Pathologic Factors Associated with Prognosis after Adjuvant Chemotherapy in Stage II/III Microsatellite-Unstable Colorectal Cancers

다국어 초록 (Multilingual Abstract)

Background: Although there are controversies regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy in patients with microsatellite instability–high (MSI-H) colorectal cancer (CRC), the pathologic features affecting postchemotherapeutic prognosis in these patients have not been fully identified yet. Methods: A total of 26 histopathologic and immunohistochemical factors were comprehensively evaluated in 125 stage II or III MSI-H CRC patients who underwent curative resection followed by fluoropyrimidine-based adjuvant chemotherapy. We statistically analyzed the associations of these factors with disease-free survival (DFS). Results: Using a Kaplan-Meier analysis with log-rank test, we determined that ulceroinfiltrative gross type (p=.003), pT4 (p<.001), pN2 (p=.002), perineural invasion (p=.001), absence of peritumoral lymphoid reaction (p=.041), signet ring cell component (p=.006), and cribriform comedo component (p=.004) were significantly associated with worse DFS in patients receiving oxaliplatin-based adjuvant chemotherapy (n=45). By contrast, pT4 (p<.001) and tumor budding-positivity (p=.032) were significant predictors of poor survival in patients receiving non-oxaliplatin–based adjuvant chemotherapy (n=80). In Cox proportional hazards regression model-based univariate and multivariate analyses, pT category (pT1-3 vs pT4) was the only significant prognostic factor in patients receiving non-oxaliplatin–based adjuvant chemotherapy, whereas pT category, signet ring cell histology and cribriform comedo histology remained independent prognostic factors in patients receiving oxaliplatin-based adjuvant chemotherapy. Conclusions: pT4 status is the most significant pathologic determinant of poor outcome after fluoropyrimidine-based adjuvant chemotherapy in patients with stage II/III MSI-H CRC.

참고문헌 (Reference)

1 Snaebjornsson P, "pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis : Shepherd’s local peritoneal involvement revisited" 135 : 467-478, 2014

2 Bosman FT, "WHO classification of tumours of the digestive system" IARC Press 2010

3 Sinicrope FA, "Thymidylate synthase expression in colon carcinomas with microsatellite instability" 12 : 2738-2744, 2006

4 Bettington M, "The serrated pathway to colorectal carcinoma: current concepts and challenges" 62 : 367-386, 2013

5 Johnston PG, "The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer" 12 : 2640-2647, 1994

6 Richards CH, "The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer" 106 : 2010-2015, 2012

7 Li J, "TNM staging of colorectal cancer should be reconsidered by T stage weighting" 20 : 5104-5112, 2014

8 Wolpin BM, "Systemic treatment of colorectal cancer" 134 : 1296-1310, 2008

9 Wick MR, "Sporadic medullary carcinoma of the colon: a clinicopathologic comparison with nonhereditary poorly differentiated enteric-type adenocarcinoma and neuroendocrine colorectal carcinoma" 123 : 56-65, 2005

10 Arnold CN, "Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines" 106 : 66-73, 2003

11 Ueno H, "Risk factors for an adverse outcome in early invasive colorectal carcinoma" 127 : 385-394, 2004

12 Marzouk O, "Review of histopathological and molecular prognostic features in colorectal cancer" 3 : 2767-2810, 2011

13 Kim GP, "Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study" 25 : 767-772, 2007

14 Chirieac LR, "Phenotype of microsatellite-stable colorectal carcinomas with CpG island methylation" 29 : 429-436, 2005

15 Jenkins MA, "Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability : a population-based study" 133 : 48-56, 2007

16 Ueno H, "Objective criteria for crohn-like lymphoid reaction in colorectal cancer" 139 : 434-441, 2013

17 Kim JH, "Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer" 20 : 4230-4243, 2014

18 Carethers JM, "Mismatch repair proficiency and in vitro response to 5-fluorouracil" 117 : 123-131, 1999

19 Kim JH, "Loss of CDX2/CK20expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer" 37 : 1532-1541, 2013

20 Popat S, "Inter-relationship between microsatellite instability, thymidylate synthase expression, and p53 status in colorectal cancer: implications for chemoresistance" 6 : 150-, 2006

21 Klintrup K, "Inflammation and prognosis in colorectal cancer" 41 : 2645-2654, 2005

22 Tesniere A, "Immunogenic death of colon cancer cells treated with oxaliplatin" 29 : 482-491, 2010

23 Ricciardiello L, "High thymidylate synthase expression in colorectal cancer with microsatellite instability : implications for chemotherapeutic strategies" 11 : 4234-4240, 2005

24 Ligtenberg MJ, "Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3’ exons of TACSTD1" 41 : 112-117, 2009

25 Kim JH, "Expression status of wild-type HSP110correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer" 27 : 443-453, 2014

26 Dorard C, "Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis" 17 : 1283-1289, 2011

27 김정호, "Differential Features of Microsatellite-Unstable Colorectal Carcinomas Depending on EPCAM Expression Status" 대한병리학회 48 (48): 276-282, 2014

28 Ross JS, "Biomarker-based prediction of response to therapy for colorectal cancer : current perspective" 134 : 478-490, 2010