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Immediate Causes of Death in Thyroid Carcinoma: Clinicopathological Analysis of 161 Fatal Cases

Department of Surgery II, Nippon Medical School (Y.K., K.Sh., S.T.), 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113; and the Surgery Branch, Ito Hospital (M.N., K.Su., O.O., T.M., Ku.I., Ko.I.), 4–3-6 Jingumae, Shibuya-ku, Tokyo 150, Japan

Address all correspondence and requests for reprints to: Yutaka Kitamura, M.D., Department of Surgery II, Nippon Medical School, 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan. E-mail: taka{at}nms.ac.jp

	Abstract

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Most patients with thyroid carcinoma have a good prognosis. Due to the small number of fatal cases, it has not been clarified what conditions result in death for patients with thyroid carcinoma. To provide appropriate management for advanced thyroid carcinoma patients, we analyzed causes of death in 161 fatal cases. Clinical characteristics and immediate (final) causes of death based on pathological conditions were analyzed in 62 anaplastic carcinomas and 99 fatal differentiated carcinomas. Single fatal conditions could not be specified in 55 patients. In the remaining 106 patients, respiratory insufficiency (43%) was the most common specific fatal condition, followed by circulatory failure (15%), hemorrhage (15%), and airway obstruction (13%). Respiratory insufficiency due to remarkable pulmonary metastasis replacing lung tissue, massive hemorrhage and airway obstruction due to uncontrolled local tumors, and circulatory failure resulting from compression of the vena cava by extensive mediastinal or sternal metastases were found to be the most important immediate causes of death. Based on this knowledge, several palliative procedures may be worth considering to improve survival and quality of life in patients with advanced thyroid carcinoma.

	Introduction

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THE PREVALENCE of thyroid carcinoma is 2–4 cases/100,000 individuals in the general population (1, 2), and mortality related to thyroid carcinoma is 0.4–0.6 cases/100,000 individuals (1) or 0.3–0.4% of all cancer-related deaths (3, 4). Thyroid carcinoma derived from follicular epithelial cells is categorized as either anaplastic (undifferentiated) or differentiated. Differentiated thyroid carcinoma comprises the papillary and follicular thyroid carcinomas. Anaplastic thyroid carcinoma is rare (seen in 2% of thyroid carcinomas in Japan) (5), but it displays the most aggressive characteristics of all human cancers. Almost all cases of anaplastic carcinoma are fatal, with only a short survival period (6, 7). In contrast, differentiated thyroid carcinoma, accounting for more than 90% of thyroid carcinomas (1, 5), is generally characterized by slow growth and a low mortality rate (8–15%) (8, 9, 10, 11, 12). Most patients with advanced differentiated thyroid carcinoma, even those who die of it, maintain a good general condition until the terminal stage despite the presence of huge local tumors and remarkable distant metastases. To provide appropriate management for patients with advanced differentiated thyroid carcinoma, it is important to recognize the immediate (final) causes of death. However, it has been difficult to study a large number of patients succumbing to thyroid carcinoma due to the low mortality rate and the long follow-up period associated with differentiated thyroid carcinoma. There have been several reports on fatal thyroid carcinoma (6, 7, 12, 13, 14, 15, 16, 17), some of which attempted to classify immediate causes of death. However, the categories overlapped, and thus the findings were somewhat nonspecific. We analyzed immediate causes of death based on specific pathological conditions that led directly to death in 161 fatal cases of thyroid carcinoma.

	Subjects and Methods

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Over 5500 patients with malignant thyroid tumors were treated at Ito Hospital in Tokyo between 1971 and 1997. Among 612 consecutive patients treated initially at Ito Hospital and reported previously (2), the 5-yr survival rate among patients with anaplastic carcinoma was 0%, and the 10-yr survival rates among papillary and follicular carcinoma patients were 95.8% and 92.5%, respectively. We studied 161 of these patients; all 161 died while under detailed observation at Ito Hospital and were determined to have died of thyroid carcinoma. Histological diagnosis was made according to the criteria of the Japanese Society of Thyroid Surgery (18) based on the findings of aspiration biopsy cytology, ⁶⁷Ga scintigraphy (19), and pathological examination of surgical, biopsy, and autopsy specimens. The histological diagnoses made at the time of initial treatment were used to classify the 161 fatal thyroid carcinomas, which comprised 62 anaplastic carcinomas and 99 differentiated carcinomas (81 papillary carcinomas and 18 follicular carcinomas). Malignant lymphoma in the thyroid was excluded by immunohistochemical determination of leukocyte common antigen and keratin (20). The clinicopathological features of the 161 fatal thyroid carcinoma patients were analyzed according to medical record descriptions. Single specific conditions arising from thyroid carcinoma that contributed directly to death were determined on the basis of clinical manifestations, examination data, and autopsy findings.

