case study bio

I need someone to do this homework:

you have to follow exactly what it says to do in your own words.

here is the link to the article that you have to read and and answer the following question below in description.




Gastric Cancer Case Study                                                               




First, download and read the case study posted on the Moodle site.  This article was originally published in the New England Journal of Medicine.  The readers of this journal are primarily practicing physicians, so some parts of the paper might be hard to understand.  You should, however, be able to understand the genetics of the condition described in this patient.


Once you have read the paper, answer each of the questions below.  Note that your work must be in your own words (consult the syllabus for the course policy on plagiarism).  You should type your responses directly into this document and upload the file to through the appropriate link on our Moodle site by the due date.


1.  The assigned article is a case study.  Briefly explain what the term “case study” means.  Is a case study considered to be a primary or a secondary source?


2.  This paper describes the inheritance of a dominant, highly penetrant susceptibility to breast and gastric cancer in an extended family. While cancer phenotype that is transmitted through this family can be described as highly penetrant, it is not completely penetrant.  Briefly define what incomplete penetrance is, then suggest reasons why this condition might not be completely penetrant.


3. The study of the inheritance of specific genes causing cancer has been extremely useful in understanding the biology of cancer, but most cancer does not run in families.  Choose either breast or gastric cancer and find an estimate for the percentage of cancer cases that are genetic.  List the source of your information and comment on the reliability of your source.


4.  Consider the patient’s medical history as described in the case study and the pedigree in figure 1.  What is it in the patient’s medical history that led her to be referred to a genetic counselor?


5.  Noting the pattern of inheritance of breast and gastric cancer in this family, several genetic syndromes were considered as possible causes (see table 1).  Choose one gene (other than CDH1) and find a peer-reviewed review article that summarizes the current understanding of that gene’s role in causing cancer.  Give the complete reference for the source you found (authors, date, title, journal and pages).  You do not need to summarize the review that you find – the exercise is to find it.


6.  Referring to the pedigree and noting that the patient was eventually diagnosed as having gastric cancer, comment on the risk that each of the patient’s children faces.


7.  The patient was found to carry the R732Q mutation in the CDH1 gene.  Briefly explain what “R732Q” means.


8.  Consider the patient’s situation once a genetic test showed she was carrying the mutated CDH1 gene.  What are your thoughts on the decision she faced? 
àeither risk gastric cancer (which has a very low cure rate once diagnosed), or have prophylactic removal of her entire stomach, likely limiting her quality of life indefinitely.  Would you have done the same thing? 


case records of the massachuset ts gener al hospital

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 357;3 july 19, 2007 283

Founded by Richard C. Cabot

Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

From the Gastroenterology Unit (D.C.C.),
the Division of Surgical Oncology and
Department of Surgery (S.S.Y.), the De-
partment of Pathology (G.Y.L.), and the
Center for Cancer Risk Analysis (D.C.C.,
D.P.), Massachusetts General Hospital; and
the Departments of Medicine (D.C.C.),
Surgery (S.S.Y.), and Pathology (G.Y.L.),
Harvard Medical School.

N Engl J Med 2007;357:283-9


Copyright © 2007 Massachusetts Medical Society.

P r e s e n t a t i o n o f C a s e

A 38-year-old woman was seen in the Gastrointestinal Cancer Genetics Clinic of this
hospital because of a family history of breast and gastric cancer.

Approximately 15 months earlier, mild chronic gastrointestinal symptoms, includ-
ing dyspepsia, heartburn, and midabdominal discomfort, increased in severity and
began to occur daily. The symptoms did not resolve with antacid therapy. She had
lost approximately 2.3 kg (5 lb) during this time, which she attributed to the stress
of caring for her maternal aunt, who was dying of gastric cancer. Seven months before
admission, an endoscopic examination of the upper gastrointestinal tract, performed
at another hospital, was normal. Thiazine staining of the biopsy specimen disclosed
no Helicobacter pylori, and a pathological examination of multiple gastric biopsy speci-
mens was negative for cancer. A test for blood in the stool was negative. Proton-
pump inhibitor therapy, calcium carbonate tablets, and clonazepam were adminis-
tered; her symptoms improved. Two weeks before evaluation, a repeat upper
endoscopic examination with biopsies at the other hospital was normal. One week
later, she came to the Gastrointestinal Cancer Genetics Clinic of this hospital.

