HISTOPATHOLOGICALEVALUATION OF COLORECTAL CARCINOMA
Background: Colorectal cancer is the most common gastrointestinal tract cancer worldwide. In Iraq, colorectal cancer was the seventh top cancers, whereas in Kurdistan, it was the fourth most common cancer for both males and females. Although the methods of the diagnosis and therapy have been improved, only about 50% of the patients who resected the tumor died from disease within 5 years, due to distant metastasis. The study was carried out to determine the frequency of histopathological types of colorectal cancer, and to evaluate the correlation between colorectal cancer regarding the grade, stage, with different histological finding which include desmoplastic reaction, lymphocytic infiltration, foamy macrophages, necrosis, intraglandular necrosis, and calcification.
Subject and Methods: This study includes (108) patients diagnosed with colorectal cancer. Cases were collected during the period January 2015 - December 2017 from the histopathological department at Central Public Health Laboratory and other private labs in Duhok city. Clinical information were obtained from the available histopathological reports. Paraffin embedded blocks were sectioned and stained with immunohistochemistry markers; Ki67 and VEGF then processed automatically according to protocols supplied by the antibody manufacturer.
Results: Patients age ranged from18-83 years with a mean of 54.42 years. The peak ages of the patients were between 60-69 years. Male: female ratio was 1.5:1. The commonest tumor location was (recto-sigmoidal region); rectum was (42.6 %) and sigmoid colon was(22.2%).Conventional adenocarcinoma was the predominant type 86(79.6%), majority of cases were moderately differentiated adenocarcinoma constituting85.2%. Stage III was the highest stage constituting 56(51.9%), followed by stage II which constitute 37(34.3%).The local invasion of the mucosa and other layers of colonic wall were associated with desmoplasia and collagen fiber remodeling. Infiltration of foamy macrophages decreased in number in relation to higher grade. Intraglandular necrosis showed significant correlation with tumor invasiveness, lymph node metastasis and grade. The frequency of both markers Ki67 and VEGF were 77 and 75 respectively. Ki67 immunoreactivity revealed significant relationship with tumor grade (P=0.014), whereas VEGF had significant relationship with TNM stage (P = 0.019), as well as the local invasion to the colorectal wall (P 0.009).
Conclusions: Moderate differentiated adenocarcinoma (85.2%) and stage III (51.9%) were the most frequent diagnosed cases with colorectal cancer. Macrophages infiltration was conversely related with grading of colorectal cancer. Histopathological changes like desmoplastic reaction and intraglandular necrosis were common findings in colorectal cancer and they were in concordance correlation with stage and grade.Ki67 had relationship with tumor grade, whereas VEGF correlate with tumor invasion
2. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Ca Epidemiol Prev Bio. 2016; 25(1): 16-27.
3. Iraqi Cancer Registry (ICR). Iraqi Cancer Board, Ministry of Health. 2012; 173.
4. Othman RT, Abdulljabar R, Saeed A, Sadiq S, Kittani HM, Mohammed SA, et al. Cancer Incidence Rates in the Kurdistan Region/Iraq from. Asian Pacific J Ca Prev. 2011; 12: 1261-4.
5. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system, WHO; 2010.
6. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annal Surg Oncol. 2010; 17(6): 1471- 4.
7. Myers RE, Balshem AM, WolfTA, Ross EA, Millner L. Screening for colorectal neoplasia: physicians' adherence to complete diagnostic evaluation. Am J Pub Healt. 1993; 83(11): 1620-2.
8. Hardingham J, Kotasek D, Sage R, Eaton M, Pascoe V, Dobrovic A. Detection of circulating tumor cells in colorectal cancer by immunobead-PCR is a sensitive prognostic marker for relapse of disease. Molecul Med. 1995; 1(7): 789-94.
9. Bodey B, BodeyJB, Siegel S, Kaiser H. Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas. In vivo (Athens, Greece). 2000;14(5): 659-66.
10. De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. Int J Ca. 2008; 123(10): 2229-38.
11. Conti J, Thomas G. The role of tumour stroma in colorectal cancer invasion and metastasis. Ca. 2011; 3(2): 2160-8.
12. Dvorak HF. Tumor stroma, tumor blood vessels, and antiangiogenesis therapy. Ca J. 2015; 21(4): 237-43.
13. Desmoulière A. Year. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. In: 2nd Scar meeting, 2008.
14. Negus R, StampG, Hadley J, Balkwill FR. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of CC chemokines. Am J pathol. 1997; 150(5): 1723-34.
15. Brigati C, Noonan DM, Albini A, Benelli R. Tumors and inflammatory infiltrates: friends or foes? Clinic Exper Metas. 2002; 19(3): 247-58.
16. Tsung K, Dolan JP, Tsung YL, Norton JA. Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection. Ca Res. 2002; 62(17): 5069-75.
17. Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymph-angiogenesis. Am J pathol. 2002; 161(3): 947-56.
18. Kanduc D, Mittelman A, Serpico R, Sinigaglia E, Sinha AA, Natale C, et al. Cell death: apoptosis versus necrosis. Int J Oncol. 2002; 21(1): 165-70.
