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PubMed2006

Hypercalcemia induced by ovarian clear cell carcinoma producing all transcriptional variants of parathyroid hormone-related peptide gene during pregnancy.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP) appears as the major causative agent responsible for the humoral hypercalcemia of malignancy (HHM). However, the use of promoters and splicing patterns of PTHrP gene in HHM have not been reported yet. CASE: A 35-year-old woman was diagnosed as an ovarian clear cell carcinoma with HHM caused by elevated serum PTHrP after delivery. An immunohistochemical study showed PTHrP expression in the tumor tissue. The Southern blot analysis following RT-PCR confirmed the presence of all types of PTHrP mRNA transcripts produced by a combination of three promoters, one 5' alternative splicing and three alternative 3' splicing events. CONCLUSION: An ovarian clear cell carcinoma induced PTHrP-related HHM, which resulted from the high expression of all isoforms for PTHrP gene.

Adenocarcinoma, Clear Cell↗
PubMed1992

[Hypercalciuria and primary hyperparathyroidism in patients with kidney calculi. II. Primary hyperparathyroidism].

Among 1819 patients with renal stone disease 44 cases with primary hyperparathyroidism (p.h.p.) were diagnosed. In all cases the diagnosis of php was confirmed by histomorphological examination. In 34 patients with php solitary adenoma was found, in 5 patients an adenoma with concomitant hyperplasia of the parathyroid glands, in 2 patients hyperplasia and in 3 patients carcinoma of the parathyroid glands. Hypercalcemia was found in 86% of patients, while elevated plasma levels of PTH in 90% of patients with php. Not in all patients PTH secretion was entirely autonomous. No significant correlation was found between plasma levels of PTH and kind of pathology of the parathyroid glands as well as clinical feature of php respectively.

Adult↗
PubMed1996

Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53.

Parathyroid hormone-related protein (PTHrP) is a normal secretory product of a variety of squamous epithelia, including epidermal keratinocytes. Only a subset of squamous carcinomas, however, express the gene at levels sufficient to cause humoral hypercalcemia. In the present study, comparison of PTHrP expression levels with p53 functional status in a series of squamous carcinoma lines has revealed an association between expression of specific mutant isoforms of p53 and very low levels of PTHrP mRNA. Evaluation of p53 isoforms with mutations in codons 248 and 273 showed them to be capable of repressing PTHrP gene expression in a high-expressing, p53-negative squamous line by approximately 50%. Conversely, inactivation of an endogenous mutant p53 with E1B proteins resulted in an increase in PTHrP expression in a low-expressing cell line. Subsequent analysis of promoter-specific PTHrP transcripts in a p53-negative squamous line transfected with mutant p53 isoforms suggested that down-regulation occurred primarily at the two TATA-based promoters. Direct testing of a murine PTHrP reporter construct in transient transfection assays confirmed the capacity of the 248 and 273 mutants to repress this TATA-based promoter, although only about half as effectively as wild-type p53.

Adenovirus E1B Proteins↗
PubMed1975

The association of parathyroid adenoma and non-medullary carcinoma of the thyroid.

Thyroid carcinoma was discovered in five of 56 (8.9%) patients operated upon for hyperparathyroidism. In only one instance was a mass palpated preoperatively. An additional 26% of the 56 patients had either multinodular goiter or follicular adenomas. It is thus important to biopsy the thyroid nodules which may represent malignancy.

Adenocarcinoma↗
PubMed1993

Region-specific methylation of the parathyroid hormone-related peptide gene determines its expression in human renal carcinoma cell lines.

Tumor production of a parathyroid hormone-related peptide (PTHrP) is a common cause of the syndrome of humoral hypercalcemia of malignancy, which is frequently associated with renal cell carcinomas. Why certain renal cell carcinomas produce PTHrP while others do not is unknown. Using a system of 12 human renal carcinoma cell lines which either do (n = 6) or do not (n = 6) produce PTHrP, we found that the expression of the PTHrP gene in these cell lines is controlled at the transcriptional level. Transfection studies failed to demonstrate variation in PTHrP promoter activity in these cell lines sufficient to account for the differential PTHrP expression, implicating a cis-acting mechanism. Transcription of the PTHrP gene in these cell lines was found to correlate with the methylation state of specific CpG dinucleotides located within the promoter region but outside a CpG island. The functional importance of this mechanism of control was confirmed by the ability of the demethylating agent, 5-azacytidine, to induce PTHrP mRNA expression in previously nonexpressing cell lines.

Azacitidine↗
PubMed1995

Patterns of DNA methylation of the parathyroid hormone-related protein gene in human lung carcinoma.

