OHL is most often confused with idiopathic clinical leukoplakia, tobacco-induced leukoplakia, frictional keratosis, edema, lichen planus, galvanic lesions, geographic tongue, maceration, white sponge nevus, oral graft-versus-host disease, and chronic hyperplastic OC (Wescott and Correll 1988; Triantos et al., 1997; Reginald and Sivapathasundharam 2010; Huber 2010). Because of that, it is imperious, the identification of the lesion (Reginald and Sivapathasundharam 2010). Uncharacteristic cases of OHL may be identified by their absence of reaction to antifungal therapy and elimination of other diseases by histologic features (Wescott and Correll 1988).

OHL clinical identification is indeterminate, so the diagnosis is defined by histologic analysis of tissues from a biopsy sample to verify tissue morphology and identification of replicating EBV (Reginald and Sivapathasundharam 2010).

Histologic features of OHL consist of epithelial hyperplasia with hyperparakeratosis and acanthosis, enlarged and ballooned cells. The cells also show nuclear changes such as: (a) margination of the nuclear chromatin against the nuclear membrane (“nuclear beading”); (b) an eosinophilic central Cowdry type A appearance with a halo homogeneous eosinophilic or basophilic aspect, with marginal chromatin clumping; and (c) nuclei with steel gray or like ground glass aspect, and the chromatin is marginated and clumped (Triantos et al., 1997; Dias et al., 2000; Reginald and Sivapathasundharam 2010).

However, biopsies are invasive procedures and might not be practicable on all patients due to their immune condition. In adding, specific and costly apparatus are necessary to identify EBV, which might not be available (Reginald and Sivapathasundharam 2010). In addition, exfoliative cytology can be used to diagnose and it may be the technique of election for OHL diagnosis for being a simple, reliable, safe, noninvasive, and nontraumatic method (Moura et al., 2007). The keratinocytes with nuclear alterations produced by EBV are present at several layers of the epithelium, including the parakeratin layer, making them readily reachable for sample collection, as an exfoliative analysis (Dias et al., 2012). Overall, the exfoliative cytology allied with EBV in situ hybridization is an easy, useful, and noninvasive diagnostic instrument for OHL (Braz-Silva et al., 2014). EBV can be identified through electronic microscopy techniques, in situ hybridization, immunohistochemistry, and polymerase chain reaction. An absence of reaction to the antifungal treatment or a verification of an immunosuppressed states may guide the presumptive diagnosis (Moura et al., 2010; Reginald and Sivapathasundharam 2010). In this way, the nuclear alterations produced by EBV and detected by cytopathology is specific and sufficient for the final diagnosis of OHL, independent of the detection of the EBV (Milagres et al., 2007).

Treatment for OHL is not necessary in most of the patients (Baccaglini et al., 2007). This lesion frequently resolves in concert with enhanced immunocompetence, as observed in a patient receiving HAART (Huber 2010). The treatments proposed in the literature for OHL include surgical excision, cryotherapy, systemic therapy with antiviral drugs, and topical therapy (Triantos et al., 1997). Topical therapy includes retinoids, podophyllin, podophyllin with penciclovir, podophyllin with acyclovir, acyclovir, and gentian violet (Goh and Lau 1994; Walling et al., 2003; Pastore et al., 2006; Moura et al., 2007; Bhandarkar et al., 2008; Moura et al., 2010). Moura et al. (2010) observed that the treatment with podophyllin with acyclovir cream was more effective in the clinical healing rate for OHL than podophyllin and podophyllin with penciclovir cream, and no recurrent OHL was observed in this first treatment. Additional studies have been conducted on the treatment for OHL with antiviral agents in topical creams (Patton et al., 2013).