title: HNF4α as a marker for invasive mucinous adenocarcinoma of the lung.
abstract: A new lung adenocarcinoma classification was recently proposed by IASLC/ATS/ERS. In this classification, invasive mucinous adenocarcinoma (IMC) is placed in a new category because of its unique radiologic, morphologic, and genetic characteristics. Minimal cytologic atypia characterizes this tumor; thus, it is occasionally difficult to make a diagnosis with a biopsy specimen. We used immunohistochemistry to examine HNF4α expression in a tissue microarray consisting of 278 lung adenocarcinoma specimens. In addition, we analyzed the clinicopathologic features, including EGFR, KRAS, and ALK mutation status. HNF4α expression was detected in 33 of the 37 surgically resected IMCs. The tumor cells were uniformly labeled with the molecule in all of the corresponding biopsy specimens, whereas the normal cells were not. Although HNF4α was also expressed in other lung adenocarcinoma subtypes, those with HNF4α expression shared IMC features, including negative TTF-1 expression (P<0.001), positive CDX2 expression (P<0.001), positive KRAS mutation status (P=0.001), and negative EGFR mutation status (P<0.001). Although some ALK-positive adenocarcinomas showed IMC morphology, the tumors were negative for HNF4α, suggesting that they belonged to a different group of tumors. We found that HNF4α labeled all of the IMC tumors except the ALK-positive adenocarcinomas. Thus, HNF4α positivity could serve as a useful marker for overcoming the diagnostic difficulties caused by minimal nuclear atypia and sparse tumor cells in small biopsy samples. Because other adenocarcinoma subtypes with HNF4α expression share clinicopathologic features with IMC, these adenocarcinomas, especially the columnar cell type of acinar-predominant adenocarcinoma, might constitute a biological spectrum of IMC.
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sugano
authors.forename: Toru
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sasaki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Waki
authors.initials: W
authors.lastname: Hosoda
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011013:Pneumonectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins