Skip to main content

Advertisement

SpringerLink
Log in

Perineural Invasion is a Better Prognostic Indicator than Lymphovascular Invasion and a Potential Adjuvant Therapy Indicator for pN0M0 Esophageal Squamous Cell Carcinoma

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) at pN0M0 can be more locally aggressive and disseminated than those with lymph node and distant metastasis. Perineural invasion (PNI) is reported as a poor prognostic factor in cancer and is thought to be related to regional tumor spread and metastasis. However, its clinicopathological role and meaning for treatment in pN0M0 ESCC are unknown.

Patients and Methods

We applied scoring methods of PNI and lymphatic and vascular invasion (LI, VI) based on immunohistochemistry staining on tumor tissues of pN0M0 ESCC patients. ROC analyses, Kaplan–Meier analyses, Cox regression, and χ2 test were performed for survival analysis, comparison of PNI with LI and VI, and exploration of the relevance between PNI and other clinicopathological features.

Results

Presence of PNI was significantly associated with poor survival in pN0M0 patients, whereas LI and VI were not predictive of outcome (P > 0.05). Neural invasion index (NII), defined as the ratio of the number of tumor-invaded nerves to the total number of nerves per tumor microsection, was the most consistent measure of PNI (P = 0.006, HR = 6.892, 1.731–27.428). Postoperative radiotherapy significantly improved survival in high-NII patients (P = 0.035, HR = 0.390, 0.163–0.936).

Conclusions

PNI is an important risk factor for the outcome of pN0M0 ESCC patients. NII can be used for risk assessment and to tailor adjuvant radiotherapy in this population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018;154(2):360–73.

    Article  PubMed  Google Scholar 

  3. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391(10125):1023–75.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lagarde SM, Phillips AW, Navidi M, Disep B, Immanuel A, Griffin SM. The presence of lymphovascular and perineural infiltration after neoadjuvant therapy and oesophagectomy identifies patients at high risk for recurrence. Br J Cancer. 2015;113(10):1427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115(15):3379–91.

    Article  CAS  PubMed  Google Scholar 

  6. Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell. 2017;31(3):342–54.

    Article  CAS  PubMed  Google Scholar 

  7. Amit M, Na’ara S, Gil Z. Mechanisms of cancer dissemination along nerves. Nat Rev Cancer. 2016;16(6):399–408.

    Article  CAS  PubMed  Google Scholar 

  8. Liebl F, Demir IE, Mayer K, et al. The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study. Ann Surg. 2014;260(5):900–7; discussion 7–8.

  9. Tachezy M, Tiebel AK, Gebauer F, et al. Prognostic impact of perineural, blood and lymph vessel invasion for esophageal cancer. Histol Histopathol. 2014;29(11):1467–75.

    PubMed  Google Scholar 

  10. Xu XL, Zheng WH, Fu ZX, et al. Topo2A as a prognostic biomarker for patients with resectable esophageal squamous cell carcinomas. Med Oncol. 2015;32(1):396.

    Article  PubMed  Google Scholar 

  11. Xu G, Feng F, Liu Z, et al. Prognosis and progression of ESCC patients with perineural invasion. Sci Rep. 2017;7:43828.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ajani JA, D’Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17(7):855–83.

  13. Khan OA, Alexiou C, Soomro I, Duffy JP, Morgan WE, Beggs FD. Pathological determinants of survival in node-negative oesophageal cancer. Br J Surg. 2004;91(12):1586–91.

    Article  CAS  PubMed  Google Scholar 

  14. Donohoe CL, MacGillycuddy E, Reynolds JV. The impact of young age on outcomes in esophageal and junctional cancer. Dis Esophagus. 2011;24(8):560–8.

    Article  CAS  PubMed  Google Scholar 

  15. Chen JW, Xie JD, Ling YH, et al. The prognostic effect of perineural invasion in esophageal squamous cell carcinoma. BMC Cancer. 2014;14:313.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ning ZH, Zhao W, Li XD, et al. The status of perineural invasion predicts the outcomes of postoperative radiotherapy in locally advanced esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8(6):6881–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang H, Deng F, Liu Q, Ma Y. Prognostic significance of lymph node metastasis in esophageal squamous cell carcinoma. Pathol Res Pract. 2017;213(7):842–7.

    Article  PubMed  Google Scholar 

  18. Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer. 2017.

    Book  Google Scholar 

  19. Liebl F, Demir IE, Rosenberg R, et al. The severity of neural invasion is associated with shortened survival in colon cancer. Clin Cancer Res. 2013;19(1):50–61.

    Article  CAS  PubMed  Google Scholar 

  20. Amit M, Na’ara S, Leider-Trejo L, et al. Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma. Oncogene. 2017;36(23):3232–9.

    Article  CAS  PubMed  Google Scholar 

  21. Na’ara S, Amit M, Gil Z. L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression. Oncogene. 2019;38(4):596–608.

