Colorectal Cancer

Colorectal cancer is a malignant epithelial neoplasm of the colon or rectum, the great majority of which are adenocarcinomas that arise from precursor adenomatous or serrated polyps. It is one of the most common cancers worldwide and is the paradigm of stepwise carcinogenesis, in which accumulating genetic and epigenetic alterations drive the progression from normal epithelium through adenoma to invasive carcinoma.

Definition

A malignant neoplasm arising from the epithelium of the colon or rectum, predominantly adenocarcinoma, developing through a multistep accumulation of genetic and epigenetic alterations from precursor polyps.

Scope

This entry covers the pathology of colorectal cancer: its precursor lesions, the adenoma-carcinoma sequence and the molecular pathways that underlie it, the histologic features of invasive adenocarcinoma, and the basis for staging. It is a reference description of disease mechanism and morphology rather than clinical management; screening and risk-factor detail are covered in neighbouring nodes.

Core questions

• How does the adenoma-carcinoma sequence transform normal colonic epithelium into invasive cancer?
• What molecular pathways (chromosomal instability, microsatellite instability, CpG island methylation) drive colorectal carcinogenesis?
• What histologic and staging features determine the behaviour of colorectal adenocarcinoma?

Key concepts

• Adenomatous and serrated precursor polyps
• Chromosomal instability pathway (APC, KRAS, TP53)
• Microsatellite instability and mismatch-repair deficiency
• CpG island methylator phenotype
• Invasive adenocarcinoma histology
• Staging and prognosis

Key theories

Adenoma-carcinoma sequence (genetic model of colorectal tumorigenesis)

Fearon and Vogelstein proposed that colorectal cancer develops through an ordered accumulation of genetic alterations—activation of oncogenes and inactivation of tumour-suppressor genes—that parallels the histologic progression from normal epithelium to adenoma to carcinoma, establishing the multistep model of carcinogenesis.

Mechanisms

Most colorectal cancers develop through the adenoma-carcinoma sequence, in which benign adenomatous polyps accumulate genetic changes and progress to invasive carcinoma. Fearon and Vogelstein's genetic model linked this morphologic progression to an ordered series of molecular events—including inactivation of the APC tumour-suppressor gene, activation of KRAS, and loss of TP53—within the chromosomal instability pathway (Fearon & Vogelstein 1990). A second major route, the microsatellite instability pathway, results from defective DNA mismatch repair, which can be sporadic (often through methylation-related silencing, related to the serrated pathway and the CpG island methylator phenotype) or inherited (Lynch syndrome) (Brenner 2014; Dekker 2019). Invasive tumours are predominantly adenocarcinomas; their depth of invasion through the bowel wall and spread to lymph nodes and distant sites form the basis of staging, which governs prognosis (Dekker 2019).

Clinical relevance

The pathology of colorectal cancer underlies the interpretation of polyp and resection specimens, the molecular classification used to characterise tumours, and the staging that determines prognosis. It also explains why removing precursor polyps can interrupt the adenoma-carcinoma sequence. This material is descriptive and educational and is not individualized medical advice (Dekker 2019).

Epidemiology

Colorectal cancer is among the most frequently diagnosed cancers and a leading cause of cancer death worldwide, with incidence influenced by age, dietary and lifestyle factors, inflammatory bowel disease, and inherited syndromes, and modified by organised screening (Dekker 2019; Brenner 2014). Detailed epidemiology and risk factors are addressed in a dedicated neighbouring node.

Evidence & guidelines

The account here draws on the foundational genetic model of colorectal tumorigenesis (Fearon & Vogelstein 1990) and on comprehensive reviews of colorectal cancer (Brenner 2014; Dekker 2019). These are cited to support the descriptive pathology rather than as prescriptive guidance; screening strategy is covered separately.

History

The modern understanding of colorectal cancer was reshaped by the 1990 genetic model of Fearon and Vogelstein, which framed the disease as a stepwise accumulation of mutations mirroring histologic progression. This model became a touchstone for the multistep theory of carcinogenesis, later complemented by the recognition of the microsatellite instability and serrated pathways (Fearon & Vogelstein 1990; Brenner 2014).

Key figures

• Eric Fearon
• Bert Vogelstein
• Hermann Brenner

Seminal works

• fearon-vogelstein-1990
• brenner-2014
• dekker-2019

Frequently asked questions

What is the adenoma-carcinoma sequence?

It is the stepwise progression by which a benign adenomatous polyp accumulates genetic alterations and develops into invasive colorectal carcinoma, the model articulated by Fearon and Vogelstein in 1990.

What are the main molecular pathways of colorectal cancer?

The principal routes are the chromosomal instability pathway (involving APC, KRAS, and TP53) and the microsatellite instability pathway caused by defective DNA mismatch repair, the latter linked to the serrated pathway and to Lynch syndrome.