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Annals of Surgical Oncology 9:57-64 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

The Effect of Surgery and Radiotherapy on Outcome of Anaplastic Thyroid Carcinoma

Jean-Pierre E. N. Pierie, MD, PhD, Alona Muzikansky, MA, Randall D. Gaz, MD, William C. Faquin, MD, PhD and Mark J. Ott, MD

From the Departments of Surgical Oncology (RDG, MJO), Cancer Statistics Center (AM), and Pathology (WCF), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the Department of Surgery, Medical Center Leeuwarden, The Netherlands (JPENP).

Correspondence: Address correspondence and reprint requests to: Mark J. Ott, MD, Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital, 626 Cox Building, 100 Blossom St., Boston MA 02114; Fax: 617-724-3895; E-mail: ott.mark{at}mgh.harvard.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Anaplastic thyroid carcinoma (ATC) is an aggressive rare tumor. We analyzed our experience for prognosis and the effect of surgery and radiotherapy on patients with ATC.

Methods: We conducted a retrospective review of all patients (n = 67) with ATC treated at a tertiary care center from 1969 to 1999. Survivor median follow-up was 51 months. Tumor and patient characteristics and therapy were assessed for effect on survival by multivariate analysis.

Results: Patients presented with a neck mass (99%), change of voice (51%), dysphagia (33%), and dyspnea (28%). Surgery was performed in 44 of 67 patients, with 12 complete resections. The 6-month and 1- and 3-year survival rates were 92%, 92%, and 83% after complete resection; 53%, 35%, and 0% after debulking; and 22%, 4%, and 0% after no resection, respectively (P < .0001). A radiation dose of >45 Gy improved survival as compared with a lower dose (P = .02). Multivariate analysis showed that age <=70 years, absence of dyspnea or dysphagia at presentation, a tumor size <=5 cm, and any surgical resection improved survival (P < .05).

Conclusions: Candidates for surgery with curative intent for ATC are patients <=70 years, tumors <=5 cm, and no distant disease. Radiotherapy >45 Gy improves outcome.

Key Words: Anaplastic thyroid cancer • Surgery • Radiotherapy • Debulking


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Thyroid cancer accounts for approximately 1% of all malignant tumors. Of all thyroid cancers, anaplastic thyroid carcinoma (ATC) constitutes 2% to 5%, although the incidence seems to be decreasing over time, for uncertain reasons.1 In contrast to differentiated carcinoma of the thyroid, ATC is one of the most aggressive solid neoplasms encountered in man.2 A poor prognosis is universally accepted, but opinions differ regarding origin, epidemiological factors, prognostic factors, and optimal treatment regimens.3

Surgical resection has been recommended in some cases involving small foci or localized ATC; however, such cases are mostly limited in number.4,5 ATC found incidentally within a differentiated cancer might have different behavior and deserve separate classification. For the more typical ATC, some authors state that surgery is generally precluded and can do more harm than good because the tumors are too far advanced at presentation. For these tumors, complete surgical resection has been difficult to achieve because of tumor size, extrathyroidal growth with direct invasion into surrounding tissues, and distant metastases.6 These issues are investigated in our study.

The potential benefit from the administration of radiotherapy, chemotherapy, or both given as the only treatment or in an adjuvant setting is also not clear, although some survival benefit and improved local control have been reported.1,7 Several prognostic factors for survival with ATC have been postulated, although no consistently established factors are reported.8,9 The main purpose of this study was to find one or more factors that might predict survival and to evaluate different treatment regimens to formulate optimal management for patients with this rare, but challenging, disease.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From January 1969 to August 1999, the data of all patients treated for presumed ATC at the Massachusetts General Hospital (MGH), Boston, MA, were collected. A diagnosis of ATC was made on the basis of fine-needle aspiration, surgical specimen, or autopsy material. Because some tumors, such as malignant lymphoma, medullary carcinoma, or metastatic disease, can be misinterpreted as ATC, confirmation of the histopathologic ATC diagnosis was performed by a board-certified surgical pathologist (W.C.F.), who reviewed the original histology, cytology, or both of each patient.10,11 A thyroid tumor was defined as an ATC on the basis of criteria defined by the World Health Organization; these criteria include a tumor that clinically arises in the thyroid and is composed, at least in part, of undifferentiated cells (usually spindle, polygonal, and giant cells).12 Additional features supporting a diagnosis of ATC include prior or concurrent evidence of a follicular or papillary thyroid carcinoma, immunohistochemical reactivity for cytokeratin, and ultrastructural evidence of epithelial differentiation. On the basis of the histological review of cases in this series, six patients were reassigned diagnoses other than ATC and were excluded from the series, leaving 67 patients for further statistical analysis. The follow-up data of all patients were prospectively collected at the MGH cancer registry. The median follow-up for the survivors was 51 months (range, 5–231).