The patient had a family history of multiple malignant tumors (Fig. 1). The pa-
tient’s mother had died of gastric cancer at 33 years of age. Invasive ductal cancer of
the right breast had developed in the patient’s maternal aunt at 58 years of age, and
invasive lobular cancer had developed at 66 years of age. When the second breast
cancer developed, her aunt was referred for genetic counseling because of the family
history of breast and ovarian cancer; testing for mutations in the BRCA1 and BRCA2
genes had shown no abnormality of BRCA1 and a variant of uncertain significance
in BRCA2. Diffuse gastric cancer developed in the maternal aunt at 67 years of age, and
a well-differentiated pancreatic endocrine cancer was detected at the time of gas-
trectomy; she died less than 1 year later.

The patient had had an eating disorder as a teenager, and she had anxiety and
panic attacks. She was gravida 3, para 3, had most recently delivered an infant 14
months earlier, and was still breast-feeding her youngest child. She had had bilat-
eral arthroscopic knee procedures in the past. She had no allergies, drank alcohol
rarely, and did not smoke or use illicit drugs. She was married and lived with her
husband and children, and she worked as a homemaker. Medications included

Case 22-2007: A Woman with a Family
History of Gastric and Breast Cancer

Daniel C. Chung, M.D., Sam S. Yoon, M.D., Gregory Y. Lauwers, M.D.,
and Devanshi Patel, M.S., C.G.C.

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n engl j med 357;3 july 19, 2007284

omeprazole, clonazepam, famotidine, sucralfate,
n!3 fatty acids, Lactobacillus acidophilus, and vi-

On examination, the patient appeared well. The
weight was 58 kg (128 lb), the temperature was
36.9°C, the pulse was 76 beats per minute, the
respirations were 16 breaths per minute, and the
blood pressure was 120/60 mm Hg. A rectus di-
astasis of the abdomen was present, with some
excess abdominal skin. The abdomen was soft,
without tenderness, distention, or masses. The re-
mainder of the examination was normal.

A diagnostic test was performed.

D i f f e r e n t i a l D i a g n o s i s

Hereditary Breast Cancer Syndromes
Ms. Devanshi Patel: The most important step in the
diagnosis of a hereditary cancer syndrome is the
compilation of a thorough family history of can-
cer. This is done by identifying all persons in the
patient’s family, all persons with cancer in the fam-
ily, the types and sites of the cancer, the age of the
family member at the time of diagnosis of each
cancer, and other phenotypes that can help to de-
lineate cancer syndromes.1 By the use of this meth-
od, the pedigree shown in Figure 1 was obtained










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1 of






65 Yr

24 Yr

38 Yr 39 Yr

5 Yr 3 Yr 1 Yr

59 Yr 56 Yr68 Yr58 Yr
56 yr

33 Yr
29 yr

45 Yr

73 Yr

66 yr

51 Yr
50 yr

33 Yr
32 yr

86 Yr
75 yr

75 Yr 65 Yr

81 Yr
77 yr

78 Yr80 Yr

69 Yr


Breast cancer

Miscellaneous cancer

Genitourinary cancer

Gastrointestinal cancer

67 Yr
58 yr

66 yr

67 yr


Circles represent female family members, and squares male family members. Slashes indicate persons who died,
and the numbers beneath the circles or squares are age at death (if there is a slash) or, for those living, age at the
time the pedigree was created. Yellow represents confirmed cancer. The diamond indicates that sex is unknown; the
number inside the diamond indicates the number of persons represented by the diamond. The patient’s (arrow)
maternal aunt had cancer of the right breast at 58 years of age, cancer of the left breast at 66 years of age, and dif-
fuse gastric cancer at 67 years of age, and she died at 67 years of age. The patient’s mother had gastric cancer at 32
years of age and died at 33 years of age. The patient’s maternal grandmother had breast cancer at 77 years of age,
and the maternal great-grandmother died of ovarian cancer. The patient’s paternal grandfather had gastric cancer at
50 years of age and died at 51 years of age. The patient’s brother, 33 years of age, had papillary thyroid cancer at 29
years of age. Her father was of German ancestry, and her mother was of German and English ancestry.

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c a se r ecor ds of the m a ssachuse t t s gener a l hospi ta l

n engl j med 357;3 july 19, 2007 285

when this 38-year-old woman came to the Cancer
Genetics Clinic.

