Commentary (Mazzaferri): Identification and Treatment of Aggressive Thyroid Cancers

April 1, 2006
Ernest Mazzaferri, MD, MACP

Oncology, ONCOLOGY Vol 20 No 4, Volume 20, Issue 4

Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer.

Sturgeon and Angelos underscore the generally good prognosis of papillary (PTC) and follicular thyroid carcinoma (FTC), tumors often referred to as well-differentiated thyroid cancer, but conclude that overall survival has not improved in the past 20 years. Data from the National Cancer Institute (NCI) suggest otherwise. They also conclude that gender, incomplete tumor resection, tumor multicentricity, and vascular invasion are less well-established prognostic factors, although long-term studies show each of these to be a potent harbinger of poor outcome.[1]

Incidence and Mortality Rates Over the Past 3 Decades

The incidence of thyroid cancer in the United States more than doubled between 1973 and 2001, almost exclusively due to a rise in PTC.[2] It is the most rapidly increasing cancer in women, and the third most rapidly rising cancer in men. This is mainly due to PTC microcarcinomas, which in France accounted for nearly half of the operated cancers between 1998 and 2001. This change is attributed to a significant increase in the use of diagnostic thyroid ultrasonography (3% to 85%) and fine-needle aspiration biopsy (8% to 36%) in the evaluation of thyroid nodules.[3]

Data from the NCI indicate that during the past 3 decades in the United States, cancer mortality rates have declined 30% in women while they have increased nearly 4% in men.[2] Among patients with well-differentiated thyroid cancer over 40 years of age at the time of diagnosis, the 10-year cancer-attributable mortality rates were 7% in 10,866 women and 13% in 4,030 men.[2] This occurred because men presented at an older age with twice the number of distant metastases than those in women, accounting for the increasing thyroid cancer death rates in men.[2] These data underscore the chilling effect of late diagnosis.

The Gap Between Our Knowledge and Care

There is a gap between our knowledge and the care that many patients with thyroid cancer receive. Long delays in therapy have been a festering problem for many years. Too many patients undergo surgery without preoperative fine-needle aspiration biopsy or neck ultrasonography, the key diagnostic tests for thyroid nodules, while others undergo incomplete or unnecessarily excessive surgery, often because of a poor understanding of the cytologic diagnoses that identify tumors as malignant, benign, or indeterminate. Indeed, indeterminate cytology (follicular tumors) is sometimes confused with cytology that is insufficient for diagnosis.[4] On a brighter note, preoperative neck ultrasonography can identify cervical lymph node metastases, which can guide the surgical approach in a substantial number of patients with well-differentiated thyroid cancer.[5]

Delayed Diagnosis and Treatment

Prompt diagnosis has a major bearing on outcome. The median diagnostic delay among patients who died of thyroid cancer in our study[6] was 18 months vs 4 months in those who survived (P < .001). Cancer mortality was more than twice as high when patients underwent a delay in therapy[6]; 30-year cancer mortality rates in the two groups, respectively, were 13% and 6% (P < .001). In another study approximately 40% of 5,583 thyroid cancer patients underwent surgery without a presurgical biopsy,[7] increasing the likelihood that the patient would undergo incomplete or excessive surgery. In yet another study,[8] a single false-negative fine-needle aspiration biopsy delayed surgical treatment by 28 months, sometimes despite clinical evidence suggesting malignancy; this caused higher than usual rates of vascular and capsular invasion, and persistent disease at follow-up (hazard ratio: 2.28). Nodule evaluations by primary care physicians are more costly and more time consuming than those performed by endocrinologists and more likely to lead to a delay of 12 months or longer or to unnecessary surgery.[9] As the delay becomes longer, it imparts a risk comparable to that of advanced patient age at the time of diagnosis.[6]

New Information That Will Alter Management Paradigms

Important new observations are being made on a regular basis. For example, the recent study by Shattuck et al[10] showed that tumor foci arising within a thyroid gland involved with multifocal PTC often have different clonal origins. This has major clinical implications. It provides compelling evidence that supports total thyroidectomy (even for small multifocal PTCs) because individual tumor foci often do not result from intrathyroidal metastases, as widely held in the past. These foci may instead arise de novo within ostensibly normal residual thyroid tissue that for some reason has the propensity to develop tumors.

For decades, tumor risk stratification has been based upon multiple clinical and tumor features, as carefully summarized by Sturgeon and Angelos. Still, newer studies suggest that the behavioral features of a tumor often are first identified only after total thyroidectomy and 131I ablation has been achieved and the patient has undergone 6 to 12 months' follow-up.[11,12] In a very recent study, Xing et al[13] found that the BRAF mutation discussed by Sturgeon and Angelos is associated with poor clinicopathologic outcomes and is an independent predictor of recurrence, even in patients with stage I or II disease; this suggests that it may be a useful marker to assist in risk stratification for patients with PTC. This information could be available from a preoperative fine-needle aspiration biopsy cytology specimen.

