer (16 follicular, 20 papillary, one Hurthle cell, one insular) who were treated with high activity radioiodine therapy (9 GBq) as the cancers had previously not responded to standard activities of 5.5 GBq.

After high activity treatment, 9.7% of patients suffered grade 3 and 3.2% suffered grade 4 WHO haematological toxicity. Significant salivary gland morbidity was observed (30% dry mouth, 27% salivary swelling). In this study repeated treatment with high activity (9 GBq) in patients with advanced differentiated thyroid carcinoma appeared to be of no apparent benefit and lead to late morbidity (359). However, other investigators have differing results. A retrospective analysis was conducted on 124 differentiated thyroid cancer patients who underwent dosimetric evaluation using MIRD methodology over a period of 15y. One hundred four RAI treatments were performed. A complete response at metastatic deposits was attained with absorbed doses of >100Gy. No permanent BM suppression was observed in patients who received absorbed doses of<3Gy to BM. The maximum administered dose was 38.5 GBq (1,040 mCi) with the BM dose limitation. Dosimetry-guided RAI treatment allowed administration of the maximum possible RAI dose to achieve the maximum therapeutic benefit. Estimation of tumor dose rates helped to determine the curative versus the palliative intent of the therapy (360).

131-I Therapy with "Negative" scans

In some patients tracer studies fail to show uptake, and serum TG is elevated. Some investigators recommend treating these individuals with large doses of 131I (100¬-150 mCi) and report that tumor uptake can be visualized after treatment, and that serum TG may fall (373,374) (Fig. 18-18). The clinical efficacy of this approach is not known. In a few cases reported by Schlumberger et al. (375) and Pineda et al. (376). TG became undetectable, which clearly is a striking and hopeful result. As of this date, there is no data proving that this treatment improves prognosis (377).

The utility of radioactive iodide treatment of patients with papillary and follicular cancer was recently reviewed in a series of articles by Wartofsky, Sherman, and Schlumberger and their associates (333). Sherman and Gopal analyzed the use of 100 mCi doses of 131I for treatment of scan negative TG-positive patients and conclude that this must, at this point, be considered an experimental procedure of uncertain benefit. They argue against its use in young patients with elevated although apparently stable TG values and without radiographic evidence of disease. Fatourechi et al. (378) analyzed results of this treatment in a series of patients treated at the Mayo Clinic and concluded that it rarely produced significant effect, although it possibly helped stabilze disease in patients with micro metastases in the lung. It is clearly ineffective in patients who have metastases large enough to be detected on chest X-ray of CAT . Wartofsky et al. (333) sug¬gests that, rather than initial treatment with 131I of patients who are scan negative and TG-positive, thorough imaging studies are appropriate. These might include a CAT scan of the chest, an MRI of the neck, 99mTc-MIBI, or 18-fluorine fluorodeoxyglucose PET scanning, or even 99mTc-tetrafosmin, or 201TI thallium. Localization of malignant tissue by any of these means may allow surgical excision or external radiotherapy. This series of articles provides many very useful thoughts on management of diffi¬cult patients with recurrent thyroid carcinoma.

Figure 18-18

Changes in serum TG after therapeutic doses of radioiodine in patients with negative basal whole-body scans. The arrows indicate the administration of therapeutic doses of 131-I. The numbers represent individual patients. In most patients, thyroglobulin decreased, although only in a few to a level that would indicate absence of residual disease. (From Pacini et al, J Nuc Med 28:18888-1891, 1987)

Maximal dose protocols

The therapeutic protocol used at Memorial Hospital in New York, by Maxon (363), and as well at some other centers, has for years been designed to give maximal-tolerable radiation doses to cancer patients (231). The dose is calculated on the basis of prior isotope tracer kinetics. The aim is to give a blood dose of under 200 rads, or less than 120 mCi retained at 48 hours, or 80 mCi retained at 48 hours if diffuse lung metastases are present. This method has theoretical advantages since it potentially provides the most cancericidal dose, but the difficulties of calculating the dose and the occasional adverse reactions have so far prevented this method from being generally employed. The dosimetric approach has been carefully reviewed by Van Nostrand et al (361).

