Resection margins and prognosis in locally invasive thyroid cancer

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1 ORIGINAL ARTICLE Resection margins and prognosis in locally invasive thyroid cancer Dana M. Hartl, MD, PhD, 1* Sophie Zago, MD, 1 Sophie Leboulleux, MD, 2 Ha ıtham Mirghani, MD, 1 Desiree Deandreis, MD, 2 Eric Baudin, MD, PhD, 2 Martin Schlumberger, MD, PhD 2 1 Department of Head and Neck Oncology Head and Neck Surgery, Institut Gustave Roussy and University of Paris-Sud, France, 2 Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy and University of Paris-Sud, France. Accepted 5 June 2013 Published online 26 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Invasive thyroid cancer is rare, and the extent of surgery controversial. The purpose of this study was to present and evaluate therapeutic prognostic factors. Methods. We conducted a retrospective single-center study of differentiated thyroid carcinoma invading the larynx, trachea, and/or esophagus treated surgically with macroscopic complete resection. Results. Forty-six patients (average age, 57 years; average followup, 4 years) were included. Free margins (R0) were obtained for 22 of 46 (49%) and microscopic residual tumor was present after surgery (R1) for 24 (51%). Ten-year actuarial local control was 100% for R0 and 75% for R1 (p 5.08). Five-year local control was lower for recurrent tumors versus inaugurally invasive disease (63% vs 87%; log-rank p 5.011). Five-year and 10-year actuarial disease-specific survival (DSS) was correlated with preoperative distant metastases (100% and 87%, respectively, for M0 vs 68% and 34% for M1; p 5.01). Conclusion. A trend toward lower local control was observed for R1 versus R0. The morbidity of surgery should be weighed against the prognosis if metastases are present. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: thyroid, cancer, trachea, larynx, margins INTRODUCTION *Corresponding author: D. M. Hartl, Department of Head and Neck Oncology Head and Neck Surgery, Institut Gustave Roussy, 114, rue Edouard Vaillant, Villejuif Cedex, France. dana.hartl@igr.fr This work was presented as a poster at the 82nd annual meeting of the American Thyroid Association, Quebec City, Canada, September 19 23, Differentiated thyroid carcinoma generally carries an excellent prognosis, with a 20-year disease-specific survival (DSS) rate of over 90%. 1,2 Rarely, however, these tumors invade the larynx, trachea, and/or esophagus. Diagnosis of local invasion may be made preoperatively because of symptoms, but often local invasion is only discovered at the time of surgery. When surgery is not performed or leaves a macroscopic tumor remnant, these invasive tumors can become symptomatic, with local complications hemoptysis or airway obstruction responsible for death in almost half of the cases. 3 With palliation, 10-year survival for patients with macroscopic remnants is about 50%, lower than for patients having undergone complete resection, which is between 75% and 90%. 4 Thus, the purpose of surgery is to optimize local control in order to decrease the risk of death from local complications. Current guidelines recommend surgical resection of all gross disease when technically feasible. 1 Surgery is, for now, the only curative treatment available, but the extent of surgery free margins (R0), close or positive microscopic margins (R1), or debulking (R2) 5 remains controversial because of a lack of high-level evidence for these rare tumors. The extent to which resection should be attempted is also controversial because of the efficacy of postoperative radioactive iodine, although up to 30% of differentiated thyroid cancers do not show radioactive iodine uptake. 6 The evidence base for the use of external beam radiation therapy is also low. The purpose of this study was to evaluate this rare type of thyroid cancer to investigate the prognostic value of histological subtype, resection margins, postoperative radiation therapy, and preoperative diagnosis of metastatic disease for local control and DSS. PATIENTS AND METHODS We performed a retrospective single-center institutional review board-approved review of patient files from 1983 to Only patients with thyroid carcinoma invading the larynx, trachea, and/or esophagus and treated surgically with the goal of complete macroscopic resection were included. Anaplastic and medullary thyroid carcinomas were excluded from this study. Resection margins were considered free (R0) if frozen section analysis (confirmed by definitive analysis) showed no tumor in the soft tissue or cartilaginous margins. Margins were considered microscopically invaded (R1) if definitive analysis showed tumor at the margin of the operating specimen or <1 mm from the margin. Local control was defined as normal radiologic findings in the neck at follow-up (ultrasound and contrast-enhanced CT and/or 18 fluorodeoxyglucose-positron emission tomography [FDG-PET]). Event-free survival was defined as 1034 HEAD & NECK DOI /HED JULY 2014

