Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118-2393
Address all correspondence and requests for reprints to: Lewis E. Braverman, M.D., 88 East Newton Street, Evans 201, Boston, Massachusetts 02118. E-mail: lewis.braverman{at}bmc.org.
It is estimated that there will be 23,600 new cases of thyroid cancer in the United States in 2004, and 1,460 thyroid cancer deaths (1). Papillary thyroid cancer accounts for approximately 85% of thyroid tumors in the United States and other iodine-sufficient countries (2). The U.S. incidence of papillary thyroid cancers overall has increased over the past several decades (3). It is estimated that in recent years, as the use of thyroid ultrasound and other neck imaging modalities has increased, nodules too small to be palpated are more often discovered, and papillary thyroid microcarcinomas, defined by the World Health Organization as less than 1.0 cm in size (4), are being identified with greater frequency (5, 6). Papillary thyroid microcarcinomas are also frequently identified incidentally at surgery for benign thyroid disorders.
Overall, clinical outcomes for patients with papillary thyroid carcinoma are excellent. Although autopsy studies have shown that occult papillary thyroid carcinoma is present in 136% of patients (7), thyroid cancer accounts for only 0.3% of cancer deaths in the United States annually (1), and the cause-specific 10-yr survival rate for papillary thyroid carcinoma is 93% (8). However, papillary thyroid carcinoma remains the cause of mortality or substantial morbidity in a small subset of patients. Various staging systems have been designed to try to identify the patients with papillary carcinoma who are most likely to have poor outcomes (9). Tumor size has traditionally been viewed as an important prognostic factor, with papillary carcinomas less than 12 cm in size considered to be associated with lower risk. Within the group of patients with papillary microcarcinoma, prognostic factors have not been well defined.
In the current issue of JCEM, Pellegriti et al. (10) describe a retrospective cohort of 299 patients with thyroid papillary microcarcinomas less than 1.5 cm who underwent surgery, in most cases total thyroidectomy, between 1975 and 2001. The relationships of incidental vs. nonincidental status, tumor size, patient age and gender, family history of thyroid cancer, dietary iodine status, and presence of concomitant Graves disease to the extent of the cancer at the time of surgery, and risk for cancer recurrence or persistence are described.
Reassuringly, in this series, papillary thyroid microcarcinoma was not associated with any mortality over a median follow-up period of 3.8 yr. Still, the papillary microcarcinomas in the series were surprisingly aggressive, with multifocal disease found in about one third of tumors, spread to local lymph nodes in 30%, extrathyroidal invasion in 20%, and distant metastases in 3%. Twenty-six percent of patients in the series had thyroid tumors that persisted despite therapy, or that relapsed during the follow-up period (although in half of the patients with relapse the only manifestation was an elevated stimulated serum thyroglobulin). This relapse rate is higher than previously reported (7, 11, 12).
Male gender and age above 45 yr were associated with worse outcomes, consistent with many previous studies. Patients with Graves disease also had worse outcomes, a finding that has been previously reported by the same group (13), but that has not been a consistent finding across other studies (14). It is plausible that thyroid-stimulating Igs could promote tumor growth in Graves disease patients. Familial papillary microcarcinomas were not more aggressive or more likely to be associated with persistence of recurrence in this series, a finding that differs from previous reports. As the study authors noted, it is likely that familial papillary microcarcinoma is not a single, unified entity, and the various forms of familial papillary carcinoma may well behave differently.
Patients with incidentally noted papillary microcarcinoma (discovered during surgery for benign thyroid disease) had a lower (5.2%) risk for tumor persistence or recurrence than the patients with nonincidental disease (10.4%). This was true despite the fact that surgery for the nonincidental tumors was more aggressive. Paratracheal lymph node dissection was performed routinely, and laterocervical lymph node dissection was performed where indicated in the patients with nonincidental cancers, but lymph node resection was not performed in the incidentally discovered cases. Whether the tumor was found incidentally or not was a more important predictor of outcome than was tumor size. In part, this may be an artifact of the study design. In 30% of the nonincidental tumors, lymph node metastasis (or, in two cases, more distant tumor spread) was the first sign of disease, so by definition there was a relatively large proportion of aggressive tumors in the nonincidental group. It is not clear whether the results would have changed if the patients with nonincidental tumors that presented only as thyroid nodules were compared with the patients with incidental thyroid tumors.
