Tuberc Respir Dis.  2017 Apr;80(2):179-186. 10.4046/trd.2017.80.2.179.

Keratinization of Lung Squamous Cell Carcinoma Is Associated with Poor Clinical Outcome

• Park HJ
• Cha YJ
• Kim SH
• Kim A
• Kim EY
• Chang YS

• KMID: 2375987
• DOI: http://doi.org/10.4046/trd.2017.80.2.179

Abstract

BACKGROUND
Although the World Health Organization (WHO) classification of lung squamous cell carcinoma (SCC) was revised in 2015, its clinical implications for lung SCC subsets remain unclear. We investigated whether the morphologic characteristics of lung SCC, including keratinization, were associated with clinical parameters and clinical outcome of patients.
METHODS
A total of 81 patients who underwent curative surgical resection of diagnosed lung SCC, were enrolled in this study. Attributes such as keratinization, tumor budding, single cell invasion, and nuclear size within the tumor, as well as immunohistochemistry of Bcl-xL and pS6 expressions, were evaluated.
RESULTS
The keratinizing and nonkeratinizing subtypes did not differ with respect to age, sex, TNM stage, and morphologic parameters such as nuclear diameter, tumor budding, and single cell invasion at the tumor edge. Most patients with the keratinizing subtype (98.0%) had a history of smoking, whereas the nonkeratinizing group had a relatively higher proportion of never-smokers relative to the keratinizing group (24.0% vs. 2.0%; p=0.008, chi-square test). Expression of pS6 (a surrogate marker of mammalian target of rapamycin complex 1 [mTORC1] signaling that regulates keratinocyte differentiation), and Bcl-xL (a key anti-apoptotic molecule that may inhibit keratinization), did not correlate significantly with the presence of keratinization. Patients with the keratinizing subtype had a significantly shorter overall survival (85.2 months vs. 135.7 months, p=0.010, log-rank test), and a multivariate analysis showed that keratinization was an independent, poor prognostic factor (hazard ratio, 2.389; 95% confidence interval, 1.090-5.233; p=0.030).
CONCLUSION
In lung SCC, keratinization is associated with a poor prognosis, and might be associated with smoking.

Keyword

Lung; Carcinoma, Squamous Cell; Bcl-X Protein

MeSH Terms

bcl-X Protein
Biomarkers
Carcinoma, Squamous Cell*
Classification
Epithelial Cells*
Humans
Immunohistochemistry
Keratinocytes
Lung*
Multivariate Analysis
Prognosis
Sirolimus
Smoke
Smoking
World Health Organization
Biomarkers
Sirolimus
Smoke
bcl-X Protein

Figure

• 

  Figure 1 Histologic parameters and patterns of keratinization applied in this study. Tumor budding is observed along tumor edge (A); this is defined as the presence of structures comprising fewer than five tumor cells (arrowheads) at higher magnification (B). Single cell invasion (C) and large nuclei (cancer cell nucleus >4 times than that of a small lymphocyte) (D), nonkeratinization (entire tumor area, <5% keratinization) (E), cytoplasmic keratinization (F), keratin pearl (G), and layered keratinization (H) (H&E stain; A, ×40; B–D, ×400; E–H, ×200).

• 

  Figure 2 Relationship of keratinization (A–D, H&E stain, ×200) with the expression of pS6 ribosomal protein (Ser235/236; E–H, ×200) and Bcl-xL (I–L, ×200). Images represent nonkeratinization (A, E, I), cytoplasmic keratinization (B, F, J), keratin pearl (C, G, K), and layered keratinization (D, H, L). Distribution of pS6 (M) and Bcl-xL (N) expression in lung squamous cell carcinoma.

• 

  Figure 3 Disease-free survival (A) and overall survival (B) of patients with lung squamous cell carcinoma according to the keratinization status (p-values were obtained using the log-rank test).

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