Brain metastases from medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer occurring in less than 10% of patients with thyroid cancer. Brain metastasis from MTC is exceedingly rare. Only six cases of brain metastasis from MTC have been reported in the literature and none had MTC as a part of multiple endocrine neoplasia (MEN) syndrome. We report a 42-year-old Caucasian male with MEN 2A who presented with neurological symptoms 25 years after total thyroidectomy with lymphadenectomy for MTC metastatic to local lymph nodes. A brain magnetic resonance imaging (MRI) showed a 4-cm cystic mass and a 1-cm nodule in the left frontal-parietal lobe in addition to a 0.8-cm cystic mass in the left frontal lobe and multiple tiny cerebellar metastatic lesions. Partial resection of the cerebral metastasis followed by whole brain radiotherapy resulted in resolution of the neurological symptoms. However, the patient had multiple systemic metastasis from the MTC and he died of systemic complications due to metastatic MTC. To our knowledge this is the first report of brain metastases from MTC in a patient with MEN 2A.

Advances and controversies in the diagnosis and management of medullary thyroid carcinoma.

Recent advances in the diagnosis and treatment of medullary thyroid carcinoma (MTC) have been significant, but some issues remain controversial. MTC may occur either as a hereditary or a nonhereditary entity. Hereditary MTC can occur either alone--familial MTC (FMTC)--or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B). These hereditary disorders are due to germline mutations in the RET proto-oncogene. Early diagnosis and treatment considerably improve the prognosis in patients with MTC. Genetic testing can identify almost all affected individuals with hereditary disease and permits early thyroidectomy in gene carriers. Plasma CT is an excellent marker for postoperative follow-up. Imaging studies help delineate recurrent or metastatic lesions. Treatment of recurrent or metastatic disease is primarily surgical, including either palliative or microdissective surgery. Radiation therapy is reserved for skeletal metastasis or nonresectable metastatic MTC. Efficacy of current chemotherapy programs is not well established. Overall, the 10-year survival rates are approximately 65%.

Prolonged remission of metastatic follicular thyroid carcinoma.

Follicular thyroid carcinoma is associated with an extremely poor prognosis when metastatic lesions occur. Although radioiodine therapy for metastatic disease can extend patient survival for several years, its effect is usually only palliative. Herein we describe a 47-year-old man with metastatic follicular thyroid carcinoma who was in clinical remission for 30 years after surgical and radioiodine treatment of the original disease. To our knowledge, this is the longest reported remission of this disease. Possible reasons for the prolonged survival were "young" age at diagnosis, diploid DNA content of the tumor, skeletal lesions responsive to 131I therapy, and limited pulmonary disease.

Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970.

We retrospectively reviewed the medical records of 65 consecutive patients with medullary thyroid carcinoma, who had had their primary surgical treatment at the Mayo Clinic during the years 1946 through 1970. Of these patients, 58 had sporadic and 7 had familial medullary thyroid carcinoma. Thyroid nodules were the most common initial manifestation. Near-total thyroidectomy was the most frequent initial operation. Survival was affected by the following factors: male sex, familial inheritance, size of the tumor, stage of the tumor (American Joint Committee on Cancer), and completeness of initial resection of the tumor. The mean duration of follow-up was 23.5 years, and the maximal follow-up was 36 years. Among 52 patients without initial distant metastatic involvement and with complete resection of the tumor, 20-year survival free of distant metastatic lesions was 81%. Overall 10- and 20-year survival rates were 63% and 44%, respectively. Because of the substantial morbidity and mortality associated with medullary thyroid carcinoma, early diagnosis and thorough initial resection of the tumor are important.

Multiple endocrine neoplasia type 2B: eighteen-year follow-up of a four-generation family.

Seven members with multiple endocrine neoplasia type 2B from a 15-member family have been followed for 18 years. All affected had the neuroma phenotype in a distribution compatible with autosomal dominant inheritance. The phenotype features have allowed 100% initial and continuing prediction of affected versus nonaffected status in as early as 1.5 years. Among the affected: immunoreactive plasma calcitonin (iCT) concentration was high in 100%; thyroid palpation was false-negative in 71%; and thyroid scintiscan was false-negative in 83%. All had total thyroidectomy, plus lymphadenectomy in three, for bilateral medullary thyroid carcinoma (MTC) or C-cell hyperplasia (in the youngest). None has died directly from MTC. The index case died at age 68 and his son at age 32 years from complications of the syndrome. All but the youngest have continuing high iCT concentrations. No patient has had parathyroid disease. During preoperative calcium infusion, immunoreactive serum parathyroid hormone concentration declined by 35% to 84% of basal. At operation, macroscopically and microscopically normal parathyroid glands were found in all. No patient has had chemical suggestion of pheochromocytomas: at postmortem the index case had no adrenal medullary disease; his son had bilateral nodular adrenal hyperplasia; his daughter has had adrenal medullary hyperplasia and a renin-secreting juxtaglomerular tumor. Initially nonaffected members remain so.

Long-term follow-up of a kindred with multiple endocrine neoplasia type IIA.

A kindred with multiple endocrine neoplasia type IIA was studied. In four of five fully documented cases, patients presented with adrenal medullary disease during the second or third decade; in three cases, medullary thyroid carcinoma was not diagnosed until the fourth decade. This kindred seems to have an aggressive variant of adrenal medullary disease in which clinical presentation is early, metastasis occurs, and oncological cure is uncommon. Early detection and operation were important, and symptoms were controlled with operations and alpha- and beta-adrenergic blockade in uncured members.

Medullary carcinoma in children. Results of early detection and surgery.

Early diagnosis and surgical treatment of medullary carcinoma of the thyroid (MCT) in children is essential to decrease the likelihood of metastatic spread. To determine the optimal timing of screening and surgery, we reviewed all children younger than 16 years old who were undergoing surgical treatment. From 1970 to 1988, 33 children 6 months old to 15.9 years old (mean, 9 years old) with MCT or C-cell hyperplasia or both underwent total thyroidectomy. Follow-up was 4 months to 15 years after surgery (mean, 9 years). Six of 31 patients presented with a neck mass. Basal immunoreactive calcitonin level was increased in 3 of 7 patients with C-cell hyperplasia alone, in 10 of 18 patients with nonmetastatic MCT, and in all 5 patients with metastatic MCT. At the time of surgery, 7 patients had C-cell hyperplasia, 19 patients had MCT without metastasis, and 7 patients had MCT with metastases. All children with metastasis were more than 12 years old. Medullary carcinoma of the thyroid was seen as early as age 6 months in a child with multiple endocrine neoplasia type IIb (MEN-IIb) and age 3 years in a child with MEN-IIa. At follow-up, 25 patients were free of disease and 8 had had recurrent disease. Two of the 8 patients with MEN-IIb had died. All 6 children with a neck mass at presentation had recurrent disease. Of 27 patients diagnosed by screening, 25 had no evident disease and 2 had persistent disease. Thus, in children with MEN-II syndromes, screening studies are highly effective in detecting MCT. All children with MEN-IIb should be studied shortly after birth, and those with MEN-IIa should be studied by 1 year old.

Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2.

Children with multiple endocrine neoplasia type 2 (MEN2) often develop medullary carcinoma of the thyroid (MCT) or its precursor, C-cell hyperplasia. Survival results are improved if malignancy is diagnosed early from the results of plasma immunoreactive calcitonin (iCT) measurement. The effect of early detection and thyroidectomy in children with MEN2 syndrome was determined by reviewing the experience between 1975 and 1985. Seventeen children with MEN2 who were 12 years old or younger underwent a total thyroidectomy for MCT or C-cell hyperplasia. iCT was measured in all patients preoperatively and postoperatively. Of the 17 children, 14 (82%) had MEN2a and 3 (18%) had MEN2b. There were 14 (82%) female and three (18%) male patients; their mean age was 6.97 years (range 1.5 to 12 years). In all patients, the diagnosis of MCT was made from initial elevated levels of iCT after stimulation with pentagastrin. Three patients had clinical evidence of disease preoperatively. All patients underwent a total thyroidectomy and lymph nodes were removed from the central zone; a neck dissection was performed in the three with clinically obvious disease. MCT with C-cell hyperplasia was found in 11 children and C-cell hyperplasia alone in six. Of the 11 with carcinoma, eight had bilateral disease and three unilateral. Six children had bilateral C-cell hyperplasia. All 17 children were alive and feeling well at the time of this report; however, three had evidence of metastatic disease according to iCT measurements. None of the children had recurrent nerve injuries; one had evidence of hypoparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral subtotal adrenal resection for bilateral pheochromocytomas in multiple endocrine neoplasia, type IIa: a case report.

