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Parathyroid carcinoma: clinical presentation and treatment
International Congress Series 1240 (2003) 991 – 995
Parathyroid carcinoma: clinical presentation and treatment S. Jakoubkova´ *, J. Vokurka, J. Cˇa´p, A. Rysˇka Department of Otolaryngology, Head and Neck Surgery, 2nd Department of Internal Medicine, Department of Pathology, University Hospital, Hradec Kra´love´ 500 05, Czech Republic
Abstract Carcinoma of the parathyroid gland is a rare cause of primary hyperparathyroidism, with incidence of less than 1%. Parathyroid carcinomas usually grow slowly, with a tendency for local invasion. The preoperative differential diagnosis between carcinoma and adenoma of parathyroid gland is often difficult because many of the signs and symptoms are similar. Patients with parathyroid carcinoma have a generally higher serum calcium level and PTH level, and incidence of renal and bone diseases, pancreatitis, peptic ulcer, and anemia. The most effective therapy for parathyroid cancer is complete resection of the tumor together with the ipsilateral thyroid lobe. We reviewed the case of a 64-year-old woman with parathyroid carcinoma, who had severe hypercalcemia, hypertension, asymptomatic nephrolithiasis, fracture of the neck of the right femur, hypertension, and anemia. A hard mass was palpable on the right side of her neck. The tumor was resected and blocked by the unilateral thyroid lobe. Histopathological examination showed parathyroid carcinoma. The patient was given adjuvant radiation therapy and there was no evidence of recurrence 32 months after surgery. D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. Keywords: Parathyroid carcinoma; Diagnosis; Treatment
1. Introduction Parathyroid tumors account for only a small percentage of all head and neck neoplasms. Carcinoma of the parathyroid gland is rarely encountered in clinical practice. Because most of these tumors retain the ability to produce active parathyroid hormone, most patients with the disease get hypercalcemia. Hypercalcemia may sometimes be asympto* Corresponding author. Fax: +42-4-9583-2033. E-mail address: [email protected] (S. Jakoubkova´). 0531-5131/ D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. doi:10.1016/S0531-5131(03)00744-1
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S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
matic for a long period. The proportions of cases of primary hyperparathyroidism vary in different studies. In most studies, about 85% of the patients have a single adenoma, 5% have multiple adenoma, 10% have hyperplasia, and less than 1% have carcinoma [1]. The first case of metastatic parathyroid tumor was described by DeQuervain (1909) [2]. Because the tumor was ‘‘nonfunctional,’’ many reviewers were skeptical and so the first description of parathyroid cancer was attributed to Armstrong (1938). He described the first patient with metastatic parathyroid tumor and hypercalcemia. Since that report, approximately 300 cases of parathyroid carcinoma have been reported in the world literature [3– 10]. At our clinic, since 1996, we have operated on 78 patients with primary hyperparathyroidism. Only one patient had carcinoma of the parathyroid gland.
2. Case report A 64-year-old woman with primary hyperparathyroidism and suspected adenoma of the right lower parathyroid gland was admitted at our clinic for operation in February l999. The familial history was negative for endocrine diseases. She had undergone partial thyroidectomy 20 years ago. She had been treated for hypertension. For 3 months, she had had a severe pain in her right hip. X-ray examination showed a fracture of the neck of the right femur. Chest X-ray examination was without pathology. Asymptomatic nephrolithiasis and severe decalcification were present. Her serum calcium level was 3.6 mmol/l, phosphate level was 0.79 mmol/l, and parathormone level was 180.1 pg/ml. A hard mass was palpable on the right side of her neck. Ultrasonography of the neck showed a mass in the region of the right inferior parathyroid gland of about the size of 24 26 mm without lymphadenopathy. During operation, the tumor was found to be localized, in contact with the right lobe of the thyroid gland. Because the tumor firmly adhered to the surrounding tissues, it was resected en bloc by the unilateral thyroid lobe. Histopathological examination showed parathyroid carcinoma. The patient was given adjuvant radiation therapy, which was tolerated well, with minimal side effects. The patient has been free of disease for 33 months since initial operation. Her serum calcium and parathormone levels are normal.
