PAPILLARY AND FOLLICULAR THYROID CARCINOMA

1. PAPILLARY AND FOLLICULAR THYROID CARCINOMA 95/07/07 The New England Journal of Medicine, January 29, 1998 ???

2. Introduction Papillary and follicular (differentiated) thyroid carcinomas are among the most curable cancers. However, some patients are at high risk for recurrent disease or even death. Most of these patients can be identified at the time of diagnosis by using well-established prognostic indicators. The extent of the initial treatment and follow-up care should therefore be tailored to the level of risk.

3. EPIDEMIOLOGY Although thyroid nodules are common, differentiated thyroid carcinomas are relatively rare. Clinically detectable thyroid carcinomas constitute less than 1 percent of all human cancers. The annual incidence rate in various parts of the world ranges from 0.5 to 10 cases per 100,000 population. Papillary and follicular cancers are rare in children and adolescents, and their incidence increases with age in adults.

4. The median age at diagnosis is 45 to 50 years. Thyroid carcinomas are two to four times as frequent in women as in men. Thyroid microcarcinomas (diameter, 1 cm) are found in 5 to 36 percent of adults at autopsy but are rare in children. The reported increase in the incidence of these small carcinomas in recent years can be attributed to an improvement in pathological techniques.

5. PATHOGENESIS Oncogenes Thyroid Irradiation Other Factors

6. Oncogenes Recent advances in molecular biology have improved our understanding of the pathogenesis of thyroid carcinomas. Rearrangements of the tyrosine kinase domains of the RET and TRK genes with the amino-terminal sequence of an unlinked gene are found in some papillary carcinomas. Activating point mutations of the RAS genes are found with a similarly high frequency in thyroid adenomas and follicular carcinomas, suggesting that RAS mutations represent an early event in thyroid tumorigenesis.

7. Thyroid Irradiation External irradiation to the neck during childhood increases the risk of papillary thyroid carcinoma The latency period between exposure and diagnosis is at least five years. The risk is maximal at about 20 years, remains high for about 20 years, and then decreases gradually. The risk is increased after a mean dose to the thyroid as low as 10 cGy. At higher doses (up to 1500 cGy), there is a linear relation between the dose and the risk of carcinoma.

8. At doses higher than 1500 cGy, the risk per gray decreases, probably because of cell killing. The risk of thyroid carcinoma is not increased in patients given iodine-131 for diagnostic or therapeutic purposes.

9. Other Factors In countries where iodine intake is adequate, differentiated cancers account for more than 80 percent of all thyroid carcinomas, with the papillary histologic type being the more frequent (accounting for 60 to 80 percent of cases). There is no increase in the incidence of thyroid carcinomas in countries where iodine intake is low, but there is a relative increase in follicular and anaplastic carcinomas.

10. A high incidence of papillary carcinomas has been reported in patients with adenomatous polyposis coli and Cowden�s disease (the multiple hamartoma syndrome). About 3 percent of cases of papillary carcinoma are familial.

11. PATHOLOGICAL FEATURES Papillary Carcinoma Follicular Carcinoma

12. Papillary Carcinoma Papillary carcinoma is an unencapsulated tumor with papillary and follicular structures that is characterized by overlapping cell nuclei that have a groundglass appearance and longitudinal grooves, with invaginations of cytoplasm into the nuclei. Encapsulated, follicular, tall-cell, columnar-cell, clearcell, and diffuse sclerosing carcinomas are recognized histologic variants; they are classified as papillary carcinomas because of their characteristic nuclear features.

13. The tumor is multicentric in 20 to 80 percent of patients (with the wide range attributable to variations in the care used to examine the thyroid) and bilateral in about one third. It spreads through the lymphatics within the thyroid to the regional lymph nodes and, less frequently, to the lungs.

14. Follicular Carcinoma Follicular carcinoma is characterized by follicular differentiation but without the nuclear changes characteristic of papillary carcinoma. Follicular carcinomas are encapsulated, and invasion of the capsule and vessels is the key feature distinguishing follicular carcinomas from follicular adenomas. Two forms are recognized according to the pattern of invasion: minimally invasive and widely invasive carcinomas.