Within this series of papillary microcarcinomas, tumors were subcategorized by size as less than 0.5 cm, 0.51 cm, and 11.5 cm. Tumor size greater than 1.0 cm was associated with the presence of multifocal or bilateral thyroid tumor, extrathyroidal invasion, and local lymph node metastases. However, there was no association between tumor size greater than 1.0 cm and the presence of distant metastases. Furthermore, tumor size was not a significant predictor of tumor persistence or recurrence. The presence of local lymph node metastases at the time of initial surgery was associated with the presence of more distant metastases and was the strongest predictor of tumor persistence or recurrence.
Patients from endemic goiter regions had a decreased risk for persistent or relapsing disease, although this finding was of borderline significance and was seen only in the nonincidental tumor group. Why might iodine deficiency be protective against papillary carcinoma? It is difficult to come up with a plausible biological explanation. If anything, the chronic increased TSH stimulation in an iodine-deficient population might be expected to result in increased thyrocyte hyperplasia and tumorigenesis. The ratio of papillary carcinoma to the more malignant follicular and anaplastic thyroid carcinomas increases after the institution of salt iodization programs in endemic goiter regions (15). However, recent studies have failed to show a significant influence of mild dietary iodine deficiency on survival (16, 17). In one small case series, it was reported that the incidence of metastases from papillary carcinoma was higher in an endemic goiter region, even in young patients, than in iodine sufficient areas (18), although these differences might be explained by socioeconomic status and differing access to health care. Differing rates of thyroid nodule detection and histologic interpretations in different geographic areas make epidemiological comparisons problematic. It may, therefore, be difficult to replicate the findings of this study with regard to dietary iodine and papillary carcinoma prognosis.
How should these study results influence clinical thyroid cancer screening? Does the finding that there is no difference in the risk for relapsing or persistent thyroid tumor between patients with tumors less than 0.5 cm, 0.51 cm, and 11.5 cm suggest that all thyroid nodules greater than 0.2 cm (the lower limit of feasibility by ultrasound guidance) should be biopsied, regardless of size? It has previously been reported that the risk for thyroid cancer is not decreased in patients with multinodular goiter (19). Should every nodule in a patient with multinodular goiter undergo fine-needle aspiration (FNA) biopsy? This would present daunting challenges from a public health perspective. Even in the United States and other iodine-sufficient regions, the prevalence of thyroid nodules in the general population detected by ultrasound is up to 50% (20). In endemic goiter regions, this figure is substantially higher. The finding that the aggressiveness of papillary microcarcinomas increased with increasing size suggests that in a larger case series, or in a cohort with longer follow-up, a gradation in risk for tumor recurrence based on microcarcinoma size might well be observed. We feel that it is reasonable to perform FNA biopsy in nodules over 1 cm and follow those that are smaller. A more rigorous approach has not been shown to increase survival, and routine FNA biopsy of smaller nodules would not only be a huge burden for health care providers, but would also lead to a substantial number of unnecessary surgeries in patients with false-positive FNA biopsy results or with benign follicular or indeterminate lesions.
How should this study influence the surgical treatment of papillary thyroid microcarcinoma? Is surgical tumor resection required at all? It has been suggested that papillary microcarcinoma simply be followed expectantly, given the relatively high prevalence of occult papillary carcinoma in autopsy studies. In one study that followed 162 patients with papillary microcarcinoma who chose observation, 70% of tumors were stable over a mean follow-up time of 3.8 yr (21). It is worth noting that, of a total of 732 patients in this study, 570 patients preferred surgery to observation, and another 56 who initially elected observation ultimately underwent surgery. Once carcinoma is detected, we suspect that most patients would prefer therapy to observation.
Is total or near-total thyroidectomy (leaving <3 gm of thyroid tissue) preferable to thyroid lobectomy for the treatment of papillary microcarcinoma? Pellegriti et al. (10) argue that total thyroidectomy is the treatment of choice for papillary microcarcinoma, and we strongly agree. It is sometimes argued that lobectomy preserves thyroid function, sparing patients the need for lifelong thyroid hormone replacement. However, L-thyroxine therapy is required in 50% of patients immediately after lobectomy (22) and is ultimately required in a majority. Total thyroidectomy may be more likely than lobectomy to result in hypoparathyroidism and recurrent laryngeal nerve injury; however, in the United States, postoperative hypocalcemia (which is usually transient) occurs in only 6% of patients and recurrent laryngeal injury in about 1% (23). In this study, tumor size correlated less well with eventual outcome than did the degree of tumor aggressiveness. The surprisingly high proportion of patients in this series with bilateral or multifocal disease suggests that, even when papillary carcinomas are small, residual tumor may frequently be left behind in the contralateral lobe if lobectomy is the procedure performed. Some (11, 24), but not all (25), studies have reported higher recurrence rates for patients with papillary microcarcinoma treated with lobectomy compared with those treated with total thyroidectomy. Performing total thyroidectomy at the time of diagnosis avoids the risk of reoperation. Although completion thyroidectomy is relatively safe in the hands of an experienced surgeon (26), avoiding the need for an additional surgical procedure is preferable.
