Distant Metastases in Differentiated Thyroid Carcinomas: A Clinical and Pathologic Study YUJI MIZUKAMI, MD, TAKATOSHI MICHIGISHI, MD, AKITAKA NONOMURA, MD, TAKUMA HASHIMOTO, MD, SHINTARO TERAHATA, MD, MASAKUNI NOGUCHI, MD, KIN-ICHI HISADA MD, AND FUJITSUGU MATSUEIARA MD Of 514 patients with differentiated thyroid carcinoma treated between 1970 and 1987, 34 (6.6%) had distant metastases. Twelve patients died of their distant metastases; eight of these patients died within 5 years from the time of initial diagnosis. Death from cancer was most frequent in the seventh decade. The metastases were most often found in tbe lungs and bones. In the fatal group, pleural, brain, and pericardial metastases were noted. Local recurrences were found only in 24% of these 34 patients. Histologic types of primary thyroid tumors and metastatic tumors were reexamined and classified using our criteria, which were mainly based on the World Health Organization nomenclature and currently obtained pathologic observations of thyroid tumors. In 31 thyroid tumors, the surgical specimens were available for review. Twenty-four tumors were papillary and seven were follicular. Of the 24 papillary carcinomas, nine were follicular, eight were well-differentiated, and seven were trabecular. On the other hand, the seven follicular carcinomas consisted of four welldifferentiated, two solid, and one oxyphilic. The majority of the thyroid tumors showed an extrathyroidal extension; however, two were intrathyroidal carcinomas and two were encapsulated carcinomas, larger than 5 cm in diameter. Distant metastases were confirmed morphologically in 18 patients (11 by surgical or biopsy material, five by autopsy, and two by cytology). The histologic types of metastatic tumors were consistent with those of primary thyroid tumors. Diagnostic Is11uptake was examined in 32 patients and absorption of diagnostic lslI in metastatic tumors was demonstrated in 21 patients. The IO-year survival rate of patients with ls’I accumulating metastases (70%) was significantly better than that of patients with metastases lacking such uptake (40%). Immunoreactivity for thyroglobulin in metastatic tumors was correlated with the Is11absorption. This finding indicated that immunostaining of thyroglobulin in metastatic tumors might be useful in the prediction of the effectiveness of Is11 therapy. HUM PATHOL 21:283-290. 0 1990 by W.B. Saunders Company.
Papillary and follicular carcinomas (differentiated carcinomas) of the thyroid are generally considered indolent diseases and are characterized by slow growth of the tumors and long natural histories. However, a considerable number of patients with dif-
ferentiated thyroid carcinoma die from distant metastases or from local tumor infiltration. Distant metastases of papillary and follicular carcinoma are frequently fatal and the patients die of respiratory insufficiency from pulmonary metastases or brain metastases.1-3 Distant metastases are usually found at the time of initial surgery, but in some patients they have developed at postoperative intervals of 10 years or more. Therefore, it is important to clarify the clinical and pathologic characteristics of differentiated thyroid carcinomas associated with distant metastases. Recently, several histologic subtypes of differentiated thyroid carcinoma have been proposed and may provide a useful basis for comparison of clinical prognosis .4-8 Therefore, we have reexamined 34 patients with distant metastases from differentiated thyroid carcinoma from the standpoint of clinicopathology.
This report describes the determinants on metastatic potential and prognosis of differentiated thyroid carcinoma, such as age of patients, extent of primary tumor, histologic type, and Is11 absorption in metastatic tumor.
PATIENTS AND METHODS The clinical and pathologic records of all patients with the diagnosis of differentiated carcinoma of the thyroid gland, treated in the Kanazawa University Hospital between the years 1970 and 1987, were reviewed. The records of 34 patients with distant metastases from differentiated thyroid carcinoma were collected. These patients had been operated on at the Kanazawa University Hospital (21 patients), the Kurobe Citizen Hospital (four patients), and
other hospitals (nine patients). In three of the 34 patients, histologic slides from the primary thyroid tumor were not
available, but those from distant metastases were available, and their histologic features were clearly suggestive of the thyroid. During the same period, 12 of 34 patients died from distant metastases of the thyroid carcinoma. One paTABLE 1. Basis for the Diagnosis of Distant Metastases
From the Pathology Section, Department of Nuclear Medicine, and Central Clinical Laboratory, Kanazawa University Hospital, Kanazawa, Japan. Accepted for publication July 26, 1989. Key words: thyroid carcinoma, distant metastases, prognosis, immunochemistry. Address correspondence and reprint requests to Yuji Mizukami, MD, Pathology Section, Kanazawa University Hospital, 131, Takara-machi, Kanazawa, 920, Japan. 0 1990 by W.B. Saunders Company. 0046-8177/90/2103-0005$5.0010
283
Basis for Diagnosis
No. of Cases
Autopsy Histologic Cytologic ClinicaVSl uptake/x-ray
5 11 2 16
Total
34
HUMAN PATHOLOGY
Volume 21, No. 3 (March 1990)
FIGURE 1. (lop left) Papillary carcinoma well-differentiated type. Well-developed papillan/ proliferation of follicular cells is visible. Distinct “ground-glass” nuclei are characterlstkz. (HematoxYlin-eosln stain; magnificatton x 182.1 uop rlght) Papillary carcinoma foilicular variant type. Prominent foiiicular structures are notable. Follicular cells contain nucleus showing “ground-glass” appearance. (Hematoxylln-eosin stain: magnification x200.) (Inset] Higher magnification of nuclei showing tvpical “ground-glass” appearance. (Hematoxylin-eosin stain; magnification x 372.) [Center left] Papillary carcinoma, trabecular type. A cord-like arrangement of follicular ceils is a promlnent histologic feature. The nuclei of folllcular cells are more hyperchromatic and polymorphic. Foci of well-differentiated papillary carcinoma are occasIonally intermingled in this tqe of the tumor. (HematoxYlin-eosin stain; magnificatton x 186.) [Center right) Folllcular carcinoma well-differentiated type. The tumor is composed of small or large follicles. Nuclei of foilicular cells are compact and hyperchromatlc. %round-glass” nuclei are not recognizable. (HematoxYlin-eosin stain; magnification x 182.) (Bottom left) Follicular carcinoma, solld type. The tumor is composed of solid clusters of folllcuiar cells contalnlng a variable number of small follicles. The nuclei are more polymorphic and mitoses are occasionally observed. (Hematoxylin-eosin stain; magnification x 190.) (Bottom right) Follicular carcinoma oxyphlilc h/pe. The tumor is composed entireh/ of oxyphillc (Hurthle) cells arranged in a solid or folllcuiar structure. The nuclei show po&norphism and occasional mitoses. (HematoxYiin-eosin stain; magnification x 182.1
284
DISTANT METASTASES INTHYROID CARCINOMA(Mizukamiet al) TABLE2. No. of Patients
Age and Sex Distributionof Patlents at lnltlal Diagnosis Age (yr)
o-9
10-19
20-29
With metastases Male Female Subtotal Without metastases Male Female Subtotal Total
30-39
40-49
50-59 5(i)
60-69
70-79
80-89
Total
3 (2) 8 (4)
4 (2)
1
6 (2) 28 (10)
1 4
4(:)
2 2
5
5 (1)
6 (3)
11 (6)
4 (2)
1
34 (12)
1
2 10
2 40
13 88
14 83
11 101
9 65
8 28
1 4
60 420
1
12
42
101
97
112
74
36
5
480
1
12
44
106
102
118
85
40
6
514
NOTE. Parentheses indicate the number of fatal cases.
4. Encapsulated carcinoma: the tumor is wellencapsulated and capsular invasion or vascular invasion is shown in only one or two foci of one or two of several sections. Distant metastases were defined as being outside the neck, thyroid, or upper mediastinal area. Lymph node metastases were excluded in this study.
Gent developed gastric cancer during follow-up, but the distant metastases was established histologically to be caused by the thyroid carcinoma. In 11 of the 34 patients,
metastatic tumors were confirmed histologically from surgical or biopsy materials, in five patients from autopsy materials and in two patients cytologically (Table 1). In the other 16 patients, distant metastases were confirmed from clinical evidence, x-ray changes, or lslI uptake in the metastases. The tumors, including anaplastic component totally or partially in the primary thyroid carcinoma, were excluded in this series. All metastatic tumors also showed histologic features of differentiated thyroid carcinoma, but in two autopsy cases, anaplastic transformation was associated partially in the metastatic tumors. The histologic slides of the whole series were revised and reclassified according to the following criteria, which is mainly based on a WHO classification9 and currently obtained pathologic observations of thyroid tumors4-s (Fig I): 1. Papillary carcinoma: well-differentiated, follicular variant, trabecular, and oxyphilic. 2. Follicular carcinoma: well-differentiated, solid, and oxyphilic. The primary thyroid tumors were further divided into four categories on the basis of the extent of the tumor. 1. Extensively extrathyroidal invasion: the tumor invades massively to the trachea and adjacent soft tissues, and occasionally fills the entire neck. 2. Extrathyroidal invasion: the tumor breaches the thyroid capsule and slightly invades the adjacent structures (muscle or trachea). 3. Intrathyroidal carcinoma: the tumor is confined to the anatomic boundaries of the thyroid gland. No thyroid capsular invasion is found. TABLE 3.
