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Differentiated Thyroid Carcinoma: Risk Group Assignment and Management Controversies: Page 2 of 2

Differentiated Thyroid Carcinoma: Risk Group Assignment and Management Controversies: Page 2 of 2

Risk Group Assignment and Surgical Management

There is little debate among clinicians regarding patients assigned to high-risk groups. Total thyroidectomy is optimal,[8,13,38-40] but regardless of risk group assignment, total thyroidectomy is also recommended for patients with a prior history of irradiation, those with gross pathology in both lobes at the time of operation, and those who present with distant metastases. This approach allows for maximal locoregional control and more effective treatment of distant metastases with radioactive iodine (RAI).

No prospective randomized trials have demonstrated superior survival in patients undergoing total thyroidectomies. One prospective analysis showed no difference in outcome in selected patients with differentiated thyroid carcinoma who underwent total vs hemithyroidectomy.[39] However, most large retrospective studies indicate that this procedure increases locoregional control in high-risk disease.[40-43]

Proponents of limited thyroid resection (total lobectomy) argue that the risk of permanent hypocalcemia and recurrent nerve damage does not justify the use of total thyroidectomy in low-risk patients.[44-46] They also point out that limited thyroid resection may obviate the need for lifelong thyroid hormone replacement.[40]

We feel that risk group assignment and surgical intervention are closely linked. However, questions can be raised regarding the benefit of risk assignment systems in the treatment of differentiated thyroid cancer:

 

  1. Do these systems provide a basis for selection of a particular therapeutic approach?
  2. Which patients benefit from the selection?

Within the risk group assignment systems that have only low- and high- risk categories, some patients classified in the low-risk group eventually succumb to their disease (Table 4).

Intermediate-Risk Groups

The Memorial Sloan-Kettering system attempts to address this issue by assigning these patients to an intermediate-risk group.[22] These patients represent 15% to 20% of all patients with differentiated thyroid cancer. By subdividing patients into low-, high-, and intermediate-risk groups, the low-risk group patients do not die of thyroid cancer (Table 5).

At present, the extent of surgical treatment in patients assigned to the intermediate-risk group remains controversial. Treatment recommendations for this group of patients are based on subjective selection criteria and are usually individualized, based on the available prognostic factors at the time of surgery. Currently, at Roswell Park Cancer Institute, most patients in the intermediate-risk group undergo total thyroidectomy.

In making surgical decisions regarding patients in the intermediate-risk group, it is helpful to consider the morbidity associated with total thyroidectomy vs the risks of leaving residual thyroid tissue. The reported rate of permanent recurrent laryngeal nerve injury and permanent hypoparathyroidism averages 4% and 5%, respectively.[47-49] Almost all permanent injuries occur in advanced disease and reoperative procedures. The incidence of temporary morbidity (recurrent laryngeal nerve injury, hypoparathyroidism) is much higher than permanent disability and ranges from 13% to 51%.[47-49] Although temporary injuries do not result in long-term disability, there is an associated increase in patient care cost and inconvenience.

The risks of leaving residual contralateral thyroid tissue in the face of unilateral confirmed differentiated thyroid cancer in one lobe are not clearly defined. These risks have been conjectured to include anaplastic transformation and recurrent contralateral disease. In addition, serum markers, such as thyroglobulin (TGB), cannot be used as a potential indicator of recurrent disease.

Treatment of the Neck

The treatment of the clinically N0 patient is somewhat controversial. Many proponents of total thyroidectomy in differentiated thyroid cancer also advocate routine dissection of the central compartment.[50,51] They point to decreased regional recurrence as the rationale to this approach.

There are no data to support the elective use of posterior-lateral neck dissection in differentiated thyroid cancer (papillary and follicular). However, faced with palpable cervical adenopathy, a modified comprehensive neck dissection should be performed, rather then selective “picking” of clinically involved nodes.[52] This recommendation is based on clinical evidence that cervical recurrences of differentiated thyroid cancer respond poorly to radioactive iodine (RAI) treatment and therefore are best treated surgically.[8,13,43,53-55] In addition, regional control, while not proven to have an impact on survival, may be important to outcome and quality of life.

Adjuvant Radioactive Iodine and TSH Suppression

The question of how to effectively treat local, regional, and distant metastatic disease raises controversial issues regarding the use of adjuvant RAI and TSH suppression.

