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Prognosis and Treatment of Brain Metastases in Thyroid Carcinoma

Sections of Endocrine Neoplasia and Hormonal Disorders (A.C.C., S.I.S.) and Clinical Nuclear Medicine (E.S.D.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Steven I. Sherman, M.D., University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 15, Houston, Texas 77030.

	Abstract

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We analyzed 47 cases of brain metastases from thyroid cancer seen at 1 institution over 5 decades. Brain metastases were a primary clinical feature at initial presentation in 15% of the cases, were identified during the subsequent course of the disease in 68%, and were only discovered at autopsy in 23%. The primary thyroid tumor was differentiated cancer in 68%, anaplastic cancer in 23%, and medullary cancer in 9%. Patients were typically older, with frequent evidence of aggressive disease and distant metastases at initial cancer diagnosis. Once brain metastases were diagnosed, disease-specific mortality was 78%, with a median product-limit survival of 4.7 months (67% and 12.4 months, respectively, for those with differentiated cancer). Resection of one or more foci of brain metastases significantly improved survival. The median disease-specific survival from diagnosis of brain metastases was 16.7 months for patients who underwent local excision of one or more brain metastases, compared with 3.4 months for those who did not (P < 0.05), independent of the presence of multifocal brain lesions. Recombinant human TSH safely stimulated radioiodine uptake for treatment of brain metastases in 1 patient. However, no evidence of survival benefit was found from radioiodine therapy, external beam radiotherapy, or chemotherapy. In summary, brain metastases from thyroid carcinoma are an extremely poor prognostic sign. Although selection bias and other unidentified factors inherent to retrospective analysis limit this conclusion, surgical resection of brain metastases may be associated with prolonged survival in differentiated carcinoma.

	Introduction

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THE PROGNOSIS of patients with differentiated or medullary thyroid carcinoma is generally favorable, with median survivals measured in decades. However, patients who are diagnosed with distant metastases of thyroid carcinoma, either at initial presentation or subsequent to initial therapy, have a considerably higher disease-specific mortality (1). This may be particularly true for patients who develop brain metastases, although this site is involved in only about 1% of patients (2, 3, 4, 5, 6, 7, 8, 9, 10). The reported survival after diagnosis of brain metastases from thyroid carcinoma is typically less than 1 yr (5, 11, 12, 13). Further, about 10% of patients who die from thyroid carcinoma have brain metastases found at postmortem examination (14). However, the actual number of reported cases of brain metastases from thyroid carcinoma remains small, and there has been little evidence of benefit from any specific mode of therapy.

In the larger realm of brain metastases from other systemic malignancies, poor overall outcome of patients is also the general rule (15). However, recent studies have suggested that surgical resection may prolong survival and improve quality of life for patients with brain metastases from diseases such as nonsmall cell lung or breast cancer (16, 17, 18). To improve our understanding of the clinical significance of brain metastases in thyroid carcinoma and to determine whether surgical intervention is beneficial, we have retrospectively analyzed a cohort of patients seen at the University of Texas M. D. Anderson Cancer Center (UT-MDACC) over 5 decades. Although most of these patients died from their disease, our analyses suggest that surgical resection may be associated with prolonged survival and should be considered as a therapeutic option for brain metastases from thyroid carcinoma.

	Subjects and Methods

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Patients with thyroid carcinoma and brain metastases were identified through a search of the central patient database maintained by Medical Informatics at UT-MDACC covering the period from March 1944 through September 1995. Search criteria included the histologic diagnoses of papillary, follicular, mixed papillary-follicular, oxyphilic (Hurthle cell), medullary, or anaplastic carcinomas. Patients were classified as having anaplastic carcinoma even if a coexistent focus of differentiated carcinoma was found. Additional cases were identified by cross-reference to an independently maintained thyroid carcinoma patient database (19). Cases were excluded if metastases were confined to the extradural space, skull, or spinal cord. Medical records were reviewed, and information abstracted regarding patient gender and age, disease histopathology, mode of presentation of brain metastases, treatment modalities for the primary and metastatic tumors, and patient outcomes. Available death notes and reports of postmortem examinations were also reviewed, and outside treating physicians and institutions were contacted for follow-up information when necessary. Disease-specific death was attributed to either death due to thyroid carcinoma or death secondary to complications of therapy.