Figure 18-19a

Chest radiographs of a patient with extensive follicular thyroid carcinoma prior to (upper) and after 131-I therapy (lower). With 131-I therapy there was resolution of the large pulmonary metastases, but a tumor in the cervical vertebrae progressed and caused instability of the spine.

Figure 18-19b

Chest radiographs of a patient with extensive follicular thyroid carcinoma prior to (upper) and after 131-I therapy (lower). With 131-I therapy there was resolution of the large pulmonary metastases, but a tumor in the cervical vertebrae progressed and caused instability of the spine.

RADIATION PRECAUTIONS

Before radiation therapy, female patients should be carefully screened for pregnancy and lactation. Confirmed or possible pregnancy constitutes a firm contraindication to therapy because of the risk of damage to the fetus.

A patient who has ingested many milliCuries of 131I can cause serious radiation contamination, and appropriate precautions must be followed. If less than 30 mCi 131I is given, it is permissible to have the patient dispose of urine and feces into general sewage. If amounts of 131I greater than 30 mCi are given, the patient should be kept in a private room in the hospital until less than 30 mCi is retained in the body. Urine can be directly disposed in sewage, or can be collected by the patient and stored in bottles behind protective lead shielding. After physical decay, usually after about 6 weeks, it may be discarded in the sewage. Contaminated bedding and utensils should be stored for 10 half-lives (80 days), thoroughly washed, and monitored for residual contamination before being used again. Alternatively, disposable bedding and utensils may be used.

Personnel caring for a patient who has received 131I therapy are often concerned about exposure to excessive radiation. This is almost never a real problem. Isotope can, at a practical level, only be passed from the patient to another person via saliva or urine. Monitoring by means of a portable counter is important in making certain that no person receives more than an allowable radiation dose from the isotope in the patient’s body. Table 18-9 gives a rough estimate of the amount of radiation received while performing ordinary hospital tasks at various distances from a patient who has received 131I. In general, all ordinary patient care can be performed without hazard. It is best to avoid close contact between hospital personnel and patient during the first 48 hours after therapy because of undue apprehension that may be induced. However, even after doses of up to 100 mCi, normal personal actvities such as eating at the same table, or driving in the same car, carry no risk to others.

The US Nuclear Regulatory Commission has published new guidelines which allow release of patients treated with isotopes from the hospital if the total effective radiation exposure from the treated person to any other individual is not likely to exceed 5mSv (0.5 rads). Grigsby et al (379) found that when using precautions such as those described above in a group of patients given on average about 100mCi 131-I, the exposure to other individuals in their household and to pets did not exceed this level. Recently, guidelines for the optimal radiation protection after treatment with 131-I have been proposed by the American Thyroid Association (380).

FOLLOW-UP OF CANCER PATIENTS: THE SERUM TG ASSAY

After initial ablation patients are given TSH-suppressive doses of l-thyroxine. This therapy as dual aims: to replace the thyroid hormone function and to inhibit the growth of potential residual disease..Two-three months later serum TSH, free thyroid hormones and Tg concentrations are measured during l-thyroxine treatment. The results of these tests will disclose whether the l-thyroxine dose is adequate in suppressing TSH levels without inducing hyperthyroidism, but will give little information on whether the patient is in remission.

To this purpose, the most informative follow-up period is at 6-12 minths after initial treatment, when the ablative dose of radioiodine should have exerted its effect. At this point, the patients have been already attributed a risk estimate based on the results of the post-ablative WBS and serum Tg measurement (397,398). This information is important at the moment of the new evaluation. If uptake was seen outside the thyroid bed on the post-therapy WBS, the patient must be considered in high risk of recurrence or persistent disease, while if no uptake was seen outside the thyroid bed on the 131-I post-therapy scan, the Patient is considered at low-risk. The 6-12 month control, consists of careful neck ultrasound to detect the lymph node status and serum Tg levels (with negative anti-Tg) after stimulation with exogenous (better) or endogenous TSH. These tests are considered by many authors as sufficient to confirm complete remission (negative US and undetectable stimulated Tg). Other advocate the usefulness of a diagnostic WBS with radioiodine, aimed to ensure that thyroid ablation has been successful and to search for foci of 131-I uptake outside the thyroid bed. However, two independent studies (357,399) have shown that this diagnostic WBS are almost always negative (and sometimes false negative) thus adding very little information to that given by neck US and serum Tg measurement. Indeed, the result of serum Tg measurement is the more sensitive predictor of complete remission or persistent disease (provided that anti-Tg autoantibodies are negative) (400-404). Nearly all patients with local or distant disease have detectable or elevated serum Tg levels, while patients in stable remission have undetectable serum Tg concentrations. Compared to serum Tg measurement, the yield of the diagnostic 131-I WBS is lower. A significant proportion of patients may have elevation of serum Tg in the presence of falsely negative diagnostic WBS. A retrospective study by Cailleaux et al. (357) has shown that when serum Tg off therapy is undetectable, routine diagnostic WBS does not add any further in¬formation on the clinical status of the patient. Similar results have been obtained at the Department of Endocrinology, University of Pisa, (399) in a retrospective series of 315 patients who had undetectable serum Tg off l-thyroxine at the time of the first control after thyroid ablation. None of these patients had evidence of disease activity at WBS, and 99.4% were in complete and stable remission after 12 years of follow-up. Only two patients (0.6%) had recurrence of lymph node metastases which were treated with radioiodine therapy. Based on these studies it is possible that in the future the need for 131-I scanning may be dictated by the results of serum TG during hypothyroidism or by rhTSH-stimulation (342).

After this follow up, low-risk patients (those with an undetectable stimulated serum Tg, negative neck US and negative WBS, when performed) are considered as cured and may be followed with periodic serum Tg measurement during l-thyroxine therapy. Thyroxine therapy may be decreased to maintain a low but not suppressed serum TSH concentration (0.1-0.4 µU/ml). The risk of recurrence is in fact so low in these patients (representing more than 80% of the total) that overdosage of l-thyroxine is unjustified.

As noted the problem of antibody interference in the TG assay makes this test unreliable in 10-15% of patients. However another aspect of the antibodies should be remembered. If patients are free of thyroid cancer and the thyroid has been ablated, it appears that the antigenic stimulation necessary to maintain an anti-TG titer is gradually lost, and these antibodies disappear with a 3-6 year half-life (302). Thus, the level of anti.Tg antibodies may be used as a surrogate marker of disease. Other approaches, including the search of Tg mRNA in the blood, have been proposed, but none has entered clinical practice. Fugazzola et al (405) point out that the combination of TG RIA and TG mRNA assay offer better positive and negative predictive value than TG alone. In some studies TGmRNA analysis has proven much less reliable than serum TG assay (406).

In high risk patients, even if considered cured, suppressive doses of l-thyroxine may be continued for some years, because the risk of relapse is greater. Pujol et al evaluated a series of patients over an average of 95 months and compared those who had TSH values constantly under 0.05 mU/l to those who had all TSH values greater than 1mU/l. A lesser degree of TSH suppression was associated with an increased incidence of relapse, with a shorter average relapse-free survival (407). This observation was not sustained in another study (408). The objective of suppressive therapy in these patients should be to attain a serum TSH level of 0.1 µU/ml or less with normal free T3. In this situation, side effects such as osteoporosis, are not observed (409). Clinical and biochemical evaluation is performed annually. If serum Tg becomes detectable during follow-up, the patient should be evaluated for the presence of disease by neck us, first, and by other imaging if neck ultrasound is negative. Some authors prefer to avoid this procedure and give directly a therapeutic dose of 131-I followed by a post-therapy scan. In the absence of uptake after therapeutic doses of 131-I, any further administration of 131-I is not justified, and the site of Tg production should be searched for by other imaging techniques. If 131-I thyroid ablation has not been performed or if the patient has undergone only partial thyroid surgery (subtotal or lobectomy), follow-up should consist of clinical and ultrasound examination and serum Tg measurement. However, in this case, the sensitivity and specificity of serum Tg assay is reduced. In such patients, ant suspicious of persistent or recurrence disease should prompt to complete the initial treatment with completion thyroidectomy and/or radioiodine ablation.

During follow-up, patients may develop isolated metastases that can be approached surgically. Osseous metastases, especially from follicular cancer, may require radiotherapy or operative procedures for stabilization. Progressive growth of soft tissue or osseous metastases that are not amenable to thyroid hormone, 131I therapy, or radiotherapy should lead to consideration of systemic therapies.

UNDIFFERENTIATED CARCINOMAS

Undifferentiated carcinomas, if operable, may be treated by thyroidectomy and resection of all involved tissue in the neck. 5-10% can apparently be completely resected, and the patient can have a discrete survival, although they are never cured. Prophylactic X-radiation (5,000 rads) should be given postoperatively in all cases.. If the lesion is obviously inoperable, X-ray therapy should be the initial treatment. In some instances, the rapidly growing tumors melt almost completely for a time after X-ray therapy, giving the pa¬tient a gratifying respite from the disease.

Some anaplastic tumors have been treated with alkylating agents, and rarely, a rapidly proliferating and highly undifferentiated tumor has responded with a temporary regression. Chemotherapy is discussed below. Kim and Leeper (410) reported partial results combining low dose adriamycin (10 mg/m2) and hyperfractionated radiotherapy (160 rads twice daily) to 5760 rads. Time of survival was prolonged and local recurrences largely prevented. There has been no confirmation of this study, unfortunately.

A prospective protocol combining surgery, chemotherapy (CT),and hyperfractionated accelerated radiotherapy (RT) was employed in anaplastic thyroid carcinoma. The main toxicity was hematologic. High long-term survival was obtained when RT-CT was given after complete surgery. This protocol avoided local tumor progression, and death was mainly caused by distant metastases (411). The clinical behaviour and therapy of anaplastic carcinoma have recently been reviewed by K. Ain (412).

Despite any combination of therapies, anaplastic thyroid cancer remains one of the most aggressive human cancer, with 80% of the patients dying within 2 6 months and the remaining within 2 years. Novel treatment regimens are badly needed for this tumor.

RADIATION THERAPY

The general indications for radiation therapy are given in Table 18-11. Other sources should be reviewed for details of the port, dose, and methods of irradiation.

Studies by Tubiana et al (416), Simpson (283), and Riccabona (417) have clearly established the efficacy of radiotherapy in all types of thyroid cancer. Although its therapeutic use is now well accepted, its prophylactic use (e.g., in papillary or follicular lesions with possible residual disease, or in papillary or follicular Stage III lesions after RAI ablation) is controversial. Currently, we would first treat all papillary or follicular invasive or possibly metastatic tumors with RAI. In patients under age 55, it is not clear that x-ray therapy should be added. Over age 55, 131I therapy should be followed by x-ray treatment for Stage III or potentially Stage III lesions, and any recurrence or metastasis not responding to 131I may also be treated (418).

The efficacy of external radiation therapy in the management of thyroid malignancy has been reviewed by Brierley et al, Lin et al, Farahati et al, and Tsang et al. (419-422). Brierley, recommends X-ray therapy in addition to 131I therapy in patients with papillary or follicular cancer who have probable or definitive microscopic residual disease. They gave 30 to 50 Gy over four weeks with the spinal cord dose less than 80% of the total. Radiotherapy was also advised for treatment of anaplastic thyroid carcinoma, in an attempt to achieve local control, using hyperfractionation, possibly with the addition of doxorubicin. Radiotherapy was used for treatment of lymphomas, with a total dose of 35 – 40 Gy given over four weeks, and was typically preceded by the use of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) delivered every three to four weeks in three to six cycles prior to the radiotherapy. Cause-specific survival was 82% inpatients who received combined therapy and 63% in those who got X-ray alone. Combined therapies were given to all patients except those with small bulk disease under 3 cm in size confined to the thyroid, who received radiation alone. Lin et al. (420) evaluated 699 patients with differentiated thyroid cancer who received external radiotherapy after surgery, compared to 172 who did not, and found no evidence that radiotherapy improved survival rate of patients with well differentiated thyroid cancer. These were patients with either neck nodes or local invasion.There were 172 patients who received no radiotherapy versus 32 who did. The patients were in clinical stages 2 and 3 at the time of treatment. Farahati et al (421) looked at patients with parathyroidal tumor invasion and found that adjuvant external radiotherapy improved recurrence-free survival in patients over 40 years of age. Benefit was confined to patients with papillary thyroid carcinoma. Tsang et al (422) also confirmed the benefit of radiotherapy in patients with papillary tumors who have microscopic or macroscopic residual disease.

