Case 1 -
Hereditary Diffuse Gastric Carcinoma (HDGC)
Yale University School of Medicine
New Haven, CT
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The patient is an asymptomatic 47 year old female of Portuguese descent,
who came to the gastroenterologist insisting for an upper gastrointestinal(GI) endoscopy due to a strong
family history of gastric cancer. Endoscopy revealed a 1cm ulcer in the gastric cardia that appeared
benign, however, biopsies revealed a signet-ring cell carcinoma. The patient underwent pre-operative
staging of the tumor with EUS and CT scans. EUS suggested that the tumor was largely limited to the
mucosa and possibly submucosa, with no spread elsewhere. She underwent partial proximal gastrectomy with
distal esophagectomy. The esophageal and gastric margins were found to be positive on permanent sections
leading to a total gastrectomy and removal of some more of the esophagus with negative margins.
Case 1 - Figure 1
Section from the edge of the gastric ulcer showing infiltration by signet-ring cells at low magnification.
Case 1 - Figure 2
Higher magnification showing the signet-ring cells.
Case 1 - Figure 3
Higher magnification showing the signet-ring cells showing the typical morphology with single large mucin vacuole and eccentrically placed nucleus .
Case 1 - Figure 4
Section from the deeper part of the gastric wall showing infiltration by tumor cells lacking a mucin vacuole and having a histiocyte-like appearance.
Case 1 - Figure 5
Immunostain for keratin AE1/AE3 showing strong positivity in the histiocyte-like tumor cells.
Case 1 - Figure 6
Section from the non-neoplastic gastric mucosa showing mild chronic gastritis and intestinal metaplasia.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Grossly the gastric
ulcer was shallow, without any thickening of the mucosal folds around it or thickening of the wall. The
histology confirmed a signet- ring cell/ diffuse-type gastric adenocarcinoma arising at the gastric
cardia. The tumor was seen infiltrating through the submucosa into the muscularis and sub-serosa, The
tumor extended extensively laterally for many cms from the ulcer, including into the proximal esophagus.
The tumor cells located superficially in the mucosa contained a single vacoule of intracytoplasmic mucin
typical of signet-ring cells. The cells that infiltrated deeper (submuosa and muscularis propria)
gradually lost this intracytoplasmic mucin and started looking more like histocytes. There was extensive
fibrosis/desmoplasia associated with the tumor. Immunostains for keratins (CAM 5.2, AE1/AE3) showed
strong positivity. The signet-ring cells were strongly positive for Alcian blue and Muc2 and negative
for Muc 5AC. Immunostain for E-Cadherin showed weak membranous positivity throughout the tumor. The
adjacent gastric mucosa showed patchy very mild chronic gastritis with focal intestinal metaplasia.
There were no Helicobacter organisms identified with special stains. The gastric cancer was
characterized as stage IIB(pT3N1MO). The patient has been regularly followed until now (9 years) and is
alive without any recurrent or residual disease.
The differential diagnosis includes sporadic signet-ring cell carcinoma and
hereditary diffuse gastric cancer.
Based on the family history of gastric cancer in her mother and an uncle, and the
occurrence of signet-ring/diffuse gastric cancer before the age of 50 years, she was diagnosed with
hereditary diffuse gastric carcinoma (HDGC) however, she tested negative for germline E-cadherin mutation
in 1999. Subsequently, 17 of her family members have been seen in our institution, and have been
regularly followed with surveillance endoscopy and multiple biopsies. Some of the family members show
mild persistent Helicobacter- negative chronic gastritis with intestinal metaplasia, but none have been
found to have gastric cancer as of yet.
This case highlights several issues and problems associated with HDGC and the
subsequent discussion addresses our current understanding of HDGC and addresses some of these issues.
Review of the Literature/Treatment Options (if applicable):
The incidence of gastric
cancer has been decreasing. However, it still remains the 4th most common cancer, and 2nd most common
cause of cancer-related death worldwide. In the United States, it constitutes the 14th most common
cancer and 7th most common cause of cancer-related deaths. The decrease in gastric cancer, most
noticeable in developed countries is due to the decrease in the intestinal-type of gastric cancer, while
the incidence of signet-ring/diffuse-type gastric cancer has either remained unchanged or slightly
The vast majority of gastric cancers (90%) occur in a sporadic setting, and only 10% of
cases show familial clustering . Familial clustering of gastric cancer has been attributed to common
environmental risk factors and/or genetic factors. Only 1-3% of gastric cancers are believed to arise
due to inherited predisposition to gastric cancer .
