Hereditary Diffuse Gastric Cancer Treated by Prophylactic Total Gastrectomy

Abstract

We herein report a rare case of hereditary diffuse gastric cancer in a Japanese man. A 41-year-old man underwent esophagogastroduodenoscopy which revealed a small gastric erosion. Biopsy specimens showed signet ring cell carcinoma, and endoscopic submucosal dissection was performed. The patient's elder sister had died of gastric cancer at 38 years old. Considering the family history, a genetic test was conducted and revealed a CDH1 germline mutation. Although no carcinomatous lesion was detected endoscopically, prophylactic total gastrectomy was performed. The resection specimen showed seven microlesions of signet ring cell carcinoma confined to the lamina propria mucosae.

Introduction

Hereditary diffuse gastric cancer syndrome (HDGC) is a type of gastric cancer for which Helicobacter pylori is not involved in carcinogenesis. Instead, it is an autosomal dominant inherited syndrome in which a CDH1 germline mutation causes E-cadherin protein deficiency, resulting in the development and invasion of signet ring cell carcinoma (SRCC) (1).

The majority of HDGC patients develop this disease by 40 years old, with a cumulative incidence of gastric cancer of 70% in men and 56% in women by 80 years old and a 42% risk of lobular breast cancer in women (2). Most HDGC cases have been reported in Europe and the United States, and hereditary gastric cancer accounts for 1-3% of all gastric cancers in Western countries. Clinically, it was reported that about 25% of families meeting the diagnostic criteria for HDGC had CDH1 germline mutations (3). However, while the incidence of gastric cancer is markedly higher in Japan than in Western countries, HDGC has been reported only rarely in Japan (4,5).

We herein report a case of HDGC treated with prophylactic total gastrectomy in Japan.

Case Report

A 41-year-old man presented to his primary care physician in February 2019 with a chief complaint of heartburn. All blood and biochemical tests were within the standard range. Esophagogastroduodenoscopy (EGD) revealed a microerosion with whitish areas on the posterior wall of the gastric angle. The microerosion was histologically diagnosed as SRCC by a biopsied specimen, and the patient was referred to our hospital for a further examination and treatment.

On EGD, a flat lesion with a well-demarcated whitish area 7 mm in diameter was observed at the posterior wall of the gastric angle. There were no atrophic changes in the stomach (Fig. 1a). Narrow-band imaging endoscopy with high magnification showed very subtle changes of expanding intervening parts and micro-vessels between pits in the whitish area (arrowheads showing a demarcation line) (Fig. 1b). Endoscopic ultrasonography using a 20-MHz miniprobe demonstrated no abnormalities in the layered structure of the lesion or gastric wall. We diagnosed the patient with a 7-mm 0-IIb, undifferentiated-type early gastric cancer (i.e. SRCC), with an invasion depth of mucosal layer (M) and no ulceration (UL0). Thoracoabdominal computed tomography (CT) showed no evidence of metastasis, and the lesion was considered to be an extended indication for endoscopic resection in the Japanese guidelines for gastric cancer (1st edition) (6).

Figure 1.

Esophagogastroduodenoscopy. (a) White-light endoscopy: No atrophic change was seen in the background mucosa (C-0), but a flat and whitish area 7 mm in diameter was observed on the posterior wall of the gastric angle. (b) Narrow-band imaging (NBI) magnification endoscopy: NBI endoscopy with high magnification showed very subtle changes of expanding intervening parts and micro-vessels between pits in the whitish area (arrowheads showing a demarcation line).

Endoscopic submucosal dissection (ESD) was subsequently performed in April 2019. Histology of the ESD specimens demonstrated SRCC with circular to irregularly shaped nuclei compressed to the periphery of the cells showing infiltrative growth confined to the lamina propria mucosae (Fig. 2). The SRCC lesion was solitary in histology, and there was no other lesion of SRCC among the ESD specimens. The patient was therefore diagnosed with undifferentiated-type early gastric cancer (i.e. SRCC), with invasion confined to the mucosal layer, and both lymphovascular invasion and the resection margins were negative.

Figure 2.