Demographic features, history of thyroid disease, presenting clinical signs and time from symptoms to the first hospital visit, an incidental finding of ATC (defined as foci of ATC found in a larger differentiated thyroid carcinoma), extent of the disease (extrathyroidal growth, lymph node and distant metastases), the size of the tumor (greatest diameter), and histopathological factors such as the predominant cell type (giant cell, spindle cell, other), the presence of a precursor follicular or papillary carcinoma (defined as the presence of differentiated carcinoma in the same specimen as the ATC), the extent of tumor necrosis, the presence of microvascular invasion of the tumor, and the mitotic index (<20 mitoses per 10 high-power fields vs. >=20 mitoses per 10 high-power fields) were recorded to describe the population under study. These factors were then analyzed as possible prognostic factors for survival.

The effects of different treatment modalities on survival were assessed, including the type of surgery (no surgery or biopsy, incomplete resection, or complete resection). A complete resection was defined as no gross or microscopic disease left behind after surgery. An extended resection was defined as the removal of lymph nodes, parts of adjacent organs, or both. Although the use of external beam radiotherapy (EBRT) has changed over the period under study, postoperative EBRT was generally considered in all patients after surgery. In patients who did not undergo surgery, EBRT was delivered with palliative intent. The dose of EBRT given (range, 25–73 Gy) was calculated according to the estimated amount of residual disease and assessed as a possible prognostic factor for survival (<=45 vs. >45 Gy) in the patients who received EBRT. Chemotherapy (usually doxorubicin) was generally given for chemo-radiosensitization. The need for a tracheostomy or gastrostomy was also recorded to assess its influence on survival.

Furthermore, complications related to one of the treatment modalities were recorded. Permanent recurrent laryngeal nerve palsy was confirmed by laryngoscopy and registered as a complication when the patient did not present with a change of voice before surgery and the palsy lasted until the end of follow-up. Permanent hypocalcemia was registered as a complication when calcium had to be supplemented until the end of follow-up. EBRT-related swallowing problems caused by radiation-induced pharyngitis or proximal esophagitis were recorded as complications when they led to the use of tube feedings.

Survival was calculated from the time of diagnosis until death or censored at the time of the latest follow-up, and survival curves were estimated by using the method of Kaplan and Meier. Univariate and multivariate analyses of prognostic factors were based on the Cox proportional hazards model. The decision regarding the inclusion of variables in the multivariate model was based on the P values of the log-rank statistic. The comparison between the groups of resection with respect to tumor size was performed with the Kruskal-Wallis test. A P value of <=.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Six (8%) of 73 patients who did not have ATC after review of the histology demonstrated thyroidal metastases of an unknown primary adenocarcinoma (n = 3), a poorly differentiated papillary carcinoma (n = 2), and a follicular carcinoma of the thyroid (n = 1).