Humoral hypercalcaemia of malignancy often results from production of parathyroid hormone-related protein (PTHrP) by the tumour. We have investigated whether malignancy is associated with epigenetic changes in the PTHrP gene in lung. In normal and tumour tissue, there was a general background of nonmethylation in the PTHrP gene. In the 5' region, there appeared to be increased methylation of sites upstream of the promoter, P2. The extent of methylation increased from germ line to normal tissue to tumour tissue to tumour cell line, indicating that new methylation events in this region mark neoplastic change in lung cells.

5-Methylcytosine↗
PubMed1994

Regulation of parathyroid hormone-related protein production in a human lung squamous cell carcinoma line.

The synthesis and release of parathyroid hormone-related protein (PTHrP) could be influenced in a paracrine or autocrine manner by substances present around or inside tumours, such as bone or stromal cell-derived cytokines, factors produced by the tumour itself or by peritumoural inflammatory cells. We investigated the effects of various cytokines known to be synthesized by osteoblasts, stromal cells, leucocytes or cancer cells, on PTHrP production by the human lung squamous cell carcinoma line BEN. The influence of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) was studied, and compared with those of insulin-like growth factors-I and -II (IGF-I, IGF-II), or macrophage- or granulocyte-macrophage colony-stimulating factors (M-CSF, GM-CSF). TNF-alpha caused a 1.9 +/- 0.1-fold increase in immunoreactive PTHrP production, which was maximal by 24 h of incubation. IL-6 caused a 2.3 +/- 0.2-fold increase, which was maximal by 16 h. These effects, which were time- and concentration-dependent, were blocked by monoclonal antibodies raised against the corresponding cytokine. An increase of PTHrP mRNA was found in IL-6-treated cells. IGF-I and IGF-II increased PTHrP production by 2.0 +/- 0.3- and 2.3 +/- 0.1-fold respectively. Neither M-CSF nor GM-CSF altered PTHrP production up to 64 h of incubation. PTHrP production was not affected by varying extracellular calcium concentrations, but was decreased by incubation with 100 nmol/l dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell↗
PubMed1996

Tumor-induced hypercalcemia and parathyroid hormone-related protein in lung carcinoma.

BACKGROUND: Although lung carcinoma is the most common cause of tumor-induced hypercalcemia (TIH), the precise incidence of TIH remains obscure. Furthermore, the role of parathyroid hormone-related protein (PTHrP) has not been clearly elucidated. METHODS: This study included 690 consecutive patients who were newly diagnosed as having lung carcinoma between 1989 and 1994 (379 adenocarcinomas, 207 squamous cell carcinomas, 75 small cell carcinomas, and 29 large cell carcinomas). All patients were treated for lung carcinoma and were also periodically monitored for their serum level of calcium (Ca). Hypercalcemia was defined as a serum Ca concentration higher than 11 mg/dL. The serum levels of PTHrP (109-141) were measured by a C-terminal-region-specific radioimmunoassay. RESULTS: TIH was observed in 17 of 690 patients (2.5%). All 17 patients demonstrated an advanced stage of lung carcinoma (Stage III or IV), 10 squamous cell carcinomas, 5 adenocarcinomas, 1 small cell carcinoma, and 1 large cell carcinoma. In 15 patients, the serum level of C-PTHrP (109-141) was substantially high, ranging from 99 pmol/L to 890 pmol/L (normal range, 21-50.7 pmol/L). There was no significant difference in the serum PTHrP level between patients with or without bone metastasis. The reduction of tumor burden decreased both the serum level of PTHrP and that of Ca in parallel. The median survival time after diagnosis of TIH was only 27 days. CONCLUSIONS: TIH in lung carcinoma was most likely attributable to PTHrP, and its occurrence appears to be an ominous prognostic sign.

Adult↗
PubMed1987

Flow cytometric DNA analysis of parathyroid glands. Relationship between nuclear DNA and pathologic classifications.

Nuclear DNA contents of 95 paraffin-embedded parathyroid glands (2 carcinomas, 56 adenomas, 10 primary and 17 secondary chief cell hyperplasias, and 10 normal glands) were determined by flow cytometric analysis. All normal parathyroid glands and secondary hyperplasias, 80% of the primary hyperplasias, and 73% of the adenomas had diploid DNA patterns, with 15% or less tetraploid cells. Twenty-one percent of the adenomas, 29% of the primary hyperplasias, and all carcinomas had diploid and tetraploid DNA distribution patterns, with greater than 15% of the cells in the tetraploid region. One of the carcinomas (Figure 4B, Case 2) had an additional near-triploid aneuploid peak. Three of the adenomas (5.4%) had near-triploid aneuploid patterns. One of the patients with carcinoma (Figure 4A, Case 1) died, 32 months after initial diagnosis, of disease-related causes. The remaining patient with carcinoma (Case 2) had a 47-month disease-free interval. All of the patients with hyperplastic and adenomatous glands are free of disease, after a mean follow-up interval of 25 months. This study indicated that flow cytometric analysis of nuclear DNA content does not complement conventional pathologic methods in distinguishing between parathyroid gland chief cell hyperplasia, adenoma, or carcinoma; however, it did suggest the possibility that parathyroid adenomas and primary chief cell hyperplasias may contain a subset of tumors that could manifest biologic malignancy if allowed to progress untreated.

Adolescent↗
PubMed1995

The value of cytometric DNA analysis as a prognostic tool in neuroendocrine neoplastic diseases.

In several traditionally non-endocrine, common, human, neoplastic diseases, it has become well established during the last few years, that cytometric analyses of the DNA distribution pattern of the nuclei of tumour cells can be an excellent supplement to the conventional prognostic tools, (such as clinical staging and histopathologic malignancy assessments). When analogous studies of the value of DNA analysis by means of flow cytometry and/or image cytometry are made in neuroendocrine (NE) neoplastic diseases, the ensuing results often become rather disappointing. Thus, clear-cut aneuploid DNA histograms can be found in the neoplastic cell nuclei of clinically and histopathologically completely benign NE adenomas (and even hyperplastic nodules). In contrast, highly aggressive NE carcinomas not seldom reveal themselves to be composed of tumour cells with nuclei, displaying an euploid, i.e. normal, DNA pattern. Statements of this kind have been based on the results of comprehensive investigations in several laboratories, analysing such NE tumours as insulomas/insular carcinomas, bronchial/gastrointestinal carcinoids, phaeochromocytomas, paragangliomas, neuroblastomas, adenomas of the anterior pituitary gland, parathyroid adenomas, medullary carcinoma of the thyroid and Merkel-cell tumours of the skin. Thus, the prognostic value of the cytometric DNA ploidy pattern of the nuclei of neoplastic parenchymal cells is definitely lower in NE tumours than in most of the traditionally non-endocrine carcinomas and sarcomas. Data from published and unpublished series of these kinds of NE tumours, and those of prostatic and breast carcinomas with NE differentiation, are given. By means of a new, consecutive double staining technique, it was shown that in idiopathic nesidioblastosis, the hyperinsulinism is caused by beta cells with a nuclear DNA ploidy pattern of euploid type. By the same technique, it can be shown that in the pathogenesis of the hypergastrinaemia-induced ECL-cell carcinoids of the stomach, a switch from an euploid to an aneuploid nuclear DNA distribution pattern occurs in the ECL-cells when they pass from a state of hyperplasia to that of a genuine neoplasia. In neuroblastomas, a triploid (i.e. aneuploid) DNA pattern is part of an algorithm capable of predicting a 96% survival rate, whereas a diploid/tetraploid (i.e. euploid) DNA pattern predicts a 0% survival.

DNA, Neoplasm↗
PubMed1985

Localization of parathyroid hormone-like substance in squamous cell carcinomas. An immunoperoxidase study with ultrastructural correlation.

Histologic sections of squamous cell carcinomas of four hypercalcemic patients were investigated for the presence of parathyroid hormone (PTH)-like substance. None of the patients had clinical or radiographic evidence of bone metastases. The Sternberger-peroxidase-antiperoxidase-immunoperoxidase technique utilizing monospecific antibody to whole (1 to 84) bovine PTH demonstrated immunoreactive material in all cases. Electron microscopy of the four tumors revealed dense-core secretory granules resembling those seen in parathyroid chief-cell adenomas. The patients did not have elevated serologic levels of PTH or evidence of bone metastases; however, in two cases, osteoclastic bone resorption was seen in bone marrow biopsy specimens. All patients became normocalcemic after definitive tumor resection. The hypercalcemia associated with some nonmetastatic squamous cell carcinomas is associated with the production of PTH-like substance.

Carcinoma, Squamous Cell↗
PubMed2002

Parathyroid hormone-related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia.

BACKGROUND: Parathyroid hormone-related protein (PTH-rP) is a major cause of tumor-induced hypercalcemia (TIH) and frequently is found to be elevated in serum of patients with TIH. In the current study, the authors examined the usefulness of PTH-rP measurement at the time of first presentation in the follow-up of lung carcinoma patients with TIH. METHODS: The authors retrospectively studied 23 of 1149 lung carcinoma patients who were found to have TIH at the time of first presentation for the correlation between serum PTH-rP and the development of bone metastases and survival compared with lung carcinoma patients without TIH who were matched by gender, age, Eastern Cooperative Oncology Group performance status, histological type of tumor, and stage of the disease. RESULTS: Twenty-three lung carcinoma patients with TIH demonstrated significantly increased serum levels of PTH-rP (mean +/- standard error [SE], 84.1 +/- 16.5 pmol/L) compared with control patients without TIH (mean +/- SE, 36.2 +/- 2.0 pmol/L) at the time of first presentation, (P < 0.001). In these hypercalcemic patients, patients whose serum PTH-rP was > 150 pmol/L (n = 16) were found to have a significantly increased rate of bone metastases (71.4% vs. 12.5%; P = 0.01) and decreased survival (median survival of 1.4 months vs. 5.4 months; P < 0.015) compared with patients whose serum PTH-rP was < 150 pmol/L (n = 7). CONCLUSIONS: The data from the current study suggest that serum PTH-rP as determined at the time of first presentation is a useful indicator of not only hypercalcemia but also bone metastasis and eventual survival in patients with lung carcinoma.

