Journal of Surgical Oncology 49:168-171 (1992)
Thyroid Carcinoma in Patients With Secondary Hyperparathyroidism HlTOSHl MIKI, MD, KAZUSHI OSHIMO, MD, HIROYUKI INOUE, MD, MUNEO KAWANO, MD, TADAOKI MORIMOTO, MD, YASUMASA MONDEN, MD, YOSUKE YAMAMOTO, MD, AND SElZO KITA, MD From the Second Department of Surgery (H.M., K.O., H.I., M.K., T .M., Y.M.), and the Second Department of Pathology (Y.Y.), School of Medicine, University of Tokushima and Department of Surgery, Higashi Tokushima National Sanatorium (S.K.), Tokushima, japan
There have been few reports of coexistence of secondary hyperparathyroidism (2" HPT) and thyroid carcinoma. Eleven consecutive patients with 2" HPT who underwent parathyroidectomy were analyzed. They consisted of six males and five females, whose age ranged from 34 to 55 years. None of the patients had a history of irradiation of the head or neck. Associated thyroid nodules were also present in seven patients (64%): four patients with benign nodules, and three patients with papillary carcinomas, and one with papillary carcinoma and two follicular adenomas. This incidence of thyroid carcinoma in the patient group with 2" HPT (36%) was significantly higher than that of the autopsy group in the same geographical area ( I I %). The level of carboxyl-terminal parathyroid hormone in the patients with thyroid carcinoma was higher than that in the patients without thyroid carcinoma ( P < 0.05). The importance of searching for possible thyroid cancer in patients with 2" HPT should be emphasized. 0 1992 Wiley-Liss, Inc. ~
KEYWORDS:thyroid cancer, hemodialysis, parathyroidectomy, parathyroid hormone
INTRODUCTION Nonmedullary thyroid carcinoma has been reported in 2.5% to 23% of patients with primary hyperparathyroidism [ 1-71. Those incidences were considered to be unexpectedly high. Various explanations have been proposed for the high incidence of association of these diseases. However, there have been few reports of thyroid carcinoma in association with secondary hyperparathyroidism [8,9]. We therefore studied the incidence of thyroid carcinoma in patients with secondary hyperparathyroidism who were undergoing hemodialysis and treated by parathyroidectomy at our hospital. PATIENTS AND METHODS Eleven patients operated upon at Higashi Tokushima National Sanatorium for treatment of secondary hyperparathyroidism from 1986 to 1987 were reviewed. All the patients were undergoing hemodialysis because of chronic renal failure. The criteria for indication of parathyroidectomy were level Of carhyperparathyroidism showing an boxylterminal parathyroid hormone (C-PTH) of more 0 1992 Wiley-Liss, Inc.
than 10 ng/ml and detection of one or more abnormal parathyroid glands in size by palpation, scintiscan, ultrasonography or CT scan. All patients underwent total parathyroidectomy with autografting [ 101 by means of a standard collar incision. When a nodular lesion was found in the thyroid gland by inspection or palpation, the lesion was resected. None of the 11 patients had received external irradiation of the head or neck. Statistical analysis of the data was performed by chisquare analysis or Student's t-test.
RESULTS The clinicopathologic findings for the 11 patients are summarized in Table I. The patients consisted of six males and five females and the age ranged from 34 to 55 years (average 43 years). In 10 patients, all of the resected parathyroid glands (39 glands) were diagnosed as Accepted for publication November 13, 1991. Address reprint requests to Hitoshi Miki, MD, Second Department of Surgery, School of Medicine, University of Tokushima, Kuramotocho, Tokushima 770, Japan.
