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Improved catheterization technique and new laboratory methods have increased the value of venography in the diagnosis of tumors, especially of hormone-producing tumors. A review of catheterization techniques for the diagnosis of tumors of the adrenal glands, pancreas, parathyroid glands and orbit is presented with examples of findings.
The effect of 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3) on parathyroid hormone secretion by porcine parathyroid glands and human parathyroid adenoma tissue was investigated by in vitro incubation. The addition of 100 nmoles 1,25-(OH)2-D3 to the medium inhibited significantly the release of immunoreactive parathyroid hormone by 63--65%. This suppression was reversible when 1,25-(OH)2-D3 was removed again. The inhibition of parathyroid hormone release observed in human parathyroid adenoma tissue was similar to that in normal porcine parathyroid glands. This indicates that adenoma tissue is sensitive to regulatory influences. As well as calcium, 1,25-(OH)2-D3 may act as another feedback inhibitor of parathyroid hormone secretion.
Light and electron microscopic localization of parathyroid hormone (PTH) in human and bovine parathyroid tissue has been achieved using an indirect peroxidase labeled antibody method. Granular deposition of the reaction product was found throughout the chief cell cytoplasm. There was no nuclear staining. At the ultrastructural level, parathyroid hormone localized by this method appeared to be largely confined to the secretory granules in the cytoplasm of cells. Mitochondria and nuclei were free of reaction product. Aggregated sacs of granular endoplasmic reticulum were minimally reactive, and Golgi apparatuses did not show reaction product.
The long term (70 days) effects of administering ethane-1-hydroxy-1,1-diphosphonate (EHDP) (4 mg. per kg. per day) on parathyroid function was investigated in pregnant cows fed a low calcium diet. Serum calcium and phosphorus were significantly lower at parturition and postpartum in EHDP-treated cows compared to pregnant control cows fed the low calcium diet. Plasma immunoreactive parathyroid hormone levels were similar prepartum, at parturition, and postpartum in cows administered EHDP and control cows. Immediately available calcium reserves were greater preparation in control cows than in cows receiving EHDP as indicated by a more rapid rate of return of serum calcium toward normal levels following ethylenediaminetetraacetic acid (EDTA)-induced hypocalcemia approximately 10 days prepartum. EHDP-treated cows responded to the hypocalcemic challenge with similar changes in plasma immunoreactive parathyroid hormone levels as in control cows; however, urinary hydroxyproline excretion increased at certain intervals only in control cows. Ultrastructurally, chief cells in parathyroid glands of both groups of cows were in an active stage of the secretory cycle with well developed organelles concerned with hormonela synthesis. Chief cells in cows administered EHDP were degranulated and contained fewer secretory granules in response to the hypocalcemia than those in control cows. Chief cells in EHDP-treated cows often had prominent perinuclear accumulations of microfilaments, scattered vacuolated mitochondria, and lysosomal bodies in the cytoplasm. Thyroid C-cells were densely granulated and thyroid calcitonin content was similar in both groups of cows. The principal defect in calcium homeostasis of EHDP-treated cows appeared to be an impairment both in bone calcium mobilization and bone matrix catabolism in response to the secretion of parathyroid hormone. In vitro uptake of 45Ca by duodenal mucosa and urinary excretion of cyclic adenosine monophosphate were similar in both groups of cows. The ability of the parathyroid glands to synthesize and secrete parathyroid hormone in response to hypocalcemia induced either by EDTA or associated with parturition was not impaired by the administration of EHDP.
An unusual parathyroid adenoma containing abundant adipose tissue is described in four patients. In one patient, hyperparathyroidism was documented; in another, studies were incomplete but the adenoma was probably functioning. Prior reports of similar lesions have been called "parathyroid hamartoma or parathyroid adenoma with myxoid stroma," and some of these also have been shown to be functional. They may create diagnostic difficulties because of the presence of adipose tissue, a feature associated with normal parathyroid glands.
