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. 2022 Feb 27;20(1):54.
doi: 10.1186/s12957-022-02528-y.

Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC)

Xiao-Long Ding #  1   2   3 , Yi-Ge Su #  2 , Liang Yu #  4 , Zhou-Lan Bai  1   3 , Xue-Hong Bai  1   3 , Xiao-Zhen Chen  5 , Xia Yang  6 , Ren Zhao  1   3 , Jin-Xi He  7 , Yan-Yang Wang  8   9
Affiliations

Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC)

Xiao-Long Ding et al. World J Surg Oncol. .

Abstract

Background: Recent studies have shown that according to the expression levels of achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3), small cell lung cancer (SCLC) can be divided into four subtypes: SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant), and SCLC-I (triple negative or SCLC-inflamed). However, there are limited data on the clinical characteristics and prognosis of molecular subtypes of SCLC.

Methods: Immunohistochemistry (IHC) was used to detect the expression levels of ASCL1, NEUROD1, and POU2F3 in 53 patient samples of resectable SCLC. The subtype was defined by the differential expression of the transcription factors for ASCL1, NEUROD1, and POU2F3 or the low expression of all three factors with an inflamed gene signature (SCLC-A, SCLC-N, SCLC-P, and SCLC-I, respectively). The clinicopathological characteristics, immunological features (programmed death ligand 1 [PD-L1] expression and CD8+ tumor infiltrating lymphocyte [TIL] density), and patient outcomes of the four subtypes of SCLC were analyzed.

Results: Positive ASCL1, NEUROD1, and POU2F3 staining was detected in 43 (79.2%), 27 (51.0%), and 17 (32.1%) SCLC specimens by IHC. According to the results of IHC analysis, SCLC was divided into four subtypes: SCLC-A (39.6%), SCLC-N (28.3%), SCLC-P (17.0%), and SCLC-I (15.1%). The 5-year overall survival (OS) rates of these four subtypes were 61.9%, 69.3%, 41.7%, and 85.7%, respectively (P=0.251). There were significant differences in smoking status among different subtypes of SCLC (P= 0.031). However, we did not confirm the correlation between subtypes of SCLC and other clinicopathological factors or immune profiles. Cox multivariate analysis showed that N stage (P=0.025), CD8+ TILs (P=0.024), Ki-67 level (P=0.040), and SCLC-P (P=0.023) were independent prognostic factors for resectable SCLC.

Conclusions: Our IHC-based study validated the proposed classification of SCLC using the expression patterns of key transcriptional regulatory factors. We found that SCLC-P was associated with smokers and was one of the poor prognostic factors of limited-stage SCLC. In addition, no correlation was found between PD-L1 expression or CD8+ TIL density and SCLC subtypes.

Keywords: ASCL1; Molecular subtype; NEUROD1; POU2F3; Prognosis; Small cell lung cancer.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Representative images of PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) in patients with small cell lung cancer (SCLC), as determined by immunohistochemistry (IHC). The first line 100× magnification. The second line 400× magnification
Fig. 2
Fig. 2
Representative immunohistochemistry (IHC) images of small cell lung cancer (SCLC) subtypes as defined by ASCL1, NEUROD1, and POU2F3 expression
Fig. 3
Fig. 3
The mean H-score of ASCL1, NEUROD1, and POU2F3 in small cell lung cancer (SCLC) subtypes
Fig. 4
Fig. 4
Kaplan-Meier analysis of overall survival (OS) in patients with different subtypes of small cell lung cancer (SCLC)
Fig. 5
Fig. 5
Kaplan-Meier analysis of overall survival (OS) based on lymph node metastasis, Ki-67, SCLC-P subtype, or CD8+ tumor infiltrating lymphocytes (TILs) density expression in patients with small cell lung cancer (SCLC)
See this image and copyright information in PMC

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