- Email: [email protected]
Parathyroid carcinoma in patients with chronic renal failure on maintenance hemodialysis
Parathyroid carcinoma in patients with chronic renal failure on maintenance hemodialysis Hitoshi Miki, MD, Masayuki Smnitomo, MD, Hiroyuki Inoue, MD, Seizo Kita, MD, and Yasumasa Monden, MD, Tokushima, Japan
From the Second Department of Surgery, School of Medicine, The University of Tokushima, and Higashi Tokushima National Sanatorium, Tokushima, Japan
RECENT IMPROVEMENTSIN hemodialysis a n d kidney transp l a n t a t i o n have r e d u c e d m o r b i d i t y a n d l e n g t h e n e d t h e life spans o f patients with c h r o n i c r e n a l failure. As a result o f this p r o l o n g a t i o n o f life, several p r o b l e m s have b e c o m e obvious a m o n g patients with c h r o n i c r e n a l failure. R e c e n t l y m o r e t h a n 10 cases o f p a r a t h y r o i d carc i n o m a were r e p o r t e d in patients with c h r o n i c r e n a l failure. >9 At Higashi T o k u s h i m a N a t i o n a l S a n a t o r i u m we also e n c o u n t e r e d a p a t i e n t with p a r a t h y r o i d carcin o m a w h o h a d b e e n o n m a i n t e n a n c e hemodialysis. Because the entity o f a p a r a t h y r o i d c a r c i n o m a in a p a t i e n t with c h r o n i c renal failure is still unclear, we reviewed 12 instances i n c l u d i n g o u r own, o f p a r a t h y r o i d c a r c i n o m a in hemodialysis patients r e p o r t e d in the English-lang u a g e literature. T h e characteristics o f these patients w e r e c o m p a r e d with those in subjects with p a r a t h y r o i d c a r c i n o m a w i t h o u t c h r o n i c r e n a l failure.
CASE REPORT The patient, a woman, has suffered from chronic glomerulonephritis since she was 21 years of age. Her renal function was considerably reduced after a pregnancy when she was 24 years old; hemodialysis was begun when she was 36 years old. Two years after the commencement of hemodialysis, the patient began to complain of muscle weakness and bilateral knee joint pain. At the age of 40 years (January 1987) the patient underwent a parathyroidectomy because of progressive secondary hyperparathyroidism refractory to the vitamin D treatment she had received for 6 months immediately preceding the parathyroidectomy. Preoperative carboxyl-terminal parathyroid hormone (C-PTH) concentrations were extremely elevated (47 to 62 ng/ml; reference value -<1.4 ng/ml) without associated hypercalcemia (7.8 to 8.5 mg/dl) (Fig. 1). Preoperative serum phosphorus and alkaline phosphatase levels Accepted for publication April 25, 1996. Reprint requests: Hitoshi Miki, MD, The Second Department of Surgery, School of Medicine, The University of Tokushima, Kuramotocho, Tokushima 770, Japan. Surgery I996;120:897-901. Copyright 9 1996 by Mosby-Year Book, Inc. 0039-6060/96/$5.00 + 0 11/57/75051
were 5.8 m g / d l (reference value, 2.7 to 4.4 mg/dl) and 37 KAU (reference value, 2.7 to 10.0 I ~ U ) , respectively. In addition, a 2 cm elastic hard tumor was palpated in the middle of the right side of her neck and was thought to be an enlarged right superior parathyroid gland. At operation all four parathyroid glands were enlarged, reddish-yellow, and had smooth surfaces; there were no adhesions between parathyroid glands and surrounding tissues. The right superior gland was heaviest among the four glands, weighing 2.7 gm. The other three glands weighed between 0.7 and 1.6 gm. Total parathyroidectomy was performed, and fragments of the left superior gland were autotransplanted into the patient's left forearm muscle. Because two small and hard nodules suspected of papillary carcinoma were found in the right lobe of the thyroid gland incidentally, right lobectomy of the thyroid gland was also performed. Lymphadenectomy was not performed because of the absence of lymphadenopathy. Microscopically, the right superior parathyroid gland had a thick fibrous capsule, and parenchymal cells resembling chief cells were arranged in seats or in a trabecular pattern (Fig. 2). Few mitoses were found. Although the chromatin was rather coarse, none of the typical findings of malignancy were present, so a parathyroid adenoma was diagnosed. Hyperplasia was diagnosed in the remaining three glands. Papillary carcinomas were diagnosed in the thyroid nodules. After the parathyroidectomy, the C-PTH concentration rapidly decreased and remained at a low level (<8 ng/ml) for 15 months. However, it gradually rose after June 1988 and reached 34 n g / m l in December 1988. Posfoperative calcium levels fluctuated between 7.3 m g / d l and 11.3 mg/dl. Although alkaline phosphatase levels increased to 59.2 KAU 1 month after the initial operation, they remained within normal limits for 17 months after June 1987 and gradually rose after November 1988. Moreover, in July 1988 a chest radiograph showed a coin lesion (1.0 cm in diameter) in the left lung. Because the size of this coin lesion was later confirmed by computed tomography (Fig. 3) to have increased to 1.4 cm, a left pulmonary local resection including nodules was performed in February 1989. Two tumors were found in S4 and SOof the left lung; both lesions were white and elastic hard. The sizes of the tumors in S4 and S9 were 1.4 cm and 0.5 cm, respectively. An immunohistochemical study of these pulmonary nodules showed immunoreactivity to anti-PTH (parathyroid hormone) antibodies, whereas two nodules of papillary carcinoma reSURGERY
897
898
Miki et al.