Note- Spinal cord dose not to exceed *3000 or ** 3500 rads.

In a recent study (423), Hurthle cell carcinoma of the thyroid gland was found to be a radiosensitive tumor. Adjuvant radiation therapy was successful in preventing recurrence in 4 of 5 patients. Salvage radiation therapy was successful in 3 of 5 patients treated with external beam radiation therapy. Palliative radiation therapy provided sustained symptomatic relief at 67% of irradiated sites. Radiation therapy may provide palliative relief from symptomatic metastases, control recurrent tumors, and prevent recurrence of advanced resected tumors.

The indications for MTC have been described above. Stage I-E lymphomas may be treated by chemotherapy or radiotherapy. Anaplastic lesions are currently given radiotherapy after operation. It is possible that chemotherapy should be used instead of or in addition to radiotherapy in these lesions, but studies are needed to establish this point.

The exact dose must be individually determined, but usually the maximal dose is 5,000-6,000 rads, using ortho-or megavoltage, and a fractionated technique over several weeks. Dosage must be planned to assure that the spinal cord receives less than 3500 rads in order to avoid myelopathy.

SYSTEMIC THERAPY FOR METASTATIC DISEASE

Sporadic experience indicates that bleomycin (424,425), adriamycin (426), vinblastine (427), methotrexate (426), cisplatinum and other agents (428) may have value in treating disseminated thyroid tumors. However, none of these drug has given more than palliation. With the advent of new molecules targeting specific metabolic pathways involve in the generation and maintainance of thyroid cancer growth, the so call “tyrosine kinase inhibitor’, chemotherapy has been almost universally abandoned. Recent ATA guidelines (39) states that whenever systemic therapy is needed, the patient should be offered the possibility to be entered in clinical trials using these new molecules. Metastatic papillary or follicular tumors refractory to conventional therapy grow slowly and systemic therapy is not indicated until the tumor is clearly growing progressively despite hormone suppression. The same apply to the treatment of MTC (264).

RE-DIFFERENTIATION’ THERAPY

RETINOIC ACID- Experimental data from in vitro studies suggest that retinoic acid can inducere-differentiation of thyroid cancer cells with regain of iodide concentrating ability. Simon et al (429) studied 28 patients with differentiated thyroid cancer using 1.5 mg/kg retinoic acid per day for five weeks. Iodide uptake increased in eight of the patients and thyroglobulin increased in 63%. Thus retinoid appeared to reinduce iodide uptake in half of the treated patients by redifferentiation. They gave 13-cis-retinoic acid. Side effects occurred in half of the patients but were generally well tolerated. A common side effect was dryness of the skin and mucosal surfaces. The reinduction of 131I uptake allowed radioiodine therapy in several of the patients. The effect on tumor size was uncertain. Retinoic acid redifferentiation therapy has recently been reviewed by Schmutzler and Kohrle (430). They note that, of twenty documented retinoic acid treated patients, at least eight had exhibited a decrease or stabilization in tumor size, and in serum TG levels, in addition to enhanced radioiodide transport. However, this relatively positive review seems enthusiastic, considering the small evidence of improvement observed in most cases. Clearly the ben¬efits of this experimental treatment are as yet uncertain, but it is nevertheless an exciting observation that retinoic acid can have an apparent beneficial redifferentiating effect on some thyroid tumors. Histone deactylase inhibitors also have been found to restore in part the function of NIS, TPO and TG in thyroid tumor cells in vitro (431), and valproic acid also has an action to restore NIS function, probably via the same mechanism (432).

