Malignant hypercalcemia induced by a parathyroid hormone-related protein secreted by a cutaneous squamous cell carcinoma.
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The cyclin D1 gene, located on chromosome 11q13, is frequently rearranged in parathyroid neoplasms and amplified in some carcinomas of other organs. Recent studies have detected amplification of cyclin D1 and other markers on chromosome 11q13 (evaluated by Southern or slot blot assays) in approximately 25-50% of squamous cell carcinomas of the esophagus and noted that amplification was associated with lessened survival time. We applied the technique of differential polymerase chain reaction to the evaluation of cyclin D1 gene amplification in squamous cell carcinomas of the esophagus. Cyclin D1 was found to be amplified in 10 of 45 (22%) primary tumors and three of 12 (25%) lymph node metastases. Lymph node metastases tended to be more common in patients with cyclin D1 amplification (70%) than in those without amplification (37%). In 36 patients with follow-up, cyclin D1 amplification was associated with decreased 1 year survival (28% vs. 59%). Cyclin D1 gene amplification in esophageal carcinomas can be evaluated by differential polymerase chain reaction and may provide useful prognostic information.
Records of patients undergoing parathyroidectomy at our institute in the period 1991-2003 were retrospectively analyzed. Pancreatitis was associated in six of 87 patients (6.8%) with primary hyperparathyroidism (PHPT). Pancreatitis was the presenting symptom in five patients, while it developed postoperatively in one case. All patients with a past history of pancreatitis had suffered two or more attacks. All patients had a history of renal stone disease. Four patients also had overt bone disease with multiple fractures. Parathyroid adenoma (4) or carcinoma (1) was the cause in all patients. All five patients who underwent successful parathyroidectomy had resolution of pancreatitis on conservative management and no further attacks during a mean follow up of 28 months (3-84 months). Surgical exploration for parathyroid adenoma failed in one patient; this patient has had further attacks of pancreatitis. Repeat surgical exploration for parathyroidectomy has been advised. Hyperparathyroidism is a rare but treatable cause of pancreatitis. Parathyroidectomy has a salutary effect on the course of pancreatitis.
It is known that malignant tumors occasionally produce hormone-like substances. However, they rarely produce two or more kinds of hormonal factors simultaneously. We describe the clinical, biochemical, and immunohistochemical findings in a patient with squamous cell carcinoma of the larynx associated with leukocytosis and hypercalcemia, without bone metastasis. The serum granulocyte colony-stimulating factor (G-CSF) level was 222 pg/ml (normal, < 38 pg/ml), and decreased to 15 pg/ml after surgery. The serum parathyroid hormone-related protein (PTHrP) level was 5.6 pmol/l (normal, < 0.5 pmol/l), and this also decreased, to less than 0.5 pmol/l. G-CSF and PTHrP increased again with tumor recurrence. The production of G-CSF from the tumor was confirmed by immunohistochemical staining with monoclonal antibody against human recombinant G-CSF. The tumor was revealed to produce both G-CSF and PTHrP. In this article, we describe this very rare case of primary squamous cell carcinoma of the head and neck with the simultaneous ectopic production of more than one hormone-like substance.
We report a case of symptomatic hypercalcemia in a patient with muscle-invasive, resectable squamous cell carcinoma of the bladder. Serum parathyroid hormone was consistent with secretion of parathyroid hormone-related protein. After radical cystoprostatectomy, calcium levels returned to normal. Patients with squamous cell carcinoma and an abnormal serum calcium level may have localized disease and should not be denied definitive local therapy.
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BACKGROUND: The vascular system of the tumor bed plays an important function in tumor growth regulation. Recent studies have suggested that the vasoactive peptides somatostatin and substance P may have a potential role in the tumor bed of selected tumors. METHODS: In the current study, somatostatin receptors were evaluated with in vitro receptor autoradiography using 125I-[Tyr3]-octreotide in the peritumoral vessels of a large group of 215 primary human tumors and 25 metastases of various tumor origin, with particular emphasis on receptor incidence, distribution, homogeneity, and density. RESULTS: High affinity somatostatin receptors were found in the peritumoral veins of 22 of 22 gastric carcinomas, 25 of 39 breast carcinomas, 15 of 20 renal cell carcinomas, 14 of 27 prostate carcinomas, 4 of 10 endometrial carcinomas, 4 of 11 pancreatic adenocarcinomas, 4 of 13 nonsmall cell lung carcinomas, as well as in 3 of 4 parathyroid adenomas, 3 of 3 medullary thyroid carcinomas, 3 of 23 gastroenteropancreatic tumors, 14 of 25 soft tissue tumors, 3 of 5 melanomas but in none (0 of 13) of the ovarian carcinomas studied. In addition, somatostatin receptors were identified in veins surrounding lymph node, bone, and lung metastases of various tumor types. In all investigated tissues, receptors could not be identified in arteries. There was a considerable variability in the relative number of veins expressing somatostatin receptors and in the receptor density levels. Evidence of an overexpression of somatostatin receptors could be established in the peritumoral veins of gastric carcinoma when compared with the receptor expression in normal gastric vessels. CONCLUSIONS: The expression of somatostatin receptors in peritumoral veins appears to be a general, tumor-related, but highly variable phenomenon. Although their pathophysiologic role is unclear, these receptors may be considered as novel targets for cancer diagnosis and therapy with somatostatin analogs.
