Combining perineural invasion with staging improve the prognostic accuracy in colorectal cancer: a retrospective cohort study

Abstract

Background: Current guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous.

Methods: This single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups.

Results: After median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087-1.531) and DFS (aHR, 1.397; 95% CI, 1.207-1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211-1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively).

Conclusion: PNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.

Keywords: Colorectal cancer; Perineural invasion; Survival; Tumor stage.

Fig. 1

Disease-free survival and overall survival in stage II & III CRC patients according to the presence or absence of PNI. The 5-year OS in stage II patients with or without PNI were 67.8% and 86.6%, respectively (A). The 5-year DFS in stage II patients with or without PNI was 57.2% and 79.0%, respectively (B). The 5-year OS in patients with stage III patients with or without PNI were 66.2% and 74.3%, respectively (C). The 5-year DFS in patients with stage III patients with or without PNI were 44.7% and 63.9%, respectively (D)

Fig. 2

Nomograms in stage II CRC patients according to risk factor of stage II diseases. A nomogram for risk factors for OS in patients with stage II CRC indicated that the weight of PNI in stage II risk factors was second only to incomplete resection (A). A nomogram for risk factors for DFS in patients with stage II CRC indicated that the weight of PNI in stage II risk factors was second only to incomplete resection (B)

Fig. 3

Disease-free survival and overall survival in non-metastatic CRC patients according to the presence or absence of PNI. OS and DFS were not significantly different between stage II patients with PNI and stage III patients (HR,1.126; 95% CI, 0.731–1.755 and HR,1.136; 95% CI. 0.795–1.646, respectively; A and B). After further inclusion of stage I CRC patients, OS and DFS were not significantly different between lymph node-negative patients with PNI and lymph node-positive patients(HR,1.075; 95% CI, 0.702–1.656 and HR, 1.105; 95% CI, 0.778–1.583, respectively; C and D)

Fig. 4

Forest plot for the effect of perineural invasion on overall survival among clinical subgroups