New Follow-up and Treatment Paradigms

Diagnostic and follow-up paradigms for patients with well-differentiated thyroid cancer have undergone major changes in the past 5 years, with a strong emphasis on performing neck ultrasonography,[14] serum thyroglobulin (Tg) measurements, and posttreatment whole-body scanning after therapeutic amounts of 131I (RxWBS). These paradigm shifts have relegated diagnostic whole-body 131I scanning (DxWBS) done with 5 to 10 mCi 131I-previously the centerpiece of follow-up-to a much lesser diagnostic role.[11,12]

Recombinant human TSH (rhTSH, Thyrogen) has changed the care of patients with well-differentiated thyroid cancer. Thyroid hormone withdrawal has been used for years to increase serum TSH levels in preparation for 131I DxWBS and 131I therapy, resulting in substantial morbidity and patient dissatisfaction. Although not approved by the US Food and Drug Administration (FDA) for preparing patients for 131I therapy, recent studies show that rhTSH is effective for this purpose.[15,16] It has been approved for thyroid remnant ablation in Europe and can be effective in carefully selected patients with metastases-especially those at greater risk of hypothyroid complications from thyroid hormone withdrawal or those unable to produce sufficient endogenous TSH to stimulate sodium-iodide symporters necessary for 131I therapy. The drug has been used safely in children at the same doses employed in adults, although it is still not FDA-approved for this purpose.[17]

Nowadays, rhTSH is a safe and effective alternative for thyroid hormone withdrawal during follow-up of patients with well-differentiated thyroid cancer. One recent study[18] shows that a single rhTSH-stimulated Tg > 2 ng/mL predicts persistent tumor over the ensuing 3 to 5 years. While no Tg value entirely excludes future recurrence, a single rhTSH-stimulated Tg < 0.5 ng/mL in a patient without anti-Tg antibodies has about a 98% or more likelihood of identifying those completely free of tumor, a large group in which TSH suppression to < 0.1 mIU/L and frequent imaging and TSH-stimulated Tg testing are unnecessary.[18] Still, repeated TSH-stimulated studies are appropriate for patients at risk of recurrence, especially those with an rhTSH-stimulated Tg > 1 ng/mL.

One of the major consequences of employing sensitive rhTSH-stimulated Tg testing is finding high serum Tg levels without being able to identify tumor by neck ultrasonography, CT scanning, or 131I DxWBS. When this happens it is best to simply follow the serum Tg levels over time, because a rising serum Tg is usually a marker of residual tumor that may require empiric 131I therapy.[19] If the RxWBS is negative following empiric 131I therapy, then an 18FDG-PET scan offers important diagnostic and prognostic information that may lead to further surgery or, if negative, provides good reason for watchful waiting.[20] Endocrinologists and nuclear medicine physicians are in a steep learning curve with these newer diagnostic and follow-up paradigms for well-differentiated thyroid cancer, bolstered by a flurry of recent publications.


Dr. Mazzaferri receives a lecture honorarium from Genzyme.


1. Mazzaferri EL, Kloos RT: Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 86(4):1447-1463, 2001.

2. Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: Incidence-SEER 9 Regs Public-Use, Nov 2003 Sub (1973-2001), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2004, based on the November 2003 submission. National Cancer Institute, 2004.

3. Leenhardt L, Grosclaude P, Cherie-Challine L: Increased incidence of thyroid carcinoma in France: A true epidemic or thyroid nodule management effects? Report from the French thyroid cancer committee. Thyroid 14(12):1056-1060, 2004.

4. Mazzaferri EL: Management of a solitary thyroid nodule. N Engl J Med 328:553-559, 1993.

5. Kouvaraki MA, Shapiro SE, Fornage BD, et al: Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 134(6):946-954, 2003.

6. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418-428, 1994.

7. Hundahl SA, Cady B, Cunningham MP, et al: Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 89(1):202-217, 2000.

8. Yeh MW, Demircan O, Ituarte P, et al: False-negative fine-needle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid carcinoma. Thyroid 14(3):207-215, 2004.

9. Ortiz R, Hupart KH, DeFesi CR, et al: Effect of early referral to an endocrinologist on efficiency and cost of evaluation and development of treatment plan in patients with thyroid nodules. J Clin Endocrinol Metab 83(11):3803-3807, 1998.

10. Shattuck TM, Westra WH, Ladenson PW, et al: Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. N Engl J Med 352(23):2406-2412, 2005.

11. Mazzaferri EL, Robbins RJ, Spencer CA, et al: A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 88(4):1433-1441, 2003.

12. Schlumberger M, Berg G, Cohen O, et al: Follow-up of low-risk patients with differentiated thyroid carcinoma: A European perspective. Eur J Endocrinol 150(2):105-112, 2004.

13. Xing M, Westra WH, Tufano RP, et al: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90(12):6373-6379, 2005.

14. Hegedus L: Clinical practice. The thyroid nodule. N Engl J Med 351(17):1764-1771, 2004.

15. Robbins RJ, Larson SM, Sinha N, et al: A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 43(11):1482-1488, 2002.

16. Luster M, Lippi F, Jarzab B, et al: rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: A comprehensive review. Endocr Relat Cancer 12(1):49-64, 2005.

17. Iorcansky S, Herzovich V, Qualey RR, et al: Serum thyrotropin (TSH) levels following recombinant human TSH injections in children and teenagers with papillary thyroid cancer. J Clin Endocrinol Metab 90(12):6553-6555, 2005.

18. Kloos RT, Mazzaferri EL: A single recombinant human thyrotrophin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab 90(9):5047-5057, 2005.

19. Mazzaferri EL: Empirically treating high serum thyroglobulin levels. J Nucl Med 46(7):1079-1088, 2005.

20. Wang W, Larson SM, Fazzari M, et al: Prognostic value of [18F] fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab 85(3):1107-1113, 2000.