Statistical comparisons between histological groups for age and survival were performed using Student’s t test. All other statistical comparisons were made by the ² test or Fisher’s exact test. P 0.05 was considered significant.

	Results

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Clinical characteristics of the 161 patients with fatal thyroid carcinoma

The clinical characteristics of the 161 patients with fatal thyroid carcinoma are shown in Table 1. The female to male (F/M) ratio for the total cases was 3.4 (2.6 for anaplastic carcinoma and 4.0 for differentiated carcinoma). Mean ages at initial treatment for total cases, anaplastic carcinomas, and differentiated carcinomas were 60.9, 65.8, and 58.7 yr, respectively; mean ages at death were 66.4, 66.0, and 66.6 yr, respectively. Mean survival times from initial treatment to death were 67.8, 6.2, and 106.4 months, respectively. Mean age at initial treatment and mean survival with differentiated carcinoma differed significantly (P < 0.001) from mean age and mean survival with anaplastic carcinoma. One anaplastic carcinoma patient survived for an unusually long period of 4 yr. This patient’s papillary carcinoma had a very small metastatic focus within a lymph node that was resected.

The treatments used in these fatal cases are summarized in Table 2. Tumor resections and/or other extensive surgical procedures with curative or palliative intent were carried out in 57% of the total cases, regional lymph node dissections were performed in 44%, tracheostomy was performed in 40%, ¹³¹I radioisotope therapy was conducted in 19%, external irradiation was given in 88%, and chemotherapy was performed in 58%. Using a ⁶⁰Co or electron beam, 40–60 Gy were delivered to tumors in the neck and 15–30 Gy were delivered to metastatic lesions of the bone to relieve pain. Generally, since 1986, adriamycin and cisplatin (22) or etoposide and cisplatin have been used in combination for both anaplastic and advanced differentiated carcinoma. However, intensive chemotherapy has been noted to have no certain effect on survival (23). The TNM clinical classifications (24) of the 161 cases are shown in Table 3. The differentiated carcinomas were considered to be stage I in 6% of cases, stage II in 5%, stage III in 76%, and stage IV in 13%. At initial treatment, 133 of 155 (86%) of patients had primary tumors 40 mm or greater in diameter, 141 of 156 (90%) had tumors showing extrathyroidal invasion, and 31 of 161 (19%) showed distant metastases. By the time of death, recurrent or persistent tumors in the neck and distant metastases were seen in 96% and 85% of all patients, respectively (Table 4). Lung and bone were the main distant metastatic sites, being identified in 78% and 28%, respectively, of the total patients with fatal thyroid carcinoma. Survival time from the diagnosis of pulmonary or bone metastasis to death with anaplastic carcinoma was significantly shorter than that with differentiated carcinoma (Table 4).

In some cases, it was not possible to determine a single specific immediate cause of death, i.e. in patients in whom serious conditions developed simultaneously in multiple organs and in patients in whom general weakness progressed gradually without specific verified organ failure (cachexia). Specific immediate causes of death were not identified in 55 of the 161 (34%) patients (40% with anaplastic carcinoma and 30% with differentiated carcinoma; Table 5). The remaining 106 patients were analyzed in detail for specific causes of death (Table 6). Respiratory insufficiency was the most common fatal condition, occurring in 46 cases (43%), followed by circulatory failure in 16 cases (15%), hemorrhage from the tumor in 16 cases (15%), and airway obstruction in 14 cases (13%). Fourteen patients (13%) died from various other causes. There were no significant differences in frequency for each specific cause of death between the anaplastic and differentiated thyroid carcinomas.

Widely spread multiple pulmonary metastases resulted in the replacement of a large amount of lung tissue by carcinoma in 38 of the 46 patients who died of respiratory insufficiency. Lethal pneumonia was induced by aspiration due to esophago-bronchial fistula in 2 cases and stenosis in the larynx and trachea by tumor invasion and recurrent nerve palsy in 3 cases. Diffuse pulmonary fibrosis occurred in 3 cases as a complication related to bleomycin therapy.

Circulatory failure

Metastasis in either the sternum or the mediastinal lymph nodes compressing the superior vena cava or inferior vena cava led to superior vena cava syndrome and serious hypotension in 7 of the 16 patients who died of circulatory failure. Cardiac failure was thought to be a critical condition in the other 9 cases, including 7 cases of unspecified cardiac complications resulting from a poor general condition associated with advanced thyroid carcinoma. The remaining 2 patients showed distant metastatic involvement of the heart. Replacement of most of the right ventricle by the metastatic papillary carcinoma resulted in cardiogenic shock in one case; pericardiac effusion from metastases in the pericardium and myocardium led to cardiac tamponade in another case.

Hemorrhage

Uncontrollable bleeding in the 16 tumor hemorrhage cases arose from tumor in the anterior neck (in 9 cases), tumor invading the oral cavity (in 5 cases), and a ruptured carotid artery due to tumor invasion (in 2 cases).

Airway obstruction

Airway stenosis followed by edema in the vocal cords and difficulty excreting sputum resulted in asphyxia in 14 patients. All but 1 of these patients died from stenosis around the vocal cords. In the 1 exceptional case, the distal trachea and main bronchus around the carina were obstructed because of mediastinal lymph node metastatic progression despite a tracheostomy. Of all 161 patients who died, 70 (44%) had airway stenosis, which was confirmed by x-ray or endoscopic examination; 19 of these 70 patients did not undergo tracheostomy. Consequently, 12 died of asphyxia.

Other causes

The causes of death in the 14 other patients were as follows: sepsis following agranulocytosis or pancytopenia related to external irradiation in 1 case and to chemotherapy in 2 cases, cerebral herniation due to brain metastasis in 3 cases, acute renal failure based on a poor general condition in 2 cases, disseminated intravascular coagulopathy due to infection of necrotic tumor tissue in 2 cases, hypercalcemia associated with malignancy in 1 case, necrosis in the cervical spinal cord due to compression by metastatic tumor in the cervical vertebra in 1 case, intestinal obstruction following multiple ip metastases in 1 case, and gastrointestinal bleeding in 1 case.

Tumor sites associated with fatal conditions

The causes of death were also classified according to the sites of tumors mainly responsible for producing the fatal conditions in the total of 161 patients (Table 7). Local lesions alone, including persistent or recurrent tumors in the thyroid or in the regional lymph nodes, were responsible for death in 35% of the patients in this series, distant metastatic lesions alone in 33%, and both local and metastatic lesions in 28%. In 4% of patients, tumor sites per se were not associated with fatal conditions; death was attributed to complications related to chemotherapy or external irradiation. Distant metastatic lesions alone were responsible for deaths significantly more frequently in cases of differentiated carcinoma than in cases of anaplastic carcinoma.

	Discussion

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Sometimes it is difficult to identify a specific cause of death even when we actually observe dying patients. Multiple serious conditions developed simultaneously in not a few cases of fatal thyroid carcinoma in this series. In one third of the autopsied cases, it was impossible to determine a single immediate cause of death despite knowing the tumor sites precisely. In previous studies, classifications of causes of death were not consistent from study to study, making comparison difficult. To avoid ambiguous results, we eliminated patients who died of nonspecific causes from detailed analysis for immediate causes of death. Consequently, it was clearly indicated that respiratory insufficiency due to remarkable pulmonary metastasis replacing lung tissue, massive hemorrhage and airway obstruction due to uncontrolled local tumors, and circulatory failure resulting from compression of the vena cava by extensive mediastinal or sternal metastases were the most important immediate causes of death in patients with thyroid carcinoma.

The lung is the most common site of distant metastasis in thyroid carcinoma (25, 27). In this series, 78% of the total cases (86% of anaplastic carcinomas and 72% of differentiated carcinomas) showed pulmonary metastasis; 70–85% of autopsy cases have shown pulmonary metastasis in other studies (13, 15). Our study showed respiratory insufficiency due to multiple pulmonary metastases to be the most important single immediate cause of death for both anaplastic (35%) and differentiated (36%) carcinomas. This statistic matched those of prior studies (2, 10, 11, 14). However, the presence of pulmonary metastasis in our patients did not always result in respiratory insufficiency. In our series, approximately half of the patients with pulmonary metastasis died of causes other than respiratory insufficiency.

