Lung cancer is the leading cause of cancer-related death worldwide, accounting for approximately 1.4 million deaths in 2010 in the USA, according to the SEER d atabase [1]. Approximately 85% of newly diagnosed lung tumors are non-small-cell lung cancer (NSCLC) and, among them, 20–30% are squamous cell lung cancer (SQCLC). The incidence of this subtype has now been surpassed by adenocarcinoma, reflecting trends in reduced tobacco exposure with the introduction of filtered and low-tar content cigarettes, as well as changes in cigarette smoke inhalation patterns [2]. The diagnosis of SQCLC is currently performed by light microscopy and relies on the presence of keratinization and/or intracellular bridges. With the increasing need of a correct histological diagnosis in order to choose the right therapeutic regimen, the dichotomy between small-cell lung cancer and NSCLC became obsolete. For such reasons when in poorly differentiated lung carcinomas there is no clear-cut cellular differentiation at light microscopy, which account for 20–30% of cases, a panel of immunohistochemistry (IHC) markers has been shown to increase the likelihood of an appropriate subtyping. This panel includes at least cytokeratin CK7, CK5, TTF-1 and p63, as demonstrated by a retrospective study performed on fine-needle aspiration cytology cell blocks [3]. Another marker, p40, an antibody that recognizes the ΔNp63-a p63 isoform, is equivalent to p63 in sensitivity but markedly superior to p63 in specificity, which eliminates the potential pitfall of misinterpreting a p63-positive adenocarcinoma or unsuspected lymphoma as a SCC [4]. Current available treatment options for advanced SQCLC rely only on systemic cytotoxic chemotherapy. Patients with a good performance status (Eastern Cooperative Oncology Group performance status 0–1) should receive a platinum agent, cisplatin (preferentially) or carboplatin, plus a third-generation drug (taxanes,