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Background
The presenting symptoms may vary by the site of the tumor. The tumors can spread by direct invasion into the surrounding tissues and also by metastasis to regional lymph nodes and internal organs such as the liver and lungs. These tumors usually present with bleeding, change in bowel habits, or lower abdomen discomfort.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION Familial polyposis syndromes Hereditary nonpolyposis colorectal cancer (HNPCC) Hyperplastic Polyposis Association With Colorectal Cancer
Barbara A. Leggett, M.D., F.R.A.C.P.; Benedict Devereaux, M.B.B.S., F.R.A.C.P.; Kelli Biden, B.Sc.; Jeffrey Searle, M.D., F.R.C.P.A.; Joanne Young, Ph.D.; Jeremy Jass, D.Sc., F.R.C.Path.
From the Conjoint Gastroenterology Research Laboratory, Royal Brisbane Hospital Research Foundation Clinical Research Center, Brisbane, Australia (B.A.L., K.B., J.Y.); the Department of Gastroenterology, Royal Brisbane Hospital (B.D.), Department of Pathology, Royal Brisbane Hospital; and the Department of Pathology, University of Queensland, Brisbane, Australia (J.J.).
Am J Surg Pathol 2001;25:177-184 Abstract quote
Hyperplastic polyposis is a loosely defined syndrome initially thought not to confer a clinically important predisposition to colorectal cancer.
The aim of the current study was to examine the clinical, histologic, and molecular features of a prospective series of cases meeting a strict definition of the condition.
Twelve patients were identified, seven of whom had developed colorectal cancer. Most polyps were hyperplastic, but 11 patients also had polyps containing dysplasia as either serrated adenomas, mixed polyps, or traditional adenomas.
The mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11% (p < 0.05). Microsatellite instability (MSI) was present in 3 of 47 hyperplastic polyps and two of eight serrated adenomas. Kras was mutated in 8 of 47 hyperplastic polyps and two of eight serrated adenomas. No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q. Two of seven cancers showed a high level of MSI.
It is concluded that hyperplastic polyposis is associated with a high risk of colorectal cancer. Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium. A higher proportion of dysplastic polyps is associated with increased cancer risk. Clonal genetic changes are observed in some hyperplastic polyps and serrated adenomas.
Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas.
Hawkins NJ, Ward RL.
School of Pathology, University of New South Wales, Sydney, Australia.
J Natl Cancer Inst 2001 Sep 5;93(17):1307-13 Abstract quote
BACKGROUND: Microsatellite instability (MSI) is seen in 10%-15% of sporadic colorectal cancers mostly in the right colon, but the precursors of cancers with MSI remain unknown. We examined whether sporadic cancers with MSI arise from pre-existing benign proliferative lesions (such as hyperplastic polyps or serrated adenomas [together denoted as "serrated polyps"]).
METHODS: The frequency of benign epithelial lesions (serrated polyps and conventional adenomas) was determined by histologic review of resection specimens from individuals (n = 29) with sporadic colorectal cancer with MSI and from a matched control group (n = 29) with cancer showing microsatellite stability (MSS). MSI status, expression of mismatch repair enzyme (product of the human mut-L homologue 1 [hMLH1] gene), and hMLH1 gene promoter methylation in the benign lesions were determined. Data were analyzed by the chi-square test, by Wilcoxon's rank-sum test, and by conditional logistic regression as appropriate, and a two-sided probability less than.05 was considered to be statistically significant.
RESULTS: Individuals with cancers showing MSI were more likely to harbor at least one serrated polyp than individuals with cancers showing MSS (odds ratio = 4.0; 95% confidence interval = 1.1 to 14.2; P =.03), but the frequency of conventional adenomas was the same in both groups (P =.52, Mann-Whitney test). Loss of hMLH1 protein expression was seen in lesions from 10 of 13 patients with MSI, but no loss was seen in lesions from four patients with MSS (P =.02, Fisher's exact test). Loss of hMLH1 protein expression was associated with MSI in assessable lesions. The hMLH1 promoter was methylated in all assessable serrated polyps from patients with cancers showing MSI but in none of the lesions from patients with MSS cancers.
CONCLUSIONS: Some right-sided hyperplastic polyps may give rise to sporadic colorectal carcinomas with MSI. Methylation of the hMLH1 gene promoter within neoplastic cell subpopulations may be a critical step in the progression to carcinoma. The frequency with which benign lesions progress to cancer with MSI is unknown.
Ulcerative colitis
PATHOGENESIS CHARACTERIZATION ADENOMA-CARCINOMA SEQUENCE In general, three major and overlapping pathways of tumor progression have been described:
Chromosomal instablilty pathway
Microsatellite instability pathway (MSI)
CpG island methylator phenotype pathway (CIMP)
Wanghai Zhang, MD, PhD, etal.
We immunohistochemically examined 75 human colorectal neoplasms (adenoma, 27; adenocarcinoma, 24; neuroendocrine carcinoma, 24) for the expression of activator protein (AP)-1 family proteins. Nuclear and cytoplasmic expression levels of c-Jun and Fra-1 proteins were markedly elevated in adenomas, adenocarcinomas, and neuroendocrine carcinomas compared with nonneoplastic colorectal epithelial cells. JunB also was overexpressed in these tumors but with a predominantly cytoplasmic staining pattern.
Overexpression of Fra-2 was evident in carcinomas but less frequent in adenomas. Expression levels of JunD and c-Fos were high in nonneoplastic colorectal epithelial cells and remained so in neoplasms. FosB was undetectable in nonneoplastic and neoplastic colorectal tissues. Neuroendocrine carcinomas exhibited an AP-1 expression profile similar to adenocarcinomas except for infrequent overexpression of c-Jun in poorly differentiated variants. Hierarchical clustering separated the majority of malignant from benign tumors based on AP-1 expression patterns. AP-1 transcription factor family members are expressed differentially in nonneoplastic and neoplastic colorectal tissues.
Up-regulation of c-Jun and Fra-1 is an early event in human colorectal tumorigenesis. Overexpression of Fra-2 may participate in tumor progression.
- Support for hMLH1 and MGMT silencing as a mechanism of tumorigenesis in the hyperplastic-adenoma-carcinoma (serrated) carcinogenic pathway in the colon.
Oh K, Redston M, Odze RD.
Hum Pathol. 2005 Jan;36(1):101-11. Abstract quote
Summary Background Down-regulation of DNA repair genes has been proposed as an important mechanism of tumorigenesis in some colon cancers. This mechanism has also recently been implicated in the newly postulated hyperplastic polyp-serrated adenoma-carcinoma ("serrated") pathway of carcinogenesis, although this has never been investigated thoroughly. The aim of this study was to evaluate hMLH1, hMSH2, MGMT, as well as MIB-1, p53, and beta -catenin immunoexpression in an uncommon cohort of mixed colonic polyps that contain a combination of hyperplastic and adenomatous features (n = 21), and in some (n = 7), carcinoma as well.
Design The clinical, pathological, and immunophenotypic (hMLH1, hMSH2, MGMT, MIB-1, p53, and beta -catenin) properties of 28 mixed hyperplastic and adenomatous polyps of the colon (7 of which also contained carcinoma within the same lesion) were evaluated for the above immunopeptides in each of the different morphologic areas of the polyps, and the results were compared to traditional hyperplastic polyps, serrated adenomas, and conventional (nonserrated) adenomas.
Results Clinically, most mixed polyps with carcinoma occurred in the ascending colon (86%), and pathologically, the adenomatous component of most mixed polyps was serrated (96%). Mixed polyps, particularly those with carcinoma, showed loss of hMLH1 (33%), MGMT (37%), and even hMSH2 (11%) with significantly higher frequency compared to hyperplastic polyps, conventional adenomas, and serrated adenomas. More specifically, loss of hMLH1 and MGMT were more frequent in epithelium of higher neoplastic grade in mixed polyps. However, hMSH2 loss was only present in the adenoma component and never in the hyperplastic or carcinomatous areas of these polyps. Defects in MIB-1 proliferation indices and p53 were not significantly different among the same epithelial components in each of the polyp groups. However, conventional adenomas showed significantly higher rates of nuclear beta -catenin staining (100%) in comparison to the adenomatous component of mixed polyps (60%).
Conclusions Loss of hMLH1 and MGMT play a prominent role in the serrated pathway of carcinogenesis in the colon.Inherited or acquired mutations of cancer suppressor genes in normal colon APC
Mismatch of repair genesMethylation abnormalities leads to mucosa at risk APC
Beta-catenin
MSH2Protooncogene mutation leads to adenoma K-ras
Homozygous loss of additional cancer suppressor genes (p53 and LOH at 18q21Additional mutations and gross chromosomal alterations leads to carcinoma Many genes Progressive acquisition of genetic mutations Populations with high prevalence of adenomas have high prevalence of cancer
Distribution of adenomas similar to carcinoma
Peak incidence of adenomas occurs before carcinoma
Early stage invasive carcinomas often associated with adenomatous tissue
Risk of cancer directly related to number of adenomas
Aggressive screening and removal of adenomas decreases the incidence of cancer
Apc
Beta-cateninNormal epithelium changes to adenoma
k-rasEarly adenoma changes to large adenoma
Takes place over many decades
BAT-26
p53Late adenoma changes to early cancer
Takes place over 2-5 yearsEarly cancer changes to late cancer GENES INVOLVED APC gene (5q21) APC is regarded as a Gatekeeper gene
APC protein binds to microtubule bundles and promotes cell migration and adhesion
APC protein binds to cytoskeletal protein beta-catenin which is bound to E-cadherinBeta-catenin binds to T cell factor-lymphoid enhancer factor (Tcf-Lef) proteins-this binding leads to stimulation of cell proliferation and inhibition of apoptosis
When APC binds to beta-catenin, it starts degradation of it, leading to inhibition of beta-catenin:Tcf signalling pathway
Mutations in the APC gene reduce the affinity of APC protein for beta-catenin
Net result is loss of intercellular contact and increased cytoplasmic pool of beta-catenin
ARP2/3
Involvement of Arp2/3 complex in the process of colorectal carcinogenesis.