Genetics and molecular pathology:
genetic syndromes associated with an increased risk of gastric cancer include hereditary non-polyposis
colon cancer (HNPCC), Li-Fraumeni Syndrome, Juvenile polyposis syndrome. Peutz-Jeghers Syndrome, Cowden
syndrome, familial adenomatous polyposis (FAP), Ataxia-Telangiectasia, BRCA-1 and BRCA 2 breast/ovary
cancer, Xeroderma-Pigmentosa and Werner Syndrome . These syndromes are associated with various other
manifestations and cancers in other organs, and the risk of gastric cancer is relatively low. It is now
recognized that besides these disorders, there exists a group of disorders with inherited predisposition
to primarily gastric cancer of either diffuse-type (HDGC) or intestinal-type [Familial intestinal gastric
cancer (FIGC)]. In many instances the histology of the tumor remains unknown and these are simply
designated as familial gastric cancers (FGC). The genetic basis of HDGC was identified in 1998 by
Guilford et al who reported three Maori families in New Zealand and described diffuse gastric cancer in
multiple generations with germline E-cadherin (CDH-1) mutation shown by genetic linkage analysis and
mutation screening . In 1999, the International gastric cancer linkage consortium defined HDGC
syndrome as any family fulfilling one of the following features: a) 2 or more cases of documented
diffuse gastric cancer in first - or second - degree relatives, with at least one being diagnosed before
50 years of age; or b) 3 or more cases of documented diffuse gastric cancer in first - or second-degree
relatives independent of the age of diagnosis . It is suggested that for populations with a low
baseline incidence of gastric cancer, such as in North America, the lst criterion could be relaxed to 2
or more cases of gastric cancer in the first – or second–degree relatives with at least 1 documented case
of diffuse gastric cancer before the age of 50 years. The criteria were expanded by Brook- Wilson et al
to include additional cancer phenotypes associated with HDGC . An elevated risk of lobular
carcinoma of breast has now also been recognized in these cases
HDGC shows autosomal dominant
pattern of inheritance, and about 30-40% of HDGC families harbour a germline mutation in CDH-1gene .
The CDH-1 gene is localized in the long arm of chromosome 16 and encodes for E- cadherin, a transmembrane
protein that is expressed at the baso-lateral cell surface and plays a role in cell-to-cell adhesion .
The extra-cellular domain of the molecule takes part in the adhesion mechanism while the intracellular
cytoplasmic domain interacts with the catenins (∝, β, γ, P120ctn) indirectly influencing
the organization of the actin cytoskeleton. By interaction with the catenins E-Cadherin plays a role in
the WNT signaling pathway and also acts as a tumor suppressor. Loss of E-Cadherin is believed to result
in the loss of cell-to-cell adhesion and to promote tumor invasiveness. Altogether 68 CDH-1 germline
mutations have been identified in 273 (24.9%)
families with HDGC reported to date . The mutations
have been typed as nonsense, splice-site and frame shift mutations, and missense mutations .
Mutations span the entire length of the gene, and so far no hot-spots are recognized. In individuals
with germline CDH-1 mutation, where only 1 of the alleles is abnormal, the histology of the gastric
mucosa appears normal and E-cadherin is normally expressed. A 2nd hit is required for the inactivation
of the other allele which occurs mostly via promoter hypermelthylation (epigenetic modification) and less
frequently by loss of hetrozygosity (LOH) and
An intragenic deletion in the
wild-type allele has also been reported . The tumor cells thus show absent or weak staining for
E-Cadherin. A few cases with germline TP53 mutations have been reported, and recently BRCA-2 germline
mutations have been identified in 21% of patients with both gastric and breast cancers
germline mutations in the catenins ( ∝, β, γ, P120 ctn) or other genes (RUNX3, caspase-10
have been found . About 70% of HDGC and 90% of FGC families screened worldwide do not show
CDH-1 mutations and remain genetically unexplained . The incidence of lobular carcinoma of the
breast, which shares loss of E- Cadherin as the mechanism with HDGC, is increased in these families and
it is estimated that the female carriers of the CHD-1 mutation have a 40% lifetime risk of developing
breast cancer . One case of signet-ring carcinoma of the colon has also been reported in a CDH-1
positive HDGC family, however, in general risk of colorectal or other malignancies is very low .
