Early diagnosis of hereditary diffuse gastric cancer: (not only) an endoscopic challenge!

Gastric cancer still represents a major cause of death worldwide mostly due to late diagnosis [1]. Moreover, given an aging and increasing global population, the number of cases is expected to increase during the next decade even as incidence declines [2]. For the intestinal subtype of gastric cancer according to Lauren’s classification, together with Helicobacter pylori eradication and diet changes, early endoscopic diagnosis is considered to be the main cornerstone of overcoming the dismal prognosis of patients who harbor gastric cancer [3,4]. However, endoscopic diagnosis of diffuse gastric cancer (DGC), even in advanced stages, has always been considered a (our first!) challenge due to its scattered cell clusters and infiltrative behavior with very often no or only minor luminal changes. One percent to 3% of all gastric cancers may be considered hereditary diffuse gastric cancer (HDGC). CDH1 germline mutations encoding the cell-to-cell adhesion protein E-cadherin cause HDGC and are detected in 25% to 40% of tested families [5]. According to the most recent guidelines, criteria for testing CDH1 mutation include the presence of 2 cases with gastric cancer, regardless of age, at least 1 with confirmed DGC; 1 case of gastric diffuse cancer before 40; or a personal or family story of DGC or lobular breast cancer, with 1 case diagnosed before age 50. In addition, this testing could be considered in patients with bilateral or familial lobular breast cancer, patients with DGC and cleft lip/palate and those with precursor lesions for signet ring cells carcinoma [6]. Management options for asymptomatic mutation carriers are (our second!) challenge. On one hand, prophylactic gastrectomy is recommended because of the significant risk of suffering of gastric cancer and, as discussed above, because neoplastic cells infiltrate the mucosa while preserving normal surface epithelium, making it easy to miss diffuse cancer on endoscopy [7]. On the other hand, a significant number of patients will never develop cancer and surgical options may lead to complications and significantly impact an individual’s quality of life. As an answer to these challenges, diverse attempts have been made to improve gastroscopy. These would serve endoscopic evaluation a) to screen all first-degree relatives of patients meeting criteria for CDH1 testing; andb) during annual endoscopic surveillance thatmaybeproposed topatientswho want to delay surgical treatment or have significant contraindications to surgery. As for other organs (eg, Barrett’s, ulcerative colitis), the lines of thoughts were: to inspect and clean themucosa, to idenfity mucosal lesions and, even in the (most probable) absence of malignancy, to perform a (significant) number of biopsies (to overcome the multiple foci of neoplastic lesions) [8]. In 2010 the Cambridge protocol was published as a way to standardize procedures and improve cancer foci detection [9]. That protocol recommended that all endoscopically visible lesions be targeted and biopsies be taken of 6 random sample in each anatomical zones, including the antrum, transitional zone, body, fundus, and cardia (i. e., at least 30 biopsies). Nevertheless, Fujita H [10] reported an interesting study aimed at modeling bioptic diagnostic yield on the basis of the topographic distribution of cancer foci in a series of 10 gastrectomies in CDH1-mutation carriers. They concluded that on thebasis of the number of sampled glands per biopsy in routine surveillance preoperative endoscopy, the theoretical number of biopsies necessary for a 90% rate of detection of (at least 1) neoplastic fociwould be 1768 (ranging from 50 to 5832). Also, and contradicting the predilection for the distal stomach and the body-antral transitional zone noted by Charlton A et al. [11], Fujita H et al. suggested that the highest density of neoplastic fociwas found in the anterior proximal fundus and cardia/proximal fundus.