title: Comprehensive histologic analysis of ALK-rearranged lung carcinomas.
abstract: A subset (1% to 5%) of non-small-cell lung carcinomas harbors the EML4-ALK fusion gene. Data from previous studies on the histomorphology of ALK-rearranged lung cancer are inconsistent, and the specific histologic parameters that characterize this subset and how accurately such parameters predict underlying ALK abnormality remain uncertain. To answer these questions, we performed a comprehensive histologic analysis of 54 surgically resected, extensively sampled ALK-rearranged lung carcinomas and compared them with 100 consecutive resections of ALK-wild-type lung cancers. All 54 cases showed at least a focal adenocarcinoma component, and 3 and 2 cases had additional squamous and sarcomatoid differentiation, respectively. Solid or acinar growth pattern, cribriform structure, presence of mucous cells (signet-ring cells or goblet cells), abundant extracellular mucus, lack of lepidic growth, and lack of significant nuclear pleomorphism were more common in ALK-positive cancers. Two recognizable constellations of findings, a solid signet-ring cell pattern and a mucinous cribriform pattern, were present at least focally in the majority (78%) of ALK-positive tumors, but were rare (1%) in ALK-negative tumors. Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement. Characteristic histologies were present both in primary sites and in metastases. Thus, histologic findings may help to identify cases for ALK testing. However, none of the histologic parameters were completely sensitive or specific to ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies. ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear.
authors.affiliation: Pathology and Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.forename: Harumi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Hisao
authors.initials: H
authors.lastname: Asamura
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000556:secondary / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010997:Pleural Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D011013:Pneumonectomy; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases