Once neuroendocrine carcinomas are excluded, the next step in the pathologic evaluation of an NSCLC is to determine whether it represents SqCC, ADC, LCC (usually diagnosed as a poorly differentiated NSCLC or NSCLC, not otherwise specified, on small samples), or one of a variety of less common histologic types of tumors. Separation of SqCC from ADC has become important for identifying patients for targeted therapies and further genetic evaluation. Bevacizumab therapy has been associated with severe pulmonary hemorrhage in patients treated for pulmonary SqCCs.31 ADCs and NSCLCs, not otherwise specified, should be evaluated for epidermal growth factor receptor mutations since the existence of mutations is predictive of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors,32,33 and ADC histology is predictive of improved outcome with pemetrexed therapy compared with squamous cell carcinoma.8 IHC is not necessarily required if glandular or squamous differentiation is evident (Figs 3A, 3B). The typical IHC profile of pulmonary ADC includes strong expression of TTF-1 (Fig 3C) (80%-90% of ADCs) and napsin-A (Fig 3E) and variable expression of p63 and CK5/6 (up to one-third of ADCs) as compared with SqCC, which is almost always nagative for TTF-1 and displays diffuse expression of p63 (Fig 3D) and CK5/6 (Fig 3F).27,34‐37 Mucinous ADCs are less likely than nonmucinous ADCs to demonstrate TTF-1 expression; in a study of 14 mucinous pulmonary neoplasms, Goldstein and Thomas38 found TTF-1 positivity in only three cases (21%), with TTF-1 reactivity being weak and focal. In practice, however, mucinous tumors do not need IHC to be classified as ADCs. Thus, practically speaking, although a positive result for TTF-1 staining is very useful for supporting a pulmonary origin and favoring ADC over SqCC, a negative result does not completely exclude a diagnosis of ADC. Although p63 and CK5/6 are valuable for confirming squamous differentiation, definitive classification still requires the presence of squamous histologic characteristics (keratinization, intercellular bridges). Other novel antibodies have also been investigated for differentiating pulmonary ADC and SqCC. Napsin-A is positive in > 60% of pulmonary ADCs, whereas < 30% of pulmonary SqCCs stain for this protein.37,39,40 Recently, desmocollin-3 has been claimed to identify squamous differentiation,41 whereas staining for surfactant proteins favors ADC over SqCC.42 In this era of small biopsies, in which sample preservation for molecular tests is important, limited IHC panels using either two antibodies (TTF-1/p63)34 or four antibodies (TTF-1/napsin-A/p63/CK5/6) have been recommended.37 Recent studies have shown that p40—an antibody that recognizes a p63 isoform (ΔNp63)—is as sensitive as p63 in detecting squamous lineage, but it is markedly superior to p63 in specificity. Unlike p63, which can be positive in about 30% of ADCs and 50% of large cell lymphomas, p40 is reportedly negative in lymphomas and focally positive in only 3% of ADCs.43,44 Some nonsquamous solid cancers can also be classified as solid-predominant ADCs with mucin production by a simple mucicarmine stain, even when TTF-1 and napsin-A are negative.