Familial Gastric Cancer Flashcards
What are the major risk factors for developing gastric adenocarcinoma?
Heliobacter pylori infection
smoked/processed foods
obesity
alcohol/tobacco use
long-term inflammation
gastroesophageal reflux disease
What percentage of gastric adenocarcinoma cases have a familial predisposition?
Up to 10%.
How is “familial gastric cancer” defined?
Having two first- or second-degree relatives with gastric cancer diagnosed before age 50
or three first- or second-degree relatives diagnosed at any age.
Besides adenocarcinoma, what other types of gastric cancer exist?
Primary gastric lymphoma (2%–8%)
gastrointestinal stromal tumor (<1%)
neuroendocrine tumor (<1%)
What are the two histological subtypes of gastric adenocarcinoma according to the Lauren classification?
Intestinal and diffuse subtypes.
What is a key characteristic of the intestinal subtype of gastric adenocarcinoma?
Tumor cells are arranged in a glandular formation.
What are common associations with the intestinal subtype of gastric adenocarcinoma?
Environmental risk factors and a more favorable prognosis.
What distinguishes the diffuse subtype of gastric adenocarcinoma histologically?
Lack of adhesion molecules and poorly cohesive cells.
Why does the diffuse subtype of gastric adenocarcinoma have a poor prognosis?
It is highly metastatic, associated with transmural, poorly differentiated lesions, and is common in younger patients.
What percentage of all gastric cancers is accounted for by Hereditary Diffuse Gastric Cancer (HDGC)?
About 1% to 3%.
Which gene mutation is associated with HDGC, and where is it located?
A loss-of-function mutation in the CDH1 gene on chromosome 16q.
What is the role of the CDH1 gene, and how does its mutation contribute to cancer?
CDH1 encodes a cell-cell adhesion protein; loss of function increases invasiveness and promotes epithelial-to-mesenchymal transition
What types of cancer are individuals with a CDH1 mutation at higher risk of developing?
Diffuse, aggressive, signet ring gastric adenocarcinoma, and lobular breast carcinoma
or cleft lip and palate
What additional conditions are associated with CDH1 mutation in HDGC families?
Up to 60% of women may develop lobular breast cancer, and about 14% of families report cleft lip and palate.
At what age is CDH1 genetic testing recommended to begin, according to the IGCLC?
Testing is recommended to begin at 18 years of age.
When should asymptomatic family members with HDGC history consider genetic testing?
5 years before the earliest age of cancer diagnosis in the family or in their second decade of life.
Family Criteria (First- or Second-Degree Blood Relatives)
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Individual Criteria
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At what average age do patients with Hereditary Diffuse Gastric Cancer (HDGC) typically develop poorly differentiated diffuse gastric cancer?
By around 38 years of age
Why is prophylactic total gastrectomy (PTG) recommended for asymptomatic CDH1 mutation carriers?
PTG offers excellent primary prevention outcomes against gastric cancer in HDGC patients.
What preoperative evaluations are essential before PTG in HDGC patients?
Nutritional assessment
discussion of surgical risks
and counseling on long-term dietary changes
What is the protocol for HDGC patients who decline PTG
Annual endoscopic surveillance starting at age 20
with multiple biopsies of visible lesions
and 30 random biopsies from all five stomach zones.
Why is endoscopic surveillance limited in detecting early diffuse gastric cancer in HDGC patients?
Diffuse gastric cancer can infiltrate the submucosa without visible lesions, resulting in a high false-negative rate.
What percentage of CDH1 mutation carriers show T1N0 malignancy upon prophylactic gastrectomy?
92% of patients have T1N0 malignancy, while only 16% were detected through endoscopic surveillance
What additional cancer risk do female CDH1 mutation carriers face?
A high lifetime risk of lobular breast cancer.
What surveillance is recommended for CDH1 mutation carriers at risk for lobular breast cancer?
Annual mammography or breast MRI starting at 30 years of age.
When might bilateral prophylactic mastectomy be considered for CDH1 mutation carriers?
Between 30 and 60 years of age, especially with a family history of multiple cases of lobular breast cancer.
Who should be included in the multidisciplinary team managing HDGC patients?
A surgical oncologist, gastroenterologist, dietician, pathologist, and genetic counselor
What genetic mutations are associated with Lynch syndrome?
Germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2
How does Lynch syndrome contribute to carcinogenesis in organs other than the colon?
MMR gene mutations lead to DNA microsatellite instability, affecting organs like the stomach, uterus, ovaries, and hepatobiliary system.
Which MMR gene mutations are responsible for 90% of microsatellite instability in CRC associated with Lynch syndrome?
Mutations in hMSH2 (chromosome 2p) and hMLH1 (chromosome 3p).
What is the approximate incidence of gastric malignancy in patients with Lynch syndrome?
4% to 8%.
At what age do Lynch syndrome patients with gastric cancer typically present?
Generally before the age of 50.
Which gastric cancer phenotype is most common in Lynch syndrome patients?
The intestinal phenotype.
Who should undergo endoscopic surveillance for gastric cancer in the context of Lynch syndrome?
Patients with HNPCC and a family history of gastric cancer, or carriers of MLH1/MSH2 mutations.
Is prophylactic gastrectomy recommended for Lynch syndrome patients?
No, prophylactic gastrectomy is not recommended; surgery is only indicated for confirmed malignancy.
Revised Bethesda Guidelines (Tested For MSI)
- CRC diagnosed in a patient who is younger than 50
- Presence of synchronous, metachronous colorectal or other HNPCC-associated tumors, regardless of age
- CRC with the MSI-H† histology diagnosed in a patient who is younger than 60 years of age.
- CRC diagnosed in one or more first-degree first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed before 50 years of age
- CRC diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.
Amsterdam Criteria II
- There should be at least three relatives with an HNPCC-associated cancer
(CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis) - One should be a first-degree relative of the other two.
- At least two successive generations should be affected.
- At least one should be diagnosed before 50 years of age.
- Familial adenomatous polyposis should be excluded
- Tumors should be verified by pathologic examination.
What gene mutation characterizes Li-Fraumeni Syndrome (LFS)?
Germline mutations in the TP53 gene on chromosome 17
What protein does the TP53 gene encode, and what is its role?
TP53 encodes the tumor suppressor protein p53, which regulates apoptosis in cells with damaged DNA, often referred to as the “guardian of the genome.”
How does a TP53 mutation contribute to cancer in LFS?
Mutations prevent cell cycle arrest, allowing unregulated cell division with mutated DNA, leading to various malignancies
Which types of cancer are commonly associated with Li-Fraumeni Syndrome (LFS)?
Sarcoma, breast cancer, leukemia, and other cancers that typically develop before age 45.
What is the median age of diagnosis for gastric cancer in LFS carriers?
36 years, though cases have been seen as early as 12 years.
Which part of the stomach is primarily affected by gastric tumors in LFS, and what phenotype is commonly observed?
The proximal stomach with the intestinal phenotype
What screening is emphasized for Li-Fraumeni Syndrome due to its phenotypic diversity?
Primarily breast and colorectal cancer screening, though periodic gastroscopy is advised for those with a family history of gastric cancer
Diagnostic Criteria for Li Fraumeni Syndrome
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What types of benign neoplasms and polyps are found in the gastric mucosa?
Adenomatous
fundic gland
hyperplastic
inflammatory
hamartomatous polyps
Which gastric polyp types are considered premalignant and associated with familial cancer syndromes?
Gastric adenomatous polyps and fundic gland polyps.
What gene mutation characterizes Familial Adenomatous Polyposis (FAP)?
Loss-of-function mutation in the APC tumor suppressor gene on chromosome 5q
What is the primary cancer risk in classic FAP?
100% of individuals with classic FAP develop colorectal cancer (CRC)
How does attenuated FAP differ from classic FAP?
It involves fewer polyps, a later age of adenoma or cancer diagnosis, and a lower CRC risk (80%).
In FAP, where are gastric polyps most commonly located?
Primarily in the body and fundus of the stomach.
What is the risk of developing gastric carcinoma in FAP patients with gastric polyps?
Approximately 2% overall, with a higher likelihood of dysplasia compared to sporadic polyps
When is upper endoscopy recommended for FAP patients?
Starting at ages 21–30, with 3- to 5-year intervals; increased frequency if adenomatous polyps or dysplasia is found
What is the management strategy for polyps larger than 1 cm in FAP?
They should be removed to confirm diagnosis and reduce the risk of malignant transformation
When might prophylactic gastrectomy be considered in FAP?
For patients with FAP or attenuated FAP who have diffuse fundic gland polyps, large polyps, or high-grade dysplasia.
What gene mutation is associated with MUTYH-associated polyposis (MAP)?
Loss-of-function mutation in the MUTYH gene on chromosome 1p
How does MAP differ from FAP in terms of inheritance?
MAP is autosomal recessive, while FAP is autosomal dominant.
What is the recommended screening for gastric polyps in MAP patients?
Endoscopic surveillance starting at ages 25–30, at intervals of 3 to 5 years.
What considerations are suggested for surgical intervention in patients with FAP undergoing gastric resection?
A wider Roux-en-Y anastomosis with a shorter biliary pancreatic limb to facilitate duodenal surveillance, though this may increase bile reflux risk
What role do NSAIDs or acid-suppressive therapy play in FAP?
They can reduce polyp formation, though their impact on overall survival is unknown.
What genetic mutation is associated with Peutz-Jeghers Syndrome (PJS)?
Mutations in the tumor suppressor gene STK11, located on chromosome 19p
How is Peutz-Jeghers Syndrome (PJS) inherited?
PJS is an autosomal dominant disease.
What are the main clinical features of Peutz-Jeghers Syndrome?
Mucocutaneous pigmentation and multiple hamartomatous polyps along the gastrointestinal (GI) tract
Where are polyps most commonly found in patients with PJS?
Small bowel (70-90%), colon (50%), and stomach (25%).
What symptoms can large gastric polyps in PJS cause?
Bleeding, abdominal pain, intussusception, and obstruction
At what age do gastric polyps typically present in PJS patients?
As early as 2 years of age, with a median age of onset at 16 years
What is the lifetime risk of gastric cancer in individuals with PJS?
Up to 30%, with additional increased risks for pancreatic, lung, breast, ovarian, and cervical malignancies
When should screening endoscopy begin in patients with Peutz-Jeghers Syndrome?
Upper and lower endoscopy screening should start by 8 years of age.
What is the surveillance recommendation for PJS patients with no evidence of polyps?
Surveillance is reinitiated by 18 years of age if no polyps are detected.
What are the indications for surgical intervention in PJS patients?
Surgical intervention is recommended for histologically confirmed malignancy or symptomatic polyps.
What annual test is recommended for PJS patients and why?
Annual CBC is recommended to screen for anemia from chronic slow-bleeding polyps.
What pharmacological treatments may help control polyp burden in PJS?
COX-2 inhibitors or mTOR inhibitors, such as rapamycin.
What is Gastric Adenocarcinoma and Proximal Polyposis Syndrome (GAPPS)?
GAPPS is an autosomal dominant disorder characterized by extensive gastric polyposis limited to the body and fundus of the stomach, without polyps in the duodenum or colon
How is GAPPS diagnosed?
Diagnosis requires exclusion of other polyposis syndromes by ruling out mutations in genes like CDH1, MUTYH, and APC
How many polyps characterize GAPPS in affected individuals?
Index cases have more than 100 polyps, while first-degree relatives of index cases have more than 30 polyps.
What is the typical size and risk associated with polyps in GAPPS?
Polyps are usually smaller than 1 cm and may harbor dysplasia, with progression to intestinal-type adenocarcinoma.
What is the relationship between GAPPS and H. pylori infection?
GAPPS shows an inverse association with H. pylori, possibly due to H. pylori being protective or due to low infection rates from altered gastric morphology.
Why are proton pump inhibitors (PPIs) discouraged in GAPPS patients?
PPIs may increase the risk of gastric fundic polyps, so affected individuals are recommended to stop PPI use and undergo repeat endoscopy
What are the management challenges for GAPPS?
Extensive polyposis makes endoscopic surveillance difficult, and total gastrectomy may be considered based on the risk of cancer versus surgical morbidity.
Syndromes Workup and intervention
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Syndromes Workup and intervention
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What preoperative assessments are performed for patients with gastric carcinoma requiring gastrectomy?
Patients undergo nutritional evaluation, radiologic and endoscopic imaging, and PET scans for staging.
How is surgical treatment approached for hereditary gastric cancer with a biopsy-proven malignancy?
Similar to sporadic gastric cancer, the goal is complete resection with a 5 cm surgical margin and frozen sections, especially for diffuse-type cancers.
What are the most important prognostic indicators in hereditary gastric cancer?
Lymph node involvement and tumor invasion depth.
What is the recommended lymphadenectomy for staging in gastric cancer patients?
A D2 lymphadenectomy with more than 15 resected lymph nodes.
What approach is taken for prophylactic total gastrectomy in patients without visible pathology?
A conservative lymph node harvest is performed due to the low risk of metastasis from unremarkable mucosa, with minimally invasive techniques often used.
How can dietary modifications help manage dumping syndrome after gastrectomy?
Consuming multiple small, protein-rich meals daily generally reduces symptoms, and few patients require further medical or surgical treatment.
What dietary recommendations are given during the early recovery phase after gastrectomy?
Patients are advised to eat well-cooked, soft, protein-rich meals, transitioning gradually to their usual diet in smaller, frequent portions.
What nutritional deficiencies are common after total gastrectomy, and why?
Deficiencies in vitamin B12, calcium, folic acid, iron, thiamine, and other minerals may occur due to loss of intrinsic factor and malabsorption
