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The results of the last decade genetic research in the field of oncogenesis of sporadic and familiar parathyroid tumors are summarised. The review of studied focuses on two main topics: multiple endocrine neoplasis syndromes as well as sporadic parathyroid adenomas and carcinomas. The current knowledge of genetic factors associated with the development of these lesions is presented.
A woman with metastatic carcinoma of the breast developed hypercalcemia 39 months after mastectomy. The hypercalcemia remitted after treatment but recurred 12 months later, accompanied by elevated levels of serum immunoreactive parathyroid hormone (PTH). A urea/HC1 extract of hepatic metastases contained immunoreactive PTH, material which stimulated the resorption of fetal rat bone in tissue culture, and material which stimulated chick renal adenylate cyclase activity. These findings strongly suggest that this breast cancer produced a PTH-like substance.
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The results of morphologic studies performed in 18 patients who had total parathyroidectomy and autotransplantation of parathyroid tissue into the forearm muscle are presented. All patients had long-standing renal disease with azotemia, hyperphosphatemia and high levels of parathyroid hormone. The histologic findings after total parathyroidectomy, before gland transplantation, are important for selection of parathyroid tissue for surgery. Diffuse hyperplasia with the development of multiple nodules of the parathyroids can possibly be adverse for the transplant. In one case, nine month after autotransplantation we found a tumor in the forearm, measuring 2.0 X 3.0 X 2.2 cm in diameter. Morphologic findings in this case before implantation showed diffuse hyperplasia with adenomatous nodules but no signs of carcinoma. The grafted parathyroid tissue after excision was seen with blood vessel invasion in the normal skeletal muscle. In the case of primary renal disease with secondary parathyroid hyperplasia, the light microscopic examination revealed an autonomous tumorlike adenomatous formation in the autografted parathyroid tissue, with graft-dependent hypercalcemia. The invasive growth with some signs of neoplasia following autotransplantation raises the question of the development of certain neoplasia.
A decrease in renal tubular reabsorption of inorganic phosphate (Pi) can be observed in hypercalcemia of malignancy. In the present study we investigated the effect of serum-free conditioned medium (CM) from cells, derived from a lung carcinoma (BEN) of a hypercalcemic patient, and of PTH on cyclic AMP (cAMP) production and sodium-dependent Pi transport (NaPiT) in epithelia of two renal cell lines. In opossum kidney cells (OK), PTH is known to enhance cAMP production and inhibit NaPiT; in contrast, in LLC-PK1 cells, PTH has no effect on NaPiT since this kidney cell line is devoid of PTH receptors. In OK cells, BEN CM induced a three- to fourfold increase of cAMP production, which was blunted by the PTH inhibitors bPTH(3-34) and bPTH(7-34). NaPiT, as assessed by measuring the initial rate of Pi uptake, was inhibited in a dose-dependent manner by BEN CM, with an effect maximal between 1h30 and 6 hr of incubation (40 +/- 4% and 47 +/- 4%, respectively), corresponding to the effect produced by 1-3 nM bPTH(1-34). The Na-dependent transport of a glucose analog was affected neither by BEN CM nor by PTH. In LLC-PK1 cells, neither BEN CM nor PTH altered cAMP production nor NaPiT after 1h30 of incubation. At 6 hr, BEN CM caused a slight decrease in NaPiT. In conclusion, these results constitute the first evidence of a direct and selective inhibition by tumor-derived factor(s) of NaPiT in cultured renal epithelia. Most of the renal NaPiT inhibitory activity produced by the lung tumor required the presence of a PTH receptor-adenylate cyclase system.(ABSTRACT TRUNCATED AT 250 WORDS)
Using technetium Tc 99m sestamibi for localization of a parathyroid adenoma in primary hyperparathyroidism, we describe the first reported case of increased uptake due to a thyroid follicular carcinoma. Prior false-positive results have been reported exclusively with follicular adenomas.
Twenty-nine patients with acute hypercalcemia secondary to carcinoma, myeloma and parathyroid adenoma have been treated with large doses of furosemide, mithramycin, or salmon calcitonin perfusion. With furosemide administration the treatment was successful in 6 of 10 patients. Furosemide was injected intravenously at the rate of 125 mg every 3 hours. With mithramycin perfusion only 2 of 8 patients have a return of the serum calcium levels to normal. With salmon thyrocalcitonin 3 of 10 patients obtained a good result. It can be interesting to suggest the association of furosemide and salmon calcitonin infusion to treat hypercalcemia of myeloma.
