Section 4 -

Early Colorectal Carcinoma Lawrence Burgart Abbott Northwestern Hospital Minneapolis, MN USA

Carcinoma of the colon and rectum affects up to 150,000 people in the United States alone, killing up to 40% of affected patients. Over the last 10 years there have been interesting advances involving several aspects of colorectal carcinoma (CRC), providing the medical community with increasing opportunities to reduce mortality and refine therapeutic approaches to what was once viewed as a monolithic disease. Like other adult epithelial malignancies, in which curative surgery is the cornerstone of treatment, early detection is essential and measurable gains have been made. As more CRC are identified at early stage, pathologists face the increasingly important task of separating early lesions amenable to local therapy from those at risk of progression. Screening does make a difference and will continue to improve. A population based study in the U.S. confirmed this general impression (Gupta). Comparing CRC presentations from 1980-84 versus 1995-99 showed a doubling in screen detected tumors from 8% to 17%. This was accompanied by a downward shift in stage and improved survival. These data are compelling but will quickly be superseded by even more encouraging data (including more early stage CRC) as population based screening becomes more prevalent and screening technologies continue to improve. Developments in CRC screening may not be specifically applicable to pathologists' daily routine, new modalities are of general interest. Massive investments on several fronts are starting to pay dividends: Increased knowledge of CRC genetics have been applied to stool tests, potentially useful for population screening (Matsushita; Osborn). The National Cancer Institute and industry sponsors have each funded large prospective trials comparing multitarget molecular assays in stool with colonoscopy control and the results have been promising, especially for detection of high molecular weight DNA and detection of microsatellite instability in "routinely" collected stool samples as markers of neoplasia. Endoscope manufacturers are evolving instruments from magnification chromoendoscopy to the more convenient and powerful narrow band endoscopy which will be to identify flat and smaller lesions (Kuznetsov). In addition, this powerful endoscopy technology will be able to quantify aberrant crypt foci (ACF) density in patients if this proves useful in stratifying an individual's CRC risk. CT colography has undergone significant trials and will no doubt find a complementary role to colonoscopy in screening. A more recent development has been the possible application of PET scanning to CRC screening. The holy grail of CRC screening, of course, is a serum marker(s). This has been a primary objective of the many expression array projects performed on CRC samples over the last 5-10 years. Clinical testing is offering some promise for candidate serum markers such as "colon cancer secreted protein-2 (CCSP-2)" (Xin). One goal of identifying colorectal neoplasia at an earlier stage is the ability to reduce morbidity by excising early carcinomas locally through the endoscope rather than by segmental surgical resection. Having received such a limited resection in the laboratory, the pathologist has the critical task of determining whether there is a significant risk of recurrence or metastasis which, once balanced by the clinical team against the risks associated with additional surgery and/or ancillary chemotherapy, may result in more aggressive therapy. Criteria for assessing adequacy of endoscopic polypectomy for adenomas harboring a component of stage T1 CRC are well established. The risk of synchronous lymph node metastasis relative to depth of invasion in a pedunculated lesion was ground breaking in this area (Haggitt). A more practical approach was subsequently developed in recognition that endoscopic polypectomies were not always intact or well oriented (Cooper; Nivatvongs). Three criteria were developed which, when present alone or in combination, indicated increased risk of recurrence/metastasis following endoscopic polypectomy: highest grade morphology, lymphovascular invasion or adenocarcinoma within 1-2 mm of the polypectomy margin. Endoscopic resections of non-pedunculated T1 adenocarcinomas have also increased in number as a result of earlier detection and improved techniques. Local resection has been especially popular in the rectum due to the significant morbidity associated with abdominal-perineal resection. Unfortunately studies have shown locally treated rectal cancer to have higher risk of adverse oncologic outcome than other sites: rectum - 15% lymph node metastasis vs. 3% in right colon and 8% in left colon (Okabe). Multiple investigators have shown that there is significant utility in subclassifying T1 colon and rectal (especially the latter) adenocarcinomas based on their depth of invasion into the submucosa. Arbitrary division of the submucosa into thirds (sm1, sm2, sm3) provides significant prognostic information which appears similar and slightly superior to measuring volume of submucosal tumor. The primary determinants of failure of local excision in T1 CRC are depth of submucosal invasion, lymphovascular invasion and location with the colorectum. Within the rectum sublocation is also important. Lesions in the distal third of the rectum do significantly worse when controlled for other variable compared to the proximal third, with the mid third being intermediate. "Tumor budding", a potentially powerful histologic marker, remains underutilized in the United States. Studies, predominately performed in Japan, have demonstrated significant association of adverse outcome with the presence of tumor budding in stage I & II CRC. In fact, studies demonstrate overlapping survival curves for stage II CRC with budding and stage III CRC (Park; Tanaka). Tumor budding is a specific finding within the broader descriptive category of