80
Surgery November 1996
PTx ~1v
-20
Left Pulmonary Resection
l...'",,.~.rl.
Right Pulmonary Resection
60 A u
O) C
40 II1.
6
9
-15
Ca.-'"-,.,-""""'-, ...... .....
"-..-"'-..,"...-"
10
E u
-5
20
87
88
89
90
91
92
93
94
95
Year Fig. 1. Serial C-PTH measurements and clinical events. PTx, Total parathyroidectomy with autotransplantation.
Fig. 2. Microscopic appearance of right superior parathyroid gland. Thick fibrous capsule and parenchymal cells arranged in seats or trabecular pattern were found. (Hematoxylin-eosin stain; original magnification •
sected during the initial operation were not stained with the same antibodies. Histologic reexamination of the right superior parathyroid gland removed in 1987 revealed features similar to pulmonary nodules. Therefore these pulmonary lesions were diagnosed as metastases of the parathyroid carcinoma, probably originating in the right superior gland. Although the C-PTH concentration decreased to 13.0 n g / m l after resection of the left pulmonary metastases, it ira-
mediately increased again and multiple ,nodules in the right lung were then detected radiogr~phically. The patient underwent a right pulmonary resection in August 1989. Eight pulmonary lesions, ranging from 5 to 8 mm in diameter, were locally resected. All the lesions were diagnosed histologically as metastases of the parathyroid carcinoma. After right pulmonary resection, C-PTH concentrations have remained elevated until now. A coin lesion suspected of being a metastasis
Surgery Volume 120, Number 5
Miki et al.
899
Fig. 3. Computed tomograph of left lung. Arrow shows coin lesion, 1.0 cm in diameter, that was diagnosed after operation as a metastasis from parathyroid carcinoma.
from the parathyroid carcinoma was found in the right lung by chest radiography in March 1990. Moreover, three rumors (ranging from 0.6 to 1.2 cm in diameter) in the patient's right neck were seen oll ultrasonogram in May 1993, although the origin of these tumors remains unclear (whether the parathy1-oid carcinoma or the thyroid carcinoma). Excision of the right lung and right neck tumors has been advised. However, the patient has refused these operations and is currently being followed up carefullywith serial G-PTH levels, ultrasonography of the neck, and chest radiography. Calcium levels recently decreased to the normal range, although they showed an upward trend until the spring of 1994. Alkaline phosphatase levels have remained within normal limits for 4 years.
