ten percent of gastric cancer ( gc ) cases are familial , with one third resulting from a mutation in the tumor suppressor gene cdh1 .
loss of this important structure can result in hereditary diffuse gastric cancer ( hdgc ) , which carries a high mortality if early diagnosis is not made . despite its clear genetic origin , optimal management of hdgc family members is controversial , as the utility and efficacy of current cancer screening programs for mutation carriers are unproven .
a 53-year - old caucasian woman was initially seen for genetic screening because multiple family members had mutations of the cdh1 gene .
her pedigree analysis demonstrated 4 generations of gastric cancer , and 2 of the generations carried the cdh1 germline mutation , consistent with hdgc . at endoscopy , the patient 's gastric mucosa was normal and random biopsies were also normal .
however , the stomach was found to have diffuse ( signet ring cell ) adenocarcinoma in - situ with 11 microscopic foci of invasive adenocarcinoma limited to the lamina propria .
our case is the first reported prophylactic total gastrectomy utilizing a laparoscopic approach , and it highlights the importance of taking a thorough family history and obtaining a pedigree analysis .
endoscopic screening in hdgc can not rule out diffuse gc , because the stomach and biopsies can be normal despite the presence of adenocarcinoma .
gastric cancer ( gc ) will account for approximately 22,000 cases of cancer in the united states in 2006 , with 10% being familial .
of the familial gastric cancers , approximately one third result from a mutation in the tumor suppressor gene cdh1 , which normally encodes for the protein e - cadherin .
patients who are cdh1 positive are at high risk for diffuse gastric cancer , which carries a poor prognosis if an early diagnosis is not made .
the cdh1 gene is located on chromosome16p22.1 and contains 2.6 kb of coding sequences with 16 exons .
it encodes for a transmembrane protein , e - cadherin , with 5 tandemly repeated extracellular domains and a cytoplasmic domain that connects to an actin cytoskeleton through a complex with  ,  , and  catenins .
e - cadherin is important for establishing cell polarity and maintaining normal tissue morphology and cellular differentiation .
loss of the cdh1 gene function impairs cell adhesiveness as well as cell proliferation pathways .
the mechanism by which these e - cadherin mutations actually lead to cancer is complex and not well understood .
the disrupted cell adhesion is likely to play a role in the initiation of cell proliferation by allowing escape from growth control signals .
alternatively , the cytoplasmic domain of e - cadherin may modulate specific signaling pathways by inhibiting the availability of free cytoplasmic -catenin , in a manner complementary to the product of the colorectal tumor - suppressor gene apc .
each individual in a cancer syndrome family has a 50% chance of inheriting the mutant gene , due to the autosomal dominant transmission .
gene carriers have a cumulative lifetime risk estimated at 67% for men and 83% for women of developing gc by the age of 80 .
hdgc is defined as families with 2 or more documented cases of pathologically proven diffuse gcs in first- or second - degree relatives with at least one diagnosed before the age of 50 , or 3 or more cases of documented diffuse gastric cancer in first- or second - degree relatives , independent of age of onset .
it is predicted that up to 25% of families that fit these criteria will have inactivating germline cdh1 mutations
. early onset of phenotypic expression is a defining feature of inherited malignancies , as evidenced by the vast majority of families with truncating cdh1 mutations that fulfill the above diagnostic criteria . despite its clear genetic origin
there are currently no methods available to predict which mutation carrier will develop phenotypic expression ( ie , diffuse gastric cancer ) .
the utility and efficacy of current surveillance programs for cdh1 mutation carriers are unproven , which has given credence to the recommendation for prophylactic gastrectomy .
endoscopic screening and surveillance is inappropriate in the great majority of cases of cdh1 germ - line mutations , as patients usually have normal - appearing gastric mucosa endoscopically .
random biopsies are often negative when in fact the histologic specimen often has multiple foci of carcinoma in situ and invasive carcinoma with negative biopsies .
a 53-year - old asymptomatic caucasian female was referred for prophylactic total gastrectomy because she was found to carry a mutation of the tumor suppressor gene cdh1 .
her grandmother died from diffuse gastric cancer at age 63 , and of her grandmother 's 8 children , 7 died from diffuse gastric cancer at ages ranging from 26 years to 67 years of age . among her
( third ) generation , 13 cousins including herself ultimately underwent prophylactic total gastrectomy after testing positive for the cdh1 mutation .
pedigree analysis of her family shows that the family has an inheritable gastric cancer that exhibits autosomal dominant transmission with high penetrance ( figure 1 ) .
