The growth pattern of peripheral squamous cell carcinoma (SCC) of the lung is divided into two types: alveolar space-filling (ASF) growth and alveolar space-destructive (ASD) growth. The aim of this study was to investigate the clinicopathological differences between cancer cells displaying ASF and ASD growth.
We analyzed 155 patients with peripheral SCC measuring 30 mm or less in diameter. The proportion of ASF in the total tumor area (%ASF) was determined using digital image analysis. We examined the clinicopathological characteristics of the cancer cells and compared the immunophenotypes of high %ASF tumors (> 30%) and low %ASF tumors (0%). Finally, we analyzed the prognostic impact of ASD area with small SCC cases (≤ 2.0 cm, n = 72).
Cases of high %ASF tumors showed significantly lower frequencies of lymphovascular invasion (p = 0.008). Immunohistochemical staining revealed that the expression score of laminin-5, invasive-related molecule, in cancer cells was significantly lower in high %ASF cases than in low %ASF cases (p = 0.001). Within the same tumor, laminin-5 expression in the ASF area was significantly lower than that in the ASD area (p = 0.001). The overall 5-year survival rate of patients with a larger ASD area (> 1.0 cm2) was significantly lower than that of patients with a smaller ASD area (≤ 1.0 cm2) (p = 0.017).
In this study, we clearly showed that cancer cells presenting with ASF represents a “less invasive phenotype” in peripheral SCC.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Alveolar space filling
Alveolar space destructive
- CD204(+) TAMs:
CD204-positive tumor-associated macrophages
Carbonic anhydrase IX
Glucose transporter 1
Programmed death-ligand 1
Squamous cell carcinoma
Statistical Package for Social Science
Victoria blue van Gieson
- 95% CI:
95% Confidence interval
Carter D (1985) Squamous cell carcinoma of the lung: an update. Semin Diagn Pathol 2:226–234
Dingemans KP, Mooi WJ (1984) Ultrastructure of squamous cell carcinoma of the lung. Pathol Annu 19(Pt 1):249–273
Funai K, Yokose T, Ishii G et al (2003) Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung. Am J Surg Pathol 27:978–984
Hayashi T, Sano H, Egashira R et al (2013) Difference of morphology and immunophenotype between central and peripheral squamous cell carcinomas of the lung. Biomed Res Int 2013:157838. https://doi.org/10.1155/2013/157838
Huhti E, Saloheimo M, Sutinen S et al (1983) Does the location of lung cancer affect its prognosis? Eur J Respir Dis 64:460–465
Kadota K, Villena-Vargas J, Yoshizawa A et al (2014) Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease. Am J Surg Pathol 38:448–460. https://doi.org/10.1097/PAS.0000000000000134
Kawabata Y, Sakamoto S, Umino T et al (1996) Growth of squamous cells lung cancer between alveolar basement membrane and alveolar epithelium. Nihon Kyobu Shikkan Gakkai Zasshi 34:878–884
Krimsky W, Muganlinskaya N, Sarkar S et al (2016) The changing anatomic position of squamous cell carcinoma of the lung—a new conundrum. J Community Hosp Intern Med Perspect 6:33299. https://doi.org/10.3402/jchimp.v6.33299
Maeshima AM, Maeshima A, Asamura H et al (2006) Histologic prognostic factors for small-sized squamous cell carcinomas of the peripheral lung. Lung Cancer (Amsterdam, Netherlands) 52:53–58. https://doi.org/10.1016/j.lungcan.2005.11.010
Malara NM, Sgambato A, Granone P et al (1999) Biological characterization of central and peripheral primary non small cell lung cancers (NSCLC). Anticancer Res 19:2249–2252
Mizushima Y, Yamashita R, Kusajima Y et al (2000) Prognostic comparison between peripheral and central types of squamous cell carcinoma of the lung in patients undergoing surgical resection. Oncol Rep 7:319–322