Given the prevalence of incidental papillary microcarcinoma, should total thyroidectomy be the surgery of choice for all nodular thyroid disease? Giles et al. (27) recently reported a clinical trial of total or near-total thyroidectomy compared with subtotal thyroidectomy (leaving at least 5 g of thyroid tissue) for patients with euthyroid multinodular goiter in whom malignancy was not suspected. They reported incidental papillary carcinoma in 8% of study patients, with a small group requiring completion thyroidectomy to enable radioactive iodine ablation. They concluded that total thyroidectomy was preferable to subtotal to prevent the need for reoperation for patients with incidental papillary microcarcinoma. This seems particularly reasonable because other groups have previously reported a risk for benign contralateral nodule growth requiring reoperation after lobectomy for nodular goiter (22, 28).
Should central lymph node dissection be routinely performed at the time of thyroidectomy in patients with papillary microcarcinoma? This was the approach in the Pellegriti et al. (10) series for all patients with nonincidental tumor, and this has yielded useful information about the extent of tumor in papillary microcarcinomas. Wada et al. (29) followed a group of 259 patients with papillary microcarcinoma, all of whom underwent lymph node dissection at the time of thyroidectomy. They concluded that routine therapeutic lymph node dissection at the time of thyroidectomy is warranted in patients with papillary microcarcinoma with palpable lymph nodes at presentation, but that prophylactic lymph node dissection was not useful in patients without palpable lymphadenopathy. As long as postoperative radioactive iodine ablation is planned, dissection of nonpalpable lymph nodes is probably not essential.
What do results of this study (10) suggest about the need for postoperative therapy and monitoring for tumor recurrence? After total or near-total thyroidectomy, patients in the series were treated with 131I for thyroid remnant ablation. After such ablation, in thyroglobulin antibody-negative patients, TSH-stimulated serum thyroglobulin values in this series were highly predictive of long-term outcome, with a 1% relapse rate and no distant metastases in the group with initial TSH-stimulated thyroglobulin less than 1 ng/ml; a 16% relapse rate in those with thyroglobulin values 110 ng/ml; and a 68% recurrence rate in those with serum thyroglobulin values greater than 10 ng/ml. It seems reasonable to consider patients with undetectable initial stimulated serum thyroglobulin values, without detectable thyroglobulin antibodies, as cured. These patients require only minimal long-term monitoring. Patients with initial TSH-stimulated serum thyroglobulin values greater than 10 ng/ml have persistent tumor and should be followed closely. Risk for recurrence of the intermediate group can be stratified based on other prognostic variables, with patients over age 45 yr, those with lymph node involvement or extrathyroidal invasion, and those with nonincidentally discovered tumor being at higher risk and requiring more intensive monitoring.
In conclusion, papillary microcarcinoma is being diagnosed with increasing frequency. It carries a low risk for mortality: 0% in this series, 1% in others (7). However, recurrent or persistent disease after total or near-total thyroidectomy is surprisingly common. Based on this series as well as previous data, we would agree with the study authors and advocate routine total or near-total thyroidectomy. We would suggest postoperative radioactive iodine thyroid remnant ablation in patients with one or more of the following: tumor multicentricity, positive lymph nodes, or capsular or vessel invasion. This may improve recurrence rates and facilitate the use of serum thyroglobulin concentrations for postoperative risk assessment. We would also argue for near-total or total thyroidectomy in patients with multinodular goiter or dominant benign nodules, given the relatively high rate both of incidentally discovered papillary microcarcinoma (which prompts reoperation for completion thyroidectomy) and recurrent contralateral benign nodular disease.
Footnotes
Abbreviation: FNA, Fine-needle aspiration.
Received June 22, 2004.
Accepted June 23, 2004.
References
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