Gastric cancer

• Gastric cancer is usually adenocarcinoma arising from the stomach lining; it is the fifth most common cancer worldwide and a leading cause of cancer death.
• It is still much commoner in East Asia, Eastern Europe and parts of Latin America than in most Western countries, where distal (non-cardia) disease has been falling while tumours of the proximal stomach and cardia have risen.
• Two main types dominate the picture: the intestinal type, which develops slowly through the Correa cascade (atrophic gastritis, then intestinal metaplasia, then dysplasia), and the diffuse type, which is poorly cohesive and is the form driven by inherited CDH1 mutations.
• It is often advanced at diagnosis: weight loss, early satiety, dyspepsia, dysphagia, vomiting, anaemia and occult bleeding are the usual clues, with spread sometimes announced by Virchow's node, Sister Mary Joseph's nodule, a Krukenberg tumour, Blumer's shelf, acanthosis nigricans or Leser-Trelat syndrome.
• Diagnosis rests on gastroscopy with multiple biopsies (at least six for suspected advanced disease), plus endoscopic ultrasound, staging CT/PET-CT and laparoscopy; testing for HER2, PD-L1, microsatellite instability and Claudin 18.2 now directs modern systemic therapy.
• Curative treatment is surgery (gastrectomy with D2 lymphadenectomy, with endoscopic resection for carefully selected early cancers), backed by perioperative FLOT chemotherapy and, in advanced disease, trastuzumab, nivolumab and zolbetuximab chosen by biomarker.

By the end of this page you should be able to:

1. Explain how the two main histological types of gastric cancer arise and how the Correa cascade links Helicobacter pylori to cancer.
2. Describe the risk factors, geography and recent shift in where in the stomach tumours occur.
3. Recognise the spread of gastric cancer from clinical signs and explain how it is staged.
4. Outline the diagnostic work-up, including the biopsies and biomarkers that change management.
5. Plan curative, adjuvant and palliative treatment, including which patients benefit from trastuzumab, nivolumab or zolbetuximab.
6. Recognise and describe briefly the other gastric neoplasms (MALT lymphoma, GIST, neuroendocrine tumours).
7. Discuss screening in high-incidence regions and the realities of low-resource practice.

Most gastric adenocarcinomas are classified on morphology into two principal groups (the Lauren system) ^[3]:

• Intestinal type. A gland-forming, relatively well-differentiated adenocarcinoma. It is the form linked to chronic mucosal injury and environmental factors, and it usually arises through the Correa cascade described below.
• Diffuse type. Poorly cohesive, often signet-ring cell tumour with deceptive margins and no gland formation. It infiltrates the wall diffusely (classically linitis plastica) and is more often the form seen in younger patients and in familial disease.

Some tumours show mixed features. The distinction matters: the intestinal type tends to be distal, is associated with Helicobacter pylori (H. pylori) and with a better prognosis when caught early; the diffuse type is more aggressive and is the form driven by E-cadherin (CDH1) mutations.

Gastric cancer is the fifth most commonly diagnosed cancer and a leading cause of cancer death worldwide; it remains a disease of older men overall, and US data report nearly twice as many diagnoses in men as in women ^{[1] [14]}. Incidence shows marked geography: rates are highest in East Asia, with high rates also in Eastern Europe, Western Asia and parts of Latin America (in particular the Andean region), and lower rates in most of Western Europe, North America and Africa, where stomach cancer has fallen sharply ^[1].

Within countries, the picture has shifted over decades. In the United States distal (non-cardia) gastric cancer has declined, while adenocarcinoma of the gastric cardia and gastro-oesophageal junction rose markedly from the mid-1970s to the late 1980s and has since remained relatively stable; there has been a more recent increase in non-cardia disease in adults aged 25 to 39 years, and in tumour rates in younger Hispanic women ^[3]. These changes reflect falling H. pylori infection in childhood, changing food preservation, and the rise of reflux-related proximal disease ^[1].

