Management of Early Cancer of the Gastrointestinal Tract
Moderators: Robert H. Riddell and Elizabeth Montgomery
Section 4 -
Early Colorectal Carcinoma
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 These data are compelling but will quickly be superseded by even more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
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.
- 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).
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)
- 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
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.
- 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.
- 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
- 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.
- 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.
- 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
- 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
- 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
- Geboes K, Ectors N, Geboes KP. Pathology of early lower GI cancer. Best Pract Res Clin Gastroenterol
- 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
- Wright CL, Stewart ID. Histopathology and mismatch repair status of 458 consecutive colorectal
carcinomas. Am J Surg Pathol 2003;27:1393-406.