Radioactive iodine therapy is proposed to serve three clinical goals:(1) to ablate residual thyroid tissue preventing local recurrence; (2) to treat distant metastatic foci; and (3) to ablate local regional recurrences that are not amenable to surgical extirpation.

No study has prospectively compared a population treated with adjuvant RAI with a matched population treated with surgery alone. Only two recent retrospective studies have demonstrated a significant reduction in recurrences using adjuvant RAI.[56,57] In addition, one study reported a survival advantage in patients treated with RAI,[57] while several other studies showed no survival advantage of adjuvant RAI treatment.[8,58-60]

Some of the differences in clinical outcome seen with adjuvant RAI may be due to differences in dosage and treatment timing paradigms.[42,61,62] The side effects of RAI should not be minimized; these include radiation thyroiditis, sialoadenitis, radiation cystitis, and potential carcinogenic risk.[63,64] We presently support the use of RAI in all high-risk patients and in selected intermediate-risk patients.

RAI for Distant Metastases

Radioactive iodine remains the mainstay of the treatment of distant metastases. Distant metastases are seen more frequently in older patients (more than 45 years) both at initial presentation and after prior surgical therapy. The uptake of RAI in this cohort of patients is poorer then that seen in the younger population, 50% vs 70% overall.[43,55]

 Although it is generally accepted that RAI is effective in the treatment of distant metastases, a recent study in patients with distant disease questions the positive impact of RAI therapy on overall survival.[65] Moreover, the same study showed no difference in survival when distant foci were treated at the time of detection by RAI scan vs detection by conventional radiography. This multivariate analysis concluded that age and involvement of multiple organs were the only significant prognostic factors affecting survival in patients treated with RAI for distant metastases.[65] The evidence from this single study needs to be confirmed. We recommend detecting distant foci as early as possible using an RAI scan.

Role of TSH Suppression

The role of TSH suppression is less controversial. Several studies have demonstrated the beneficial effect of TSH suppression on survival and recurrence in patients with differentiated thyroid cancer.[31,60,63,66] We presently advise all patients with differentiated thyroid cancer to receive suppressive therapy. A TSH level below normal but detectable has been shown to be as effective as nondetectable TSH levels in suppressing serum TGB levels.[67]

H3> Patterns of Failure and Surveillance

In differentiated thyroid cancer, the two most common sites of failure are the neck (62%) and the lung (56%). Locoregional recurrences to the neck and mediastinum as well as distant metastases are responsible for most deaths.[56,68,69] Multiple surgeries improve survival and aggressive surgical attempts are essential in regaining local-regional control.[68,70] In patients with unresectable recurrent disease, external-beam therapy is effective and provides reasonable local control (50%).[61] Interestingly, two independent studies found that the extent of initial surgery did not significantly affect survival in advanced disease.[56,68]

Up to 5% of all treatment failures (locoregional and distant) occur after 20 years or more.[61] There are two reported cases of death from local and regional relapse of DTC more then 40 years after initial therapy. Interestingly, both patients received total thyroidectomies as initial therapy.[71]

In conclusion, an apparently benign course over 20 to 30 years does not preclude a fatal relapse; repeated aggressive attempts at surgical locoregional control seem justified; and external-beam radiation offers an effective tool in the control of locoregional disease that is not amenable to surgery.

Patients treated for differentiated thyroid cancer require long-term follow-up. No single modality is completely effective in detecting all recurrences.[72] A combination of clinical examination, serum TGB measurements, repeat FNA, and chest radiog- raphy are recommended. The frequency of RAI scanning after initial evaluation is a matter of clinical debate.

At present, we prefer to perform an initial RAI scan and to follow these patients with a repeat RAI scan at 3- to 5-year intervals. Thyroglobulin is a very sensitive marker of recurrence, but its specificity is low in the presence of residual thyroid tissue. A rise in TBG above 3 ng/mL is suggestive of recurrent disease.[73]

Our current practice is to clinically follow patients on at least a yearly basis indefinitely. Since most recurrences occur in the first 4 to 5 years,[72] more frequent examinations during this period would be considered safe practice.