DISCUSSION Parathyroid carcinoma is a rare a n d unusual clinical entity. Since the first case was described in 1933, only approximately 300 cases of parathyroid carcinoma have been reported. Berland et al. 1 reported the first ease of a parathyroid carcinoma in a patient receiving hemodialysis because of chronic renal failure that did not result from elevated serum calcium concentrations. O u r survey of the English-language literature revealed 12 patients with parathyroid carcinoma a n d chronic renal failure on m a i n t e n a n c e hemodialysis, including our own (Table).l~ The cause of parathyroid carcinoma is usually difficult to determine. In patients o n hemodialysis, however,
the possibility of m a l i g n a n t transformation of b e n i g n lesions has been proposed. This is because b e n i g n lesions of the parathyroid glands (i.e., hyperplasia and adenoma) coexisted in all the patients with chronic renal failure and c o n c u r r e n t parathyroid carcinoma, which was mostly f o u n d 4 to 7 years after the start ofhemodialysis. Also the occurrence of multiple primary lesions of parathyroid carcinoma, which is usually thought to be quite rare, was f o u n d in 2 of the 12 reported cases.t' 5 Parathyroid carcinoma in subjects without chronic renal failure tends to occur in males and females at even rates, l~ In contrast, only 2 of the 12 patients with parathyroid carcinoma who had b e e n on m a i n t e n a n c e hemodialysis were male. Although the reason for this female p r e d o m i n a n c e is unclear, sex h o r m o n e s may have some effect o n the initiation or p r o m o t i o n of parathyroid carcinoma, or both. The m e a n age of patients with carcinoma ~a4thout chronic renal failure has b e e n reported to range from 44 to 55 years] ~ and m e a n age of the 12 reviewed cases was comparable. Patients with parathyroid carcinomas frequently have clinically severe hyperparathyroidism caused by the effects of the excessive secretion of PTH; the most comm o n symptoms are related to hypercalcemia. However, half the patients reviewed with parathyroid carcinoma on hemodialysis did n o t show signs of hypercalcemia. Preoperative calcium levels in patients with parathyroid
900
Miki et al.
Surgery November 1996
T a b l e . Characteristics of 12 patients with parathyroid carcinoma and associated chronic renal failure
Case no.
Authors
Age at Duration of Preoperative diagnosis hemohyperNo. of cancerous Year (yr) Gender dialysis calcemia glands Metastases
1 Berland et al.
1982
62
F
2 Anderson et al.
1983
44
F
3 Ireland et al.
1985
34
M
4 Sherlock et al.
1985
42
5 Krishna et al.
1989
6 Kodama et al.
3 yr
2 +
1
5 yr
+
1
F
7 yr
+
1
64
F
9 yr
1989
53
F
7 yr
7 Iwamoto et al. 1990 8 Iwamoto et al. 1990 9 Rademaker et al. 1990
46 55 46
M F F
10 Rademaker et al. 1990
52
11 Ljutic et al. 12 Miki et al.
40
1994 1996
2 +
1
11 yr, 3 mo 5 yr, 4 mo 3 yr
+
1 1 1
F
2 yr
+
1
F
4 yr, 10 mo
-
1
carcinoma on hemodialysis ranged from 8.5 m g / d l to 12.6 m g / d l , and the m e a n level was 10.8 -+ 1.4 m g / d l . Normocalcemia in these patients may have b e e n caused by the chronic renal failure itself, which decreased serum calcium concentrations, by hemodialysis, which regularly corrected the serum calcium concentration, or by both. Preoperative serum phosphorus levels were elevated in all patients o n hemodialysis with parathyroid carcinoma (6.7 _+ 1.2 m g / d l ) . Alkaline phosphatase levels were also at least 1.7 times higher than n o r m a l in all patients. Because the most significant preoperative finding in patients o n hemodialysis with parathyroid carcinoma is only elevated PTH concentrations, which were more than two times the n o r m a l level in all 12 patients, it is difficult to distinguish parathyroid carcinoma in patients with chronic renal failure from secondary hyperparathyroidism caused by b e n i g n lesions. Actually, there was n o patient in whom parathyroid carcinoma was diagnosed before operation a m o n g those reviewed. Five patients were diagnosed d u r i n g the initial operation because of local invasion, a n d four patients were diagnosed by the p e r m a n e n t sections of primary lesion after the initial operation. In two patients, including ours, the diagnosis of parathyroid carcinoma could n o t be established until the detection of distant metastases. Five of 12 patients u n d e r w e n t parathyroidectomy only. Parathyroidectomy associated with partial resection of the thyroid gland necessitated by the local inva-
Lung
Follow-up Status No evidence of disease Death from disease Death from other cause No evidence of disease No evidence of disease No evidence of disease
No evidence of disease No evidence of disease Lung
Mive with disease
(too) 5 17 84 12 36 4
84 48
115
sion of parathyroid carcinoma was performed in five patients. Both parathyroidectomy and lymphadenectomy were performed in two patients, although lymph n o d e metastases were n o t found. No patients received a kidney transplant before or after parathyroidectomy. Parathyroid carcinoma carries the risk of local recurrence or distant metastases even after a successful resection; the rate of r e c u r r e n t disease has b e e n reported to range from 41% to 67%. l~ Most deaths are the result of u n c o n t r o l l e d hypercalcemia rather than t u m o r growth itself; the 5-year survival rate after initial operation for parathyroid carcinoma is reported to range from 40% to 69%. l~ The rate of recurrent disease in patients with chronic renal failure is similar, a n d one third of patients suffer a recurrence after parathyroidectomy. In contrast, only one patient on hemodialysis died of hypercalcemia caused by recurrent disease. Moreover, our reported patient is still alive with disease 115 m o n t h s after the primary operation. T h e r e f o r e the prognosis in hemodialysis patients with parathyroid carcinoma may be better than in those with parathyroid carcinoma that caused primary hyperparathyroidism despite similar rates of recurrent disease. This may be attributable tO the regular correction of the serum calcium concentration with hemodialysis. Alternatively, the biologic behavior of parathyroid carcinoma that develops in. patients with chronic renal failure may naturally differ from that in patients without chronic renal failure.
Surgery Volume 120, Number 5 REFERENCES
1. Berland Y, Olmer M, Lebreuil G, Grisoli J. Parathyroid carcinoma, adenoma and hyperplasia in a case of chronic renal insufficiency on dialysis. Clin Nephrol 1982;18:154-8. 2. Anderson BJ, Samaan NA, Vassil0poulou-Sellin R, Ordonez NG, Hickey RC. Parathyroid carcinoma: features and difficulties in diagnosis and management. Surgery 1983;94:906-15. 3. Ireland JP, Fleming SJ, Levison DA, Cattell WR, Baker LRI. Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck.J Clin Pathol 1985;38:1114-8. 4. Sherlock DJ, Newman J, Hol]-Allen RTJ. Parathyroid carcinoma presenting as tertiary hyperparathyroidism. Postgrad Med J 1985;6i:243-4. 5. lga-ishnaGG, Mendez M, Levy B, Ritchie W, Mat-ksA, Narins RG. Parathyroid carcinoma in a chronic hemodialysis patient. Nephton 1989~52:194-5.
Miki et al.
901
6. Kodama M, Ikegami M, Imanishi M, et al. Parathyroid carcinoma in a case of chronic renal failure on dialysis. Urol Int 1989;44: 110-2. 7. Iwamoto N, Yamazaki S, Fukuda T, et al. Two cases of parathyroid carcinoma in patients on long-term hemodialysis. Nephron 1990;55:429-31. 8. Rademaker P, Meijer S, OosterhuisJW, et al. Successful surgical treatment of parathyroid carcinoma in two haemodialysis patients. Nephrol Dial Transplant 1990;5:545-8. 9. Ljutic D, Cameron JS, Ogg CS, Turner C, Hicks JA, Owen WJ. Long-term follow-up after total parathyroidectomy without parathyroid implantation in chronic renal failure. Q J Med 1994;87:685-92. 10. Miki H, Fitzpatrick LA. Parathyroid carcinoma. In: Sheaves R, Jenkins P, WassJ,.editors. Clinical endocrine oncology. Oxford: Blackwell Scientific Publications, Ltd, In press.
Surgery is abstracted a n d / o r i n d e x e d in Index Medic~s, Science Citation Index, Current Contents/ Clinical Medicine, Current Contents/Life Sciences, Exeerpta Medica, a n d MEDLINE. This J o u r n a l has b e e n registered with C o p y r i g h t Clearance Center, Inc., 222 Rosewood Dr., Danvers, MA 01923. C o n s e n t is given for t h e copying o f articles for p e r s o n a l or i n t e r n a l use of specific clients. This c o n s e n t is given o n the c o n d i t i o n t h a t the copier pay directly to the C e n t e r the per-copy fee stated o n t h e first page o f each article for copying b e y o n d t h a t p e r m i t t e d by U.S. Copyright Law. This c o n s e n t does n o t e x t e n d to o t h e r kinds of copying, such as for general distribution, resale, advertising a n d p r o m o t i o n a l purposes, or for creating new collective works. All inquiries r e g a r d i n g copyrighted material f r o m this publication o t h e r t h a n those that can be h a n d l e d t h r o u g h Copyright C l e a r a n c e C e n t e r s h o u l d b e d i r e c t e d to Associate J o u r n a l Publisher, Permissions, Mosby-Year Book, Inc., 11830 Westline Industrial Dr., St. Louis, M O 63146; p h o n e (314)579-2808; fax (314)432-1380.
