Rates of Cell Proliferation in Adenomatous, Suppressed, and Normal Parathyroid Tissue: Implications for Pathogenesis¹

Abstract

In previous studies, the birth rate of new cells in parathyroid adenomas measured at the time of surgical excision was shown to be much too low to account for growth of the tumors from a single cell in the time available, but comparison with normal rates was not possible. We measured the prevalence of cells expressing the Ki-67 antigen, a cell cycle marker, in 55 parathyroid adenomas using the MIB-1 antibody and microwave antigen retrieval; in 22 cases, separate measurements were made in nonadenomatous tissue from the same glands. In 10 cases complete maps of the gland profile were reconstructed to study the distribution of labeled cells. The proportion of Ki-67-positive cells, estimated by systematic random sampling, was used to calculate cell birth rate assuming a duration of Ki-67 expression of 24 h; the results were compared to rates previously determined in normal parathyroid glands by the same method. The geometric mean cell birth rate was 9.97%/yr, about double the normal rate of 5.4%/yr, but less than a third of the cases had values above the normal range. The corresponding value in nonadenomatous tissue was 2.58%/yr, about half the normal rate. In 10 cases studied in more detail, the cell birth rate was 12.3%/yr in the peripheral regions and 6.2%/yr in the central regions, a value not significantly different from normal. The results in adenomas are in reasonable agreement with previous estimates of cell birth rate of 13.7%/yr using [3H]thymidine labeling and 6.4%/yr using prevalence of the mitotic karyotype. The proportion of Ki-67-positive cells using unbiased sampling was about 50 times smaller than that in previous studies using selective sampling. Cell birth rates at the time of excision were about 20-25 times lower than initial rates estimated from modeling tumor growth by the Gompertz function. We conclude that 1) cell birth rate in parathyroid adenomas has fallen substantially during the growth of the tumors and is only modestly greater than normal; 2) the fall in cell birth rate had been greater in the central and presumably older regions of the adenoma than in the peripheral and presumably younger regions; 3) nonadenomatous tissue was suppressed with respect to its proliferative as well as its secretory function, presumably as a result of hypercalcemia; and 4) the progressive fall in cell birth rate, despite the accumulation of mutations that are supposed to increase cell birth rate, is most readily explained by the set-point hypothesis.

A proteomic approach to study parathyroid glands

“…A combination of weak immunoreactive expression of mutated p53 and a relatively strong expression of bcl-2 was reported by Hadar et al 19 in a subset of parathyroid adenomas and interpreted as a contributing mechanism accounting for the characteristic slow progression of these tumours. 20 In the present study we found an increased expression of 14-3-3 z/d, but not of wild-type p53 protein, in parathyroid adenomas compared to normal parathyroid. In light of the slow proliferating activity of parathyroid tumours we hypothesize that the direct interaction between 14-3-3 z/d and p53 outlined from pathway analysis might lead to an increase of p53 transcriptional activity with consequent regulation (direct or indirect) of proteins involved in apoptosis and growth arrest.…”

“…The significant down regulation of these proteins we observed in parathyroid adenomas is in line with the slow rate of proliferation of these tumours. 20 A group of proteins consistently up-regulated in parathyroid adenoma tissues are COX-5A, PARK-7, peroxiredoxin-3 (PRDX-3) and chaperones endoplasmin (HSP90), 60 kDa heat shock protein mitochondrial precursor (HSP60), and CCT5. All these proteins are implicated in the early response to increased cellular oxidative stress, which is a common event in adenomas characterized by high proliferation and low angiogenesis.…”

Correlations between Vitamin D Status and Biochemical/Clinical and Pathological Parameters in Primary Hyperparathyroidism

“…It was previously shown that parathyroid tumor growth eventually stops when there is sufficient number of parathyroid cells to increase the PTH to achieve the new set-point for plasma calcium. 14 Predictably, parathyroid adenoma weight was significantly higher in patients with low vitamin D concentrations. Our results add additional clues to the studies pointing out the deleterious effects of vitamin D deficiency on disease severity and parathyroid tumor growth in primary hyperparathyroidism.…”