Thyroid Cancer and Hyperparathyroidism
hyperplasia histologically. In one patient (case l), one resected parathyroid gland was diagnosed as adenocarcinoma and the other three glands as hyperplasia. This patient showed pulmonary metastasis of the parathyroid carcinoma two years after parathyroidectomy. Seven (cases 1-7) of the I 1 patients (64%) were found to have unsuspected thyroid lesions. Four patients had benign nodules of the thyroid, and four (cases 1-4) (36%) had thyroid carcinomas (Figs. 1, 2), including one with concurrent follicular adenoma and carcinoma. All of the carcinomas showed histologic features of the papillary type. None of the patients had any symptoms due to the thyroid disease. In one patient (case 4) two cervical lymph nodes with metastases of thyroid carcinoma were detected (Fig. 2), but the primary lesion in the thyroid gland could not be identified. The thyroid carcinomas in 3 cases were small, having a diameter of less than 5 mm. None of the thyroid carcinomas have shown evidence of distant metastases or signs of recurrence of thyroid carcinoma to date. In the 11 patients the duration of hemodialysis was 107 ? 33 months. The level of C-PTH was 33 & 15 ng/ml (normal: less than I .4), the level of serum calcium was 8.8 -1- 0.8 mg/dl (normal: 8.2 to l0.2), and the level of serum calcitonin was 235 2 54 pgiml (normal: less than 170) before operation. There was no difference in age or sex between the patients with thyroid carcinoma and those without carcinoma (Table 11). However, the duration of hemodialysis in the patients with thyroid carcinoma (74.3 2 29.9 months) was shorter than that in the patients without thyroid carcinoma (125.9 2 15.8 months; P < 0.01), and the level of C-PTH in the patients with thyroid carcinoma (45.0 & 13.1 ng/ml) was higher than that in the patients without thyroid carcinoma (25.7 ? 12.0; P < 0.05). The levels of serum calcium and calcitonin were similar in these two patient groups.
DISCUSSION Some studies have reported that the combination of nonmedullary thyroid carcinoma and primary hyperparathyroidism might be more common than was previously believed [ 1,3-61. However, the association of thyroid carcinoma and secondary hyperparathyroidism is less well known [8,9]. Accordingly, we studied the incidence of thyroid carcinoma in 1I patients with secondary hyperparathyroidism who were undergoing hemodialysis and treated by parathyroidectomy at Higashi Tokushima National Sanatorium. As a result of the operation, we found an unexpectedly high incidence of thyroid carcinoma in these patients with secondary hyperparathyroidism. Four of the 11 patients (36%) had thyroid carcinomas, which were all papillary. In regard to this association of thyroid carcinoma and secondary hyperparathyroidism, Linos and Ziroyannis reported that it might be coincidental and without a com-
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Fig, 1. Papillary carcinoma of the thyroid in case 2. Invasion of the fibrous capsule is seen.
Fig. 2. Metastatic papillary thyroid carcinoma was found in cervical lymph nodes in case 4.
mon pathogenic mechanism [8]. However, Yamamoto et al. reported that histologic examination of the thyroid glands of 408 consecutive autopsy cases, consisting of 247 males and 161 females, in the district where our patients live, occult papillary carcinomas were found in 46 cases ( 1 1.3%) [ 111. The incidence (36%) of thyroid carcinoma in our 11 patients with secondary hyperparathyroidism was significantly higher than that in the autopsy group ( P < 0.05). Irradiation of the head or neck during infancy or childhood [12-141, TSH [15], and sex hormones [16] have been proposed as initiating or promoting factors of thyroid carcinoma. None of our patients had received external irradiation of the head or neck. Unfortunately, we were unable to assay TSH, sex hormones, or sex hormone receptors in any of our cases. In addition to the above factors, various factors have been proposed as a common pathogenic mechanism for the coexistence of thyroid carcinoma and hyperparathyroidism, such as the goitrogenic effects of calcium [17,18] and excessive production of calcitonin in response to hypercalcemia [2,6,19]. Taylor theorized that
TABLE 11. Characteristics of Patients With/Without Thyroid Carcinoma? Characteristics No. of cases Age (yr) Sex ratio (M:F) Duration of HD (mo) C-PTH (ng/ml) Ca (rng/dl) Calcitonin (pg/ml)
Patients with thvroid carcinoma
Patients without thvroid carcinoma
4 40.5 & 1.7 2:2 74.3 & 29.9 45.0 f 13.1 8.9 f 1.0 223 f 24
7 44.9 f 8.9 4:3 125.9 k 15.8* 25.7 12.0** 8.7 f 0.8 243 f 67
*
t HD, hemodialysis; C-PTH, carboxyl-terminal parathyroid hormone; Ca, calcium. Data are presented as mean values f standard deviation. * P < 0.01: patients with thyroid carcinoma versus without thyroid carcinoma. **P< 0.05: patients with thyroid carcinoma versus without thyroid carcimna. calcium carbonate has a goitrogenic effect either by inhibiting the synthesis of thyroxine or by increasing iodine clearance by the kidney [18], and Ellenberg et al. reported that hypercalcemia also might be carcinogenic [ I ] .