Hyperfunctioning parathyroid carcinoma is a relatively rare endocrine tumor, accounting for approximately 1% of all cases of primary hyperparathyroidism. The diagnosis is suspected when the tumor is large, parathyroid hormone (iPTH) levels are high, and a palpable tumor is present in the neck. Patients who have recurrence of hyperparathyroidism several months after surgical treatment should be suspected of having a recurrent or persistent parathyroid carcinoma. At operation, a large invasive tumor is usually found. The fibrous, inflammatory-like reaction is the most characteristic indication of malignancy. Even in tumors with minimal invasiveness, the possibility of a carcinoma should be considered if the tumor has mitotic activity and a monotonous instead of a pleomorphic cellular population. If the surgeon can recognize the possibility of parathyroid malignancy and adequately treat the patient during the initial operation, more gratifying results should be obtained.
The parathyroid gland of healthy senile dogs aged 8.5 to 15 years was compared with that of mature control dogs by examination with the electron microscope. Preparations fixed by perfusion with glutaraldehyde showed the cytoplasmic matrix of most parenchymal cells to be uniformly dense. None of the cells were of the extremely light type and dark cells were much less frequently noted than in preparations fixed by immersion in glutaraldehyde or osmium tetroxide. Syncytial cells and so-called coloid follicles were more frequent in senile dogs than in control dogs. It was suggested that the content of the latter structures is not colloid but necrotic substance hiving origin from the parenchymal cells and that perhaps the occasional cells containing large, membrane-bound inclusions may be degenerating cells which ultimately produce this necrotic substance. Oxyphil cells and mitochondria-rich cells of another type were found in all senile dogs, but not in the controls. These cells, especially the mitochondria-rich cells, frequently contained bizarre mitochondria that were modified in shape, size and arrangement. The most striking feature of these mitochondria was the concentric arrangement of elongated mitochondria which seemed to consist of densely layered cup-shaped mitochondria. Such mitochondria were noted in all senile dogs aged ten years and over. The significance of mitochondrial ple-morphism in the parathyroid gland of senile dogs was discussed.
Parathyroid function, defined as the ability to maintain normocalcemia without substitution, was evaluated in 36 patients following total thyroidectomy for carcinoma. In 16 patients, all visualized parathyroid tissue was sliced and autotransplanted into muscle pockets; one year after the operation, 11 patients had substitution for lack of parathyroid function. In 20 patients, the parathyroid glands were preserved in situ with intact vascular supply; one year postoperatively, three patients had evidence of persistent hypoparathyroidism. The difference in the parathyroid insufficiency rate is significant, p less than 0.005. We conclude that parathyroid autotransplantation has been a failure io preserve the parathyroids in situ whenever this is feasible, autotransplantation being reserved for parathyroids unfortunately removed or devascularized.
Morphology, histology and seasonal changes in the parathyroid gland of the lizard, Uromastix hardwickii are reported. The lizard possesses a pair of glands consisting of a single type of cells. Parathyroid gland undergoes well defined seasonal changes. During breeding season (Summer) gland showed hyperactivity, whereas in winter, when lizard is quiescent, parathyroid gland shows degenerative changes. Though parathyroid gland from both male and female exhibited hyperactive phase during summer, plasma calcium and phosphorus concentration of female only has increased during this period suggesting that the changes in the parathyroid gland are not due to the endogenous circulating calcium level.
Electron-microscopic studies were made on the parathyroid gland of cadmium-treated mice. Most chief cells in treated mice were rich in free ribosomes and secretory granules compared to the control mice. In the parathyroid gland after 3 and 4 weeks of administration of cadmium, interdigitations between adjacent chief cells became more complex than in the control mice. In most chief cells of the parathyroid gland after 2, 3 and 4 weeks of administration of cadmium, the Golgi complexes associated with numerous prosecretory granules were better developed than in the control mice. These ultrastructural appearances suggest that parathyroid gland cellular activity was stimulated in response to cadmium treatment.
