Case 5 -

Signet ring cell/diffuse carcinoma in the setting of Hereditary Diffuse Gastric Cancer (HDGC) Professor Fatima Carneiro Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)

Clinical history: Man, asymptomatic, with a family history of gastric cancer. In his family, the proband was a 23-year old female who presented epigastric pain. Multiple endoscopic biopsies revealed the presence of diffuse carcinoma (signet ring cell type). Upon total gastrectomy, a large tumour was observed in the body of the stomach with lymph node metastases. The patient died 9 months after surgery. Mutation screening revealed the presence of a germline mutation of E-cadherin gene (CDH1) leading to an aminoacid substitution for an Ala to Val at position 1901 (C>T) in codon 634. The proband had an older brother who had died with diffuse gastric carcinoma at the age of 26. The proband had also six asymptomatic siblings who were tested after informed consent, and one (the present case) harbored the same Ala634Val germline alteration. This individual was informed, during genetic counseling, he was a carrier of the CDH1 germline mutation that was identified in the proband. He was recommended to undergo a program of endoscopic screening and both gastroscopy and random biopsies were negative for malignancy. The early death of two siblings and the putative pathogenic potential of the CDH1 mutation were the main factors leading to the decision of prophylactic gastrectomy, albeit no alterations were revealed by gastroscopy and random biopsies. Elective total prophylactic gastrectomy was carried out on June 7, 2005. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathologic features: The surgical specimen (total gastrectomy) was grossly normal both in appearance and by palpation. The stomach was opened along the greater curvature, pinned onto wax board, and fixed in 10% formalin. The specimen was sectioned in its entirety, with the source of each section noted on a corresponding map (the number of blocks was 197, each containing one or more tissue fragments). In the microscopic evaluation of the surgical specimen, 14 foci of intramucosal diffuse carcinoma (signet ring cell type) were identified. Neoplastic cells displayed a pure signet ring cell phenotype, those in the deepest levels of invasion were smaller than neoplastic cells present in the superficial zone of the mucosa. Vascular (lymphatic or venous) invasion and nodal metastases were not observed. Surgical resection margins (oesophageal and duodenal) were free of neoplasia. Additionally, in situ signet ring cell carcinomas (2 lesions) were identified in the surgical specimen, characterized by the lining of foveolae and glands by signet ring cells with hyperchromatic nuclei and lack of polarity with respect to the basement membrane. Furthermore, three glands/foveolae displayed a two-layer structure, an inner layer composed of benign mucous cells and an outer layer of continuous or discontinuous tumour signet ring cells, displaying the features of the so-called pagetoid spread. Background changes identified in the gastric mucosa encompassed mild chronic gastritis, foveolar hyperplasia and tufting of surface epithelium (focally with globoid change). Intestinal metaplasia was not found and Helicobacter pylori infection was not detected. Diagnosis: Signet ring cell/diffuse carcinoma in the setting of Hereditary Diffuse Gastric Cancer (HDGC). Discussion: The syndrome of HDGC was defined after Parry Guilford and colleagues described germline truncating E-cadherin gene (CDH1) mutations in three Maori families with autosomal dominant diffuse gastric cancer [1, 2]. In 1999, the International Gastric Cancer Linkage Consortium (IGCLC) was constituted with the aim to develop common terminology for this disease, and to produce evidence-based guidelines for the management of patients [3]. The IGCLC defined the syndrome of Hereditary Diffuse Gastric Cancer (HDGC) (OMIM #137215) as any family fulfilling one of the following criteria: (1) two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50; or (2) three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age. Families with aggregation of gastric cancer and an index case with diffuse gastric cancer, but not fulfilling the IGCLC criteria for HDGC, are termed familial diffuse gastric cancer (FDGC). Once CDH1 mutations are identified in asymptomatic individuals, they are presented with the options of intensive endoscopic surveillance or prophylactic gastrectomy [3]. The aim of surveillance is to