2 INVASIVE THYROID CANCER TABLE 1. Histopathologic tumor subtypes. TABLE 2. Tumor extension, surgical margins, and treatment. No. of patients Classic tumor subtypes n 5 28 Classic papillary carcinoma 14 Follicular form of papillary carcinoma 12 Follicular carcinoma 2 Tumor subtypes associated with poor prognosis ( aggressive pathological subtypes ) n 5 18 H urthle cell papillary carcinoma 2 Diffuse sclerosing papillary carcinoma 1 Tall cell carcinoma 4 Clear cell carcinoma 2 Poorly differentiated carcinoma 9 (including trabecular and insular subtypes) survival without macroscopic local, regional, or distant disease visible on imaging, but with the possibility of persistent stable thyroglobulin levels. Histological subtype, resection margins, postoperative radiation therapy, and preoperative diagnosis of metastatic disease were evaluated with respect to local control and DSS. RESULTS Forty-six patients (sex ratio, 1:1; average age, 57 years; range, 9 80 years) with an average postoperative followup of 4 years after surgery of the aerodigestive structures (median, 3 years; SD, 4 months; range, 4 months 13 years) were included. Eleven patients were between the ages of 20 and 45, and 33 patients (72%) were older than 45. Twenty-eight tumors (61%) were of a classic histopathological subtype and 18 (39%) were aggressive subtypes (Table 1). Diagnosis For 34 patients (74%), diagnosis of invasive disease was made at the time of the initial diagnosis of thyroid cancer, either preoperatively or intraoperatively. Nine patients were treated for a true local recurrence invading the aerodigestive structures diagnosed between 16 months to 17 years after initial thyroid surgery. For 3 patients, this information was unavailable. The invasive tumor was diagnosed before surgery of the visceral axis in 29 of 46 patients (63%). Of these 29 patients, 23 were symptomatic with hemoptysis in 9 cases, recurrent nerve paralysis in 6 cases, or an isolated large thyroid mass (>5 cm) in 8 cases. In the 6 asymptomatic patients, invasion was found on routine follow-up of a known and treated thyroid cancer, with CT scan and/ or 18 FDG-PET/CT performed when tumor recurrence was suspected on ultrasound and/or thyroglobulin measurements. On the contrary, invasion was discovered only intraoperatively in 17 of 46 patients. In 11 of these patients, initial surgery was incomplete, and patients were referred to our center for more extensive surgery. Treatment All patients underwent or had already undergone complete therapeutic central and lateral neck dissection if No. of patients (total 5 46) Site of invasion Larynx and/or trachea 25 Pharynx and/or esophagus 8 Both airway and digestive tracts 13 Timing of airway resection At the time of thyroidectomy 26 Secondary procedure within 6 mo 11 True tumor recurrence 9 Surgical approach Cervicotomy 44 Cervico-sternotomy 2 Type of airway resection Shaving 3 Tracheal resection-anastomosis 11 Cricotracheal anastomosis 12 Partial laryngectomy 5 Total laryngectomy 7 Type of digestive tract resection Muscle resection only 16 Partial esophagectomy (with mucosa) 2 Circumferential resection 3 Resection margins R0 22 R1 24 Adjuvant radiation therapy Yes 23 No 23 lymph nodes were present. An 18 FDG-PET-CT was performed preoperatively for 24 patients and all but 1 showed tracer uptake at the tumor site. Fourteen patients (28%) had distant metastases at the time of surgery of the aerodigestive tract: 8 had only lung micrometastases (<1 cm), 1 had an isolated bone metastasis, 1 had bone and lung metastases, and 4 patients had multiple bone, lung, and liver metastases. Table 2 shows the tumor extensions and surgical techniques used. The partial laryngectomies consisted of 4 vertical partial laryngectomies and 1 supracricoid partial laryngectomy. The circumferential esophageal defects were reconstructed with 1 gastric pull-up, 1 esocoloplasty, and 1 antebrachial free flap. Resection margins were R0 for 22 patients (49%) and R1 for 