Glial cells missing 2 (GCM2) is an essential transcription factor for the development of parathyroid glands. Germline GCM2 variants that repress or enhance transcriptional activity predispose a subset of patients to hypoparathyroidism or hyperparathyroidism, respectively. A recurrent germline heterozygous activating missense variant of GCM2, p.Y394S has been identified in some patients with primary hyperparathyroidism. A genetically engineered knock-in mouse model of this variant corresponding to p.Y392S in the mouse Gcm2 gene (Gcm2 +/Y392S) did not show obvious parathyroid tumors. However, in GCM2-binding site mediated luciferase reporter assays in HEK293 cells, the mouse and the human variant both exhibited enhanced transcriptional activity. Therefore, we assessed the effect of this variant on gene expression in vivo in parathyroid glands from Gcm2 +/Y392S and WT mice. Using the 10x Genomics Visium platform, spatially resolved transcriptomic analysis was performed on formalin-fixed and paraffin-embedded (FFPE) tracheal tissue sections of Gcm2 +/Y392S and WT mice to capture RNA from parathyroid glands together with other cell types in the tissue sections. Transcriptome sequence data analysis detected 8 different clusters in the tissue sections based on similarity of gene expression profiles. Cluster-1, which contained parathyroid gland cells expressing Pth and Gcm2, was further evaluated for transcripts that were differentially expressed more than 2-fold in Gcm2 +/Y392S compared to WT. Increased transcript level of Lgals3 (galectin-3) was seen in Gcm2 +/Y392S parathyroid gland cells which is among markers of parathyroid carcinoma. Galectin-3 protein was detected in available FFPE human parathyroid samples of patients with germline heterozygous activating GCM2 variants, p.Y394S (n = 4/10) or p.L379Q (n = 2/2). These results indicate a potential for growth and malignancy of parathyroid glands expressing GCM2 variants. The transcriptomic data of mouse parathyroid gland cells generated in this study can serve as a valuable resource for investigating genes and pathways in normal or abnormal parathyroid gland growth and physiology.
Of 53 patients who had hyperparathyroidism assocated with multiple parathyroid gland enlargement, 39 (74%) had primary hyperparathyroidism without clinical or laboratory evidence of associated endocrine gland dysfunction, 2 had documented familial primary hyperparathyroidism, and 12 had hyperparathyroidism as part of the multiple endocrine neoplasia syndrome. When last studied, 31 of the 39 patients with nonfamilial hyperparathyroidism had normal serum calcium levels, 3 had permanent hypoparathyroidism, 2 had recurrent hyperparathyroidism, and 3 were lost to follow-up. The two patients with familial hyperparathyroidism were treated by removal only of enlarged parathyroid glands, and in each, hyperparathyroidism recurred. Five patients with multiple endocrine neoplasia, type 1, were treated by removal only of enlarged parathyroid glands, and hyperparathyroidism recurred in four. Four patients with multiple endocrine neoplasia, type 1, were treated by removal of three or more parathyroid glands, and there were no instances of recurrent hyperparathyroidism. In one patient, permanent hypoparathyroidism developed. Three patients with multiple endocrine neoplasia syndrome, type 2, had total parathyroidectomies as a part of thyroidectomy for medullary thyroid carcinoma. In each patient, permanent hypoparathyroidism developed. When primary hyperparathyroidism occurs in the absence of a definite history of polyendocrine or familial disease, only the glands that are definitely enlarged should be removed, and normal-appearing glands should be tagged rather than risk the possibility of permanent hypoparathyroidism that may attend routine subtotal parathyroid gland excision.
A canine model for cryopreservation and autotransplantation of parathyroid glands was developed as a prototype for cryopreservation of human parathyroid glands; Each of 18 dogs had two parathyroids removed, sectioned, and cooled at a controlled rate to -80 degrees in media containing 10% dimethylsulfoxide and 10% autologous serum. After storage for two months at -196 degrees the tissue was thawed and implanted in muscle; the remaining two parathyroid glands were removed from the neck. Function was assessed by monitoring serum calcium levels and measuring parathyroid hormone levels in venous effluent from the graft beds. Autograft function was demonstrated in ten of 18 dogs; graft failure occurred in four dogs. In the remaining four dogs, function could not be evaluated because of accessory parathyroid tissue. Parathyroid tissue cryopreserved for nine months was documented to function in six of seven dogs. Histologic study of the cryopreserved, autografted tissue showed normal parathyroid architecture.
