Evaluation of the expression of Bmi-1 stem cell marker in sinonasal melanomas and its correlation with the expression of cell cycle proteins

Harim Tavares Dos Santos,Juliana De Souza Do Nascimento ,Felipe Paiva Fonseca,João Figueira Scarini ,Fernanda Meireles,Fernanda Viviane Mariano,Érika Said Abu Egal ,Victor Ângelo Martins Montalli ,Albina Altemani

doi:10.1186/s42047-019-0034-y

Abstract

BackgroundSinonasal melanomas (SNM) are aggressive neoplasms, which present distinct clinicopathological and molecular aspects when compared to cutaneous melanomas (CM). B-cell-specific moloney murine leukemia virus integration site-1 (Bmi-1) is a stem cell marker involved in the regulation of the cell cycle and has been found to be expressed in 70% of CM and 100% of benign nevi. Regarding the cell cycle, Bmi-1 is known to be an upstream repressor of p16, which is a tumor suppressor encoded by the INK4a/Arf locus. Considering this, the aim of this study is to evaluate the immunohistochemical expression of Bmi-1 in a series of SNM and its correlation with the expression of cell cycle proteins (p16 and Ki-67, a nuclear antigen of proliferating cells).MethodsIn 16 cases of SNM, nuclear expression of Bmi-1 and nuclear and cytoplasmic of p16 was classified as: absent, low (> 5 to < 50% of cells) and high (≥50%). Ki-67 proliferation index was represented by the ratio positive cells/ total cells.ResultsHistologically, all cases presented varying amount of necrosis and 75% contained undifferentiated cells. Bmi-1 was detected in 6 cases (37.5%) with high level of expression in 2; p16 expression was seen in 10 cases (62.5%) with high level in 7. The frequency of p16 expression did not differ significantly between tumors with or without Bmi-1 expression. Ki-67 index ranged from 8 to 22%. Neither Bmi-1 nor p16 expression showed correlation with Ki-67 index. Bmi-1 negative tumors presented more extensive necrosis (71.4%); no association between Bmi-1 expression and undifferentiated phenotype was observed.ConclusionsIn our SNM series, low immunohistochemical expression of Bmi-1 was a common phenomenon favoring the hypothesis that mucosal melanoma possibly presents molecular pathways different from the cutaneous counterpart. In SNM, Bmi-1 and p16 expression levels did not correlate with each other or with the cell proliferative index.

Highlights

Sinonasal melanomas (SNM) are aggressive neoplasms, which present distinct clinicopathological and molecular aspects when compared to cutaneous melanomas (CM)
Sinonasal melanomas (SNM) are rare, their etiology is poorly understood, and they present distinct clinicopathological and molecular aspects when compared to their cutaneous counterpart, which is etiologically related to ultraviolet radiation (Franchi et al, 2006)
Deregulation of B-cell-specific moloney murine leukemia virus integration site-1 (Bmi-1) expression has been described in several types of cancer and associated with histological features of tumor aggressiveness as well as with tumor biological behavior (Bachmann et al, 2006; Vrzalikova et al, 2008; Song et al, 2006; Liu et al, 2008; Mihic-Probst et al, 2007; Silva et al, 2007; Bonora et al, 2015) P16 is a tumor suppressor protein, cyclin dependent kinase inhibitor involved in cell proliferation pathways.(Li et al, 2006)

Summary

Introduction

Sinonasal melanomas (SNM) are aggressive neoplasms, which present distinct clinicopathological and molecular aspects when compared to cutaneous melanomas (CM). SNM are associated with poor overall survival at 5 years, frequent undifferentiated phenotype and higher rates of mutations involving C-Kit (CD 117) pathway (López et al, 2016). These particularities show the need to deepen knowledge about SNM, in order to better understand its pathogenesis, which is important for the development of therapeutic strategies. Deregulation of Bmi-1 expression has been described in several types of cancer and associated with histological features of tumor aggressiveness (increased number of mitotic figures and necrosis) as well as with tumor biological behavior (metastatic capacity, predictor of prognosis) (Bachmann et al, 2006; Vrzalikova et al, 2008; Song et al, 2006; Liu et al, 2008; Mihic-Probst et al, 2007; Silva et al, 2007; Bonora et al, 2015) P16 is a tumor suppressor protein, cyclin dependent kinase inhibitor involved in cell proliferation pathways.(Li et al, 2006). As Bmi-1 is a suppressor of the Ink4a / Arf locus, which encodes p16, it has been proposed that this interaction could lead to increased cell proliferation, affecting the biological behavior of the tumor (Song et al, 2006; Mihic-Probst et al, 2007; Allegra et al, 2012; Vormittag et al, 2009; Chen et al, 2011)

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