CRC with infiltrative (as opposed to pushing) interface. Budding is seen and/or suspected with assessment of H&E, but is best seen and quantitated with cytokeratin immunostain. Tumor budding refers to the conceptually simple finding of numerous single, or small nests of, infistrative cancer cells at the leading edge of the tumor. Additional studies may show this to have the prognostic and predictive characteristics of positive lymph nodes. It will be of great interest to identify the molecular-histologic correlation of tumor budding. Components of Type IV collagen and Laminen-5 have been implicated (Ikeda; Pyke). Interestingly there is a strong inverse correlation of tumor budding and the positive prognostic finding of sporadic defective DNA mismatch repair (microsatellite instability)(Wright). References (by topic) ACF Alrawi SJ, Schiff M, Carroll RE, Dayton M, Gibbs JF, Kulavlat M, Tan D, Berman K, Stoler DL, Anderson GR. Aberrant crypt foci. Anticancer Res 2006;26:107-19. Hurlstone DP, Karajeh M, Sanders DS, Drew SK, Cross SS. Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: biomarkers for flat and depressed neoplasia. Am J Gastroenterol 2005;100:1283-9. Defective DNA mismatch repair - prognosis Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000;119:921-8. Parc Y, Gueroult S, Mourra N, Serfaty L, Flejou JF, Tiret E, Parc R. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut 2004;53:371-5. Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 2001;10:917-23. Malignant polyps Cooper HS. Surgical pathology of endoscopically removed malignant polyps of the colon and rectum. Am J Surg Pathol 1983;7:613-23. Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising in adenomas: implicationsfor lesions removed by endoscopic polypectomy. Gastroenterology 1985;89:328-36. Nivatvongs S, Rojanasakul A, Reiman HM, Dozois RR, Wolff BG, Pemberton JH, Beart RW Jr, Jacques LF. The risk of lymph node metastasis in colorectal polyps with invasive adenocarcinoma. Dis Colon Rectum 1991;34:323-8. Methylation in adenoma and normal mucosa Kim YH, Petko Z, Dzieciatkowski S, Lin L, Ghiassi M, Stain S, Chapman WC, Washington MK, Willis J, Markowitz SD, Grady WM CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer. Genes Chromosomes Cancer 2006;45:781-9. Nuovo GJ, Nakagawa H, Sotamaa K, Chapelle Ade L. Hypermethylation of the MLH1 promoter with concomitant absence of transcript and protein occurs in small patches of crypt cells in unaffected mucosa from sporadic colorectal carcinoma. Diagn Mol Pathol 2006;15:17-23. Screening for CRC Gupta AK, Melton LJ 3rd, Petersen GM, Timmons LJ, Vege SS, Harmsen WS, Diehl NN, Zinsmeister AR, Ahlquist DA. Changing trends in the incidence, stage, survival, and screen-detection of colorectal cancer: a population-based study. Clin Gastroenterol Hepatol 2005;3:150-8. Kuznetsov K, Lambert R, Rey JF. Narrow-band imaging: potential and limitations. Endoscopy 2006;38:76-81. Matsushita H, Matsumura Y, Moriya Y, Akasu T, Fujita S, Yamamoto S, Onouchi S, Saito N, Sugito M, Ito M, Kozu T, Minowa T, Nomura S, Tsunoda H, Kakizoe T. A new method for isolating colonocytes from naturally evacuated feces and its clinical application to colorectal cancer diagnosis. Gastroenterology 2005 ;129:1918-27. Osborn NK, Ahlquist DA. Stool screening for colorectal cancer: molecular approaches. Gastroenterology 2005;128:192-206. Sakamoto K, Takahashi M, Yaginuma Y, Ishido Y, Matsuoka T, Sakamoto S, Tomiki Y, Kamano T. Early colon cancer detected by 18F-FDG PET. Int J Gastrointest Cancer.;36:95-8. Xin B, Platzer P, Fink SP, Reese L, Nosrati A, Willson JK, Wilson K, Markowitz S. Colon cancer secreted protein-2 (CCSP-2), a novel candidate serological marker of colon neoplasia. Oncogene 2005;24:724-31. T1 lesions - prognosis Kikuchi R, Takano M, Takagi K, Fujimoto N, Nozaki R, Fujiyoshi T, Uchida Y. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995;38:1286-95. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002;45:200-6.. Nascimbeni R, Nivatvongs S, Larson DR, Burgart LJ. Long-term survival after local excision for T1 carcinoma of the rectum. Dis Colon Rectum 2004;47:1773-9. Okabe S, Shia J, Nash G, Wong WD, Guillem JG, Weiser MR, Temple L, Sugihara K, Paty PB. Lymph node metastasis in T1 adenocarcinoma of the colon and rectum. J Gastrointest Surg 2004;8:1032-9. 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;48:1182-92. Yamamoto S, Watanabe M, Hasegawa H, Baba H, Yoshinare K, Shiraishi J, Kitajima M. The risk of lymph node metastasis in T1 colorectal carcinoma. Hepatogastroenterology 2004;51:998-1000. Tumor Budding Geboes K, Ectors N, Geboes KP. Pathology of early lower GI cancer. Best Pract Res Clin Gastroenterol 2005;19:963-78. Guzinska-Ustymowicz K. The role of tumour budding at the front of invasion and recurrence of rectal carcinoma. Anticancer Res 2005;25:1269-72. Hase K, Shatney C, Johnson D, Trollope M, Vierra M. Prognostic value of tumor "budding" in patients with colorectal cancer. Dis Colon Rectum 1993;36:627-35. Ikeda K, Iyama K, Ishikawa N, Egami H, Nakao M, Sado Y, Ninomiya Y, Baba H. Loss of expression of type IV collagen alpha5 and alpha6 chains in colorectal cancer associated with the hypermethylation of their promoter region. Am J Pathol 2006;168:856-65. Okuyama T, Nakamura T, Yamaguchi M. Budding is useful to select high-risk patients in stage II well-differentiated or moderately differentiated colon adenocarcinoma. Dis Colon Rectum 2003;46:1400-6. 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;48:1597-602. Pyke C, Romer J, Kallunki P, Lund LR, Ralfkiaer E, Dano K, Tryggvason K. The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol 1994;145:782-91. Pyke C, Salo S, Ralfkiaer E, Romer J, Dano K, Tryggvason K. Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res 1995;55:4132-9. 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;46:1054-9. Wright CL, Stewart ID. Histopathology and mismatch repair status of 458 consecutive colorectal carcinomas. Am J Surg Pathol 2003;27:1393-406.