Statistical analysis

Data were recorded using FileMaker Pro (version 3.0, Claris Corp., Santa Clara, CA), and statistical analyses were performed using JMP (version 3.0.1, SAS Institute, Cary NC). Statistical tests used included univariate ² and log-rank tests, as appropriate (20). Time to disease-specific death was analyzed using the product-limit estimate, and log-rank tests were applied in identifying univariate predictors of disease-specific death. Proportional hazards modelling was used to evaluate independent predictors of disease-specific death (20, 21). Tests for significance were performed using two-sided = 0.05.

	Results

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Of 3117 patients with carcinoma of the thyroid seen at UT-MDACC during the 51-yr period of study, 47 cases (1.5%) of metastases to the brain were identified. Sixty-one percent of these patients were diagnosed with brain metastases within the last 20 yr studied. The clinical characteristics of these patients with brain metastases are presented in Table 1. The female to male ratio for the cohort with brain metastases was 1.2:1, in contrast to the overall gender ratio of 2:1 in the UT-MDACC thyroid carcinoma patient base.

View larger version (15K): [in this window] [in a new window]   Figure 1. Product-limit estimates of disease-specific survival after diagnosis of brain metastases from all histologies of thyroid carcinoma.

View larger version (15K): [in this window] [in a new window]   Figure 2. Product-limit estimates of disease-specific survival after diagnosis of brain metastases from differentiated thyroid carcinoma.

Fourteen of the 47 patients had no evidence of distant metastases at initial preoperative or postoperative staging. The median primary tumor size was 2.5 cm, significantly smaller than 4.5 cm for the group of 33 with initial distant metastases (P < 0.05). The median interval between the diagnosis of thyroid carcinoma to diagnosis of brain metastases was 6.5 yr, which was significantly longer than the 0.9 yr for those with any initial distant metastases (P < 0.0005). Disease-specific mortality was 71%. The median disease-specific survival after diagnosis of brain metastases was 4.7 months for patients without any initially diagnosed distant metastases, which did not differ from those with brain metastases who had distant metastases in any site at initial disease staging (3.4 months).

Anaplastic thyroid carcinoma

The 11 patients with anaplastic carcinoma as their primary thyroid pathology did not differ significantly from the patients with differentiated or medullary carcinoma with respect to age of initial diagnosis of thyroid cancer, gender distribution, or tumor size. The group with anaplastic carcinoma had a higher proportion of patients with any distant metastases at initial perioperative staging (P < 0.05) and a shorter median interval between the initial diagnosis of thyroid carcinoma and identification of brain metastasis (0.7 vs. 6.1 yr; P < 0.05). The frequency of multifocal brain metastases tended to be higher (P < 0.1), and median disease-specific survival once brain metastases were diagnosed was significantly shorter (P < 0.01) than in patients with differentiated carcinoma. Additionally, 2 other patients had an anaplastic focus found in a metastatic brain lesion without evidence of anaplastic disease identified within the primary thyroid tumor.

Role of treatment

Patient outcomes were analyzed with respect to initial treatment directed toward the thyroid malignancy as well as therapy specific for the brain metastases. None of the initial treatment modalities for the primary thyroid tumor appeared to affect disease-specific mortality in patients with brain metastases. In particular, for patients with differentiated carcinoma, neither total/near-total thyroidectomy (median survival, 12 vs. 4 months for those with lesser operations; P > 0.2) nor radioiodine ablation (median survival, 12 vs. 3 months for those who did not receive any radioiodine within 12 months of diagnosis; P > 0.2) significantly affected survival.

