Hereditary Diffuse Gastric Cancer

Fig. 18.1

Hereditary diffuse gastric cancer (HDGC) is associated with loss of E-cadherin gene expression. Immunohistochemistry of E-cadherin expression ( brown cells) in a patient with HDGC demonstrates that the signet ring cancer cells ( arrows) no longer express E-cadherin (lack of brown color). (From Norton et al. [3]. Reprinted with permission from Wolters Kluwer Health)

Recommended screening criteria for CDH1 mutations are as follows:

Families with one or more cases of diffuse gastric cancer.
Individuals with diffuse gastric cancer before the age of 40 years without a family history.
Families or individuals with cases of diffuse gastric cancer (one case below the age of 50 years) and lobular breast cancer.
Cases where pathologists detect in situ signet ring cells or pagetoid spread of signet ring cells adjacent to diffuse type gastric cancer [2, 10].

After obtaining informed consent, a team comprising a geneticist, gastroenterologist, surgeon, and oncologist should discuss the possible outcomes of testing and the management options. Genetic testing should first be performed on a family member with HDGC or on a tissue sample if no affected relative is living. In addition to direct sequencing, multiplex ligation-dependent probe amplification is recommended to test for large genomic rearrangements. If a CDH1 mutation is identified, asymptomatic family members may proceed with genetic testing, preferably by the age of 20 [4]. If no mutation is identified in a family member with diffuse gastric cancer, the value of testing others is negligible so testing is not indicated.

Among individuals found to carry a germ line CDH1 mutation, clinical screening for stomach cancer has been poor. Histologically, diffuse gastric cancer is characterized by multiple infiltrates of malignant signet ring cells that may underlie normal mucosa [11]. Because these malignant foci are small in size and widely distributed, they are difficult to identify via random endoscopic biopsy. Chromoendoscopy and positron emission tomography (PET) have reportedly been used, but the clinical utility of these tools in early detection is minimal. Lack of a sensitive screening test for HDGC makes early diagnosis problematic. By the time patients are symptomatic and present for treatment, patients have diffuse stomach cancer or linitis plastica, and prognosis is poor (Table 18.1). Published case reports describe patients who have extensive diffuse gastric cancer despite normal endoscopy with biopsies [12]. The 5-year survival rate for individuals who develop clinically apparent diffuse gastric cancer is only 10 %, with the majority dying before age 40.

Table 18.1

Outcome of patient with hereditary diffuse gastric cancer based on symptoms. Patients who were diagnosed not by symptoms but presence of CDH1 mutation did better. Each had cancer and was cured by total gastrectomy, while only 20 % of patients who presented with symptoms were cured. No patient died from gastric cancer in the asymptomatic group, while 60 % died in the symptomatic group. (Data are from Chen et al. [17])

n	Symptoms	Age (range) y	Positive endoscopy (%)	Disease-free (%)	Dead of disease (%)
13	No	48 (18–70)	2 (15)	100	0 (0)
5	Yes	40 (23–52)	5 (100)	20	3 (60)

Because of high cancer penetrance, poor outcome, and inadequacy of clinical screening tools for HDGC prophylactic total gastrectomy is recommended for asymptomatic CDH1 mutation carriers [2]. Although total gastrectomy is prophylactic, most specimens have multiple foci of diffuse signet ring cell cancer [3, 12, 13]. This is seen even in patients who have undergone extensive screening, including high-resolution computed tomography (CT), PET scan, chromoendoscopy-guided biopsies, and endoscopic ultrasonography [3]. However, HGDC in asymptomatic CDH1 carriers is usually completely resected by prophylactic gastrectomy, as pathological analysis of resected specimens shows only T1N0 disease.

Because these signet ring cell cancers are multifocal and distributed throughout the entire stomach, especially in the cardia [14] prophylactic gastrectomy must include the entire stomach (Table 18.2). Furthermore, it should be performed by a surgeon experienced in the technical aspects of the procedure and familiar with HDGC. In asymptomatic patients, lymph node metastases are usually not detected; although, D2 lymph node resection is still recommended. The optimal timing of prophylactic gastrectomy in individuals with CDH1 mutations is unknown, but most recommend that it be performed 5 years earlier than the youngest patient in the family with HDGC [2].

Table 18.2

Distribution of signet ring cell hereditary diffuse gastric cancer in 8 asymptomatic patients who were diagnosed by CDH-1 mutation. Signet ring cell cancer was present in multiple sites in each patient and although it was distributed throughout the entire stomach the most common site was the cardia. This demonstrates the need for total gastrectomy. (Data are from Rogers et al. [14])