Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone related protein (PTHrP) is a well characterized tumor derived product that also has integral functions in normal development and homeostasis. PTHrP is produced by virtually all tumor types that metastasize to bone and numerous studies have demonstrated a correlation between PTHrP expression and skeletal localization of tumors. PTHrP has prominent effects in bone via its interaction with the PTH-1 receptor on osteoblastic cells. Through indirect means, PTHrP supports osteoclastogenesis by upregulating the receptor activator of NFkappaB ligand (RANKL) in osteoblasts. PTHrP also regulates osteoblast proliferation and differentiation in manners that are temporal and dose dependent. Bone turnover has been implicated in the localization of tumors to bone and PTHrP increases bone turnover. Bone turnover results in the release of growth factors such as TGFbeta and minerals such as calcium, both of which impact tumor cell growth and contribute to continued PTHrP production. PTHrP also has anabolic properties and could be in part responsible for osteoblastic type reactions in prostate cancer. Finally, emerging roles of PTH and PTHrP in the support of hematopoietic stem cell development in the bone marrow microenvironment suggest that an interaction between hematopoietic cells and tumor cells warrants further investigation.
Cancer Metastasis Rev 2006 Dec
PMID:Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP). 1716 29

Parathyroid carcinoma (PC) is an uncommon finding, accounting for only 1-2% of patients with primary hyperparathyroidism (HPT), but a relatively higher incidence has been reported in Italy and Japan. The etiology of the tumour remains unclear, but molecular analysis studies have hypothesised the involvement of mutations of several genes in the pathogenesis of PC, including the oncogene cyclin Dl or PRADI located at the chromosome 13, the retinoblastoma and the p53 tumour suppressor gene. The clinical presentation of patients with PC is mainly related to the increased secretion of PTH rather than to the tumour burden. The pre-operative diagnosis of malignancy is very difficult to obtain, and, thus, intra-operative recognition of PC is mandatory. However, reliable signs of malignancy are rarely detectable. Probably, only vascular invasion, that correlates with tumour recurrence and metastases, should be considered useful in confirming malignancy, although both Ki-67 and Cyclin D1 have been recently used to aid in the definitive diagnosis. The en bloc resection of the tumour, together with ipsilateral thyroid lobe and adjacent structures, only if involved, avoiding any capsular rupture of the mass, represents the gold standard of surgical treatment of patients. Although the PC has traditionally been considered as a radioresistant tumour, there are some retrospective data holding a possible benefit from post-operative irradiation. No cytotoxic regimen with proven efficacy is currently available for patients with PC, but since hypercalcemia is ultimately the most frequent cause of death, several studies have suggested the usefulness of bisphosphonates (i.e., clodronate, pamidronate and zoledronate), calcitonin, and calcimimetic agents (i.e., cinacalcet) in patients with PC and severe hypercalcemia. In conclusion, PC is a rare malignancy and the NCDB survey reports an overall five- and ten-year survival rate of 85% and 49%, respectively. However, it is very difficult to predict the clinical behaviour of patients with PC and probably the ultimate prognosis depends on successful resection of the tumour at the initial surgery.
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PMID:Parathyroid cancer: etiology, clinical presentation and treatment. 1721 44

We encountered an unusual case of hyperparathyroidism with both hemosiderin deposits on the ribs and low intensity on T2-weighted magnetic resonance imaging (MRI) caused by a parathyroid adenoma with multiple brown tumors that mimicked metastatic bone tumor due to false positive results on computed tomography (CT) and Tc-99m sestamibi (MIBI) imaging. The patient, a middle-aged woman, had very high serum levels of calcium (14.1 mg/dl), alkaline phosphatase (9,369 IU/l) and intact-PTH (12,400 pg/ml), and a large tumor (2.5 cm in diameter) in the lower portion of the left lobe of the thyroid. Plain X-ray revealed a soft tumor in the left chest wall. On CT scan, there were multiple destructive masses in the ribs, including large intramedullary masses on both 3rd ribs. On MIBI scintigraphy, there was strong late uptake in the lower portion of the left cervical region, both 3rd ribs, and the left 7th, 8th, and 10th ribs. T2-weighted image MRI scans showed that both 3rd ribs had a low intensity with hemosiderin deposits. These findings suggested that the patient had hyperparathyroidism with multiple bone metastases due to carcinoma of the parathyroid gland. However, on pathology, the resected tumor of lower portion of the left lobe of thyroid was diagnosed as a parathyroid adenoma, and the tumors of the left 3rd and 7th ribs, as well as the right 2nd rib, were shown to be brown tumors. After resection, the patient's serum levels of calcium, alkaline phosphatase, and intact-PTH normalized. At 1.5-years follow-up, CT, MIBI, and MRI scans showed no abnormal findings. It is necessary to determine whether MRI can be used to distinguish between brown tumors and metastases caused by carcinoma of the parathyroid gland.
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PMID:Multiple brown tumors in primary hyperparathyroidism caused by an adenoma mimicking metastatic bone disease with false positive results on computed tomography and Tc-99m sestamibi imaging: MR findings. 1723 12