The tumors seem to have no site predilection in the stomach
They consistently show
signet-ring morphology, especially in the superficial part of the mucosa and become more histiocyte like
as they infiltrate deeper. The tumor cells in cases with CDH-1 mutations tend to show weak or absent
membranous staining for E-cadherin. The immunostaining for cytokeratin and mucin core-polypeptides is no
different from that of sporadic signet-ring cell/diffuse gastric carcinoma. In prophylactic gastrectomy
specimens performed in at-risk family members, foci of carcinoma are identified in almost all patients
when extensive sampling is undertaken
Many times the overlying mucosa appears normal and the
tumor is very small, superficial and limited to mucosa. Another lesion commonly identified in such
specimens is "in-situ signet-ring cell carcinoma" composed of signet-ring cells lining the gastric
foveolae/glands and limited by the basement membrane. Sometimes these signet ring cells demonstrate
pagetoid spread along the gastric glands or foveolae. These are considered precursor lesions for HDGC,
and also show reduced or absent membranous E-cadherin staining. Non-neoplastic gastric mucosa in
gastrectomy specimens may show mild chronic gastritis, focal granulomatous inflammation around collapsing
glands, foveolar hyperplasia, sometimes with globoid-cell change, and vacuolization of the surface
epithelium . Most cases lack intestinal metaplasia or active Helicobacter pylori infection. Clinical
features, management and prevention: The age of presentation in patients who clinically manifest has
been extremely variable (14-85 years), even within families. The cumulative risk of developing
clinically significant gastric carcinoma by the age of 80 years is estimated to be 67% for men and 83%
for women . Recent data may suggest that this risk is higher. Since prophylactic gastrectomy in
mutation-positive family members invariably shows gastric cancer, even if at an early stage, the data
implies that some individuals probably live with their cancer without ever manifesting clinical disease
or any complications. The prognosis in patients with only mucosal disease following total gastrectomy is
expected to be excellent, although long-term survival in HDGC still remains unknown. The patient
presented here, despite nodal metastasis and stage IIB disease is doing well and is under surveillance
along with her family members. She is currently free of disease after 9 years. A very important issue
in HDGC is screening and surveillance of the family members, and useful guidelines for a practical
approach and management have been published
Genetic testing and identification of at-risk
individuals often allows prophylactic gastrectomy in asymptomatic individuals. In patients with
identifiable CDH-1 mutation, at-risk family members can be identified by testing for germline mutations.
It is suggested that family members should be tested for CDH-1 mutation in their early teens or 20s.
Prophylactic total gastrectomy in mutation-positive family member is recommended after the age of 20
years. If missense mutations are identified that are considered non-pathogenic, the individuals are
considered low risk carriers and can undergo clinical surveillance similar to mutation- negative
Individuals with missense CDH-1 mutations considered to be pathogenic or with
truncating mutations should be advised to undergo prophylactic gastrectomy. Individuals who are
surgically unfit for total gastrectomy or who refuse this option, should undergo regular clinical
surveillance with knowledge of the limitations of this procedure. Individuals with biopsy proven diffuse
gastric carcinoma should undergo total gastrectomy irrespective of their age. Prophylactic gastrectomy
has a mortality of about 2%, and major complications have occurred in 17% of these cases.
Mutation-positive female patients should also undergo appropriate screening for breast cancer . As
noted earlier, in about 70-90% of patients with HDGC no underlying genetic mutation is identified, and
their surveillance poses significant practical issues, a situation that is exemplified by this case. The
only currently available option is to perform screening upper GI endoscopy in these patients with
multiple biopsies, even of normal appearing mucosa. Advanced or improved methods of visualizing the
mucosa with chromoendoscopy or narrow-band imaging (NBI) may improve the chances of finding early cancer
however, studies show that many tumors underlie normal mucosa and are likely to be missed
The limitation of the screening tools should be clearly explained to these patients and their family
In summary, much has been learned about hereditary diffuse gastric cancer in recent
years, however, lack of an identifiable germline pathogenic mutation in a majority of families still
remains a major problem leading to critical management issues.
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