Adenocarcinoma of the stomach; H. pylori-driven; often diagnosed late with poor prognosis.
Also known as: gastric cancer, stomach cancer, gastric adenocarcinoma
Overview
Malignant neoplasm of the stomach, predominantly adenocarcinoma (>90%). Lauren classification: intestinal type (well-differentiated, glandular, associated with H. pylori/atrophic gastritis) and diffuse type (poorly cohesive, signet-ring cells, linitis plastica, hereditary CDH1 mutation in some).
Epidemiology
~27,000 new cases and ~11,000 deaths annually in the US. Worldwide, 5th most common cancer; high incidence in East Asia, Eastern Europe, and Latin America. 5-year survival ~33% (US); >60% in countries with screening (Japan, South Korea).
Try two board-style Gastric Cancer questions
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Question 1GastrointestinalMedium
A 50-year-old male with metastatic gastric adenocarcinoma (HER2-negative, programmed death-ligand 1 (PD-L1) combined positive score (CPS) 15, microsatellite stable (MSS) disease) asks about first-line treatment. Which of the following is the preferred first-line systemic regimen?
APembrolizumab as single-agent immunotherapy
BZolbetuximab plus oxaliplatin-based chemotherapy
CNivolumab plus oxaliplatin-based chemotherapy
DFluoropyrimidine plus oxaliplatin chemotherapy
Reveal answer & full explanation
Correct answer: C — Nivolumab plus oxaliplatin-based chemotherapy
APembrolizumab as single-agent immunotherapy
BZolbetuximab plus oxaliplatin-based chemotherapy
CNivolumab plus oxaliplatin-based chemotherapy✓
DFluoropyrimidine plus oxaliplatin chemotherapy
Why nivolumab plus oxaliplatin-based chemotherapy is correct
This patient has human epidermal growth factor receptor 2 (HER2)-negative disease with programmed death-ligand 1 (PD-L1) combined positive score (CPS) 15, at or above the threshold of CPS 5
CheckMate 649 trial: nivolumab plus FOLFOX (fluorouracil, leucovorin, oxaliplatin) or XELOX (capecitabine, oxaliplatin) improved overall survival (OS) from 11.1 to 14.4 months (hazard ratio (HR) 0.71) in HER2-negative, PD-L1 CPS 5 or higher gastric adenocarcinoma
Why the others are wrong
Pembrolizumab as single-agent immunotherapy — checkpoint inhibitor monotherapy is reserved for microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors; this tumor is microsatellite stable, so immunotherapy without a chemotherapy backbone is inadequate first-line treatment (right-drug-class-wrong-biomarker)
Zolbetuximab plus oxaliplatin-based chemotherapy — a legitimate first-line regimen, but only for claudin 18.2-positive tumors (SPOTLIGHT and GLOW); claudin 18.2 status is never reported here, whereas the PD-L1 CPS of 15 directly supports adding nivolumab (right-concept-untested-biomarker)
Fluoropyrimidine plus oxaliplatin chemotherapy — a doublet is the chemotherapy backbone of first-line therapy, but at PD-L1 CPS 5 or higher the addition of nivolumab improved overall survival in CheckMate 649, so the doublet is no longer the preferred regimen for this patient (premature closure)
Additional high-yield points
Microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) disease: pembrolizumab monotherapy or plus chemotherapy, with markedly improved outcomes
Claudin 18.2 positive: zolbetuximab plus capecitabine-oxaliplatin (CAPOX) per SPOTLIGHT trial (FDA approved 2024)
Ramucirumab plus paclitaxel: second-line standard of care
Question 2GastrointestinalMedium
A 68-year-old man presents with 3 months of epigastric discomfort, early satiety, and a 9 kg unintentional weight loss. He has a remote history of Helicobacter pylori infection that was never treated. Vital signs are normal. Examination shows mild epigastric tenderness without a palpable mass. Laboratory studies reveal hemoglobin 9.8 g/dL with a mean corpuscular volume of 76 fL and a positive fecal occult blood test. Which of the following is the most appropriate next diagnostic test?
ACT scan of the abdomen and pelvis
BSerum carcinoembryonic antigen test
CEndoscopic ultrasound with aspiration
DUpper endoscopy with mucosal biopsy
Reveal answer & full explanation
Correct answer: D — Upper endoscopy with mucosal biopsy
ACT scan of the abdomen and pelvis
BSerum carcinoembryonic antigen test
CEndoscopic ultrasound with aspiration
DUpper endoscopy with mucosal biopsy✓
Why Upper endoscopy with mucosal biopsy is correct
An older adult with new dyspepsia, weight loss, and iron-deficiency anemia (microcytic, MCV 76, positive fecal occult blood test) has alarm features that mandate prompt evaluation for gastric cancer.
Upper endoscopy with biopsy is the diagnostic study of choice because it directly visualizes any ulcer or mass and provides tissue for the histologic confirmation required to establish the diagnosis.
