AXIN2 and SNAIL expression predict the risk of recurrence in cutaneous squamous cell carcinoma after Mohs micrographic surgery

Abstract

Recurrence is a common complication observed during cutaneous squamous cell carcinoma (cSCC) treatment; however, biomarkers for predicting recurrence in cSCC remain unknown. The present study aimed to investigate the predictive value of axis inhibition protein 2 (AXIN2) and SNAIL expression in cSCC recurrence. AXIN2 and SNAIL expression was evaluated using immunohistochemistry in 111 cSCC tissue samples obtained from 18 patients who presented recurrence (recurrence interval, 1-91 months) and 93 patients who did not experience recurrence following Mohs micrographic surgery (MMS) during the follow-up period (156 months). Nomogram construction was performed using patients' clinicopathological characteristics and AXIN2 and SNAIL protein expression. The results demonstrated that high AXIN2 (histoscore >100) and SNAIL (histoscore >100) expression was detected in 35 and 44 cSCC tissues, respectively. Furthermore, the expression levels of AXIN2 and SNAIL were significantly associated in patients with cSCC (P=0.001). AXIN2 and SNAIL expression levels were significantly associated with tumor size (P=0.021 and P=0.044, respectively) and recurrence of cSCC (P=0.017 and P=0.042, respectively). In addition, the results of the Kaplan-Meier curve analysis revealed that recurrence-free survival was significantly associated with tumor size (P=0.025), differentiation status (P<0.001), AXIN2 expression (P=0.001) and SNAIL expression (P=0.001). Furthermore, the results of the multivariate analysis demonstrated that age (P=0.043), AXIN2 expression (P=0.001) and SNAIL expression (P=0.045) were independent risk factors for cSCC recurrence in the present cohort. A nomogram for predicting the 1-, 2-, 3-, and 5-year recurrence-free survival was developed for patients with cSCC by including independent risk factors with a concordance index of 0.75. The results suggested that high AXIN2 and SNAIL expression may be considered as potential risk factors for cSCC recurrence. This nomogram may therefore be useful to assess the probability of recurrence in patients with cSCC following MMS.

Keywords: SNAIL; axis inhibition protein 2; cutaneous squamous cell carcinoma patients; mohs micrographic surgery; predictive nomogram; recurrence.

Figure 1.

Representative expression patterns of AXIN2 and SNAIL proteins in cutaneous squamous cell carcinoma tissue samples. Magnification, ×400. Scale bar, 20 µm. Cytoplasmic expression of AXIN2 and cytoplasmic and nuclear expression of SNAIL were considered as positive patterns. AXIN2, axis inhibition protein 2.

Figure 2.

AXIN2 and SNAIL expression in cSCC tissue samples. (A) AXIN2 expression was significantly associated with SNAIL expression in cSCC tissues (χ² test, P=0.001). Recurrence occurred more frequently in patients with (B) high AXIN2 or (C) SNAIL expression compared with patients with low AXIN2 or SNAIL expression (Fisher's exact test, P=0.017 and P=0.042, respectively). Patients with (D) larger tumors, (E) poorly differentiated histological grade, (F) high AXIN2 expression and (G) high SNAIL expression presented decreased recurrence-free survival rates (log-rank test, P=0.025, P<0.001, P=0.001 and P=0.001, respectively). AXIN2, axis inhibition protein 2; cSCC, cutaneous squamous cell carcinoma.

Figure 3.

Nomogram for predicting the probability of RFS of cSCC patients. Probability of 1-, 2-, 3- and 5-year RFS for each patient with cSCC may be identified using the nomogram. AXIN2, axis inhibition protein 2; cSCC, cutaneous squamous cell carcinoma; RFS, recurrence-free survival.

Figure 4.

(A-a and A-b) HTML format for the nomogram presenting highest accuracy. HTML showed the total score and the associated 1-, 2-, 3- and 5-year RFS for patients with cSCC. (Ba-Bd) Calibration of the nomogram. An ideal nomogram would demonstrate perfect consensus (x=y) between data predicted by the nomogram and actual RFS for each patient in the cohort. The calibration of the nomogram demonstrated a relatively solid line, especially for the prediction of RFS after 1 and 2 years. AXIN2, axis inhibition protein 2; cSCC, cutaneous squamous cell carcinoma; HTML, Hypertext Markup Language; RFS, recurrence-free survival.