Invasive front of colorectal cancer: Dynamic interface of pro-/anti-tumor factors

World Journal of Gastroenterology

Volumn 15, Issue 47, 2009, Pages 5898-5906

  Zlobec, Inti ^a   Lugli, Alessandro ^a  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

Author keywords

Colorectal cancer; Microsatellite instability; Prognosis; Tumor budding; Tumor growth pattern; Tumor immunity; Tumor infiltrating lymphocytes; Tumor invasive front

Indexed keywords

CD20 ANTIGEN; CD3 ANTIGEN; CD4 ANTIGEN; CD8 ANTIGEN; GRANZYME B; TRANSCRIPTION FACTOR FOXP3;

BREAST CANCER; CANCER GROWTH; CANCER INVASION; CANCER PATIENT; CANCER STAGING; CANCER SURVIVAL; CARCINOMA CELL; CD3+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL TYPE; COLORECTAL CANCER; DENDRITIC CELL; DESMOSOME; GLEASON SCORE; HUMAN; IMMUNE RESPONSE; IMMUNOTHERAPY; INFLAMMATION; LYMPH NODE METASTASIS; MACROPHAGE; MAST CELL; MESENCHYME; NEUTROPHIL; OUTCOME ASSESSMENT; PROGNOSIS; PROSTATE CANCER; REVIEW; SURVIVAL TIME; T LYMPHOCYTE; TUMOR GROWTH;

EID: 75449108186     PISSN: 10079327     EISSN: None     Source Type: Journal    
DOI: 10.3748/wjg.15.5898     Document Type: Review

References (103)

1. Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 2004; 54: 295-308
2. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004; 96: 1420-1425
3. Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000; 88: 1739-1757
4. Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, Hammond ME, Henson DE, Hutter RV, Nagle RB, Nielsen ML, Sargent DJ, Taylor CR, Welton M, Willett C. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000; 124: 979-994
5. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113-130
6. Natalwala A, Spychal R, Tselepis C. Epithelial-mesenchymal transition mediated tumourigenesis in the gastrointestinal tract. World J Gastroenterol 2008; 14: 3792-3797
7. Prall F. Tumour budding in colorectal carcinoma. Histopathology 2007; 50: 151-162
8. Jass JR. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 1986; 39: 585-589
9. Zlobec I, Lugli A, Baker K, Roth S, Minoo P, Hayashi S, Terracciano L, Jass JR. Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J Pathol 2007; 212: 260-268
10. Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW, McKee RF, McArdle CS. The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 2005; 92: 651-654
11. Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Menegaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 2009; 58: 520-529
12. Dadabayev AR, Sandel MH, Menon AG, Morreau H, Melief CJ, Offringa R, van der Burg SH, Janssen-van Rhijn C, Ensink NG, Tollenaar RA, van de Velde CJ, Kuppen PJ. Dendritic cells in colorectal cancer correlate with other tumor-infiltrating immune cells. Cancer Immunol Immunother 2004; 53: 978-986
13. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313: 1960-1964
14. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of postsurgical metastasis: a longitudinal study. Lancet Oncol 2009; 10: 877-884
15. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353: 2654-2666
16. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27: 186-192
17. Gabbert H. Mechanisms of tumor invasion: evidence from in vivo observations. Cancer Metastasis Rev 1985; 4: 293-309
18. Gabbert H, Wagner R, Moll R, Gerharz CD. Tumor dedifferentiation: an important step in tumor invasion. Clin Exp Metastasis 1985; 3: 257-279
19. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour 'budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 2002; 40: 127-132
20. Shinto E, Jass JR, Tsuda H, Sato T, Ueno H, Hase K, Mochizuki H, Matsubara O. Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia. Dis Colon Rectum 2006; 49: 1422-1430
21. Shinto E, Mochizuki H, Ueno H, Matsubara O, Jass JR. A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology 2005; 47: 25-31
22. Brabletz S, Schmalhofer O, Brabletz T. Gastrointestinal stem cells in development and cancer. J Pathol 2009; 217: 307-317
23. Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, Knuechel R, Kirchner T. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 2001; 98: 10356-10361
24. Baldus SE, Monig SP, Huxel S, Landsberg S, Hanisch FG, Engelmann K, Schneider PM, Thiele J, Holscher AH, Dienes HP. MUC1 and nuclear beta-catenin are coexpressed at the invasion front of colorectal carcinomas and are both correlated with tumor prognosis. Clin Cancer Res 2004; 10: 2790-2796
25. Gosens MJ, van Kempen LC, van de Velde CJ, van Krieken JH, Nagtegaal ID. Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol 2007; 20: 221-232
26. Guzinska-Ustymowicz K. MMP-9 and cathepsin B expression in tumor budding as an indicator of a more aggressive phenotype of colorectal cancer (CRC). Anticancer Res 2006; 26: 1589-1594
27. Horkko TT, Klintrup K, Makinen JM, Napankangas JB, Tuominen HJ, Makela J, Karttunen TJ, Makinen MJ. Budding invasive margin and prognosis in colorectal cancer - no direct association with beta-catenin expression. Eur J Cancer 2006; 42: 964-971
28. Masaki T, Sugiyama M, Matsuoka H, Abe N, Izumisato Y, Sakamoto A, Atomi Y. Coexpression of matrilysin and laminin-5 gamma2 chain may contribute to tumor cell migration in colorectal carcinomas. Dig Dis Sci 2003; 48: 1262-1267
29. Sordat I, Rousselle P, Chaubert P, Petermann O, Aberdam D, Bosman FT, Sordat B. Tumor cell budding and laminin-5 expression in colorectal carcinoma can be modulated by the tissue micro-environment. Int J Cancer 2000; 88: 708-717
30. Portyanko A, Kovalev P, Gorgun J, Cherstvoy E. beta(III)-tubulin at the invasive margin of colorectal cancer: possible link to invasion. Virchows Arch 2009; 454: 541-548
