GCT is a benign tumor that occasionally induces PEH of the covering epithelium, mimicking an invasive oral SCC, which can make diagnosis difficult in some cases [2, 4]. However, some studies have reported the coexistence of the two lesions in the dorsum of the tongue and another one showed that is also a common site of an oral SCC [9–13]. For this reason, and given the history of heavy smoking, alcoholism and the fast growth of the tongue lesion, it was important to investigate the neoplastic potential of GCT using the immunohistochemical panel of S-100, vimentin, CD68, p53, Ki-67, E-cadherin, collagen IV and cytokeratin AE1/AE3 antibodies.
Several immunohistochemistry studies have been conducted to investigate the origin of GCT [1–3], while others have investigated its clinical behavior and possible association between this neoplasm and other malignant lesions in the oral cavity [4, 5, 9–12]. Most authors consider that Schwann cells are the precursors of GCT because of positivity for S-100 and vimentin [1, 2, 4]. In line with the literature, immunohistochemical analysis of S-100 and vimentin in the present case revealed strong and diffuse staining in GCT [1, 2]. This result reinforces the diagnosis of GCT.
With regard to S-100 and vimentin expressions in oral SCC, Albuquerque et al.  found an increased number of reactive cells for S-100 protein in dendritic cells from the tumor site. Furthermore, vimentin expression has frequently been detectable in the majority of finger-like invasive fronts of tumors and may be associated with the metastatic conversion of epithelial cells and tumor invasion . In our clinical case, the expression of vimentin was negative in epithelial cells of GCT.
Another common immunohistochemical marker that has been traditionally used for identifying GCT is CD68, a marker of lysosomes, mostly associated with macrophages, which is also usually positive in GCT [2, 16], as shown in the present case. In contrast, the immunohistochemical staining of CD68 in oral SCC was distributed diffusely along the inflammatory infiltrate .
It is important to emphasize that few studies have investigated the expression of p53 protein, an important tumor suppressor gene related to oral carcinogenesis, in benign GCT [18–20]. Caltabiano et al.  evaluated the expression of oncoprotein p53 in a case of GCT and SCC colocalized at the same site. They showed that immunohistochemical reactivity for p53 was increased within the nuclei of the invasive tumor cells in the full thickness of the epithelium as found by Zarovnaya et al.  in SCC. According to our findings, Zarovnaya et al.  showed that nuclear staining of p53 was limited to the basal cells and the cells adjacent in a linear pattern in cases of benign mucosa with varying degrees of PEH. Furthermore, p53 protein accumulation can be found in benign lesions and may represent a response to cellular stresses .
The immunostaining of Ki-67 in GCT showed a very low number of positive cells in basal and parabasal layers and some isolated granular cells [8, 16, 19]. Coincidentally, in cases of oral SCC the basal and parabasal layers also exhibit staining of Ki-67. However, high Ki-67 expression levels of neoplastic cells at the invasive tumor front are noted [17, 20]. Thus, the increase of Ki-67 immunostaining in cases of GCT could be considered an important signal of the predilection of tumor behavior and may suggest a possible association with other malignant lesions such as SCC.
With regard to E-cadherin and collagen IV expressions, we found a uniform membranous staining of E-cadherin, an intercellular calcium-dependent cell adhesion molecule, in the overlying epithelium. This is in accordance with the study of Zarovnaya et al. , which showed no loss of cell adhesion in benign PEH. This same study revealed decreased or absent staining for E-cadherin in malignant cell clusters in oral SCC. In addition, the main component of basement membrane, collagen IV, was absent in our case as found in benign inflamed areas within PEH . Therefore, our results also suggested that collagen IV is not useful for differentiating PEH of SCC. Another important molecular marker for characterizing GCT was cytokeratin AE1/AE3, which showed negative in granular cells.
The association of clinical data with immunohistochemical findings was essential to confirm the diagnosis of the lesion. Neither cellular atypia, pleomorphism, necrosis, high mitotic index or other histological signs of malignancy were identified in our case. However, in cases where there is doubt, the immunohistochemical panel could be useful for excluding characteristics of a malignant neoplasm and avoiding an aggressive therapy.
The aim of this case report was to use the immunohistochemistry panel as a tool complementary to hematoxylin and eosin to help distinguish invasive SCC of GCT-PEH (granular cell tumor-pseudoepitheliomatous hyperplasia), especially when risk factors such as alcohol and tobacco are associated. It is important to emphasize that a characteristic microscopic finding of GCT is the presence of varying degrees of pseudoepitheliomatous hyperplasia of the overlying epithelium. Our results showed that GCT behaves as a benign neoplasia, but tumors with rapid growth, high Ki-67 and p53 expressions should be viewed with caution and require a long-term follow-up.