Thyroid Cancer and Hyperparathyroidism
In our study, no difference was found in the level of serum calcium or the level of calcitonin between the patients with thyroid carcinoma and those without thyroid carcinoma. Immunologic surveillance is generally accepted as a major defense against neoplastic cells. However, uremic patients are considered to be in a state of reduced immunocapacity [20,21], and it has been suggested that renal failure per se may predispose the patient to malignant disease [22-251. Naturally, patients with secondary hyperparathyroidism have chronic renal failure and are undergoing maintenance dialysis treatment. Therefore, the incidence of thyroid carcinoma might be high in those patients for this reason. Moreover, parathyroid carcinoma was found in one patient, and the reduced immunocapacity in uremic patients might have an effect on the development of the parathyroid carcinoma. The level of C-PTH in our patients with thyroid carcinoma was significantly higher than that in the patients without thyroid carcinoma. This parathyroid hormone thus might play a role in the development of thyroid carcinoma in patients with secondary hyperparathyroidism. Since thyroid carcinoma is usually an incidental finding at operation for secondary hyperparathyroidism, full mobilization and careful palpation of both thyroid lobes must be performed during the surgical procedure.
REFERENCES 1. Ellenberg AH, Goldman L, Gordan GS, Lindsay S: Thyroid car-
2. 3. 4.
5.
cinoma in patients with hyperparathyroidism. Surgery 5 1:708717, 1962. Laing VO,Frame B, Block MA: Associated primary hyperparathyroidism and thyroid lesions. Arch Surg 98:709-7 12, 1969. LiVolsi VA, Feind CR: Parathyroid adenoma and nonmedullary thyroid carcinoma. Cancer 38:1391-1393, 1976. Kairaluoma MI, Heikkinen E, Mokka R, et al.: Non-medullary thyroid carcinoma in patients with parathyroid adenoma. Acta Chir Scand 142:447-449, 1976. Newman HK, Plucinski TE: Unsuspected nonmedullary carcinoma of the thyroid in patients with hyperparathyroidism. Am J Surg 134:799-802, 1977.
171
6. Linos DA, van Heerden JA, Edis AJ: Primary hyperparathyroidism and non-medullary thyroid cancer. Am J Surg 143:301303, 1982. 7. Lever EG, Refetoff S , Straus FH, 11, et al.: Coexisting thyroid and parathyroid disease. Surgery 94393-900, 1983. 8. Linos DA, Ziroyannis PN: Secondary hyperparathyroidism and thyroid cancer. Int Surg 70:263-264, 1985. 9. Inoue S , Azuma M, Hirabayashi T, et al.: Studies on the small thyroid carcinoma in the dialysis patients with hyperparathyroidism. Nippon Naibunpi Gakkai Zasshi 62: 1 194-1 202, 1986. 10. Wells SA, Gunnells JC, Shelbume JD, et al.: Transplantation of the parathyroid glands in man. Surgery 78:34-44, 1975. 11. Yamamoto Y, Maeda T, Izumi K, Otsuka H: Occult papillary carcinoma of the thyroid. Cancer 65:1173-1179, 1990. 12. McConahey WM, Hayles AB: Radiation to the head, neck, and upper thorax of the young, and thyroid neoplasia. J Clin Endocrinol Metab42:1182-1183, 1976. 13. Favus MJ, Schneider AB, Stachura ME, et al.: Thyroid cancer occurring as a late consequence of head-and-neck irradiation. N EnglJ Med 294:1019-1025, 1976. 14. Royce PC, MacKay BR, DiSabella PM: Value of postirradiation screening for thyroid nodules. JAMA 242:2675-2678, 1979. 15. Hall WH: The role of initiating and promoting factors in the pathogenesis of tumours of the thyroid. Br J Cancer 2:273-280, 1948. 16. Miki H, Oshimo K, Inoue H, et al.: Sex hormone receptors in human thyroid tissues. Cancer 66:1759-1762, 1990. 17. Hellwig CA: Thyroid adenoma in experimental animals. Am J Cancer 23:550-555, 1935. 