Hypercalcemia is the most common paraneoplastic syndrome in adult malignancies (10%-30%) and rare in pediatric cancers (0.5%-1.3%). Hypercalcemia in malignancies is categorized into two groups: 1) Humoral hypercalcemia of malignancy (HHM)-caused by substances that are produced by the tumor cells and secreted into the blood circulation such as parathyroid hormone-related protein (PTH-rP), parathyroid hormone-intact (PTH-i), the enzyme 1-alpha-hydroxylase that catalyzes the synthesis of the active form of vitamin D (1,25-dihydroxyvitamin D3), and other substances; 2) Hypercalcemia due to bone destruction by metastases. Hypercalcemia occurs in less than 5% of female genital tract malignancies and virtually in all cases (95%) it is HHM. Female genital tract malignancy-associated HHM is caused most often (80%) by PTH-rP. Ovarian cancer is the most common female genital tract malignancy that is associated with HHM. Although HHM occurs in only 5% of ovarian cancers, it occurs in a relatively high percentage in the following rare ovarian tumors: a). Small cell carcinoma of the ovary - a rare tumor that accounts for only 1% of all ovarian cancers and is associated with HHM in 66% of the cases; b). Clear cell carcinoma of the ovary - an uncommon tumor that accounts for 5% of all ovarian cancers and is associated with HHM in 5%-10% of the cases. Since dysgerminoma is the most common malignant ovarian tumor in children, in girls it is the second most common ovarian neoplasm, after ovarian small cell carcinoma, to be associated with HHM.
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PMID:[Hypercalcemia in malignancies of the female genital tract]. 1848 65

The cloning of the calcium sensing receptor (CaR) confirmed that parathyroid cells monitor extracellular calcium concentration ([Ca2+]ext) via a receptor-type mechanism. This lead to the hypothesis that abnormalities in the expression and/or function of the CaR could explain the biochemical abnormalities in primary hyperparathyroidism (PHPT). Cultured cells from parathyroid adenomas of patients operated for PHPT were used to monitor real-time changes in intracellular calcium concentration ([Ca2+]i) as measured by fluorescent microscopy using the Fura-2/AM dye. We found that CaR agonists trigger release of intracellular calcium pools and such responses are amplified by increasing the affinity of IP3 receptors. Using confocal microscopy to monitor membrane trafficking in living parathyroid cells labelled with the fluorescent dye FM1-43, we found that a decrease in [Ca2+]i rather than an absolute change in [Ca2+]ext is the main stimulus for exocytosis from human parathyroid cells. These data suggest that, in PHPT, a defective signalling mechanism from the CaR allows cells from parathyroid adenomas to maintain low [Ca2+]i with uninhibited PTH secretion in the face of hypercalcaemia. Over longer periods of time, CaR controls parathyroid proliferation via changes in tyrosine phosphorylation. We found that multiple proteins of molecular weight 20-65 kDa are phosphorylated within 10-60 min in response to CaR agonists. Further work demonstrated that high [Ca2+]i stimulates the expression of bcl-2 oncoprotein in cultured human parathyroid cells and that, in parathyroid adenomas, predominant expression of bcl-2 rather than bax oncoprotein might prevent apoptosis and explain the slow growth rate of these tumours. More recently, it became apparent that CaR stimulates cell proliferation in several cell types not involved in calcium homeostasis. Using archived histological material from 65 patients who died with metastatic breast cancer, we identified CaR expression predominantly in tumours from patients who developed bone rather than visceral metastases (35 of 49 versus 7 of 16; P < 0.01, chi-squared test). These data suggest that CaR expression has the potential to become a new biological marker predicting the risk of bone metastases in patients with breast cancer. A prospective study should investigate if patients with CaR-positive tumours are more likely to develop bone metastases and whether they could benefit more from prophylactic treatment with bisphosphonates or the newly developed CaR antagonists.
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PMID:The calcium sensing receptor: from understanding parathyroid calcium homeostasis to bone metastases. 1849 87

