Tissular expression of mismatch repair proteins, tumoral lymphocytic infiltration and prognosis in resected colorectal carcinoma
DOI:
https://doi.org/10.23938/ASSN.0093Keywords:
Neoplasias colorrectales. Histopatología. Inmunohistoquímica. Pronóstico.Microsatélites.Abstract
Fundamento. En el cáncer colorrectal se discute la posible relación entre la expresión patológica de proteínas reparadoras (EPPR) y la infiltración linfocítica tumoral (ILT), así como el posible efecto pronóstico de ambos factores.
Material y métodos. Se han revisado 243 cánceres colorrectales, resecados consecutivamente. Estudiamos inmunohistoquímicamente la EPPR de MLH1, MSH2 y MSH6. La ITL se valoró mediante la tinción de CD3 en el epitelio tumoral. Comparamos la mortalidad y progresión tumoral post-operatoria entre los casos con y sin EPPR y con y sin ITL. Adicionalmente estudiamos la mortalidad y progresión tumoral entre los casos EPPR (+), según presentaran o no ITL.
Resultados. El 13,6% tumores expresaron EPPR (+) y el 25,5% ITL (+). El seguimiento fue: 73,8±34,6 meses. La frecuencia de ITL (+) resultó similar entre tumores EPPR (+): 27,3% y EPPR (-): 25,2% (p = 0,80). Los casos EPPR (+) mostraron menor mortalidad: 12,1% versus 23,3% (p = 0,15) y menor progresión tumoral: 21,2% versus 29% (p = 0,35). Las neoplasias ITL (+) tuvieron menor mortalidad: 9,7% versus 26% [p = 0,007; OR = 3,27(1,25-9,05)] y progresión tumoral: 12,9% versus 33,1% [p = 0,002; OR = 3,35 (1,42-8,15)]. Los 9 tumores EPPR (+) e ILT (+) no presentaron mortalidad ni progresión tumoral, frente a una mortalidad: 16,7% y progresión: 29,2% de los 24 casos EPPR (+) e ITL (-) p = 0,19 y p = 0,07 respectivamente.
Conclusiones. No se ha encontrado relación entre EPPR e ITL, con tasas muy similares de ILT (+) entre casos con y sin EPPR. La ILT (+) mostró un efecto pronóstico favorable superior a la EPPR (+). La combinación de ILT (+) e EPPR (+) parece tener un efecto protector acumulativo, aunque su escasa frecuencia resta significación al hallazgo.
Downloads
References
1. FEARON ER, VOLGESTEIN B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-767.
https://doi.org/10.1016/0092-8674(90)90186-I
2. SMITH G, CAREY FA, BEATTIE J, SALES M, KERNOHAN NM, SMITH G et al. Mutations in APC, Kirsten-ras, and p53-alternative genetic pathways to colorectal cancer. Z Gastroenterol 2003; 42: 201-203.
3. SORËIDE K, JANSSEN EAM, SÖILAND H, KÖRNER H, BAAK JPA. Microsatellite instability in colorectal cancer. Br J Surg 2006; 93: 395-406.
https://doi.org/10.1002/bjs.5328
4. LANZA G, GAFÀ R, SANTINI A, MAESTRI I, GUERZONI L, CAVAZZINI L. Immunohistochemical test for MLH1 and MSH2 in stage II and III colorectal cancer patients. J Clin Oncol 2006; 24: 2359-2367.
https://doi.org/10.1200/JCO.2005.03.2433
5. PONZ DE LEON M, BENATTI P, DI GREGORIO C, PEDRONI M, LOSI L, GENUARDI M et al. Genetic testing among high-risk individuals in families with hereditary nonpoyposis colorectal cancer. Br J Cancer 2004; 90: 882-887.
https://doi.org/10.1038/sj.bjc.6601529
6. PAPP J, KOVACS ME, OLAH E. GERMLINE MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing. World Gastroenterol 2007; 13: 2727-2732.
https://doi.org/10.3748/wjg.v13.i19.2727
7. PIÑOL V, CASTELLS A, ANDREU M, CASTELLVÍ-BEL S, ALENDA C, LLOR X et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 2005; 293: 1986-1994.
https://doi.org/10.1001/jama.293.16.1986
8. WARRIER SK, TRAINER AH, LYNCH AC, MITCHELL C, HISCOCK R, SAWYER S et al. Preoperative diagnosis of Lynch syndrome with DNA mismatch repair immunohistochemistry on a diagnostic biopsy. Dis Colon Rectum 2011; 54: 1480-1487.
https://doi.org/10.1097/DCR.0b013e318231db1f
9. ARDANAZ E, MORENO-IRIBAS C, PÉREZ DE RADA ME, EZPONDA C, FLORISTÁN Y, NAVARIDAS N et al. Incidencia y mortalidad por cáncer en Navarra. Evolución en los últimos 30 años. An Sist Sanit Navar 2007; 30: 245-270.
https://doi.org/10.4321/S1137-66272007000300009
10. POPAT S, HUBNER R, HOULSTON RS. Systematic review of microsatellite inestability and colorectal cancer prognosis. J Clin Oncol 2005; 23: 609-618.
https://doi.org/10.1200/JCO.2005.01.086
11. 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: 2788-2798.
https://doi.org/10.1016/j.ejca.2010.05.009
12. CHANG EY, DORSEY PB, FRANKHOUSE J, LEE RG, WALTS D, JOHNSON W et al. Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator in colon cancer. Arch Surg 2009; 144: 511-515.
https://doi.org/10.1001/archsurg.2009.40
13. DESCHOOLMEESTER V, BAAY M, VAN MARCK E, WEYLER J, VERMEULEN P, LARDON F et al. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC. Immunol 2010; 11: 19-30.
https://doi.org/10.1186/1471-2172-11-19
14. HALAMA N, ZOERNIG I, SPILLE A, MICHEL S, KLOOR M, GRAULING-HALAMA S et al. Quantification of prognostic immune cell markers in colorrectal cancer using whole slide imaging tumor maps. Anal Quant Cytol Histol 2010; 32: 333-340.
15. GALON J, COSTES A, SANCHEZ-CABO F, KIRILOVSKY A, MIECNIK B, LAGORCE-PAGES C et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 31: 1960-1964.
https://doi.org/10.1126/science.1129139
16. NOSHO K, BABA Y, TNAKA N, SHIMA K, HAYASHI M, MEYERHARDT JA Et al. Tumor-infiltrating T-cells subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222: 350-366.
https://doi.org/10.1002/path.2774
17. BAKER K, ZLOBEC I, TORNILLO L, TERRACCIANO L, JASS JR, LUGLI A. Differential significance of tumour infiltrating lymphocytes in sporadic mismatch repair deficient versus proficient colorectal cancers: a potential role for dysregulation of the transforming growth factor-beta pathway. Eur J Cancer 2007; 43: 624-631.
https://doi.org/10.1016/j.ejca.2006.11.012
18. DAHLIN AM, HENRIKSSON ML, VAN GUELPEN B, STENLING R, OBERG A, RUTEGARD J et al. Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Mod Pathol 2011; 24: 671-682.
https://doi.org/10.1038/modpathol.2010.234
19. CUNNINGHAM JM, CHRISTENSEN ER, TESTER DJ, KIM CY, ROCHE PC, BURGART LJ et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998; 58: 3455-3460.
20. KUISMANEN SA, HOLMBERG MT, SALOVAARA R, DE LA CHAPELLE A, PELTOMÄKI P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 2000; 15: 1773-1779.
https://doi.org/10.1016/S0002-9440(10)65048-1
21. PAYÁ A, ALENDA C, JOVER R, ARANDA FI. Cáncer colorrectal con alteración de la vía reparadora. Claves para su identificación y relevancia clínica. Rev Esp Patol 2006; 39: 201-208.
https://doi.org/10.1016/S1699-8855(06)70042-3
22. NAITO Y, SAITO K, SHIIBA K, OHUCHI A, SAIGENJI K, NAGURA H et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998; 58: 3491-3494.
23. RUSZKIEWICZ A, BENNETT G, MOORE J, MANAVIS J, RUDZKI B, SHEN L et al. Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours. Pathology 2001; 34: 541-547.
https://doi.org/10.1080/0031302021000035965-2
24. OHRLING K, EDLER D, HALLSTRÖM M, RAGNHAMMAR P. Mismatch repair protein expression in an independent prognostic factor in sporadic colorectal cancer. Acta Oncol 2010; 49: 797-804.
https://doi.org/10.3109/02841861003705786
25. FORSTER S, SATTLER HP, HACK M, ROMANAKIS K, ROHDE V, SEITZ G et al. Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features. Surgery 1998; 123: 13-18.
https://doi.org/10.1016/S0039-6060(98)70223-5
26. JASS JR, BIDEN KG, CUMMINGS MC, SIMMS LA, WALSH M, SCHOCH E et al. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 1999; 52: 455-460.
https://doi.org/10.1136/jcp.52.6.455
27. LINNEBACHER M, GEBERT J, RUDY W, WOERNER S, YUAN YP, BORK P et al. Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 2001; 93: 6-11.
https://doi.org/10.1002/ijc.1298
28. SINICROPE FA, REGO RL, ANSELL SM, KNUTSON KL, FOSTER NR, SARGENT DJ. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009; 137: 1270-1279.
https://doi.org/10.1053/j.gastro.2009.06.053
29. JASS JR. Pathology of hereditary non polyposis colorectal cancer. Ann N Y Acad Sci 2000; 910: 62-73.
https://doi.org/10.1111/j.1749-6632.2000.tb06701.x
30. KUMAR S, CHANG EY, FRANKHOUSE J, DORSEY PB, LEE RG, JOHNSON N. Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator for adjuvant therapy in colon cancer. Arch Surg 2009; 144: 835-840.
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
La revista Anales del Sistema Sanitario de Navarra es publicada por el Departamento de Salud del Gobierno de Navarra (España), quien conserva los derechos patrimoniales (copyright ) sobre el artículo publicado y favorece y permite la difusión del mismo bajo licencia Creative Commons Reconocimiento-CompartirIgual 4.0 Internacional (CC BY-SA 4.0). Esta licencia permite copiar, usar, difundir, transmitir y exponer públicamente el artículo, siempre que siempre que se cite la autoría y la publicación inicial en Anales del Sistema Sanitario de Navarra, y se distinga la existencia de esta licencia de uso.