24 patients (51%). There was no statistical relationship between the quality of the resection (R0 or R1) and the moment of resection (at initial surgery, n 5 35; or secondarily after an initial incomplete resection and referral to our center, n 5 11) nor between the quality of the resection and whether the tumor was initially locally invasive or a true recurrence (Fisher exact test, p 5.49 and.99, respectively). Full-thickness resections (tracheal resection and anastomosis, partial and total laryngectomies, and pharyngo-esophagectomies) performed for 35 of 46 patients (76%) resulted in a significantly higher rate of R0 resections (57% vs 18% without full-thickness resection; Fisher exact test, p 5.02). However, there was no difference in the rate of free margins (R0) between resections with significant permanent morbidity (tracheostoma in 7 patients) and resections without this type of morbidity (Fisher exact test, p 5.13). HEAD & NECK DOI /HED JULY

3 HARTL ET AL. FIGURE 1. Kaplan Meier local control for patients treated with resections staged as R0 versus R1. No local recurrences were noted after 5 years of follow-up. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] FIGURE 2. Kaplan Meier disease-specific survival for patients with metastases at the time of resection of the aerodigestive tract (M1, solid line) versus patients without metastases at the time of surgery (M0, dotted line). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] All patients received radioactive iodine. Fourteen had previously received radioactive iodine and were refractory. Twenty-four received 1 postoperative dose of radioiodine (3.7 GBq with thyroid hormone withdrawal) and no further treatment was administered because of the absence of abnormal uptake on the whole body scan. Eight patients received more than 1 dose of radioiodine for iodine uptake in the neck or for pulmonary micrometastases. Twenty-three patients underwent adjuvant external beam radiation therapy (9 of 22 R0 resections and 14 of 24 R1 resections) with an average of 63 gray to the neck and mediastinum. Four patients received systemic treatment for progressive distant metastases with conventional chemotherapy (1 case in 1996, 13 years after surgery of the aerodigestive tract) or sorafenib (3 cases) in the context of a clinical trial at 5, 6, and 21 months after surgery, respectively. Local control Five-year and 10-year actuarial local control, defined as normal radiologic findings in the neck at follow-up (CT and/or 18 FDG-PET-CT) was 83% (there were no additional local recurrences after 5 years): 100% for R0 resections and 75% for R1 (Figure 1; Fisher exact test, p 5.08). Five-year local control was lower for patients treated for invasive tumor recurrence versus patients treated for inaugurally invasive disease (63% vs 87%; log-rank, p 5.011). All 9 with true recurrences had 18 FDG-PET positive tumors, 5 of 9 had aggressive histological subtypes (poorly differentiated, n 5 4; tall cell, n 5 1), and 7 of 9 had adjuvant radiation therapy after surgery of the aerodigestive tract. Radiation therapy did not significantly affect local control, nor did the presence of an aggressive histopathological subtype (p 5.66 and p 5.49, respectively, log-rank). Radiation therapy did not significantly modify local control for the group of patients with R1 resection, although the Kaplan Meier 5-year local control was 92% for the tumors with R1 resection not treated with radiation therapy versus 53% for R1 tumors treated with radiation therapy (log-rank, p 5.35). Local control was not significantly different if the aerodigestive resection was performed at initial surgery or secondarily, after an incomplete initial surgery that was diagnostic for invasive disease (n 5 11). The 5-year actuarial local control was 82% in the first case and 86% in the second (p 5.62 log-rank). Disease-specific and overall survival The 5-year actuarial DSS was 89%: 95% for R0 resections and 84% for R1 resections (log-rank p 5.5). Five-year and 10-year actuarial DSS was significantly correlated with the preoperative diagnosis of distant metastases (100% and 87%, respectively, for patients with M0 resection vs 68% and 34% for patients with M1 resection; p 5.01; Figure 2). No significant difference in DSS was noted according to age: age above or below 20 years (p 5.31), age above or below 45 years (p 5.81), or age above or below 60 years (p 5.15). Patients with aggressive pathology did not have a significantly different 