31. Akishima-Fukasawa Y, Nakanishi Y, Ino Y, Moriya Y, Kanai Y, Hirohashi S. Prognostic significance of CXCL12 expression in patients with colorectal carcinoma. Am J Clin Pathol 2009; 132: 202-210; quiz 307
32. Hori H, Fujimori T, Fujii S, Ichikawa K, Ohkura Y, Tomita S, Ono Y, Imura J, Kuroda Y. Evaluation of tumor cell dissociation as a predictive marker of lymph node metastasis in submucosal invasive colorectal carcinoma. Dis Colon Rectum 2005; 48: 938-945
33. Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Yokoo T, Ishii T. Histopathologic determinants of regional lymph node metastasis in early colorectal cancer. Cancer 2008; 112: 924-933
34. Kanazawa H, Mitomi H, Nishiyama Y, Kishimoto I, Fukui N, Nakamura T, Watanabe M. Tumour budding at invasive margins and outcome in colorectal cancer. Colorectal Dis 2008; 10: 41-47
35. Masaki T, Matsuoka H, Sugiyama M, Abe N, Sakamoto A, Watanabe T, Nagawa H, Atomi Y. Tumor budding and evidence-based treatment of T2 rectal carcinomas. J Surg Oncol 2005; 92: 59-63
36. Okuyama T, Oya M, Ishikawa H. Budding as a useful prognostic marker in pT3 well- or moderately-differentiated rectal adenocarcinoma. J Surg Oncol 2003; 83: 42-47
37. Prall F, Nizze H, Barten M. Tumour budding as prognostic factor in stage I/II colorectal carcinoma. Histopathology 2005; 47: 17-24
38. Sohn DK, Chang HJ, Park JW, Choi DH, Han KS, Hong CW, Jung KH, Kim DY, Lim SB, Choi HS, Jeong SY. Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type. J Clin Pathol 2007; 60: 912-915
39. Ueno H, Mochizuki H, Hashiguchi Y, Hatsuse K, Fujimoto H, Hase K. Predictors of extrahepatic recurrence after resection of colorectal liver metastases. Br J Surg 2004; 91: 327-333
40. Choi DH, Sohn DK, Chang HJ, Lim SB, Choi HS, Jeong SY. Indications for subsequent surgery after endoscopic resection of submucosally invasive colorectal carcinomas: a prospective cohort study. Dis Colon Rectum 2009; 52: 438-445
41. Ogawa T, Yoshida T, Tsuruta T, Tokuyama W, Adachi S, Kikuchi M, Mikami T, Saigenji K, Okayasu I. Tumor budding is predictive of lymphatic involvement and lymph node metastases in submucosal invasive colorectal adenocarcinomas and in non-polypoid compared with polypoid growths. Scand J Gastroenterol 2009; 44: 605-614
42. Ohtsuki K, Koyama F, Tamura T, Enomoto Y, Fujii H, Mukogawa T, Nakagawa T, Uchimoto K, Nakamura S, Nonomura A, Nakajima Y. Prognostic value of immunohistochemical analysis of tumor budding in colorectal carcinoma. Anticancer Res 2008; 28: 1831-1836
43. Yamauchi H, Togashi K, Kawamura YJ, Horie H, Sasaki J, Tsujinaka S, Yasuda Y, Konishi F. Pathological predictors for lymph node metastasis in T1 colorectal cancer. Surg Today 2008; 38: 905-910
44. Bayar S, Saxena R, Emir B, Salem RR. Venous invasion may predict lymph node metastasis in early rectal cancer. Eur J Surg Oncol 2002; 28: 413-417
45. Kazama S, Watanabe T, Ajioka Y, Kanazawa T, Nagawa H. Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2. Br J Cancer 2006; 94: 293-298
46. Park KJ, Choi HJ, Roh MS, Kwon HC, Kim C. Intensity of tumor budding and its prognostic implications in invasive colon carcinoma. Dis Colon Rectum 2005; 48: 1597-1602
47. Ueno H, Mochizuki H, Hashiguchi Y, Shimazaki H, Aida S, Hase K, Matsukuma S, Kanai T, Kurihara H, Ozawa K, Yoshimura K, Bekku S. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology 2004; 127: 385-394
48. Yasuda K, Inomata M, Shiromizu A, Shiraishi N, Higashi H, Kitano S. Risk factors for occult lymph node metastasis of colorectal cancer invading the submucosa and indications for endoscopic mucosal resection. Dis Colon Rectum 2007; 50: 1370-1376
49. Choi HJ, Park KJ, Shin JS, Roh MS, Kwon HC, Lee HS. Tumor budding as a prognostic marker in stage-III rectal carcinoma. Int J Colorectal Dis 2007; 22: 863-868
50. Tanaka M, Hashiguchi Y, Ueno H, Hase K, Mochizuki H. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum 2003; 46: 1054-1059
51. Wang LM, Kevans D, Mulcahy H, O'Sullivan J, Fennelly D, Hyland J, O'Donoghue D, Sheahan K. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol 2009; 33: 134-141
52. Suzuki A, Togashi K, Nokubi M, Koinuma K, Miyakura Y, Horie H, Lefor AT, Yasuda Y. Evaluation of venous invasion by Elastica van Gieson stain and tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer. Am J Surg Pathol 2009; 33: 1601-1607