A total of 15 patients with parathyroid tumours were scanned preoperatively using high-resolution real-time sonography (7 MHz). Of these, 14 had a single adenoma or primary hyperplasia, one had a carcinoma. In 13 out of 15 patients the echogenicity of the parathyroid tumours was consistently less than of the adjacent normal thyroid tissue; in 2 out of 15 cases parathyroid neoplasms were barely distinguishable in echogenicity from thyroid tissue. No specific echomorphologic differences were proved to exist between primary parathyroid hyperplasia, adenoma or carcinoma. The smallest parathyroid neoplasia in this study detected by sonography measured 5 x 8 mm in diameter. The value and limits of parathyroid sonography were discussed with regard to our own experience and the reports in the literature.
Eleven patients who had clinical and biochemical evidence of primary hyperparathyroidism were studied using dual isotope technetium-thallium parathyroid subtraction imaging. The parathyroid scans correctly identified all surgically proven parathyroid adenomas. Three abnormal foci also were identified that were not parathyroid adenomas. These were caused by adenocarcinoma metastatic to a lymph node, primary papillary carcinoma of the thyroid, and parathyroid hyperplasia. This report also demonstrates the importance of surgically examining all abnormal sites of uptake.
Hypercalcemia is a common and serious complication associated with squamous cell carcinoma (SCC) and is considered to be caused by a tumor-derived factor, parathyroid hormone-related protein (PTHrP). However, the correlation between serum levels of calcium and PTHrP and the kinetics of PTHrP in SCC of the head and neck is unknown, because the behavior of the circulating form of PTHrP in patients has not been determined. In the present study, the PTHrP concentrations in serum samples from 54 patients (37 with SCC and 17 with benign tumors) were measured by a recently developed radioimmunoassay directed toward the C-terminal region of PTHrP, and the laboratory data including those calcium levels in corresponding samples were reviewed retrospectively. Results showed hypercalcemia in four patients with advanced cancer and in whom elevation of the serum PTHrP concentration was observed simultaneously. The regression analysis also revealed the linear relationship of the calcium level to the PTHrP concentration, but not to the concentration of phosphorus or creatinine, suggesting that monitoring of serum PTHrP level is useful for prediction of hypercalcemia associated with head and neck cancer.
High-resolution thyroid and parathyroid ultrasonography can play an integral part in the diagnosis and management of patients with clinically undifferentiated cervical masses, thyroid carcinomas or adenomas, and primary parathyroid hyperplasia or neoplasia. Because the study is inexpensive, noninvasive, and easily performed, ultrasonography can be performed as a screening test early in the evaluation of a patient, and ultrasound findings can corroborate the results of other diagnostic procedures, leading to a more accurate diagnosis.
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Chromogranin A, the protein that is co-stored and co-released with catecholamines from the adrenal medulla, has recently been identified in a variety of human endocrine tissues, both normal and neoplastic. We investigated the secretion of chromogranin A by peptide hormone-producing human tumors in studies of patients with the following neoplastic disorders: pheochromocytoma, parathyroid adenoma, primary parathyroid hyperplasia, medullary thyroid carcinoma, thyroidal C-cell hyperplasia, carcinoid tumor, oat-cell lung carcinoma, pancreatic islet-cell tumor, and aortic-body tumor. All these patient groups had elevated concentrations of plasma chromogranin A. We distinguished different forms of immunoreactive plasma chromogranin A by size with the use of gel filtration. Plasma chromogranin A levels were not elevated in patients with diverse "control" conditions--both benign and malignant and both endocrine and nonendocrine--in which peptide hormones are not produced. The sensitivity and specificity of plasma chromogranin A elevations in the diagnosis of peptide-producing endocrine neoplasms were 81 and 100 percent, respectively. The elevation of plasma chromogranin A in our subjects suggests that their neoplasms co-release chromogranin A along with the usual resident hormone of the tumor, that these neoplasms could be characterized as "chromograninomas," and that measurement of plasma chromogranin A may be a useful diagnostic procedure in subjects with endocrine tumors, especially multiple endocrine neoplasia.
