Molecular Aspects of Thyroid Calcification

Abstract

In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in benign lesions and in other subtypes of thyroid carcinomas. Thyroid calcifications are classified according to their diameter and location. At ultrasonography, microcalcifications appear as hyperechoic spots ≤ 1 mm in diameter and can be named as stromal calcification, bone formation, or psammoma bodies (PBs), whereas calcifications > 1 mm are macrocalcifications. The mechanism of their formation is still poorly understood. Microcalcifications are generally accepted as a reliable indicator of malignancy as they mostly represent PBs. In order to progress in terms of the understanding of the mechanisms behind calcification occurring in thyroid tumors in general, and in PTC in particular, we decided to use histopathology as the basis of the possible cellular and molecular mechanisms of calcification formation in thyroid cancer. We explored the involvement of molecules such as runt-related transcription factor-2 (Runx-2), osteonectin/secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteopontin (OPN) in the formation of calcification. The present review offers a novel insight into the mechanisms underlying the development of calcification in thyroid cancer.

Keywords: calcifications; osteopontin; psammoma bodies; thyroid cancer.

Figure 1

Graphical representation of the different types of calcification in thyroid tissue sections: (A) focus of stromal calcification (in purple color) in the tumor stroma, (B) inspissated colloid calcified, (C) psammoma bodies (PBs) (in purple color) located in the papillary thyroid carcinoma present inside lymphatic vessels or in the stalk of the papillae, and (D) coarse macrocalcification (in purple color). Shapes in pink correspond to non-tumor thyroid; shapes in deeper pink correspond to tumor thyroid.

Figure 2

Psammoma bodies (PBs) in a papillary thyroid carcinoma: (A) visible PBs with purple color in hematoxylin and eosin (HE) staining, 10×; (B) magnified inset with PBs marked with the black arrows, 40×.

Figure 3

Molecular mechanism of calcification in papillary thyroid cancer (PTC) cells. Macrophages can be recruited to the PTC microenvironment and release matrix vesicles (MVs) to the extracellular matrix (ECM). MVs contain hydroxyapatite (HA), which initiates the calcification process. Osteopontin (OPN) and runt-related transcription factor-2 (Runx-2) are overexpressed in PTC cells and this increases the expression of alkaline phosphatase (ALP), osteocalcin (OCN), collagen type I, metalloproteinases (MMPs), and bone sialoprotein (BSP). All these molecules are involved in the induction of calcium deposits in the ECM, culminating in the calcification process in thyroid tissues, and also induce the expression of epithelial–mesenchymal transition genes (snail family transcriptional repressor (SNAI)2, SNAI3, and twist-related protein 1 (TWIST1)) and angiogenic factors (vascular endothelial growth factor (VEGF)A and VEGFC). Up arrows mean increase; The cells expressing CD68 correspond to macrophages.