Otsubo T, Iwaya K, Mukai Y, Mizokami Y, Serizawa H, Matsuoka T, Mukai K.
Department of Pathology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
Mod Pathol. 2004 Apr;17(4):461-7. Abstract quote
Increased motility is one of the characteristics of cancer cells, and actin polymerization and disassembly are essential for cellular motility. Since actin-related protein (Arp) 2/3 complex acts as a nucleus for actin polymerization, in this study, we immunohistochemically investigated the expression of Arp2 and Arp3 in 175 colorectal tumors in various stages of neoplastic progression. Arp2 and Arp3 showed identical expression patterns, and both were expressed in the stromal cells around neoplastic tubules or glands and in the tumor cells themselves. The frequency of expression of Arp2 and Arp3 (Arp2 and 3) by the stromal cells increased with the atypia of the colorectal neoplasms, from 5.5% (3/55) in adenoma with mild or moderate atypia, to 11.8% (2/17) in adenoma with severe atypia, 53.3% (16/30) in intramucosal carcinoma, and 91.8% (67/73) in invasive carcinoma (P<0.0001). The frequency of expression of Arp2 and 3 in the tumor cells was similar and was 1.8% (1/55) in adenoma with mild or moderate atypia, 23.5% (4/17) in adenoma with severe atypia, 23.5% (7/30) in intramucosal carcinoma, and 32.9% (24/73) in invasive carcinoma.
Expression of Arp2 and 3 by the stromal cells was significantly correlated with nuclear accumulation of p53 in the tumor cells and stromal expression of CD10.
These results suggest that formation of Arp2/3 complex by both neoplastic and stromal cells contributes to the increased motility of both cell types and thus provides suitable conditions for invasion.HNPCC genes HNPCC is considered the caretaker genes
These are human mismatch repair genes and consist of 4 genes
hMSH2
HMLH1
hPMS1
hPMS2Involved in genetic proofreading during DNA replication
Mutations in these genes lead to alterations in repeat sequences leading to microsatellite instability
An inherited mutant gene would still have normal repair activity because of remaining normal allele, however, these cells are susceptible to a second mutation
CpG ISLAND METHYLATION
- Phenotype of Microsatellite-Stable Colorectal Carcinomas With CpG Island Methylation.
Chirieac LR, Shen L, Catalano PJ, Issa JP, Hamilton SR.
From the *Department of Pathology, Division of Pathology and Laboratory Medicine, and daggerDepartment of Leukemia, Division of Cancer Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX; double daggerDepartment of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; and section signEastern Cooperative Oncology Group, Boston, MA.
Am J Surg Pathol. 2005 Apr;29(4):429-436. Abstract quote
A distinctive pathway of colorectal carcinogenesis termed CpG island methylator phenotype is characterized by extensive DNA methylation in colorectal carcinoma (CRC) cells but not in nonneoplastic mucosa. Many CRCs with CpG island methylator phenotype have methylation of the hMLH1 mismatch repair gene and consequently have high levels of microsatellite instability (MSI-H). MSI-H confers distinctive clinical-pathologic features, but the phenotype of microsatellite-stable CRC with methylation has not been characterized in detail.
We therefore examined the clinical-pathologic features of 87 sporadic microsatellite-stable CRCs that had been characterized for methylation of p16, p14, MGMT, hMLH1, MINT1, MINT2, and MINT31. Regression analyses of each clinical-pathologic characteristic were run against the individual and aggregated methylation markers to evaluate and quantify associations. CpG island methylation was associated with right-sided carcinoma (odds ratio = 6.9, P = 0.03). Paucity of gland formation, indicating poor differentiation, was strongly associated with methylation (beta = -42.6, P = 0.0008), as were presence of cribriform glands (beta = 34.3, P = 0.02) and lack of corkscrew/serrated glandular pattern (beta = -32.5, P = 0.03).
Our epigenotype-phenotype correlation study shows that microsatellite-stable CRC with CpG island methylation have a distinctive pathologic phenotype with both similarities to and differences from MSI-H tumors.K-ras (12p12) Most frequent activated oncogene, mutated in 50% of adenomas >1 cm DCC (18q21)
(Deleted in Colon CA)Expression is reduced or absent in 70-75% of cancers p53 (17p) Variable losses in adenomas Deletions of chromosome 4 occur early during the pathogenesis of colorectal carcinoma Hum Pathol 2001:32:169-177
Performed loss of heterozygosity (LOH) studies using 19 polymorphic microsatellite markers
After precise microdissection of archival surgical cases, we determined LOH in DNA obtained from 23 colorectal adenocarcinomas, 20 colorectal adenomas, and from corresponding histologically normal-appearing colonic epithelial samples adjacent to the tumors and at the resection marginsWe observed localized deletions of chromosome 4 at multiple regions in both carcinomas and adenomas
Identified deletions at 4 previously identified regions: R1 at 4q33-34 (18%-33%), R2 at 4q25-26 (45%-65%), R3 at 4p15.1-15.3 (35%-47%), and R4 at 4p16.3 (40%-49%).Six of fifteen (40%) cases examined with deletions of chromosome 4 in either adenocarcinomas or adenomas had loss of the same parental alleles in adjacent histologically normal epithelium but not in epithelial samples from the surgical resection margins
The deletions, which commenced on the short arm of chromosome 4 (regions R3 and/or R4), were more extensive in adenocarcinomas, intermediate in length in adenomas, and least extensive in histologically normal epithelium
Conclusions:
Suggest that there may be multiple putative tumor suppressor genes located on both arms of chromosome 4 whose inactivation are important early events in the pathogenesis of colorectal carcinomaExpression of the ets-1 Proto-Oncogene in Human Colorectal Carcinoma
Toshiyuki Nakayama, etal.
Mod Pathol 2001;14:415-422 Abstract quote
The proto-oncogene, ets-1, is a transcription factor known to control the expression of a number of genes involved in extracellular matrix remodeling and has been postulated to play a role in cell migration and tumor invasion.
To elucidate the involvement of ets-1 in human colorectal carcinomas, we examined 41 cases of colorectal adenoma and 122 cases of colorectal carcinoma by immunohistochemistry and compared the degree of Ets-1 expression with the depth of carcinoma invasion.
In adenomas, 12 of 41 cases (29.3%) showed immuno-positivity for Ets-1. 12 of 27 cases (44.4%) of adenoma with high grade dysplasia showed immunopositivity for Ets-1. However, there was no positive case in low or moderate dysplasia of adenoma. In contrast, 103 of 122 cases (84.4%) of colorectal adenocarcinoma showed immunoreactivity for Ets-1 in the carcinoma cells themselves.
We investigated the relationship between pathological features in colorectal carcinoma and Ets-1 immunoreactivity of the tumor cells. Among the 122 cases of invasive carcinomas, Ets-1 immunoreactivity was significantly correlated with the depth grading of tumor invasion (P < .0001), the presence of lymph node metastasis (P < .05), lymphatic invasion (P < .01) and venous invasion (P < .05). However, Ets-1 expression did not correlate with histological differentiation. In situ hybridization also confirmed the presence of ets-1 mRNA in colorectal carcinomas. Expression of ets-1 mRNA was also detected in two of three human colorectal carcinoma tissues and in four of six different kinds of carcinoma cell lines by the reverse transcription polymerase chain reaction method.
These findings suggest that the expression of Ets-1 is one of the important factors related to carcinogenesis and/or tumor invasion of colorectal carcinoma.
ABERRANT CRYPT FOCI Proliferating cell nuclear antigen as a marker of cell kinetics in aberrant crypt foci, hyperplastic polyps, adenomas, and adenocarcinomas of the human colon.
Shpitz B, Bomstein Y, Mekori Y, Cohen R, Kaufman Z, Grankin M, Bernheim J.
Department of Surgery B, Meir General Hospital, Kfar Saba, Israel
Am J Surg 1997 Oct;174(4):425-30 Abstract quote
BACKGROUND: One of the first steps in multistage colonic carcinogenesis is increased cell proliferation and an upward shift of the proliferation zone of colonic crypts. In the present study, progression in cell kinetics was followed up at all sequential stages of colonic carcinogenesis, starting with aberrant crypt foci (ACF), the earliest putative preneoplastic lesions, hyperplastic and dysplastic polyps, and invasive carcinomas.