53. Xu F, Xu J, Lou Z, Di M, Wang F, Hu H, Lai M. Micropapillary component in colorectal carcinoma is associated with lymph node metastasis in T1 and T2 Stages and decreased survival time in TNM stages I and II. Am J Surg Pathol 2009; 33: 1287-1292
54. Hase K, Shatney C, Johnson D, Trollope M, Vierra M. Prognostic value of tumor "budding" in patients with colorectal cancer. Dis Colon Rectum 1993; 36: 627-635
55. Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet 1987; 1: 1303-1306
56. Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, Todd IP. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology 1986; 10: 437-459
57. Turner RR, Li C, Compton CC. Newer pathologic assessment techniques for colorectal carcinoma. Clin Cancer Res 2007; 13: 6871s-6876s
58. Zlobec I, Terracciano LM, Lugli A. Local recurrence in mismatch repair-proficient colon cancer predicted by an infiltrative tumor border and lack of CD8+ tumor-infiltrating lymphocytes. Clin Cancer Res 2008; 14: 3792-3797
59. Zlobec I, Baker K, Minoo P, Hayashi S, Terracciano L, Lugli A. Tumor border configuration added to TNM staging better stratifies stage II colorectal cancer patients into prognostic subgroups. Cancer 2009; 115: 4021-4029
60. Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22: 3408-3419
61. Minoo P, Baker K, Baumhoer D, Terracciano L, Lugli A, Zlobec I. Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer. Hum Pathol 2010; 41:70-78
62. Mazzolini G, Murillo O, Atorrasagasti C, Dubrot J, Tirapu I, Rizzo M, Arina A, Alfaro C, Azpilicueta A, Berasain C, Perez-Gracia JL, Gonzalez A, Melero I. Immunotherapy and immunoescape in colorectal cancer. World J Gastroenterol 2007; 13: 5822-5831
63. Nizar S, Copier J, Meyer B, Bodman-Smith M, Galustian C, Kumar D, Dalgleish A. T-regulatory cell modulation: the future of cancer immunotherapy? Br J Cancer 2009; 100: 1697-1703
64. Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 2007; 7: 4
65. Kaneko I, Tanaka S, Oka S, Kawamura T, Hiyama T, Ito M, Yoshihara M, Shimamoto F, Chayama K. Lymphatic vessel density at the site of deepest penetration as a predictor of lymph node metastasis in submucosal colorectal cancer. Dis Colon Rectum 2007; 50: 13-21
66. Wang HS, Liang WY, Lin TC, Chen WS, Jiang JK, Yang SH, Chang SC, Lin JK. Curative resection of T1 colorectal carcinoma: risk of lymph node metastasis and long-term prognosis. Dis Colon Rectum 2005; 48: 1182-1192
67. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC. Comparison of the prognostic value of inflammationbased pathologic and biochemical criteria in patients undergoing potentially curative resection for colorectal cancer. Ann Surg 2009; 249: 788-793
68. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, Satomi S. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004; 91: 1711-1717
69. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998; 58: 3491-3494
70. Ali AA, McMillan DC, Matalka II, McNicol AM, McArdle CS. Tumour T-lymphocyte subset infiltration and tumour recurrence following curative resection for colorectal cancer. Eur J Surg Oncol 2004; 30: 292-295
71. 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
72. Katz SC, Pillarisetty V, Bamboat ZM, Shia J, Hedvat C, Gonen M, Jarnagin W, Fong Y, Blumgart L, D'Angelica M, DeMatteo RP. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol 2009; 16: 2524-2530
73. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma VM. Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997; 182: 318-324
74. Diederichsen AC, Hjelmborg JB, Christensen PB, Zeuthen J, Fenger C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother 2003; 52: 423-428
75. Milasiene V, Stratilatovas E, Norkiene V. The importance of T-lymphocyte subsets on overall survival of colorectal and gastric cancer patients. Medicina (Kaunas) 2007; 43: 548-554
76. Frey DM, Droese RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L. High frequency of tumor-infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 2009; Epub ahead of print
77. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, van Krieken JH. Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect - a histopathological and immunohistochemical study. BMC Cancer 2001; 1: 7
78. Gulubova M, Vlaykova T. Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 2009; 24: 1265-1275