19. Caruso RA, Branca G, Fedele F, Irato E, Finocchiaro G, Parisi A, et al. Mechanisms of coagulative necrosis in malignant epithelial tumors. Oncol letters. 2014; 8(4): 1397-402.
20. Omami G. Soft tissue calcification in oral and maxillofacial imaging: a pictorial review. Int J Dentist Oral Sci. 2016; 3(4): 219-24.
21. Bernardino M, Chuang V, Wallace S, Thomas J, Soo C. Therapeutically infarcted tumors: CT findings. Am J Roentgenol. 1981;136(3): 527-30.
22. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M, et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg–Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature. 1982; 299(5878):65-7
23. Zhao WY, Xu J, Wang M, Zhang ZZ, Tu L, Wang CJ, et al. Prognostic value of Ki67 index in gastrointestinal stromal tumors. Int J Clinic and Exp Pathol. 2014; 7(5):2298-304.
24. Salminen E, Palmu S, Vahlberg T, Roberts PJ,Söderström KO. Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J Gastroenterol: WJG, 2005; 11(21):3245-49.
25. Reimers, MS, Zeestraten EC, van Alphen TC, Dekker JWT, Putter H, Saadatmand S, et al. Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry based study using tissue microarray. Int J Colorectal Dis. 2014; 29(9): 1043-52.
26. Ellis LM. A targeted approach for antiangiogenic therapy of metastatic human colon cancer. Am Surg. 2003; 69(1):3-10.
27. Guba M, Seeliger H, Kleespies A, Jauch KW, Bruns C. Vascular endothelial growth factor in colorectal cancer. Int J Colorectal Dis. 2004;19:510-17.
28. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature Med. 2003; 9(6):669-76.
29. Fluge Ø, Gravdal K, Carlsen E, Vonen B, Kjellevold K, Refsum S, et al. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Ca. 2009; 101(8):1282-9.
30. Inoue K, Ozeki Y, Suganuma T, Sugiura Y, Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma: association with angiogenesis and tumor progression. Ca. 1997; 79(2):206-13.
31. Fondevila C, Metges J, Fuster J, Grau J, Palacin A, Castells A, et al. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Ca. 2004; 90(1):206-15.
32. Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van den Heuvel E, et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J of Pathol: J Pathol Soci. Gr Br & Ireland. 2001; 195(3):336-42.
33. Nyström H, Naredi P, Berglund A, Palmqvist R, Tavelin B,Sund M. Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour. AntiCa Res. 2012; 32(12):5183-91.
34. Majid TA, Shakir WM, Mahmmod AS. “Colorectal Carcinoma Presentation and Management”. Iraqi Postg Med J. 2009; 8(3): 204-11.
35. Tatar M, TatarF. Colorectal cancer in Turkey: current situation and challenges for the future. Europ J of Health Econ. 2010; 10(1): 99.
36. MansoorI, Zahrani IH, Aziz SA. Colorectal cancers in Saudi Arabia. Saudi Med J. 2002; 23(3): 322-7.
37. Al-Allawi NA, Ismaeel AT, Ahmed NY, Merza NS. The frequency and spectrum of K-ras mutation among Iraqi patients with sporadic colorectal carcinoma. Ind J Ca. 2012; 49(1):163-8.
38. Noor WK. Histopathological study of colorectal cancer in AL–Najaf province. Al-Kufa Uni J Biol. 2016; 8(3):17-26.
39. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. New Eng J Med. 1988; 319(9): 525-32.
40. Kheirelseid EA, Miller N Kerin MJ. Molecular biology of colorectal cancer: Review of the literature. Am J Molecul Bio. 2013; 3:72-80.
41. Smith C, Butter JA. Colorectal cancer in younger than 40 years of age. Dis Colon & Rec. 1989; 32(10): 843-6.
42. Rahman Ma ad M, Al-Janabyi KhA. A pattern of colorectal and anal tumor and its surgical treatment, J. Fac, Med. Baghdad. 2000; (1): 38-44.
43. Najim MM. A study of angiogenesis in human colorectal tumors by using anti CD34 antibody (assessment by light microscope and computer – aided image analysis system). Ph.D. Thesis Department of Pathology, College of Medicine, Al- Mustansiriya Uni, Baghdad, 2006.
44. Pahlavan PS, Kanthan R. The epidemiology and clinical findings of colorectal cancer in Iran. Women. 2006; 86(34): 11.
45. Azadeh S, Moghimi-Dehkordi B, Fatem S, Pourhoseingholi M, Ghiasi S, Zali M. Colorectal cancer in Iran: an epidemiological study. Asian Pacific J Ca Prev: APJCP. 2008;9(1): 123-6.
46. Douglas K, Facg M, Suthat L.Colorectal cancer screening. 2007. Internet:www.acg.gi.org.
47. AL-Bayati SM, Jasim F. Colorectal cancer in a group of Iraqi patients. Mustansiriya Med J. 2017; 8(1): 36-9.
48. Thörn M, Bergström R, Kressner U, Sparén P, Zack M, Ekbom A. Trends in colorectal cancer incidence in Sweden 1959-93 by gender, localization, time period, and birth cohort. Ca Causes & Control. 1998; 9(2):145-52.