The intestinal type is the endpoint of a long chain ^[1]:

1. Chronic H. pylori infection inflames the gastric mucosa.
2. Chronic inflammation progresses to atrophic gastritis (loss of normal glands).
3. Atrophic mucosa is replaced by intestinal metaplasia.
4. Dysplasia develops.
5. Invasive adenocarcinoma.

Because H. pylori is the principal driver, eradicating it reduces gastric cancer risk; eradication is the single best preventive measure where infection is endemic ^[1].

Acknowledged factors include ^{[1] [3]}:

• H. pylori infection (the strongest and most modifiable; strongest for distal and middle gastric cancer).
• Diet: high in salted, smoked or preserved foods; low in fruit and vegetables.
• Tobacco smoking (and smoking reduces the effectiveness of H. pylori eradication).
• Pernicious anaemia and chronic atrophic gastritis with intestinal metaplasia.
• Previous gastric surgery, especially partial gastrectomy, with bile reflux.
• Epstein-Barr virus infection.
• Family history and inherited syndromes: hereditary diffuse gastric cancer (germline CDH1), Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers, juvenile polyposis, Li-Fraumeni, gastric adenocarcinoma with proximal polyposis of the stomach.
• Menetrier disease and, more rarely, adenomatous gastric polyps.
• Obesity and gastro-oesophageal reflux for tumours of the proximal stomach and cardia.

A subset carries a germline CDH1 mutation that produces diffuse signet-ring gastric cancer at a young age. HDGC carrier management follows specialist consensus guidance, and prophylactic total gastrectomy is standard for many carriers after careful counselling; families with a proved mutation should be managed in a specialist centre ^[3].

Most of what the disease does follows from three things: it grows silently in a hollow organ; it spreads early by lymphatic and peritoneal routes as well as blood; and the tumour is biologically aggressive by the time it declares itself.

• Local growth. The stomach is distensible and its mucosa poorly sensitive, so early tumours rarely hurt. By the time there are symptoms there is usually substantial wall or nodal disease.
• Lymphatic spread is early and extensive, which is why gastrectomy must include a comprehensive node dissection (see Management).
• Peritoneal spread explains malignant ascites, Krukenberg tumours (below), Blumer's shelf (below) and positive peritoneal washings, which is why staging laparoscopy is used for apparently non-metastatic disease.
• Haematogenous spread most often targets liver (via portal venous drainage), then lung, bone and adrenals.

• Gross. Advanced tumours are ulcerated, polypoid or an infiltrating (linitis plastica) mass; mucinous and signet-ring tumours may be deceptively subtle on endoscopy.
• Microscopic. Intestinal-type shows gland formation with variable differentiation; diffuse-type shows poorly cohesive signet-ring cells. HER2 (ERBB2) overexpression, PD-L1 expression, microsatellite instability and Claudin 18.2 positivity are now reported because they select therapy ^[2].
• Early gastric cancer is carcinoma confined to mucosa or submucosa, regardless of node status; this is the window in which endoscopic cure is possible.

Early disease produces indigestion and stomach discomfort, a bloated feeling after eating, mild nausea, loss of appetite and heartburn; these are easily mistaken for dyspepsia or reflux and are usually investigated only if persistent or accompanied by alarm features ^{[1] [2]}. Advanced disease adds:

• Weight loss for no known reason.
• Early satiety and dysphagia, especially with proximal tumours.
• Vomiting, which may be haematemesis if the tumour bleeds.
• Anaemia and fatigue from chronic occult or overt blood loss.
• Abdominal pain, distension, ascites or jaundice with spread.

These physical signs mean advanced disease and should be looked for in every patient ^{[7] [8] [10] [11] [12]}:

• Virchow's node: a hard, palpable left supraclavicular lymph node, most often from gastric cancer ^[7].
• Sister Mary Joseph's nodule: a firm nodule in the umbilicus, a cutaneous metastasis from an intra-abdominal cancer ^[9].
• Krukenberg tumour: metastatic disease in the ovary, most often from the stomach, which can be the first presenting sign; mean survival after diagnosis is about 14 months ^[8].
• Blumer's shelf: a metastatic deposit in the recto-uterine or recto-vesical pouch, palpable on digital rectal (or pelvic) examination ^[10].
• Malignant acanthosis nigricans: velvety, hyperpigmented plaques, especially with tripe palms, strongly suggesting an internal malignancy; it is a paraneoplastic skin marker most classically linked to gastric adenocarcinoma ^[11].
• Leser-Trelat sign: a sudden eruption of seborrhoeic keratoses, a paraneoplastic clue to an underlying GI cancer ^[12].

Look for epigastric tenderness or a mass, hepatomegaly from metastases, umbilical or Virchow nodes, an ovarian mass, ascites, and signs of anaemia or malnutrition.

A persistent gastric ulcer that fails to heal, or dyspepsia in a patient over 55 with new onset or alarm features, must be biopsied to exclude cancer ^{[2] [3]}.

First-line and confirmatory

• Upper gastrointestinal endoscopy is the diagnostic test of choice; it allows visual inspection, mucosal staging and biopsy, and resection of early tumours ^{[2] [3]}.
• Multiple biopsies from the lesion and surrounding mucosa (at least six for suspected advanced cancer) ^[13].
• Biopsy of every suspicious ulcer and every gastric mass; early and scirrhous tumours can sit beneath normal mucosa, so repeat when suspicion is high ^{[3] [13]}.
• Endoscopic ultrasound (EUS) is the most accurate local (T and N) staging test before surgery when metastatic disease is not already obvious ^{[2] [3]}.
• Staging CT of chest, abdomen and pelvis (with PET-CT where useful) for metastatic disease (liver, lung, bone, peritoneum) ^{[2] [3]}.
• Staging laparoscopy with peritoneal washings in anyone with T3/T4 or node-positive disease before curative surgery, because peritoneal disease changes the plan entirely ^[3].

Biomarkers (tissue)

These are now routine in advanced or metastatic disease and, increasingly, at diagnosis for all ^[2]:

• HER2 immunohistochemistry/ISH (selects trastuzumab when positive).
• PD-L1 expression (combined positive score, CPS) by immunohistochemistry (informs nivolumab use).
• Microsatellite instability / mismatch repair deficiency (predicts benefit from immune checkpoint inhibitors).
• Claudin 18.2 positivity (at least 75% of tumour cells with moderate-to-strong membranous staining selects zolbetuximab) ^[4].

Gastric cancer is staged by the AJCC TNM system (8th edition), separating T (depth of wall invasion: T1a/b, T2, T3, T4a/b), N (0/1/2/3a/3b by node count) and M (M1 distant or peritoneal disease), which maps to stages 0 through IV ^[3]. The two operational points are: (1) stage 0/Tis disease is curable endoscopically, and (2) any M1 disease is palliative.

All patients are discussed in a multidisciplinary team (gastroenterology, surgery, oncology, radiology, pathology). Nutrition, iron/B12 replacement, thromboprophylaxis and pain control should be addressed early.

Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is curative for selected stage 0 / intramucosal lesions (Tis or T1a, up to 2 cm, predominantly differentiated type, without ulceration) with a low risk of nodal spread; the larger specimen from ESD also improves pathological staging ^[3]. Strict selection and an experienced endoscopist are essential; incomplete or potentially lymph-node-bearing lesions are sent for surgery ^[3].

Radical gastrectomy (subtotal or total, depending on tumour site and extent) with D2 lymphadenectomy is the standard curative operation. Regional lymphadenectomy is performed with all resections; splenectomy is not routine ^[3]. Subtotal gastrectomy is preferred when margins allow, with equivalent survival and less morbidity than total gastrectomy ^[3].

For resectable stage II-III and selected stage IB disease, perioperative FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel, four 2-week cycles before and after surgery) is superior to older anthracycline-based regimens: in FLOT4, median overall survival rose from 35 to 50 months (hazard ratio 0.77) and R0 resection from 78% to 85% ^[3]. Standard curative regimens therefore now default to FLOT in fit patients ^[3].

Where radiation is used, the classic SWOG-directed strategy is surgery followed by chemoradiation (5-FU/leucovorin with concurrent 45 Gy), which improved median survival from 27 to 35 months versus surgery alone ^[3].