The first person in this patient’s family to seek
genetic counseling was her maternal aunt, who
had two primary breast cancers. At the time of the
diagnosis of the second breast cancer, the mater-
nal aunt was referred to the Center for Medical
Genetics at Evanston Northwestern Healthcare,
Evanston, Illinois, for risk assessment. Because of
the preponderance of breast cancer in the family,
with an autosomal dominant pattern of inheri-
tance, hereditary breast cancer syndromes were
considered. It is estimated that approximately 7 to
10% of breast cancers have an identifiable heri-
table component.2,3 Several hereditary syndromes
have breast cancer as component tumors; features
of the autosomal dominant syndromes are sum-
marized in Table 1.

Cowden’s disease is associated with both breast
and thyroid cancers, both of which were seen in
this family, but the family did not exhibit any of
the other characteristics of this syndrome. Peutz–
Jeghers syndrome is associated with breast, ovar-
ian, and gastric cancers, but the family did not
have the characteristic mucocutaneous lesions or
hamartomatous polyps. The average age of the
patient at cancer diagnosis was older than is typi-
cal for the Li–Fraumeni syndrome and none of the
other typical Li–Fraumeni syndrome tumors were
present in the family. Hereditary diffuse gastric
cancer syndrome was not considered at the time
of the maternal aunt’s presentation, even though
there were two gastric cancer diagnoses in the
family, because there was no information as to
whether the cancers were diffuse on histologic
examination. The most common hereditary breast
cancer syndrome is hereditary breast and ovarian
cancer syndrome. In this family, the confirmed
case of ovarian cancer provided support for this
diagnosis. Reports have suggested an increased
risk of gastric cancer in families with hereditary
breast and ovarian cancer syndrome,4 but this
link remains unclear.

Thus, the family history at that time was most
consistent with hereditary breast and ovarian can-
cer syndrome, and the patient’s aunt was offered
genetic testing to detect mutations in the BRCA1
and BRCA2 genes. The change that was found in
BRCA2 (E2175Q) had not been previously reported,
and thus was of uncertain clinical significance; the
family was advised to manage cancer risks on the
basis of family history alone, and no testing to
detect the BRCA2 variant was offered to unaffected

relatives. Less than 4 months after the maternal
aunt received the results of the BRCA1/2 genetic
test, the diagnosis of diffuse gastric cancer was
made, and the differential diagnosis was changed.

Hereditary Gastric Cancer Syndromes
Dr. Daniel C. Chung: This 38-year-old woman came
to us because of a strong family history of gastric
cancer, with some of the cases occurring at a
young age; this finding suggests that in addition
to a hereditary breast cancer syndrome, the fam-
ily has a hereditary gastric cancer syndrome.

Gastric cancer is the second leading cause of
cancer deaths worldwide, but it is less common in
the West than in other parts of the world. In the
United States, it is the seventh leading cause of
cancer death, with about 22,000 cases diagnosed
per year and about 11,000 deaths per year.5 There
are two major histologic subtypes of gastric can-
cer: intestinal and diffuse. The intestinal subtype
is associated with environmental risk factors in-
cluding H. pylori infection, smoking, and diets high
in salted and cured foods; this subtype has been
decreasing in incidence.6 Only 1 to 3% of the cases
are probably attributable to a high-penetrance ge-
netic syndrome. Five entities confer a risk of gas-
tric cancer (Table 1), all of which are inherited in
an autosomal dominant manner.

Colorectal Cancer Syndromes
The Lynch syndrome, also known as hereditary
nonpolyposis colorectal cancer syndrome, is caused
by a germ-line mutation in DNA mismatch-repair
genes (MSH2, MLH1, or MSH6). It confers a 60 to
80% lifetime risk of colon cancer and a high risk
of both uterine and gastric cancers. A 10% lifetime
risk of gastric cancer — predominantly the intes-
tinal subtype7 — is estimated in the Western world,
but families of Asian ancestry with the Lynch syn-
drome have up to a 30% lifetime risk.8 Breast can-
cer is not a feature of this syndrome; this fact,
coupled with the absence of colon cancers in the
family, makes the diagnosis of the Lynch syndrome
unlikely in this patient.

Gastric cancer also occurs in the familial ade-
nomatous polyposis syndrome, which is caused by
germ-line mutations in the APC gene. This syn-
drome is characterized by thousands of colonic
adenomatous polyps and a 100% risk of colon
cancer unless the patient undergoes a prophylac-
tic colectomy.9 Gastric fundic-gland polyps occur
in at least 50% of affected persons.10 These pol-
yps are generally thought to have no precancerous

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n engl j med 357;3 july 19, 2007286

potential, but there are case reports of gastric can-
cer developing in some kindreds, predominantly
in families in Asia (Japan or Korea). Again, breast
cancer is not a feature of this syndrome, and co-
lonic polyposis was not observed, so this diagno-
sis is unlikely in this patient.