3. Discussion 3.1. Etiology The etiology of parathyroid carcinoma is unknown, although patients with familial hyperparathyroidism and irradiation to the head and neck in history are at increased risk of developing the disease [7]. 3.2. Clinical symptomatology Parathyroid carcinoma is a rare malignancy that usually shows nonspecific symptoms associated with hypercalcemia. These are weakness, bone pain, fatigue, nervousness,
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
993
depression, weight loss, anorexia, nausea, vomiting, thirst, abdominal discomfort, and palpitations. The clinical picture that carcinoma of the parathyroid gland gives is the same as that of hyperparathyroidism due to adenoma. Patients with parathyroid carcinoma have a greater incidence of renal and bone disease compared with patients with benign hyperparathyroidism [7]. About 70% of patients have skeletal disease, which is usually manifested as osteoporosis or ostitis fibrosa cystica/brown tumor [11]. About 30% of patients have renal disease, which is manifested as nephrolithiasis, polyuria, or polydypsia. About 15% of patients have pancreatitis [11]. About 50% of the patients have a palpable cervical mass. The other physical findings are hypertension or, in rare cases, vocal cord paralysis. 3.3. Biochemical findings The patients are usually markedly hypercalcemic and usually hypophosphatemic. Serum calcium levels are 3.5 mmol/l or higher. The serum parathormone level is generally increased usually more than five times the normal. The serum alkaline phosphatase level is mildly elevated; serum creatinine and erythrocyte sedimentation rate are elevated, too. Patients usually have anemia. 3.4. Imaging studies for parathyroid tumors Imaging studies for parathyroid tumors include noninvasive and invasive methods [1]. Noninvasive imaging includes: ultrasound sensitivity of 57%, sesta-mibi nuclear scan sensitivity of 80% and higher, CT scan able to image mediastinum, difficult to distinguish lymph node from parathyroid gland, and MRI same as CT with increased sensitivity. Invasive imaging includes selective angiogram and selective venous sampling for parathormone; both are expensive and require a skilled interventional radiologist, and very helpful before reoperation, ultrasound, or CT-guided FNAB. 3.5. Preoperatively Several operative findings have been described, which, when present, help to distinguish benign parathyroid adenomas from parathyroid carcinoma. Parathyroid carcinoma is frequently described as a lobulated, firm-to-stonyhard mass, white-grayish in color, and with infiltration to surrounding structures [10,12]. If there is gross infiltration of adjacent thyroid nerves, muscles, or esophagus, or obvious cervical node metastases, the diagnosis of carcinoma is not difficult. However, some or all of these operative findings may be absent. The frozen section diagnosis may be difficult and is of little value. 3.6. Histology It is widely accepted that histological diagnosis of parathyroid carcinoma is established usually with great difficulty. The final histological diagnosis is based on the presence of diffuse sheet-like growth of monotonous small cell; capsular or vascular invasion; growth into surrounding structures; high mitotic activity, more than five mitoses per high-power
994
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
field; trabecular fibrous septa; and thick hyalinized tumor capsule [2,10]. Unfortunately, none of these features is diagnostic of parathyroid carcinoma. Some of them can be found in parathyroid adenomas [11]. However, the presence of more than two of the abovementioned criteria makes the diagnosis of carcinoma highly probable [12]. Sometimes, immunohistochemistry and electron microscopy may be used, but are only of limited value. 3.7. Therapy 3.7.1. Surgical therapy Surgical resection is the only effective treatment for parathyroid carcinoma [7,9]. En bloc tumor resection with unilateral hemithyroidectomy is the procedure of choice and offers the best chance of cure. Great care must be exercised to avoid rupture of the capsule of the gland because this will increase the likelihood of local seeding of the tumor. 3.7.2. Radiation and chemotherapy The nonsurgical forms of treatment for parathyroid carcinoma are generally not effective [1]. This cancer is not a radiosensitive tumor. Some investigators have reported that radiation to the neck after surgery may be helpful in preventing tumor regrowth [7,10,11,13]. Chemotherapy has been used without response [2,7,10]. 3.7.3. Medical therapy When hypercalcemia is refractory to surgical resection, medical treatment has a beneficent effect [7]. Management includes infusion of saline to restore fluid volume, furosemide, and dialysis [2,7]. The bisphosphonates mithramycin, gallium nitrate, calcitonin have been reported to inhibit bone resorption. Octreotide has been reported to inhibit PTH secretion, as does the immunization with human and bovine PTH peptides. 3.8. Postoperative Patients who have undergone surgical treatment for parathyroid carcinoma require long-term follow-up since the risk of local recurrence or distant metastases, mostly to the lungs or bones, remains high even after many years after initial operation. Since the tumor cells in recurrent lesions or metastatic sites generally continue to produce metabolically active parathormone, postoperative serial monitoring of serum calcium levels is important and elevated levels may herald recurrence or metastasis. In addition to physical examination for local mass, lymphadenopathy, and vocal cord paralysis, the following measures are recommended: X-ray, CT imaging of the chest and neck, ultrasonography, thallium technetium subtraction, barium swallow, and possibly MRI. 3.9. Prognosis Development of the cancer is slow but life prognosis depends on the successful resection of the tumor at the time of the initial surgery. Therefore, diagnosis of cancer before operation is very important.
