Background.—Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive fa...

/pdf/prognostic-factors-in-colorectal-cancer-29c3n2ip7d.pdf

Prognostic Factors in Colorectal Cancer

Background The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma. Methods A multidisciplinary consensus conference using published literature developed an arbitrary classification system of prognostic marker value (Category I, IIA, IIB, III, and IV), which forms the framework for this report. Results The working party concluded that several T categories should be subdivided: pTis into intraepithelial carcinoma (pTie) and intramucosal carcinoma (pTim); pT1 into pT1a and pT1b corresponding to the absence or presence of blood or lymphatic vessel invasion, respectively; and pT4 into pT4a and pT4b according to the absence or presence of tumor involving the surface of the specimen, respectively. The working party also recommended that TNM groups be stratified based on the presence or absence of elevated serum levels of carcinoembryonic antigen (CEA) (>/= 5 ng/mL) on preoperative clinical examination. In addition, the working party also concluded that carcinoma of the appendix should be excluded from the colorectal carcinoma staging system because of fundamental differences in natural history. Conclusions The TNM categories and stage groupings for colorectal carcinoma published in the current AJCC manual have clinical and academic value. However, a few categories require subdivision to provide increasing discrimination for individual patients. The serum marker CEA should be added to the staging system, whereas multiple other factors should be recorded as part of good clinical practice. Although many molecular and oncogenic markers show promise to supplement or modify the current staging systems eventually, to the authors' knowledge none have yet been evaluated sufficiently to recommend their inclusion in the TNM system.

American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.

Mucins are high-molecular weight epithelial glycoproteins with a high content of clustered oligosaccharides O-glycosidically linked to tandem repeat peptides rich in threonine, serine, and proline. There are two structurally and functionally distinct classes of mucins: secreted gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6) and transmembrane mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC17), although the products of some MUC genes do not fit well into either class (MUC7, MUC8, MUC9, MUC13, MUC15, MUC16). MUC1 mucin, as detected immunologically, is increased in expression in colon cancers, which correlates with a worse prognosis. Expression of MUC2 secreted gel-forming mucin is generally decreased in colorectal adenocarcinoma, but preserved in mucinous carcinomas, a distinct subtype of colon cancer associated with microsatellite instability. Another secreted gel-forming mucin, MUC5AC, a product of normal gastric mucosa, is absent from normal colon, but frequently present in colorectal adenomas and colon cancers. The O-glycosidically linked oligosaccharides of mucins can be described in terms of core type, backbone type, and peripheral structures. Colon cancer mucins have differences in both core carbohydrates and in peripheral carbohydrate structures that are being investigated as diagnostic and prognostic markers, and also as targets for cancer vaccines. Colon cancer mucins typically have increases in three core structures: Tn antigen (GalNAcalphaThr/Ser), TF antigen (Galbeta3GalNAc) and sialyl Tn (NeuAcalpha6GalNAc). The type 3 core (GlcNAcbeta3Ga1NAc) predominant in normal colonic mucin is lacking in colon cancer mucins. There are cancer-associated alterations in the peripheral carbohydrates of colonic mucins including a decrease in O-acetyl-sialic acid and a decrease in sulfation. There are, however, cancer-associated increases in sialyl LeX and related structures on mucins and other glycoproteins that can serve as ligands for selectins, increasing the metastatic capacity of colon cancer cells. The endogenous galactoside-binding protein galectin-3, which is expressed at higher levels in colon cancers than normal colon, binds to colon cancer mucin as well as other glycoproteins. Interference of the binding of selectins and galectin-3 to mucin may show therapeutic or preventative promise for colon cancer.

Mucins and mucin binding proteins in colorectal cancer.

Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging. We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence. Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10-135) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT. These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.

/pdf/emt-is-the-dominant-program-in-human-colon-cancer-1u5sa9et6q.pdf

EMT is the dominant program in human colon cancer

BACKGROUND

The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma.



METHODS

A multidisciplinary consensus conference using published literature developed an arbitrary classification system of prognostic marker value (Category I, IIA, IIB, III, and IV), which forms the framework for this report.



RESULTS

The working party concluded that several T categories should be subdivided: pTis into intraepithelial carcinoma (pTie) and intramucosal carcinoma (pTim); pT1 into pT1a and pT1b corresponding to the absence or presence of blood or lymphatic vessel invasion, respectively; and pT4 into pT4a and pT4b according to the absence or presence of tumor involving the surface of the specimen, respectively. The working party also recommended that TNM groups be stratified based on the presence or absence of elevated serum levels of carcinoembryonic antigen (CEA) (≥ 5 ng/mL) on preoperative clinical examination. In addition, the working party also concluded that carcinoma of the appendix should be excluded from the colorectal carcinoma staging system because of fundamental differences in natural history.



CONCLUSIONS

The TNM categories and stage groupings for colorectal carcinoma published in the current AJCC manual have clinical and academic value. However, a few categories require subdivision to provide increasing discrimination for individual patients. The serum marker CEA should be added to the staging system, whereas multiple other factors should be recorded as part of good clinical practice. Although many molecular and oncogenic markers show promise to supplement or modify the current staging systems eventually, to the authors' knowledge none have yet been evaluated sufficiently to recommend their inclusion in the TNM system. Cancer 2000;88:1739–57. © 2000 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819991201%2986%3A11%3C2436%3A%3AAID-CNCR35%3E3.0.CO%3B2-%23

American Joint Committee on Cancer Prognostic Factors Consensus Conference

Objective To assess the clinical and biological significance of histological typing of colorectal carcinomas. Patients and methods The retrospective analysis of 142 consecutive patients who underwent surgical resection of a mucinous (MC; n = 27; 19%) or a nonmucinous (nMC; n = 115; 81%) colorectal adenocarcinoma was carried out. The two groups were compared in terms of the clinical features, p53 gene expression (antiserum CM1), proliferating cell nuclear antigen (PCNA) labeling index, DNA ploidy (by flow cytometry), histopathological features, prognosis and recurrence rate. Results The two types of tumors differed with respect to patient age, location, morphology, pattern of genetic lesions and type of tumor recurrences. Twenty-five percent of the patients with MC and 9% of those with nMC (p = 0.04) were under 50 years of age. The incidences of right MC and left MC were similar, while the majority of the nMC were located on the left side (p = 0.04). The MC were of higher grade and their margins more infiltrative than those of the nMC (p = 0.001 and p = 0.01, respectively), p53 nuclear staining was observed less frequently in the MC than in the nMC (30% vs 55%; p = 0.03). The PCNA labeling index was higher in the nMC (46% vs 21%; p = 0.05). We observed no significant differences with respect to tumor stage, incidence of vascular invasion or prevalence of lymphocytic infiltration. The prognosis was similar in both groups, although their recurrence patterns differed, with a tendency toward locoregional recurrence in the cases of MC. Conclusion These findings suggest that, despite their similar prognoses, these two types of lesions are epidemiologically, phenotypically and genotypically different and, thus, result from distinct carcinogenic pathways.

Clinical, histopathological, cytogenetic and prognostic differences between mucinous and nonmucinous colorectal adenocarcinomas.

OBJECTIVE To determine the predictive value of p53 nuclear overexpression in comparison with established prognostic pathological features in colorectal adenocarcinoma. PATIENTS AND METHODS 61 patients operated on for cure between January 1989 an December 1991 were included. Expression of p53 protein was examined by immunohistochemistry in paraffin-embedded sections. Tumor localization, depth of bowel wall involvement, lymph nodes metastasis, vascular invasion and PCNA Labelling index were studied in all patients. RESULTS Nuclear staining was detected in 27 (44.2%) cases. Positivity was more frequent in tumors with venous invasion and in rectal cancer. p53-positive tumours exhibited a higher likelihood of relapse and lower survival. After adjustment for the other covariates, p53 overexpression was the only factor showing independent prognostic significance on the risk of recurrence. None of the factors analysed evinced independent significant relationship with the risk of death. CONCLUSION Nuclear p53 protein overexpression is closely related to the development of postoperative recurrences and has higher predictive value than standard pathological variables.

[A comparative study on the prognostic value of the nuclear expression of protein p53 vis-à-vis histopathology in colorectal cancer].

This study investigated the predictive value of p53 nuclear overexpression on recurrence of colorectal adenocarcinomas compared with established prognostic pathological features. Sixty-one paraffin-embedded sections from primary tumours were examined by immunohistochemistry. Specific nuclear staining was detected in 27 (44.2%) cases. Positivity was more frequent in tumours with venous invasion (76.9%) ( P = 0.06) and in rectal cancer (68.4%) ( P = 0.06). After a median observation time of 46 months, p53-positive tumours exhibited a higher percentage of recurrence (40.7% vs 11.7%) ( P = 0.03), and a higher likelihood of relapse at 5-year follow-up (46% vs 13%) ( P = 0.006). Among the pathological variables analysed, only the extent of bowel wall invasion showed a relationship with recurrence. After adjustment for the other covariates in a Cox's regression model, p53 overexpression was the only factor showing independent prognostic significance (hazard ratio: 4.96; 95% Confidence Interval (CI): 1.47–16.71) ( P = 0.012). The results of this study show that nuclear p53 protein overexpression has higher predictive value than standard pathological variables.

Prediction of recurrence in B-C stages of colorectal cancer by p53 nuclear overexpression in comparison with standard pathological features

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Papers

Clinical, histopathological, cytogenetic and prognostic differences between mucinous and nonmucinous colorectal adenocarcinomas.

[A comparative study on the prognostic value of the nuclear expression of protein p53 vis-à-vis histopathology in colorectal cancer].

Prediction of recurrence in B-C stages of colorectal cancer by p53 nuclear overexpression in comparison with standard pathological features