    Article  PubMed  Google Scholar 

  22. Eveno C, Nemeth J, Soliman H, et al. Association between a high number of isolated lymph nodes in T1 to T4 N0M0 colorectal cancer and the microsatellite instability phenotype. Arch Surg. 2010;145(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  23. Laccourreye O, Marret G, Rubin F, et al. Ten-year outcome of curative “exclusive” chemotherapy in N0M0 squamous cell carcinoma of the larynx and pharynx with complete clinical response. Head Neck. 2019;41(7):2190–6.

    Article  PubMed  Google Scholar 

  24. Moy AP, Duncan LM, Kraft S. Lymphatic invasion and angiotropism in primary cutaneous melanoma. Lab Invest. 2017;97(2):118–29.

    Article  CAS  PubMed  Google Scholar 

  25. Koelzer VH, Gisler A, Hanhart JC, et al. Digital image analysis improves precision of PD-L1 scoring in cutaneous melanoma. Histopathology. 2018;73(3):397–406.

    Article  PubMed  Google Scholar 

  26. Campanella G, Hanna MG, Geneslaw L, et al. Clinical-grade computational pathology using weakly supervised deep learning on whole slide images. Nat Med. 2019;25(8):1301–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the research staff in the Department of Pathology for their supports to this project, especially for Dr. Hao Ye and Dr. Jing Lin, who helped us collect and organize tumor samples and H&E slides, and Dr. Rui-jing Yan, who helped us in immunohistochemistry techniques. We also thank Dr. Zhen He from Department of Preventive Medicine for advices in statistical analysis. We thank all patients, medical doctors, and nurses from Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College.

Funding

This work was partially funded by the National Natural Science Foundation of China (Grant Nos. 81572684 and 81772997), and the Li Ka Shing Foundation Grant for Joint Research Program between Shantou University and Technion – Israel Institute of Technology (Grant No. 43209505).

Author information

Author notes

  1. Yuan-ning Guo and Dong-ping Tian have contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, China

    Yuan-ning Guo MD, MSc, Dong-ping Tian MD, PhD, Qing-yun Gong MD, Hao Huang MD, Peng Yang MPH, Jia-yu He MD, Pan Xiong MD, Wen-ting Lin BSc, Dan Guo BSc & Min Su MD, MSc

  2. Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, China

    Shao-bin Chen MD

  3. The Radiation Oncology Institute, The Head and Neck Center, Rambam Healthcare Campus, Haifa, Israel

    Salem Billan MD

  4. Department of Pathology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China

    Hai-Hua Huang MD, PhD

  5. Guangdong Dynavolt Renewable Energy Technology, Shantou, China

    Moshe Marom PhD

  6. The Laboratory for Applied Cancer Research, The Head and Neck Center, Department of Otolaryngology Head and Neck Surgery, Technion – Israel Institute of Technology, Haifa, Israel

    Ziv Gil MD, PhD

Authors
  1. Yuan-ning Guo MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dong-ping Tian MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing-yun Gong MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Huang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peng Yang MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shao-bin Chen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salem Billan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jia-yu He MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hai-Hua Huang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pan Xiong MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wen-ting Lin BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dan Guo BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Moshe Marom PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ziv Gil MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Min Su MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.S., Z. G., Y.N.G., and D.P.T. conceived the idea and designed the study. Y.N.G., Q.Y.G., H.H., P.X., W.T.L., and D.G. carried out the immunohistochemical experiment. Y.N.G., Q.Y.G., H.H., D.P.T., and J.Y.H. participated and were responsible for the scoring of PNI, LI, and VI. M.S., Z.G., D.P.T., and H.H.H. supervised the pathology data analysis and interpretation. P.Y. and Y.N.G. were responsible for clinical and follow-up information. J.Y.H., Q.Y.G, H.H., and S.B.C. participated in the collection and organization of this information. Y.N.G. and J.Y.H. performed the analyses, and P.Y. helped with the statistical analysis. Y.N.G. drafted the manuscript, and all the authors read and revised the manuscript. S.B.C, S.B, and M.M. helped with the design of the study, participated in discussion, and gave valuable suggestions.

Corresponding authors

Correspondence to Ziv Gil MD, PhD or Min Su MD, MSc.

Ethics declarations

Disclosure

The authors declare no competing interests.

Ethics Approval and Consent to Participate

Ethical approval was obtained from the ethical committee of Shantou University Medical College (SUMC-2015-15). All patients or their families gave their signed informed consent, and the study was conducted in accordance with the Declaration of Helsinki.

Additional information

Publisher's Note

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.

Supplementary material 1 (PDF 6791 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, Yn., Tian, Dp., Gong, Qy. et al. Perineural Invasion is a Better Prognostic Indicator than Lymphovascular Invasion and a Potential Adjuvant Therapy Indicator for pN0M0 Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 27, 4371–4381 (2020). https://doi.org/10.1245/s10434-020-08667-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08667-4

Search

Navigation