Histopathological findings. (a) Hematoxylin and Eosin (H&E) staining (×20): A microscopic image shows invasive proliferation of signet ring cell carcinoma with round-to-irregular-shaped nuclei compressed at the periphery of the cell. The carcinoma invasion is confined to the lamina propria mucosae. (b) H&E staining (×400): Eccentric nuclei and intracytoplasmic mucin are seen in signet ring cell carcinoma cells. (c) Periodic acid-Schiff (PAS) staining (×400): The signet ring cells have mucin positive for PAS staining.

Regarding the patient's family history, his elder sister had been diagnosed with gastric cancer (unknown histological type) at 35 years old, dying of the cancer at 38 years old. Furthermore, his father's younger brother also had a history of gastric cancer surgery at 62 years old (an advanced cancer with predominantly undifferentiated type on the surgical resection specimen; Fig. 3). We suspected this case to be one of HDGC because of the presence of multiple cases of young-onset gastric cancer in the patient's immediate family (elder sister) and in the patient himself.

Figure 3.

Family tree. This case is indicated as a double square. His elder sister died of gastric cancer at 38 years old (unknown histological type), and his father’s younger brother underwent surgery for advanced gastric cancer at 62 years old.

After obtaining the patient's consent, we performed a genetic test, which revealed a CDH1 germline mutation (frameshift mutation), and the diagnosis of HDGC was confirmed. Although there were no endoscopically visible cancerous lesions on surveillance endoscopy after ESD, we were concerned about the possibility of multiple microlesions of SRCC, based on previous reports (4,7-11). We recommended prophylactic total gastrectomy to the patient and his family. After providing five counseling sessions to him, his consent was obtained, and he underwent prophylactic total gastrectomy in July 2020. Histology of the surgically resected specimen showed 7 microlesions (＜1 mm) of SRCC localized mainly in the upper part of the gastric body (Fig. 4). None of the SRCCs had lymphovascular invasion, and all had negative margins. None of the micro cancer lesions detected in the total gastrectomy specimens had been visible by preoperative endoscopy. Two years after surgery, the patient is alive and doing well without recurrence.

Figure 4.

Mapping of micro cancer lesions in the total gastrectomy specimens. Seven microlesions of signet ring cell carcinoma limited to the lamina propria mucosae were detected (red lines), all smaller than 1 mm. They were negative for lymphovascular invasion, and there was no exposure of tumor cells at the resection margin.

Discussion

HDGC is an autosomal dominant form inherited syndrome in which a CDH1 germline mutation results in a deficiency of E-cadherin protein, leading to the development and invasion of diffuse gastric cancer (DGC) pathologically corresponding to SRCC (1). According to the 2015 edition of the International Gastric Cancer Linkage Consortium (IGCLC) guidelines, HDGC should be suspected if any of the following three conditions is met: 1) families with two or more patients with gastric cancer at any age, one confirmed DGC; 2) individuals with DGC before 40 years old; 3) families with diagnoses of both DGC and lobular breast cancer (one diagnosis before 50 years old) (12).

Given the above, carefully evaluating a patient's family history is crucial to diagnosing HDGC. Although the present patient was older than 40, we still suspected HDGC in this case of young-onset SRCC because of his family history of gastric cancer in his elder sister (before 40 years old but unknown histological type) and uncle (undifferentiated-type corresponding to DGC). Based on this suspicion, a genetic test was performed, leading to a definitive diagnosis of HDGC. Although HDGC is extremely rare in Japan, it should be considered when clinicians encounter a case of young-onset gastric cancer of SRCC, especially in patients younger than their early 40s.

Table summarizes nine cases of early-stage HDGC with germline mutations of the CDH1 gene (including this case), in which the endoscopic and histopathological findings were described in detail. The reported cases were all from Japan, as reports from western countries did not show detailed findings of preoperative endoscopy and/or histology of total gastrectomy specimens.

Table.

Hereditary Diffuse Gastric Cancer (HDGC) Case Reports Including Detailed Findings of Endoscopy and Histology.

