Relationships of parathyroid hormone, parathyroid secretory protein, parathyroid hormone messenger RNA, parathyroid secretory protein mRNA, and replication in human parathyroid adenoma and secondary hyperplasia tissues and cultures.

BACKGROUND: The purpose of this study was to clarify the relationships of extractable and secreted parathyroid hormone (PTH) and parathyroid secretory protein (PSP) in human parathyroid tumors to PTH messenger RNA (mRNA), PSP mRNA, and cell replication. METHODS AND RESULTS: In tissue cultures of seven adenomas and five secondary hyperplasias, we found a direct correlation for secreted PTH versus PSP for both adenomas and secondary hyperplasias. Secreted PTH:PSP was elevated for adenomas (11:1) compared to that of secondary hyperplasias (2:1), and adenomas secreted significantly more PTH and PSP than did secondary hyperplasias. In extracts of eight adenomas and six secondary hyperplasias, the ratio of PTH:PSP was unexpectedly low (2:1) and similar for both adenomas and secondary hyperplasias. The ratio of extractable PTH mRNA:PSP mRNA was extremely low for both adenomas (1:7) and for secondary hyperplasias (1:5). Flow cytometry indicated that percent replication was inversely correlated with PTH mRNA and PSP mRNA. CONCLUSIONS: Increased PTH secretion by adenomas cannot be attributed to increased biosynthetic capacity because it is less than expected. Hypersecretion of PTH by adenomas and coincident marked reductions in PTH mRNA suggest either a defect in cytoplasmic storage of PTH or impairment of normal posttranslational degradation of PTH. As parathyroid tumor cells increase replication, PTH mRNA is reduced. Possible explanations for this include decreased PTH gene transcription or decreased mRNA half-life.

Vasoactive intestinal polypeptide-, neurotensin-, substance P-, gastrin-releasing peptide-, calcitonin-, calcitonin gene related peptide-, and somatostatin-like immunoreactivities in human parathyroid glands.

We have found vasoactive intestinal polypeptide (VIP)-, neurotensin-, substance P-, gastrin-releasing peptide-, calcitonin-, calcitonin gene related peptide (CGRP-2)-, and somatostatin-like immunoreactivities in extracts of sporadic human parathyroid adenomas (n = 18). The content of CGRP-2, substance P, and somatostatin in adenomas correlated directly with that of parathyroid hormone. In addition, concentrations of VIP versus substance P and somatostatin versus CGRP-2 in adenomas were directly correlated. Neuropeptide content of parathyroid hyperplasias differed from that of adenomas. VIP was detected in only one of seven parathyroid hyperplasias, and neurotensin was undetectable (0/7), whereas substance P was present in six of seven cases and GRP in five of seven hyperplasias. In hyperplasias, content of substance P correlated directly with that of gastrin-releasing peptide. Peroxidase immunohistochemistry localized VIP-like immunoreactivity to 20% to 50% of both chief and oxyphilic cells and rare clear cells and capillary endothelium in 11 of 12 adenomas studied. Focal staining was present in glandular epithelium of the rim of adjacent normal parathyroid tissue and in two of three normal parathyroid glands removed with thyroid goiters. This staining was both cytoplasmic and apical membrane. By contrast, in adenomas, neurotensin- and substance P-like positivities were confined to scattered (5% to 10%) oxyphilic cells. Cytoplasmic positivity for parathyroid hormone, noted in 30% to 70% of cells in serial sections, confirmed that these tissues were indeed parathyroid glands.

Rotational ablation of chronic coronary occlusions.

Rotational ablation was performed successfully in three chronic coronary occlusions. At 3 months follow-up, two of the three lesions were patent. These cases illustrate the overall advantages and unique technical aspects of this device.

Effects of tamoxifen and somatostatin analogue on growth of human medullary, follicular, and papillary thyroid carcinoma cell lines: tissue culture and nude mouse xenograft studies.