Hemorrhage from the tumors and airway obstruction due to uncontrollable local tumors were the second most important causes of death. In previous studies, including a former Ito Hospital study of cases between 1967 and 1978 (16), the frequency of airway obstruction was much higher (28–77%) (7, 13, 14, 15, 17, 26, 28). Two thirds of the patients who had airway stenosis without tracheostomy died of asphyxia in the present series. Since 1986, we have performed tracheostomy in almost all thyroid carcinoma patients with airway stenosis, and only one patient with the distal tracheal stenosis treated between 1986 and 1997 died of airway obstruction. Thus, tracheostomy is likely to be important in preventing death by airway obstruction in thyroid carcinoma patients. It should also be noted that tracheostomy relieves airway stenosis patients from the fear of suffocation.

Remarkable mediastinal tumors (n = 5) and extensive sternal metastases (n = 2) resulted in compression of the vena cava followed by critical hypotension. There are few descriptions in the literature of circulatory failure due to compression of the vena cava. Growing metastatic tumors in either the sternum or mediastinum should be considered potentially lethal. The heart is not a rare site for metastatic thyroid carcinoma. According to autopsy reports, approximately 20% of patients with thyroid carcinoma have shown metastasis in the heart (7, 13, 15). In one reported case (13) and in two cases of our series, metastases in the myocardium and the pericardium became the immediate causes of death. Thus, it is necessary to check cardiac involvement by echocardiogram in patients with advanced thyroid carcinoma.

The frequency of metastasis in the brain has been reported to be 9–22% in autopsy cases (13, 15). Metastasis in the central nervous system, including the brain and spinal cord, has been described as a relatively common cause of death (10–21%) (10, 14, 17). Nevertheless, brain metastasis resulting in death was less frequent (3%) in our series. Recently, resection of metastatic brain tumors has been performed (29, 30) in certain circumstances. One papillary thyroid carcinoma patient in our series underwent removal of a metastatic brain tumor 8 yr before death and showed no recurrence in the brain.

Bone is the second most common metastatic site in thyroid carcinoma (25, 28), involving the vertebrae, sternum, ribs, and skull. The incidence of bone metastasis has been reported to be approximately 40% (13, 15). It was 28% in our series. The reported frequency of bone metastasis as an immediate cause of death is not consistent and ranges from 0–24% (2, 10, 11, 14, 17). Tollefsen et al. described seven deaths from inanition with extensive bone metastasis (14). However, fatal pathological conditions due to bone metastasis in other reports were ambiguous. In our series, metastases in the cervical vertebrae and sternum clearly led to death. In two recent cases, sternal metastases of papillary and follicular carcinoma were treated with excision of the sternum and replacement with a resin board. There was no relapse in the anterior mediastinum before death in these cases. Several of our differentiated carcinoma patients with vertebral metastasis underwent successful decompression and fixation surgeries to avoid paralysis and relieve pain; these patients continued without paralysis for at least 3 yr. Palliative surgery for bone metastasis of differentiated thyroid carcinoma is reported to favorably affect the quality of life and prognosis (29, 31).

Six of our patients died of conditions associated with therapeutic procedures, including pulmonary fibrosis induced by chemotherapy and serious bone marrow suppression after external irradiation and chemotherapy. Treatment-related pulmonary fibrosis and treatment-related aplastic anemia have been reported previously (15).

Malignancy-associated hypercalcemia (MAH) is of 2types: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (32). MAH is a serious condition, leading to renal failure and fatal arrhythmia. One patient in our series with anaplastic carcinoma died of hypercalcemia. This patient’s condition was thought to be renal failure in association with HHM, as there was no clinical evidence of bone metastasis. In this series, MAH was identified in 10 of 154 (6.5%) cases (in 8.9% of anaplastic carcinomas and in 5.1% of differentiated carcinomas; Table 8). The hypercalcemia seen in 8 of these cases was thought to derive from HHM, since there was little or no bone metastasis, and elevation of the serum level of PTH-related protein (33) was detected in a case of anaplastic carcinoma. The remaining 2 showed remarkable multiple bone metastases and mild renal function disturbances and thus were considered local osteolytic hypercalcemia cases (34). Although the incidence of MAH in thyroid carcinoma is low compared with that in most other cancers (35), hypercalcemia should be considered, possibly leading to death in thyroid carcinoma.

	Acknowledgments

 
We thank Ms. Dolly Baker for her assistance in preparing this manuscript.

Received March 25, 1999.

Revised July 1, 1999.

Accepted July 25, 1999.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor 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 Kitamura, Y. Articles by Tanaka, S. Search for Related Content PubMed PubMed Citation Articles by Kitamura, Y. Articles by Tanaka, S. Pubmed/NCBI databases Medline Plus Health Information Thyroid Cancer