Conclusions

Based on prognostic factors and risk group analysis, treatment of the majority of patients with differentiated thyroid cancer follows generally accepted guidelines. These are outlined in a consensus conference that included proponents of both total thyroidectomy and hemithyroidectomy.[74] Total lobectomy (lobectomy including isthmus), and near-total or total thyroidectomy are all reasonable therapeutic options for differentiated thyroid cancer. For a papillary carcinoma less than 2 cm, confined to one lobe, without extrathyroidal extension, and in the absence of distant metastases or contralateral cervical lymph node metastases, total lobectomy can be considered. It is also an accepted treatment for a follicular cancer confined to one lobe with low-grade histology (microinvasive) and in the absence of regional and distant metastases, particularly if the diagnosis of follicular cancer is obtained only after surgical intervention.

Total thyroidectomy and RAI ablation is recommended in all other patients. However, in selected inter- mediate-risk patients, morbidity and oncologic benefit should be carefully weighed. The impact of initial surgery and adjuvant RAI therapy on recurrence and death still needs to be clearly defined by conclusive clinical studies.

 It is hoped that the study of molecular mechanisms in differentiated hyroid cancer may reveal specific prognostic markers of progression and recurrence and help resolve some of the shortcomings of the current risk assignment systems.

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References

1. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1996. CA Cancer J Clin 46:5-27, 1996.

2. Jensen MH, Davis K, Derrick L: Thyroid cancer: A computer-assisted review of 5287 cases. Otolaryngol Head Neck Surg 102:51-65, 1990.

3. Nikiforov Y, Gnepp DR, Fajin JM: Thyroid lesions in children and adolescent after the Chernobyl disaster: Implications for the study of radiation tumorigenesis. J Clin Endocrinol Metab 81:9-14, 1996.

4. Cuello C, Correa P, Eisenberg H: Geographic pathology of thyroid carcinoma. Cancer 23:230-239, 1969.

5. Thompson NW: Endocrine neoplasia, in Niederhuber JE (ed): Current Therapy in Oncology, pp 240-248. St. Louis, Mosby Year Book-B.C. Decker, 1993

6. Shaha AR, Loree TL, Shah JP: Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 118:1131-1138, 1995.

7. Lang W, Choritz H, Hundeshagen H: Risk factors in follicular thyroid carcinomas: A retrospective follow-up study covering a 14 year period with emphasis on morphological findings. Am J Surg Pathol 10:246-255, 1986.

8. DeGroot LJ, Kaplan EL, McCormick M, et al: Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 71:414-424, 1990.

9. Farid NR, Shi Y, Minjing Z: Molecular basis of thyroid cancer. Endocrine Rev 15:202-232, 1994.

10. Taruscio D, Carcangui ML, Ried T, et al: Numerical chromosome alterations in thyroid tumors detected by double fluorescence in situ hybridization. Genes Chromosomes Cancer 9:180-185, 1994.

11. Grieco M, Santoro M, Berlingieri MT, et al: PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinoma. Cell 60:557-563, 1990.

12. Bongarzone I, Butti MG, Coronelli S, et al: Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 54:2979-2985, 1994.

13. Hay ID, Grant CS, van Heerden JA, et al: Papillary thyroid microcarcinoma: A study of 535 cases observed in a 50-year period. Surgery 112:1139-1147, 1992.

14. Lin JD, Chao TC, Weng HF, et al: Clinical presentation and treatment of 74 occult thyroid carcinomas. Am J Clin Oncol 19:504-508, 1996.

15. Woeber KA: Cost-Effective evaluation of the patient with a thyroid nodule. Surg Clin North Am 75:357-363, 1995.

16. Saunders LE, Rossi RL: Occult well differentiated carcinoma presenting as cervical node disease. World J Surg 19:642-647, 1995

17. Reverter RL, Lucas A, Salinas I, et al: Suppressive therapy with levothyroxine for solitary nodules. Clin Endocrinol 36:25-29, 1992.

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

19. Hay ID, Grant CS, Taylor WF, et al: Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102:1088- 1095, 1987.

20. Hay ID, Bergstrath EJ, Goellner JR, et al: Predicting outcome in papillary carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 114:1050-1058, 1993.

21. Shah, JP, Loree TL, Dharker D, et al: Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surgery 164:658-661, 1992.

22. Shaha AR, Loree TL, Shah JP: Intermediate-risk group for differentiated carcinoma of the thyroid. Surgery 116:1036-1041, 1994.