MATERIALS AND METHODS: Colonic tissue and tumor specimens were prospectively obtained from 65 patients treated at our hospital for adenocarcinoma or malignant polyps. For identification of ACFs, dissected mucosal strips obtained from patients with colorectal cancer were stained with 0.1% methylene blue and scanned under dissecting microscope. Paraffin-embedded ACFs and macroscopic lesions were serially sectioned, deparaffinized, and stained with a monoclonal antiproliferating cell nuclear antigen (PCNA) antibody. The PCNA-labelling index (PCNA-LI), expressed as a ratio of positively stained nuclei to total nuclei counted, was calculated separately for basal, middle, and upper colonic crypt compartments. A comparison of the PCNA-LI was made for each compartment in normal mucosa, and hyperplastic and dysplastic lesions.
RESULTS: A stepwise increase in the PCNA-LI was observed during neoplastic progression of colonic lesions. The two most important variables of increased cell proliferation, expressed as PCNA-LI per crypt compartment, were the presence of dysplasia and the size of dysplastic lesions. CONCLUSIONS: In colorectal carcinogenesis, hyperproliferation with upward expansion of proliferative compartment is a characteristic feature at all stages of malignant progression.
Phenotypic and genotypic characteristics of aberrant crypt foci in human colorectal mucosa.
Nucci MR, Robinson CR, Longo P, Campbell P, Hamilton SR.
Department of Pathology and Oncology Center, The Johns Hopkins University School of Medicine and Hospital, Baltimore, MD 21205-2196, USA.
Hum Pathol 1997 Dec;28(12):1396-407 Abstract quote
Aberrant crypt foci (ACF) in colorectal mucosa are proposed to be the earliest morphological lesion in the development of neoplasia, but their characteristics remain controversial.
We therefore studied the epithelial phenotype and genotype of ACF from patients with familial adenomatous polyposis (FAP) and of sporadic ACF by evaluating glycoprotein markers associated with neoplasia (lectins Dolichus biflorus agglutinin and peanut agglutinin; monoclonal antibody CA 19-9 against sialyl Lewis-a blood group substance), expression of proliferating cell nuclear antigen, and ras proto-oncogene mutations. The utility of the markers was established by comparing adenomas and hyperplastic polyps. Most FAP ACF resembled adenomas and were found to differ from sporadic ACF in their high frequency of dysplasia, staining with Dolichus biflorus agglutinin, expression of sialyl Lewis-a, proliferation in the epithelium of upper crypts, and low frequency of ras gene mutations (P = .04 to < .0000001). By contrast, sporadic ACF and a subset of FAP ACF had phenotypic characteristics resembling hyperplastic polyps but usually had ras mutations, which were inversely related to dysplasia (P = .00009).
Our findings suggest that "aberrant crypt focus" is a generic term analogous to "polyp" and requires further histopathologic, phenotypic, or genotypic classification into dysplastic and heteroplastic (hetero = other, plasia = form) types. Dysplastic ACF represent potential precursors to colorectal adenomas and adenocarcinomas, but heteroplastic ACF appear to be associated, rather than precursor, lesions.
APOPTOSIS
Catherine Miquel, MD, etal.
Half of colorectal tumors with microsatellite instability contain frameshift mutations in the (G)8 tract of bax, a major apoptosis effector, but their functional significance remains unclear.
We studied the role of bax mutations on bax expression and apoptosis in 59 primary colorectal cancers of which 41 were microsatellite unstable. Tumors were screened for bax(G)8 mutations and evaluated immunohistochemically for bax, bcl-2, and p53 protein expression and apoptotic (M30 cytoDEATH) and proliferative (Ki-67) indexes.
We identified bax(G)8 mutations in 20 (49%) of 41 unstable tumors; the mutations were associated significantly with proximal, poorly differentiated, or mucinous adenocarcinomas. Most bax-mutated cases displayed a bax-immunonegative zone in all or part of the tumor that was proved to correspond to biallelic bax(G)8 mutations by microdissection and to confer growth advantage to the tumor by decreasing apoptosis compared with adjacent bax-immunopositive tumor. Biallelic bax(G)8 mutations are subject to positive selection pressure and might disable apoptosis in colorectal cancer.
Increased apoptosis in infiltrating mononuclear cells of colorectal cancer.Chen GG, Lee JF, Chan UP, Xu H, Ip PC, Lau WY.
Department of Surgery (Drs Chen, Lee, Xu, and Lau and Ms Chan and Ms Ip) and Sir Y. K. Pao Center for Cancer (Dr Chen), Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Arch Pathol Lab Med 2002 Jun;126(6):686-91 Abstract quote Context.-Disturbance in apoptosis has been proposed as one of the mechanisms involved in the immune response targeting tumor outgrowth. How colorectal cancer cells escape from attack by the immune system is not yet fully understood.
Objective.-To investigate apoptotic molecules associated with colorectal cancer counterattack. Design and Setting.-Tissue samples of colon from 12 patients with colorectal cancer were collected and analyzed by immunostaining. In addition to tumorous tissues, corresponding nontumorous specimens of colon were obtained as controls.
Main Outcome Measures.-We examined the expression of Bcl-2, Bcl-xl, Bax, caspase-3, and inducible nitric oxide synthase in infiltrating mononuclear cells of colorectal cancer tissues and also in colorectal cancer tissues. The TUNEL assay was used to detect in situ apoptosis.
Results.-Apoptosis was barely detectable in specimens of colorectal cancer, which was consistent with an increase in Bcl-2 level and a decrease in caspase-3 level. In contrast, infiltrating mononuclear cells of tumorous tissues showed a marked increase in apoptosis compared with those of nontumorous tissues. The increased apoptosis might have resulted from an imbalance of antiapoptotic and proapoptotic molecules, as reflected by reduction of Bcl-2 level and elevation of Bax level. The elevated caspase-3 levels found in this study could be a downstream effector of the Bcl-2 and Bax apoptotic pathways. A significant increase in inducible nitric oxide synthase observed in the infiltrating mononuclear cells might contribute to immunosuppression seen in colorectal cancer.
Conclusion.-It is tempting to speculate that aberrant expression of apoptotic molecules and inducible nitric oxide synthase in infiltrating mononuclear cells provides the underlying mechanism through which colorectal cancer cells escape attack by the immune system and subsequently grow without control.
High Apoptotic Activity and Low Epithelial Cell Proliferation With Underexpression of p21WAF1/CIP1 and p27Kip1 of Mucinous Carcinomas of the Colorectum
Comparison With Well-Differentiated Type
Fumiyuki Akino, MD,1 Hiroyuki Mitomi, MD,1 Takatoshi Nakamura, MD,2 Yoshimasa Ohtani, MD,2 Masaaki Ichinoe, MD,1 and Isao Okayasu, MDAm J Clin Pathol 2002;117:908-915 Abstract quote
We comparatively assessed 41 mucinous colorectal carcinomas (MUCs) and 620 non-MUC (well-, moderately, and poorly differentiated adenocarcinoma) cases for clinicopathologic findings; and 41 MUCs and 115 randomly selected non-MUCs also were studied for the following: (1) apoptotic activity and Ki-67 immunoreactivity; (2) immunohistochemical expression of p21WAF1/CIP1, p27Kip1, p53, and bcl-2; and (3) c-Ki-ras mutations.The rates for lymph node involvement and peritoneal dissemination were higher in MUCs than in non-MUCs. Multivariate analysis showed MUCs to have a worse prognosis than well-differentiated adenocarcinomas. The Ki-67 labeling for MUCs was significantly lower than that for non-MUCs, whereas the apoptotic index was significantly higher than for the well-differentiated type. The labeling for p21WAF1/CIP1 and p27Kip1 was lower in MUCs (2.7% and 35.3%, respectively) than in well-differentiated adenocarcinomas (4.2% and 48.6%, respectively).
MUCs can be considered a different tumor from the well-differentiated type, with a poor prognosis owing to frequent lymph node metastasis and peritoneal dissemination, and characterized by high apoptotic and low proliferative activities associated with low p21WAF1/CIP1 and p27Kip1 expression.
CD10
Expression of CD10 by stromal cells during colorectal tumor development.Ogawa H, Iwaya K, Izumi M, Kuroda M, Serizawa H, Koyanagi Y, Mukai K.
Department of Pathology, Tokyo Medical University, Tokyo, Japan, and the Division of Surgical Pathology and the Third Department of Surgery, Tokyo Medical University Hospital, Tokyo, Japan.
Hum Pathol 2002 Aug;33(8):806-11 Abstract quote CD10 is a cell surface metalloprotease expressed by a variety of normal cell types, including lymphoid precursor cells, germinal center B lymphocytes, and some epithelial cells.
We noticed that stromal cells of some cancers are positive for CD10. In this study, we investigated the role of CD10 produced by the stromal cells of colorectal neoplasms in the progression of colorectal neoplasms. Immunohistochemical examination of CD10 and p53 was performed in 169 colorectal epithelial neoplasms representing various stages of carcinogenesis. The results were correlated with the morphologic characteristics of the neoplasms. There was no expression of CD10 in the stromal cells of normal colorectal tissue. CD10-positive stromal cells were present adjacent to the tumor cells in 16 of 73 adenomas with mild or moderate dysplasia. More frequent expression of CD10 by the stromal cells was detected in adenomas with severe dysplasia (12 of 17), intramucosal carcinomas (10 of 16), and invasive carcinomas (50 of 63) than in adenomas with mild or moderate dysplasia (P < 0.0001). Expression of CD10 by > 10% of the stromal cells was detected only within the area of the invasive growth front of invasive carcinomas, not in adenomas and in only 1 of the intramucosal carcinomas. The difference between invasive and non invasive tumors was significant (P < 0.0001). The stromal expression of CD10 was significantly associated with the accumulation of p53 and a larger tumor size.