18. Taylor S: Calcium as a goitrogen. J Clin Endocrinol Metab 14:1412-1422, 1954. 19. Wolfe HJ,DeLellis RA, Scott RT, Tashjian AH, Jr: C-cell hyperplasia in chronic hypercalcemia in man (Abstr). Am J Pathol 78:20a, 1975. 20. Wilson WEC, Kirkpatrick CH, Talmage DW: Suppression of immunologic responsiveness in uremia. Ann Intern Med 62: 1-14, 1965. 21. Birkeland SA: Uremia as a state of immune deficiency. Scand J Immunol5:107-115, 1976. 22. Matas AJ, Simmons RL, Kjellstrand CW, et al.: Increased incidence of malignancy during chronic renal failure. Lancet 195383886, 1975. 23. Miach PJ, Dawborn JK, Xipell J: Neoplasia in patients with chronic renal failure on long-term dialysis. Clin Nephrol 5:101104, 1976. 24. Sutherland GA, Glass J, Gabriel R: Increased incidence of malignancy in chronic renal failure. Nephron 18:182-184, 1977. 25. Lindner A, Farewell VT, Sherrard DJ: High incidence of neoplasia in uremic patients receiving long-term dialysis. Nephron 27:292-296. 1981.
Thyroid Carcinoma in Patients With Secondary Hyperparathyroidism HlTOSHl MIKI, MD, KAZUSHI OSHIMO, MD, HIROYUKI INOUE, MD, MUNEO KAWANO, MD, TADAOKI MORIMOTO, MD, YASUMASA MONDEN, MD, YOSUKE YAMAMOTO, MD, AND SElZO KITA, MD From the Second Department of Surgery (H.M., K.O., H.I., M.K., T .M., Y.M.), and the Second Department of Pathology (Y.Y.), School of Medicine, University of Tokushima and Department of Surgery, Higashi Tokushima National Sanatorium (S.K.), Tokushima, japan
There have been few reports of coexistence of secondary hyperparathyroidism (2" HPT) and thyroid carcinoma. Eleven consecutive patients with 2" HPT who underwent parathyroidectomy were analyzed. They consisted of six males and five females, whose age ranged from 34 to 55 years. None of the patients had a history of irradiation of the head or neck. Associated thyroid nodules were also present in seven patients (64%): four patients with benign nodules, and three patients with papillary carcinomas, and one with papillary carcinoma and two follicular adenomas. This incidence of thyroid carcinoma in the patient group with 2" HPT (36%) was significantly higher than that of the autopsy group in the same geographical area ( I I %). The level of carboxyl-terminal parathyroid hormone in the patients with thyroid carcinoma was higher than that in the patients without thyroid carcinoma ( P < 0.05). The importance of searching for possible thyroid cancer in patients with 2" HPT should be emphasized. 0 1992 Wiley-Liss, Inc. ~
KEYWORDS:thyroid cancer, hemodialysis, parathyroidectomy, parathyroid hormone
INTRODUCTION Nonmedullary thyroid carcinoma has been reported in 2.5% to 23% of patients with primary hyperparathyroidism [ 1-71. Those incidences were considered to be unexpectedly high. Various explanations have been proposed for the high incidence of association of these diseases. However, there have been few reports of thyroid carcinoma in association with secondary hyperparathyroidism [8,9]. We therefore studied the incidence of thyroid carcinoma in patients with secondary hyperparathyroidism who were undergoing hemodialysis and treated by parathyroidectomy at our hospital. PATIENTS AND METHODS Eleven patients operated upon at Higashi Tokushima National Sanatorium for treatment of secondary hyperparathyroidism from 1986 to 1987 were reviewed. All the patients were undergoing hemodialysis because of chronic renal failure. The criteria for indication of parathyroidectomy were level Of carhyperparathyroidism showing an boxylterminal parathyroid hormone (C-PTH) of more 0 1992 Wiley-Liss, Inc.