PURPOSE: We provide the necessary tools to study the biology of bone metastasis using renal cell carcinoma as a model. A relevant renal cell carcinoma cell line developed from a human bone metastasis is described and an experimental model in the nude mouse was established. MATERIALS AND METHODS: The novel cell line RBM1 was developed from bone metastasis from a patient with renal cell carcinoma. In vitro methods used to study the cell line included karyotype analysis, reverse-transcriptase polymerase chain reaction, ribonuclease protection assay and Western blot analysis. An intratibial injection model in the nude mouse resulted in bone lesions similar to those in human patients. RESULTS: Chromosomal analysis of this cell line revealed characteristic cytogenetic abnormalities common in renal cell carcinoma. RBM1 cells expressed parathyroid hormone parathyroid hormone related peptide, interleukin-6 and macrophage colony-stimulating factor, which are cytokines involved in osteoclast activation and subsequent bone resorption. Western blot analysis revealed the presence of high levels of epidermal growth factor receptor and c-MET. Reproducible osteolytic lesions developed in the nude mouse after injecting 1 x 106 cells into the tibia. CONCLUSIONS: This cell line and animal model may allow further study of the biology and mechanism of renal cell carcinoma bone metastasis.
A retrospective review of 1550 cases of hyperparathyroidism (HPT) treated surgically over a 30-year period reveals a past history of exposure to neck irradiation in 10 cases (0.7 per cent). The indication for radiotherapy was benign disease in nine and papillary thyroid carcinoma in one case. The mean interval between radiation exposure and the detection of HPT was 32 years (range 3-63 years). Patients treated with radioactive iodine alone developed HPT after a mean of 5 years while the interval for those treated with external beam therapy alone was a mean of 44 years. The parathyroid histology was adenoma in six cases, carcinoma in three cases and nodular hyperplasia in one case. All patients had coincident benign thyroid disease apart from one that had previously had papillary carcinoma and another with follicular carcinoma. Neck irradiation has been shown to confer an increased risk of HPT due to parathyroid adenoma and carcinoma. Radiotherapy for benign disease has generally been abandoned and these cases demonstrate a further contra-indication for the use of neck irradiation.
Altogether 107 patients were operated on at the Department of Transplantation and Surgery of Semmelweis University in the past four years, for clinical symptoms of hyperparathyroidism. Clinical and laboratory data of the patients supported the diagnosis of primary or secondary hyperparathyroidism. Chronically impaired renal function was found in 52 cases. The removed parathyroid glands showed hyperplasia in 54, adenoma in 50 and carcinoma in 3 cases. The majority of parathyroid lesions in primary hyperparathyroidism were adenomas (41 cases) and in secondary hyperparathyroidism were hyperplasias (43 cases). The ratio of oxyphil to chief cells as well as occasional mitotic and apoptotic figures were determined. The oxyphil component was present in both hyperplastic and tumorous lesions. Apoptosis and mitosis were rarely seen in hyperplasias and adenomas (under 2%), whereas in carcinomas 3% of the tumor cells were apoptotic and 4% showed mitosis. Cytoplasmic p53 positivity could be observed in 3 of the adenomas and in 2 of the hyperplasias. The carcinomas, four adenomas and 3 hyperplasias showed nuclear p53 positivity. Bcl-2 and Bax were detected in the cytoplasm of the tumor cells in the majority of adenomas and in the cells of hyperplasias. Oxyphil cells were more frequently positive than chief cells or clear cells. Colocalization of Bcl-2 and Bax was found randomly in all types of lesions. The very low incidence of carcinoma, the low mitotic and apoptotic ratio in adenomas and hyperplasias suggest a potent antiproliferative defense mechanism in the parathyroid cell population. This may also be reflected in the cytoplasmic colocalization of various gene products which regulate cell death and cell proliferation. No significant differences in the p53, Bcl-2 and Bax spectrum were found between the primary and secondary (i.e. renal failure) parathyroid alterations.
The term 'Multiple Endocrine Neoplasia' (MEN) denotes a genetically determined syndrome characterized by the independent appearance of benign or malignant changes of several endocrine organs as well as occasional changes of neural, muscular and connective tissue. Three different forms have been identified: MEN 1 (Werner's syndrome) includes parathyroid hyperplasia in combination with pancreatic islet cell and pituitary tumours; MEN 2a (Sipple's syndrome) includes medullary thyroid carcinoma in association with phaeochromocytoma and parathyroid hyperplasia; MEN 2b includes medullary thyroid carcinoma, phaeochromocytoma and mucosal neuromas. MEN syndrome is transmitted as an autosomal dominant trait with a high degree of penetrance. The changes in the individual glands appear to be causally and temporally independent of each other. A spectrum of pathological changes exist in the affected glands which range from hyperplasia to adenoma to carcinoma. The pathological process is almost always multicentric, often resulting in bilateral disease of organs. The appearance of an endocrine tumour known to be associated with MEN should alert the physician to the possibility of a MEN syndrome. When the possibility of such a syndrome exists, screening and long-term observation should be initiated to diagnose a carcinoma in its earliest stage, or before the development of clinical manifestations of hormone excess.