Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure. Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce). Adenocarcinoma can also be distinguished by staining for TTF-1, a cell marker for adenocarcinoma.As discussed previously, the category of adenocarcinoma includes are range of subtypes, and any one tumor tends to be heterogeneous in composition. Several major subtypes are currently recognized by the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) / American Thoracic Society (ATS) / European Respiratory Society (ERS): lepidic predominant adenocarcinoma, acinar predominant adenocarcinoma, papillary predominant adenocarcinoma, micropapillary predominant adenocarcinoma, solid predominant adenocarcinoma, and solid predominant with mucin production. In as many as 80% of these tumors, components of more than one subtype will be recognized. Surgically resected tumors should be classified by comprehensive histological subtyping, describing patterns of involvement in increments of 5%. The predominant histologic subtype is then used to classify the tumor overall. The predominant subtype is prognostic for survival after complete resection.To reveal the adenocarcinomatous lineage of the solid variant, demonstration of intracellular mucin production may be performed. Foci of squamous metaplasia and dysplasia may be present in the epithelium proximal to adenocarcinomas, but these are not the precursor lesions for this tumor. Rather, the precursor of peripheral adenocarcinomas has been termed atypical adenomatous hyperplasia (AAH).
As the most common cause of acquired resistance to first-generation TKIs is a second EGFR mutation on codon 790, a third-generation EGFR TKI, osimertinib, has been developed to target this new mutation as well. MET amplification is another known mechanism of acquired resistance.ALK inhibitors such as crizotinib showed to be effective against tumors harboring ALK fusions. Most patients previously treated with crizotinib benefited from second-generation ALK inhibitors including ceritinib, alectinib and brigatinib. Resistance to ALK inhibitors can occur with novel acquired ALK mutations or amplifications.Also ROS1-positive tumors have shown high sensitivity to ALK inhibitors due to the high homology between the kinase domains of ROS1 and ALK. Immunotherapy
Immune response can be prevented via activation of immune checkpoints, which consist in the binding of a ligand protein (e.g. PD-L1) to a receptor (e.g. PD-1) on the immune cell surface. As a consequence, cancer cells expressing PD-L1 can inactivate T cells thus fostering tumor growth. Immune checkpoint inhibitors have been developed to restore T cell-mediated antitumor immunity by blocking either the ligand or the receptor.Immune checkpoint inhibitors have been approved for NSCLC, including anti-PD-1 nivolumab and pembrolizumab. Anti-PD-1 agents are used for patients with advanced NSCLC whose tumors progress after first-line cytotoxic chemotherapy. Pembrolizumab was established as a new standard of care for patients with advanced or metastatic NSCLC with high PD-L1 expression levels, and responses are even more pronounced for tumor with a high mutational burden (i.e.