Tumors of stomach

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Tumors of the Stomach

The stomach can give rise to several distinct tumor types. About 90% of gastric malignancies are adenocarcinomas. The remainder consist of gastrointestinal stromal tumors (GISTs), lymphomas, neuroendocrine tumors (NETs), and rare others. Each has a distinct biology, clinical behavior, and treatment approach.

1. Gastric Adenocarcinoma

Epidemiology

Since the 1920s, the incidence of gastric cancer has steadily declined, coinciding with widespread refrigeration and reduced food preservation. Despite this, globally it remains the third most common cause of cancer mortality. High-incidence areas include China, Korea, Japan, Chile, and Eastern Europe. In 2023, approximately 27,500 new cases and 11,130 deaths were estimated in the United States alone. Notably, while distal gastric cancer rates have fallen in Western countries, adenocarcinoma of the gastroesophageal junction (GEJ) has markedly increased over recent decades, including in younger patients.

Harrison's Principles of Internal Medicine 22E, p. 689

Risk Factors

Factor	Detail
H. pylori infection	Present in ~50% of humans; drives chronic inflammation; increases cancer risk especially with high-risk CagA+ strains
Diet	High-nitrate foods (smoked, salted, dried); protective effect of fresh fruits/vegetables less robust than once thought
EBV infection	Associated with ~10% of gastric cancers; distinct molecular phenotype
CDH1 germline mutations	Markedly increase risk for diffuse (signet cell) subtype; prophylactic gastrectomy is an option
Pernicious anemia / autoimmune gastritis	Hypochlorhydria promotes bacterial overgrowth and carcinogenesis
Prior gastric surgery	Achlorhydria, bile reflux, and H. pylori promote remnant gastric cancer
Obesity	Promotes GEJ cancer via reflux; not the sole cause
MSI/hypermutation	MLH1 silencing; Gastric-CIMP phenotype

Yamada's Textbook of Gastroenterology, 7th ed., pp. 1099-1104
Harrison's, p. 690

Classification

Lauren Classification (histological - still widely used)

Intestinal type (~50%): Well-differentiated; malignant cells form glandular-like structures; associated with H. pylori, atrophic gastritis, intestinal metaplasia
Diffuse type (~33%): Poorly differentiated; cells infiltrate through the gastric wall without cohesion, causing a rigid "leather bottle" stomach (linitis plastica); associated with CDH1/E-cadherin mutations; signet ring cells are the pathognomonic feature
Mixed/unclassified (~17%)

Intestinal type gastric adenocarcinoma (H&E):

Intestinal type gastric adenocarcinoma - glandular structures with dense stroma

Fig. 52.1 - Intestinal type: glandular structures of varying differentiation within a fibrous stroma (Yamada's Textbook of Gastroenterology)

Diffuse type gastric cancer (H&E):

Diffuse type gastric cancer with signet ring cell morphology - lack of cellular cohesion

Fig. 52.2 - Diffuse type: lack of cellular cohesion, invasion throughout stroma, signet ring cell morphology (Yamada's Textbook of Gastroenterology)

TCGA Molecular Classification (4 subtypes)

Molecular/genomic subtypes of gastric carcinoma showing CIN, EBV, GS, and MSI categories with their genomic features mapped to gastric locations

FIGURE 35-2 - Molecular/genomic characterization of gastric carcinoma subtypes (Harrison's Principles of Internal Medicine 22E)

Subtype	Key Features	Location
EBV	PIK3CA mutation, PD-L1/2 overexpression, EBV-CIMP, immune cell signaling	Fundus/body
MSI (Microsatellite instability)	Hypermutation, Gastric-CIMP, MLH1 silencing	Antrum/pylorus
GS (Genomically stable)	Diffuse histology, CDH1/RHOA mutations, CLDN18-ARHGAP fusion, cell adhesion defects	Antrum/pylorus
CIN (Chromosomal instability)	Intestinal histology, TP53 mutation, RTK-RAS activation	GEJ/cardia

Clinical Features

Symptoms:

Vague upper abdominal discomfort (most common early symptom)
Hematemesis or melena
Anorexia and early satiety
Unexplained weight loss
Dysphagia/odynophagia (GEJ tumors)
Iron-deficiency anemia from occult bleeding

