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To better define early and long-term outcomes of patients undergoing thoracic metastasectomy for thyroid cancer.
We identified, reviewed, and analyzed the medical records of all patients who underwent thoracic metastasectomy for thyroid cancer in our institution from 1971 to 2006.
There were 48 patients (25 men, 23 women). A complete resection (R0) of all known disease was performed in 33 (69%) patients, while 15 (31%) underwent incomplete resection (R1 or R2). By histology, the majority were papillary 31 (65%), follicular 8 (17%), medullary 5 (10%), and Hürthle cell 4 (8%). Ninety percent were confined to a single side of the chest, with 10% presenting with bilateral metastases. Thoracotomy was performed in 28 (58%), sternotomy in 12 (25%), and thoracoscopy was used in 8 (17%). Operative mortality was zero and postoperative complications occurred in 8 patients (17%). There are currently 18 surviving patients from the cohort (37%) with a median follow-up of 10 years (range, 1 month to 17 years). The overall 5-year survival after thoracic metastasectomy was 60%. Based on histology, 5-year survival for papillary cancer was 64% compared to 37% for follicular and Hürthle cell neoplasms (p = 0.03). All five medullary thyroid cancer patients were alive at 5 years. Five-year survival was also improved for patients less than 45 years old at the time of diagnosis of their initial thyroid malignancy (94% vs 49%; p = 0.03). Disease-free interval of >3 years between initial thyroid malignancy diagnosis and thoracic metastasectomy demonstrated improved 5-year survival (67% vs 52%; p = 0.01).
Pulmonary resection for thyroid metastasis is safe with low morbidity and mortality. Retrospective analysis demonstrates improved long-term survival in patients with papillary histology, longer disease-free interval (>3 years) and younger age at diagnosis of initial thyroid malignancy. Excellent long-term survival was also achievable in selected patients with medullary thyroid metastasis.
Thyroid cancer is the most common endocrine malignancy accounting for approximately 25,000 and 30,000 new cases each year in Europe and the United States of America respectively. It is only one of four malignancies in the United States that has an increasing death rate [1,2]. Of those with thyroid cancer, 30% develop distant metastasis during their lifetime, with the majority of these arising in the chest [3,4]. As a result surgical resection of these thoracic lesions has developed as a treatment option. Several groups have reported surgical case series of thoracic metastasectomies for non-medullary thyroid metastases, of which the largest to date includes 29 cases [3,5–9].
Nevertheless, pulmonary metastasectomy remains controversial and the strength of the data supporting aggressive thoracic metastasectomy in general has been denounced as a ‘common practice based on weak evidence’ . Since the 1960s the literature is speckled with reports describing periods marked by radical surgical approaches to cervical, thoracic, and osseous metastasis while other reports relied on radioactive iodine ablation as the targeted treatment for metastatic thyroid disease . We reviewed our single-institution experience with the goal of analyzing our results and clarifying the specific factors that promote long-term survival.
A retrospective review of our surgical database from 1971 to 2006 at Mayo Clinic in Rochester, Minnesota, identified 48 patients who underwent thoracic metastasectomy (lobectomy, wedge resection, or mediastinal mass excision) for thyroid neoplasms. Excluded from consideration were patients with anaplastic thyroid cancer, non-thoracic metastasis, malignant pleural effusions, or thoracic explorations for diagnosis without treatment intent.
Operative mortality was defined as death within 30 days of operation or during the initial perioperative hospitalization. The time of thoracic metastasectomy was used as the starting date for survival analysis. Survival for all living patients was recorded up to December 31, 2006. The length of survival was determined for all patients who died. Survival was estimated using the Kaplan—Meier method. The effects on long-term survival of potential risk factors including age, sex, thyroid histology, disease-free interval, postoperative therapy, extent of surgical procedure, extent of resection, post-operative complications were evaluated using log-rank tests. All statistical tests were two-sided, and the threshold of significance was 0.05. The analysis was conducted using SAS version 8.2 (SAS Institute Inc, Cary, NC). The Mayo Foundation institutional review board approved this study.
Of the 48 patients, 25 (52%) were male and 23 (48%) were female with a median age at initial thyroid resection of 53 years (range, 20–79 years). All 48 patients had resection of their primary thyroid tumor, 41 (85%) by initial or completion bilobar thyroidectomy and the remaining 7 (15%) by unilateral thyroid lobectomy alone. In all patients the thoracic histopathology matched the histologic diagnosis from the thyroidectomy. Papillary thyroid cancer was present in 31 (65%) patients, follicular in 8 (17%), medullary in 5 (10%) and Hürthle cell in 4 (8%). All 43 patients without medullary thyroid cancer had a history of treatment with radioactive iodine ablation. The median age at the time of thoracic metastasectomy was 63 years (range 23–79). The median time between thyroid and thoracic resection was 3.4 years (range 0–42 years). We identified 5 (10%) patients who presented with synchronous disease that we defined as the presence of thoracic metastasis within 6 months of thyroidectomy. One patient underwent thyroidectomy within 1 week of an initial thoracic metastasectomy performed for diagnosis and treatment of suspicious pulmonary nodules of unknown pathology.
The majority of patients, 33 (69%) had unilateral pulmonary disease while 6 (13%) required bilateral wedge resections, and 9 (19%) had mediastinal metastasis excised. There was no operative mortality. There were 11 complications in 8 patients (17%) (Table 1).
