Recurrence After Treatment of Micropapillary Thyroid Cancer

Abstract

Background:

Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine.

Methods:

The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocal micropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years.

Results:

Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p = 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine.

Conclusions:

Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer.

Introduction

M icropapillary thyroid cancer is defined as a papillary cancer that is 10 mm or less in its maximal diameter. These cancers are quite prevalent, and are found in approximately 6% of the population at autopsy in the United States (1) and in as high as 36% of the population of some countries (2). Comparing the prevalence of thyroid cancer at autopsy with the Surveillance, Epidemiology, and End Results data from the National Cancer Institute suggests that fewer than 2% of micropapillary cancers come to clinical attention (3,4). However, the annual incidence of papillary cancer has increased over twofold between 1973 and 2002 (5), presumably due in part to ascertainment bias from the widespread use of high-resolution ultrasonography and ultrasound-guided fine-needle aspiration biopsy. In one hospital, micropapillary carcinoma represented 22% of surgical thyroid cancer pathology cases between 1991 and 2000, compared with only 5% of cases between 1960 and 1980 (6).

Despite the very low mortality rates associated with micropapillary thyroid cancers, locoregional recurrence is a relatively common clinical problem and considerable controversy exists regarding the optimal use of surgery and adjunctive radioiodine (7,8). In the 2006 guidelines published by the American Thyroid Association, micropapillary cancers were not specifically addressed, but radioiodine was recommended for “selected patients with stage I disease, especially those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and/or more aggressive histologies” (9).

Many reasons have been cited for the lack of randomized, controlled trials to guide such treatment decisions. The low mortality associated with this disease has kept the priority for funding low; some investigators have refused to subject their patients to treatments they feel are unnecessary, while other investigators have refused to allow their patients to forgo treatment which they feel is necessary, and there is concern that trials would need to continue for decades to provide meaningful data (10). In response to concerns that there may never be a long-term randomized, controlled trial to assess therapy in thyroid cancer, the National Thyroid Cancer Treatment Cooperative Study Group established a registry in 1987, which prospectively follows a large nonrandomized cohort of thyroid cancer patients from 11 North American centers. Treatment of the enrolled patients is solely at the discretion of their physicians. In the most recent publication, outcome data after initial therapy were assessed in the entire cohort of patients with differentiated cancer (11). Despite clear benefits of more extensive surgery and radioiodine for patients with registry stage II, III, and IV disease, no beneficial impact of these therapies was seen on stage I patients (11). In view of the increasing prevalence of micropapillary cancer, we now report outcome data from our subgroup of patients with micropapillary thyroid cancer.

Methods

Patients and data collection

The data collection and analysis methods of the registry have been described previously (11 –14). New patients are registered on an ongoing basis after their initial surgery. Between January 1987 and July 2006, about 4830 patients were registered. Three thousand nine hundred twenty-three of these patients had papillary thyroid cancer (all variants), of which 710 had micropapillary (10 mm or less) cancer. Twelve patients were excluded from the analysis due to missing data. Of the remaining 698 patients, 27 patients had gross extrathyroidal invasion, 9 patients had distant metastases, and 1 patient had both gross extrathyroidal invasion and distant metastases. The remaining 661 patients had intrathyroidal tumors with complete data regarding initial treatment modalities and tumor characteristics.

Patients registered at each institution received the treatment and follow-up testing that their physician determined to be appropriate, independent of registry participation. Initial therapy included surgery, with or without radioiodine (I-131) administered within 6 months of the patient's surgery. There was no uniform protocol among the institutions for the extent of node sampling at initial surgery, or subsequent methods of surveillance. Disease stage was assigned using the previously described registry staging system (Table 1) (11). Clinical status at entry was classified by the individual investigator at each institution based on imaging studies and serum thyroglobulin measurements as no residual disease, biochemical evidence of disease only, or residual disease with documentation of the site(s) of residual disease.

Table 1.

Registry Staging Classification for Intrathyroidal Micropapillary Cancers

	Age < 45	Age ≥ 45
Unifocal	I	I
Microscopic multifocal	I	II
Macroscopic multifocal or macroscopic tumor capsule invasion	I	II
Cervical node metastases	I	III

Recorded data were entered into a personal computer–based clinical data management system (Medlog, version 2007-2, Incline Village, NV) at each site, and transmitted to a central repository, currently maintained at the University of Texas M.D. Anderson Cancer Center. Approval was obtained from the Institutional Review Board at each participating institution, and informed consent obtained before registration if required. Institutional Review Board approval was also obtained at University of Texas M.D. Anderson Cancer Center for maintaining the central data repository and performing subsequent analysis.

Statistical methods

Chi-squared analysis was performed to examine nominal data, and product-limit survival analysis was performed to determine univariate predictors of recurrence-free survival (RFS). As the primary goal of the study was to examine recurrence, patients who died during follow-up were censored, and death was not considered to be an event for analysis of RFS. Wilcoxon and log-rank statistics were used, as appropriate. The therapies examined in the analysis were a less than near-total thyroidectomy (NTT) versus a total (T)/NTT, and no adjuvant radioiodine versus postoperative adjuvant radioiodine (within 6 months after initial surgery). The tumor characteristics examined in this analysis were multifocality versus unifocality, and cervical nodal metastases versus none. A p-value of less than 0.05 was considered statistically significant. All analyses were performed using the SAS JMP (version 5.0.1.2, copyright 1989–2003) statistical software package.

Results

Six hundred sixty-one patients with micropapillary cancer had intrathyroidal tumors without evidence of distant metastases at entry. Median and mean duration of follow-up was 3 and 4 years, respectively; the range was 0–18 years, for a total of 2884 person-years of documented follow-up. The percentage of micropapillary cancers compared with all papillary thyroid cancers increased from 13% in 1987–1991 to 23% in 2002–2006. Seventy-eight percent of the patients were female, and 46% of the patients were under age 45 at the time of diagnosis. Seventy-two percent were classified as stage I, 17% as stage II, and 11% as stage III according to the registry staging system. Thirty-nine percent had multifocal disease and 28% had cervical lymph node metastases at presentation.

There was only one death related to thyroid cancer (0.15%). A 78-year-old woman who was treated with a T/NTT and radioiodine (80 mCi) recurred with anaplastic carcinoma after 11 months, and subsequently died.

Six hundred eleven patients were considered disease-free after initial therapy and are the focus of the analysis for RFS. Their median and mean duration of follow-up was 4 and 3 years, respectively, for a total of 2572 person-years of documented follow-up. Their characteristics are shown in Table 2.

Table 2.

Micropapillary Thyroid Cancer Patients Disease-Free After Initial Therapy

	All	Stage I	Stage II	Stage III
All	611	446 (73%)	109 (18%)	56 (9%)
Female	477 (78%)	362 (81%)	86 (79%)	29 (52%)
Male	133 (22%)	83 (19%)	23 (21%)	27 (48%)
Age < 45	276 (45%)	276 (62%)	0	0
Age ≥ 45	332 (54%)	167 (38%)	109	56
Unifocal	381 (62%)	348 (78%)	6 (6%)	27 (48%)
Multifocal	230 (38%)	98 (22%)	103 (95%)	29 (52%)
No nodal metastases	476 (78%)	367 (82%)	109	0
Nodal metastases present	135 (22%)	79 (18%)	0	56

Thirty-eight patients considered disease-free after initial therapy recurred during follow-up. The mean time to recurrence was 2.8 ± 2.4 years (range 0.5–10.9 years). The mean time to recurrence was shorter in the patients who received postoperative radioiodine (2.3 ± 2.2 years) compared with those who did not receive radioiodine (4.4 ± 2.2 years, p < 0.02). The locations of the recurrences were recorded for 34 of the 38 patients and are indicated in Table 3.

Table 3.

Sites of Recurrence in Patients with Micropapillary Cancer

Site	n	%
Total recurrences	38	6.2
Thyroid bed	17	2.8
Regional (nodes ± thyroid bed)	14	2.3
Mediastinal nodes	2	0.3
Distant	1	0.2
Not recorded	4	0.6

Recurrence-free survival

RFS was analyzed based on the following comparisons: (a) unifocal versus multifocal (more than one focus) disease, (b) absence versus presence of cervical lymph node metastases (node positive vs. node negative), (c) T/NTT versus less surgery (with T/NTT vs. without T/NTT), and (d) use versus nonuse of adjunctive radioiodine (with radioiodine vs. without radioiodine) (Table 4; Figs. 1 and 2).

FIG. 1.

Product-limit estimates of recurrence-free survival after initial therapy for patients with node-positive (dotted lines) versus node-negative (solid lines) micropapillary thyroid cancer. (A) Patients who had a total or NTT. (B) Patients who had less than an NTT. (C) Patients who had adjunctive radioiodine. (D) Patients who did not have adjunctive radioiodine. NTT, near-total thyroidectomy.

FIG. 2.

Product-limit estimates of recurrence-free survival after initial therapy for patients with multifocal (dotted lines) versus unifocal (solid lines) micropapillary thyroid cancer. (A) Patients who had a total or NTT. (B) Patients who had less than an NTT.

Table 4.

Recurrence-Free Survival

	n	Recurrences	p
All	611	38 (6%)
Effects of RAI and surgical extent on node-positive versus node-negative patients
Node positive with T/NTT	126	19 (15%)	<0.0001
Node negative with T/NTT	345	10 (3%)
Node positive without T/NTT	9	2 (22%)	0.003
Node negative without T/NTT	131	7 (5%)
Node positive with RAI	107	18 (17%)	0.006
Node negative with RAI	159	10 (6%)
Node positive without RAI	28	3 (11%)	0.003
Node negative without RAI	317	7 (2%)
Node positive with RAI	107	18 (17%)	NS
Node positive without RAI	28	3 (11%)
Node negative with RAI	159	10 (6%)	0.05
Node negative without RAI	317	7 (2%)
Effects of RAI and surgical extent on multifocal versus unifocal patients
Multifocal (all)	230	17 (7%)	NS
Unifocal (all)	381	21 (6%)
Multifocal with T/NTT	208	13 (6%)	NS
Unifocal with T/NTT	263	16 (6%)
Multifocal without T/NTT	22	4 (18%)	0.0096
Unifocal without T/NTT	118	5 (4%)
Multifocal with RAI	155	12 (8%)	NS
Unifocal with RAI	111	16 (14%)
Multifocal without RAI	75	5 (7%)	0.02
Unifocal without RAI	270	5 (2%)
Effects of RAI and surgical extent on patients with multifocal disease
Multifocal with T/NTT	208	13 (6%)	0.058
Multifocal without T/NTT	22	4 (18%)
Multifocal with RAI	155	12 (8%)	NS
Multifocal without RAI	75	5 (7%)
Multifocal node positive with RAI	62	7 (11%)	NS
Multifocal node positive without RAI	10	1 (10%)
Multifocal with T/NTT with RAI	144	10 (7%)	NS
Multifocal with T/NTT without RAI	64	3 (5%)

T/NTT, total or near-total thyroidectomy; RAI, radioiodine; NS, not significant.

Patients with nodal metastases at presentation had higher rates of recurrence than those patients without metastases, whether or not they received a T/NTT or adjunctive radioiodine (Table 4; Fig. 1). There was no significant difference in the recurrence rate between patients with nodal metastases who received or did not receive radioiodine. In patients who did not have nodal metastases, radioiodine treatment was associated with an increased rate of recurrence.

There was no significant difference in the recurrence rate among patients with unifocal and multifocal disease (Table 4).

Patients with multifocal disease who had less than T/NTT had a higher rate of recurrence than patients with unifocal disease who also had less than T/NTT (18% vs. 4%, p < 0.01; Table 4 and Fig. 2). Recurrence rates were lower in patients with multifocal disease who had a T/NTT compared with less extensive surgery (6% vs. 18%), but did not quite achieve statistical significance (p = 0.058).

Patients with multifocal disease who did not receive radioiodine had a higher rate of recurrence than patients with unifocal disease who did not receive radioiodine (7% vs. 2%, p < 0.02; Table 4). However, there was no statistical difference in recurrence rates in patients with multifocal disease who did or did not receive radioiodine. Recurrence rates were higher in patients with unifocal disease who received radioiodine.

We also analyzed the outcomes of the 28 patients who had gross extrathyroidal invasion and who were excluded from the RFS analysis above (one of whom also had distant metastases). Of the 17 considered disease-free after initial therapy, 4 were found to have recurrences. Of the 10 patients who had distant metastases at entry, 1 was considered disease-free after initial therapy and has not had a recurrence. Combining all the patients who were disease-free after initial therapy, the overall recurrence rate was 6.7% (38 of 611 with intrathyroidal disease at entry, 4 of 17 with extrathyroidal invasion at entry, and 0 of 1 with distant metastases at entry).