5-year DSS (75% vs 84% for patients without aggressive pathological subtypes; log-rank p 5.72). Event free survival survival without macroscopic local, regional, or distant disease visible on imaging, but with persistent stable thyroglobulin levels for some patients was 67% at 5 and 10 years for the 32 patients without initial distant metastases. In all cases, the event was the diagnosis of distant metastases occurring in 5 patients (1 patient with a concurrent local and regional recurrence), between 6 months and 13 years after surgery of the aerodigestive tract (average, 49 months; median, 31 months). Five-year and 10-year actuarial overall survival was 73% and 59%, respectively. There was no significant difference in overall survival between patients with and without aggressive pathological subtypes (70% vs 65%; log-rank p 5.81). Eleven patients died during the course of the follow-up, 6 from thyroid cancer and 5 from other causes. Two patients died from hemorrhage because of local recurrence, 2 patients died from hemorrhage because of mediastinal lymph nodes eroding the mediastinal vessels, and the 2 remaining patients died because of distant metastases HEAD & NECK DOI /HED JULY 2014

4 INVASIVE THYROID CANCER DISCUSSION The incidence of invasive thyroid cancer is estimated at 5.8% 7 but may be much lower in nonspecialized centers. Management is controversial because of the absence of high-level evidence regarding resection margins or adjuvant radiation therapy. The current evidence is based on retrospective studies, with cohort sizes ranging from 6 to 262 patients. 7 There is currently sufficient evidence in favor of macroscopic complete resection (R0 or R1) for curative intent, with improved survival as opposed to macroscopically incomplete resection (debulking or R2). 3,4,8 12 There has been a wide debate regarding the type of resection required for tracheal invasion. Some authors have shown that tracheal shaving (with or without external beam radiation therapy) can provide excellent local control as compared to sleeve resection. In the study by McCarty et al, 13 local recurrence occurred in 17% of patients treated with shave resection after a 7-year average follow-up. Tsukahara et al 14 obtained a 95% local control rate with tracheal shaving. The study by Park et al, 15 however, found a 63% recurrence rate after a shaving procedure. The classification of tracheal invasion developed by Shin et al 16 may explain these discrepancies. It highlights the tendency of these tumors to invade between tracheal rings, through the soft tissue down to the submucosa or the mucosa, sometimes without true invasion of the cartilage itself. Superficial invasion (Shin et al 16 stages 1 or 2) may be amenable to shaving but deeper infiltration of the trachea is often difficult to evaluate intraoperatively. A shaving procedure for tumors with deeper infiltration is at risk of leaving gross disease behind. A systematic segmental sleeve resection of the trachea can optimize the rate of complete resections with very low morbidity. 7,15 However, for slowly growing differentiated thyroid carcinoma, microscopically incomplete resection followed by radioactive iodine or external beam radiation therapy may be sufficient for prolonged local control and survival. 1,13,17 There is much less information in the literature concerning resection margins in soft tissue or the esophagus and no classification of esophageal or laryngeal invasion. In the study by Gaissert et al, 12 resection was considered complete if the tracheal resection was R0 but also if there was no gross residual disease at the tumor margins, leaving room for R1 resections in the soft tissues, with the tumor shaved off from the esophageal wall, with a thin margin of muscle, as opposed to a fullthickness resection with wide margins and resection of the mucosa as well. This study concluded that this type of complete resection provided higher overall and disease-free survival than incomplete resections leaving gross residual tumor. In the study by Kasperbauer, 18 no difference in cancer-specific survival was found between R0 and R1 resections. To our knowledge, ours is the first to analyze the soft tissue margins as well as tracheal margins: we did not find a difference in local control or DSS between patients with R0 resection (airway and soft tissue) versus patients with R1 resections, although a trend was noted (p 5.08) and no local recurrences occurred in the group with R0 resection. Sia et al 19 