Malignant insulinomas are rare tumors (10% of insulinomas) that often present as mnulticentric macro nodules with multiple liver metastases before diagnosis. We report the case of a 55 year old female with a medical history of severe hypoglycemic attacks for two months. Blood tests showed a decreased value of glycemia (30 mg/dl) associated with increased insulin level (l6 microU/ml) and an increased glycemia/insulinemia ratio of 1.87 supporting the diagnosis of insulinoma. Abdominal CT showed a 1.5 cm mass localized in the head of the pancreas with disseminated hepatic tumors, confirmed as neuroendocrine metastases by biopsy (which proved the presence of a malignant insulinoma). Primary hyperparathyroidism was diagnosed based on mild elevation of calcium (10.4 mg/dl) associated with a high level of PTH (71.2 pg/ml). The coexistence of the two endocrinopathies suggested the presence of type 1 multiple endocrine neoplasia (MEN 1). Because of multiple hepatic masses and liver function impairment, surgery and hepatic artery embolization were not performed. Somatostatin analog therapy was started with symptomatic control in the beginning, but rapid loss of beneficial effect. Finally, systemic chemotherapy with doxorubicin was administered, but the disease was progressive and after three months we decided to stop it. The patient died at home after one month, probably in hypoglycemic coma.
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PMID:Malignant insulinoma with hepatic and pulmonary metastases associated with primary hyperparathyroidism. Case report and review of the literature. 2010 68

Paragangliomas are relatively uncommon neoplasms that arise in adrenal and extra-adrenal paraganglia of the autonomic nervous system. Parasympathetic paraganglioma develop predominantly in the head and neck. It is exceedingly uncommon to develop a primary intraparathyroid paraganglioma. There is only a single case report in the English literature. The information from the single previous case report (Medline 1960-2009) was combined with this case report. Our patient was a 69 year old woman who presented with a thyroid gland mass, with extension into the substernal space. The patient had a history of renal cell carcinoma removed 18 months before. At surgery, a thyroid lobectomy and a parathyroidectomy were performed. The parathyroid tissue showed a very well defined zellballen arrangement of paraganglion cells within the parenchyma of the parathyroid gland. The cells had ample basophilic, granular cytoplasm. The nuclei were generally round to oval with 'salt-and-pepper' nuclear chromatin distribution. There was a richly vascularized stroma. Mitotic figures, necrosis, invasive growth, and profound nuclear pleomorphism were absent. The neoplastic cells were strongly and diffusely immunoreactive with chromogranin, synaptophysin, CD56, and focally with cyclin-D1. The paraganglioma showed a delicate S-100 protein positive supporting sustentacular framework. Keratin, CD10, PTH, calcitonin and RCC markers were negative. The patient showed no stigmata of Multiple Endocrine Neoplasia (MEN) and has no paraganglioma in any other anatomic site. She is alive without any additional findings 12 months after surgery. Isolated paraganglioma within the parathyroid is rare, and should be separated from parathyroid adenoma, hyperplasia or metastatic disease to assure appropriate management.
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PMID:Primary paraganglioma of the parathyroid: a case report and clinicopathologic review. 2023 87