lmmunostaining Immunoperoxidase staining for thyroglobulin (TG) and thyroxine (T4) was done on the metastatic tumors from 16 patients using the peroxidase-antiperoxidase method. Both TG antiserum and T, antiserum were polyclonal in rabbit (Ortho Inc, Raritan, NJ; prediluted). Negative controls consisted of substituting normal serum for the primary antisera. Statistical analysis was performed using Student’s t test; differences were judged to be significant at a level greater than 95% of confidence (P < .05). The length of survival of each patient was studied by the Kaplan-Meier method and a generalized Wilcoxon’s test or Cox-Mantle test was used to assess the statistical significance. RESULTS Clinical Findings of 34 patients by Age and sex. The distribution sex and by age at the time of initial diagnosis is shown in Table 2. There were 28 women (82.4%) and six men (17.6%), ranging in age from 27 to 83 years.
Surgical Treatment of Primary Thyroid Lesions and Distant Metastases or Local Recurrences No operation
Development of distant metastases Same time yr Withinthan 5 5 yr Later
1
Total Thyroidectomy + Neck Dissection
Total Thyroidectomy
Hemithyroidectomy
Insufficient Information
17
3
32
:
2
3
Local recurrences Yes No
1
4 18
1 5
1 1
2 1
Total
1
22
6
2
3
285
HUMANPATHOLOGY TABLE A
Volume 21, No. 3 (March1990)
Time After Initial Diagnosis of First Distant Metastases
Time
No. of Patients
At diagnosis 20 yr
21
Total
34
: 1 5 :
Distant metastases were seen more frequently in older patients; the median age in patients with distant metastases was 55.3 years compared with 48.9 in those without. Also, there was a sex difference with respect to the frequency of distant metastases. Distant metastases were found in 9.1% of the male patients, as opposed to 6.3% of the females, but the difference was not significant. Of the patients who died, the average age at the time of initial diagnosis was 62.8 years, while the average age for the surviving group was 50.4 years. The risk of death from distant metastases of differentiated thyroid carcinoma increased after 40 years of age. Treatment of p&nay tumor. Of the 34 patients, 33 were treated with surgery and one was treated with chemotherapy alone because of the development of widespread distant metastases with pleural effusion at the time of initial diagnosis. Because the patients had been operated on at different hospitals, the surgical procedures varied. Three patients referred to us from other hospitals had thyroid surgery before referral, and information about the operation method was insufficient. Twenty-two patients had received a total thyroidectomy and neck dissection. Six patients had received a total thyroidectomy and two patients had received only a hemilateral lobectomy (Table 3). Most of the 33 patients who underwent operations were given I3 l I treatment either after surgery or after distant metastases were apparent. Period from initial diagnosis of first distant metastases. In 21 of the 34 patients (62%), distant metastases had already developed by the time of initial diagnosis (Table 4). In eight patients, metastases developed postoperatively within 10 years; in five patients, metastases developed after more than 10 years. The longest postoperative interval was 34 years. Sites of metastases. The most frequent metastatic site was pulmonary, and the lungs were involved in most patients (82%; Table 5). The other common TABLE 5. Lungs Fatal group (12 patients) Autopsy (5 patients) Others (7 patients) Surviving group (22 patients) Total (34 patients)
Bone
sites of distant metastases, in descending order of frequency, were the bone (440/o), pleura (21%), kidneys (18%), and brain or liver (15%). The five autopsy patients had widespread metastases involving several organ systems. In the fatal group, metastases to pleura, brain, pericardium, and liver were noted, whereas in the surviving group, metastases were limited to lungs, bone, or kidneys. Local recurrences and distant metastases. Local recurrences and distant metastases were both predictive for death from differentiated thyroid carcinoma. Therefore, it is important to examine the relationship between local recurrences and distant metastases. In this series, eight of the 34 patients (23.5%) with distant metastases had local recurrences during the course of their disease. However, the other 26 patients (76.5%) had no local recurrences. In eight patients with local recurrences, only three had local recurrences before the development of distant metastases. This finding suggests local recurrences had no influence on the development of distant metastases (Table 6). Survival with distant metastases. Distant metastases portend a poor prognosis. Survival of 34 patients after the initial diagnosis was seriously reduced (Fig 2). Survival rates after 5 and 10 years were 72% and 58%, respectively. 