These results indicate that CD10 expression is an integral part of colorectal carcinogenesis. CD10 expression seems to contribute to the invasion and thus probably facilitates metastasis.
E-CADHERINS AND CATENINS The expression of E-cadherin and catenins in sporadic colorectal carcinoma
Mona A. El-Bahrawy, MBBCh
Richard Poulsom, PhD
Rosemary Jeffery
Ian Talbot, MD, FRCPath
Malcolm R. Alison, DScHum Pathol 32:1216-1224. Abstract quote
The E-cadherin/catenin complex plays a major role in epithelial cell–cell adhesion. Immunohistochemical studies have highlighted perturbation in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms.
In this study, we compared the expression of E-cadherin and catenins (-, -, and -catenin) in 30 sporadic colorectal carcinomas with that in the adjacent nonneoplastic mucosa and assessed whether any perturbation in the level of expression occurred at the messenger RNA (mRNA) or protein level. We also compared the expression of E-cadherin and catenins in 13 lymph node deposits and the primary tumors. Immunohistochemistry was used to study the level of expression and cellular distribution of E-cadherin and catenins. Levels of mRNA were studied by in situ hybridization. E-cadherin and catenin immunoreactivity was increased with cytoplasmic accumulation in more than 85% of the neoplasms.
There were marked increases in the levels of mRNA in the carcinomas compared with the nonneoplastic mucosa. Nuclear localization of -catenin was higher at the invasive margin of some tumors, but expression of E-cadherin and catenin transcripts in the lymph node deposits showed no consistent relationship to that in the primary tumors.
CYCLIN A
Cyclin a correlates with carcinogenesis and metastasis, and p27 correlates with lymphatic invasion, in colorectal neoplasms.Li JQ, Miki H, Wu F, Saoo K, Nishioka M, Ohmori M, Imaida K.
First Department of Pathology and the Third Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan.
Hum Pathol 2002 Oct;33(10):1006-15 Abstract quote Cyclin A binds to CDK2 and plays critical roles when cells proliferate; staining for Ki67 can monitor the proliferation. The cyclin A expression pattern remains unclear in colorectal carcinogenesis and remote metastasis, however, and no one has reported on the association of its expression with key clinicopathologic factors in primary cancer. p27(kip1) protein-an extremely important inhibitor of CDK2-seems unchanged as colorectal cancers metastasize to the lymph nodes, a result contrary to that seen in gastric and prostatic cancers.
To clarify the role of cyclin A in multistage colorectal neoplasms, cyclin A, CDK2, and Ki67 were immunohistochemically stained in 22 normal mucosa, 9 hyperplastic polyps, 61 adenomas, 197 primary carcinomas, 21 lymph node metastases, and 10 hepatic metastases. To clarify the alteration of p27(kip1) during lymphatic invasion, p27(kip1) was also stained in 21 primary cancers and paired lymph node foci. Situated in nuclei, cyclin A expression gradually increased from mild through moderate to severe dysplasia in adenomas and from normal tissue through hyperplasia to adenoma to early carcinoma. Expression was significantly decreased in the hepatic metastases and in the primary cancers showing venous invasion, deep infiltration, lymph node metastasis, mucinous type, advanced stage, or short postoperative survival time. Elevated cyclin A not only was linked with elevated CDK2 in primary cancers, but also was associated with increased Ki67 in both adenomas and primary carcinomas. Lymph node metastases lost more p27(kip1) than primary foci and hepatic lesions.
Thus, dysregulation of cyclin A and its control mechanisms may contribute to colorectal carcinogenesis; abatement of overexpression of cyclin A is associated with hepatic metastasis and cancerous invasion. Loss of p27(kip1) may promote lymph node metastasis.
CYTOMEGALOVIRUS
Olaronke Akintola-Ogunremi, MD, Qing Luo, MD, Tong-Chuan He, MD, PhD, and Hanlin L. Wang, MD, PhD
Despite the rapid advance in the understanding of molecular pathways underlying human colorectal tumorigenesis, the causes that initiate dysregulation of the pathways remain largely unknown. Human cytomegalovirus (CMV) has been implicated as a potential etiopathogenetic agent.
To further investigate whether CMV participates in human colorectal tumorigenesis, we examined 23 colorectal hyperplastic polyps, 65 colorectal adenomas, and 51 colorectal adenocarcinomas by immunohistochemical analysis using 2 antibody mixtures that recognize CMV immediate early, early, and delayed gene products. The results show that while typical nuclear staining (with or without cytoplasmic positivity) was observed in control cases of CMV colitis, no nuclear positivity was detected in any cases studied. Focal and weak cytoplasmic staining was noted in a subset of cases, particularly when a higher antibody concentration was used. This staining was believed to be nonspecific, however, because it also was observed in normal-appearing colonic mucosa. In addition, polymerase chain reaction failed to detect the presence of CMV DNA in 24 selected cases showing nonspecific cytoplasmic immunostaining.
These observations demonstrate an absence of CMV proteins and DNA in human colorectal adenocarcinomas and their precursor lesions.MICROSATELLITE INSTABILITY (MISMATCH REPAIR GENE MUTATIONS)
Robert E. Fechner Surgical Pathology Laboratory, University of Virginia, Charlottesville, VA.
Small cell neuroendocrine carcinoma (SCNC) of the colorectum is a rare and highly aggressive malignancy. It can be associated with conventional-type adenocarcinoma, and an overlying adenoma can often be identified. A disproportionate number has been noted to arise in the right colon. Although some phenotypes (eg, mucinous adenocarcinoma) have been shown to be associated with deficient mismatch repair (MMR) and thus microsatellite instability (MSI), the MMR protein status of colorectal SCNCs has not been investigated.
This study investigated the status of 3 MMR proteins, hMLH1, hMSH2, and hMSH6, in SCNCs of the colorectum. Fifteen SCNCs were identified on the basis of previous descriptions and the World Health Organization histologic criteria for the diagnosis of pulmonary small cell carcinoma and immunohistochemical evidence of epithelial and neuroendocrine differentiation. Patient age and sex and tumor size and location were recorded. Immunohistochemistry was performed with antibodies to pancytokeratin (cocktail), CD56, neuron specific enolase, synaptophysin, chromogranin, hMLH1, hMSH2, and hMSH6.
Patients' ages ranged from 44 to 87 years (mean age=73 y) and there were 9 men and 6 women. Tumors were located in the right colon (6), sigmoid colon (4), and rectum (3) (the locations of 2 cases were not recorded) and ranged in size from 0.4 to 15 cm in greatest dimension (mean=6.6 cm). All tumors showed immunoreactivity with antibodies to pancytokeratin and with antibodies to at least 1 neuroendocrine antigen. MMR proteins were intact by immunohistochemistry in all but a single case that had neither an identifiable precursor lesion nor positive internal control (hMLH1 loss). Colorectal SCNCs are rare and are often right-sided. They are aggressive and tend to occur in older individuals. Most colorectal SCNCs have intact MMR proteins, suggesting that they develop secondary to chromosomal instability rather than MSI.
Our single case showing potential MMR protein loss suggests that this phenotype may be independent of the developmental pathway (ie, chromosomal instability vs. MSI). This may explain the rare cases of SCNC that have been identified in patients with hereditary nonpolyposis colon cancer.
- Value of Immunohistochemical Detection of DNA Mismatch Repair Proteins in Predicting Germline Mutation in Hereditary Colorectal Neoplasms.
Shia J, Klimstra DS, Nafa K, Offit K, Guillem JG, Markowitz AJ, Gerald WL, Ellis NA.
From the Departments of *Pathology, daggerMedicine, and double daggerSurgery, Memorial Sloan-Kettering, Cancer Center, New York, NY.
Am J Surg Pathol. 2005 Jan;29(1):96-104. Abstract quote
The utility of immunohistochemistry (IHC) as a screening method for the identification of persons with mutations in the DNA mismatch repair (MMR) genes in hereditary nonpolyposis colorectal cancer (HNPCC) remains to be defined.
In this study, we analyzed the value of IHC versus that of microsatellite instability (MSI) testing in predicting mutation status of the MLH1, MSH2, and MSH6 genes in colorectal carcinomas and adenomas, and explored the frequency and significance of immunohistochemical staining variability. The study samples included 83 carcinomas and 29 adenomas derived from 110 patients who had strong family histories of colorectal cancer.
Our results showed that IHC correctly predicted MSI status in 76% of the cases with a specificity of 100%. The overall sensitivity of IHC in predicting a germline mutation was 79% (30 of 38) with a specificity of 89% (48 of 54), whereas that of MSI testing was 97% (30 of 31) with a specificity of 83% (35 of 42). Six of 31 analyzable cases that had a disease-causing mutation and exhibited MSI showed normal IHC. The lower sensitivity of IHC was caused mainly by its low sensitivity in detecting MLH1 gene mutation (4 of 9). Coexisting adenomas and carcinomas observed in the same slide (n = 12) showed a similar or identical staining pattern for all three proteins. No significant difference was detected in the sensitivity of IHC or MSI in detecting a germline mutation between isolated adenomas and carcinomas. In IHC-positive cases, heterogeneous staining was noted in 30% to 40% of the cases with the three different antibodies, and cytoplasmic staining in 5% to 13%. Weak IHC (defined as positive staining in <10% of the tumor with weak intensity) was noted in 14 tumors: 5 for the MLH1 antibody, 1 for MSH2, and 8 for MSH6. One of the 5 MLH1 cases exhibited MSI and had an MLH1 germline mutation. Five of the 8 MSH6 cases exhibited MSI and had MSH2 germline mutations.
