RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: their distribution patterns and biologic significance.

OBJECTIVES: To determine the distribution patterns of bone resorption regulators, receptor activator of nuclear factor κ-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in recurrent ameloblastoma (RAs) and to clarify their impact on the biologic behavior of these neoplasms. MATERIALS AND METHODS: Fifteen paraffin-embedded RA cases were subjected to immunohistochemistry for expression of RANK, RANKL, and OPG. RESULTS: The RANK-RANKL-OPG triad was heterogeneously detected in RA samples. RANK, essential for osteoclast differentiation, was strongly expressed in tumoral epithelium. Conversely, RANKL, an osteoclast activator, was markedly underexpressed, and protein localization was predominantly stromal. OPG, an osteoclastogenesis inhibitory factor, was detected in neoplastic epithelium more than in stroma, suggesting functional inactivation of RANKL. Most RA (n = 12/15; 80%) exhibited a bimolecular spatial expression pattern, the most common being RANK-positive/OPG-positive (n = 8/15; 53.3%). All three proteins showed no significant correlation with the clinical/histopathologic parameters in RA patients (P > .05). CONCLUSIONS: The RANK(+)/RANKL(low/-)/OPG(+) phenotype observed in RA suggests an altered local bone metabolism characterized by low bone resorptive activity in these recurrent tumors.

Intra-epithelially entrapped blood vessels in ameloblastoma.

BACKGROUND: The ameloblastoma is a benign but locally aggressive odontogenic neoplasm with a high recurrence rate. While significant progress has been made in our understanding regarding the role of tumoral vasculature relative to the diverse behavioral characteristics of this tumor, no attention has been paid to a distinct subset of blood vessels entrapped within its epithelial compartment. As vascular niches are known to influence tumoral growth, clarification of these vessels is important. The objectives of this study were to investigate the morphologic characteristics of intra-epithelially entrapped blood vessels (IEBVs) in ameloblastoma and to speculate on their relevance. MATERIALS AND METHOD: Here, we evaluated the frequency, microvessel density (MVD), morphology, and distribution pattern of IEBVs in 77 ameloblastoma of different subtypes based on their immunoreactivity for endothelial markers (CD34, CD31, CD105), vascular tight junction protein (claudin-5), pericyte [α-smooth muscle actin (α-sma)], and vascular basement membrane (collagen IV). RESULTS: IEBVs were heterogeneously detected in ameloblastoma. Their mean MVD (CD34 = 15.46 ± 7.25; CD31 = 15.8 ± 5.04; CD105 = 0.82 ± 0.51) showed no significant correlation with different subtypes, and between primary and recurrent tumors (P > 0.05). These microvessels may occur as single/clusters of capillary sprouts, or formed compressed branching/non-branching slits entrapped within the epithelial compartment, and in direct apposition with polyhedral/granular neoplastic epithelial cells. They expressed proteins for endothelial tight junctions (claudin-5-positive) and pericytes (α-sma-positive) but had deficient basement membrane (collagen IV weak to absent). Aberrant expression for CD34, CD31, and CD105 in tumor epithelium was variably observed. CONCLUSIONS: Although rare in occurrence, identification of IEBVs in ameloblastoma could potentially represent a new paradigm for vascular assessment of this neoplasm.

Podoplanin, E-cadherin, ß-catenin, and CD44v6 in recurrent ameloblastoma: their distribution patterns and relevance.

BACKGROUND: Ameloblastoma is a benign but locally infiltrative odontogenic epithelial neoplasm with a high risk for recurrence. Podoplanin, a lymphatic endothelium marker, putatively promotes collective cell migration and invasiveness in this neoplasm. However, its role in the recurrent ameloblastoma (RA) remains unclear. As morphological, signaling, and genetic differences may exist between primary and recurrent tumors, clarification of their distribution patterns is of relevance. MATERIALS AND METHODS: Podoplanin was examined immunohistochemically in conjunction with E-cadherin, ß-catenin, and CD44v6 in 25 RA. Immunostaining according to tumor area, cellular type, and location, and relationship of these proteins were analyzed. Findings were compared with 25 unrelated primary ameloblastomas (UPA). RESULTS: All four proteins were detected in RA and UPA samples. Expression rates for each protein were not significantly different between these two groups. RA demonstrated significant upregulation of podoplanin at the invasive front (P < 0.05), whereas upregulation of ß-catenin and CD44v6 and downregulation of E-cadherin at this site were not statistically significant (P > 0.05). Immunolocalization for all four proteins was predominantly membranous and less frequently cytoplasmic. Pre-ameloblast-like cells were podoplanin(+) /CD44v6(-), while stellate reticulum-like cells were podoplanin(-)/CD44v6(+). Acanthomatous, granular cell, and desmoplastic variants in both RA and UPA were podoplanin(-/low) but stained weak-to-moderate for E-cadherin, ß-catenin, and CD44v6. Stromal fibroblasts and lymph channels were variably podoplanin-positive. CONCLUSIONS: Podoplanin, ß-catenin, and CD44v6 upregulation at the tumor invasive fronts in RA and UPA supports a differential regulatory role by these molecules in mediating collective cell migration and local invasiveness. E-cadherin downregulation suggests altered cell adhesion function during tumor progression.