Moriya Y, Niki T, Yamada T et al (2001) Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size. An immunohistochemical analysis of 102 cases. Cancer 91:1129–1141
Paakko P, Risteli J, Risteli L, Autio-Harmainen H (1990) Immunohistochemical evidence that lung carcinomas grow on alveolar basement membranes. Am J Surg Pathol 14:464–473
Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108. https://doi.org/10.3322/canjclin.55.2.74
Perez-Moreno P, Brambilla E, Thomas R et al (2012) Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res 18:2443–2451. https://doi.org/10.1158/1078-0432.CCR-11-2370
Rami-Porta R, Bolejack V, Crowley J et al (2015) The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 10:990–1003. https://doi.org/10.1097/JTO.0000000000000559
Saijo T, Ishii G, Nagai K et al (2006) Differences in clinicopathological and biological features between central-type and peripheral-type squamous cell carcinoma of the lung. Lung Cancer (Amsterdam, Netherlands) 52:37–45. https://doi.org/10.1016/j.lungcan.2005.12.006
Sakurai H, Asamura H, Watanabe S et al (2004) Clinicopathologic features of peripheral squamous cell carcinoma of the lung. Ann Thorac Surg 78:222–227. https://doi.org/10.1016/j.athoracsur.2004.01.029
Saruwatari K, Ikemura S, Sekihara K et al (2016) Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations. Lung Cancer (Amsterdam, Netherlands). 91:7–14. https://doi.org/10.1016/j.lungcan.2015.11.012
ten Velde GP, Havenith MG, Volovics A et al (1991) Prognostic significance of basement membrane deposition in operable squamous cell carcinomas of the lung. Cancer 67:3001–3005
Tomashefski JF Jr, Connors AF Jr, Rosenthal ES et al (1990) Peripheral vs central squamous cell carcinoma of the lung. A comparison of clinical features, histopathology, and survival. Arch Pathol Lab Med 114:468–474
Travis WD, Brambilla E, Riely GJ (2013) New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 31:992–1001. https://doi.org/10.1200/JCO.2012.46.9270
Travis WD, Asamura H, Bankier AA et al (2016) The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 11:1204–1223. https://doi.org/10.1016/j.jtho.2016.03.025
Tsim S, O’Dowd CA, Milroy R et al (2010) Staging of non-small cell lung cancer (NSCLC): a review. Respir Med 104:1767–1774. https://doi.org/10.1016/j.rmed.2010.08.005
Udagawa H, Ishii G, Morise M et al (2015) Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung. J Cancer Res Clin Oncol 141:1417–1425. https://doi.org/10.1007/s00432-015-1912-7
Watanabe Y, Yokose T, Sakuma Y et al (2011) Alveolar space filling ratio as a favorable prognostic factor in small peripheral squamous cell carcinoma of the lung. Lung Cancer (Amsterdam, Netherlands) 73:217–221. https://doi.org/10.1016/j.lungcan.2010.12.001
Wohlschlager J, Wittekind C, Theegarten D (2010) New TNM classification of malignant lung tumours. Pathologe 31:355–360. https://doi.org/10.1007/s00292-010-1303-4
Yousem SA (2009) Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling. Hum Pathol 40:861–867. https://doi.org/10.1016/j.humpath.2008.11.008
This study was supported in part by the National Cancer Center Research and Development Fund (29-A-9) and JSPS KAKENHI (16H05311).
Conflict of interest
The authors have no conflict of interest to disclose.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Omori, T., Aokage, K., Nakamura, H. et al. Growth patterns of small peripheral squamous cell carcinoma of the lung and their impacts on pathological and biological characteristics of tumor cells. J Cancer Res Clin Oncol 145, 1773–1783 (2019). https://doi.org/10.1007/s00432-019-02937-9
- Peripheral lung cancer
- Squamous cell carcinoma
- Alveolar space filling (ASF)
- Alveolar space destructive (ASD)