than 10 ng/ml and detection of one or more abnormal parathyroid glands in size by palpation, scintiscan, ultrasonography or CT scan. All patients underwent total parathyroidectomy with autografting [ 101 by means of a standard collar incision. When a nodular lesion was found in the thyroid gland by inspection or palpation, the lesion was resected. None of the 11 patients had received external irradiation of the head or neck. Statistical analysis of the data was performed by chisquare analysis or Student's t-test.
RESULTS The clinicopathologic findings for the 11 patients are summarized in Table I. The patients consisted of six males and five females and the age ranged from 34 to 55 years (average 43 years). In 10 patients, all of the resected parathyroid glands (39 glands) were diagnosed as Accepted for publication November 13, 1991. Address reprint requests to Hitoshi Miki, MD, Second Department of Surgery, School of Medicine, University of Tokushima, Kuramotocho, Tokushima 770, Japan.
Thyroid Cancer and Hyperparathyroidism
hyperplasia histologically. In one patient (case l), one resected parathyroid gland was diagnosed as adenocarcinoma and the other three glands as hyperplasia. This patient showed pulmonary metastasis of the parathyroid carcinoma two years after parathyroidectomy. Seven (cases 1-7) of the I 1 patients (64%) were found to have unsuspected thyroid lesions. Four patients had benign nodules of the thyroid, and four (cases 1-4) (36%) had thyroid carcinomas (Figs. 1, 2), including one with concurrent follicular adenoma and carcinoma. All of the carcinomas showed histologic features of the papillary type. None of the patients had any symptoms due to the thyroid disease. In one patient (case 4) two cervical lymph nodes with metastases of thyroid carcinoma were detected (Fig. 2), but the primary lesion in the thyroid gland could not be identified. The thyroid carcinomas in 3 cases were small, having a diameter of less than 5 mm. None of the thyroid carcinomas have shown evidence of distant metastases or signs of recurrence of thyroid carcinoma to date. In the 11 patients the duration of hemodialysis was 107 ? 33 months. The level of C-PTH was 33 & 15 ng/ml (normal: less than I .4), the level of serum calcium was 8.8 -1- 0.8 mg/dl (normal: 8.2 to l0.2), and the level of serum calcitonin was 235 2 54 pgiml (normal: less than 170) before operation. There was no difference in age or sex between the patients with thyroid carcinoma and those without carcinoma (Table 11). However, the duration of hemodialysis in the patients with thyroid carcinoma (74.3 2 29.9 months) was shorter than that in the patients without thyroid carcinoma (125.9 2 15.8 months; P < 0.01), and the level of C-PTH in the patients with thyroid carcinoma (45.0 & 13.1 ng/ml) was higher than that in the patients without thyroid carcinoma (25.7 ? 12.0; P < 0.05). The levels of serum calcium and calcitonin were similar in these two patient groups.
DISCUSSION Some studies have reported that the combination of nonmedullary thyroid carcinoma and primary hyperparathyroidism might be more common than was previously believed [ 1,3-61. However, the association of thyroid carcinoma and secondary hyperparathyroidism is less well known [8,9]. Accordingly, we studied the incidence of thyroid carcinoma in 1I patients with secondary hyperparathyroidism who were undergoing hemodialysis and treated by parathyroidectomy at Higashi Tokushima National Sanatorium. As a result of the operation, we found an unexpectedly high incidence of thyroid carcinoma in these patients with secondary hyperparathyroidism. Four of the 11 patients (36%) had thyroid carcinomas, which were all papillary. In regard to this association of thyroid carcinoma and secondary hyperparathyroidism, Linos and Ziroyannis reported that it might be coincidental and without a com-
h
3
i
0 .C
E 0
-.--$ a
a
0
2
a,
P F L
0 0 0
22:
0 0 10N -
0 0 0 0 0
wm-CIo
-NmrnN
170
Miki et al.