• HER2-positive: trastuzumab (Herceptin) plus platinum/fluoropyrimidine chemotherapy. Dose per the product label: 8 mg/kg intravenously loading over 90 minutes, then 6 mg/kg intravenously every 3 weeks until progression ^[5]. Benefit was established in ToGA ^[3].
• PD-L1-positive / CPS at or over 5: nivolumab (Opdivo) with fluoropyrimidine- and platinum-containing chemotherapy. Label doses are 360 mg intravenously every 3 weeks or 240 mg intravenously every 2 weeks, keyed to the chemotherapy schedule; CheckMate-649 showed survival benefit with CPS at or over 5 ^{[6] [3]}.
• Claudin 18.2-positive, HER2-negative: zolbetuximab (Vyloy) with mFOLFOX6 or CAPOX (label dose 800 mg/m² intravenously first dose, then 600 mg/m² intravenously every 3 weeks or 400 mg/m² intravenously every 2 weeks) ^[4]. In the label, zolbetuximab is given before chemotherapy on the same day; mFOLFOX6 in the trials was oxaliplatin 85 mg/m², folinic acid 400 mg/m², 5-FU 400 mg/m² bolus plus 2400 mg/m² infusion, repeated with the antibody every 3 weeks ^[4]. Median progression-free survival improved over chemotherapy alone (SPOTLIGHT, GLOW) ^[4].
• HER2-negative and non-Claudin18.2 disease: standard platinum + fluoropyrimidine doublet (FOLFOX, CAPOX or cisplatin + 5-FU/capecitabine), with further lines including paclitaxel + ramucirumab, trifluridine/tipiracil and trastuzumab deruxtecan in HER2-positive later lines according to local guidance ^[3].

For obstruction or bleeding: endoscopic stenting, bypass or palliative surgery, radiotherapy for pain or bleeding, and endoscopic haemostasis. Best supportive care and nutrition support (enteral where possible) run throughout ^[3].

Any suspected gastric cancer on endoscopy; any early gastric cancer amenable to endoscopic resection for a specialist endoscopist; any locally advanced disease for multidisciplinary tumour board review; and any sign of spread for oncology input.

• Bleeding and iron/folate deficiency from the primary tumour.
• Gastric outlet or cardia obstruction, with vomiting, cachexia and dehydration.
• Perforation (rare but catastrophic) or fistula.
• Metastatic complications: liver failure from metastases, bone pain or fracture, spinal cord compression, malignant ascites, malnutrition.
• Treatment complications: chemotherapy myelosuppression and nausea; major morbidity and (small) mortality from gastrectomy; late nutritional deficiencies (B12, iron, calcium) after total gastrectomy require lifelong supplementation and monitoring.
• Microsatellite-unstable disease responds well to immunotherapy but can be paradoxically complicated by immune-related adverse events.

Prognosis is determined by stage and location. In localized distal gastric cancer more than half of patients can be cured, but early-stage disease accounts for only 10% to 20% of cases diagnosed in the West; the 5-year overall survival of regional disease ranges from almost none when disseminated to roughly half when localized. Even with apparent localized disease, proximal gastric cancer carries a 5-year survival of only 10% to 15% ^[3]. Node involvement, depth of invasion, diffuse type, signet cells and poor performance status all worsen outcome ^[3].

• H. pylori eradication in infected individuals, especially high-risk families, reduces risk ^[1].
• Dietary advice (less salted/smoked, more fruit and vegetables), stopping smoking and (where relevant) reducing alcohol ^[1].
• Screening is routine in Japan and South Korea (population-based high-quality endoscopy) because it detects early, curable disease; no major Western guideline recommends screening the average-risk population ^[3].
• The AGA clinical practice update recommends considering screening endoscopy in US residents who are first-generation immigrants from high-incidence regions (East Asia, Eastern Europe, Andean Latin America, other groups at moderate-high incidence), in those with a family history of gastric cancer in a first-degree relative, and in selected hereditary cancer or polyposis syndromes (including Lynch syndrome, FAP, Peutz-Jeghers and Li-Fraumeni).
• In hereditary diffuse gastric cancer carriers, prophylactic total gastrectomy and/or careful 6- to 12-monthly surveillance is advised in specialist centres.