Both breast and gastric cancers can occur in
the Peutz–Jeghers and Li–Fraumeni syndromes,
but both are unlikely, for the reasons indicated by
Ms. Patel.

Hereditary Diffuse Gastric Cancer Syndrome
The hereditary diffuse gastric cancer syndrome is
caused by a germ-line mutation in the E-cadherin
(CDH1) gene; only about 50 families with this syn-
drome have been reported.11 The gastric cancers
in this syndrome are of the diffuse type, and the
mean age at the diagnosis of gastric cancer is ap-
proximately 40 years. The lifetime risk of gastric
cancer is estimated to be 83% in women and 67%
in men.12 In contrast to other gastrointestinal can-
cer syndromes, there is also an important risk of

breast cancer (39% in women), particularly the
lobular type. Thus, this syndrome could explain the
cancers seen in this family.

Before the genetic abnormality was identified,
the International Gastric Cancer Linkage Con-
sortium developed clinical criteria for the diagno-
sis of this syndrome.13 One of two criteria must
be met: at least two cases of histologically con-
firmed diffuse gastric cancer in first- or second-
degree relatives, one of which must have devel-
oped before the relative was 50 years of age, or
three or more cases of histologically confirmed
diffuse gastric cancer in first- or second-degree
relatives of any age. This patient’s family does
not strictly fulfill these criteria, because the pres-
ence of diffuse gastric cancer was histologically
confirmed only in the patient’s maternal aunt.
Only 30 to 50% of families who do fulfill these
criteria are found to have a CDH1 germ-line muta-
tion,14 suggesting that in at least half the fami-
lies, other genes are involved that have not been


Syndrome Gene Cancers Other!Features

Hereditary breast and
ovarian cancer

BRCA1, BRCA2 Breast, ovarian Pancreatic cancer

Cowden’s PTEN Breast, thyroid (nonmedullary),

Mucocutaneous lesions (trichilem-
momas, papillomatous pap-
ules, facial acral keratoses, mu-
cosal lesions), macrocephaly,
Lhermitte–Duclos disease,
hamartomatous gastrointesti-
nal polyps, mental retardation,
fibrocystic disease of the
breast, lipomas, fibromas,
genitourinary tumors

Peutz–Jeghers STK11 Esophagus, stomach, small intes-
tine, colon, pancreas, lung, breast,
endometrial, ovarian (sex cord),
adenoma malignum of the cervix,
testicular Sertoli-cell tumors

Hamartomatous gastrointestinal
polyps, mucocutaneous pig-

Li–Fraumeni TP53 Breast, sarcoma, brain, adrenocorti-
cal, leukemia

Childhood cancers

Familial adenomatous

APC Colon, duodenal, and ampullary

Adenomatous polyps of colon, fun-
dic-gland gastric polyps, thyroid
cancer, gastric cancer (rare)

Lynch (hereditary non-
polyposis colorec-
tal cancer)

or MSH6

Colon, uterine, gastric Ovarian cancer, renal pelvis and
ureteral tumors, glioblastoma,
sebaceous-skin tumors, small-
bowel tumors, biliary-tract

Hereditary diffuse gas-
tric cancer

CDH1 Diffuse gastric, breast (typically

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n engl j med 357;3 july 19, 2007 287

Genetic Testing

When the patient’s maternal aunt received a di-
agnosis of gastric cancer, she was offered tests to
detect the CDH1 gene. These tests were performed
in the laboratory of Dr. David Huntsman15,16 and
showed an R732Q mutation resulting in a substi-
tution of glutamine for arginine at amino acid 732.
This information was known to the patient and
to us at the time of her evaluation in our clinic.
We offered this patient germ-line testing for the
R732Q mutation that had previously been identi-
fied in the family; these tests showed the same
mutation in our patient.

Mutations in E-cadherin, the protein encoded
by the gene CDH1, result in a loss of normal adhe-
sion and an increase in cellular migration and in-
vasion. About 75% of the CDH1 mutations that
have been described lead to a premature trunca-
tion, a shortened peptide, and a loss of function
and immunoreactivity of the protein, which results
in failure to identify the protein on immunohis-
tochemical staining of the cancer. The mutation
in this family is a missense mutation, rather than
a truncating mutation. Missense mutations are not
necessarily pathogenic, but the R732Q mutation
has been described previously in the literature, and
in vitro assays have shown that it is indeed patho-
genic.14 This family is described in two reports
that will be published elsewhere.15,16

Thus, in this patient with a family history of
documented diffuse gastric cancer, a high preva-
lence of breast cancer, including lobular cancer,
and a mutation in the CDH1 gene, the diagnosis of
hereditary diffuse gastric cancer syndrome was
confirmed. The patient’s mother was an obligate
carrier of the same mutation, since she had gas-
tric cancer at a very young age. It is likely that the
patient’s maternal grandfather, who had gastric
cancer, also carried the CDH1 mutation.

D i s c u s s i o n o f M a n a g e m e n t

Management of the Risk of Gastric Cancer
The care of persons such as our patient with he-
reditary diffuse gastric cancer syndrome focuses
primarily on managing their risk of gastric can-
cer. The lifetime risks are high, and they are age-
dependent. By 30 years of age, the risk is approxi-
mately 4%, but by 50 years of age, the risk is 21%
for men and 46% for women. At all ages, it appears
that women have a higher risk of the development

of gastric cancer, and the reason for this remains
unknown. As compared with the intestinal type of
gastric cancer, environmental factors do not appear
to have a major role in diffuse gastric cancers.10

There are two major options for screening for
gastric cancer in this patient: surveillance upper
endoscopy with random biopsies and prophylac-
tic gastrectomy. No controlled data provide sup-
port for either approach, but the momentum has
shifted toward prophylactic gastrectomy. In gas-
trectomy specimens from patients in whom gas-
trectomy had been performed without a preopera-
tive diagnosis of cancer, histopathological analysis
of the entire stomach revealed previously unrecog-
nized cancer in more than 90% of the patients.11,17
These microscopic cancer foci are not visible with
conventional white-light endoscopy, are often mul-
tifocal, with up to 500 foci per stomach, and can
lie beneath a layer of normal epithelium. Thus,
prophylactic gastrectomy may be the only way to
detect these cancers at an early stage.

The timing of gastrectomy in this patient is an
important question. Gastric cancers have been re-
ported in teenagers in affected families, so gas-
trectomy is often offered to patients before their
early 20s. Although microscopic foci of cancer are
seen in nearly all gastrectomy specimens, even in
patients at an early age, the risk of a clinically sig-
nificant cancer by 50 years of age is less than 50%.
Thus, not all of these microscopic cancers pro-
gress, and the rate at which they do so is vari-
able. Nonetheless, for the time being, the con-
servative route is to treat each microscopic focus
as if it is potentially an invasive cancer.

Are there alternatives to prophylactic gastrec-
tomy? Chromoendoscopy is a procedure in which
the gastric mucosa is coated with dyes such as
methylene blue and Congo red. Methylene blue
is taken up by cells in regions of intestinal meta-
plasia, which is a precursor to intestinal-type can-
cer, and Congo red stains areas that are acidic and
contain parietal cells. Since gastric cancer is typi-
cally devoid of parietal cells, it should appear as
a pale area on endoscopic examination. In the
one published observational study,18 chromoen-
doscopy detected foci of early diffuse gastric
cancer in 10 of 33 patients; only two of these foci
were detected by means of routine endoscopy.
18F-fluorodeoxyglucose–positron-emission tomo-
graphic scanning was reported to detect foci of
early gastric cancer in a patient with a CDH1 mu-

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n engl j med 357;3 july 19, 2007288

tation and no macroscopic evidence of gastric
cancer.19 Studies of large numbers of patients will
be required to determine whether either of these
techniques will be clinically useful.

In this 38-year-old patient with a CDH1 muta-
tion, we recommended prophylactic gastrectomy.
If she declined, upper endoscopy every 6 months
with random biopsies would have been recom-
mended. She was initially hesitant to proceed with
gastrectomy, so an upper endoscopy with methy-
lene blue stain was performed. The examination
was normal, and pathological examination of ran-
dom biopsy specimens detected no cancer. After
additional consultation with the surgeon, the pa-
tient elected to have a prophylactic gastrectomy.

Prophylactic Gastrectomy
Dr. Sam S. Yoon: To make an educated decision re-
garding prophylactic surgery, patients with germ-
line E-cadherin mutations must understand certain
technical aspects of prophylactic total gastrecto-
my and outcomes after total gastrectomy.

Technical Considerations
In performing prophylactic total gastrectomy for
patients with germ-line E-cadherin mutations, it is
critically important to remove all gastric mucosa.
Gastric cancer in residual gastric-cardia mucosa
has been reported as long as 24 years after prophy-
lactic gastrectomy.20 The distal division across the
duodenum should be performed at least 1 to 2 cm
beyond the pylorus, and the proximal division
should be performed at least 2 cm above the squa-
mocolumnar junction. Some authors recommend
intraoperative endoscopy to ensure accurate iden-
tification of the squamocolumnar junction.20 The
gastrectomy specimen should be sent for frozen-
section analysis of the proximal and distal margins
to confirm that all gastric mucosa has been re-
moved. Some perigastric lymph nodes, especially
those along the lesser and greater curvatures, may
be removed with the stomach, but no formal lymph-
node dissection is required if no cancer has been
detected preoperatively. Reconstruction by means
of Roux-en-Y esophagojejunostomy is generally
performed with at least a 50-cm Roux limb to pre-
vent bile reflux.21 Creation of a jejunal pouch may
result in better food intake in the early period af-
ter gastrectomy.22

Morbidity and Mortality
Operative mortality after prophylactic total gastrec-
tomy for a germ-line E-cadherin mutation has not
been reported, but mortality after gastrectomy for
diagnosed gastric cancer ranges from less than
1% at specialized, high-volume centers23 to 7% in
a large survey of U.S. hospitals.24 Prophylactic op-
erations also are associated with the risk of early
complications such as ileus, wound and intraab-
dominal infections, and anastomotic leaks, as well
as with late complications such as anastomotic
stricture. These risks should be lower for pro-
phylactic total gastrectomy than for total gastrec-
tomies performed for invasive cancer, since the
patient population is generally younger and health-
ier, and lymphadenectomy, which increases com-
plications, is not required.25

Total gastrectomy has clear nutritional conse-
quences. Nearly all patients lose weight, with a
nadir after 3 to 6 months at about 75% of preop-
erative weight.26 Dumping syndrome and diarrhea
are common.27 Patients are initially instructed to
eat small amounts continuously over the course
of the day and after several months can eat three
to five meals per day. Patients should receive
monthly intramuscular vitamin B12 and a daily oral
multivitamin with ferrous sulfate. Since some pa-
tients have difficulty maintaining an adequate
nutritional status after total gastrectomy, regular
follow-up visits with the surgeon and nutrition-
ist are essential.

In an older person with germ-line E-cadherin
mutations, it is not clear at what age the risks of
prophylactic gastrectomy outweigh its potential
benefits. Since no formal lymph-node dissection
is required, laparoscopic total prophylactic gastrec-
tomy28,29 with a surgeon experienced with this
technique may be a reasonable option for patients
with germ-line E-cadherin mutations.

This patient was extremely well informed about
the risks and benefits of prophylactic surgery
through discussions with her physicians, nutri-
tionist, and support groups. I performed a total
gastrectomy and Roux-en-Y reconstruction consist-
ing of a jejunal pouch and hand-sewn esophago-
jejunostomy. A study with diatrizoate meglumine
and diatrizoate sodium on the fifth postoperative
day showed no evidence of anastomotic leak, and
she started a clear liquid diet. She was discharged

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n engl j med 357;3 july 19, 2007 289






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Figure has been redrawn and type has been reset.

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2a-d of 2







Gross photograph (Panel A) shows normal gastric mucosa with a small central scar (arrowhead), which proved to
be benign and of unknown cause. Glistening, gray esophageal mucosa is present at the proximal end (thin arrows),
and the pylorus is seen at the distal end (thick arrow). More than 200 sections were obtained for microscopy; the
overlay (Panel B) indicates the initial sections that were obtained. Eventually the entire specimen was submitted for
microscopy. A single focus (Panel C, arrows) of intramucosal signet-ring–cell carcinoma was identified; it is shown
at high magnification in Panel D. The location of the cancer is shown in the red circle on Panel B.

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n engl j med 357;3 july 19, 2007290

on the eighth postoperative day, tolerating a soft
solid diet. Five months after the operation, her
weight had stabilized at 52 kg (115 lb) (decreased
from 58 kg [128 lb]), and she was eating six to
eight meals per day.