Our treatment philosophy for the management of the adrenal glands in patients with multiple endocrine neoplasia, type IIa has been bilateral total adrenalectomy. In the patient described, exceptional and pressing reasons necessitated preservation of adrenocortical function. Bilateral pheochromocytomas were resected with preservation of the adrenal cortices. Adrenocortical function was normal 36 months after resection. Although the patient remained symptom free, elevated basal immunoreactive plasma calcitonin levels suggested the presence of residual or metastatic medullary thyroid carcinoma. There was no evidence of recurrent pheochromocytoma.

Medullary carcinoma of thyroid. Biologic behavior of the sporadic and familial neoplasm.

Three groups of patients with medullary thyroid carcinoma treated for cure from an institution under standardized tumor stage were compared. For sporadic cases and all cases across groups, the observed survival rates at 10 years were significantly lower than expected based on persons from the West North Central region of the US of like age and sex born in the same calendar year. They were not different for patients with multiple endocrine neoplasia (MEN), type 2a and 2b. Mean ages were significantly different among the three groups: they were 48.5 years for sporadic, 37.7 for MEN 2a, and 23.4 for MEN 2b. Tumor-free survival rate after surgical treatment of MEN 2b was 36.6% at 5 years and 27.3% at 10 years, and was significantly lower in comparison with that of sporadic cases. Medullary carcinoma in patients with MEN 2b appeared to develop at an earlier mean age, with a higher frequency of nodal metastasis and a higher rate of tumor recurrence.

Use of 131I-MIBG scintigraphy in the evaluation of suspected pheochromocytoma.

Studies at the University of Michigan have shown that 131I-metaiodobenzylguanidine (131I-MIBG) is an effective agent for the diagnosis and localization of pheochromocytomas and paragangliomas. We conducted a study that confirmed and expanded that finding. From January 1983 to March 1984, 48 patients at our institution had 51 131I-MIBG scans during the workup of suspected sporadic or metastatic pheochromocytoma. Scintigrams were obtained after 500 microCI of 131I-MIBG had been administered intravenously. The final diagnosis (true-positive, false-negative, or false-positive result) was made at operation and pathologic examination. A true-negative diagnosis was confirmed by normal plasma and fractionated urinary levels of catecholamines and metabolites and, in most patients, computed tomography (CT). There were 20 true-positive studies (6 pheochromocytomas, 4 paragangliomas, and 10 metastatic or recurrent pheochromocytomas) and 24 true-negative studies. One patient with a suspected recurrent paraganglioma near the bladder had a false-positive 131I-MIBG scan (and also a false-positive (CT). Among six patients with false-negative scintigrams (three pheochromocytomas, one paraganglioma, and two metastatic lesions), one also had a false-negative CT. The overall sensitivity of 131I-MIBG scanning was 77%, specificity was 96%, and accuracy was 86%. This test is fairly sensitive in the workup of patients with known or suspected recurrent or metastatic pheochromocytoma. It may also be helpful in the evaluation of suspected sporadic pheochromocytoma when CT findings are normal.

Pentagastrin promotes prolactin release in patients with medullary carcinoma of the thyroid.

Both calcitonin and gastrin have been found in the mammalian central nervous system, including the pituitary. Following a pentagastrin infusion in several patients with medullary carcinoma of the thyroid, we noted a coincident increase in plasma calcitonin and prolactin (PRL) levels. In order to evaluate further the influence of pentagastrin on human PRL release, a pentagastrin infusion was administered to 13 patients with active medullary carcinoma of the thyroid (MTC), eight subjects with inactive MTC, eight family members without MTC, and ten normal subjects. Plasma mean +/- SE PRL levels were significantly (P less than 0.01) increased in the active MTC patients from 7.6 +/- 0.5 to 12 +/- 1.4 ng/mL by 15 minutes post pentagastrin. Plasma mean +/- SE calcitonin levels increased in parallel with the plasma PRL levels from 0.28 +/- 0.1 to a peak of 1.9 +/- 0.9 ng/mL at 5 minutes post pentagastrin. A significant (P less than 0.05) correlation was found between the percentage increase in plasma calcitonin concentrations and plasma PRL levels at five and ten minutes post pentagastrin stimulation in this group of active MTC patients. Significant increases in serum calcitonin levels in the other groups post pentagastrin were of lesser magnitude and were not associated with a significant increase in PRL release. This latter observation suggested that neither the stress of the infusion nor the multiple endocrine neoplasia type 2 nor the pentagastrin was responsible for the observed increase in plasma PRL levels in the active MTC patients. These findings suggest, but do not prove, that calcitonin is a PRL-releasing factor in humans.

Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Surgical experience.

Forty-five patients with biochemically documented primary hyperparathyroidism as part of multiple endocrine neoplasia syndrome types 1 or 2 were surgically treated from 1960 through 1980. Hyperplasia occurred in 69% of the patients, single adenoma in 27%, and double adenomas in 4%. All but two patients with hyperplasia underwent subtotal parathyroidectomy. In this group, the cure rate was 93% and the incidence of permanent postoperative hypoparathyroidism 23%. In the adenoma group, treatment included excision of the adenoma and biopsy of at least one other gland. The cure rate was 76%, with no postoperative hypoparathyroidism. Analysis of patients with persistent hyperparathyroidism suggested that failure to recognize multiple gland disease was the principal cause of postoperative hypercalcemia. In view of the high incidence of hypocalcemia after subtotal parathyroidectomy, approximately 500 mg of tissue should be cryopreserved to allow transplantation should hypocalcemia ensue postoperatively.

The surgical management of medullary thyroid carcinoma.

Medullary carcinoma of the thyroid may occur in three patient groups: multiple endocrine neoplasia, type 2b (MEN2b), MEN2a, and sporadic. The prognosis is best in MEN2a and worst in MEN2b. Multicentric disease occurs in approximately 90% of patients in the MEN groups and in 20% of the patients in the sporadic group. The minimal surgical procedure advocated is total thyroidectomy with dissection of the central compartment nodes. When neck dissection is performed, there appears to be no advantage in resecting the internal jugular vein or the sternomastoid muscle. Primary relatives of all patients with medullary carcinoma should be screened by measurement of plasma immunoreactive calcitonin to identify C-cell disease in a generally unsuspecting group/reservoir and because it results in earlier diagnosis, which leads to a less extensive surgical procedure and a higher percentage of patients with a disease-free state.

Hypercalcemia and primary hepatic tumors.

We treated a case of hypercalcemia and primary liver tumor and reviewed a series of such cases treated at the Mayo Clinic (Rochester, Minn). Primary tumor of the liver was diagnosed in 192 patients (152 had hepatocellular carcinomas; 40, cholangiocarcinomas) between 1969 and 1980. Hypercalcemia of unknown cause was found in eight patients with hepatocellular carcinoma (5.3%) and seven with cholangiocarcinoma (17.5%). Five hypercalcemic patients had serum immunoreactive parathyroid hormone values consistent with ectopic hyperparathyroidism. An additional five patients had high serum calcium, low phosphate, and low chloride concentrations that met Lafferty's criteria for pseudohyperparathyroidism. Our results suggest that hypercalcemia associated with primary hepatic tumors is relatively common, and incidences vary according to the type of primary tumor. Hypercalcemia may be controlled when surgical excision of the primary tumor is possible.