The characteristics of the remaining 67 patients with ATC are listed in Table 1. There were no perioperative deaths, although some patients died from disease progression within 1 month after the diagnosis. The median age at presentation was 73 years (range, 40–92). There were 22 men and 45 women, with a median tumor size of 7 cm (range, 2–20 cm). Thirty-three patients (49%) presented with distant metastases, mostly in the lung (28 of 33; 85%) but also in the brain, liver, and bone. Thirty-seven patients (55%) did not have a history of thyroid disease, 19 (28%) had a history of benign thyroid disease, and 11 (16%) had a history of a previous differentiated thyroid cancer. The median time of symptoms until presentation at MGH was 4 weeks (range, 1–60 weeks). The patients who presented shortly (<=4 weeks) after the beginning of their complaints had a poor outcome as compared with patients with more protracted symptoms (P = .0018). The most common signs and symptoms were a mass in the neck (99%), change of voice (51%), dysphagia (33%), and dyspnea (28%). Dyspnea (P < .001) and, to a lesser extent, dysphagia (P = .078) were associated with diminished survival (Table 2).


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  		TABLE 1. Patient characteristics and possible prognostic factors for disease-specific death
 

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  		TABLE 2. Presenting symptoms and disease-specific death
 
Table 1 also shows the univariate analysis of the effect of possible prognostic factors on survival. The overall 6-month and 1- and 3-year survival rates were 49%, 35%, and 16%, respectively (Fig. 1). Male sex, age <=70 years, an incidentally found ATC, an associated differentiated (papillary) carcinoma in the specimen, a tumor size <=5 cm, detection of microvascular invasion in the tumor, and the absence of distant metastases were all associated with increased survival. When the ATC was discovered incidentally, the 6-month and 1- and 3-year survival was 90%.



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  		FIG. 1. Overall cumulative survival of 67 patients with anaplastic thyroid carcinoma.

 
Table 3 depicts the univariate analysis of outcome by treatment modality for ACT. Surgery was performed in 44 (66%) of 67 patients, and in 12 (18%) a complete resection was accomplished. In 8 (67%) of these 12 patients, the ATC was found incidentally in patients undergoing operations for differentiated carcinoma, and in 3 patients (25%) extended surgery was needed to achieve complete resection. Complete resection was associated with 6-month and 1- and 3-year survival rates of 92%, 92%, and 83%; incomplete resection was associated with 6-month and 1- and 3-year survival rates of 53%, 35%, and 0%; and no resection was associated with 6-month and 1- and 3-year survival rates of 22%, 4%, and 0%, respectively. The survival after complete resection was significantly improved as compared with incomplete or no resection (P < .0001). Furthermore, the median survival was significantly higher after incomplete resection versus no resection (7 vs. 3 months, P = .0076; Fig. 2). The percentage of patients with a tumor >5 cm in the complete resection group was 0%, versus 75% in the other groups (P < .0001). The percentage of patients with a tumor >5 cm in the incomplete resection group was 66%, versus 87% in the no-resection group. This difference was not statistically significant.


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  		TABLE 3. Treatment modality and disease-specific death
 


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  		FIG. 2. The effect of surgical treatment on cumulative survival after complete resection (n = 12; solid line), incomplete resection (n = 32; dashed line), and no resection (n = 23; fine dashed line). Survival is improved after complete resection as compared with the other treatments (P < .0001). Survival is improved after incomplete resection as compared with no resection (P = .0076).

 
EBRT was given to 56 patients (84%) and as such did not influence survival. However, patients who received a dose of >45 Gy had a significantly better outcome than the patients who received a dose of <=45 Gy (P = .019), with 6-month and 1- and 3-year survival rates of 66%, 54%, and 18%, respectively, versus 31%, 17%, and 10% after a dose <=45 Gy (Fig. 3). The administration of chemotherapy did not have an effect on survival. The need for a tracheostomy or a gastrostomy likewise did not affect survival.



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  		FIG. 3. The effect of the radiotherapy dose on cumulative survival after >45 Gy (n = 27; solid line) or <=45 Gy (n = 29; dashed line) in the patients who received radiotherapy. Survival is improved after a dose >45 Gy (P = .019).

 
Complications were noted in 12 (21%) of the 63 patients who were treated by surgery, EBRT, or both. Two (8%) of 24 patients who had no voice changes at presentation and underwent surgery with or without radiotherapy experienced unilateral recurrent nerve palsy. Three (7%) of 44 patients needed permanent calcium supplements after surgery with or without radiotherapy. Seven (13%) of 56 patients needed tube feeding for a median of 4 weeks (range, 1–10 weeks) because of radiation-induced swallowing problems, but symptoms were self-limiting in most patients and could be treated with conservative measures.