Follow-up was complete in the 30 (63%) deceased patients in the cohort and the median follow-up on the 18 living patients was 10 years (range, 1 month to 17 years). The overall survival following thoracic metastasectomy was 60% at 5 years. The 5-year survival for papillary metastases was 64% compared to 37% for follicular and Hürthle cell neoplasms (p = 0.03) (Fig. 1).
The five patients with medullary thyroid cancer metastases had a 5-year survival of 100% and two remain alive with follow-up of 2.6 and 5.2 years. In all five patients, this was the only disease visible by advanced imaging and they all underwent a complete (R0) resection. The three deaths were all secondary to complications of non-thoracic distant metastatic disease not evident at the time of thoracic metastasectomy.
There is also a significant difference in survival based on age at diagnosis of the initial thyroid malignancy. The 5-year survival of those less than 45 years of age at diagnosis of the initial thyroid malignancy was 94% while it was only 49% for those over 45 years of age (p = 0.03). When the disease-free interval was greater than 3 years, the 5-year survival was significantly improved (67% vs 52%; p = 0.01).
Fifteen patients had incomplete metastasectomy. There was no difference in 5-year survival between those who had a complete R0 resection compared with those who underwent resection of a dominant nodule leaving residual sub-centimeter or miliary metastases in one or both lungs.
Thoracic metastasectomy is a treatment option used for various malignancies. Thoracic thyroid metastases have been removed with curative intent but as a group make up a small percentage of the whole number of thoracic metastasectomies being performed . Because of this relatively small number of patients, there are no randomized or prospective trials studying the role of resection of thyroid metastases . To date, only a small number of series with limited numbers of patients have been reported (Table 2).
In the present series, the cohort of patients is sufficiently large to allow for some limited statistical analyses of relevant subgroups. Perhaps predictably, patients with papillary thyroid cancer metastases have a better long-term prognosis. This is in keeping with the better known prognosis of this histologic group with regards to primary thyroid cancer.
The role of adjuvant radioactive iodine, a frequent adjunct in treating recurrent, well-differentiated thyroid malignancies, is not discernible in our series, as all patients with these histologies received this therapy and did not respond to it prior to being considered for metastasectomy. In two prior series of patients with thyroid metastases treated non-surgically with radioactive iodine only, 10-year survival was approximately 60% [13,14]. However, in these two studies, if one examines those patients who did not respond to radioactive iodine therapy, as was the case for the patients in the current report, the 10-year survival was in the range of 10–20%.
As with other reviews of metastasectomy for other types of cancer, disease-free interval emerges an important factor. Longer disease-free intervals suggest either less aggressive tumor biology or a decreased likelihood of further metastases appearing at a later date, given that they have not appeared up to that point.
Age at diagnosis of initial thyroid cancer was also found to be a meaningful prognostic indicator. This may relate simply to the likelihood of less comorbidities in these patients. It is interesting to note that this factor corroborates with the MACIS score data for primary thyroid cancer (distant metastasis, age, completeness of resection, local invasion, tumor size). In this widely used prognostic scoring system, patients diagnosed prior to the age of 45 years have an overall improved survival .
Medullary thyroid cancer, not part of the well-differentiated thyroid cancer group, has typically not been considered for aggressive surgical treatment of distant metastases. There are only rare reports of these types of metastases being resected. Nevertheless, in the present study, five patients were resected with 100% 5-year survival. This demonstrates that in selected patients with medullary thyroid cancer metastases, who are otherwise fit for thoracic metastasectomy and in whom a complete resection can be expected, metastasectomy appears to provide a survival benefit.
There are admittedly a number of limitations to this study. Despite being the largest single series of resected thoracic metastases of thyroid origin in the literature to date, the current study remains underpowered to conclude that R0 resections are equivalent to R1 or R2 resections in terms of long-term survival.
The findings of this study are also subject to the known limitations of retrospective analysis such as selection bias. Specifically, a retrospective analysis impairs our ability to accurately discern a posteriori which of the incomplete resection cases were planned as only ‘diagnostic’ versus those that were planned as curative but could not be completed as such.
In order to accrue enough patients to this retrospective cohort, we reviewed a 36-year experience. This has the potential pitfall of incorporating different treatment trends by era or by surgeon. This is mitigated to a certain extent in that this remains a single-institution study of cases performed by a relatively limited number of surgeons. Treatment options for these patients have, in general, remained remarkably unchanged over the course of this cohort’s history. What may be the most variable over this time period may be the process of patient selection and advances in intra-operative and postoperative monitoring and care. However, the effect of these potential differences is also difficult to quantify.
Pulmonary resection for thyroid metastasis is safe with low morbidity and mortality. This retrospective analysis demonstrates improved long-term survival in patients with papillary histology, longer disease-free interval (>3 years) and younger age at diagnosis of the initial thyroid malignancy. Excellent long-term survival was also achievable in selected patients with medullary thyroid metastasis. Therefore, thoracic metastasectomy should be offered to those patients with thoracic metastasis able to tolerate surgical resection and in whom either a complete resection is foreseeable or resection of progressing dominant lesions is possible.
The authors would like to acknowledge the expert statistical assistance of Dirk R. Larson, M.S. of the Mayo Clinic Department of Biostatistics.
✩Presented at the 16th European Conference on General Thoracic Surgery, Bologna, Italy, June 8–11, 2008.
✩✩Funding provided by Mayo Clinic Foundation, Department of Surgery.