79. Sandel MH, Dadabayev AR, Menon AG, Morreau H, Melief CJ, Offringa R, van der Burg SH, Janssen-van Rhijn CM, Ensink NG, Tollenaar RA, van de Velde CJ, Kuppen PJ. Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization. Clin Cancer Res 2005; 11: 2576-2582
80. Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T, Weissleder R, McNagny KM, Khazaie K. Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA 2007; 104: 19977-19982
81. Halazun KJ, Aldoori A, Malik HZ, Al-Mukhtar A, Prasad KR, Toogood GJ, Lodge JP. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol 2008; 34: 55-60
82. Sandel MH, Speetjens FM, Menon AG, Albertsson PA, Basse PH, Hokland M, Nagelkerke JF, Tollenaar RA, van de Velde CJ, Kuppen PJ. Natural killer cells infiltrating colorectal cancer and MHC class I expression. Mol Immunol 2005; 42: 541-546
83. Suzuki A, Masuda A, Nagata H, Kameoka S, Kikawada Y, Yamakawa M, Kasajima T. Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J Pathol 2002; 196: 37-43
84. Xie ZJ, Jia LM, He YC, Gao JT. Morphological observation of tumor infiltrating immunocytes in human rectal cancer. World J Gastroenterol 2006; 12: 1757-1760
85. Walsh MD, Dent OF, Young JP, Wright CM, Barker MA, Leggett BA, Bokey L, Chapuis PH, Jass JR, Macdonald GA. HLA-DR expression is associated with better prognosis in sporadic Australian clinicopathological Stage C colorectal cancers. Int J Cancer 2009; 125: 1231-1237
86. Banerjea A, Ahmed S, Hands RE, Huang F, Han X, Shaw PM, Feakins R, Bustin SA, Dorudi S. Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity. Mol Cancer 2004; 3: 21
87. 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: 527-535
88. Gafa R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 2000; 89: 2025-2037
89. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, Trougouboff P, Tomsho LD, Kim E, Low M, Almog R, Rennert G, Gruber SB. Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 2003; 27: 563-570
90. Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, Searle J, Radford-Smith G, Young J, Leggett B. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998; 42: 673-679
91. Jenkins MA, Hayashi S, O'Shea AM, Burgart LJ, Smyrk TC, Shimizu D, Waring PM, Ruszkiewicz AR, Pollett AF, Redston M, Barker MA, Baron JA, Casey GR, Dowty JG, Giles GG, Limburg P, Newcomb P, Young JP, Walsh MD, Thibodeau SN, Lindor NM, Lemarchand L, Gallinger S, Haile RW, Potter JD, Hopper JL, Jass JR. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007; 133: 48-56
92. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145: 148-156
93. Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 2001; 91: 2417-2422
94. Shia J, Ellis NA, Paty PB, Nash GM, Qin J, Offit K, Zhang XM, Markowitz AJ, Nafa K, Guillem JG, Wong WD, Gerald WL, Klimstra DS. Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer. Am J Surg Pathol 2003; 27: 1407-1417
95. Baker K, Raut P, Jass JR. Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta. J Pathol 2007; 213: 257-265
96. Malesci A, Laghi L, Bianchi P, Delconte G, Randolph A, Torri V, Carnaghi C, Doci R, Rosati R, Montorsi M, Roncalli M, Gennari L, Santoro A. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 2007; 13: 3831-3839
97. Baker K, Chong G, Foulkes WD, Jass JR. Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes. Histopathology 2006; 49: 371-380
98. Michael-Robinson JM, Biemer-Huttmann A, Purdie DM, Walsh MD, Simms LA, Biden KG, Young JP, Leggett BA, Jass JR, Radford-Smith GL. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 2001; 48: 360-366
99. Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 2004; 91: 469-475
100. Prall F, Duhrkop T, Weirich V, Ostwald C, Lenz P, Nizze H, Barten M. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol 2004; 35: 808-816
101. Houston AM, Michael-Robinson JM, Walsh MD, Cummings MC, Ryan AE, Lincoln D, Pandeya N, Jass JR, Radford-Smith GL, O'Connell J. The "Fas counterattack" is not an active mode of tumor immune evasion in colorectal cancer with high-level microsatellite instability. Hum Pathol 2008; 39: 243-250
102. Drescher KM, Sharma P, Watson P, Gatalica Z, Thibodeau SN, Lynch HT. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam Cancer 2009; 8: 231-239
103. Lugli A, Karamitopoulou E, Panayiotides I, Karakitsos P, Rallis G, Peros G, Iezzi G, Spagnoli G, Bihl M, Terracciano L, Zlobec I. CD8+ lymphocytes/ tumour-budding index: an independent prognostic factor representing a 'pro-/antitumour' approach to tumour host interaction in colorectal cancer. Br J Cancer 2009; 101: 1382-1392