1311 absorption in distant metastases. Since 1968, r3r1 scintigraphy was done routinely, preoperatively and postoperatively, in our hospital. In this series, however, two of the 34 patients did not receive diagnostic 1311 scintigraphy after surgery because both patients were referred to us from other hospitals. Absorption of Is11 in the metastatic tumors was demonstrated in 21 patients (65.6%), whereas 11 patients (34.4%) had no Is11 uptake in the metastatic tumors. Survival rate curves of 32 patients by lslI absorption in the metastatic tumors are shown in Fig 3. The lo-year survival rate of patients with lslI accumulating metastases was 70%, while that of patients with metastases lacking such uptake was 40% (CoxMantle test, P < .05). Pathologic Findings Extent of primq tumor. In three of the 34 patients, a pathology report or histologic slides were not available and macropathologic and micropathologic characteristics of the primary tumor were unknown. In the other 31 patients, the extent of the primary thyroid tumors in relation to their histologic type is shown in Table 7. In 11 patients, primary tumors
Sites of Distant Metastases Pleura
Brain
Liver
Kidneys
Pericardium
Diaphragm
16
4 3 8
4 3 0
3 2 0
4 0 1
4 0 2
4 0 0
3 0 0
28
15
7
5
5
6
4
3
;:
286
DISTANT METASTASES IN WROID
TABLE 6.
CARCINOMA (Mizukami et al)
Relationship Between Local Recurrences and Distant Metastases
follicular carcinoma. With respect to the extent of the primary tumor, the follicular variant and trabecular types of papillary carcinoma showed a tendency toward extensive extrathyroidal invasion. Immunohistochemical stainings for thyroglobulin and thyroxine in m&static tumors. It is of interest to examine whether absorption of 13iI in the metastatic tumors is correlated with an ability of tumor cells to produce TG or T,. Sixteen tumors from 16 patients were examined immunohistochemically for the presence of TG and T,. Two patients did not receive diagnostic 1311 scintigraphy after surgery. All four metastatic tumors accumulating isi1 showed a positive staining for TG. On the other hand, six of 10 tumors lacking isi1 accumulation showed a negative staining for TG, but the other four tumors showed a positive staining for TG (Table 8). From this evidence, TG production seemed to be correlated with an absorption of isi1 in the metastatic tumors, although the results of four tumors (40%) without lslI accumulation were inconsistent. Immunohistochemical demonstration of TG might be a useful method for predicting isi1 absorption in metastatic tumors. In contrast to TG, staining for T, was negative in all metastatic tumors.
Time of Local Recurrences No. of Patients (%)
Before Distant Metastases
After Distant Metastases
8 (23.5) 26 (76.5)
3
5
No Total
34
Local Recurrences Yes
showed an extensive extrathyroidal invasion, involving cervical soft tissue, trachea, upper mediastinum, or esophagus. In the other 16 patients, the tumors showed an extrathyroidal invasion, involving thyroid capsule and adjacent soft tissues. Only two patients showed an intrathyroidal carcinoma, and the tumors were limited within the thyroid gland. Encapsulated carcinoma was also seen in two patients. Tumor size seems to be an important prognostic factor in encapsulated carcinomas. In both encapsulated carcinomas, the tumor size was larger than 5 cm in diameter (the approximately greatest diameters were 6 cm and 7 cm, respectively). Encapsulated carcinomas larger than 5 cm should be observed for distant metastases. Histologic types of primq tumor. Of the 3 1 differentiated thyroid carcinomas examined histologically, 24 were papillary carcinoma and seven were follicular carcinoma (Table 7). In the papillary tumors, nine were follicular variant type, eight were welldifferentiated type, and seven were trabecular type. In the follicular tumors, four were well-differentiated type, two were solid type, and one was oxyphilic type. The follicular variant and trabecular types of papillary carcinoma appeared to develop distant metastases with greater frequency than the welldifferentiated type of papillary carcinoma. When we examined the prognosis of the patients in relation to the histologic subtypes, the well-differentiated type of either papillary or follicular carcinoma showed a better prognosis than the follicular variant and trabecular types of papillary carcinoma or the solid type of %
FIWRE 2. Survival curve of 34 paItents wtth distant metastases. Survbal rates after five and 10 years were 72% and 58%. respectively.