Of the 36 patients diagnosed with brain metastases before death, 9 (differentiated carcinoma, n = 7; anaplastic carcinoma, n = 2) underwent surgical resection of 1 or more intracranial lesions; clinical characteristics of those who did and those who did not have surgery are presented in Table 2. Patients who underwent resection of 1 or more foci of brain metastases had significantly longer survival than those who did not (P < 0.05; Fig. 3). For the subgroup of patients with differentiated carcinoma, those who underwent surgical excision had a median disease-specific survival of 22 months (n = 7), compared with 3.6 months for those who had no surgery (n = 16; P < 0.01). One potential caveat would be the possibility that patients with slower growing tumors or with a greater expected survival were selected for surgery, particularly given the high early mortality seen in those patients who did not have surgery. As metastasectomy is usually not recommended for patients with an expected survival of less than 3 months (18), all patients who died within 3 months of the diagnosis of brain metastases were then removed from the analysis regardless of the treatment regimen used. Nevertheless, the median survival of this subgroup of 8 patients who underwent surgery remained significantly longer than that for the 12 who did not (20 vs. 11 months; P < 0.05). Another potential confounding factor was the presence or absence of multiple radiographically detectable brain metastases. Limiting the analysis to those patients who had a single brain metastasis, median survival was 25.2 months (n = 6) after metastasectomy, compared with 2.4 months without surgery (n = 5; P < 0.005). Using a proportional hazards model that included the parameters metastasectomy (no vs. yes) and unifocality of brain lesions (radiographic evidence of 1 vs. >1 metastasis), only metastasectomy remained a significant predictor of prolonged survival [P < 0.05; ß = 0.91 (95% confidence interval, 0.15–1.91)]. However, when the proportional hazards analysis was limited to the smaller subgroup of patients who survived at least 3 months, the model lost statistical significance (P < 0.07).

View larger version (22K): [in this window] [in a new window]   Figure 3. Effect of surgical resection of brain metastases on disease-specific survival (all histologies of thyroid carcinoma).

Neurological complications after radioiodine therapy, such as worsening focal deficits and headaches, occurred in two of three patients with positive uptake. The one patient with documented radioiodine uptake who did not develop neurological complications after radioiodine therapy had surgical excision of a single metastatic lesion before scanning and therapy. Another patient was treated with radioiodine for multiple foci of uptake in the brain and experienced focal motor weakness and severe headaches that developed during thyroid hormone withdrawal. Subsequently, she underwent resection of two of the largest intracranial lesions (Fig. 4). Approval of a compassionate use protocol for recombinant human TSH (Thyrogen, Genzyme Corp., Cambridge, MA) was obtained from the institutional review board, and informed consent was obtained from the patient. While remaining on thyroid hormone to maintain endogenous TSH suppression and dexamethasone to prevent peritumor edema (22), she was treated with recombinant human TSH (0.9 mg, im, each day for 2 days). Radioiodine scanning demonstrated persistent uptake in the remnants of tumor in the brain. After two additional daily doses of recombinant human TSH, she was treated with 200 mCi ¹³¹I sodium iodide, without further neurological compromise. Posttreatment scanning confirmed radioiodine uptake into the intracranial lesions (Fig. 4) (23).

View larger version (102K): [in this window] [in a new window]   Figure 4. Magnetic resonance imaging and 131I scan from a patient with brain metastases of tall cell variant of papillary thyroid carcinoma. Lesion A was partially resected after the magnetic resonance imaging but before the 131I imaging. The lesions designated C seen on the 131I scan represent inoperable cervical recurrence. The radioiodine scan was performed 96 h after the first of two daily im injections of recombinant human TSH (0.9 mg) and 48 h after oral administration of 200 mCi 131I sodium iodide.

Eleven patients were found to have brain metastases from thyroid carcinoma as a result of postmortem examination, eight (73%) of whom had differentiated thyroid carcinoma. No feature could be identified that significantly separated this group from those with a premortem diagnosis of brain metastases, including age at initial diagnosis of thyroid cancer, extent of initial thyroid surgery, or proportion of patients with any distant metastasis at initial diagnosis.

	Discussion

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Brain metastases are a rare complication of thyroid carcinoma, identified before death in only 1.2% of patients with thyroid carcinoma seen at our tertiary referral oncology center. Patients who developed brain metastases tended to have characteristics at initial disease presentation typical of an aggressive thyroid carcinoma: older age, larger primary tumor, and frequent evidence of extrathyroidal invasion and locoregional and distant metastases (5, 11, 12, 13). Brain metastases tended to be identified more commonly in patients with more aggressive histologies as well, such as oxyphilic (Chiu, A. C., Oliveira A. A., Schultz P. N., Ordonez N. G., Sherman S. I., in preparation) and anaplastic carcinomas (24, 25). Once diagnosed, the prognosis of a patient with brain metastases was grim. The median survival for patients with thyroid carcinoma with brain metastases (4.7 months) was similar to that recently reported for a large cohort of patients with brain metastases from any systemic malignancy (4 months) (18). Similarly, the 12 month median survival for differentiated thyroid carcinoma was parallel to that reported for brain metastases from prostate carcinoma, the longest survival seen in that same cohort (18). Given the frequent association of brain metastases with other sites of distant metastases, as documented in this study and by others (26), it would seem reasonable to consider routine imaging of the brain in an older patient with papillary carcinoma who develops any evidence of distant metastatic disease. Similarly, the high frequency of brain metastases in anaplastic carcinoma suggests that initial evaluation of a patient with this histological subtype should include computerized tomography of the brain.