Classic physical exam findings (all indicate advanced disease):

Virchow's node - left supraclavicular adenopathy
Sister Mary Joseph nodule - periumbilical mass (peritoneal spread)
Blumer's shelf - pelvic mass on rectal exam
Krukenberg tumor - ovarian metastasis
Ascites
Harrison's, p. 690

Diagnosis & Staging

Upper endoscopy + biopsy - primary diagnostic tool; intestinal type shows ulcerated mass; diffuse type may show only thickened rugae (initial biopsies often negative - EUS-guided biopsy needed)
EUS - depth of invasion and regional lymph node staging
CT chest/abdomen/pelvis - metastatic disease
Diagnostic laparoscopy - to rule out peritoneal metastases before curative resection
HER2/ERBB2 testing, PD-L1 CPS, MSI testing - guides targeted/immune therapy selection

Treatment

Localized disease (stages I-III):

Surgery remains the cornerstone - total or subtotal gastrectomy with D1+ or D2 lymphadenectomy (D2 standard in high-volume centers)
Perioperative chemotherapy (before + after surgery): platinum + fluorinated pyrimidine (e.g., FOLFOX or FLOT regimen) is standard-of-care
Preoperative chemoradiation often used for GEJ tumors
For MSI-high/hypermutated tumors: PD-1/PD-L1 immune checkpoint blockade is increasingly used
CDH1 germline mutation carriers: prophylactic gastrectomy is an option

Metastatic/palliative disease:

Chemotherapy backbone: platinum + fluoropyrimidine (FOLFOX, XELOX)
Nivolumab + chemotherapy (CheckMate 649 trial): significantly improved overall survival vs. chemotherapy alone in HER2-negative patients, especially with PD-L1 CPS >5 - now a first-line standard
Trastuzumab for HER2-overexpressing/amplified cancers (ToGA trial)
DOTATATE-guided therapy for NETs (see below)
Harrison's, pp. 692-695

2. Gastrointestinal Stromal Tumors (GISTs)

GISTs are rare mesenchymal tumors arising from the interstitial cells of Cajal (pacemaker cells of the gut wall). The stomach is the most common location (>60% of all GISTs). The majority (>70%) are benign; malignant GISTs metastasize to the peritoneal cavity and liver.

Pathology & Molecular Biology

CD117 (c-KIT) positive by immunohistochemistry in >95% of cases - the key diagnostic marker
Other markers: CD34, vimentin, smooth muscle actin
Molecular driver: activating mutation in KIT receptor tyrosine kinase → ligand-independent constitutive activation of MAPK pathway
Minority have PDGFRA mutations (mutually exclusive with KIT)
A subset are "wild type" (no KIT/PDGFRA mutation) - CD117 negativity does not exclude diagnosis

Clinical Presentation

GI bleeding or anemia (when ulceration occurs)
Gastric outlet obstruction (distal GISTs)
Dysphagia (proximal GISTs)
~20% found incidentally on endoscopy or imaging
Patients have increased risk of synchronous and metachronous malignancies

Treatment

Surgical resection with curative intent is primary treatment
Imatinib (tyrosine kinase inhibitor targeting KIT/PDGFRA): first-line for unresectable, metastatic, or recurrent GIST; also used adjuvantly
Sunitinib: second-line after imatinib resistance
Prognostic factors: tumor size, location, mitotic index, presence of rupture
Resistance develops due to kinase mutations
Yamada's Textbook of Gastroenterology, 7th ed., pp. 1099

3. Primary Gastric Lymphoma

Gastric lymphoma accounts for ~5% of gastric malignancies and is the most common extranodal lymphoma site. There is a strong geographic correlation between H. pylori prevalence and gastric lymphoma incidence.

