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Characterization of Perineural Invasion As a Component of Colorectal Cancer Staging

Ueno, Hideki MD*; Shirouzu, Kazuo MD; Eishi, Yoshinobu MD; Yamada, Kazutaka MD§; Kusumi, Takaya MD; Kushima, Ryoji MD; Ikegami, Masahiro MD#; Murata, Akihiko MD**; Okuno, Kiyotaka MD††; Sato, Toshihiko MD‡‡; Ajioka, Yoichi MD§§; Ochiai, Atsushi MD∥∥; Shimazaki, Hideyuki MD¶¶; Nakamura, Takahiro PhD##; Kawachi, Hiroshi MD; Kojima, Motohiro MD∥∥; Akagi, Yoshito MD; Sugihara, Kenichi MD***Study Group for Perineural Invasion projected by the Japanese Society for Cancer of the Colon and Rectum (JSCCR)

The American Journal of Surgical Pathology: October 2013 - Volume 37 - Issue 10 - p 1542–1549
doi: 10.1097/PAS.0b013e318297ef6e
Original Articles

Perineural invasion (PN) in colorectal cancer (CRC) is a site-specific prognostic marker, as mentioned by the AJCC Cancer Staging Manual, but it remains to be clearly defined. We aimed to identify an optimal characterization of PN as a component of cancer staging. On the basis of the anatomic features of the nervous system of the large bowel, site-specific pathologic criteria were assigned to PN according to the location of PN. Multi-institutional pathologic review based on these criteria was performed for 962 patients with stage I to III CRC at 2 institutions (1999 to 2004, cohort 1) and 1883 patients from 8 other institutions (2000 to 2004, cohort 2). In cohort 1, intramural and extramural PN were observed in 152 and 101 patients, respectively, which had a different impact on disease-free survival (hazard ratio, 2.6 [1.9 to 3.5] vs. 4.7 [3.4 to 6.5], respectively). A 3-tiered grading system (Pn0; Pn1a, intramural PN; Pn1b, extramural PN) distinguished 5-year disease-free survival as 88%, 70%, and 48%, respectively; and multivariate analysis identified PN grade as a significant prognostic marker independent of T or N stage. These results were similar in cohort 2. Interinstitutional difference of the prognostic impact of PN grade was acceptably small among all institutions. Interobserver study among 6 gastrointestinal pathologists showed superior judgment reproducibility for PN compared with vascular invasion. The results of our study indicate that PN is an important prognostic marker in CRC. The value of cancer staging could be enhanced by PN assessment using site-specific criteria and a simple grading system based on PN location within the bowel.

Departments of *Surgery

¶¶Laboratory Medicine

##Laboratory for Mathematics, National Defense Medical College, Tokorozawa

Department of Surgery, Kurume University Faculty of Medicine, Kurume

Departments of Human Pathology

***Surgery, Tokyo Medical and Dental University

Department of Pathology, National Cancer Center Hospital

#Department of Pathology, Jikei University School of Medicine, Tokyo

§Department of Surgery, Coloproctology Center, Takano Hospital, Kumamoto

Department of Surgery, Keiyukai Sappro Hospital, Sapporo

**Department of Surgery, Hirosaki University School of Medicine, Hirosaki

††Department of Surgery, Kinki University School of Medicine, Osakasayama

‡‡Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata

§§Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Course for Molecular and Cellular Medicine, Niigata University, Niigata

∥∥Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Hideki Ueno, MD, Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan (e-mail:

© 2013 by Lippincott Williams & Wilkins.