The knowledge that (1) the normal thyroid contains somatostatin, (2) polypeptide growth factors influence thyroid cell function, and (3) thyroid cells contain steroid hormone receptors prompted us to add somatostatin analogue No. 201-995 (SMS) (5 ng/ml) and/or tamoxifen citrate (TAM) (5 mumol/L) to 7-day monolayer cultures (50,000 cells/well) of three separate human thyroid carcinoma cell lines: DR081 (medullary), WR082 (follicular), and NPA'87 (papillary). Results, tabulated as cell numbers/well (X10(5) on day 7, revealed that TAM inhibited growth of medullary and follicular cells and that TAM plus SMS inhibited growth of papillary cells. In vivo studies of subcutaneous tumor cell xenografts in nude mice have documented that TAM (5 mg subcutaneous pellet) significantly inhibits the growth of medullary implants. Flow cytometric DNA studies of medullary cell cultures demonstrated a reduced G2 + M phase with TAM treatment. For papillary cell implants, TAM plus SMS (5 micrograms subcutaneously, twice daily) did not suppress tumor growth. All three cell lines were negative for estrogen receptor; addition of estradiol (5 ng/ml) to medullary cell cultures neither stimulated replication nor reversed the inhibitory effects of TAM in vitro. We conclude that (1) TAM slowed the growth of a cell line of human medullary carcinoma, both in vitro and in vivo; (2) this effect was not reversed by estradiol; (3) TAM plus SMS inhibited replication of a papillary carcinoma cell line in vitro, but not in vivo; and (4) TAM alone and TAM plus SMS inhibited replication of cultures of a human follicular thyroid carcinoma cell line. TAM and SMS may be useful in treatment of some human thyroid carcinomas.

Fine needle cytologic diagnosis of thyroid nodules. Review and report of 300 cases.

Three hundred patients with thyroid nodules were evaluated with fine needle biopsy and cytologic evaluation. Nineteen of 23 cancers were diagnosed by fine needle biopsy alone, for a yield of 83 percent. Four of 300 diagnoses (1 percent) were false-positive, and the evidence of neoplasm at operation was 68 percent. We believe that fine needle biopsy will greatly decrease the number of unnecessary thyroid resections.

Effect of TSH stimulation on serum thyroglobulin in metastatic thyroid cancer.

Thyroglobulin (TG) is a glycoprotein which has been found to be produced by almost all nonmedullary thyroid cancers, and is present in elevated levels in the serum of most patients with metastatic thyroid cancer. It has long been a clinical impression that many metastatic thyroid cancers are "responsive" to TSH suppression as manifested by a decrease in the size and/or symptoms of the tumor. Five athyroid patients with metastatic thyroid cancer were studied to determine the effect of TSH stimulation on their serum TG levels and attempt to correlate this effect with their clinical response. Three of the five patients showed a definite rise in their serum TG once serum thyroxine (T4Y replacement was withdrawn, which correlated with an increase in TSH, and two of these patients have had no progression of their disease while on T4 suppression. The remaining two patients have shown no change in their TG levels after T4 withdrawal, and both have had progression of their metastatic disease while on T4 suppression. Thus, we see that in some patients, TG production by their metastatic thyroid cancer is responsive to TSH suppression, and there is some suggestion that TSH-responsive cancers are less aggressive; but it will require further studies to determine this.

Incidental medullary thyroid carcinoma in sporadic hyperparathyroidism. An expansion of the concept of C-cell hyperplasia.

Two patients with sporadic primary hyperparathyroidism were found to harbor tiny medullary thyroid carcinomas. In addition, parafollicular-cell hyperplasia was recognized in one of these thyroids by the use of immunoperoxidase stain to localize calcitonin. The possible relationships between these lesions are discussed.

Coexistent parathyroid adenomas and thyroid carcinoma. Can radiation be blamed?

The coexistence of parathyroid adenomas and thyroid cancer in a substantial number of patients with primary hyperparathyroidism has led to speculation implicating ionizing radiation as a possible cause. Experience with a group of 40 individuals harboring both tumors was reviewed and evidence of roentgen ray exposure to the head and neck was found in only one of these patients. Association of parathyroid adenomas and thyroid carcinoma cannot be explained on the basis of prior irradiation to the neck.

Parathyroid adenoma and nonmedullary thyroid carcinoma.

The incidence of thyroid carcinoma in patients with hyperparathyroidism has been reported as higher than expected. We record our experience with 272 cases of primary hyperparathyroidism. Malignant thyroid lesions were found in 11.4%. We conclude that this is more than a fortuitous association.