Cancer Res Treat.  2019 Jul;51(3):1135-1143. 10.4143/crt.2018.392.

Prognostic Implications of Extranodal Extension in Relation to Colorectal Cancer Location

• Kim CW
• Kim J
• Park Y
• Cho DH
• Lee JL
• Yoon YS
• Park IJ
• Lim SB
• Yu CS
• Kim JC

• KMID: 2454305
• DOI: http://doi.org/10.4143/crt.2018.392

Abstract

PURPOSE
Extranodal extension (ENE) is closely associated with the aggressiveness of both colon and rectal cancer. This study evaluated the clinicopathologic significance and prognostic impact of ENE in separate populations of patients with colon and rectal cancers.
MATERIALS AND METHODS
The medical records of 2,346 patients with colorectal cancer (CRC) who underwent curative surgery at our institution between January 2003 and December 2011 were clinically and histologically reviewed.
RESULTS
ENE was associated with younger age, advanced tumor stage, lymphovascular invasion (LVI), and perineural invasion (PNI) in both colon and rectal cancer. ENE rates differed significantly in patients with right colon (36.9%), left colon (42.6%), and rectal (48.7%) cancers (right vs. left, p=0.037; left vs. rectum, p=0.009). The 5-year disease-free survival (DFS) rate according to ENE status and primary tumor site differed significantly in patients with ENE-negative colon cancer (80.5%), ENE-negative rectal cancer (77.4%), ENE-positive colon cancer (68.6%), and ENE-positive rectal cancer (64.2%) (p<0.001). Multivariate analysis showed that advanced tumor stage, ENE, LVI, PNI, and absence of adjuvant chemotherapy were independently prognostic of reduced DFS in colon and rectal cancer patients.
CONCLUSION
ENE is closely associated with the aggressiveness of colon and rectal cancers, with its frequency increasing from the right colon to the left colon to the rectum. ENE status is a significant independent predictor of DFS in CRC patients irrespective of tumor location. ENE might be more related with distally located CRC.

Keyword

Colonic neoplasms; Rectal neoplasms; Extranodal extension; Prognosis

MeSH Terms

Chemotherapy, Adjuvant
Colon
Colonic Neoplasms
Colorectal Neoplasms*
Disease-Free Survival
Humans
Medical Records
Multivariate Analysis
Prognosis
Rectal Neoplasms
Rectum

Figure

• 

  Fig. 1. Representative examples of lymph node metastasis patterns. (A) Tumor cells invading fat tissue (arrows) beyond the boundary of the lymph node (dashed line). Extranodal extension positive (×1.25 objective lens, scale bar=2 mm). (B) Tumor deposits with an invasive margin separate from the primary tumor. Extranodal extension negative (×1.25 objective lens, scale bar=2 mm). (C) Tumor cells outside the lymph node but in continuum with the primary tumor. Extranodal extension negative (×4 objective lens). (D) Tumor cells outside the lymph node but confined to endolymphatic spaces (arrow). Extranodal extension negative (×10 objective lens, scale bar=200 μm).

• 

  Fig. 2. (A) Disease-free survival curves in patients with colon cancer according to tumor location (right colon vs. left colon) and extranodal extension (ENE) status (n=1,363). (B) Disease-free survival curves in patients with colon and rectal cancer according to tumor location (colon vs. rectum) and ENE status (n=2,346).

Reference

References

1. Lee IS, Park YS, Ryu MH, Song MJ, Yook JH, Oh ST, et al. Impact of extranodal extension on prognosis in lymph node-positive gastric cancer. Br J Surg. 2014; 101:1576–84.

2. Suh S, Pak K, Seok JW, Kim IJ. Prognostic value of extranodal extension in thyroid cancer: a meta-analysis. Yonsei Med J. 2016; 57:1324–8.

3. Fajkovic H, Cha EK, Jeldres C, Robinson BD, Rink M, Xylinas E, et al. Extranodal extension is a powerful prognostic factor in bladder cancer patients with lymph node metastasis. Eur Urol. 2013; 64:837–45.

4. Nottegar A, Veronese N, Senthil M, Roumen RM, Stubbs B, Choi AH, et al. Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis. Eur J Surg Oncol. 2016; 42:919–25.