DISCUSSION The results of this study support the concept that differentiated thyroid carcinomas associated with distant metastases are more lethal than commonly believed. After 10 years, the survival rate in our study was 58%. The mortality rates for distant metastases from differentiated thyroid carcinoma in other institutions have been studied. Nemec et allo reported loand 15-year survival rates for patients with pulmonary metastases from follicular carcinoma to be 28.9% and 11.4%, respectively. Hoie et al” also reported that mortality within 1 year of the diagnosis of distant metastases in patients with papillary thyroid cancer exceeded 50%. In our study, better prognostic
I
2 ‘2 1 W
5
10
15
20
Time after initial diagnosis
207
25
30
3 5
yrs
HUMANPATHOLOGY
Volume 21, No. 3 (March1990)
% 100
-
90
-
80
-
70
-
a,
I-
131 uptake
positive
(21
patients)
I-
131 uptake
negative
(11
patients)
CI
:
3. Survival CUIVB by absorption of diagnostic 13$1 in metastatic tumor. The 10 year survival rate in j3’l uptake posiiive tumors was 70% and that in ? uptake negativetumors was 40%. FIQURE
60
P
Papillary and follicular carcinomas (differentiated carcinomas) of the thyroid are generally considered indolent diseases and are characterized by slow growth of the tumors and long natural histories. However, a considerable number of patients with dif-
ferentiated thyroid carcinoma die from distant metastases or from local tumor infiltration. Distant metastases of papillary and follicular carcinoma are frequently fatal and the patients die of respiratory insufficiency from pulmonary metastases or brain metastases.1-3 Distant metastases are usually found at the time of initial surgery, but in some patients they have developed at postoperative intervals of 10 years or more. Therefore, it is important to clarify the clinical and pathologic characteristics of differentiated thyroid carcinomas associated with distant metastases. Recently, several histologic subtypes of differentiated thyroid carcinoma have been proposed and may provide a useful basis for comparison of clinical prognosis .4-8 Therefore, we have reexamined 34 patients with distant metastases from differentiated thyroid carcinoma from the standpoint of clinicopathology.
This report describes the determinants on metastatic potential and prognosis of differentiated thyroid carcinoma, such as age of patients, extent of primary tumor, histologic type, and Is11 absorption in metastatic tumor.
PATIENTS AND METHODS The clinical and pathologic records of all patients with the diagnosis of differentiated carcinoma of the thyroid gland, treated in the Kanazawa University Hospital between the years 1970 and 1987, were reviewed. The records of 34 patients with distant metastases from differentiated thyroid carcinoma were collected. These patients had been operated on at the Kanazawa University Hospital (21 patients), the Kurobe Citizen Hospital (four patients), and
other hospitals (nine patients). In three of the 34 patients, histologic slides from the primary thyroid tumor were not
available, but those from distant metastases were available, and their histologic features were clearly suggestive of the thyroid. During the same period, 12 of 34 patients died from distant metastases of the thyroid carcinoma. One paTABLE 1. Basis for the Diagnosis of Distant Metastases
From the Pathology Section, Department of Nuclear Medicine, and Central Clinical Laboratory, Kanazawa University Hospital, Kanazawa, Japan. Accepted for publication July 26, 1989. Key words: thyroid carcinoma, distant metastases, prognosis, immunochemistry. Address correspondence and reprint requests to Yuji Mizukami, MD, Pathology Section, Kanazawa University Hospital, 131, Takara-machi, Kanazawa, 920, Japan. 0 1990 by W.B. Saunders Company. 0046-8177/90/2103-0005$5.0010
283
Basis for Diagnosis
No. of Cases
Autopsy Histologic Cytologic ClinicaVSl uptake/x-ray
5 11 2 16
Total
34
HUMAN PATHOLOGY
Volume 21, No. 3 (March 1990)