Pa t h o l o g i c a l D i s c u s s i o n

Dr. Gregory Y. Lauwers: On gross examination, the
gastrectomy specimen contained normal-appear-
ing gastric mucosa, with a single, well-defined,
tan-white superficial scar, 1.0 by 0.8 cm, distant
from all margins (Fig. 2A). The entire stomach
was submitted for microscopical examination
(Fig. 2B). A total of 206 slides were reviewed. One
focus of intramucosal signet-ring–cell adenocar-
cinoma, 2 mm in diameter, was identified on a
single slide (Fig. 2C and 2D). In patients with a
CDH1 mutation, intramucosal adenocarcinomas
are difficult to detect on surveillance endoscopy
and biopsy specimens.30,31 No in situ carcinomas
or pagetoid spread of signet-ring cells beneath
the preserved epithelial lining of preexisting fo-
veolae, as reported by others, were observed.32,33
Thirteen lymph nodes removed with the stomach
contained no cancer. The final staging of this
cancer was stage pT1N0M0 (tumor–node–metas-
tasis stage IA).

Ms. Patel: The lifetime risk of breast cancer in
this patient is approximately 40%; the mean age
at breast-cancer diagnosis is 53 years.12 The ma-
jority of breast cancers in patients with CDH1 mu-
tations are of the infiltrating lobular type, which
may be more difficult than ductal cancers to de-
tect by means of screening and surveillance. Cur-
rently, there are no standard guidelines for the
management of breast-cancer risk in carriers of
the CDH1 mutation. However, a referral to a pro-
gram for patients at high risk for breast cancer is
warranted. This patient was referred to the Breast
and Ovarian Cancer Genetics Clinic at this hos-
pital, and the options of screening and prophylac-
tic mastectomy were discussed. She elected to un-
dergo screening (including magnetic resonance
imaging [MRI], mammography, and clinical
breast examination twice each year and a month-
ly breast self-examination) and is considering the
option of prophylactic mastectomy. Breast MRI
performed 2 months and 10 months after the
gastrectomy showed no suspicious lesions.

Dr. Bruce Chabner (Hematology/Oncology): Is

there any role for chemoprevention for patients
like this who are at risk for breast cancer?

Ms. Patel: There are no data on the efficacy of
agents such as tamoxifen in the prevention of
breast cancer in patients with CDH1 mutations.

Dr. Nancy Lee Harris (Pathology): I invited the pa-
tient to comment on the effect of this diagnosis
on herself and her family.

The Patient: I always feared I would die young of
stomach cancer, as my mother had, and the fear
worsened after my three children were born.
Learning that my aunt had the CDH1 mutation and
helping care for her as she died, I became increas-
ingly anxious. When I learned that I had the muta-
tion, I was shocked to know that I was at great risk
for the development of cancer, yet relieved I could
do something about it — but it would be a radi-
cal choice. My husband researched the issue and
helped us both realize that gastrectomy was the
best option. It helped me tremendously to talk
with others who had had this operation, and a
support group for families with this diagnosis is
available (
HDGC/). I learned that recovery would be very
difficult, but that I would be okay. My husband
and I were honest with our children (1, 3, and
5 years of age), and reading a children’s book
with them helped the older ones understand.34
It was a very difficult recovery, but a year later,
I feel almost normal, with even a 5-lb weight
gain! When I consider that each of our children
has a 50% chance of having this mutation, I
know they at least have the same option I did,
and I hope to show them what a livable solution
it is.

A n a t o m i c a l D i a g n o s i s

Hereditary diffuse gastric cancer syndrome due to
germ-line E-cadherin mutation, with gastric in-
tramucosal signet-ring–cell carcinoma.

Dr. Chung reports receiving consulting fees from Myriad Ge-
netics. Dr. Lauwers reports receiving consulting fees from
Sanofi-Aventis. No other potential conflict of interest relevant to
this article was reported.

We thank Scott M. Weissman, M.S., C.G.C., and Wendy S.
Rubinstein, M.D., Ph.D., from Evanston Northwestern Health-
care, Evanston, IL, and the Feinberg School of Medicine,
Northwestern University, Chicago, for providing details of the
genetic evaluation of the patient’s maternal aunt and for help-
ful comments on the manuscript; and Dr. David Huntsman,
Department of Pathology and Laboratory Medicine, University
of British Columbia, Vancouver, Canada, for performing the
analysis of the CDH1 gene.

Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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