genealogy demonstrating 4 generations of stomach cancer , 2 of which carried the cdh1 germline mutation , consistent with hereditary diffuse gastric cancer ( hdgc ) .
thirteen patients had prophylactic gastrectomy , including the proband who underwent successful total laparoscopic gastrectomy .
eighteen patients were identified as having gastric cancer , and 11 of those were identified as carrying the cdh1 tumor suppressor gene mutation .
three patients were identified as carrying the cdh1 tumor suppressor gene mutation but did not have cancer .
after extensive genetic counseling and discussions regarding the risks and benefits , she elected to undergo a prophylactic total gastrectomy .
laparoscopic hand - assisted total gastrectomy was performed with roux - en - y reconstruction .
the patient was placed in the lithotomy position with the operating surgeon positioned between the legs .
a total of 4 ports were used ( three 5-mm ports and one 12-mm port ) in addition to the hand port ( figure 2 ) .
the jejunojejunostomy ( jj ) was created with a linear laparoscopic stapling device , and the common channel enterostomy was closed with a running full - thickness suture .
the roux limb was brought in a retrocolic fashion , and the mesocolic defect including peterson 's defect was closed .
the roux limb was 60 cm in length . with the patient in full reverse trendelenberg ,
diagram of patient in lithotomy position with location of surgeon , assistants , and placement of laparoscopic ports .
only microscopic examination of the entire gastric mucosa revealed widespread adenocarcinoma in situ ( figure 3 ) and 11 foci of invasive adenocarcinoma limited to the lamina propria ( figures 4 ) .
an additional finding was of hypervacuolation of the foveolar epithelium ( globoid changes ) , and slight chronic active gastritis .
the histological features of the tumor , including its signet ring cell morphology , its multifocality , and its superficial distribution , and the associated globoid changes of normal foveolar mucosa have been described in prophylactic gastrectomy of patients with e - cadherin germ - line mutations .
adenocarcinoma in situ , showing neoplastic goblet cells within foveolar epithelium ( as outlined by black arrows ) .
focus of invasive adenocarcinoma , showing signet ring cells in the lamina propria distorting gastric glands ( as outlined by black arrows ) .
she had return of bowel function on postoperative day 3 and was allowed to eat .
she developed a stricture at the esophagojejunal anastomosis 6 weeks postoperatively , which was successfully treated with endoscopic balloon dilation .
more than one year after the surgery , she is disease free and doing well .
sokoloff is credited for the earliest recognition of a gastric cancer prone family ( the bonaparte family ) .
his postmortem examination revealed a perforated malignant gastric ulcer . at 52 , on his death bed , he was heard to utter
his father died from an autopsy proven gastric cancer , and it has been proposed that his grandfather , his brother , and 3 sisters also died from gc . familial gastric cancer in a kindred of new zealand maori ethnicity was originally reported in 1964 , and the pedigree pattern was consistent with an autosomal dominant inheritance .
it was not until 1998 that germline truncating mutations of the chd1 tumor suppressor gene were described in 3 new zealand maori families predisposed to diffuse gc .
this led to the formation of the international gastric cancer linkage consortium ( igclc ) where the name  hereditary diffuse gastric cancer 
there have been several reports of prophylactic gastrectomy for cdh1 gene mutation carriers in the literature ( table 1 ) .
lewis et al reported on 6 patients from 2 families , and all patients recovered uneventfully and were discharged on average 7 days postoperatively .
chun et al reported on 5 patients from a single family with no reported complications .
two other groups reported a total of 12 patients , but the details of their perioperative care was not reported .
summary of all previous documented open prophylactic gastrectomies based on this review , our case brings the total number of prophylactic gastrectomies to 26 , and , to the best of our knowledge , our case is the first prophylactic laparoscopicassisted total gastrectomy performed for hdgc .
the patient had early return of bowel function , tolerated oral intake early , and was discharged on postoperative day 4 .
this is in contrast to open gastrectomies where the average length of stay ranges from 7 days to 11 days .
a noteworthy observation is that 23 of 26 patients who underwent prophylactic gastrectomy , including our patient , had foci of adenocarcinoma despite normal surveillance endoscopy .
this further establishes the role of prophylactic gastrectomy in these patients ; in fact , the surgery that was intended to be prophylactic proved to be therapeutic and curative . in regards to the laparoscopic versus the open technique , definite conclusions can not be made from one case , but our preference for the laparoscopic approach is supported by usui et al who showed that time to first flatus , time to initial oral intake , and postoperative hospital stay were significantly shorter ( p < 0.05 ) in laparoscopic gastric surgery than in open gastric surgery .
