Familial occurrence of parathyroid adenomas, pheochromocytoma, and medullary carcinoma of the thyroid with amyloid stroma (Sipple's syndrome).
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A 55-year-old man with multiple brown tumors who initially was thought to have multiple bone metastases is described. He had elevated parathyroid hormone levels and was referred to the nuclear medicine department, where a parathyroid adenoma was diagnosed. At surgery, abnormal lymph nodes were seen, which were found to contain metastatic thyroid papillary carcinoma cells. On further exploration, the patient's bone scintigraph revealed multiple sites of increased uptake but no bone abnormalities on whole-body iodine and Tc-99m MIBI scans.
A patient with primary small cell carcinoma of the esophagus is reported, in whom we have studied the secretion of a variety of hormones and cytokines. The tumor was an intermediate cell type of small cell carcinoma and had either epithelial and neuroendocrinological characteristics. Furthermore, hypercalcemia and neutrophilia were present, and the tumor was shown to produce PTHrp, secretin, and G-CSF. The present case is the first report of primary small cell carcinoma of the esophagus with ectopic production of PTHrp, secretin, and G-CSF.
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The nuclear DNA content of 85 parathyroid glands (4 carcinomas, 39 adenomas, 21 secondary parathyroid hyperplasias, and 21 normal parathyroid glands) were determined by flow cytometric analysis. All normal parathyroid glands, 85% of the adenomas, and 83.3% of the secondary hyperplastic glands had DNA indices within values of 0.85-1.1. Paraffin-embedded fixed glands showed less DNA staining than that found with fresh or normal glands. Glands from patients with carcinoma showed DNA indices outside the normal DNA index range. When the percent of nuclei within the G0/G1 phase of the cell cycle was compared between the study groups, highly significant results were found. While patients with secondary hyperplasia showed a similar distribution to the normal glands studied, only 48% of primary adenomas showed over 80% of cells within the G0/G1 region. A clear subgroup of adenomas was defined with more rapidly cycling tetraploid cells, and showing classical adenoma pathology. This group showed negative correlation with gland weight, plasma calcium, and ionized calcium. These findings suggested that a different etiology of the disease process occurs between secondary hyperplasia and parathyroid adenoma. Such abnormal adenomas may form a group worthy of long-term follow-up.
The Multiple Endocrine Neoplasia syndromes are familial disorders in which neoplastic changes develop in multiple endocrine tissues. Almost all of these diseases are inherited as autosomal dominant traits with complete penetrance but variable expressivity. Classification of the Multiple Endocrine Neoplasias is based on the pattern of endocrine organ involvement. Multiple Endocrine Neoplasia Type I (MEN-I) is characterized by the concurrence of pituitary adenomas, parathyroid hyperplasia and pancreatic islet cell neoplasms. Multiple Endocrine Neoplasia Type II (MEN-II or IIa) consists of medullary thyroid carcinoma (MTC), parathyroid hyperplasia and pheochromocytomas. Multiple Endocrine Neoplasia Type IIb (MEN-IIb) is similar to MEN-IIa in that affected patients have MTC and pheochromocytomas. Multiple mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract are also present in patients with MEN-IIb, but these individuals rarely manifest hyperparathyroidism. The Multiple Endocrine Neoplasia syndromes have attracted a great deal of attention because of their characteristic clinical features and familial pattern of occurrence. By utilizing recently developed "provocative tests" it is possible through aggressive screening of kindred members at risk to detect certain of these diseases (particularly MTC and pancreatic islet cell neoplasia) at an early stage. Therapeutic intervention in selected patients is associated with a high cure rate.
A 69-year-old female having a large left adrenal mass and a nodular lesion in thyroid gland was admitted to the hospital. Endocrinologically she showed high levels of plasma ACTH and cortisol, which were not suppressed by high dose dexamethasone, elevated serum parathyroid hormone and markedly increased daily urinary excretion of catecholamines. She died of sepsis, and postmortem examination was performed. A left adrenal pheochromocytoma, which was immunohistochemically proven to be ACTH producing, a papillary thyroid carcinoma and parathyroid adenomas were found. To our knowledge this is the first report of coexistence of these three endocrine tumors in a single patient.
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Hypercalcemia associated with metastatic cancer may be due to osteolytic invasion or paraendocrine effects of the neoplasm. A patient with refractory hypercalcemia of long duration underwent cervical parathyroid exploration; three glands were found, but hypercalcemia persisted. After localization studies, a fourth gland was uncovered from the mediastinum. Hypercalcemia persisted, and at operation for kidney stones, squamous cell carcinoma of the renal pelvis was discovered, which progressed to cause the patient's death in hypercalcemia.
