CaSR expression in normal parathyroid and PHPT: new insights into pathogenesis from an autopsy-based study

Abstract

Purpose Calcium sensing receptor (CaSR), on the surface of normal parathyroid cells, is essential for maintaining serum calcium levels. The normal pattern of CaSR immunostaining remains undefined and is presumptively circumferential. Given the physiological variation in serum calcium, we postulated that CaSR expression could not be uniformly circumferential. Also, cytoplasmic expression has not been evaluated either in normal or pathological tissues. We studied normal parathyroid tissues derived from forensic autopsies and those rimming parathyroid adenomas for membranous and cytoplasmic CaSR immunoexpression. Results were compared with primary hyperparathyroidism (PHPT) to look for any pathogenetic implications. Materials and methodsWe evaluated 34 normal parathyroid tissues from 11 autopsies, 30 normal rims, 45 parathyroid adenoma, 10 hyperplasia, and 7 carcinoma cases. Membranous expression was categorized complete/incomplete and weak/ moderate/strong; scored using Her2/Neu and Histo-scores; predominant pattern noted. Cytoplasmic expression was categorized negative/weak/moderate/strong; predominant intensity noted. Results Normal autopsy-derived parathyroid tissues were Her2/Neu 3 + , but incomplete membranous staining predominated in 85%. Their immune-scores were significantly more than the cases (p < < 0.05). The mean histo-score of normal rims was intermediate between the two (p < < 0.05). Cytoplasmic expression was strong in all autopsy-derived tissues, weak/negative in hyperplasia (100%), moderate in 16% adenomas, and 43% carcinomas. Conclusions Normal autopsy-derived parathyroid tissues showed strong but predominantly incomplete membranous expression. Surface CaSR expression decreased in PHPT and is probably an early event in parathyroid adenoma, seen even in normal rims. Whether there is a defect in CaSR trafficking from the cytoplasm to the cell surface in adenoma and carcinoma needs further evaluation.

Single‐Cell Transcriptomic Atlas of Parathyroid Adenoma and Parathyroid Carcinoma

“…In the parathyroid glands, calcium‐sensing receptors are present on the surface and regulate serum calcium levels by inhibiting PTH synthesis and secretion. Previous studies have found that CASR expression is decreased in parathyroid tumors, ( 31,32 ) which results in insensitivity to the inhibitory feedback of calcium, altering the calcium‐PTH set point and driving parathyroid cell proliferation, suggesting a link to pathogenesis. ( 31 ) In contrast to these finding, the CASR gene was found to be more highly expressed in PC than in PA in our study.…”

“…Previous studies have found that CASR expression is decreased in parathyroid tumors, ( 31,32 ) which results in insensitivity to the inhibitory feedback of calcium, altering the calcium‐PTH set point and driving parathyroid cell proliferation, suggesting a link to pathogenesis. ( 31 ) In contrast to these finding, the CASR gene was found to be more highly expressed in PC than in PA in our study. This is probably because previous studies were performed at the bulk‐tumor level, and the cytoplasmic expression of CASR was not precisely assessed.…”

“…Agarwal and colleagues evaluated 45 parathyroid adenoma and seven carcinoma cases; moderate intensity of cytoplasmic CASR expression was detected in a greater proportion in carcinoma compared with adenoma. ( 31 ) The upregulation of the CASR gene in PC may be partly due to its high cytoplasmic expression, which requires further evaluation.…”

Immune Checkpoint Inhibitor-Induced Primary Hyperparathyroidism in a Small-Cell Lung Cancer Patient: A Case Report

“…Although our patient did not undergo parathyroid imaging, abnormal laboratory tests and effective methylprednisolone therapy provided the basis for diagnosis. PHPT occurs due to an increase in the number and/or volume of parathyroid cells and/or a decrease in calcium-sensing receptor (CaSR) expression [ 28 ]. However, we did not find any relevant literature on the pathophysiological mechanisms of ICI-induced PHPT.…”