From the Second Department of Surgery, School of Medicine, The University of Tokushima, and Higashi Tokushima National Sanatorium, Tokushima, Japan
RECENT IMPROVEMENTSIN hemodialysis a n d kidney transp l a n t a t i o n have r e d u c e d m o r b i d i t y a n d l e n g t h e n e d t h e life spans o f patients with c h r o n i c r e n a l failure. As a result o f this p r o l o n g a t i o n o f life, several p r o b l e m s have b e c o m e obvious a m o n g patients with c h r o n i c r e n a l failure. R e c e n t l y m o r e t h a n 10 cases o f p a r a t h y r o i d carc i n o m a were r e p o r t e d in patients with c h r o n i c r e n a l failure. >9 At Higashi T o k u s h i m a N a t i o n a l S a n a t o r i u m we also e n c o u n t e r e d a p a t i e n t with p a r a t h y r o i d carcin o m a w h o h a d b e e n o n m a i n t e n a n c e hemodialysis. Because the entity o f a p a r a t h y r o i d c a r c i n o m a in a p a t i e n t with c h r o n i c renal failure is still unclear, we reviewed 12 instances i n c l u d i n g o u r own, o f p a r a t h y r o i d c a r c i n o m a in hemodialysis patients r e p o r t e d in the English-lang u a g e literature. T h e characteristics o f these patients w e r e c o m p a r e d with those in subjects with p a r a t h y r o i d c a r c i n o m a w i t h o u t c h r o n i c r e n a l failure.
CASE REPORT The patient, a woman, has suffered from chronic glomerulonephritis since she was 21 years of age. Her renal function was considerably reduced after a pregnancy when she was 24 years old; hemodialysis was begun when she was 36 years old. Two years after the commencement of hemodialysis, the patient began to complain of muscle weakness and bilateral knee joint pain. At the age of 40 years (January 1987) the patient underwent a parathyroidectomy because of progressive secondary hyperparathyroidism refractory to the vitamin D treatment she had received for 6 months immediately preceding the parathyroidectomy. Preoperative carboxyl-terminal parathyroid hormone (C-PTH) concentrations were extremely elevated (47 to 62 ng/ml; reference value -<1.4 ng/ml) without associated hypercalcemia (7.8 to 8.5 mg/dl) (Fig. 1). Preoperative serum phosphorus and alkaline phosphatase levels Accepted for publication April 25, 1996. Reprint requests: Hitoshi Miki, MD, The Second Department of Surgery, School of Medicine, The University of Tokushima, Kuramotocho, Tokushima 770, Japan. Surgery I996;120:897-901. Copyright 9 1996 by Mosby-Year Book, Inc. 0039-6060/96/$5.00 + 0 11/57/75051
were 5.8 m g / d l (reference value, 2.7 to 4.4 mg/dl) and 37 KAU (reference value, 2.7 to 10.0 I ~ U ) , respectively. In addition, a 2 cm elastic hard tumor was palpated in the middle of the right side of her neck and was thought to be an enlarged right superior parathyroid gland. At operation all four parathyroid glands were enlarged, reddish-yellow, and had smooth surfaces; there were no adhesions between parathyroid glands and surrounding tissues. The right superior gland was heaviest among the four glands, weighing 2.7 gm. The other three glands weighed between 0.7 and 1.6 gm. Total parathyroidectomy was performed, and fragments of the left superior gland were autotransplanted into the patient's left forearm muscle. Because two small and hard nodules suspected of papillary carcinoma were found in the right lobe of the thyroid gland incidentally, right lobectomy of the thyroid gland was also performed. Lymphadenectomy was not performed because of the absence of lymphadenopathy. Microscopically, the right superior parathyroid gland had a thick fibrous capsule, and parenchymal cells resembling chief cells were arranged in seats or in a trabecular pattern (Fig. 2). Few mitoses were found. Although the chromatin was rather coarse, none of the typical findings of malignancy were present, so a parathyroid adenoma was diagnosed. Hyperplasia was diagnosed in the remaining three glands. Papillary carcinomas were diagnosed in the thyroid nodules. After the parathyroidectomy, the C-PTH concentration rapidly decreased and remained at a low level (<8 ng/ml) for 15 months. However, it gradually rose after June 1988 and reached 34 n g / m l in December 1988. Posfoperative calcium levels fluctuated between 7.3 m g / d l and 11.3 mg/dl. Although alkaline phosphatase levels increased to 59.2 KAU 1 month after the initial operation, they remained within normal limits for 17 months after June 1987 and gradually rose after November 1988. Moreover, in July 1988 a chest radiograph showed a coin lesion (1.0 cm in diameter) in the left lung. Because the size of this coin lesion was later confirmed by computed tomography (Fig. 3) to have increased to 1.4 cm, a left pulmonary local resection including nodules was performed in February 1989. Two tumors were found in S4 and SOof the left lung; both lesions were white and elastic hard. The sizes of the tumors in S4 and S9 were 1.4 cm and 0.5 cm, respectively. An immunohistochemical study of these pulmonary nodules showed immunoreactivity to anti-PTH (parathyroid hormone) antibodies, whereas two nodules of papillary carcinoma reSURGERY
897
898
Miki et al.