49. Aljebreen AM. Clinico-pathological patterns of colorectal cancer in Saudi Arabia: younger with an advanced stage presentation. Saudi J of Gastroenterol. 2007; 13(2):84-7.
50. Mosli MH, Al-Ahwal MS. Colorectal cancer in the Kingdom of Saudi Arabia: need for screening. Asian Pacific J Ca Prev. 2012; 13(8):3809-13.
51. Aykan NF, Yalçın S, Turhal NS, Özdoğan M, Demir G, Özkan M, et al. Epidemiology of colorectal cancer in Turkey: A cross-sectional disease registry study (A Turkish Oncology Group trial). Turk J Gastroenterol. 2015;26(2):145-53.
52. Demers RY, Severson RK, Schottenfeld D, LazarL. Incidence of colorectal adenocarcinoma by anatomic subsite. Ca. 1997; 79(3):441-7.
53. Vassilopoulos PP, Kelessis N, PlataniotisG, Gondikakis E, Galanos A. Colorectal cancer trends by anatomic sides, age and staging. A twenty-year study of 1412 Greek cases. Antica Res. 2000; 20(6C): 4773-6.
54. Okamoto M, Shiratori Y, Yamaji Y, Kato J, Ikenoue T, Togo G, et al. Relationship between age and site of colorectal cancer based on colonoscopy findings. Gastrointestinal Endo. 2002; 55(4): 548-51.
55. Neagoe A, Molnar AM, Acalovschi M, Seicean A, Serban A. Risk factors for colorectal cancer: an epidemiologic descriptive study of a series of 333 patients. Rom J Gastroenterol. 2004; 13(3): 187-93.
56. Rahman Ma ad M, Mohanad AW. Analysis of colorectal and anal malignancies.A thesis submitted to Iraqi Commission for Medical specializations, 2001.
57. Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer: College of American Pathologists consensus statement 1999. Arch Pathol & Lab Med. 2000; 124(7): 979-94.
58. Malehi AS, Rahim F. Prognostic classification index in Iranian colorectal cancer patients: Survival tree analysis. South Asian J Ca. 2016; 5(1): 23-6.
59. Ueno H, Jones AM, Wilkinson KH, Jass J, Talbot I. Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut. 2004; 53(4): 581-6.
60. Ohtani H. Stromal reaction in cancer tissue: pathophysiologic significance of the expression of matrix‐degrading enzymes in relation to matrix turnover and immune/inflammatory reactions. Pathol Int. 1998; 48(1):1-9.
61. De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J pathol. 2003; 200(4): 429-47.
62. Väyrynen J, Tuomisto A, Klintrup K, Mäkelä J, Karttunen T, Mäkinen M. Detailed analysis of inflammatory cell infiltration in colorectal cancer. Br J Ca. 2013; 109(7): 1839-47.
63. Mantovani A, Sozzani S, Locati M, Allavena P, Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunol. 2002; 23(11): 549-55.
64. Centeno BA. Pathology of liver metastases. Ca Cont. 2006; 13(1): 13-26.
65. Saleh HA, Jackson H, Khatib G,Banerjee M. Correlation of bcl-2 oncoprotein immunohistochemical expression with proliferation index and histopathologic parameters in colorectal neoplasia. Pathol Oncol Res. 1999; 5(4):273-9.
66. Shepherd NA, Richman PI,England J. Ki‐67 derived proliferative activity in colorectal adenocarcinoma with prognostic correlations. J pathol. 1988; 155(3):213-9.
67. Kyzer S,Gordon PH. Determination of proliferative activity in colorectal carcinoma using monoclonal antibody Ki67. Dis Colon & Rec. 1997; 40(3): 322-5.
68. Michael-Robinson JM, Reid LE, Purdie DM, Biemer-Hüttmann AE, Walsh MD, Pandeya N, et al. Proliferation, apoptosis, and survival in high-level microsatellite instability sporadic colorectal cancer. Clinic Ca Res. 2001; 7(8): 2347-56.
69. Ellis LM, Yutaka T, Wenbiao L, Raymond MS. Vascular Endothelial Growth Factor in Human Colon Cancer: Biology and Therapeutic Implications. Oncol. 2000; 5(1):11-5.
70. Akagi K, Ikeda Y, Miyazaki M, Abe T, Kinoshita J, Maehara Y, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Ca. 2000; 83(7): 887-91.
71. Zlobec I, Steele R, Compton CC. VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy. Cancer: Interdiscip Int J Am Ca Soci. 2005; 104(11): 2517-21.
72. Kamel AA, Yossef WT, Mohamed M. Correlation of vascular endothelial growth factor expression and neovascularization with colorectal carcinoma: A pilot study. J Adenocarcinoma. 2016;1(1): 5.
73. Soumaoro LT, Uetake H, Takagi Y, Iida S, Higuchi T, Yasuno M, et al. Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis. Dis Colon & Rec. 2006; 49(3):392-8.
74. Welti J, Loges S, Dimmeler S, Carmeliet P. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clinic Inves. 2013; 123(8):3190-200.