FIGURE 1. (lop left) Papillary carcinoma well-differentiated type. Well-developed papillan/ proliferation of follicular cells is visible. Distinct “ground-glass” nuclei are characterlstkz. (HematoxYlin-eosln stain; magnificatton x 182.1 uop rlght) Papillary carcinoma foilicular variant type. Prominent foiiicular structures are notable. Follicular cells contain nucleus showing “ground-glass” appearance. (Hematoxylln-eosin stain: magnification x200.) (Inset] Higher magnification of nuclei showing tvpical “ground-glass” appearance. (Hematoxylin-eosin stain; magnification x 372.) [Center left] Papillary carcinoma, trabecular type. A cord-like arrangement of follicular ceils is a promlnent histologic feature. The nuclei of folllcular cells are more hyperchromatic and polymorphic. Foci of well-differentiated papillary carcinoma are occasIonally intermingled in this tqe of the tumor. (HematoxYlin-eosin stain; magnificatton x 186.) [Center right) Folllcular carcinoma well-differentiated type. The tumor is composed of small or large follicles. Nuclei of foilicular cells are compact and hyperchromatlc. %round-glass” nuclei are not recognizable. (HematoxYlin-eosin stain; magnification x 182.) (Bottom left) Follicular carcinoma, solld type. The tumor is composed of solid clusters of folllcuiar cells contalnlng a variable number of small follicles. The nuclei are more polymorphic and mitoses are occasionally observed. (Hematoxylin-eosin stain; magnification x 190.) (Bottom right) Follicular carcinoma oxyphlilc h/pe. The tumor is composed entireh/ of oxyphillc (Hurthle) cells arranged in a solid or folllcuiar structure. The nuclei show po&norphism and occasional mitoses. (HematoxYiin-eosin stain; magnification x 182.1
284
DISTANT METASTASES INTHYROID CARCINOMA(Mizukamiet al) TABLE2. No. of Patients
Age and Sex Distributionof Patlents at lnltlal Diagnosis Age (yr)
o-9
10-19
20-29
With metastases Male Female Subtotal Without metastases Male Female Subtotal Total
30-39
40-49
50-59 5(i)
60-69
70-79
80-89
Total
3 (2) 8 (4)
4 (2)
1
6 (2) 28 (10)
1 4
4(:)
2 2
5
5 (1)
6 (3)
11 (6)
4 (2)
1
34 (12)
1
2 10
2 40
13 88
14 83
11 101
9 65
8 28
1 4
60 420
1
12
42
101
97
112
74
36
5
480
1
12
44
106
102
118
85
40
6
514
NOTE. Parentheses indicate the number of fatal cases.
4. Encapsulated carcinoma: the tumor is wellencapsulated and capsular invasion or vascular invasion is shown in only one or two foci of one or two of several sections. Distant metastases were defined as being outside the neck, thyroid, or upper mediastinal area. Lymph node metastases were excluded in this study.
Gent developed gastric cancer during follow-up, but the distant metastases was established histologically to be caused by the thyroid carcinoma. In 11 of the 34 patients,
metastatic tumors were confirmed histologically from surgical or biopsy materials, in five patients from autopsy materials and in two patients cytologically (Table 1). In the other 16 patients, distant metastases were confirmed from clinical evidence, x-ray changes, or lslI uptake in the metastases. The tumors, including anaplastic component totally or partially in the primary thyroid carcinoma, were excluded in this series. All metastatic tumors also showed histologic features of differentiated thyroid carcinoma, but in two autopsy cases, anaplastic transformation was associated partially in the metastatic tumors. The histologic slides of the whole series were revised and reclassified according to the following criteria, which is mainly based on a WHO classification9 and currently obtained pathologic observations of thyroid tumors4-s (Fig I): 1. Papillary carcinoma: well-differentiated, follicular variant, trabecular, and oxyphilic. 2. Follicular carcinoma: well-differentiated, solid, and oxyphilic. The primary thyroid tumors were further divided into four categories on the basis of the extent of the tumor. 1. Extensively extrathyroidal invasion: the tumor invades massively to the trachea and adjacent soft tissues, and occasionally fills the entire neck. 2. Extrathyroidal invasion: the tumor breaches the thyroid capsule and slightly invades the adjacent structures (muscle or trachea). 3. Intrathyroidal carcinoma: the tumor is confined to the anatomic boundaries of the thyroid gland. No thyroid capsular invasion is found. TABLE 3.
lmmunostaining Immunoperoxidase staining for thyroglobulin (TG) and thyroxine (T4) was done on the metastatic tumors from 16 patients using the peroxidase-antiperoxidase method. Both TG antiserum and T, antiserum were polyclonal in rabbit (Ortho Inc, Raritan, NJ; prediluted). Negative controls consisted of substituting normal serum for the primary antisera. Statistical analysis was performed using Student’s t test; differences were judged to be significant at a level greater than 95% of confidence (P < .05). The length of survival of each patient was studied by the Kaplan-Meier method and a generalized Wilcoxon’s test or Cox-Mantle test was used to assess the statistical significance. RESULTS Clinical Findings of 34 patients by Age and sex. The distribution sex and by age at the time of initial diagnosis is shown in Table 2. There were 28 women (82.4%) and six men (17.6%), ranging in age from 27 to 83 years.
