Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: implications for the mechanism of hypercalcaemia

Abstract

Summary The infiltrated tissues from seven West Indian patients with HTLV-1 positive adult T cell lymphoma/leukaemia (ATLL) have been analysed by immunocytochemical techniques for the presence of immunoreactive parathyroid hormone-related protein (PTHrP), a hormonal mediator of humoral hypercalcaemia of malignancy. Six of the seven were hypercalcaemic at some stage of the course of their disease. Four of the six evaluable patients showed evidence of specific cellular and extracellular expression of PTHrP protein in neoplastic tissues. This finding suggests that PTHrP may be involved in the production of hypercalcaemia in at least some cases of T cell lymphoma -proof of a causal relationship however must await the demonstration of tissue release of PTHrP resulting in raised circulating hormone levels.Adult T cell lymphoma/leukaemia (ATLL) (reviewed in Uchiyama, 1988;Neely, 1989) is a neoplasm of lymphocytes presumptively caused by the human T cell lymphotropic virus, HTLV-1, (Yamaguchi et al., 1984) and exhibiting a characteristic morphology. It has a pronounced geographical distribution originally being described in south-western Japan (Uchiyama et al., 1977) and later also shown to have a particular prevalance in Caribbean emigrants to the UK and USA (Catovsky et al., 1982;Blayney et al., 1983;Bunn et al., 1983;Swerdlow et al., 1984). The disease is frequently associated with hypercalcaemia, which taken with its resistance to chemotherapy, contributes to the uniformly poor prognosis.The aetiology of hypercalcaemia in ATLL has not been fully elucidated. Abnormalities in parathyroid hormone, prostaglandin E and vitamin D metabolism have been suggested, but investigation of a large series of cases of ATLL has failed to demonstrate significant abnormalities (Cohn et al., 1987;Kiyokawa et al., 1987;Fukumoto et al., 1988). Recent studies have implicated a role for the hypercalcaemia-associated parathyroid hormone related protein (PTHrP) (Suva et al., 1987;Mangin et al., 1988) in the generation of hypercalcaemia in ATLL. Motokura et al. (1988) have demonstrated elevated levels of PTHrP mRNA and secretion of PTHrP from a cell line MT-2, derived from a case of ATLL. More recently, PTHrP protein has been isolated from leukaemic effusions in two patients with ATLL (Motokura et al., 1989) and peripheral blood of another . It has also been reported that a dog lymphosarcoma, capable of inducing hypercalcaemia upon transplantation (Weir et al., 1988), has raised PTHrP mRNA levels.In this study we have localised PTHrP in ATLL by immunocytochemical techniques using a series of antibodies to synthetic peptides derived from the N-terminal and Cterminal segments of PTHrP. Table I.Standard histopathology, formalin-fixed wax-embedded, biopsy material was used for immunohistological analysis.All was archival and had not been prepared especially for the study; of note, tissue fixation times (ideally less than 24 h for detection of PTHrP) may have been prolonged, particularly with the marrow trephine biopsy samples. All available biop...

Mechanisms in the skeletal complications of breast cancer.

“…With an N-terminal radioimmunoassay, circulating levels of PTHrP have been found to be elevated in 100% of hypercalcemic patients with solid cancers and no detectable bone metastases (Fig. 3) (Grill et al 1991). Elevated PTHrP levels were found also in 65% of patients with hypercalcemia and breast carcinoma metastatic to bone.…”

“…Further confirmation of the etiological link between elevated levels of PTHrP and hypercalcemia associated with malignancy has been achieved by measurements of circulating levels by radioimmunoassay and immunoradiometric assays, which have documented circulating levels of PTHrP in subjects with malignancy-associated hypercalcemia (Burtis et al 1990, Grill et al 1991. With an N-terminal radioimmunoassay, circulating levels of PTHrP have been found to be elevated in 100% of hypercalcemic patients with solid cancers and no detectable bone metastases (Fig.…”

“…By contrast, clinical studies in which renal handling of calcium and phosphate and nephrogenous cyclic AMP were examined, suggested that in up to 60% of hypercalcemic breast cancer patients humoral-mediating factors were operative in the production of hypercalcemia (Percival et al 1985, Isales et al 1987, Gallacher et al 1990. Further evidence that there is at least a humoral component in breast cancer came from the discovery of elevated plasma PTHrP levels in 70% of hypercalcemic patients with bone metastases in breast cancer (Grill et al 1991).…”

“…The most common cause of this is squamous cell carcinoma of the lung, as well as squamous cell cancers at other sites, including skin, esophagus, and head and neck, and also renal cortical carcinoma, primary liver cancer, pancreatic cancer, bladder carcinoma, and melanoma, and rarely, breast and prostate cancer. In the absence of secondary lesions, removal of the primary tumor leads to resolution of the hypercalcemia (Burtis et al 1990, Grill et al 1991. Tumor factors are secreted that act on the skeleton generally to increase bone resorption, and on the kidney to reduce calcium excretion and increase phosphorus excretion.…”

Hypercalcemia Due to Vitamin D Toxicity

“…PTHrP is most strongly implicated as the major mediator in this syndrome [168]. PTHrP messenger RNA has been demonstrated in HTLV-1-infected T cells [169] and tumor cells from adult T-cell lymphoma/leukemia (ATLL) patients with hypercalcemia [170]. Nevertheless, there are two welldocumented instances of elevated 1,25(OH) 2 D 3 levels in ATLL [142,150].…”