Current thoughts on the histopathogenesis of gastric cancer

F Carneiro, J C Machado, L David, C Reis, A M M F Nogueira, M Sobrinho-Simões Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of Porto, Porto, Portugal. Correspondence to: F Carneiro. Fax: (+351) 22 5570 799. E-mail: [email protected] *This paper was an invited presentation at the 18 th Annual Symposium of European Cancer Prevention Organisation (ECP): Precancerous lesions of the digestive tract held in Maastricht, The Netherlands, 12–14 October, 2000 Carcinomas of the stomach are very heterogeneous from the morphologic standpoint. This heterogeneity, which is amply reflected in the diversity of histopathological classifications on record, is based on different approaches: histological profile, degree of differentiation, pattern of growth and histogenesis. The classification of Laurén is one of the most widely used, recognizing two major types of gastric cancer: ‘intestinal’ carcinoma and ‘diffuse’ carcinoma, which display different clinicopathologic profiles and occur in distinct epidemiological settings. The available evidence supports the existence of two main histogenetic pathways of carcinogenesis of the gastric mucosa: one leading to ‘intestinal carcinoma’ via chronic atrophic gastritis, incomplete intestinal metaplasia, namely type III (Filipe et al., 1994) and adenomatous dysplasia (Correa, 1992), and the other leading to diffuse carcinoma, either de novo or via hyperplastic changes (Carneiro et al., 1993a;Solcia et al., 1996). Both pathways appear to develop on the background of Helicobacter pylori -associated gastritis (Solcia et al., 1996). The initially suggested sequential evolution of intestinal metaplasia, from type I to type III, via a type II intermediate step, has been recently challenged by Reis et al. (1999), who suggested that complete intestinal metaplasia and incomplete intestinal metaplasia represent, ab initio, divergent differentiation programmes. Ultrastructural studies of gastric carcinoma (Fiocca et al., 1987;Carneiro et al., 1992) and the study of the expression of trefoil peptides and mucins in premalignant lesions and gastric carcinomas (Machado et al., 1996, 2000Nogueira et al., 1999) showed that ‘intestinal’ carcinoma is heterogeneous regarding cell differentiation, encompassing gastric and non-gastric phenotypes. Without denying the validity of the histogenetic pathway via intestinal metaplasia to ‘intestinal’ carcinoma, these data support the suggestion that a subset of ‘intestinal’ carcinomas may derive from gastric-type epithelium, either de novo or through hyperplastic changes (Machado et al., 1996). This observation led us to suggest that gastric carcinomas with gland formation should be designated as ‘glandular’ carcinomas, instead of ‘intestinal’ carcinomas (Carneiro et al., 1995b), thus avoiding the mixture of structural and cell differentiation concepts. The histogenetic pathway of diffuse carcinoma is less well elucidated. It has been suggested that this type of gastric carcinoma may derive from a non-metaplastic dysplasia of gastric mucosa (Ghandur-Mnaymneh et al., 1988). Further, different studies of our group (Carneiro et al., 1993b, 1995aCarneiro and Sobrinho-Simões, 1996) provided enough evidence to claim that foveolar hyperplasia/hyperplastic polyps may serve as precursor lesions of the diffuse type of gastric carcinoma. Very interesting insights regarding the histogenetic pathway of diffuse carcinoma are emerging from the study of prophylactic gastrectomies performed in asymptomatic carriers of germline E-cadherin mutations in the setting of Hereditary Diffuse Gastric Cancer (HDGC), as defined by an International Gastric Cancer Linkage Consortium (Caldas et al., 1999). At this stage we remain with an unsolved problem regarding the histogenesis of the heterogeneous group of gastric carcinomas designated as ‘indeterminate’ carcinomas according to Laurén's classification. This group encompasses two major morphologic variants: solid carcinomas and mixed carcinomas (Carneiro et al., 1995b). Histogenesis of solid carcinomas is largely unknown. The same does not hold true for mixed carcinomas, characterized by the coexistence in the same tumour of at least two distinct histological components, ‘intestinal’ and diffuse. The studies of our group on cell differentiation (Machado, 1999;Machado et al., 2000) and E-cadherin expression/gene changes (Machado et al., 1998, 1999) suggest that most of these tumours derive from ‘intestinal’/glandular carcinomas with gastric phenotype, by the occurrence of E-cadherin mutations leading to the establishment of a diffuse histological component (Machado et al., 1999).