	Reference	Age/Sex	Symptoms	Detection of gastric cancer	Family history of gastric cancer	Helicobacter pylori infection	Variant of the CDH1	Treatment	Number of SRCCs detected by preoperative endoscopy	Number of SRCCs detected in total gastrectomy specimens	Recurrence (follow up period)
									Size/Macroscopic type	Tumor depth
1	4	55/woman	No	Health checkup endoscopy	Father, son	Uninfected	Large deletion variant	Total gastrectomy	12**	Approximately 200**	No
							(Exons 7-16)		<10 mm/Flat	LPM
2	4	30/man	No	Health checkup endoscopy*	Mother, grandfather	Not listed	Large deletion variant	Total gastrectomy	3**	32**	No
							(Exons 7-16)		<10 mm/Flat	LPM
3	7	41/man	No	Health checkup endoscopy	No	Uninfected	Large deletion variant	ESD→Total gastrectomy	1**	90**	Unknown
							(Exons 11)		<10 mm/Flat	LPM
4	8	27/woman	No	Health checkup endoscopy*	Father, grandmother	Uninfected	Nonsense	Total gastrectomy	1**	3**	Unknown
									<10 mm/Flat	LPM
5	9	24/man	Epigastric dysfunction		mother	Uninfected	Nonsense	Total gastrectomy	5**	10**	Unknown
									<10 mm/Flat	LPM
6	9	35/man	No	Health checkup endoscopy	Father, uncle	Uninfected	Frameshift	Total gastrectomy scheduled	1	Total gastrectomy scheduled	Unknown
									<10 mm/Flat
7	10	25/man	No	Health checkup endoscopy*	Sister, father	Not listed	Missense	Total gastrectomy scheduled	6**	36**	No (36 months)
									<10 mm/Flat	LPM
8	11	34/man	Discomfort in his throat		No listed	Not listed	Frameshift	Total gastrectomy scheduled	2**	42**	Unknown
									<10 mm/Flat	LPM
9	Present case	41/man	Heartburn		Sister, uncle	Uninfected	Frameshiftt	ESD→Total gastrectomy	1**	7**	No (27 months)
									<10 mm/Flat	LPM

ESD: endoscopic submucosal dissection, SRCC: signet ring cell carcinoma, LPM: lamina propria mucosae

* Screening for HDGC due to family member of HGDC, ** the difference was significant (p=0.030, Wilcoxon test) between the numbers of SRCCs detected by endoscopy and in the total gastrectomy specimens.

In the present case, EGD was performed because of heartburn and we identified the micro SRCC lesion, resecting it endoscopically. But in most previous cases, the disease was asymptomatic and incidentally detected by EGD during medical checkups. The oldest age of the onset was 55 years old, 8 of the 9 cases were younger than their early 40s, and 7 cases had a family history of gastric cancer. Endoscopic features were flat-type lesions ＜10 mm in all cases. The number of SRCC lesions detected by preoperative endoscopy ranged from 1 to 12. The number of SRCC lesions histologically detected in the gastrectomy specimens ranged from 3 to 200, and all were intramucosal carcinomas. We compared the number of preoperative endoscopically detected SRCC lesions with that of the SRCC lesions detected in the total gastrectomy specimens of the eight patients. The number of cancerous (SRCC) lesions in the total gastrectomy specimen was significantly greater than that detected by preoperative endoscopy (p=0.030, Wilcoxon test). We therefore deduced that micro SRCC lesions invisible by endoscopy were latent in the total gastrectomy specimens.

A recent case report showed that magnification endoscopy was useful for detecting very micro SRCC lesions in an HDGC case (11). That patient underwent total gastrectomy, and the resected specimens had 42 intramucosal SRCCs, probably including SRCC lesions undetected by magnification endoscopy. As with the present case and the other reported cases, micro SRCC lesions invisible even using magnification endoscopy were multifocally detected in total gastrectomy specimens (4,7,11-13). These reports suggest that prophylactic total gastrectomy rather than ESD should be recommended according to the Western guidelines, even if magnification endoscopy was used for the preoperative inspection (14).

Our patient was the ninth case of HDGC in Japan and the third case of frameshift mutation, with more than 150 CDH1 germline mutations reported thus far as the cause of HDGC. We encountered a very rare case of HDGC treated by prophylactic total gastrectomy in Japan.

The authors state that they have no Conflict of Interest (COI).