PPARgamma agonists-In vitro studies show that PPAR gamma agonists can slow thyroid tumor cell growth and induce apoptosis (433). Results of clinical trials are awaited.

ONYX-015is an E1B deleted adenovirus that replicates in cells with impaired p53 function. p53 is commonly inactivated in anaplastic thyroid cancers. In vitro studies demonstrate that this virus induced cell death in in vitro trials in anaplastic cancer cell lines, and synergized with treatment with doxorubicin and pacitaxel (434).

Adenoviral vectors producing tk, IL-2, IL-12, and GM-CSF in a cell specific manner are currently under study in animals with encouraging results. Studies in humans are so far very limited, but the methods appear to be safe and effective, especially with the immunomodulator IL-12 (434,435).

A variety of ideas on possible treatments for thyroid cancer have been reviewed by Braga-Basaria and Ringel (436).

TYROSINE KINASE INHIBITORS

Several oncogenes involved in thyroid cancer progression are tyrosine kinase receptor. Molecules that block kinase activity at distal steps in the MAP kinase pathway are logical candidate drugs for thyroid cancer. TKI being tested against differentiated thyroid cancer in clinical trials include motesanib diphosphate, axitinib, gefitinib, sorafenib and sunitinib. None of these is specific for one oncogene protein but they target several TK receptors and pro-angiogenic growth factor receptors. The results of phase II-III clinical trials conducted so far are promising with partial responses ranging 14- 32% and stable disease 50-67% (437). In addition, very recently one of this drug, vandetanib, have been approved for the treatment of progressive, metastatic MTC, based in clear evidence of beneficial effects in clinical trials (438,439). All together, the preliminary results of these trials are promising and indicate that target therapy might become the first line treatment of metastatic refractory thyroid cancer patients in the near future.

Sunitinib is a multitargeted tyrosine kinase inhibitor (TKI) that is is currently approved for the therapy of renal cell carcinoma and gastrointestinal stromal tumor. Some eficacy was found in both differentiated thyoid cancer and medullary cancer in Phase II studies, with partial response rates of 13-30%.

Sorafenib is a similar agent, also achieving significant levels of partial responses and stabilized disease. Several Phase II stuies have been reported, and a Phase III trial has been completed.

Vandetanib has been studies in Phase II trials and in a randomized, placebo-controlled phase III study in patients with both hereditary and sporadic MTC, using vandetanib 300 mg or placebo. A 54% reduction in the risk of progression was observed and also objective tumor responses in 45% of patients. The FDA approved it for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Motesanib, Axitinib, Pazopanib, Lenvatinib and several other related TKIs that more specifically block VEGF receptors are in Phase II or III trials.

These agents appear to block progression and in some studies decrease tumor bulk, but are not specifically cytotoxic, and tend to loose efficacy over months, presumably by mutational events in the tumor. Future studies will surely investigate serial or combined treatments, and use with other possibly cytotoxic agents.

Progress in the last few years has reinvigerated therapy for these difficult tumors, but comes with a price. Since TRK Iinhibitors affect many sites in the body, side effects are very common and often serious, but generally tolerable The major side-effects include hypertension in 20-50% of cases, diarrhea in 37-77%, fatigue in 40-50%, weight loss in 20-60%, frequent nausea, skin sensitivity, and very frequent rashes, depending on the study, dosage,and drug (439). Some of the agents induce hypothyroidism during therapy.

Most reports available are the result of clinical investigations, often by consortia made up of physicians specializing in therapy of thyroid cancer, and patients are generally advised to enter such a trial if a newer agent is used.. However these agents gradually spread into more generaized usage, by therapists who may not have extensive experience. The MD Anderson group has published suggested institutional guidelines to help provide safeguards for non-investigative use of TKIs(440).

Presentation of this chapter is supported in part by Genzyme, the makers of rhTSH (THYROGEN)

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