A morphometric comparison of the changes in the laryngeal skeleton associated with invasion by tumor and by external-beam radiation.

Patterns of cartilage invasion by squamous carcinoma were examined in 40 laryngectomy specimens with particular reference to selective involvement of ossified cartilage. The study determines whether external radiation administered at therapeutic levels to the human larynx has selective effects on the osteoclast cell population and subsequent bone resorption. Radiated and nonirradiated tissues were compared as were cases with and without laryngeal framework involvement by cancer. Morphologic changes in ossified laryngeal cartilage showed that invasion is a largely indirect process dominated by local bone destruction with osteoclasts operating in front of the advancing tumor. Morphometric studies indicate that framework invasion correlates significantly with both increased numbers of osteoclasts and increased bone resorption. An original finding here was that radiation therapy resulted in similarly increased osteoclast activity among cases without framework involvement by cancer. In these cases radiation appeared to act independently of tumor in producing osteoclast activation.

Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy is a common but incompletely understood syndrome in humans. In an effort to define an animal model of this syndrome, we studied the transplantable Rice-500 Leydig cell tumor in male Fisher rats. Animals were studied 4-9, 10-12, and 13-14 days after tumor transplantation. By days 13-14, tumor-bearing animals were significantly hypercalcemic, hypercalciuric, and hyperphosphaturic compared to control animals. Fractional phosphorus excretion was elevated 4-fold in the tumor-bearing group despite hypophosphatemia. Mean nephrogenous cAMP in the tumor-bearing animals was 5 times the value in controls at days 13-14, while simultaneous immunoreactive PTH levels were undetectable. Plasma 1,25-dihydroxyvitamin D was significantly elevated in the tumor-bearing animals on day 14. Quantitative bone histomorphometry showed uncoupling of bone cell function in the tumor group, with marked suppression of bone formation, while indices of bone resorption were more than 2-fold elevated. Conditioned medium from tumor cells grown in culture consistently showed activity in a fetal bone-resorbing assay. This activity was heat stable and had an estimated mol wt of 30,000-50,000 daltons. Incubation of cells with indomethacin had no effect on bone-resorbing activity. These data indicate that the mediator in the model shares some of the actions of PTH, but is clearly distinct from native PTH. The findings exactly parallel those in human humoral hypercalcemia of malignancy, with the elevated 1,25-dihydroxyvitamin D values being the sole exception. The demonstration of in vitro bone-resorbing activity will aid in further characterization of the mediator.