Surgical Treatment of Primary Thyroid Lesions and Distant Metastases or Local Recurrences No operation
Development of distant metastases Same time yr Withinthan 5 5 yr Later
1
Total Thyroidectomy + Neck Dissection
Total Thyroidectomy
Hemithyroidectomy
Insufficient Information
17
3
32
:
2
3
Local recurrences Yes No
1
4 18
1 5
1 1
2 1
Total
1
22
6
2
3
285
HUMANPATHOLOGY TABLE A
Volume 21, No. 3 (March1990)
Time After Initial Diagnosis of First Distant Metastases
Time
No. of Patients
At diagnosis 20 yr
21
Total
34
: 1 5 :
Distant metastases were seen more frequently in older patients; the median age in patients with distant metastases was 55.3 years compared with 48.9 in those without. Also, there was a sex difference with respect to the frequency of distant metastases. Distant metastases were found in 9.1% of the male patients, as opposed to 6.3% of the females, but the difference was not significant. Of the patients who died, the average age at the time of initial diagnosis was 62.8 years, while the average age for the surviving group was 50.4 years. The risk of death from distant metastases of differentiated thyroid carcinoma increased after 40 years of age. Treatment of p&nay tumor. Of the 34 patients, 33 were treated with surgery and one was treated with chemotherapy alone because of the development of widespread distant metastases with pleural effusion at the time of initial diagnosis. Because the patients had been operated on at different hospitals, the surgical procedures varied. Three patients referred to us from other hospitals had thyroid surgery before referral, and information about the operation method was insufficient. Twenty-two patients had received a total thyroidectomy and neck dissection. Six patients had received a total thyroidectomy and two patients had received only a hemilateral lobectomy (Table 3). Most of the 33 patients who underwent operations were given I3 l I treatment either after surgery or after distant metastases were apparent. Period from initial diagnosis of first distant metastases. In 21 of the 34 patients (62%), distant metastases had already developed by the time of initial diagnosis (Table 4). In eight patients, metastases developed postoperatively within 10 years; in five patients, metastases developed after more than 10 years. The longest postoperative interval was 34 years. Sites of metastases. The most frequent metastatic site was pulmonary, and the lungs were involved in most patients (82%; Table 5). The other common TABLE 5. Lungs Fatal group (12 patients) Autopsy (5 patients) Others (7 patients) Surviving group (22 patients) Total (34 patients)
Bone
sites of distant metastases, in descending order of frequency, were the bone (440/o), pleura (21%), kidneys (18%), and brain or liver (15%). The five autopsy patients had widespread metastases involving several organ systems. In the fatal group, metastases to pleura, brain, pericardium, and liver were noted, whereas in the surviving group, metastases were limited to lungs, bone, or kidneys. Local recurrences and distant metastases. Local recurrences and distant metastases were both predictive for death from differentiated thyroid carcinoma. Therefore, it is important to examine the relationship between local recurrences and distant metastases. In this series, eight of the 34 patients (23.5%) with distant metastases had local recurrences during the course of their disease. However, the other 26 patients (76.5%) had no local recurrences. In eight patients with local recurrences, only three had local recurrences before the development of distant metastases. This finding suggests local recurrences had no influence on the development of distant metastases (Table 6). Survival with distant metastases. Distant metastases portend a poor prognosis. Survival of 34 patients after the initial diagnosis was seriously reduced (Fig 2). Survival rates after 5 and 10 years were 72% and 58%, respectively. 1311 absorption in distant metastases. Since 1968, r3r1 scintigraphy was done routinely, preoperatively and postoperatively, in our hospital. In this series, however, two of the 34 patients did not receive diagnostic 1311 scintigraphy after surgery because both patients were referred to us from other hospitals. Absorption of Is11 in the metastatic tumors was demonstrated in 21 patients (65.6%), whereas 11 patients (34.4%) had no Is11 uptake in the metastatic tumors. Survival rate curves of 32 patients by lslI absorption in the metastatic tumors are shown in Fig 3. The lo-year survival rate of patients with lslI accumulating metastases was 70%, while that of patients with metastases lacking such uptake was 40% (CoxMantle test, P < .05). Pathologic Findings Extent of primq tumor. In three of the 34 patients, a pathology report or histologic slides were not available and macropathologic and micropathologic characteristics of the primary tumor were unknown. In the other 31 patients, the extent of the primary thyroid tumors in relation to their histologic type is shown in Table 7. In 11 patients, primary tumors
Sites of Distant Metastases Pleura
Brain
Liver
Kidneys
Pericardium
Diaphragm
16
4 3 8
4 3 0
3 2 0
4 0 1
4 0 2
4 0 0
3 0 0
28
15
7
5
5
6
4
3
;:
286
DISTANT METASTASES IN WROID
TABLE 6.