identify an early curable lesion but the value of endoscopy is unproven due to the difficulty of detecting intramucosal lesions [4]. Antral predominance of early cancers was reported by some authors (5) but not confirmed by others [6]. In an effort to improve the diagnostic yield of surveillance endoscopy in the upper gastrointestinal tract, techniques such as chromoendoscopy have been recommended [7]. Several prophylactic gastrectomies have been performed in carriers of CDH1 germline mutations. To date, it has been demonstrated that resected stomachs from different familiesall carried multifocal signet ring cell carcinoma [6, 8]. The systematic study of the prophylactic gastrectomies led to the proposal of a model of the early development of Hereditary Diffuse Gastric Cancer [9] encompassing the following lesions: in situ signet ring cell carcinoma, pagetoid spread of signet ring cells below the preserved epithelium of glands/foveolae, and early invasive intramucosal signet ring cell carcinoma. The discrepancy between the numerous invasive carcinoma foci identified in some gastrectomy specimens and the low number of in situ carcinoma lesions suggests that invasion of the lamina propria by signet ring cells may occur without a morphologically detectable in situ carcinoma [9]. The prophylactic gastrectomy specimen here described displayed the different lesions that have been reported in the setting of HDGC. Noteworthy, the present family was identified after the histopathologic evaluation of the surgical specimen obtained from the proband. In this stomach, besides a widely invasive signet ring cell carcinoma, we identified in situ carcinoma and pagetoid spread of signet ring cells in the adjacent gastric mucosa. These findings raised the possibility of HDGC and led to the search of CDH1 mutation that was performed in non-neoplastic mucosa of the surgical specimen from the proband [10]. A CDH1 germline mutation was identified and genetic screening was offered to other family members leading to the identification of the asymptomatic individual herein reported, who was submitted to prophylactic surgery. This study highlights the role of pathology in the identification of Hereditary Diffuse Gastric Cancer [10]. Data on screening of germline CDH1 mutations were recently reviewed [11]. A large number of families with aggregation of gastric cancer, from distinct geographic backgrounds, have been analyzed to date and 56/439 (12.8%) families have been found to carry CDH1 germline mutations. Families fulfilling the ICGLC criteria for HDGC are now 118 (26.9% of 439 families) and 43/118 (36.4%) were shown to carry germline mutations, which are spread along all CDH1 gene sequence. References: Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE. E-cadherin germline mutations in familial gastric cancer. Nature 392:402-405, 1998 Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher JM, Shaw DW, Findlay MP, Reeve AE. E-cadherin germ-line mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat 14:249-255, 1999 Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, Lewis FR, Huntsman DG, Pharoah PD, Jankowski JA, MacLeod P, Vogelsang H, Keller G, Park KG, Richards FM, Maher ER, Gayther SA, Oliveira C, Grehan N, Wight D, Seruca R, Roviello F, Ponder BA, Jackson CE. Familial gastric cancer: overview and guidelines for management. J Med Genet 36:873-880, 1999 Fitzgerald RC, Caldas C. Clinical implications of E-cadherin associated hereditary diffuse gastric cancer. Gut 53:775-778, 2004 Charlton A, Blair V, Shaw D, Parry S, Guilford P, Martin IG. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut 53:814-820, 2004 Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 344:1904-1909, 2001 Shaw D, Blair V, Framp A, Harawira P, McLeod M, Guilford P, Parry S, Charlton A, Martin I. Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy? Gut 54:461-468, 2005 Chun YS, Lindor NM , Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH. Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer 92:181-187, 2001 Carneiro F, Huntsman DG, Smyrk TC, Owen DA, Seruca R, Pharoah P, Caldas C, Sobrinho-Simoes M. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 203:681-687, 2004 Oliveira C, Moreira H, Seruca R, de Oliveira MC, Carneiro F. Role of pathology in the identification of Hereditary Diffuse Gastric Cancer: Report of a Portuguese family. Virchows Arch 446:181-184, 2005 Oliveira C, Seruca R, Carneiro F: Genetics, pathology and clinics of familial gastric cancer. Int J Surg Pathol 14:21-33, 2006