In conclusion, our study shows that 1) IHC identifies a significant portion of colorectal tumors derived from MMR gene germline mutation carriers and can be used as an adjunct measure in the identification of HNPCC families, but IHC cannot replace MSI testing; 2) adenomas have similar MMR protein expression patterns as carcinomas and may serve as an adequate sample for screening purposes in the identification of patients with MMR mutations; 3) not all IHC-positive cases show uniform positivity throughout the tumor; and 4) weak and focal staining of an MMR protein may be associated with MSI or gene mutation or both, suggesting the need to incorporate staining intensity in further IHC studies.
- What Is the Best Way to Assess Microsatellite Instability Status in Colorectal Cancer?: Study on a Population Base of 462 Colorectal Cancers.
Chapusot C, Martin L, Puig PL, Ponnelle T, Cheynel N, Bouvier AM, Rageot D, Roignot P, Rat P, Faivre J, Piard F.
From *Service d'Anatomie Pathologique, Dijon, Faculte de Medecine, Dijon; daggerINSERM EMI 0106-IFR 100, Faculte de Medecine, Dijon; double daggerHopital europeen Georges Pompidou Assistance Publique Hopitaux de Paris, Paris; section signU490 Laboratoire de Toxicologie Moleculaire, Paris; and paragraph signCentre de Pathologie de Dijon, Dijon, France.
Am J Surg Pathol. 2004 Dec;28(12):1553-1559. Abstract quote
The assessment of the microsatellite instability (MSI) status in colorectal cancers is presently warranted for three reasons: 1) as a screening tool for hereditary nonpolyposis colorectal cancer, 2) as a prognostic marker, and 3) as a potential predictive factor of chemotherapy response.
The aim of this study was to evaluate, on a large scale with tissue samples coming from a number of different sources, the difficulties met with routine use of immunohistochemistry (IHC) and to determine if it really does offer an accurate alternative to PCR genotyping. Colorectal carcinomas from 462 consecutive patients resected in public or private hospitals were assessed for MSI status by two methods: MSI testing (with BAT-26 microsatellite) and IHC detection of hMLH1, hMSH2, and hMSH6 proteins. Of the 398 cancers tested, immunohistochemistry was noncontributory in 42 (10.5%), focal in 9 (2.3%), and discordant with the PCR results in 36 (9%). For these 87 cases, complementary analyses were performed to explain discrepancy. After additional IHC assay with modified processing protocols, 8 cases remained noncontributory, 2 focal, and 28 discordant: 18 microsatellite stability IHC/MSI PCR and 10 MSI IHC/microsatellite stability PCR. For these discordant cases, we performed a multiplex PCR assay on DNA extracted from the frozen sample and BAT-26 was amplified from DNA extracted from the paraffin blocks used for IHC. Four discordant cases were reclassified after PCR multiplex assay (3 as MSI and 1 as microsatellite stability). Five other cases displayed intratumoral heterogeneity and 19 remained discordant. The discrepancy could be partly explained by variable technical protocols of fixation in the different laboratories, leading to variations in staining quality and difficulties in IHC interpretation.
This population-based study is the first one to show that IHC is not sensitive and specific enough to be used routinely. Immunohistochemistry analysis of MMR proteins must be performed in standardized conditions and interpreted by confirmed pathologists. It cannot replace PCR as long as protocols are not optimized and harmonized.
Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer.
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.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10002, USA.
Am J Surg Pathol. 2003 Nov;27(11):1407-17. Abstract quote
Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI.
The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies.
In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23-80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31 cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31-84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR.
Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases.
Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.
Histopathology and mismatch repair status of 458 consecutive colorectal carcinomas.
Wright CL, Stewart ID.
Surgical Pathology Unit, North Shore Hospital, Takapuna, Auckland, New Zealand.
Am J Surg Pathol. 2003 Nov;27(11):1393-406. Abstract quote
Defects in the mismatch repair (MMR) genes hMLH1 and hMSH2 have been found in 10% to 20% of sporadic colorectal carcinomas and also many cases of hereditary nonpolyposis colorectal cancer syndrome. Patients with these tumors have an improved prognosis and may show greater sensitivity to chemotherapy.
We examined 458 resected colorectal carcinomas from 430 consecutive patients and used immunohistochemistry to determine which tumors lacked expression of these genes (MMR-d). We correlated the status of MMR-d or "intact" expression with stage, site, and histology. Eighty-nine of 458 tumors (19.4%) were MMR-d, including 80 hMLH1 and 9 hMSH2 tumors. A total of 6% of patients had synchronous tumors, and 37.7% of these were MMR-d (P=0.0008). A high proportion of patients with previous breast cancer (4 of 6 patients) had hMLH1-defective colorectal carcinomas. MMR-d tumors presented at an earlier stage than intact tumors, and the node-positive MMR-d tumors were less likely than intact tumors to have pericolonic extranodal tumor deposits (18.2% vs. 44%). The proportion of tumors at each site that were MMR-d increased progressively from cecum (32%) to ascending (35%) to transverse colon, where 41% of all tumors were defective.
The proportions then rapidly decreased, reaching the lowest rate (4.7%) in the rectum. Both types of MMR-d tumors more often had expansive borders, intraepithelial lymphocytosis, peritumoral lymphoid, and Crohn's-like lymphoid responses than the intact tumors; the frequencies of these features diminished with advancing stage. Tumor budding was less common in stage II and III MMR-d tumors than in intact tumors. Keloid and myxoid type stromas correlated with stage and vascular invasion and were not related to mismatch repair status. Significant differences existed between the hMLH1 and hMSH2 tumors. The reported right-sided preponderance of MMR-d tumors is due to most hMLH1, but not hMSH2, tumors being found there (87.5% vs. 44.4%). hMSH2 tumors were most common in the rectum (55.6%). Mucinous tumors were common in hMLH1 tumors (36.3%) but not in hMSH2 tumors (11.1%). hMLH1 tumors were most likely to be poorly differentiated (70%), which was uncommon with hMSH2 tumors (22.2%). hMSH2 tumors were more likely to be confined to the wall (66.7%) than hMLH1 (20%) or intact tumors (23%).
We conclude that hMLH1 and hMSH2-defective tumors have distinctly differing histologic features from each other.Microsatellite Instability in Double Primary Cancers of the Colorectum and Stomach
Hee Sung Kim, M.D., Ph.D., Nam Bok Cho, M.D., Ph.D., Jae Hyung Yoo, M.D., Ph.D., Ki-Hyuk Shin, Ph.D., Jae-Gahb Park, M.D., Ph.D., Yong Il Kim, M.D., Ph.D. and Woo Ho Kim, M.D., Ph.D.
Department of Pathology (HSK, YIK, WHK) and Surgery (JGP) and Cancer Research Institute (KHS, JGP, WHK), Seoul National University College of Medicine, Seoul, Korea; and Department of Pathology (NBC, JHY), Chung-Ang University College of Medicine, Seoul, Korea
Mod Pathol 2001;14:543-548 Abstract quote
Little is known about genetic alterations of patients who present multiple primary cancers. We hypothesized that microsatellite instability (MSI) is one of the underlying genetic factors in the development of double primary cancers in colorectal cancer patients.
We examined for MSI in 41 colorectal cancer patients who presented with extra-colonic primary cancers consisted of 17 gastric and 24 non-gastric cancers.
Coincident MSI+ in tumors of two organs were observed in 3 (17.7%) of 17 patients with colon and stomach cancers and 0 of 24 patients with colon and non-gastric cancers (P = .03). In 17 patients with colon and stomach cancers, 6 (31.6%) of 19 colon cancers and 3 (17.7%) of 17 gastric cancers exhibited MSI+. Among four patients with metachronous colon cancers who were identified within the 41 double primary cancer patients, two patients were associated with the MSI+ phenotype.
In summary, the prevalent coincidence of MSI suggests that genetic defect of mismatch repair deficiency may be responsible for a small subset of double primary cancers of the colorectum and stomach.
Detection of Microsatellite Instability From Archival, Hematoxylin-Eosin–Stained Colorectal Cancer Specimen
Joerg Trojan, MD, Jochen Raedle, MD, Guenter Herrmann, MD, Angela Brieger, PhD, and Stefan Zeuzem, MDFrom the Second Department of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany (Drs Trojan, Raedle, Brieger, and Zeuzem); and the Department of Pathology, Klinikum Ludwigsburg, Ludwigsburg, Germany (Dr Herrmann)
Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 202–204 Abstract quote Microsatellite instability (MSI) is characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). Owing to early onset of colorectal cancer before the age of 50 years and/or familial clustering of HNPCC-related malignancies, the diagnosis of HNPCC was suspected in 2 patients.
Because no paraffin-embedded tumor tissue was available, we used archival 5-m, hematoxylin-eosin–stained tumor specimen slides for direct MSI analysis. Tissue was microdissected and cells were lysed using 1% Triton. Fluorescence polymerase chain reaction amplification of a panel of 7 microsatellite markers, including all markers of the current international reference panel (BAT-25, BAT-26, D2S123, D5S346, and D17S250), demonstrated MSI in one patient and excluded MSI in the other.