Previously we have established a clonal squamous cell carcinoma cell line OKa-C-1 derived from lung cancer of a patient with marked leukocytosis and hypercalcemia. OKa-C-1 cells simultaneously produce granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP) at the single cell level and cause paraneoplastic syndromes in nude mice bearing the tumor. It is known that the production of G-CSF and PTHrP is individually regulated by inflammatory cytokines in various malignant cells. To investigate the common factors in the regulation of G-CSF and PTHrP production in OKa-C-1 cells, we examined the effects of some inflammatory agents [lipopolysaccharide (LPS), phorbol-12-myristate-13-acetate (PMA), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) beta and IL-6] on G-CSF and PTHrP production, by means of enzyme-linked immunosorbent assay (ELISA), immunoradiometric assay (IRMA) and quantitative reverse transcription-polymerase chain reaction (RT-PCR). TNF-alpha or IL-1beta induced both G-CSF and PTHrP production in the conditioned medium. TNF-alpha synergized with IL-1beta to significantly increase G-CSF production. In addition, TNF-alpha and IL-1beta strongly induced G-CSF mRNA with peaks at 2 and 6 h respectively. Although PTHrP production was also strongly induced by TNF-a PTHrP mRNA expression was more strongly induced by PMA than by TNF-alpha. Thus, TNF-alpha and IL-1beta could be common factors that individually and synergistically regulate G-CSF and PTHrP production in OKa-C-1 cells. Moreover, G-CSF and PTHrP production could be not only transcriptionally, but also posttranscriptionally regulated by other factors.
An experience with 316 patients operated upon with a presumptive diagnosis of primary hyperparathyroidism is presented. Of the 316 patients, 291 (92.1 per cent) were cured after the initial cervical exploration without using any technique for preoperative localization of parathyroid tissue. Persistent and recurrent hyperparathyroidism occurred in 4.0 and 3.7 per cent, respectively. The success rate for secondary operations (cervical and mediastinal) was 82 per cent. Permanent unilateral vocal cord paralysis occurred in three patients and persistent symptomatic hypercalcemia occurred in another two. Twelve (4 per cent) of the patients had hyperparathyroid crisis and five (1.8 per cent) had carcinoma of the parathyroid gland. The mean follow-up time was six years. Removal of a single macroscopically enlarged gland, if the other glands are normal, is all that needs to be done in most instances. Subtotal parathyroidectomy should be preserved for those patients who have diffuse glandular hyperplasia.
A 54-year-old man with general fatigue and lumbago was admitted for further examination of hypercalcemia and leukocytosis. CT showed a huge renal tumor and extension of the tumor thrombus to the inferior vena cava (IVC). Moreover, the serum granulocyte colony-stimulating factor (G-CSF) and the C-terminal of parathyroid hormone-related protein (PTHrP) were elevated. Under the diagnosis of advanced renal tumor, we performed nephro-ureterectomy and throbectomy. Pathological examination revealed squamous cell carcinoma of the renal pelvis. To our knowledge, this is the first case in Japan that of the simultaneous production of G-CSF and PTHrP in squamous cell carcinoma of the renal pelvis accompanied with IVC thrombus.
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Prostaglandin E concentrations were measured in a patiet with breast carcinoma, hypercalcemia, undetectable parathyroid hormone (PTH) and no evidence of bone metastases. Catheterization of the drainage bed of her tumor documented production of E series prostaglandins. Treatment with the largest recommended doses of indomethacin for 10 days failed to lower her plasma prostaglandin E (PGE) concentrations or to correct the hypercalcemia, but it normalized urinary excretion of PGE. Subsequent chemotherapy reduced prostaglandin concentrations toward normal values concomitant with a reduction of clinically estimated tumor burden. During this period of time, serum calcium concentrations had no consistent relationship to the plasma PGE levels. We suggest that PGE merely reflected the tumor burden of this patient and did not directly contribute to the genesis of her hypercalcemia. The pertinent literature relating PGE and hypercalcemia is reviewed.