CARCINOMA (Mizukami et al)
Relationship Between Local Recurrences and Distant Metastases
follicular carcinoma. With respect to the extent of the primary tumor, the follicular variant and trabecular types of papillary carcinoma showed a tendency toward extensive extrathyroidal invasion. Immunohistochemical stainings for thyroglobulin and thyroxine in m&static tumors. It is of interest to examine whether absorption of 13iI in the metastatic tumors is correlated with an ability of tumor cells to produce TG or T,. Sixteen tumors from 16 patients were examined immunohistochemically for the presence of TG and T,. Two patients did not receive diagnostic 1311 scintigraphy after surgery. All four metastatic tumors accumulating isi1 showed a positive staining for TG. On the other hand, six of 10 tumors lacking isi1 accumulation showed a negative staining for TG, but the other four tumors showed a positive staining for TG (Table 8). From this evidence, TG production seemed to be correlated with an absorption of isi1 in the metastatic tumors, although the results of four tumors (40%) without lslI accumulation were inconsistent. Immunohistochemical demonstration of TG might be a useful method for predicting isi1 absorption in metastatic tumors. In contrast to TG, staining for T, was negative in all metastatic tumors.
Time of Local Recurrences No. of Patients (%)
Before Distant Metastases
After Distant Metastases
8 (23.5) 26 (76.5)
3
5
No Total
34
Local Recurrences Yes
showed an extensive extrathyroidal invasion, involving cervical soft tissue, trachea, upper mediastinum, or esophagus. In the other 16 patients, the tumors showed an extrathyroidal invasion, involving thyroid capsule and adjacent soft tissues. Only two patients showed an intrathyroidal carcinoma, and the tumors were limited within the thyroid gland. Encapsulated carcinoma was also seen in two patients. Tumor size seems to be an important prognostic factor in encapsulated carcinomas. In both encapsulated carcinomas, the tumor size was larger than 5 cm in diameter (the approximately greatest diameters were 6 cm and 7 cm, respectively). Encapsulated carcinomas larger than 5 cm should be observed for distant metastases. Histologic types of primq tumor. Of the 3 1 differentiated thyroid carcinomas examined histologically, 24 were papillary carcinoma and seven were follicular carcinoma (Table 7). In the papillary tumors, nine were follicular variant type, eight were welldifferentiated type, and seven were trabecular type. In the follicular tumors, four were well-differentiated type, two were solid type, and one was oxyphilic type. The follicular variant and trabecular types of papillary carcinoma appeared to develop distant metastases with greater frequency than the welldifferentiated type of papillary carcinoma. When we examined the prognosis of the patients in relation to the histologic subtypes, the well-differentiated type of either papillary or follicular carcinoma showed a better prognosis than the follicular variant and trabecular types of papillary carcinoma or the solid type of %
FIWRE 2. Survival curve of 34 paItents wtth distant metastases. Survbal rates after five and 10 years were 72% and 58%. respectively.
DISCUSSION The results of this study support the concept that differentiated thyroid carcinomas associated with distant metastases are more lethal than commonly believed. After 10 years, the survival rate in our study was 58%. The mortality rates for distant metastases from differentiated thyroid carcinoma in other institutions have been studied. Nemec et allo reported loand 15-year survival rates for patients with pulmonary metastases from follicular carcinoma to be 28.9% and 11.4%, respectively. Hoie et al” also reported that mortality within 1 year of the diagnosis of distant metastases in patients with papillary thyroid cancer exceeded 50%. In our study, better prognostic
I
2 ‘2 1 W
5
10
15
20
Time after initial diagnosis
207
25
30
3 5
yrs
HUMANPATHOLOGY
Volume 21, No. 3 (March1990)
% 100
-
90
-
80
-
70
-
a,
I-
131 uptake
positive
(21
patients)
I-
131 uptake
negative
(11
patients)
CI
:
3. Survival CUIVB by absorption of diagnostic 13$1 in metastatic tumor. The 10 year survival rate in j3’l uptake posiiive tumors was 70% and that in ? uptake negativetumors was 40%. FIQURE
60
P
