J Pathol Transl Med.  2021 Jan;55(1):53-59. 10.4132/jptm.2020.10.06.

A comparative prognostic performance of definitions of Crohn-like lymphoid reaction in colorectal carcinoma

• Kim Y
• Bae JM
• Kim JH
• Cho NY
• Kang GH

• KMID: 2511513
• DOI: http://doi.org/10.4132/jptm.2020.10.06

Abstract

Background
The prognostic potential of Crohn-like lymphoid reaction (CLR) in colorectal carcinoma (CRC) has been investigated through the assessment of different criteria.
Methods
The prognostic impact of CLR was investigated in 636 CRC patients to compare methods from previously published articles. These methods included CLR measured by number of lymphoid aggregates (LAs) (CLR count), LA size greater than or equal to 1 mm (CLR size), CLR density with a cutoff value of 0.38, and subjective criteria as defined by intense CLR.
Results
In univariate survival analysis, CLR-positive CRC as defined by the four aforementioned methods was associated with better overall survival (OS) (hazard ratio [HR], 0.463; 95% confidence interval [CI], 0.305 to 0.702; p <.001; HR, 0.656; 95% CI, 0.411 to 1.046; p=.077; HR, 0.363; 95% CI, 0.197 to 0.669; p=.001; and HR, 0.433; 95% CI, 0.271 to 0.690; p<.001, respectively) and disease-free survival (DFS) (HR, 0.411; 95% CI, 0.304 to 0.639; p<.001; HR, 0.528; 95% CI, 0.340 to 0.821; p=.004; HR, 0.382; 95% CI, 0.226 to 0.645, p=.004; and HR, 0.501; 95% CI, 0.339 to 0.741; p<.001, respectively) than CLR-negative CRC, regardless of criteria with the exception of OS for CLR density. In multivariate analysis, two objective criteria (CLR count and CLR density) and one subjective criterion (intense CLR) for defining CLR were considered independent prognostic factors of OS and DFS in CRC patients.
Conclusions
CLR has similar traits regardless of criteria, but CLR-positivity should be defined by objective criteria for better reproducibility and prognostic value.

Keyword

Colorectal neoplasms; Crohn-like lymphoid reaction; Histology; Prognosis

Figure

• 

  Fig. 1 Examples of Crohn-like lymphoid reaction (CLR)–positive cases according to each criterion. (A) At least three lymphoid aggregates (LAs) (arrow), positive according to CLR count. (B) A single LA, which is greater than or equal to 1 mm in diameter, positive by CLR size. (C) The number of LAs divided by the length of the invasion front (bold line) is greater than or equal to 0.38 (positive according to CLR density). (D) An intense LA in the proper muscle and subserosa.

• 

  Fig. 2 Correlations between each Crohn-like lymphoid reaction (CLR) criterion and survival (overall survival and disease-free survival). (A) Kaplan-Meier curves for CLR count (at least three lymphoid aggregates [LAs]). (B) Kaplan-Meier curves for CLR size (LA ≥ 1 mm in diameter). (C) Kaplan-Meier curves for CLR density (the number of LAs divided by the length of the invasion front ≥ 0.38). (D) Kaplan-Meier curves for intense CLR.

Reference

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017; 67:7–30.

2. Donehower LA, Creighton CJ, Schultz N, et al. MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes. J Pathol. 2013; 229:99–110.

3. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21:1350–6.

4. Ueno H, Hashiguchi Y, Shimazaki H, et al. Objective criteria for crohn-like lymphoid reaction in colorectal cancer. Am J Clin Pathol. 2013; 139:434–41.

5. Graham DM, Appelman HD. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990; 3:332–5.

6. Kim JH, Kim KJ, Bae JM, et al. Comparative validation of assessment criteria for Crohn-like lymphoid reaction in colorectal carcinoma. J Clin Pathol. 2015; 68:22–8.

7. Vayrynen JP, Sajanti SA, Klintrup K, et al. Characteristics and significance of colorectal cancer associated lymphoid reaction. Int J Cancer. 2014; 134:2126–35.

8. Williams DS, Mouradov D, Jorissen RN, et al. Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes. Gut. 2019; 68:465–74.

9. Ogino S, Nosho K, Irahara N, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res. 2009; 15:6412–20.

10. Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam Cancer. 2004; 3:93–100.

11. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001; 158:527–35.

12. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007; 50:113–30.

13. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313:1960–4.

14. Juo YY, Johnston FM, Zhang DY, et al. Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol. 2014; 25:2314–27.

15. Ording AG, Horvath-Puho E, Erichsen R, et al. Five-year mortality in colorectal cancer patients with ulcerative colitis or Crohn’s disease: a nationwide population-based cohort study. Inflamm Bowel Dis. 2013; 19:800–5.

16. Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer. 2010; 46:2788–98.

17. Lewis B, Lin J, Wu X, et al. Crohn’s disease-like reaction predicts favorable prognosis in colitis-associated colorectal cancer. Inflamm Bowel Dis. 2013; 19:2190–8.

18. Ferris RL, Galon J. Additional support for the introduction of immune cell quantification in colorectal cancer classification. J Natl Cancer Inst. 2016; 108:djw033.

19. Bae JM, Kim JH, Rhee YY, Cho NY, Kim TY, Kang GH. Annexin A10 expression in colorectal cancers with emphasis on the serrated neoplasia pathway. World J Gastroenterol. 2015; 21:9749–57.

20. Lee DW, Kim KJ, Han SW, et al. KRAS mutation is associated with worse prognosis in stage III or high-risk stage II colon cancer patients treated with adjuvant FOLFOX. Ann Surg Oncol. 2015; 22:187–94.

21. Buckowitz A, Knaebel HP, Benner A, et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer. 2005; 92:1746–53.

22. Rozek LS, Schmit SL, Greenson JK, et al. Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst. 2016; 108:djw027.

23. Kakar S, Aksoy S, Burgart LJ, Smyrk TC. Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival. Mod Pathol. 2004; 17:696–700.

24. Titu LV, Monson JR, Greenman J. The role of CD8(+) T cells in immune responses to colorectal cancer. Cancer Immunol Immunother. 2002; 51:235–47.

25. Ling A, Edin S, Wikberg ML, Oberg A, Palmqvist R. The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues. Br J Cancer. 2014; 110:2551–9.

26. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005; 353:2654–66.

27. Mei Z, Liu Y, Liu C, et al. Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis. Br J Cancer. 2014; 110:1595–605.

28. Kim Y, Bae JM, Li G, Cho NY, Kang GH. Image analyzer-based assessment of tumor-infiltrating T cell subsets and their prognostic values in colorectal carcinomas. PLoS One. 2015; 10:e0122183.

29. Nosho K, Baba Y, Tanaka N, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010; 222:350–66.

30. Frey DM, Droeser RA, Viehl CT, et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010; 126:2635–43.

31. Turksma AW, Coupe VM, Shamier MC, et al. Extent and location of tumor-infiltrating lymphocytes in microsatellite-stable colon cancer predict outcome to adjuvant active specific immunotherapy. Clin Cancer Res. 2016; 22:346–56.

32. Li Y, Liang L, Dai W, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer. 2016; 15:55.

33. Jakubowska K, Kisielewski W, Kanczuga-Koda L, Koda M, Famulski W. Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma. Oncol Lett. 2017; 14:6421–32.