In conclusion, this study demonstrates the feasibility of MSI analysis by direct fluorescence polymerase chain reaction amplification using hematoxylin-eosin–stained tissue specimens without the need for prior DNA extraction.
Immunohistochemical Pattern of MLH1/MSH2 Expression Is Related to Clinical and Pathological Features in Colorectal Adenocarcinomas with Microsatellite Instability.Lanza G, Gafa R, Maestri I, Santini A, Matteuzzi M, Cavazzini L.
Department of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara (GL, RG, IM, MM, LC).
Mod Pathol 2002 Jul;15(7):741-9 Abstract quote Detection of colorectal carcinomas with high-frequency microsatellite instability (MSI-H) is clinically important for several reasons. Recent studies suggested that immunohistochemical analysis of MLH1 and MSH2 expression is a rapid and accurate method for identifying large bowel tumors of the MSI-H phenotype.
In this study, we evaluated by immunohistochemistry MLH1 and MSH2 protein expression in 132 MSI-H, 23 MSI-L (low-frequency MSI), and 150 microsatellite stable (MSS) colorectal adenocarcinomas. Loss of MLH1 or MSH2 expression was detected in 120 (90.9%) MSI-H carcinomas, whereas all MSI-L and MSS tumors showed normal expression of both proteins. Lack of MLH1 nuclear staining was observed much more often than absence of MSH2 nuclear staining (106 and 14 cases, respectively). Among MSI-H carcinomas, MLH1/MSH2 pattern of expression was significantly related to several clinical and pathological variables. In particular, MSI-H MLH1/MSH2-positive carcinomas were more often located in the distal colon, were more frequently classified as ordinary adenocarcinomas, and were more likely to be well or moderately differentiated, p53 positive, and <7 cm in diameter than were MLH1-negative and MSH2-negative carcinomas. In addition, MLH1-negative carcinomas were less common among patients with hereditary nonpolyposis colorectal cancer (HNPCC) or suspected HNPCC and in the group of patients aged <50 years. Patients with MLH1-negative carcinomas more frequently died of disease than did patients with MLH1/MSH2-positive and MSH2-negative MSI-H tumors, but the difference was not statistically significant.
The results of the present investigation strongly indicate that immunohistochemical analysis of MLH1 and MSH2 expression is a practical and reliable method for the routine detection of the vast majority of MSI-H large bowel adenocarcinomas. Our data also point out that MSI-H MLH1/MSH2-positive colorectal carcinomas are characterized by distinctive pathological features.
MYOFIBROBLASTS
Martin Illemann, MSc, etal.
Plasminogen activator inhibitor-1 (PAI-1) is up-regulated strongly in various cancer tissues, including colon cancer tissue. Highly specific rabbit polyclonal antibodies against PAI-1 were used for immunohistochemical localization of PAI-1 in 12 invasive colorectal adenocarcinomas. PAI-1 immunoreactivity was observed in endothelial cells of some vessels located in the submucosa and in several fibroblast-like cells located at the invasive front. No PAI-1 immunoreactivity was seen in cancer cells in any of the 12 cases.
Double immunofluorescence using the PAI-1 antibodies together with antibodies against a-smooth muscle actin for myofibroblast/smooth muscle cells and CD34 for endothelial cells showed that more than 80% of the PAI-1–positive fibroblast-like cells in all 12 cases were myofibroblasts. In 4 of 12 cases, a few of the PAI-1–positive fibroblast-like cells in the invasive front were CD34+.
We conclude that the majority of PAI-1–positive fibroblast-like cells located at the leading edge of the invasive colon cancers are myofibroblasts.
LABORATORY/
RADIOLOGIC/OTHERCHARACTERIZATION RADIOLOGIC LABORATORY
Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence?Sirovich BE, Schwartz LM, Woloshin S.
VA Outcomes Group, 111B, Department of Veterans Affairs Medical Center, White River Junction, VT 05009.
JAMA 2003 Mar 19;289(11):1414-20 Abstract quote CONTEXT: The debate about the efficacy of prostate-specific antigen (PSA) screening for prostate cancer has received substantial attention in the medical literature and the media, but the extent to which men are actually screened is unknown. If practice were evidence-based, PSA screening would be less common among men than colorectal cancer screening, a preventive service of broad acceptance and proven efficacy.
OBJECTIVE: To compare the prevalences of PSA and colorectal cancer screening among US men.
DESIGN, SETTING, AND POPULATION: The 2001 Behavioral Risk Factor Surveillance System, an annual population-based telephone survey of US adults conducted by the Centers for Disease Control and Prevention, was used to gather data on a representative sample of men aged 40 years or older from all 50 states and the District of Columbia (n = 49 315).
MAIN OUTCOME MEASURES: Proportions of men ever screened and up to date on screening for prostate cancer (with PSA testing) and colorectal cancer (with fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy).
RESULTS: Overall, men are more likely to report having ever been screened for prostate cancer than for colorectal cancer; 75% of those aged 50 years or older have had a PSA test vs 63% for any colorectal cancer test (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.18-1.21). Up-to-date PSA screening is also more common than colorectal cancer screening for men of all ages. Among men aged 50 to 69 years (those for whom there is the greatest consensus in favor of screening), 54% reported an up-to-date PSA screen, while 45% reported up-to-date testing for colorectal cancer (RR, 1.19; 95% CI, 1.16-1.21). In state-level analyses of this age group, men were significantly more likely to be up to date on prostate cancer screening compared with colorectal cancer screening in 27 states, while up-to-date colorectal cancer screening was more common in only 1 state.
CONCLUSION: Among men in the United States, prostate cancer screening is more common than colorectal cancer screening. Physicians should ensure that men who choose to be screened for cancer are aware of the known mortality benefit of colorectal cancer screening and the uncertain benefits of screening for prostate cancer.
OTHER APC
Detection of APC mutations in fecal DNA from patients with colorectal tumors.Traverso G, Shuber A, Levin B, Johnson C, Olsson L, Schoetz DJ Jr, Hamilton SR, Boynton K, Kinzler KW, Vogelstein B.
Graduate Program in Human Genetics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins School of Medicine, Baltimore, USA.
N Engl J Med 2002 Jan 31;346(5):311-20 Abstract quote BACKGROUND: Noninvasive methods for detecting colorectal tumors have the potential to reduce morbidity and mortality from this disease. The mutations in the adenomatous polyposis coli (APC) gene that initiate colorectal tumors theoretically provide an optimal marker for detecting colorectal tumors. The purpose of our study was to determine the feasibility of detecting APC mutations in fecal DNA with the use of newly developed methods.
METHODS: We purified DNA from routinely collected stool samples and screened for APC mutations with the use of a novel approach called digital protein truncation. Many different mutations could potentially be identified in a sensitive and specific manner with this technique.
RESULTS: Stool samples from 28 patients with nonmetastatic colorectal cancers, 18 patients with adenomas that were at least 1 cm in diameter, and 28 control patients without neoplastic disease were studied. APC mutations were identified in 26 of the 46 patients with neoplasia (57 percent; 95 percent confidence interval, 41 to 71 percent) and in none of the 28 control patients (0 percent; 95 percent confidence interval, 0 to 12 percent; P<0.001). In the patients with positive tests, mutant APC genes made up 0.4 to 14.1 percent of all APC genes in the stool.
CONCLUSIONS: APC mutations can be detected in fecal DNA from patients with relatively early colorectal tumors. This feasibility study suggests a new approach for the early detection of colorectal neoplasms.
Detection of proximal colorectal cancers through analysis of faecal DNA.Traverso G, Shuber A, Olsson L, Levin B, Johnson C, Hamilton SR, Boynton K, Kinzler KW, Vogelstein B.
Lancet 2002 Feb 2;359(9304):403-4 Abstract quote Detection of mutations in faecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average-risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers in sporadic cancers with mismatch-repair deficiencies. Since such cancers nearly always occur in the proximal colon, this test might be useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions.
We report here the first in-depth analysis of faecal DNA from patients with proximal cancers to determine the feasibility, sensitivity, and specificity of this approach. Using a sensitive method for microsatellite mutation detection, we found that 18 of 46 cancers had microsatellite alterations and that identical mutations could be identified in the faecal DNA of 17 of these 18 cases.
p53 Circulating p53 antibody in patients with colorectal cancer: relation to clinicopathologic features and survival.
Shiota G, Ishida M, Noguchi N, Oyama K, Takano Y, Okubo M, Katayama S, Tomie Y, Harada K, Hori K, Ashida K, Kishimoto Y, Hosoda A, Suou T, Kanbe T, Tanaka K, Nosaka K, Tanida O, Kojo H, Miura K, Ito H, Kaibara N, Kawasaki H.
Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.
Dig Dis Sci 2000 Jan;45(1):122-8 Abstract quote
The presence of serum anti-p53 antibody has been reported to be associated with survival of patients with breast cancer, ovarian cancer, and hepatocellular carcinoma. To clarify prognostic significance of p53 antibody in colorectal cancer, serum p53 antibody was measured in patients with colorectal cancer.