23. Shaha AR, Loree TL, Shah JP: Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 118:1131-1138, 1995.

24. Terry JH, St. John SA, Karkowski FJ et al: Tall cell papillary thyroid cancer: Incidence and prognosis. Am J Surg 168:459-461, 1994.

25. Russel MA, Gilbert EF, Jaeschke WR: Prognostic features of thyroid cancer. Cancer 36:553-559, 1975.

26. Tollefsen HR, Shah JP, Huvos AG: Papillary carcinoma of the thyroid: Recurrence in the thyroid gland after initial surgical treatment. Am J Surg 124:468-472, 1972.

27. McConahey WM, Hay ID, Woolner LB, et al: Papillary thyroid cancer treated at the Mayo Clinic 1946 through 1970: Initial manifestations, pathologic findings, therapy and outcome. Mayo Clin Proc 61:968-975, 1986.

28. Rossi RL, Cady B, Silverman ML, et al: Current results of conservative surgery for differentiated thyroid carcinoma. World J Surg 10:612- 622, 1986.

29. Coburn MC, Wanebo HJ: Prognostic factors and management considerations in patients with cervical metastases of thyroid cancer. Am J Surg 164:671-676, 1992.

30. Hay ID: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 19:545-576, 1994.

31. Cunningham MP, Duda RB, Recant W, et al: Survival discriminants for differentiated thyroid cancer. Am J Surg 160:344-347, 1990.

32. Hirabayashi RN, Lindsay S: Carcinoma of the thyroid gland: A statistical study of 390 patients. J Clin Endocrinol Metab 21:1596-1610, 1961.

33. Cady B, Sedwick CE, Meissner WA, et al: Changing clinical, pathological, therapeutic, and survival patterns in differentiated thyroid cancer. Ann Surg 18:541-553, 1976.

34. Rossi RL, Nieroda C, Cady B, Wool MS: Malignancies of the thyroid gland: The Lahey Clinic experience. Surg Clin North Am 65:211-230, 1985.

35. Hughes CJ, Shaha AR, Shah JP, et al: Impact of lymph node metastases in differentiated carcinoma of the thyroid: a matched pair analysis. Head & Neck 18:127-132, 1996.

36. Harwood J, Clark OH, Dunphy JE: Significance of lymph node metastasis in differentiated thyroid cancer. Am J Surg 136:107-112, 1978.

37. Sellers M, Beenken S, Blankenship A: Prognostic significance of cervical lymph node metastasis in differentiated thyroid cancer. Am J Surg 164:578-581, 1992.

38. Mazzaferri E, Young RL: Papillary thyroid carcinoma: A 10 year follow-up report of the impact of therapy in 576 patients. Am J Med 70:511-518, 1981.

39. Shah JP, Loree TR, Dharker D, et al: Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: A matched pair analysis. Am J Surg 166:331-335, 1993.

40. Clark OH, Levin K, Zeng Q, et al: Thyroid cancer: The case for total thyroidectomy. Eur J Clin Oncol 24:305-313, 1988.

41. Beierwaltes WH, Rabbani R, Dmuchowski C, et al: An analysis of “ablation of thyroid remnants” with I131 in 511 patients from 1947-1984: Experience at University of Michigan. J Nucl Med 25:1287-1293, 1984.

42. Varma VM, Beierwaltes WH, Nofal MM, et al: Treatment of thyroid cancer. Death rates after surgery and after surgery followed by sodium iodide I-131. JAMA 214:1437-1442, 1970.

43. Hay ID, Grebe SK: Relative value of medical treatment with radioactive iodine and thyroid suppression as adjuvants after primary surgery for differentiated follicular-cell derived thyroid carcinoma. Proc 4th Int Conf Head Neck Cancer, pp 988-994, 1996.

44. Cohn KH, Backdahl M, Forsslund G, et al: Biologic considerations and operative strategy in papillary thyroid carcinoma: Arguments against the routine performance of total thyroidectomy. Surgery 96:957-970, 1984.

45. Schroder DM, Chambers A, France CJ: Operative strategy for thyroid cancer: Is total thyroidectomy worth the price? Cancer 58:2320-2328, 1986.

46. Loree TR: Therapeutic implications of prognostic factors in differentiated carcinoma of the thyroid gland. Semin Surg Oncol 11:246-255,1995.