5. Zhang ZL, Yu CP, Liu ZW, Velet L, Li YH, Jiang LJ, et al. The importance of extranodal extension in penile cancer: a meta-analysis. BMC Cancer. 2015; 15:815.

6. Lee YC, Wu CT, Kuo SW, Tseng YT, Chang YL. Significance of extranodal extension of regional lymph nodes in surgically resected non-small cell lung cancer. Chest. 2007; 131:993–9.

7. van der Velden J, van Lindert AC, Lammes FB, ten Kate FJ, Sie-Go DM, Oosting H, et al. Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival. Cancer. 1995; 75:2885–90.

8. Luchini C, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, et al. Significance of the prognostic stratification of extranodal extension in colorectal cancer. Ann Oncol. 2016; 27:1647.

9. Edge SB, Greene FL, Byrd DR, Brookland RK, Waashington MK, Gershenwald JE, et al. AJCC cancer staging manual. 8th ed. New York: Springer;2017.

10. Yamauchi M, Lochhead P, Morikawa T, Huttenhower C, Chan AT, Giovannucci E, et al. Colorectal cancer: a tale of two sides or a continuum? Gut. 2012; 61:794–7.

11. Tamas K, Walenkamp AM, de Vries EG, van Vugt MA, Beets-Tan RG, van Etten B, et al. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015; 41:671–9.

12. Wei EK, Giovannucci E, Wu K, Rosner B, Fuchs CS, Willett WC, et al. Comparison of risk factors for colon and rectal cancer. Int J Cancer. 2004; 108:433–42.

13. Huang Q, Yang H. Prognostic impact of extra-nodal extension on colon and rectal cancer should be investigated separately. Ann Oncol. 2016; 27:956–7.

14. Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002; 101:403–8.

15. Kim CW, Kim J, Yeom SS, Lee JL, Yoon YS, Park IJ, et al. Extranodal extension status is a powerful prognostic factor in stage III colorectal cancer. Oncotarget. 2017; 8:61393–403.

16. Wang B, Yang J, Li S, Lv M, Chen Z, Li E, et al. Tumor location as a novel high risk parameter for stage II colorectal cancers. PLoS One. 2017; 12:e0179910.

17. Luchini C, Wood LD, Cheng L, Nottegar A, Stubbs B, Solmi M, et al. Extranodal extension of lymph node metastasis is a marker of poor prognosis in oesophageal cancer: a systematic review with meta-analysis. J Clin Pathol. 2016; 69:956–91.

18. Veronese N, Nottegar A, Pea A, Solmi M, Stubbs B, Capelli P, et al. Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis. Ann Oncol. 2016; 27:42–8.

19. Gervaz P, Bucher P, Morel P. Two colons-two cancers: paradigm shift and clinical implications. J Surg Oncol. 2004; 88:261–6.

20. Ghazi S, Lindforss U, Lindberg G, Berg E, Lindblom A, Papadogiannakis N, et al. Analysis of colorectal cancer morphology in relation to sex, age, location, and family history. J Gastroenterol. 2012; 47:619–34.

21. Butcher D, Hassanein K, Dudgeon M, Rhodes J, Holmes FF. Female gender is a major determinant of changing subsite distribution of colorectal cancer with age. Cancer. 1985; 56:714–6.

22. Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn. 2008; 10:13–27.

23. Bertario L, Russo A, Sala P, Eboli M, Radice P, Presciuttini S, et al. Survival of patients with hereditary colorectal cancer: comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer. Int J Cancer. 1999; 80:183–7.

24. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 2009; 361:2449–60.

25. Alotaibi AM, Lee JL, Kim J, Lim SB, Yu CS, Kim TW, et al. Prognostic and oncologic significance of perineural invasion in sporadic colorectal cancer. Ann Surg Oncol. 2017; 24:1626–34.

26. Lim SB, Yu CS, Jang SJ, Kim TW, Kim JH, Kim JC. Prognostic significance of lymphovascular invasion in sporadic colorectal cancer. Dis Colon Rectum. 2010; 53:377–84.

27. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343–51.