The 89 patients included 71 with colorectal cancer and 18 with colon polyp. An enzyme-linked immunosorbent assay was used to detect p53 antibodies in serum. Clinicopathological parameters such as age, sex, degree of differentiation of cancer, location of tumor, liver metastasis, stage classification, Dukes classification, CEA, CA19-9, and immunostaining of p53 and anti-p53 antibody were evaluated as prognostic factors of colorectal cancer. p53 antibody was positive in 18 of 71 (25%) with colorectal cancer, whereas it was positive in only 1 of 18 (6%) with colon polyp. The patients with p53 antibody had higher CEA and CA19-9 levels, higher positive rates of p53 protein expression in cancer cells, and higher liver metastasis rates. The p53 antibody positivity at stage classification I-IIIb/ Dukes classification A-C was significantly lower than that at stage classification IV/Dukes classification D.
Overall survival in colorectal cancer patients with p53 antibody was significantly shorter than in those without p53 antibody. A Cox regression analysis showed that liver metastasis, stage classification, Dukes classification, CA19-9, and p53 antibody were significant prognostic factors in colorectal cancer. Serum anti-p53 antibody could serve as one of the prognostic factors in patients with colorectal cancer.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General description Right sided lesions tend to be polypoid exophytic masses
Left sided lesions are usually annular lesions producing a characteristic napkin ring lesion in the bowelLymph node recovery from colorectal resection specimens removed for adenocarcinoma. Trends over time and a recommendation for a minimum number of lymph nodes to be recovered.
Goldstein NS, Sanford W, Coffey M, Layfield LJ.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1996 Aug;106(2):209-16 Abstract quote
Recovery of pericolorectal lymph nodes from colectomy specimens has long been part of colorectal cancer staging. Recently, adjuvant therapy has been added for high stage carcinomas, providing further impetus for performing careful lymph node dissections. Pericolorectal lymph nodes were examined to determine if there has been a change over time in the number of lymph nodes recovered and proportion of specimens with pericolonic lymph node metastases from colorectal carcinoma resection specimens. Also, the authors attempted to establish a recommendation for a minimum number of lymph nodes that should be recovered before a colon can be considered free of metastases.
Slides and reports of the first 20 consecutive pT3 colorectal carcinoma resections in each year from 1955 to 1995 at William Beaumont Hospital that did not have known metastases at the time of surgery were reviewed (750 specimens total). The mean number of lymph nodes recovered per specimen and incidence of detected lymph node metastases increased over the 41-year period, with the greatest increase occurring during 1992-1995. The greatest proportion of patients with lymph node metastases detected occurred in the 17 to 20 lymph nodes recovered per specimen group. Specimens with more than 20 lymph nodes did not have a higher proportion of lymph node metastases detected compared to specimens with 17 to 20 lymph nodes. Approximately 20% of the specimens with metastases had more than 17 lymph nodes recovered.
These results suggest that pathologists should retrieve all the lymph nodes that can be recovered, but at least 17 lymph nodes should be recovered to insure accurate documentation of nodal metastases when present.
Disparate surgical margin lengths of colorectal resection specimens between in vivo and in vitro measurements. The effects of surgical resection and formalin fixation on organ shrinkage.
Goldstein NS, Soman A, Sacksner J.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA
Am J Clin Pathol 1999 Mar;111(3):349-51 Abstract quote
We noticed almost routine disparate results in margin lengths when colorectal specimens are measured in vivo by the surgeon and in vitro by the pathologist.
We studied 26 sigmoid and rectum specimens to document the amount of organ shrinkage after surgical removal and fixation. Each specimen had a 5.0-cm segment at each end of the specimen marked by serosal sutures before vascular devitalization. The segments were measured after the specimen sat unfixed for 10 to 20 minutes and after 12 to 18 hours of formalin fixation. The segments shrank to a median length of 3.0 cm (40% of the in vivo length) after 10 to 20 minutes and an additional 0.85 cm, to a median length of 2.15 cm, after fixation. Overall after fixation, the segments shrank 57% of the in vivo length. Approximately 70% of the shrinkage occurred during the first 10 to 20 minutes after removal, and the remaining 30% occurred after fixation.
For optimal accuracy, margin distance must be obtained immediately after surgical removal. Once the specimen has been removed for several minutes, the difference between unfixed and fixed margin lengths is 30%. A correction factor of approximately 2x should be applied when interpreting the margin length.
Cecum and ascending colon 38% Transverse colon 18% Descending colon 8% Sigmoid colon 35% Multiple sites 1%
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
*Department of Pathology, Brigham and Women's Hospital, Harvard Medical School daggerSection of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA.
Rarely, adenocarcinomas of the colorectum develop as small (</=1.0 cm) rapidly invasive tumors without an obvious adenomatous or "in situ" component. These tumors have been termed "de novo" carcinomas. Although it is believed by some that these tumors are more aggressive than conventional large adenocarcinomas with an identifiable in situ component, little is known about the biologic characteristics and natural history of these lesions.
The aim of this study was to evaluate and compare the pathologic features, biologic characteristics, and natural history of small apparently de novo invasive colorectal adenocarcinomas with conventional large (>1.0 cm) carcinomas. Routinely processed specimens from 20 patients (M/F ratio: 13/7; mean age: 65 y) with small apparently de novo invasive colorectal adenocarcinomas (all </=1.0 cm in size) were evaluated for a variety of clinical and pathologic features. In addition, immunostains for p53, beta-catenin, DPC4, hMLH1, hMSH2, and MGMT were evaluated in all cases.
The findings in this group of cases were compared with those from 20 control patients (M/F ratio: 8/12; mean age: 60 y) with stage-matched conventional "large" colorectal adenocarcinomas (all >1.0 cm in size). Patients were followed for a mean of 52.6 and 60.6 months, respectively, for the 2 groups. Small apparently de novo invasive adenocarcinomas were present in the left colon, transverse colon, and right colon in 85%, 10%, and 5% of cases, respectively. Their mean size was 7 mm (range: 3 to 10 mm). All cases were stage T1 and the majority were moderately differentiated (75%). Only 1 (5%) patient had lymph node metastases. Two (10%) cases were mucinous and only 1 (5%) showed prominent tumor infiltrating lymphocytes. Upon complete sectioning of the tissue blocks of tumor, residual foci of adenomatous epithelium were present in 16/20 (80%) cases, of which 75% contained foci of high-grade dysplasia. P53 and nuclear beta-catenin staining was present in 70% and 85% of cases, respectively, but only 5 cases (25%) showed loss of DPC4. Loss of MGMT expression was seen in 5 cases (25%), loss of hMSH2 in only 1 case (5%), and none showed loss of hMLH1. Only 2 patients (10%) developed visceral metastases upon follow-up. Control patients had similar demographic features, clinical outcome, anatomic distribution of tumors, degree of differentiation, and prevalence of positivity for the immunostains noted above, to the study cases.
In our patient population, true small de novo colorectal adenocarcinomas, tumors that lack an identifiable adenomatous component, are exceedingly rare, because complete tissue sectioning reveals residual adenomatous tissue in the majority of cases. The biologic characteristics and natural history of small carcinomas with a minimal dysplastic component, and those with no identifiable adenomatous component, are similar to conventional large (>1 cm) adenocarcinomas, and, thus, they should probably be treated similarly.Accuracy of pathologic interpretation of colorectal polyps by general pathologists in community practice.
Rex DK, Alikhan M, Cummings O, Ulbright TM.
Departments of Medicine, Gastroenterology, and Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Gastrointest Endosc 1999 Oct;50(4):468-74 Abstract quote
BACKGROUND: The histologic features of colorectal polyps often guide colonoscopic surveillance and the need for surgical intervention. Our objective was to evaluate the pathologic interpretation of colorectal polyps by general pathologists in community practice.
METHODS: Twenty histologic slides of colorectal polyps were reviewed by 20 randomly selected general pathologists in community practice. There were 5 malignant polyps, 9 adenomas, and 6 miscellaneous polyps.
RESULTS: Cancer was correctly identified in 91% of readings and adenoma in 94%. The grade of differentiation of cancer was provided in 55% of readings, and comment regarding whether the resection margin was free of cancer was made by 50% of pathologists. Tubular adenoma was called tubulovillous or villous in 35% of readings, but tubulovillous or villous adenoma was seldom (2%) called tubular. High-grade dysplasia was correctly identified in 47% of 60 readings, was called invasive cancer in 22%, and was missed in 31%. Among miscellaneous polyps, hyperplastic polyp was correctly recognized in 75% of cases, and inflammatory polyp and juvenile polyp each were recognized by 16 of 20 pathologists (80%). Peutz-Jeghers hamartoma was identified by 4 of 20 pathologists (20%), and the polypoid phase of solitary rectal ulcer syndrome was recognized by 2 pathologists (10%).
CONCLUSION: Areas of strength with regard to interpretation of colon polyps by general pathologists in community practice included identification of cancer, adenoma, and certain non-neoplastic polyps (e.g., inflammatory and juvenile polyps). Areas of weakness included lack of comment on cancer differentiation and proximity to the resection line, erroneous identification of high-grade dysplasia, and identification of rare lesions. The results of this study suggest areas on which to focus continuing education and continuous quality improvement efforts with regard to polyp interpretation.
Usual type Raggedly infiltrating glands lined by pleomorphic columnar cells
A prominent desmoplastic stromal host response is often elicited by the infiltrating tumorADENOSQUAMOUS Malignant gland mixed with squamous cell carcinoma EOSINOPHILIA Stromal eosinophilia in colonic epithelial neoplasms.