MALT Lymphoma (Low-grade)

Pathogenesis:

H. pylori infection → chronic gastritis
Accumulation of CD4+ T cells and B cells in gastric lamina propria
H. pylori antigens → T-cell activation → IL-2 release → B-cell proliferation
Progressive genetic rearrangements → IL-2-independent B-cell proliferation
Cumulative genetic defects → progression to high-grade lymphoma

Key features:

H. pylori present in 90% of gastric MALT lymphoma cases
Resembles Peyer patches histologically
Lymphoepithelial lesions are characteristic (lymphoma cells invading gastric glands)
Often multifocal
Less likely to penetrate transmurally or involve lymph nodes vs. high-grade

Treatment:

H. pylori eradication is first-line antineoplastic therapy
Complete regression reported in 70-100% of cases with antibiotics
Median time to complete response: 5 months
Radiation and chemotherapy for antibiotic failures or H. pylori-negative cases
About 40% of gastric lymphomas are low-grade MALT type

Non-MALT Lymphomas (High-grade)

Most are diffuse large B-cell lymphomas (DLBCL) (previously called "high-grade MALT lymphoma")
More aggressive behavior, worse prognosis
Other histologies: mantle cell, follicular, peripheral T-cell lymphomas
Prognosis closely linked to stage at diagnosis
Treatment: chemotherapy (R-CHOP); gastrectomy no longer routinely recommended (chemoradiation preferred over surgery)
Mulholland & Greenfield's Surgery, 7th ed., pp. 2342
Harrison's Principles of Internal Medicine 22E

4. Gastric Neuroendocrine Tumors (NETs / Carcinoid Tumors)

Gastric NETs represent 7-9% of all gastrointestinal NETs but account for <1% of gastric neoplasms. They are classified by WHO into:

Well-differentiated NETs (grades 1-3; graded by Ki-67% positivity)
Poorly differentiated neuroendocrine carcinomas (NECs) - fully malignant
Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs)

Types of Gastric NETs

Type	Association	Behavior
Type 1	Autoimmune gastritis with hypergastrinemia (most common ~70-80%)	Usually small, multiple, benign course; low malignant potential
Type 2	MEN-1 / Zollinger-Ellison syndrome with hypergastrinemia	Less common; intermediate malignant potential
Type 3	Sporadic, no hypergastrinemia	Single large lesion; more aggressive; metastasizes

Diagnosis & Treatment

Upper endoscopy + biopsy: initial evaluation
EUS: depth of invasion, lymph node assessment
DOTATATE scan (Ga-68 or Cu-64): somatostatin receptor imaging for metastatic disease - guides both staging and PRRT therapy
FDG-PET/CT: for high-grade NECs

Treatment:

Type 1 small tumors: endoscopic resection (EMR/ESD)
Larger or higher-grade: surgical resection
Small-cell/large-cell NECs: chemotherapy ± radiation (similar regimens to small-cell lung cancer)
Metastatic DOTATATE-avid NETs: somatostatin receptor-targeted therapy (octreotide/lanreotide) or PRRT (Peptide Receptor Radionuclide Therapy)
Harrison's Principles of Internal Medicine 22E, pp. 695-696

Summary Table: Gastric Tumors at a Glance

Tumor Type	Frequency	Key Marker / Mutation	H. pylori Link	Primary Treatment
Adenocarcinoma (intestinal)	~60% of gastric Ca	Lauren intestinal; TP53, RTK-RAS	Strong	Surgery ± periop chemo
Adenocarcinoma (diffuse)	~20-25% of gastric Ca	CDH1/E-cadherin, signet ring cells	Moderate	Surgery; CDH1 carriers: prophylactic gastrectomy
GIST	~2-3%	CD117 (KIT), PDGFRA	None	Surgery; imatinib
MALT lymphoma	~4-5%	Lymphoepithelial lesions	Very strong (90%)	H. pylori eradication
DLBCL	~3-4%	B-cell markers	Moderate	R-CHOP chemotherapy
Gastric NET (type 1)	~1%	Chromogranin A, synaptophysin	Indirect (autoimmune)	Endoscopic resection
Gastric NET (type 3)	Rare	DOTATATE avidity	None	Surgery; PRRT

Sources:

Harrison's Principles of Internal Medicine 22E (2025), Chapter 35 - Tumors of the Stomach, pp. 689-696
Yamada's Textbook of Gastroenterology, 7th ed., Chapter 52 - Tumors of the Stomach, pp. 1099-1104
Mulholland & Greenfield's Surgery, 7th ed., Chapter 47 - Gastric Lymphoma, p. 2342

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