Identification of parathyroid glands during surgery for treatment of hyperparathyroidism remains difficult. The staining with methylene blue was first described by Dudley. Twenty-one patients were explored. Thirty to sixty minutes before surgical incision, an intravenous perfusion of methylene blue was started. The dose varied between 5 to 10 mg per kg. Thirty-seven enlarged glands were found of which 33 were obviously stained; 13 showed some color that could not be attributed with certainty to the dye; 1 adenome was not stained at all. In 89.2% of the cases the staining had the favorable effect of shortening the operation. Only 4 normal glands showed the blue stain. The affinity for methylene blue is thus mainly found in pathological parathyroid glands.
The author studied functional reserves of the parathyroid glands in patients with diffuse toxic goiter with thyrotoxicosis and in euthyroidism, and also at various periods after subtotal resection of the thyroid gland, in patients with autoimmune thyroiditis, and with postoperative hypothyroidism. Functional reserves of the parathyroid glands proved to decrease in 15 to 54 patients with toxic goiter and in 6 of 16 patients with hypothyroidism. Surgical intervention on the thyroid gland usually led to functional parathyroid insufficiency which compensated later. Calciemia (below 8.5 mg%) 4 hours after the beginning of the test pointed to the parathyroid gland insufficiency the intensity of which could be more accurately determined by checking calcium level 12 and 24 hours after the beginning of the test.
We investigated some effects of prostaglandin E1 on the metabolism of rat parathyroid glands using a culture system containing basal Eagle's medium supplemented with 5--10% heat-inactivated rat serum. Rat parathyroid glands incorporate [3H]fucose and 14C-labeled amino acids into cellular glycoproteins and secrete some of these into the culture medium. Gel filtration chromatography separates these glycoproteins into three classes, the smallest of which (peak 3) is secreted with immunoreactive parathyroid hormone. In cultures of 48 h, prostaglandin E1 (1 microgram/ml) specifically inhibits the secretion of peak 3 and of parathyroid hormone but has no effect on the incorporation of [3H]fucose, 14C-labeled amino acids, or [3H]uridine into parathyroid glands. Cytochalasin B inhibits the secretion of parathyroid hormone and the incorporation of isotopic fucose and amino acids. Cortisol stimulates incorporation of [3H]fucose and the secretion of parathyroid hormone even in the presence of inhibitory doses of prostaglandin E1. It is concluded that, in organ culture, prostaglandin E1 inhibits the secretion of parathyroid hormone and of a specific glycoprotein the function of which may be related to the secretion of the hormone.
The densities of human parathyroid glands were measured in density gradient columns of various media. Percoll (an aqueous colloidal solution of polyvinylpyrrolidone-coated silica), equilibrated to 300 mOsm with sodium chloride, was found to be the ideal gradient medium for density measurements of tissues with a density greater than 1.0 g/ml. which includes most parathyroid glands. The densities of the glands varied between 0.96 and 1.06 g/ml. Density measurements in gradients of Percoll were simple and reproducible and were made with an accuracy of approximately 0.001 g/ml. In other gradient media (aqueous solutions of sucrose and Ficoll, and organic solvents) there was a drift in density caused by osmotic or lipid-solving effects of the media. For measurements of densities less than 1.0 g/ml no ideal gradient medium was found, but a silicon oil or carbon tetrachloride/kerosone gradient could be used with somewhat reduced accuracy. It is concluded that the density gradient technique with the use of Percoll is potentially useful as a complement to routine histopathological parathyroid diagnosis, as glandular density is a good indicator of the relative proportions of parenchymal and fat tissue.
The similarity of adenomas of the parathyroid gland with other tumours of the APUD-system elements was investigated. The structure of 10 adenomas was studied. The ultrastructural characteristics were compared with the histological structure of the tumour. Various histological variants of the neoplasias were shown to have similar ultrastructure. The tumour tissue was represented by clear transitional and dark cells. In their cytoplasm, osmiophilic granules of the secrete, villae, laminar structures resembling Nissl bodies, fine granular and fine fibrous substances, and lipid inclusions were found. The structural similarity of adenomas with other endocrine-active tumours developing from cells of the neuroectodermal origin (carcinoids, paragangliomas, etc.) was noted. It is suggested that parathyroid glands belong to the APUD-system.