Per ACG dyspepsia guidance, patients over 60 or with alarm features (weight loss, anemia, GI bleeding, dysphagia) should undergo endoscopy rather than empiric therapy.
Why the others are wrong
CT scan of the abdomen and pelvis is used for staging after a tissue diagnosis is made; it cannot confirm malignancy and is the wrong sequence as the first test.
Endoscopic ultrasound with aspiration refines T and N staging and samples regional nodes once cancer is confirmed; it is not the initial step before the primary lesion has been identified and biopsied.
Serum carcinoembryonic antigen test (like CA 19-9 and CA 72-4) is nonspecific and not diagnostic; it may aid surveillance but cannot establish or exclude gastric cancer.
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Older adult with new dyspepsia, weight loss, and iron-deficiency anemia.
Differential diagnosis
Peptic ulcer disease — Benign ulcers can mimic; biopsy ALL gastric ulcers; repeat EGD to confirm healing
Gastric lymphoma (MALT or DLBCL) — H. pylori association; biopsy with immunohistochemistry; MALT may regress with H. pylori treatment
GIST (gastrointestinal stromal tumor) — Submucosal mass; KIT/PDGFRA+; biopsy via EUS; treat with imatinib
Functional dyspepsia — Normal EGD; same symptoms; diagnosis of exclusion
Gastroparesis — Early satiety, vomiting undigested food; gastric emptying study
Pancreatic cancer (with gastric outlet obstruction) — Painless jaundice, weight loss; pancreatic mass on CT
Diagnostic workup
Diagnostic criteria
Histologic confirmation on biopsy. HER2, MMR/MSI, PD-L1 testing on all advanced/metastatic cases to guide systemic therapy. Staging by AJCC 8th edition TNM.
Labs
CBC (microcytic anemia)
BMP, LFTs, albumin
H. pylori testing
CEA, CA 19-9, CA 72-4 — not diagnostic; may aid in surveillance
Imaging
Upper endoscopy with biopsy — diagnostic; multiple biopsies of any ulcer or mass
Endoscopic ultrasound (EUS) — accurate T and N staging; allows FNA of lymph nodes
CT chest/abdomen/pelvis with contrast — staging, metastases
PET-CT — selected cases; useful for detecting distant disease
Diagnostic laparoscopy with peritoneal washings — recommended for T3/T4 or node-positive disease before definitive therapy (10-30% have occult peritoneal disease)
Diagnostic algorithm
Lauren Subtype
Intestinal
Diffuse
Histology
Well-differentiated glands
Poorly cohesive, signet-ring cells
Distribution
Sporadic, regional clusters
More uniform global incidence
Precursor
H. pylori → atrophic gastritis → metaplasia → dysplasia
Often de novo; CDH1 mutation in hereditary
Age
Older
Younger
Sex
Male > female
Equal
Prognosis
Better
Worse (linitis plastica)
Pattern
Mass lesion
Diffuse infiltration
Lauren classification of gastric adenocarcinoma — intestinal vs diffuse type.
Treatment
First-line
Multidisciplinary management
H. pylori eradication if present
Stage-directed treatment (see by_subtype)
Early gastric cancer (T1a, well-differentiated, non-ulcerated, <2 cm)
Endoscopic submucosal dissection (ESD) — curative in carefully selected lesions
Surveillance EGD
Locally advanced (T2-T4 or node-positive)
Perioperative chemotherapy with FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) × 4 cycles before and after surgery — current standard (FLOT4 trial)
Total or subtotal gastrectomy with D2 lymphadenectomy
Adjuvant chemoradiation (capecitabine + RT) — alternative for patients who did not receive neoadjuvant therapy (MAGIC/INT-0116)
Biopsy ALL gastric ulcers — 4% are malignant; repeat EGD in 8-12 weeks to confirm healing.
H. pylori eradication reduces gastric cancer risk; effect strongest when treated before atrophic gastritis or metaplasia develops.
FLOT regimen replaced ECF as preferred perioperative chemotherapy for resectable disease (FLOT4 trial).
HER2-positive metastatic gastric cancer benefits from trastuzumab — test all advanced cases.
Diagnostic laparoscopy detects peritoneal disease missed by CT in 10-30% of locally advanced cases.
Linitis plastica (diffuse infiltration) carries the worst prognosis and is typically not amenable to curative resection.
Hereditary diffuse gastric cancer (CDH1 mutation): consider prophylactic total gastrectomy in carriers.
Japan/Korea perform screening EGD due to high prevalence; not cost-effective in low-incidence US population.
References
NCCN 2024 — NCCN Guidelines Version 2.2024 — Gastric Cancer
FLOT4 — Al-Batran SE et al. Perioperative chemotherapy with FLOT versus ECF/ECX for resectable gastric or GEJ adenocarcinoma. Lancet 2019;393:1948-1957
ToGA Trial — Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or GEJ cancer. Lancet 2010;376:687-697
MAGIC Trial — Cunningham D et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. NEJM 2006;355:11-20
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