80
Surgery November 1996
PTx ~1v
-20
Left Pulmonary Resection
l...'",,.~.rl.
Right Pulmonary Resection
60 A u
O) C
40 II1.
6
9
-15
Ca.-'"-,.,-""""'-, ...... .....
"-..-"'-..,"...-"
10
E u
-5
20
87
88
89
90
91
92
93
94
95
Year Fig. 1. Serial C-PTH measurements and clinical events. PTx, Total parathyroidectomy with autotransplantation.
Fig. 2. Microscopic appearance of right superior parathyroid gland. Thick fibrous capsule and parenchymal cells arranged in seats or trabecular pattern were found. (Hematoxylin-eosin stain; original magnification •
sected during the initial operation were not stained with the same antibodies. Histologic reexamination of the right superior parathyroid gland removed in 1987 revealed features similar to pulmonary nodules. Therefore these pulmonary lesions were diagnosed as metastases of the parathyroid carcinoma, probably originating in the right superior gland. Although the C-PTH concentration decreased to 13.0 n g / m l after resection of the left pulmonary metastases, it ira-
mediately increased again and multiple ,nodules in the right lung were then detected radiogr~phically. The patient underwent a right pulmonary resection in August 1989. Eight pulmonary lesions, ranging from 5 to 8 mm in diameter, were locally resected. All the lesions were diagnosed histologically as metastases of the parathyroid carcinoma. After right pulmonary resection, C-PTH concentrations have remained elevated until now. A coin lesion suspected of being a metastasis
Surgery Volume 120, Number 5
Miki et al.
899
Fig. 3. Computed tomograph of left lung. Arrow shows coin lesion, 1.0 cm in diameter, that was diagnosed after operation as a metastasis from parathyroid carcinoma.
from the parathyroid carcinoma was found in the right lung by chest radiography in March 1990. Moreover, three rumors (ranging from 0.6 to 1.2 cm in diameter) in the patient's right neck were seen oll ultrasonogram in May 1993, although the origin of these tumors remains unclear (whether the parathy1-oid carcinoma or the thyroid carcinoma). Excision of the right lung and right neck tumors has been advised. However, the patient has refused these operations and is currently being followed up carefullywith serial G-PTH levels, ultrasonography of the neck, and chest radiography. Calcium levels recently decreased to the normal range, although they showed an upward trend until the spring of 1994. Alkaline phosphatase levels have remained within normal limits for 4 years.