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
995
4. Conclusion Parathyroid cancer is a rare neoplasm affecting both sexes equally [10]. The tumor is relatively slow-growing. The local recurrence rate approximates 30% [5]. Distant metastasis, via lymphatic or blood vessels, occurs in about 30% of the patients [5]. The 5-year survival varies from 50% to 86% [1,5,7]. Patient survival depends on an aggressive surgical approach to the primary lesion and recurrent disease. The death is usually due to long-term effects of hypercalcemia.
References [1] D.L. Fraker, Update on the management of parathyroid tumors, Curr. Opin. Oncol. 12 (2000) 41 – 48. [2] J.T. Vetto, M.F. Brennan, J. Woodruf, M. Burt, Parathyroid carcinoma: diagnosis and clinical history, Surgery 114 (1993) 882 – 892. [3] G. Bednarek-Tupikowska, K. Dunajska, A. Milewicz, Parathyroid cancer, Pol. Merkuriuasz Lek. 8 (45) (2000) 121 – 123. [4] A.C. Cordeiro, F.l. Montenegro, M.A. Kulcsar, et al., Parathyroid carcinoma, Am. J. Surg. 175 (1998) 52 – 55. [5] M.A. Mashburn, G.D. Chonkich, D.R. Chase, G.H. Petti, L. Linda, Parathyroid carcinoma: two new cases—diagnosis, therapy and treatment, Laryngoscope 97 (1987) 215 – 218. [6] T. Obara, Y. Fujimoto, Diagnosis and treatment of patients with parathyroid carcinoma: an update and review, World J. Surg. 15 (1991) 738 – 744. [7] E. Shane, Parathyroid carcinoma, J. Clin. Endocrinol. Metab. 86 (2) (2000) 485 – 493 (E. Chow). [8] C. Spinelli, P. Berti, P. Miccoli, Carcinoma of the parathyroids. Surgical experience in 3 cases, Minerva Chir. 49 (12) (1994) 1343 – 1347. [9] C. Wang, R. Gaz, Natural history of parathyroid carcinoma: diagnosis, treatment, and results, Am. J. Surg. 149 (1985) 522 – 527. [10] A. Wynne, J.v. Heerden, J. Camey, L. Fitzpatrick, Parathyroid carcinoma: clinical and pathological features in 43 patients, Medicine 71 (1992) 197 – 205. [11] K. Levin, M. Galante, O. Clark, Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia, Surgery 101 (1987) 647 – 660. [12] J.K.C. Chan, W.Y.W. Tsang, Endocrine malignancies that may mimic benign lesions, Semin. Diagn. Pathol. 12 (1) (1995) 45 – 61. [13] E. Chow, R.W. Tsang, J.D. Brierley, S. Filice, Parathyroid carcinoma—the Princess Margaret Hospital experience, Int. J. Radiat. Oncol. Biol. Phys. 41 (1998) 569 – 572.