Patients with brain metastases who underwent surgical resection of at least one intracranial lesion had a longer survival than those who did not have metastasectomy. Although the presence of single brain metastases also appeared to predict a similar improved survival, multivariate analysis identified surgical resection as an independent predictor of better outcome. No other individual therapy or combination of therapies appeared to prolong survival, although the numbers of patients were low. Given the retrospective nature of this study, several important caveats must be applied to any conclusion about the role of surgical therapy. Most importantly, selection bias may have influenced the choice of patients to undergo surgery, limiting metastasectomy to those patients with an a priori potentially better outcome. However, the older age of patients who underwent surgery and the failure of intracranial multifocality to affect the conclusion of the multivariate analysis would mitigate against this argument. Surgical resection has been demonstrated to prolong survival by nearly 3-fold in one randomized prospective study of patients with a variety of solid tumors that metastasized to the brain (16). Other retrospective studies of single disease entities have also supported a survival benefit from surgery (27, 28, 29, 30). Thus, our evidence in favor of surgical resection is concordant with that reported for other solid tumors metastatic to the brain (31). In contrast to pulmonary metastases, brain metastases can cause acutely disabling symptoms, increasing the clinician’s desire to offer a therapy capable of minimizing morbidity and improving patient survival. In this context, we recommend consideration of surgical resection of accessible brain metastases from thyroid carcinoma, particularly for patients with differentiated primary tumors whose locoregional disease or other sites of distant metastases are adequately controlled. Morbidity that can be attributed to a specific intracranial lesion in the setting of multifocal brain metastases may also trigger consideration of resecting the causative lesion, although our data did not specifically address this particular question.

For patients who are unable to undergo surgery, who have disseminated or inaccessible intracranial lesions that preclude metastasectomy or whose life expectancy is less than 3 months, whole brain radiotherapy is probably a reasonable option (18). Our data failed to identify a specific survival benefit from this therapy, perhaps due to the small numbers of patients, but analogy to other solid tumors might support this recommendation (15). Similarly, there are little data to substantiate routine postoperative whole brain radiotherapy after removal of a single brain lesion, but this therapy could be considered after incomplete resection, as has been common practice (15). The unique ability of differentiated thyroid carcinoma to respond to radioiodine may prompt scanning and therapy, but the complications of thyroid hormone withdrawal and treatment may be considerable (32). Further study may support a role for recombinant human TSH-aided scanning and therapy combined with dexamethasone, as our patient appeared to tolerate this approach without complications.

Retrospective reports of disease outcome and therapy from a single institution generally have limited applicability due to potential for biases in patient referral, secular trends due to the prolonged duration of patient accrual, and the often inbred treatment biases of a limited number of clinicians. For brain metastases from this disease, however, it is unlikely that randomized, multicenter, controlled clinical trials will supplant this type of retrospective study. The relative rarity of thyroid carcinoma combined with the low incidence of brain metastases may require a prohibitive number of centers recruiting and treating patients over an extended number of years to produce a study with sufficient power to determine the optimal treatment.

	Acknowledgments

 
The authors thank Pamela Schultz, R.N., for assisting with identification of cases; Roberto V. Reyes for assistance with preparation of figures; Deirdre Maxted and the Genzyme Corp. for supplying the recombinant human TSH; and Padma Horvit, M.D., Ziya L. Gokaslan, M.D., and Michele Smith, R.N., for assisting with the care of the patient treated with recombinant human TSH.

Received March 17, 1997.

Revised June 24, 1997.

Revised July 30, 1997.

Accepted August 5, 1997.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiu, A. C. Articles by Sherman, S. I. Search for Related Content PubMed PubMed Citation Articles by Chiu, A. C. Articles by Sherman, S. I.