A new cell line, designated EC-GI, was established from a 65-year-old patient with esophageal carcinoma who developed humoral hypercalcemia. The original tumor as well as the cell line caused marked hypercalcemia in tumor-bearing nude mice, in which a marked increase in osteoclastic bone resorption was demonstrated. The conditioned medium of EC-GI cells contained potent bone resorbing activity which stimulated cyclic AMP production in parathyroid hormone (PTH)-responsive osteoblast-like cells (ROS 17/2.8). EC-GI cells will be useful for characterization and purification of the PTH-like factor responsible for humoral hypercalcemia of malignancy.
Germ line mutations of the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2A (MEN 2A), an inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. To study the mechanism of tissue-specific tumor development by RET with a MEN2A (cysteine 634-->arginine) mutation, we generated transgenic mice by introducing the RET-MEN2A gene fused to Moloney murine leukemia virus long terminal repeat. Expression of the transgene and its product was detected at variable levels in a variety of tissues including thyroid, heart, liver, colon, parotid gland, and brain. All of 29 mice analyzed developed thyroid C-cell hyperplasia or medullary carcinoma, accompanying high levels of serum calcitonin. In addition, development of mammary or parotid gland adenocarcinoma was observed in one-half of the transgenic mice. RET dimerization and its complex formation with Shc and Grb2 adaptor proteins were detected in tumor tissues. Unexpectedly, no tumor formation was found in other tissues despite RET-MEN2A expression where RET dimerization was undetectable. Because these tissues but not tumors expressed glial cell line-derived neurotrophic factor family receptor alpha (GFR alpha) at high levels, this suggested that GFR alpha expression may interfere in the dimerization of the RET-MEN2A mutant proteins, leading to tissue-specific tumor development in vivo.
In malignancy-associated hypercalcemia (MAH) elevated plasma calcium levels are believed to inhibit parathyroid secretion independently of the underlying tumor. This predicts that correction of hypercalcemia should disinhibit circulating parathyroid hormone (PTH) levels, irrespective of the underlying disease. We have tested this hypothesis in subjects with multiple myeloma (MM) and squamous cell carcinoma (SCC) treated with pamidronate. In the MM group, PTH levels returned to normal as hypercalcemia was corrected. In contrast, PTH levels remained low in the SCC group despite a similar fall in plasma calcium. Calcitriol levels were significantly higher and magnesium levels slightly lower in the SCC group than those in the MM group. We conclude that the parathyroid response to the correction of hypercalcemia is blunted in subjects with SCC but not MM. In addition to hypercalcemia, other factors, perhaps related to tumor secretion of PTH-related protein, may therefore contribute to suppressing PTH secretion in MAH due to SCC.
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A 78-year old male with ureteral carcinoma manifesting hypercalcemia is reported. He was diagnosed as having ureteral carcinoma of the left side 2 years previously and was treated by nephrectomy with ureterovesicostomy. In October 1991, he was admitted for anorexia. A clinical examination revealed recurrence of the ureteral carcinoma with metastasis to the rectum and liver. His serum calcium level was elevated (13.9 mg/dl). In addition to rehydration and furosemide, treatment with eel-calcitonin and prednisolone failed to decrease his serum calcium level. Finally, he was administered mithramycin but he died 13 days later. He had no evidence of bone metastasis or hyperparathyroidism. Nephrogenic cAMP and urinary parathyroid hormone-related protein (PTHrP) were markedly elevated. Immunohistochemical study demonstrated expression of PTHrP in the tumor cells. Thus, the hypercalcemia was thought to be mediated by PTHrP secreted from the neoplastic tumor. Although there have been several reports of ureteral carcinoma associated with humoral hypercalcemia of malignancy, this is considered to be the first case associated with elevation of PTHrP.
The multiple endocrine neoplasia type 2 (MEN2) syndromes and Hirschsprung's disease (HSCR) are inherited neurocristopathies characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid disease, and gastrointestinal neuromatosis. Mutations in the RET proto-oncogene are the underlying cause of the MEN2 syndromes and some cases of HSCR. In this report, we show that Cys 618 Arg mutation cosegregates with familial MTC and HSCR in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A single haplotype shared by chromosomes bearing the Cys 618 Arg mutation in both families strongly suggests a founder effect for this mutation. We have observed in our and in several other previously reported families, an excess of maternal over paternal mutated RET alleles in offsprings affected by HSCR. We suggest that parental imprinting may play a role in the ethiology of HSCR caused by mutations in the RET protooncogene.