The switch from in situ to invasive tumor growth represents a crucial stage in the evolution of lung adenocarcinoma. However, the biological understanding of this shift is limited, and ‘Noguchi Type C’ tumors, being early lung adenocarcinomas with mixed in situ and invasive growth, represent those that are highly valuable in advancing our understanding of this process. All Noguchi Type C adenocarcinomas (n = 110) from the LATTICE-A cohort were reviewed and two patterns of in situ tumor growth were identified: those deemed likely to represent a true shift from precursor in situ to invasive disease (‘Noguchi C1’) and those in which the lepidic component appeared to represent outgrowth of the invasive tumor along existing airspaces (‘Noguchi C2’). Overall Ki67 fraction was greater in C2 tumors and only C1 tumors showed significant increasing Ki67 from in situ to invasive disease. P53 positivity was acquired from in situ to invasive disease in C1 tumors but both components were positive in C2 tumors. Likewise, vimentin expression was increased from in situ to invasive tumor in C1 tumors only. Targeted next generation sequencing of 18 C1 tumors identified four mutations private to the invasive regions, including two in TP53, while 6 C2 tumors showed no private mutations. In the full LATTICe-A cohort, Ki67 fraction classified as either less than or greater than 10% within the in situ component of lung adenocarcinoma was identified as a strong predictor of patient outcome. This supports the proposition that tumors of all stages that have ‘high grade’ in situ components represent those with aggressive lepidic growth of the invasive clone. Overall these data support that the combined growth of Noguchi C tumors can represent two differing biological states and that ‘Noguchi C1’ tumors represent the genuine biological shift from in situ to invasive disease.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $52.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ishizumi T, McWilliams A, MacAulay C, et al. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev. 2010;29:5–14.
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.
Murakami S, Ito H, Tsubokawa N, et al. Prognostic value of the new IASLC/ATS/ERS classification of clinical stage IA lung adenocarcinoma. Lung Cancer. 2015;90:199–204.
Nakanishi H, Matsumoto S, Iwakawa R, et al. Whole genome comparison of allelic imbalance between noninvasive and invasive small-sized lung adenocarcinomas. Cancer Res. 2009;69:1615–23.
Soh J, Toyooka S, Ichihara S, et al. Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung. J Thorac Oncol. 2008;3:340–7.
Yoo SB, Chung JH, Lee HJ, et al. Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung. J Thorac Oncol. 2010;5:964–9.
Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109–21.
Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545:446–51.
Yatabe Y, Takahashi T, Mitsudomi T. Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res. 2008;68:2106–11.
Murphy SJ, Wigle DA, Lima JF, et al. Genomic rearrangements define lineage relationships between adjacent lepidic and invasive components in lung adenocarcinoma. Cancer Res. 2014;74:3157–67.
Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844–52.
Nagayoshi Y, Yamamoto K, Hashimoto S, et al. An autopsy case of lepidic pulmonary metastasis from cholangiocarcinoma. Intern Med. 2016;55:2849–53.
Okafuji T, Sakai S, Yoshimitsu S, et al. Pulmonary metastasis from pancreatic cancer: a case showing biphasic radiological and histological patterns. CMIG Extra: Cases. 2004;28:68–71.
Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25:5240–7.
Choi Y, Lee HJ, Jang MH, et al. Epithelial-mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol. 2013;44:2581–9.
Vellinga TT, den Uil S, Rinkes IH, et al. Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion. Oncogene. 2016;35:5263–71.
von der Thüsen JH, Tham YS, Pattenden H, et al. Prognostic significance of predominant histologic pattern and nuclear grade in resected adenocarcinoma of the lung: potential parameters for a grading system. J Thorac Oncol. 2013;8:37–44.
Aokage K, Miyoshi T, Ishii G, et al. Influence of ground glass opacity and the corresponding pathological findings on survival in patients with clinical stage I non-small cell lung cancer. J Thorac Oncol. 2018;13:533–42.
Moon Y, Sung SW, Lee KY, et al. Pure ground-glass opacity on chest computed tomography: predictive factors for invasive adenocarcinoma. J Thorac Dis. 2016;8:1561–70.
Suh YJ, Lee HJ, Kim YT, et al. Added prognostic value of CT characteristics and IASLC/ATS/ERS histologic subtype in surgically resected lung adenocarcinomas. Lung Cancer. 2018;120:130–6.
Yoshizawa A, Sumiyoshi S, Sonobe M, et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol. 2013;8:52–61.
Lewis BC, Klimstra DS, Socci ND, et al. The absence of p53 promotes metastasis in a novel somatic mouse model for hepatocellular carcinoma. Mol Cell Biol. 2005;25:1228–37.
Wang SP, Wang WL, Chang YL, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol. 2009;11:694–704.
Moore DA, Balbi K, Ingham A, et al. Analysis of a large cohort of non-small cell lung cancers submitted for somatic variant analysis demonstrates that targeted next-generation sequencing is fit for purpose as a molecular diagnostic assay in routine practice. J Clin Pathol. 2018;71:1001–6.
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.
Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res. 2008;68:6913–21.
Samuels Y, Diaz LA Jr, Schmidt-Kittler O, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7:561–73.
Yuan W, Stawiski E, Janakiraman V, et al. Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene. 2013;32:318–26.
This work was supported by a CRUK Center infrastructure award [C1362/A18081] and a Hope Against Cancer Small Grant.