Discussion

The optimal extent of surgery and especially the role of adjunctive radioiodine treatment for patients with micropapillary cancer are controversial. This analysis of prospectively collected registry data was undertaken to clarify the roles of these treatments. The presenting features and subsequent clinical course of our study patients were consistent with previous retrospective series of patients with micropapillary cancer in terms of multifocality, nodal metastases, extrathyroidal extension, and distant metastases (15 –20). Thirty-eight percent of our patients had multifocal disease compared with 20% to 40% in several other reports; 4% of our patients had extrathyroidal extension compared with 2% to 21% in other series; 28% of our patients had cervical node involvement compared with 13% to 43% reported in the literature; 1.3% of our patients had distant metastases compared with 0.2% to 3% reported elsewhere. Our mortality rate of 0.15% compares to 0.2% to 1% in other reports, and our recurrence rate of 6.7% is similar to reports of 1.8% to 7.4% in the literature.

Since clinical management varied among the participating institutions, we used this heterogeneity to test if significant differences in outcomes exist as a function of therapeutic interventions. Our data support the need for T/NTT in patients with multifocal micropapillary disease, but failed to show a benefit of radioiodine in these patients. Our study data have significant limitations, however, which are inherent in the design of a nonrandomized cohort study. Additionally, because of the small numbers of patients in each group, we were unable to analyze groups based on age, and differences among groups were not significant in multivariate analysis. Two factors may have been responsible for the nonintuitive findings that radioiodine use was associated with a higher risk of recurrence in patients with unifocal disease, or patients without nodal metastases, as well as the finding that recurrences occurred earlier in patients who received radioiodine. First, radioiodine may have been selectively employed in cases with nondocumented clinical features that led the treating physicians to suspect greater recurrence risk. For example, our database records tumor size as “less than 10 mm.” It is unknown but likely that radioiodine would have been used more frequently in patients with tumors close to 10 mm in size compared with those with tumors that measured only a few millimeters. Second, radioiodine remnant ablation enhances the ability to detect residual disease by virtue of improving the specificity of serum thyroglobulin monitoring. In our prior publication (11), propensity score analysis was used to score strata of stage I patients with similar likelihoods of having received adjunctive radioiodine. By proportional hazards modeling, the propensity-score–adjusted hazard ratio for no radioiodine versus adjunctive radioiodine was no longer a significant predictor of disease-free survival. In the current study, adjunctive radioiodine was a significant negative predictor of RFS, but there were insufficient patients for propensity score analysis to determine if this finding would be mitigated.

The failure of this analysis to clarify optimal adjunctive therapy highlights the importance of a randomized, controlled trial. Our data suggest the feasibility of such a study for patients with micropapillary thyroid cancer. Since death is so uncommon, it is unlikely that any study can demonstrate a benefit of treatment on mortality. Our analysis demonstrated an overall 6% to 7% rate of recurrence with a mean follow-up of 3–4 years. Significant differences in disease-free survival were noted between patients with multifocal and unifocal disease who did not receive radioiodine, or who did not receive T/NTT, as well as between patients with or without cervical nodes regardless of initial therapy. It would therefore appear likely that a multicenter randomized, controlled trial of adjunctive radioiodine in patients with multifocal, intrathyroidal, micropapillary cancer is feasible, and adequate enrollment and follow-up could provide meaningful data within a decade.

Multifocality (38%) and nodal metastases (28%) are common in patients with micropapillary cancer and are associated with increased rates of recurrent disease. Patients with multifocal disease may have an increased risk of recurrence if they have less than an NTT. A randomized, controlled trial is necessary to determine if radioiodine ablation of thyroid remnants is advantageous for patients with intrathyroidal micropapillary cancer.

Footnotes

Acknowledgments

The National Thyroid Cancer Treatment Cooperative Study Group is supported in part by a research grant from Genzyme Corporation, Cambridge, MA, and Saudi Arabian Oil Company, Dhahran, Saudi Arabia.

Disclosure Statement

The authors declare that no competing financial interests exist.

Presented in part at the 79th Annual Meeting (2008) of the American Thyroid Association.

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