Impact of Degree of Extrathyroidal Extension of Disease on Papillary Thyroid Cancer Outcome

Introduction

Papillary thyroid cancer (PTC) is a common malignancy with increasing incidence in the United States (1). While disease-specific mortality is low in patients with PTC, persistent and recurrent disease rates remain significant (2). Surgical resection is the initial therapy for all differentiated thyroid carcinomas with adjunctive therapies, such as radioactive iodine (¹³¹I) providing clinical benefit for larger tumors, extrathyroidal extension (ETE), and other known risk factors for disease recurrence (3).

The completeness of resection of PTC has prognostic implications that have been well described (4). Disease-free survival (DFS) and the requirement for further adjuvant treatment modalities are impacted by surgical margin positivity and extension of PTC beyond the thyroid capsule (5). Currently, minimal ETE requires an upstaging of tumors to T-Stage of T3, and more advanced local invasion to T-Stage of T4A or T4B, according to the American Joint Committee on Cancer (AJCC) TNM staging system, with a resulting increase to Stage III or Stage IV for individuals older than 45 years of age (6). Patients with AJCC Stage III and Stage IV tumors are routinely treated with radioiodine (RAI) remnant ablation, or with external beam radiation therapy if they are older and have non–radioiodine avid tumors (7). Recent studies have shown that merely microscopic ETE may not have the same impact on outcomes as gross ETE evident at time of operation (8,9). The implication of tumor extending to the border of the surgical margin or thyroidal capsule (“close” microscopic margin), while technically margin negative, has not been well defined and is a source of concern with debate at our institution over inclusion of RAI in proposed treatment.

To investigate the risk factors and the resulting impact on DFS and utilization of adjuvant therapies for margin negative, close-margin resection (≤1 mm), microscopic ETE, and gross ETE, a retrospective analysis of a prospectively maintained database at our institution was performed. Given recent literature stratifying outcomes according to extent of ETE (microscopic versus gross ETE), we hypothesized that patients with close-margin (≤1 mm) resection of PTC would fare similarly to those with traditionally negative microscopic surgical resection margin.

Methods

This study was approved by the Walter Reed National Military Medical Center Institutional Review Board. This was a retrospective review of a prospective database maintained by the Endocrinology Department including patients undergoing thyroidectomy for PTC from 1955 to 2004 at Walter Reed Army Medical Center (WRAMC), Washington, DC. Demographic and treatment data included information concerning sex, age, prior radiation exposure, tumor size, presence of multifocal disease, positive lymph nodes, or metastases, type (extent) of surgery, RAI use, and persistence or clinical recurrence during postsurgical follow-up. All data were transferred to an Excel (Microsoft, Redmond, WA) spreadsheet.

Patients from the WRAMC database were considered as having no evidence of disease (NED) if the stimulated thyroglobulin (Tg) level was <2 ng/mL with negative Tg antibodies and no tumor was identified on whole-body scan or ultrasonography, if obtained. Persistent disease was classified as structural if found on cross-sectional imaging, biopsy, and/or post–radioactive iodine remnant ablation scan; or biochemical, defined as a stimulated Tg value >2 ng/mL in the absence of structural evidence of disease. Disease recurrence was defined as anatomic or biochemical evidence of disease following an interval period during which the patient had been NED.

The patients were grouped according to the margin status of their primary resections or extrathyroidal disease. Margin-negative resection was defined as having >1 mm of normal tissue at the surgical resection margin. Close-margin categorization required the presence of carcinoma within ≤1 mm of the specimen border. Microscopic ETE was defined as having microscopic disease extending beyond the thyroid capsule per official report of histopathological evaluation. Gross ETE was defined as obvious extension of disease beyond the thyroid gland at time of operation. For pathological results, multifocality was defined as two or more discrete areas of PTC within the surgical specimen.

Results

A total of 276 patients were included in the study. These patients were categorized according to their margin of resection. The number of patients according to margin status (negative, close, microscopic ETE, and gross ETE) was as follows: 199, 19, 39, and 19, respectively. Median follow-up for these four groups ranged from 3.1 to 6.8 years with DFS ranging from 1 to 37 years. Table 1 shows patient-specific clinical data including age, sex, and radiation exposure as well as tumor-specific data including tumor size, multifocality, ETE, and the presence of distant metastases. Data about treatment, such as extent of operation and utilization of adjuvant RAI, are also presented in Table 1. Outcomes such as persistence and clinical recurrence of disease are presented in Table 2.

Statistically significant differences were noted between the four groups when comparing prior radiation exposure (p=0.035), tumor size (p<0.001), lymph node positivity (p=0.002), and multifocality (p=0.014). The use of adjuvant RAI (p=0.001) as well as persistence of disease (p=0.006) and clinical recurrence (p=0.007) were also statistically different between groups. All these features were unfavorable prognostic factors for the gross ETE cohort.

The extent of local disease correlated significantly with subsequent clinical recurrence after a disease-free period; however, there were no differences in DFS between negative and close margin resection (Table 2). The margin-negative group exhibited lower lymph node positivity (26% vs. 45%, p=0.031) and lower postoperative RAI utilization (81% vs. 100% p=0.001) than the microscopic ETE group. In a comparison of the microscopic ETE and the gross ETE cohorts, there were higher rates of tumors >4 cm in the gross ETE group (50% vs. 9%), p=0.006).

Discussion

In the current study, we show for the first time to our knowledge that there is a lack of any significant difference in outcomes between patients with PTC undergoing margin-negative and close-margin resection. The lack of difference in oncological outcomes suggests that the findings of tumor close to the surgical margin should not independently influence the decision to use adjuvant RAI therapy. Also, there do not appear to be any preoperative clinical features predictive of a close-margin result.

In a retrospective analysis of etiologic factors, clinical parameters, disease-specific therapies, and outcomes, we found that the risk of clinical recurrence appears similar between patients undergoing margin-negative resection and those with tumor extending to the surgical margin. As anticipated, outcome was worse (29% vs. 9% disease recurrence) in patients with gross extrathyroidal disease extension than in those with microscopic local invasion apparent on histopathological assessment, taking into consideration that all patients with ETE received adjuvant RAI therapy.

Limitations of this study include modest sample size and the retrospective nature of the data analysis. While the database was maintained in a prospective manner, the time-span over which data were collected is extensive, and methodologies of pathological analysis and different pathologists, RAI administration, and data collection among other factors evolved during this period. Given that a high proportion of active-duty and veteran service members were included in the database, the occupational exposure to radiation was potentially higher than in the general population. However, the type, duration, and dose of exposure were not recorded. In addition, some characteristics of more aggressive phenotypes, which have been published in the literature, including histological appraisal of vascular invasion or genetic mutations such as BRAF, were not recorded in this database (10,11). Thus, there may be subsets of patients for whom ≤1 mm margins of resection were inadequate but who were not delineated in this analysis. Thirdly, the histologic appearance of the tumor at its margin, be it an infiltrating pattern or an expanding-pattern, was associated with poor prognostic factors (12). These histologic subtypes and variants such as columnar, tall-cell, or sclerosing were not consistently recorded in the database. Lastly, the median follow-up was only 3.1–6.8 years depending on the study subgroup. This was a relatively short period of time given the potential for well-differentiated thyroid cancer to recur many years after initial, apparently successful therapy.

In conclusion, surgical resection margins of PTC to within 1 mm of the capsule does not appear to be associated with a higher likelihood of persistence or recurrence of PTC compared to cases with negative margins on histopathological assessment. To fully elucidate the effects of a close margin on clinical outcomes in PTC, prospective evaluation is required.