Fig, 1. Papillary carcinoma of the thyroid in case 2. Invasion of the fibrous capsule is seen.
Fig. 2. Metastatic papillary thyroid carcinoma was found in cervical lymph nodes in case 4.
mon pathogenic mechanism [8]. However, Yamamoto et al. reported that histologic examination of the thyroid glands of 408 consecutive autopsy cases, consisting of 247 males and 161 females, in the district where our patients live, occult papillary carcinomas were found in 46 cases ( 1 1.3%) [ 111. The incidence (36%) of thyroid carcinoma in our 11 patients with secondary hyperparathyroidism was significantly higher than that in the autopsy group ( P < 0.05). Irradiation of the head or neck during infancy or childhood [12-141, TSH [15], and sex hormones [16] have been proposed as initiating or promoting factors of thyroid carcinoma. None of our patients had received external irradiation of the head or neck. Unfortunately, we were unable to assay TSH, sex hormones, or sex hormone receptors in any of our cases. In addition to the above factors, various factors have been proposed as a common pathogenic mechanism for the coexistence of thyroid carcinoma and hyperparathyroidism, such as the goitrogenic effects of calcium [17,18] and excessive production of calcitonin in response to hypercalcemia [2,6,19]. Taylor theorized that
TABLE 11. Characteristics of Patients With/Without Thyroid Carcinoma? Characteristics No. of cases Age (yr) Sex ratio (M:F) Duration of HD (mo) C-PTH (ng/ml) Ca (rng/dl) Calcitonin (pg/ml)
Patients with thvroid carcinoma
Patients without thvroid carcinoma
4 40.5 & 1.7 2:2 74.3 & 29.9 45.0 f 13.1 8.9 f 1.0 223 f 24
7 44.9 f 8.9 4:3 125.9 k 15.8* 25.7 12.0** 8.7 f 0.8 243 f 67
*
t HD, hemodialysis; C-PTH, carboxyl-terminal parathyroid hormone; Ca, calcium. Data are presented as mean values f standard deviation. * P < 0.01: patients with thyroid carcinoma versus without thyroid carcinoma. **P< 0.05: patients with thyroid carcinoma versus without thyroid carcimna. calcium carbonate has a goitrogenic effect either by inhibiting the synthesis of thyroxine or by increasing iodine clearance by the kidney [18], and Ellenberg et al. reported that hypercalcemia also might be carcinogenic [ I ] .
Thyroid Cancer and Hyperparathyroidism
In our study, no difference was found in the level of serum calcium or the level of calcitonin between the patients with thyroid carcinoma and those without thyroid carcinoma. Immunologic surveillance is generally accepted as a major defense against neoplastic cells. However, uremic patients are considered to be in a state of reduced immunocapacity [20,21], and it has been suggested that renal failure per se may predispose the patient to malignant disease [22-251. Naturally, patients with secondary hyperparathyroidism have chronic renal failure and are undergoing maintenance dialysis treatment. Therefore, the incidence of thyroid carcinoma might be high in those patients for this reason. Moreover, parathyroid carcinoma was found in one patient, and the reduced immunocapacity in uremic patients might have an effect on the development of the parathyroid carcinoma. The level of C-PTH in our patients with thyroid carcinoma was significantly higher than that in the patients without thyroid carcinoma. This parathyroid hormone thus might play a role in the development of thyroid carcinoma in patients with secondary hyperparathyroidism. Since thyroid carcinoma is usually an incidental finding at operation for secondary hyperparathyroidism, full mobilization and careful palpation of both thyroid lobes must be performed during the surgical procedure.
REFERENCES 1. Ellenberg AH, Goldman L, Gordan GS, Lindsay S: Thyroid car-
2. 3. 4.
