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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
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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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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.
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Results |
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The clinical characteristics of the 161 patients with fatal
thyroid carcinoma are shown in Table 1
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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.
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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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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Acknowledgments |
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Received March 25, 1999.
Revised July 1, 1999.
Accepted July 25, 1999.
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References |
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