The case of a parathyroid carcinoma in a 61-year-old woman is described. The patient was referred to our hospital, with the diagnosis of medullary thyroid carcinoma, after a prior thyroidectomy performed at another hospital. On admission, serum calcium was 3.92 mmol/l (n.r. 2.2-2.5), PTH level was 320 ng/l (n.r. 10-65), urinary cAMP was 508.9 mmol/mmol creatinine (n.r. 330- 630) and serum calcitonin was 2.1 ng/l (n.r.<10). The patient was then submitted to a complete neck exploration and multiple nodules were removed. Histopathological diagnosis of parathyroid carcinoma was made by local recurrence and retrospectively upon closer examination of the original specimen. After surgery, normocalcemia was achieved and maintained for about four months. Serum PTH decreased to 28.8 ng/l after surgery but increased quickly to 75.6 ng/l ten days later. Three months later, there was both biochemical and clinical evidence of disease. In the following eight months, calcium levels ranged from 2.99 mmol/l to 4-24 mmol/l and PTH from 135 ng/l to 1431 ng/l. However no distant metastases were found. To Control hypercalcemia, the patient was treated with bisphosphonates but normocalcemia was never achieved. A slight and transient reduction in serum calcium as response to an acute administration of octreotide, made us not to consider this eventual modality of therapy. Sonographically guided percutaneous injection of ethanol was performed but the treatment was not found to be effective. Finally, the use of chemotherapy with 5-fluorouracil, cyclophosphamide and dacarbazine was also unsuccessful. The patient died two years after the initial diagnosis.
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PMID:Difficulties in the management of a parathyroid carcinoma - case-report. 2160 21

The incidence of primary hyperparathyroidism (pHPT) combined with nonmedullary thyroid carcinoma (NMTC) has been reported between 2-13%. To date, it remains controversial whether these 2 pathologies occur coincidental or are caused by specific risk factors or genetic changes. The aim of this study was to evaluate the clinical and histological characteristics of NMTC associated with pHPT. We reviewed prospective database records of 1 464 unselected, consecutive patients who were treated for pHPT in our institution between 1986 and 2012 and identified 41 NMTC (2.8%). The collective consisted of 35 papillary (PTC) and 6 follicular (FTC) thyroid carcinomas. Our collective of 41 NMTC including 34 single adenomas and 7 multiglandular diseases consisted of 33 females and 8 males. Patients with FTC demonstrated significant lower preoperative PTH levels compared to PTC. Interestingly, NMTC were predominantly located on the right side. FTC had significant larger tumors as well as demonstrated increased extrathyroidal growth and lymph node metastases. In 71% pHPT and NMTC were diagnosed synchronously. The comorbidity of pHPT and NMTC occurs in about 3%. As pHPT is often operated by a focal minimally invasive approach, we advocate a mandatory preoperative thyroid ultrasound for all patients with pHPT to be able to identify synchronous thyroid disease.
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PMID:Coincidence of primary hyperparathyroidism and nonmedullary thyroid carcinoma. 2375 16

The intact parathyroid hormone (iPTH) assay is a critical test in the diagnosis and management of PTH-mediated hypercalcemia, including parathyroid carcinoma (PCa). We hypothesized that the survival of patients diagnosed with PCa has improved since adoption of the iPTH assay into clinical practice. We identified all confirmed cases of PCa within the Surveillance, Epidemiology and End Results database from 1973 to 2006. Patients were categorized into two eras based upon introduction of the iPTH assay: 1973 to 1997 (era I) and 1997 to 2006 (era II, when the iPTH assay was in standard use). We estimated overall survival (OS) and disease-specific survival (DSS) using the Kaplan-Meier method, with differences among survival curves assessed via log rank. Multivariate Cox proportional hazards models compared the survival rates between treatment eras while controlling for patient age, sex, race/ethnicity, tumor size, nodal status, extent of disease, and type of surgery. Multivariate models included patients undergoing potentially curative surgery and excluded those with distant metastases. Risks of overall and disease-specific mortality were reported as hazard ratios with 95% confidence intervals. Study criteria were met by 370 patients. Median survival was 15.6 years. Five-year rates of OS and DSS were 78% and 88% for era I and 82% and 96% for era II. On multivariate analysis, age, black race, and unknown extent of disease predicted an increased risk of death from any cause. Treatment era did not predict OS. No factor predicted PCa-specific mortality. In multivariate analysis, neither OS nor DSS have improved in the current era that utilizes iPTH for the detection and management of PCa.
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PMID:Parathyroid carcinoma survival: improvements in the era of intact parathyroid hormone monitoring? 2377 98


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