The likelihood of nodal metastasis mainly depends on histologic grading and depth of submucosal invasion of any T1 carcinoma as well as on macroscopic type and anatomical localisation in the gastrointestinal tract.

Well-differentiated mucosal cancer shows a relatively structured and continuous infiltrative growth pattern of glandular crowding, branching, and budding with clear histologic borders to normal localised tissue being reflected by clear endoscopic margins of the neoplasia. Relative loss of polar structure of epithelial cell layers, enhanced nucleus/cytoplasm ratio, and bulky growth of epithelial cell layer in the neoplasm (as compared to normal epithelium and mucosa) alter the surface aspect of mucosal neoplasias – inducing a mucosal pattern most often visible on IEE. In case of massive submucosal invasion of coherently growing carcinoma, the surface gland structure (typical for differentiated mucosal cancer) becomes destroyed – yielding highly irregular or even non-structured surface (amorphous pattern) on stereomicroscopic observation as well as on IEE. In addition, differentiated mucosal cancers require neoangiogenesis for deep submucosal invasion – showing on IEE irregular microvessels in mucosal proper layer as demonstrated by immunohistochemistry in resected early cancers and correlated with imaging features on IEE [1, 3, 5, 14].

Likelihood of lymph node metastasis generally increases with depth of invasion of well-differentiated early cancer [2, 3, 15]. The best data on these correlations have been collected in large surgical series of resected early cancers with dissection of regional lymph nodes [2, 15–21], as summarised in Table 2.3. To predict risk of metastasis to locoregional lymph nodes for well-differentiated early cancers, T1 lesions of the colon are categorised into “low risk”, i.e. grading G1 or G2, no invasion of lymphatic vessels (L0) or submucosal veins (V0), and submucosal extension of less than 1,000 μm, vs. “high risk” in the presence of any feature like tumour budding (isolated tumour cells at the invasive tumour front), submucosal invasion ≥1,000 μm, lymphatic or venous vascular invasion, or grading G3 or G4 [15].

The macroscopic type (Paris classification, Fig. 4.​2) is another indicator of risk of lymphatic and/or vascular spread of early cancer [1–4, 15], probably reflecting heterogenous morphogenic and molecular pathways of oncogenesis (compare Sect. 2.2 on pathways of colonic carcinogenesis).

Poorly or undifferentiated early cancers (G3/G4) show loss of cell–cell adhesion, discontinuous growth pattern, high nucleus/cytoplasm ratio paralleled by more rapid tumour cell replication/proliferation, and higher metastatic potential (e.g. anoikis) on a cell biology level. Therefore, lymphatic vessel or blood vessel permeation is frequent with even small, poorly differentiated intraepithelial early cancer, and so are higher rates of lymph node (or haematogenous) metastases as compared with well-differentiated mucosal cancer [2, 15, 17]. The risk of metastatic spread to locoregional lymph nodes is increased for poorly differentiated early gastric cancer exceeding lateral extension of 20 mm [2, 17]. Also, margins of undifferentiated mucosal cancers tend to be less clear, the epithelial surface structure in the central part of the cancer may be destroyed by epithelial invasion with undifferentiated cancer cells, and the microcapillary pattern in the lamina propria mucosae tends to be very irregular on magnifying NBI endoscopy.

Based on extensive quantitative histopathologic analysis of surgical resection specimens of early gastrointestinal cancers, the likelihood of cure from early cancer achievable by endoscopic en bloc resection with free margins can now be predicted on based histologic characteristics, lateral size, depth of submucosal invasion, absence of lymphovascular invasion, and organ location in the GI tract (Table 2.4 Criteria of curative resection). Magnifying endoscopic analysis of early cancers attempts to predict from characteristic alterations of the macroscopic type, surface and microvascular structure, whether the lesion allows endoscopic resection en bloc for cure (Indication criteria, see Chaps. 3 and 6–10).

On colonoscopy, most protruded or flat lesions classify as adenomatous or hyperplastic according to histomorphology – see Fig. 2.1. Whereas strictly hyperplastic lesions are non-neoplastic, the similarly looking serrated adenomas are – like polypoid adenomas – cancer precursor lesions.

The usual perception of morphological carcinogenesis still focusses on the classical “polyp–cancer sequence” [23], although at least four other precursor–cancer pathways exist in the colon – the depressed neoplasia pathway, non-polyposis (HNPCC) pathway, serrated adenoma pathway, and in ulcerative colitis and in colitis Crohn the “inflammation–dysplasia (DALM)–carcinoma pathway” [1, 4, 7, 23–27] (Table 2.5).