5.
cinoma in patients with hyperparathyroidism. Surgery 5 1:708717, 1962. Laing VO,Frame B, Block MA: Associated primary hyperparathyroidism and thyroid lesions. Arch Surg 98:709-7 12, 1969. LiVolsi VA, Feind CR: Parathyroid adenoma and nonmedullary thyroid carcinoma. Cancer 38:1391-1393, 1976. Kairaluoma MI, Heikkinen E, Mokka R, et al.: Non-medullary thyroid carcinoma in patients with parathyroid adenoma. Acta Chir Scand 142:447-449, 1976. Newman HK, Plucinski TE: Unsuspected nonmedullary carcinoma of the thyroid in patients with hyperparathyroidism. Am J Surg 134:799-802, 1977.
171
6. Linos DA, van Heerden JA, Edis AJ: Primary hyperparathyroidism and non-medullary thyroid cancer. Am J Surg 143:301303, 1982. 7. Lever EG, Refetoff S , Straus FH, 11, et al.: Coexisting thyroid and parathyroid disease. Surgery 94393-900, 1983. 8. Linos DA, Ziroyannis PN: Secondary hyperparathyroidism and thyroid cancer. Int Surg 70:263-264, 1985. 9. Inoue S , Azuma M, Hirabayashi T, et al.: Studies on the small thyroid carcinoma in the dialysis patients with hyperparathyroidism. Nippon Naibunpi Gakkai Zasshi 62: 1 194-1 202, 1986. 10. Wells SA, Gunnells JC, Shelbume JD, et al.: Transplantation of the parathyroid glands in man. Surgery 78:34-44, 1975. 11. Yamamoto Y, Maeda T, Izumi K, Otsuka H: Occult papillary carcinoma of the thyroid. Cancer 65:1173-1179, 1990. 12. McConahey WM, Hayles AB: Radiation to the head, neck, and upper thorax of the young, and thyroid neoplasia. J Clin Endocrinol Metab42:1182-1183, 1976. 13. Favus MJ, Schneider AB, Stachura ME, et al.: Thyroid cancer occurring as a late consequence of head-and-neck irradiation. N EnglJ Med 294:1019-1025, 1976. 14. Royce PC, MacKay BR, DiSabella PM: Value of postirradiation screening for thyroid nodules. JAMA 242:2675-2678, 1979. 15. Hall WH: The role of initiating and promoting factors in the pathogenesis of tumours of the thyroid. Br J Cancer 2:273-280, 1948. 16. Miki H, Oshimo K, Inoue H, et al.: Sex hormone receptors in human thyroid tissues. Cancer 66:1759-1762, 1990. 17. Hellwig CA: Thyroid adenoma in experimental animals. Am J Cancer 23:550-555, 1935. 18. Taylor S: Calcium as a goitrogen. J Clin Endocrinol Metab 14:1412-1422, 1954. 19. Wolfe HJ,DeLellis RA, Scott RT, Tashjian AH, Jr: C-cell hyperplasia in chronic hypercalcemia in man (Abstr). Am J Pathol 78:20a, 1975. 20. Wilson WEC, Kirkpatrick CH, Talmage DW: Suppression of immunologic responsiveness in uremia. Ann Intern Med 62: 1-14, 1965. 21. Birkeland SA: Uremia as a state of immune deficiency. Scand J Immunol5:107-115, 1976. 22. Matas AJ, Simmons RL, Kjellstrand CW, et al.: Increased incidence of malignancy during chronic renal failure. Lancet 195383886, 1975. 23. Miach PJ, Dawborn JK, Xipell J: Neoplasia in patients with chronic renal failure on long-term dialysis. Clin Nephrol 5:101104, 1976. 24. Sutherland GA, Glass J, Gabriel R: Increased incidence of malignancy in chronic renal failure. Nephron 18:182-184, 1977. 25. Lindner A, Farewell VT, Sherrard DJ: High incidence of neoplasia in uremic patients receiving long-term dialysis. Nephron 27:292-296. 1981.