Multivariate analysis in all 67 patients showed that age <=70 years, absence of dyspnea or dysphagia at presentation, a tumor size <=5 cm, the detection of histological microvascular invasion by the tumor, and a complete or any surgical resection improved survival (Table 4).


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  		TABLE 4. Prognostic factors for disease-specific death (all patients, n = 67)
 
Multivariate analysis in the 56 patients who received EBRT showed that besides the absence of dyspnea (hazards ratio [HR] = .2, P < .0001), any surgical resection (HR = .49, P = .041), an incidental finding of the tumor (HR = .056, P = .0068), microvascular invasion (HR = .41, P = .023), and EBRT given in a dose >45 Gy all independently improved survival (HR = .35, P = 0074).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although well-differentiated carcinoma of the thyroid is a relatively favorable cancer with excellent outcome after surgical and medical treatment, ATC has a dismal prognosis with a median survival that is usually <12 months.5,8,13,14 Although the presentation can be impressive, the histopathologic diagnosis may be difficult because ATC can be mimicked by several other malignancies, including malignant lymphoma, medullary carcinoma, and poorly differentiated metastatic carcinoma.8,15 To avoid contamination of the study group, we reviewed the histology. Eight percent of diagnoses were altered, and this indicates that even in a high-volume center the diagnosis of ATC can be difficult.

The most frequent symptoms at presentation are a large and often rapidly growing cervical mass, change of voice, dyspnea, and dysphagia. Whereas a change of voice did not effect survival, dyspnea and, to a lesser extent, dysphagia adversely affected survival and heralded advanced disease. The time from onset of symptoms to the first hospital visit was an important factor in predicting outcome. A short interval reflected a fast-growing tumor and therefore a poor outcome. The frequency of symptoms and the worse outcome of patients with rapid- as compared with slow-growing tumors were comparable to what others have reported.13 The median tumor size of 7 cm at presentation is another sign of the aggressiveness of this disease, because this is significantly larger than most differentiated thyroid carcinomas.

The disease has its peak incidence in the elderly, with a mean age at presentation of 73 years. The poor outcome that we found in older patients has also been reported by others.8,9 Other authors have reported a history of preexisting goiter, differentiated thyroid cancer, or previous radiation exposure to be risk factors for ATC.5 Analysis of our patient population could not confirm these to be important risk factors. Furthermore, concomitant follicular or papillary thyroid cancer cells detected in the same specimen as the ATC were favorable factors as compared with no differentiated carcinoma being found. This could be explained by the assumption that the ATC arose from the differentiated carcinoma and that this was an early less aggressive lesion that still maintained some better differentiated histologic architecture. The same phenomenon might explain the observation that the detection of microvascular invasion by the tumor, a well-known predictor for worse outcome in many malignancies, is a favorable factor in ATC. Tumors that still retained enough architecture to detect microvascular invasion might in this case be an earlier variant of ATC. It is of no surprise that extrathyroidal extension, tumors >5 cm, and the presence of distant metastases are adverse prognostic factors.8 However, pathological lymph nodes, either detected by clinical examination or in the specimen, seem to have no predictive value in ATC. This is similar to the phenomenon also seen in differentiated papillary thyroid carcinoma. However, in the case of ATC, the lack of effect of nodal metastases is probably due to other prognostic factors that have such adverse effects that the nodal metastases become irrelevant.