Moezzi J, Gopalswamy N, Haas RJ Jr, Markert RJ, Suryaprasad S, Bhutani MS.
Department of Veterans Affairs Medical Center, and Wright State University School of Medicine, Dayton, Ohio 45428, USA
Am J Gastroenterol 2000 Feb;95(2):520-3 Abstract quote
OBJECTIVE: The purpose of this retrospective study was to determine the frequency and intensity of eosinophilic infiltration (or tissue eosinophilia) in the stroma of colonic adenomas, hyperplastic polyps, and colorectal adenocarcinomas. Eosinophilic infiltration in various malignancies has been reported but has not been evaluated in benign colorectal adenomas and hyperplastic polyps.
METHODS: We analyzed 488 colonic neoplasms: 176 tubular adenomas, 55 tubulovillous adenomas, 82 villous adenomas, 15 early carcinomas in polyps, 95 invasive adenocarcinomas, and 65 hyperplastic polyps for the presence of eosinophilic infiltration. The eosinophilic infiltration was graded as negative (< or =5%), mild to moderate (>5-40%), or marked (>40%), depending on the percentage of eosinophils relative to total inflammatory cells in the stroma.
RESULTS: Mild to moderate eosinophilia was noted in 75% of all adenomas. The transitional zone in all cases of invasive adenocarcinoma (zone between normal tissue and adenocarcinoma) revealed a high percentage of tissue eosinophilia. There was a striking absence of TE in the stroma of invasive adenocarcinomas. Only 5% of hyperplastic polyps had any eosinophilic infiltration.
CONCLUSIONS: These data suggest that, in the spectrum of colonic neoplasms, stromal eosinophilia is most prominent in adenomas and seems to decrease with progression through the adenoma-carcinoma sequence. The ramifications of this study may alter management plans and provide some prognostic information for clinical evaluation.
FLAT Flat and polypoid adenocarcinomas of the colorectum: A comparative histomorphologic analysis of 47 cases.
Nasir A, Boulware D, Kaiser HE, Bodey B, Siegel S, Crawley S, Yeatman T, Marcet JE, Coppola D.
Hum Pathol. 2004 May;35(5):604-11. Abstract quote
"Flat" colorectal adenomas and adenocarcinomas are well documented in the Japanese literature but only sporadically reported in the English literature.
The present study involved systematic morphological analysis of a large series of colorectal carcinomas (CRCs) to determine the frequency of these "flat" CRCs (FCRCs) and analyze their pathological characteristics and associated patient survival.
The study group comprised 47 patients (19 females and 28 males) with primary CRC who underwent colorectal resection at the H. Lee Moffitt Cancer Center between 1997 and 2002. These cases were selected based on the gross appearance of the tumors and after review of all of the hematoxylin and eosin-stained tumor sections in a series of 190 consecutive colorectal resections for CRCs. Application of strict morphological criteria classified 22 tumors as FCRCs. For comparison, 25 "polypoid" CRCs (PCRCs) were also identified. Cases of ulcerative fungating annular CRCs and CRCs with mixed gross appearance were excluded from this analysis. Clinicopathologic data, including patient survival, were compared for FCRCS and PCRCs. Statistical analyses were carried out using the chi(2) or Fisher's exact test and log-rank tests. Overall, 22 of 190 CRCs (11%) were found to meet the morphological criteria of FCRCs. Mean patient age was 70.6 years (range, 55 to 87) for FCRCs versus 68.5 years (range, 54 to 91) for PCRCs, and mean tumor size was 4.7 cm (range, 1.6 to 9) for FCRCs versus 4.4 cm (range, 0.5 to 10) for PCRCs. None of the 22 FCRCs and only 1 of 25 (4%) PCRCs were well differentiated; 17 of 22 (77%) FCRCs and 23 of 25 (92%) PCRCs were moderately differentiated; and 5 of 22 (22%) FCRCs and 1 of 25 (4%) PCRCs were poorly differentiated (P = 0.0087). FCRC cases were staged as 0 stage T1, 3 (14%) stage T2, and 19 (86%) stage T3; PCRC cases, as 4 (16%) stage T1, 14 (56%) stage T2, and 7 (28%) stage 3 (P = 0.000031). Similarly, angiolymphatic invasion was identified in 12 of 22 (54%) FCRCs versus 4 of 25 (16%) PCRCs (P = 0.0123). Although some differences between FCRCs and PCRCs were observed on resection in terms of nodal status (N), presence of metastases (M), and perineural invasion, these differences were not statistically significant. In comparison with PCRCs, FCRCs were associated with significantly shorter postresection patient survival at 1 to 5 years (P = 0.028).
We have demonstrated in this report that a proportion of primary CRCs resected at our institution were indeed "flat." Furthermore, these FCRCs exhibited higher histological grades, higher T stage, more frequent angiolymphatic invasion, and shorter patient survival compared with PCRCs. Based on these data, FCRC appears to be a worse subtype of colon cancer than PCRC. Further appraisal of FCRCs and additional studies to further elucidate the molecular mechanisms underlying their morphogenesis are warranted.MEDULLARY
Mark R. Wick, MD, etal.
We studied 68 sporadic colorectal carcinomas (CRCs) with medullary features (MCRCs) and compared them with 35 poorly differentiated purely "enteric" CRCs (ECRCs) and 15 purely neuroendocrine carcinomas (NECs) of grades II and III, all in patients lacking a family history of CRC.
Potential clinicopathologic differences between the study groups were assessed. MCRCs were significantly more common in the ascending colon than were ECRCs, but there was no significant dissimilarity to NECs. ECRCs occurred more often in the rectosigmoid than MCRCs or NECs. MCRCs arose in older patients, and a marked sex difference also was noted. Despite an infiltrative growth pattern, MCRC was less likely than ECRC to manifest with stage III or IV disease, but there was no stage-related difference from NECs.
Although the histologic images of MCRCs were evocative of neuroendocrine differentiation, chromogranin positivity and synaptophysin reactivity in that group did not differ meaningfully from that of ECRCs but was dissimilar to the 100% labeling of NECs. p53 immunolabeling was similar in the 3 tumor groups. Follow-up data in the study cases showed that 5-year mortality was 40% (27/68) for MCRC, 59% (19/32) for ECRC, and 93% (14/15) for NEC.
Medullary CRC seems to be a distinct clinicopathologic variant of CRC, which does not have a neuroendocrine lineage. The biologic behavior of MCRC was better than that of ECRC or NEC.
Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly.
Arai T, Esaki Y, Sawabe M, Honma N, Nakamura K, Takubo K.
Department of Pathology, Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan.
Mod Pathol. 2004 Feb;17(2):172-9 Abstract quote.
To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, P<0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.MUCINOUS (COLLOID) Abundant mucin lakes which dissect the connective tissue Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival.
Kakar S, Aksoy S, Burgart LJ, Smyrk TC.
1Department of Pathology, University of California San Francisco and Veteran Affairs Medical Center, San Francisco, CA, USA.
Mod Pathol. 2004 Jun;17(6):696-700. Abstract quote
Colorectal carcinoma with microsatellite instability (MSI-H) has a characteristic clinicopathologic profile, typically forming right-sided, lymphocyte-rich tumors that are often mucinous. Mucinous histology in general has been linked to adverse prognosis in some studies, but not in others. MSI-H carcinoma, in contrast, has a better prognosis than microsatellite stable carcinoma in most studies.
We assessed the relationship between MSI status, clinicopathologic features and outcome for 248 consecutive patients with resected mucinous carcinoma. All cases were reviewed to confirm mucinous histology. Immunohistochemical stains for DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 were performed on a representative block from each case. Tumors lacking expression of a mismatch repair enzyme were designated MSI-H; all others were classified as microsatellite stable. Age, sex, tumor size, site, grade, stage, growth pattern, Crohn's-like reaction, vascular invasion and number of tumor-infiltrating lymphocytes were evaluated without knowledge of MSI status or patient outcome. 72 (29.3%) mucinous carcinomas were MSI-H. Compared to microsatellite stable mucinous cancers, they were more likely to be right-sided (83.3 vs 48.6%, P<0.001), have a Crohn's -like reaction (65.7 vs 29.8%, P<0.001) and have many tumor infiltrating lymphocytes (72.2 vs 20.8%, P<0.001). MSI-H mucinous cancers presented more often as localized disease (66.7 vs 38.1%, P<0.001) and less often with lymph node (26.4 vs 44.9%) or distant (4.2 vs 16.5%) metastases. In univariate analysis, MSI had a favorable effect on age-adjusted survival (hazard ratio 0.597, P=0.02).
In multivariate analysis, age, grade, Crohn's-like reaction and stage were independent predictors of survival, but MSI status was not. In conclusion, MSI-H mucinous carcinomas are right-sided, low-stage tumors with Crohn's-like reaction and tumor-infiltrating lymphocytes. The outcome for MSI-H mucinous carcinoma is better than that of microsatellite-stable mucinous carcinoma, but MSI status is not an independent predictor of survival.NEUROENDOCRINE Small cell carcinoma with positive staining for neuroendocrine markers
Increased endocrine cells in treated rectal adenocarcinomas: a possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy.Shia J, Tickoo SK, Guillem JG, Qin J, Nissan A, Hoos A, Stojadinovic A, Ruo L, Wong WD, Paty PB, Weiser MR, Minsky BD, Klimstra DS.