BACKGROUND: Humoral hypercalcemia of malignancy is a paraneoplastic syndrome associated with a variety of solid neoplasms including squamous cell carcinomas of various sites. Parathyroid hormone-related protein (PTHrP) is a newly recognized hormone that has been implicated as one of the major causative factors in the pathogenesis of this syndrome. A canine oral squamous carcinoma cell line (SCC 2/88) was used to investigate the regulation of production of PTHrP in response to agents that alter keratinocyte differentiation/proliferation in vitro. EXPERIMENTAL DESIGN: SCC 2/88 cells grown in serum-free media were exposed to various factors and PTHrP production was measured by radioimmunoassay. This cell line spontaneously produced substantial amounts of PTHrP (up to 7,000 pg/ml) without the need for a fibroblast-feeder layer. Production of PTHrP decreased at cellular confluence, and with increasing passage number. RESULTS: Epidermal growth factor, cholera toxin, calcium, 1,25-dihydroxyvitamin D, ionomycin, trans-retinoic acid, transforming growth factor-beta 1 and hydrocortisone stimulated production of PTHrP by SCC 2/88 cells to various degrees. Transforming growth factor-beta 1 was the most potent stimulator of PTHrP production, with a maximal stimulation of 25-fold over control. Monensin decreased PTHrP secretion as early as 6 hours post-treatment and by 48 hours, there was no detectable PTHrP in the conditioned cell culture medium. Calcium, cholera toxin, ionomycin, and transforming growth factor-beta 1 decreased keratinocyte proliferation as measured by cell counts at all doses tested. CONCLUSIONS: The results of this study revealed that SCC 2/88 cells spontaneously produced substantial amounts of PTHrP under baseline conditions and that compounds known to affect keratinocyte differentiation/proliferation up-regulated production of PTHrP. These cells will be valuable to investigate the molecular regulation of PTHrP production by squamous cell carcinomas.
A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/l), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64,787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.
A patient with recurrent squamous carcinoma of the neck showed hypercalcemia with the immunoreactive parathyroid hormone (PTH) level within the upper limits of normal range, this being inappropriate for the degree of hypercalcemia. An immunoreactive peak of PTH was found in the tumor tissue extract, which appeared on column chromatography to be in the region of elution of pure bovine PTH. The tumor tissue showed positive immunoperoxidase reaction for PTH compared with negative reaction when the patient had normocalcemia. These findings are strong evidence that the tumor produced a PTHlike substance.
AIM: To assess parathyroid hormone related protein (PTHrP) as a candidate biochemical marker of invasion of the mandible by oral squamous cell carcinoma. METHODS: Tumour PTHrP concentrations were quantitated by immunoassay, and PTHrP was detected by immunohistochemistry, in a cohort of 24 primary squamous cell carcinomas of the mandible. RESULTS: PTHrP was identified in all tumours examined, but no correlation was found between scores of the intensity and/or consistency of staining or tumour PTHrP concentrations and the histological classification of tumour invasion. CONCLUSION: Although PTHrP was present in all squamous tumours studied, there was no correlation between PTHrP expression and pattern of tumour invasion. However, tumour derived PTHrP may act locally to influence tumour growth and differentiation and resorption of bone.
BACKGROUND: For papillary thyroid carcinoma, we have used our standard operative method consisting of total thyroidectomy, bilateral lymph node dissection, and parathyroid autotransplantation. Our special parathyroid transplantation method involves transplantation of the minced glands into the pectoralis major muscle. We investigated whether this method is useful for preserving parathyroid function. METHODS: In 17 patients who underwent our standard operation for papillary thyroid carcinoma, the intact parathyroid hormone (PTH) and serum calcium levels were determined for 4 weeks after the operation. RESULTS: In all cases the intact PTH levels fell below detectable limits immediately after operation and then recovered to the preoperative level about 2 weeks after the operation. The same recovery patterns were observed in two groups undergoing transplantation of two glands and three or four glands. CONCLUSIONS: These recovery patterns of intact PTH levels seem to indicate that the glands were grafted successfully and recovered their function. Our method is thought to be useful for preserving parathyroid function after surgery.
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During a 20 year period, 27 patients have undergone reoperations for primary hyperparathyroidism. Hypercalcemia has been successfully controlled in 21 of the 27 patients after a total of 64 operations. Reasons for failure at initial exploration included surgical error in 12, multiple gland disease in five, unusual parathyroid gland location in five, carcinoma of the parathyroid gland in two and unknown in three. A variety of techniques were used to localize missing parathyroid glands prior to reoperation. Selective venous sampling was the most helpful but gave correct localizing information in only nine of 18 patients. Postoperatively, hypoparathyroidism was temporary in two patients and permanent in four. Recurrent laryngeal nerve injury was temporary in one patient, permanent and unilateral in two and bilateral in one patient. Reoperations for hyperparathyroidism are associated with increased morbidity and decreased success. Most importantly, failure at the initial operation is preventable in most patients.
Humoral hypercalcemia caused by parathyroid hormone-related peptide (PTHrP), associated with cholangiocellular carcinoma (CCC), has rarely been documented. There have been no reports of CCC associated with extensive calcification of the tumor with psammoma body formation. A 66-year-old man was admitted with a large calcified tumor in the liver detected on an abdominal X-ray. An ultrasound-guided fine needle biopsy specimen of the liver tumor showed evidence of adenocarcinoma. He had hypercalcemia with an elevated PTHrP level. The patient died because of disseminated intravascular coagulation and progressive hepatic failure. A postmortem examination revealed a large poorly differentiated CCC in the liver. Immunohistochemical examination showed the presence of PTHrP-positive tumor cells. The calcified lesion consisted of a number of accumulated psammoma bodies. We present a case of PTHrP producing CCC with a marked psammoma formation.
A 26-year-old male presented with the symptoms and signs of acute congestive heart failure and hypertension. The left ventricle was shown to be thickened and displayed reversible hypokinesia. Further investigations revealed the underlying pathology of a phaeochromocytoma, bilateral medullary thyroid carcinoma (MTC), parathyroid adenoma and macro-prolactinoma. There was a family history of MTC. The echocardiographic features of catecholamine-induced cardiomyopathy were important in this diagnosis. Our research revealed no previous report of Sipple's syndrome associated with a macroprolactinoma. This case, along with the other 13 reports of mixed (type I and II) multiple endocrine neoplasia (MEN), are not within the classical subsets of MEN.