15. The growth pattern may also vary, ranging from a well-differentiated pattern with macrofollicular structures to a poorly differentiated pattern with areas of solid growth and a high degree of atypia. Multicentricity and lymph-node involvement are less frequent than in papillary carcinoma, and metastases to the lungs and bones stem from hematologic spread.

17. DIAGNOSIS Most differentiated thyroid carcinomas present as asymptomatic thyroid nodules, but the first sign of the disease is occasionally lymph-node metastases or in rare cases lung or bone metastases. Hoarseness, dysphagia, cough, and dyspnea suggest advanced disease. On physical examination, the carcinoma, usually single, is firm, moves freely during swallowing, and is not distinguishable from a benign nodule.

18. Among patients with thyroid nodules, the nodule is more likely to be a carcinoma in children and adolescents, patients older than 60 years, and men than in women 20 to 60 years old. Carcinoma should be suspected if a hard, irregular thyroid nodule is found, ipsilateral lymph nodes are enlarged or compressive symptoms are present, and there is a history of a progressive increase in the size of the nodule. Virtually all patients with thyroid carcinoma are clinically euthyroid and have normal serum thyrotropin concentrations.

19. Whatever the presentation, fine-needle aspiration cytology is the best test for distinguishing between benign and malignant thyroid nodules. Provided an adequate specimen is obtained, three cytologic results are possible: benign, malignant, or indeterminate (or suspicious). False negative results, usually from sampling or interpretive errors, and false positive results are rare. Only about 20 percent of patients with indeterminate findings have malignant nodules, reflecting the difficulty of differentiating benign follicular adenomas from their malignant counterparts.

20. Thyroid ultrasonography is useful for assessing the size of the nodule, detecting other nodules, and guiding fine-needle biopsy in the case of a nodule that is small or difficult to palpate.

21. PROGNOSTIC FACTORS The overall survival rate at 10 years for middle-aged adults with thyroid carcinomas is about 80 to 95 percent Five to 20 percent of patients have local or regional recurrences, and 10 to 15 percent have distant metastases. The prognostic indicators of recurrent disease and of death are the patient�s age at diagnosis and the histologic subtype and extent of the tumor.

22. Figure 2. Survival Rate among 1701 Patients with Papillary or Follicular Carcinoma and No Distant Metastases at the Time of Diagnosis.

24. INITIAL TREATMENT Surgery Iodine-131 Therapy External Radiotherapy

25. Surgery The goal of surgery is to remove all tumor tissue in the neck. Therefore, the thyroid gland and affected cervical lymph nodes should be resected. Although there is still some controversy about the extent of thyroid surgery, there are strong arguments in favor of a total or near-total thyroidectomy (leaving no more than 2 to 3 g of thyroid tissue) in all patients.

26. Total or near-total thyroidectomy results in a lower recurrence rate than more limited thyroidectomy because many papillary carcinomas are multifocal and bilateral. Furthermore, removal of most, if not all, of the thyroid gland facilitates total ablation with iodine-131. The argument against total thyroidectomy is that it increases the risk of surgical complications such as recurrent laryngeal-nerve injuries and hypoparathyroidism. Even with total thyroidectomy, often some thyroid tissue remains, as detected by postoperative scanning with iodine-131.

27. Iodine-131 Therapy Iodine-131 therapy is given postoperatively for three reasons. First, it destroys any remaining normal thyroid tissue, thereby increasing the sensitivity of subsequent iodine-131 total-body scanning and the specificity of measurements of serum thyroglobulin for the detection of persistent or recurrent disease. Second, iodine-131 therapy may destroy occult microscopic carcinoma, thereby decreasing the longterm risk of recurrent disease.