Parathyroid carcinoma: clinical presentation and treatment S. Jakoubkova´ *, J. Vokurka, J. Cˇa´p, A. Rysˇka Department of Otolaryngology, Head and Neck Surgery, 2nd Department of Internal Medicine, Department of Pathology, University Hospital, Hradec Kra´love´ 500 05, Czech Republic
Abstract Carcinoma of the parathyroid gland is a rare cause of primary hyperparathyroidism, with incidence of less than 1%. Parathyroid carcinomas usually grow slowly, with a tendency for local invasion. The preoperative differential diagnosis between carcinoma and adenoma of parathyroid gland is often difficult because many of the signs and symptoms are similar. Patients with parathyroid carcinoma have a generally higher serum calcium level and PTH level, and incidence of renal and bone diseases, pancreatitis, peptic ulcer, and anemia. The most effective therapy for parathyroid cancer is complete resection of the tumor together with the ipsilateral thyroid lobe. We reviewed the case of a 64-year-old woman with parathyroid carcinoma, who had severe hypercalcemia, hypertension, asymptomatic nephrolithiasis, fracture of the neck of the right femur, hypertension, and anemia. A hard mass was palpable on the right side of her neck. The tumor was resected and blocked by the unilateral thyroid lobe. Histopathological examination showed parathyroid carcinoma. The patient was given adjuvant radiation therapy and there was no evidence of recurrence 32 months after surgery. D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. Keywords: Parathyroid carcinoma; Diagnosis; Treatment
1. Introduction Parathyroid tumors account for only a small percentage of all head and neck neoplasms. Carcinoma of the parathyroid gland is rarely encountered in clinical practice. Because most of these tumors retain the ability to produce active parathyroid hormone, most patients with the disease get hypercalcemia. Hypercalcemia may sometimes be asympto* Corresponding author. Fax: +42-4-9583-2033. E-mail address: [email protected] (S. Jakoubkova´). 0531-5131/ D 2003 International Federation of Otorhinolaryngological Societies (IFOS). All rights reserved. doi:10.1016/S0531-5131(03)00744-1
992
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
matic for a long period. The proportions of cases of primary hyperparathyroidism vary in different studies. In most studies, about 85% of the patients have a single adenoma, 5% have multiple adenoma, 10% have hyperplasia, and less than 1% have carcinoma [1]. The first case of metastatic parathyroid tumor was described by DeQuervain (1909) [2]. Because the tumor was ‘‘nonfunctional,’’ many reviewers were skeptical and so the first description of parathyroid cancer was attributed to Armstrong (1938). He described the first patient with metastatic parathyroid tumor and hypercalcemia. Since that report, approximately 300 cases of parathyroid carcinoma have been reported in the world literature [3– 10]. At our clinic, since 1996, we have operated on 78 patients with primary hyperparathyroidism. Only one patient had carcinoma of the parathyroid gland.
2. Case report A 64-year-old woman with primary hyperparathyroidism and suspected adenoma of the right lower parathyroid gland was admitted at our clinic for operation in February l999. The familial history was negative for endocrine diseases. She had undergone partial thyroidectomy 20 years ago. She had been treated for hypertension. For 3 months, she had had a severe pain in her right hip. X-ray examination showed a fracture of the neck of the right femur. Chest X-ray examination was without pathology. Asymptomatic nephrolithiasis and severe decalcification were present. Her serum calcium level was 3.6 mmol/l, phosphate level was 0.79 mmol/l, and parathormone level was 180.1 pg/ml. A hard mass was palpable on the right side of her neck. Ultrasonography of the neck showed a mass in the region of the right inferior parathyroid gland of about the size of 24 26 mm without lymphadenopathy. During operation, the tumor was found to be localized, in contact with the right lobe of the thyroid gland. Because the tumor firmly adhered to the surrounding tissues, it was resected en bloc by the unilateral thyroid lobe. Histopathological examination showed parathyroid carcinoma. The patient was given adjuvant radiation therapy, which was tolerated well, with minimal side effects. The patient has been free of disease for 33 months since initial operation. Her serum calcium and parathormone levels are normal.
3. Discussion 3.1. Etiology The etiology of parathyroid carcinoma is unknown, although patients with familial hyperparathyroidism and irradiation to the head and neck in history are at increased risk of developing the disease [7]. 3.2. Clinical symptomatology Parathyroid carcinoma is a rare malignancy that usually shows nonspecific symptoms associated with hypercalcemia. These are weakness, bone pain, fatigue, nervousness,
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
993
depression, weight loss, anorexia, nausea, vomiting, thirst, abdominal discomfort, and palpitations. The clinical picture that carcinoma of the parathyroid gland gives is the same as that of hyperparathyroidism due to adenoma. Patients with parathyroid carcinoma have a greater incidence of renal and bone disease compared with patients with benign hyperparathyroidism [7]. About 70% of patients have skeletal disease, which is usually manifested as osteoporosis or ostitis fibrosa cystica/brown tumor [11]. About 30% of patients have renal disease, which is manifested as nephrolithiasis, polyuria, or polydypsia. About 15% of patients have pancreatitis [11]. About 50% of the patients have a palpable cervical mass. The other physical findings are hypertension or, in rare cases, vocal cord paralysis. 3.3. Biochemical findings The patients are usually markedly hypercalcemic and usually hypophosphatemic. Serum calcium levels are 3.5 mmol/l or higher. The serum parathormone level is generally increased usually more than five times the normal. The serum alkaline phosphatase level is mildly elevated; serum creatinine and erythrocyte sedimentation rate are elevated, too. Patients usually have anemia. 3.4. Imaging studies for parathyroid tumors Imaging studies for parathyroid tumors include noninvasive and invasive methods [1]. Noninvasive imaging includes: ultrasound sensitivity of 57%, sesta-mibi nuclear scan sensitivity of 80% and higher, CT scan able to image mediastinum, difficult to distinguish lymph node from parathyroid gland, and MRI same as CT with increased sensitivity. Invasive imaging includes selective angiogram and selective venous sampling for parathormone; both are expensive and require a skilled interventional radiologist, and very helpful before reoperation, ultrasound, or CT-guided FNAB. 3.5. Preoperatively Several operative findings have been described, which, when present, help to distinguish benign parathyroid adenomas from parathyroid carcinoma. Parathyroid carcinoma is frequently described as a lobulated, firm-to-stonyhard mass, white-grayish in color, and with infiltration to surrounding structures [10,12]. If there is gross infiltration of adjacent thyroid nerves, muscles, or esophagus, or obvious cervical node metastases, the diagnosis of carcinoma is not difficult. However, some or all of these operative findings may be absent. The frozen section diagnosis may be difficult and is of little value. 3.6. Histology It is widely accepted that histological diagnosis of parathyroid carcinoma is established usually with great difficulty. The final histological diagnosis is based on the presence of diffuse sheet-like growth of monotonous small cell; capsular or vascular invasion; growth into surrounding structures; high mitotic activity, more than five mitoses per high-power
994
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
field; trabecular fibrous septa; and thick hyalinized tumor capsule [2,10]. Unfortunately, none of these features is diagnostic of parathyroid carcinoma. Some of them can be found in parathyroid adenomas [11]. However, the presence of more than two of the abovementioned criteria makes the diagnosis of carcinoma highly probable [12]. Sometimes, immunohistochemistry and electron microscopy may be used, but are only of limited value. 3.7. Therapy 3.7.1. Surgical therapy Surgical resection is the only effective treatment for parathyroid carcinoma [7,9]. En bloc tumor resection with unilateral hemithyroidectomy is the procedure of choice and offers the best chance of cure. Great care must be exercised to avoid rupture of the capsule of the gland because this will increase the likelihood of local seeding of the tumor. 3.7.2. Radiation and chemotherapy The nonsurgical forms of treatment for parathyroid carcinoma are generally not effective [1]. This cancer is not a radiosensitive tumor. Some investigators have reported that radiation to the neck after surgery may be helpful in preventing tumor regrowth [7,10,11,13]. Chemotherapy has been used without response [2,7,10]. 3.7.3. Medical therapy When hypercalcemia is refractory to surgical resection, medical treatment has a beneficent effect [7]. Management includes infusion of saline to restore fluid volume, furosemide, and dialysis [2,7]. The bisphosphonates mithramycin, gallium nitrate, calcitonin have been reported to inhibit bone resorption. Octreotide has been reported to inhibit PTH secretion, as does the immunization with human and bovine PTH peptides. 3.8. Postoperative Patients who have undergone surgical treatment for parathyroid carcinoma require long-term follow-up since the risk of local recurrence or distant metastases, mostly to the lungs or bones, remains high even after many years after initial operation. Since the tumor cells in recurrent lesions or metastatic sites generally continue to produce metabolically active parathormone, postoperative serial monitoring of serum calcium levels is important and elevated levels may herald recurrence or metastasis. In addition to physical examination for local mass, lymphadenopathy, and vocal cord paralysis, the following measures are recommended: X-ray, CT imaging of the chest and neck, ultrasonography, thallium technetium subtraction, barium swallow, and possibly MRI. 3.9. Prognosis Development of the cancer is slow but life prognosis depends on the successful resection of the tumor at the time of the initial surgery. Therefore, diagnosis of cancer before operation is very important.
S. Jakoubkova´ et al. / International Congress Series 1240 (2003) 991–995
995
4. Conclusion Parathyroid cancer is a rare neoplasm affecting both sexes equally [10]. The tumor is relatively slow-growing. The local recurrence rate approximates 30% [5]. Distant metastasis, via lymphatic or blood vessels, occurs in about 30% of the patients [5]. The 5-year survival varies from 50% to 86% [1,5,7]. Patient survival depends on an aggressive surgical approach to the primary lesion and recurrent disease. The death is usually due to long-term effects of hypercalcemia.
References [1] D.L. Fraker, Update on the management of parathyroid tumors, Curr. Opin. Oncol. 12 (2000) 41 – 48. [2] J.T. Vetto, M.F. Brennan, J. Woodruf, M. Burt, Parathyroid carcinoma: diagnosis and clinical history, Surgery 114 (1993) 882 – 892. [3] G. Bednarek-Tupikowska, K. Dunajska, A. Milewicz, Parathyroid cancer, Pol. Merkuriuasz Lek. 8 (45) (2000) 121 – 123. [4] A.C. Cordeiro, F.l. Montenegro, M.A. Kulcsar, et al., Parathyroid carcinoma, Am. J. Surg. 175 (1998) 52 – 55. [5] M.A. Mashburn, G.D. Chonkich, D.R. Chase, G.H. Petti, L. Linda, Parathyroid carcinoma: two new cases—diagnosis, therapy and treatment, Laryngoscope 97 (1987) 215 – 218. [6] T. Obara, Y. Fujimoto, Diagnosis and treatment of patients with parathyroid carcinoma: an update and review, World J. Surg. 15 (1991) 738 – 744. [7] E. Shane, Parathyroid carcinoma, J. Clin. Endocrinol. Metab. 86 (2) (2000) 485 – 493 (E. Chow). [8] C. Spinelli, P. Berti, P. Miccoli, Carcinoma of the parathyroids. Surgical experience in 3 cases, Minerva Chir. 49 (12) (1994) 1343 – 1347. [9] C. Wang, R. Gaz, Natural history of parathyroid carcinoma: diagnosis, treatment, and results, Am. J. Surg. 149 (1985) 522 – 527. [10] A. Wynne, J.v. Heerden, J. Camey, L. Fitzpatrick, Parathyroid carcinoma: clinical and pathological features in 43 patients, Medicine 71 (1992) 197 – 205. [11] K. Levin, M. Galante, O. Clark, Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia, Surgery 101 (1987) 647 – 660. [12] J.K.C. Chan, W.Y.W. Tsang, Endocrine malignancies that may mimic benign lesions, Semin. Diagn. Pathol. 12 (1) (1995) 45 – 61. [13] E. Chow, R.W. Tsang, J.D. Brierley, S. Filice, Parathyroid carcinoma—the Princess Margaret Hospital experience, Int. J. Radiat. Oncol. Biol. Phys. 41 (1998) 569 – 572.