have demonstrated an improvement in local control in patients with R2 resection treated with adjuvant external beam radiation therapy confirming previous results by Tubiana et al 20 and by Farahati et al. 21 In our study, we were not able to show any difference in local control rates according to adjuvant external beam radiation therapy, possibly because of biases inherent in our retrospective study. Eleven patients in our series (24%) had incomplete initial surgery, when an invasive tumor was not initially suspected. The tumor mass invading the visceral axis was left in place and removed in a second procedure, usually performed a few months later. This did not statistically affect the rate of local control nor the quality of the resection (R0 or R1), confirming the conclusions of other studies. 12,22 Patients with true recurrences invading the visceral axis, after an interval of complete remission after initial thyroid surgery, had a lower local control rate, although there was no difference in the quality of the resection (R0 or R1) or in the number of patients receiving adjuvant radiation therapy. All of these patients had already undergone total thyroidectomy and radioactive iodine treatment and all of these patients for whom PET-CT was performed had PET-positive tumors, indicating that no or little benefits could be expected from radioiodine treatment and that these tumors were aggressive. 23,24 Age has also been shown to be a prognostic factor in differentiated thyroid cancer. 25 Extrathyroidal extension of thyroid cancers are proportionally more frequent in children than in adults, 26 and in patients over 50 years old. 27,28 We were unable to find a difference in survival according to age, however. We did not find a significant relationship between outcomes and age or aggressive histology, which are classic prognostic factors. This may be because of the small number of patients in our series and the heterogeneity of the group, which also may account for the absence of any effect of external beam radiation therapy on prognosis. Unfortunately, these tumors are rare and present with various local extensions. Treatment is always a la carte on a case-by-case basis according to tumor and patient characteristics. Thus, large homogeneous case series are rare and prospective randomized studies difficult or even impossible to implement. We found a 67% 10-year event-free survival rate for patients initially M0 without distant metastases at the time of surgery. Similarly, Hotomi et al 29 found a 71% 10-year disease-free survival rate for patients initially M0 resection. In our study, as in others, 12 the presence of distant metastases was a significant factor for DSS. Longterm survival can be very high for some patients with metastatic disease, particularly younger patients with small, slow growing lung metastases from a well differentiated thyroid cancer that show radioactive iodine uptake. 2,6,30 These are the patients that potentially benefit the most from complete resection to optimize local control of invasive tumors. Nonetheless, in our study, 5-year DSS for patients with distant metastases at the time of resection was 68%, better than most other solid tumors, which may justify more aggressive local resection, even in patients with larger metastases, to avoid premature death from airway obstruction or hemorrhage. We observed 2 deaths from recurrences in mediastinal lymph nodes, and this may suggest that it may be appropriate to HEAD & NECK DOI /HED JULY

5 HARTL ET AL. perform a complete upper mediastinal lymph node dissection in these rare cases to decrease the risk of regional recurrences and death from hemorrhage, although this needs to be confirmed in further studies. CONCLUSIONS A trend toward lower local control was observed in patients treated with R1 margins versus R0, and a higher rate of R0 resection was obtained with full-thickness resections. Adjuvant radiation therapy did not influence local control or DSS. Local control was lower for true tumor recurrences as compared with tumors invading the aerodigestive tract at initial presentation. The main prognostic factor was the presence of distant metastases at the time of surgery. When macroscopically complete resection is possible, the morbidity of extensive surgery should be weighed against the prognosis for patients with metastatic disease, keeping in mind that locally progressive disease may be fatal. REFERENCES 1. 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