• Children and young adults. Diffuse disease in the young should raise hereditary diffuse gastric cancer; gastric adenocarcinoma is rare in childhood.
• Pregnancy. Decisions are individualised; where metastatic disease presents with acute complications in pregnancy, multidisciplinary obstetric-oncology input is required. Treatment algorithms for pregnant women are not well established; for localized, resectable disease, surgery may be timed to fetal maturity where safe.
• Older adults. Comorbidity limits surgery; the same perioperative FLOT benefit is less clear in frail or very elderly patients, and palliation is often the kinder option.
• Immunocompromised patients (Lynch syndrome, transplant recipients) need lower thresholds for endoscopy.

• H. pylori is the commonest identifiable cause; test and treat where inexpensive tests (stool antigen, urea breath test) or endoscopy are available ^[1].
• A barium meal and careful clinical exam are imperfect but usable when endoscopy is scarce; any gastric ulcer should be followed to healing.
• Total gastrectomy with D2 dissection requires specialist surgery and (often) blood products; refer early to centres that can perform it.
• Chemotherapy access is often the binding constraint; 5-FU, leucovorin and platinum (FOLFOX/CAPOX) are cheaper and widely used backbones; trastuzumab, nivolumab and zolbetuximab may be unavailable.
• Palliation (endoscopic stenting, radiotherapy or bypass where available, good symptom control) is often the realistic goal.
• Regional endoscopy outreach and short training courses in systematic gastric inspection raise diagnostic yield more than expensive equipment.

GISTs account for the second commonest gastric neoplasm after adenocarcinoma and are grouped with sarcomas in staging; see your local sarcoma pathway ^[3].

• Gastric adenocarcinoma is the fifth most common cancer worldwide and a leading cause of cancer death, with highest rates in East Asia, Eastern Europe, Western Asia and Andean Latin America ^{[1] [14]}.
• Non-cardia (distal) disease is falling in much of the West; proximal/cardia tumours have risen and carry the worse prognosis.
• Intestinal type develops through the Correa cascade driven by H. pylori; diffuse type is often signet-ring cell and is the form driven by CDH1 mutations, with prophylactic gastrectomy for carriers.
• Key modifiable risks are H. pylori infection, salted/smoked/preserved food, low fruit and vegetables and smoking; pernicious anaemia, EBV, prior gastric surgery and Lynch/CDH1 also matter ^[1].
• Presentation is late and subtle: dyspepsia, weight loss, early satiety, vomiting, dysphagia, anaemia; signs of spread include Virchow's node, Sister Mary Joseph's nodule, Krukenberg tumour, Blumer's shelf, acanthosis nigricans and Leser-Trelat syndrome.
• Diagnosis is by upper endoscopy with at least six biopsies for suspected advanced disease, plus EUS, CT/PET-CT, staging laparoscopy and biomarkers (HER2, PD-L1, MSI, Claudin 18.2) ^{[2] [3]}.
• Early gastric cancer (Tis/T1a, well differentiated, up to 2 cm, no ulceration) can be cured endoscopically; otherwise radical gastrectomy with D2 lymphadenectomy is standard ^[3].
• Perioperative FLOT improves median survival from 35 to 50 months over older anthracycline regimens (FLOT4) ^[3].
• Advanced disease is treated by biomarker: trastuzumab 8 then 6 mg/kg every 3 weeks for HER2-positive disease; nivolumab 360 mg every 3 weeks or 240 mg every 2 weeks for PD-L1 CPS at or over 5; zolbetuximab 800 then 600 mg/m² every 3 weeks for Claudin 18.2-positive, HER2-negative disease ^{[4] [5] [6]}.
• Endoscopy-based screening reduces mortality in Japan and Korea; elsewhere it is offered selectively to high-risk groups and carriers.

None yet published on MedGrasp for this topic.