28. Third, the use of a large amount of iodine-131 for therapy permits postablative iodine-131 total-body scanning, a sensitive test for detecting persistent carcinoma. Postoperative iodine-131 therapy should be used selectively. In low-risk patients, the longterm prognosis after surgery alone is so favorable that iodine-131 ablation is not usually recommended. However, all patients who are at high risk for recurrent disease should be treated with iodine-131, because it decreases both recurrence and death rates.

29. Iodine-131 scanning is performed four to six weeks after surgery, with no thyroid hormone treatment given in the interim. At our center, we use a dose of 2 mCi (74 MBq) of iodine-131 and obtain a total-body scan three days later. If any iodine-131 uptake is detected in the thyroid bed or elsewhere, a treatment dose is given. Another total-body scan is obtained four to seven days later, and thyroxine therapy is initiated. Total ablation is verified by performing iodine-131 total-body scanning 6 to 12 months later with 2 mCi.

31. External Radiotherapy External radiotherapy to the neck and mediastinum is indicated only in patients in whom surgical excision is incomplete or impossible and the tumor tissue does not take up iodine-131.

32. FOLLOW-UP The goals of follow-up after initial therapy are to maintain adequate thyroxine therapy and to detect persistent or recurrent thyroid carcinoma. Recurrences are usually detected during the early years of follow-up, but may be detected later. Therefore, follow-up is necessary throughout the patient�s life.

33. Thyroxine Treatment The growth of thyroid-tumor cells is controlled by thyrotropin, and the inhibition of thyrotropin secretion with thyroxine improves the recurrence and survival rates. Therefore, thyroxine, in the form of levothyroxine sodium, should be given to all patients with thyroid carcinoma, whatever the extent of thyroid surgery and other treatment. The effective dose in adults is between 2.2 and 2.8 ug per kilogram of body weight; children require higher doses.

34. The adequacy of therapy is monitored by measuring serum thyrotropin three months after treatment is begun, the initial goal being a serum thyrotropin concentration of 0.1 u U per milliliter or less and a serum free triiodothyronine concentration within the normal range.

35. Clinical and Ultrasonographic Examinations Palpation of the thyroid bed and lymph-node areas should be performed routinely. Ultrasonography is performed in patients at high risk for recurrent disease and in any patient with suspicious clinical findings. Palpable lymph nodes that are small, thin, or oval or that are reduced in size after an interval of three months are considered benign.

36. Serum thyroglobulin concentrations are undetectable in 20 percent of patients receiving thyroxine treatment who have isolated lymph-node metastases, and therefore, undetectable values do not rule out metastatic lymph-node disease. If there is a question of metastasis, an ultrasonographically guided lymph-node biopsy may be performed.

37. Chest Radiography Chest radiography is no longer routinely performed in patients with undetectable serum thyroglobulin concentrations. The reason is that virtually all patients with abnormal radiographs have detectable serum thyroglobulin concentrations.

38. Serum Thyroglobulin Measurements Thyroglobulin is a glycoprotein that is produced only by normal or neoplastic thyroid follicular cells. It should not be detectable in patients who have undergone total thyroid ablation, and its detection in such patients signifies the presence of persistent or recurrent disease.

39. The production of thyroglobulin by both normal and neoplastic thyroid tissue is in part dependent on thyrotropin. Thus, when interpreting the serum thyroglobulin value, one should take into account the serum thyrotropin value, as well as the presence or absence of thyroid remnants . If the serum thyroglobulin concentration is detectable during thyroxine treatment, it will increase after the treatment has been withdrawn. The serum thyroglobulin concentration is an excellent prognostic indicator.

41. Iodine-131 Total-Body Scanning The results of iodine-131 total-body scanning depend on the ability of thyroid-cancer tissue to take up iodine-131 in the presence of high serum thyrotropin concentrations, which are achieved by withdrawing thyroxine for four to six weeks.

43. CONCLUSIONS Most patients with papillary or follicular carcinomas can be cured. However, both the initial treatment and follow-up should be individualized according to prognostic indicators and any subsequent evidence of disease.

44. The End Thank you for your attention.