DISCUSSION Parathyroid carcinoma is a rare a n d unusual clinical entity. Since the first case was described in 1933, only approximately 300 cases of parathyroid carcinoma have been reported. Berland et al. 1 reported the first ease of a parathyroid carcinoma in a patient receiving hemodialysis because of chronic renal failure that did not result from elevated serum calcium concentrations. O u r survey of the English-language literature revealed 12 patients with parathyroid carcinoma a n d chronic renal failure on m a i n t e n a n c e hemodialysis, including our own (Table).l~ The cause of parathyroid carcinoma is usually difficult to determine. In patients o n hemodialysis, however,
the possibility of m a l i g n a n t transformation of b e n i g n lesions has been proposed. This is because b e n i g n lesions of the parathyroid glands (i.e., hyperplasia and adenoma) coexisted in all the patients with chronic renal failure and c o n c u r r e n t parathyroid carcinoma, which was mostly f o u n d 4 to 7 years after the start ofhemodialysis. Also the occurrence of multiple primary lesions of parathyroid carcinoma, which is usually thought to be quite rare, was f o u n d in 2 of the 12 reported cases.t' 5 Parathyroid carcinoma in subjects without chronic renal failure tends to occur in males and females at even rates, l~ In contrast, only 2 of the 12 patients with parathyroid carcinoma who had b e e n on m a i n t e n a n c e hemodialysis were male. Although the reason for this female p r e d o m i n a n c e is unclear, sex h o r m o n e s may have some effect o n the initiation or p r o m o t i o n of parathyroid carcinoma, or both. The m e a n age of patients with carcinoma ~a4thout chronic renal failure has b e e n reported to range from 44 to 55 years] ~ and m e a n age of the 12 reviewed cases was comparable. Patients with parathyroid carcinomas frequently have clinically severe hyperparathyroidism caused by the effects of the excessive secretion of PTH; the most comm o n symptoms are related to hypercalcemia. However, half the patients reviewed with parathyroid carcinoma on hemodialysis did n o t show signs of hypercalcemia. Preoperative calcium levels in patients with parathyroid
900
Miki et al.
Surgery November 1996
T a b l e . Characteristics of 12 patients with parathyroid carcinoma and associated chronic renal failure
Case no.
Authors
Age at Duration of Preoperative diagnosis hemohyperNo. of cancerous Year (yr) Gender dialysis calcemia glands Metastases
1 Berland et al.
1982
62
F
2 Anderson et al.
1983
44
F
3 Ireland et al.
1985
34
M
4 Sherlock et al.
1985
42
5 Krishna et al.
1989
6 Kodama et al.
3 yr
2 +
1
5 yr
+
1
F
7 yr
+
1
64
F
9 yr
1989
53
F
7 yr
7 Iwamoto et al. 1990 8 Iwamoto et al. 1990 9 Rademaker et al. 1990
46 55 46
M F F
10 Rademaker et al. 1990
52
11 Ljutic et al. 12 Miki et al.
40
1994 1996
2 +
1
11 yr, 3 mo 5 yr, 4 mo 3 yr
+
1 1 1
F
2 yr
+
1
F
4 yr, 10 mo
-
1
carcinoma on hemodialysis ranged from 8.5 m g / d l to 12.6 m g / d l , and the m e a n level was 10.8 -+ 1.4 m g / d l . Normocalcemia in these patients may have b e e n caused by the chronic renal failure itself, which decreased serum calcium concentrations, by hemodialysis, which regularly corrected the serum calcium concentration, or by both. Preoperative serum phosphorus levels were elevated in all patients o n hemodialysis with parathyroid carcinoma (6.7 _+ 1.2 m g / d l ) . Alkaline phosphatase levels were also at least 1.7 times higher than n o r m a l in all patients. Because the most significant preoperative finding in patients o n hemodialysis with parathyroid carcinoma is only elevated PTH concentrations, which were more than two times the n o r m a l level in all 12 patients, it is difficult to distinguish parathyroid carcinoma in patients with chronic renal failure from secondary hyperparathyroidism caused by b e n i g n lesions. Actually, there was n o patient in whom parathyroid carcinoma was diagnosed before operation a m o n g those reviewed. Five patients were diagnosed d u r i n g the initial operation because of local invasion, a n d four patients were diagnosed by the p e r m a n e n t sections of primary lesion after the initial operation. In two patients, including ours, the diagnosis of parathyroid carcinoma could n o t be established until the detection of distant metastases. Five of 12 patients u n d e r w e n t parathyroidectomy only. Parathyroidectomy associated with partial resection of the thyroid gland necessitated by the local inva-
Lung
Follow-up Status No evidence of disease Death from disease Death from other cause No evidence of disease No evidence of disease No evidence of disease
No evidence of disease No evidence of disease Lung
Mive with disease
(too) 5 17 84 12 36 4
84 48
115
sion of parathyroid carcinoma was performed in five patients. Both parathyroidectomy and lymphadenectomy were performed in two patients, although lymph n o d e metastases were n o t found. No patients received a kidney transplant before or after parathyroidectomy. Parathyroid carcinoma carries the risk of local recurrence or distant metastases even after a successful resection; the rate of r e c u r r e n t disease has b e e n reported to range from 41% to 67%. l~ Most deaths are the result of u n c o n t r o l l e d hypercalcemia rather than t u m o r growth itself; the 5-year survival rate after initial operation for parathyroid carcinoma is reported to range from 40% to 69%. l~ The rate of recurrent disease in patients with chronic renal failure is similar, a n d one third of patients suffer a recurrence after parathyroidectomy. In contrast, only one patient on hemodialysis died of hypercalcemia caused by recurrent disease. Moreover, our reported patient is still alive with disease 115 m o n t h s after the primary operation. T h e r e f o r e the prognosis in hemodialysis patients with parathyroid carcinoma may be better than in those with parathyroid carcinoma that caused primary hyperparathyroidism despite similar rates of recurrent disease. This may be attributable tO the regular correction of the serum calcium concentration with hemodialysis. Alternatively, the biologic behavior of parathyroid carcinoma that develops in. patients with chronic renal failure may naturally differ from that in patients without chronic renal failure.
Surgery Volume 120, Number 5 REFERENCES
1. Berland Y, Olmer M, Lebreuil G, Grisoli J. Parathyroid carcinoma, adenoma and hyperplasia in a case of chronic renal insufficiency on dialysis. Clin Nephrol 1982;18:154-8. 2. Anderson BJ, Samaan NA, Vassil0poulou-Sellin R, Ordonez NG, Hickey RC. Parathyroid carcinoma: features and difficulties in diagnosis and management. Surgery 1983;94:906-15. 3. Ireland JP, Fleming SJ, Levison DA, Cattell WR, Baker LRI. Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck.J Clin Pathol 1985;38:1114-8. 4. Sherlock DJ, Newman J, Hol]-Allen RTJ. Parathyroid carcinoma presenting as tertiary hyperparathyroidism. Postgrad Med J 1985;6i:243-4. 5. lga-ishnaGG, Mendez M, Levy B, Ritchie W, Mat-ksA, Narins RG. Parathyroid carcinoma in a chronic hemodialysis patient. Nephton 1989~52:194-5.
Miki et al.
901
6. Kodama M, Ikegami M, Imanishi M, et al. Parathyroid carcinoma in a case of chronic renal failure on dialysis. Urol Int 1989;44: 110-2. 7. Iwamoto N, Yamazaki S, Fukuda T, et al. Two cases of parathyroid carcinoma in patients on long-term hemodialysis. Nephron 1990;55:429-31. 8. Rademaker P, Meijer S, OosterhuisJW, et al. Successful surgical treatment of parathyroid carcinoma in two haemodialysis patients. Nephrol Dial Transplant 1990;5:545-8. 9. Ljutic D, Cameron JS, Ogg CS, Turner C, Hicks JA, Owen WJ. Long-term follow-up after total parathyroidectomy without parathyroid implantation in chronic renal failure. Q J Med 1994;87:685-92. 10. Miki H, Fitzpatrick LA. Parathyroid carcinoma. In: Sheaves R, Jenkins P, WassJ,.editors. Clinical endocrine oncology. Oxford: Blackwell Scientific Publications, Ltd, In press.
Surgery is abstracted a n d / o r i n d e x e d in Index Medic~s, Science Citation Index, Current Contents/ Clinical Medicine, Current Contents/Life Sciences, Exeerpta Medica, a n d MEDLINE. This J o u r n a l has b e e n registered with C o p y r i g h t Clearance Center, Inc., 222 Rosewood Dr., Danvers, MA 01923. C o n s e n t is given for t h e copying o f articles for p e r s o n a l or i n t e r n a l use of specific clients. This c o n s e n t is given o n the c o n d i t i o n t h a t the copier pay directly to the C e n t e r the per-copy fee stated o n t h e first page o f each article for copying b e y o n d t h a t p e r m i t t e d by U.S. Copyright Law. This c o n s e n t does n o t e x t e n d to o t h e r kinds of copying, such as for general distribution, resale, advertising a n d p r o m o t i o n a l purposes, or for creating new collective works. All inquiries r e g a r d i n g copyrighted material f r o m this publication o t h e r t h a n those that can be h a n d l e d t h r o u g h Copyright C l e a r a n c e C e n t e r s h o u l d b e d i r e c t e d to Associate J o u r n a l Publisher, Permissions, Mosby-Year Book, Inc., 11830 Westline Industrial Dr., St. Louis, M O 63146; p h o n e (314)579-2808; fax (314)432-1380.