47. Harness JK, Fung L, Thompson MN, et al: Total thyroidectomy: Complications and technique. World J Surg 10:781-786, 1986.

48. Flynn MB, Lyons KJ, Tarter JW, et al: Local complications after surgical resection for thyroid carcinoma. Am J Surg 168:404-407, 1994.

49. Van Heerden JA, Groh MA, Grant GS: Early postoperative morbidity after surgical treatment of thyroid carcinoma. Surgery 101:224-227, 1987.

50. Goepfert H, Callender DL: Differentiated thyroid cancer: Papillary and follicular carcinomas. Am J Otol 15:164-179, 1994.

51. Scheumann GFW, Grimm O, Wegener G, et al: Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg 18:559-568, 1994.

52. McGregor GI, Luoma A, Jackson SM: Lymph node metastases from well differentiated thyroid cancer: A clinical review. Am J Surg 149:610-612, 1985.

53. Mazzaferri EL: Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Semin Oncol 14:315-332, 1987.

54. Joensuu H, Klemi PJ, Paul R, et al: Survival and prognostic factors in thyroid carcinoma. Acta Radiol Oncol 25:243-248, 1986.

55. Maxon HR, Smith HS: Radioiodine-131 in the diagnosis and treatment of metastatic well-differentiated thyroid cancer. Endocrinol Metab Clin North Am 19:685-718, 1990.

56. Samaan NA, Schultz PN, Hickey RC, et al: The results of various modalities of treatment of well-differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 75:714-720, 1992.

57. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 95:418-428, 1994.

58. DeGroot LJ, Kaplan EL, Shukla MS, et al: Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab 80:2946-2953, 1995.

59. Hay ID: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 19:545-576, 1990.

60. Young RL, Mazzaferri EL, Rahe SM, et al: Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 21:733-738, 1980.

61. Tubiana M, Schlumberger M, Rougier P, et al: Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 55:794-804, 1985.

62. Snyder J, Gorman C, Scanlon P: Thyroid remnant ablation: Questionable pursuit of an ill-defined goal. J Nucl Med 24:659-665, 1983.

63. Edmonds CJ, Smith T: The long-term hazards of the treatment of thyroid cancer with radioiodine. Br J Radiol 59:45-51, 1986.

64. Szanto J, Ringwald G, Karika Z, et al: Follicular cancer of the thyroid gland. Oncology 48:483-489, 1991.

65. Ruegemer J, Hay ID, Bergstrahl EJ, et al: Distant metastases in differentiated thyroid carcinoma: A multivariate analysis of prognostic variables. J Clin Endocrinol Metab 67:501-508, 1988.

66. Mazzaferri EL, Young RL, Oertel JE, et al: Papillary thyroid carcinomas: The impact of therapy in 576 patients. Medicine 56:171-196, 1977.

67. Roti E, Minelli R, Gardini E, et al: The use and misuse of thyroid hormone. Endocrinol Rev 14:401-418, 1993.

68. Kobayashi T, Asakawa H, Yasuhiro T, et al: Fatal differentiated thyroid cancer. J Surg Oncol 62:123-127, 1996.

69. Brown AP, Greening WP, McCready VR, et al: Radioiodine treatment of metastatic thyroid carcinoma: The Royal Marsden Hospital experience. Br J Radiol 57:323-327, 1984.

70. Har-El G: Locally aggressive differentiated thyroid cancer. Proc 4th Int Conf Head Neck, pp 972-987, 1996.

71. Powell S, Harmer C: Thyroid cancer causing death after 40 years: Rationale for initial intensive treatment. Eur J Surg Oncol 16:457-461, 1990.

72. Ross DS: Long-term management of differentiated thyroid cancer. Endocrinol Clin North Am 19:719-739, 1990.

73. Ozaka M, Suzuki S, Miyamoto T, Lui TR, et al: Serum thyroglobulin in the follow-up of patients with treated differentiated thyroid cancer. J Clin Endocrinol Metab 79:98-105, 1994.

74. Van de Velde CJH, Hamming JF, Goslings BM, et al: Report of the consensus development conference on the management of differentiated thyroid cancer in the Nederlands. Eur J Cancer Clin Oncol 24:287-292, 1988.

 
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