Adult↗
PubMed2002

Hypercalcemia and acute renal failure caused by production of parathyroid hormone-related protein from renal cell carcinoma.

A 69-year-old male patient was diagnosed with right-sided renal cell carcinoma and humoral hypercalcemia of malignancy caused by an excessive production of parathyroid hormone-related protein. The hypercalcemia led to acute tubular necrosis, so the patient had to be put on hemodialysis. The renal failure was accompanied by hyponatremic encephalopathy. Rapid correction of the hyponatremia might have initiated central pontine myelinolysis.

Acute Kidney Injury↗
PubMed1998

Comparative genomic hybridization analysis of human parathyroid tumors.

Primary hyperparathyroidism is characterized by hypercalcemia and elevated parathyroid hormone levels. It can be caused by overactivity of one (adenoma or carcinoma) or more (hyperplasia or multiple adenoma) parathyroid glands. Parathyroid adenoma and hyperplasia are usually mono- or oligoclonal neoplasms. To establish whether parathyroid cancer has a genetic composition distinct from parathyroid adenoma, we analyzed 10 adenoma and 10 carcinoma cases by comparative genomic hybridization (CGH). Results show clear differences between the constitution of adenoma and carcinoma genomic DNA. The most frequent genomic alterations in adenoma included deletions on chromosomes 11, 17 (5 of 10 cases), and 22 (7 of 10 cases). In parathyroid carcinoma, frequent chromosomal deletions were on chromosome arm 1p (4 of 10 cases) and chromosome 17 (3 of 10 cases), and gains were on chromosome 5 (3 of 10 cases). Our data indicate that different genetic changes could contribute to the development of parathyroid adenoma and carcinoma; genomic losses predominate in adenoma, and gains along with some losses are found in carcinoma. Furthermore, the CGH results implicate several chromosomal regions that may harbor genes that could be potentially involved in the development of parathyroid adenoma and carcinoma.

Adenoma↗
PubMed1995

Ultrastructure of human parathyroid cells in health and disease.

Parathyroid glands (n = 271) removed from 130 patients were examined by light and electron microscopy. A standardized method of tissue processing was employed and morphometry was performed. The aim of the paper is to provide a description of the human parathyroid chief cell ultrastructure in health and disease, with quantitative evaluation of structures involved in secretion of parathyroid hormone in a large case series, and to discuss their role in current diagnostic histopathology. The patients were euparathyroid (n = 10), or affected by primary (n = 97), secondary (n = 8), or tertiary (n = 15) hyperparathyroidism. In normal glands, solid parenchyma was composed of chief cells, large clear cells, transitional-oxyphil cells, and oxyphil cells. Chief cell hyperplasia, pseudo-adenomatous hyperplasia, adenoma, water-clear cell hyperplasia, and carcinoma were the most usual forms of parathyroid disease responsible for primary hyperparathyroidism. In chief cell hyperplasia, all the parathyroid glands were enlarged and the chief cells were in an active state of hormone secretion, with a large Golgi complex, abundant rough endoplasmic reticulum (RER), small lipid droplets, and tortuous plasma membrane. In pseudo-adenomatous hyperplasia, one gland was enlarged and the others displayed a normal size; however, electron microscopic examination and morphometric analysis showed that all the glands had active cells. Adenomas displayed a pattern similar to those of pseudo-adenomatous hyperplasia, with one gland enlarged and the others of normal size. However, ultrastructural examination and morphometry showed that the normal-size glands were hypo-active. Water-clear cell hyperplasia showed cells filled with cytoplasmic vacuoles. In these cells, structures with intermediate features between secretory granules and vacuoles were visible. Nucleo-cytoplasmic atypias were frequently visible in parathyroid carcinoma cells. In secondary and tertiary hyperplasia, active chief cells were regularly mixed with oxyphil or transitional-oxyphil cells. The tertiary hyperplasia was characterized by RER-associated structures that were not found in the normal or other pathological conditions. These results demonstrate that electron microscopy and morphometry represent useful tools in parathyroid histopathology.

Adult↗