Overall 1- and 3-year survival was 35% and 16% and is comparable to the 23% and 15% reported by the National Cancer Data Base. These figures are, however, higher than the 1- and 3-year survival rates of 10% to 18% and 4% to 10%, respectively, in most series where histology slides were reviewed.1,8,13,16 The ATC that is found incidentally in patients undergoing an operation for a presumed differentiated carcinoma of the thyroid seems to be a separate group, but this group is included with the other ATC patients in the outcome reporting in our series. Two of the 10 patients with incidental ATC died of their disease despite complete resection of the primary tumor and EBRT, indicating that this can still be an aggressive tumor. At the same time, 4 of 57 patients survived who did not have incidentally found ATC; this indicates that there is also potential for survival for this group of ATC patients. This is one reason for keeping these two groups of patients combined for the purposes of survival analysis. Clearly the incidental ATC tumors have a more favorable prognosis with smaller tumor size and a survival curve similar to the favorable curves of differentiated carcinoma of the thyroid. The National Cancer Data Base demonstrates an overall 1- and 3-year survival rate of 99% and 97% for papillary carcinoma and 96% and 93% for follicular carcinoma, respectively. By comparison, the 1- and 3-year survival rate for incidentally found ATC was 90% in our series.16 A second reason to include the incidental and nonincidental ATC patients together for survival analysis is that the present AJCC staging system for ATC classifies all cases of ATC as stage IV disease.17 Perhaps this point in the staging system warrants re-evaluation. Unfortunately, the number of patients with ATC that was found incidentally in this series10 was too small for any statistically significant conclusions.

Sixty-six percent of all patients underwent surgery. Complete resection significantly improved survival but was possible in only 12 (27%) of the 44 patients who underwent attempted resection. Given the retrospective nature of this study, some bias is reflected in the significantly smaller tumor size in this group compared with the incomplete resection and no-resection groups. Furthermore, the ATC was found incidentally in 67% of the complete resection patients. However, there was improved short-term survival for the incomplete resection as compared with the no-resection group. These two groups were otherwise similar for the prognostic markers of tumor size. These data further emphasize the beneficial effect of surgery on the outcome of ATC in our experience, which has either been confirmed or disputed by others.1,3,8,13,18

ATC is a relatively radio-resistant tumor in comparison to other solid malignancies. Nonetheless, EBRT has been advocated to be beneficial for local control and in some instances even survival, although these results are not consistent between different research groups.1,18 Other authors have argued that when more than 30 Gy was delivered, prolonged survival could be demonstrated.19,20 The results from this study show that in the patients receiving EBRT, a beneficial effect was seen when a dose of more than 45 Gy was delivered (Fig. 3). Regardless of the specific dose, there seems to be an appropriate role for EBRT in the treatment of patients with ATC.

ATC is often a systemic disease at the time of diagnosis, because many patients either initially present with distant metastases (49% in this series, mostly in the lung) or eventually die from metastases. Surgery and radiotherapy would not be expected to affect already established metastatic disease. Unfortunately, none of the currently available chemotherapy agents have demonstrated sufficient antineoplastic activity to prevent death.6 In our study, chemotherapy, although often used as radiosensitizer, had no effect on survival.

Surgery and high-dose EBRT were beneficial in our experience, but complications did occur in 21% of patients. The 8% unilateral recurrent laryngeal nerve and 7% parathyroid injuries are acceptable, given the aggressive nature of this malignancy. These complications can be managed effectively and are comparable to the 7% recurrent laryngeal nerve injuries and the 12% hypocalcemia reported by others.1 However, they are higher than the usual 1% to 2% incidence of recurrent laryngeal nerve injuries and hypoparathyroidism after surgery for benign disease or for differentiated carcinomas of the thyroid in high-volume centers. The reason for this higher complication rate is probably the size of the tumor and more frequent extrathyroidal invasion. Furthermore, because survival was short in many patients, recurrent laryngeal nerve dysfunction due to neuropraxis and temporary parathyroid insufficiency could have been scored as permanent complications. Pharyngitis and esophagitis are well known after irradiation of the neck region but are mostly self-limiting after several weeks with conservative measures.21

We conclude that candidates for surgery with curative intent for ATC are patients <=70 years, tumors <=5 cm, and no distant disease. Whenever feasible, debulking should be considered for palliation. Radiotherapy >45 Gy improves outcome, with acceptable morbidity.


   Acknowledgments
 
The authors thank Eileen G. Sharkey, RHIA, CTR, of the MGH cancer registry for her help in collecting data for this study. Support from the Niels Stensen Foundation the Netherlands is gratefully acknowledged.


   Footnotes
 
Presented at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March, 2001.

Received for publication March 16, 2001. Accepted for publication August 16, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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