The detection of a driver mutation in a patient does not suggest that he/she can receive precision medicine owing to factors such as the lack of therapy or rapid progression of the disease. diagnosis. In this article, we focused on genetic and epigenetic abnormalities in non-small cell carcinoma (adenocarcinoma and squamous cell carcinoma), neuroendocrine tumor (including carcinoids, small cell carcinoma, and large cell neuroendocrine carcinoma), and carcinoma with rare histological subtypes. In addition, we summarize the therapeutic targeted reagents that are currently available and undergoing clinical trials. A good understanding of the morphological and molecular profiles will be necessary in routine practice when the NGS platform is widely used. (46%), (33%), (17%), (17%), (14%), (11%), (10%), (9%), (8%), (8%), (7%), (7%), (7%), (6%), (4%), (4%), (3%) and (2%). In the signaling pathway, around 75% of the examined ADCs presented with driver gene mutations (and and (pathway suppressor gene, 8.3%) and (constitutes pathway, 2.2%) mutations. mRNA profiling subdivided ADC into three transcriptional subtypes: the terminal respiratory unit (TRU), the proximal-inflammatory (PI) and the proximal-proliferative (PP) mRNA subtypes . The TRU subtype presented with frequent mutations and kinase fusions, while the PI subtype was characterized by co-mutations of and mutation and inactivation. This clustering was partially overlapped by those observed in the protein expression profiles. DNA methylation profiling also divided the ADC into three categories; CpG island methylator phenotype (CIMP)-high, CIMP-intermediate and CIMP-low subtypes . CIMP-high tumors have frequent methylated and mutation, the most common therapeutic targeted driver mutation in ADC, is associated with a micropapillary pattern . Lepidic ADC (categorized as bronchioloalveolar carcinoma in the Fulvestrant S enantiomer previous WHO classification) is also reported to be related to mutations [7,8,9]. rearrangements are Fulvestrant S enantiomer observed in approximately 4C5% of ADCs , and are characterized by the presence of signet ring cells forming an acinar structure with mucin production [11,12,13]. The morphological characteristics of fusions and psammomatous calcifications [15,16]. ADCs with fusions presented with poorly-differentiated histology when compared to those with mutations or rearrangements . RYBP Micro-RNAs are now considered as attractive targets of diagnostic and predicting markers. Nadal et al. performed clustering of 356 miRNAs, and identified three major clusters of lung ADCs that were correlated with the histologic subtype of lung ADC . Cluster 1 included lepidic or mucinous invasive ADCs, while clusters 2 and 3 comprised acinar and solid tumors. Nineteen miRNAs were detected with solid pattern and 30 with lepidic pattern. Three miRNAs encoded at 14q32 (miR-411, miR-370 and miR-376a) were associated with poor survival. The Fulvestrant S enantiomer mucin-rich subtype including mucinous ADC (IMA) and colloid ADC (CA), is shown to harbor mutations more often than Fulvestrant S enantiomer the non-mucinous subtype [19,20,21,22,23]. fusion genes have been observed in 13C27% of have been detected by NGS analysis [20,26]. mutations have been observed along with repression, and associated with mucinous carcinoma development  and Napsin A downregulation . The most common genetic abnormality in enteric carcinomas (EC) was mutation followed by fusion, mutations and mutations [29,30]. Moreover, four out of five enteric ADCs had mutations in mismatch-repair genes, and tumor mutational burden (TMB) levels were higher than those seen in control ADCs . CDX2 and MUC2, the intestinal IHC markers frequently positive in EC, are reported to be expressed in CA . Furthermore, IMA, CA and EC are occasionally assumed as tumors on the same spectrum [20,26,28]. A recent study attempted to reclassify these tumors according to the IHC status . Fetal ADC (FA) is occasionally subdivided into low- and high-grade carcinomas according to the nuclear characteristics. Genetic abnormalities in the Wnt pathway and aberrant beta-catenin overexpression are observed due to mutation in low-grade FA . A recent analysis with NGS showed and mutations in FA . High-grade FA, on the other hand, was characterized by p53 overexpression and mutations in both (20%) and (7%) . 2.3. Squamous Cell Carcinoma 2.3.1. Morphological Subtypes SQCs are divided into keratinizing, non-keratinizing, and basaloid types. Non-keratinizing SQC is sometimes difficult to distinguish from poorly-differentiated solid ADCs, and due to which, IHC analysis is warranted for diagnosis. Basaloid type SQC is also positive for the IHC markers of Fulvestrant S enantiomer SQC, but consists of unique molecular profiles. The prognostic difference between each histological subtype is controversial . 2.3.2. Molecular Abnormalities in SQC Confirmed by TCGA In 2012, the TCGA project released the results of the molecular.