their report concluded that laparoscopic - assisted total gastrectomy is suitable and feasible for early gastric cancer and has the advantage of a shorter recovery time compared with that for open total gastrectomy .
laparoscopic total gastrectomy has been criticized because of the doubts that remain about its ability to satisfy all the oncologic staging criteria met during conventional open surgery .
although no long - term studies have been conducted , adenocarcinoma in hdgc , when present , exists at a very early stage ( tisn0m0 ) .
the guideline given by the igclc is that when a total gastrectomy is performed , it is essential to document the complete removal of gastric mucosa by pathologically identifying rims of esophageal and duodenal mucosa at the 2 ends of the surgical specimen .
laparoscopic total gastrectomy with roux - en - y reconstruction can satisfy this requirement and , given the improved postoperative recovery and decreased morbidity , it is well suited for the asymptomatic , cancer - susceptible patients found in hdgc families . however , only surgeons experienced in advanced laparoscopy should attempt laparoscopic gastrectomy .
however , considering that gastrectomy is usually performed in older patients , the complication rate in a younger , healthier population , such as those with hdgc undergoing prophylactic gastrectomy , are expected to be much less , with an estimated mortality of 1% to 2% .
long - term morbidity after total gastrectomy is related to alteration of eating habits , dumping syndrome , diarrhea , and weight loss .
there is usually a 10% to 15% decrease in body weight , which is principally a decrease in body fat .
laparoscopic total gastrectomy for hdgc should not be performed without genetic counseling and genetic testing .
the modified screening criteria as proposed by suriano et al should be used to determine which families should be screened .
the age at which genetic screening should be initiated is controversial , because patients younger than age 18 have undergone prophylactic gastrectomy .
this is highlighted in our case , in which a patient with a cdh1 mutation within a family of hdgc underwent prophylactic laparoscopic gastrectomy . despite the normal appearance of the stomach endoscopically , many microscopic foci of invasive adenocarcinoma were present .
this review highlights the poor prognosis in those family members who did not receive gastrectomy , as death ensued within 1 year to 2 years after diagnosis .
the penetrance in this family was high , with > 70% of family members who acquired the cdh1 gene mutation developing diffuse gastric cancer .
endoscopic screening in hdgc can not be recommended because the stomach will appear normal and biopsies can and often fail to demonstrate the ( signet ring cell ) adeno - carcinoma in situ or invasive adenocarcinoma that is invariably found in resected stomachs .
prophylactic gastrectomy has provided many members of this family with relief from gastric cancer with minimal complications .
this case further supports the current recommendation in the literature for prophylactic gastrectomy in hdgc .
furthermore , we report that successful complete gastrectomy can be accomplished laparoscopically without complication , thus reducing the length of hospitalization and providing a minimally invasive alternative to more traditional open surgery .
 background : ten percent of gastric cancer ( gc ) cases are familial , with one third resulting from a mutation in the tumor suppressor gene cdh1 . 
 loss of this important structure can result in hereditary diffuse gastric cancer ( hdgc ) , which carries a high mortality if early diagnosis is not made . despite its clear genetic origin , optimal management of hdgc family members is controversial , as the utility and efficacy of current cancer screening programs for mutation carriers are unproven.methods:a 53-year - old caucasian woman was initially seen for genetic screening because multiple family members had mutations of the cdh1 gene . 
 her pedigree analysis demonstrated 4 generations of gastric cancer , and 2 of the generations carried the cdh1 germline mutation , consistent with hdgc . at endoscopy , the patient 's gastric mucosa was normal and random biopsies were also normal . 
 the patient underwent a laparoscopic total gastrectomy.results:the gross examination of her stomach appeared normal . 
 on histologic examination , however , the stomach was found to have diffuse ( signet ring cell ) adenocarcinoma in - situ with 11 microscopic foci of invasive adenocarcinoma limited to the lamina propria.conclusions:our case is the first reported prophylactic total gastrectomy utilizing a laparoscopic approach , and it highlights the importance of taking a thorough family history and obtaining a pedigree analysis . 
 endoscopic screening in hdgc can not rule out diffuse gc , because the stomach and biopsies can be normal despite the presence of adenocarcinoma . 
 therefore , our case supports the recommendation for prophylactic gastrectomy in hdgc . 
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INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSION