Upper GastrointestinalTract Cancers¶
Chapter 85 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 85
Key Clinical Points¶
- Esophageal cancer has two distinct forms: Squamous Cell Carcinoma (SCC) and Adenocarcinoma (AC).
- SCC is common in high-incidence areas (Asia, Iran) and linked to alcohol/tobacco; AC is common in the West (US/Europe) and linked to Barrett's esophagus/obesity.
- Metastatic signs of gastric cancer: Virchow's node (left supraclavicular), Sister Mary Joseph nodule (periumbilical), Blumer's shelf (pelvic), and Krukenberg tumor (ovarian).
- H. pylori eradication reduces gastric cancer risk, especially in high-risk patients.
- Metastatic HER2-positive gastric/esophageal cancer: Trastuzumab + chemotherapy is standard; Trastuzumab-deruxtecan is approved for HER2-low (1+ or 2+ IHC).
- For metastatic HER2-negative gastric cancer with MSI-High or dMMRP: Immune checkpoint inhibitors (pembrolizumab, nivolumab) are indicated.
- Esophageal SCC locally advanced: CROSS regimen (carboplatin/5-FU or cisplatin/5-FU + radiation); Nivolumab for residual disease.
- Esophageal adenocarcinoma: FLOT is preferred neoadjuvant systemic therapy; Trastuzumab added if HER2-positive. Trastuzumab-deruxtecan for second-line therapy.
- Capecitabine requires DPYD gene testing to avoid severe toxicity in patients with mutations.
- Peritoneal cytology positive for cancer rules out curative resection intent for gastric cancer.
1. DEFINITION & OVERVIEW¶
• Scope: Includes malignancies of the esophagus, stomach, and small bowel. • Prevalence: Esophageal, gastroesophageal junction (GEJ), and gastric cancers are common; small intestine cancers are rare.
1.1 Classification by Histology¶
• Esophageal Cancer Types: ◦ Squamous Cell Carcinoma (SCC): → Located in upper and mid esophagus. → Common in high-incidence areas (Asia, Iran). → Associated with alcohol/tobacco. ◦ Adenocarcinoma (AC): → Located in lower esophagus and at the GEJ. → Predominant in US and Western Europe (>75% of cases). → Associated with Barrett's esophagus, obesity, and chronic reflux.
2. EPIDEMIOLOGY¶
• Global Incidence: ◦ Esophageal: 1.693 million new cases (2020); 544,076 deaths (2020). ◦ US (2023): 21,560 new esophageal cases; 16,120 deaths. 26,500 new gastric cases; 11,130 deaths. ◦ Geographic Variation: Up to 20-fold difference in incidence; high in Asia (China), France (Normandy coast), and Middle East (Iran). ◦ Trends: Increase in GEJ and gastric cancers in the US since mid-1990s. Rise in Early-onset GI cancers (EOGI) in patients <50 years old.
2.1 Risk Factors¶
• SCC Risk Factors: Alcohol or tobacco abuse; ingestion of extremely hot substances (tea, mate); chewing areca (betel) nut; chronic achalasia, radiation therapy, lye ingestion, Plummer-Vinson syndrome. ◦ Adenocarcinoma Risk Factors: Chronic reflux esophagitis leading to Barrett's esophagus; obesity; H. pylori infection; inherited genes (CDH1, Lynch syndrome, BRCA).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Esophageal Cancer Genomics: ◦ SCC: Resembles other primary sites (head/neck); HPV not identified; 5 types of structural variations in Chinese patients. ◦ Adenocarcinoma: HER2/ERBB2 frequently amplified; MSI found in both esophageal and GEJ adenocarcinomas; EBV is a driver; TP53 mutations/aneuploidy in Barrett's regions. ◦ Barrett's Progression: Risk of progression to cancer ≈ 0.4–0.5% per year. ◦ Inherited Susceptibility: Rare exception is tylosis palmaris and plantaris (RHBDF2 mutation); Lynch syndrome and germline BRCA mutations have modestly increased risk for gastric/GEJ adenocarcinomas. • Gastric Cancer Genomics: ◦ H. pylori: Known driver; treatment reduces overall risk of gastric cancer. ◦ Inherited Genes: CDH1 mutations (e-cadherin) markedly increase risk for diffuse cell (signet cell) gastric cancer; Lynch and BRCA mutations slightly increase risk. ◦ Microbiome/Viral: Higher bacterial load in patients; EBV associated with increased risk. ◦ TCG Subtypes: High EBV burden, MSI with hypermutation, genomically stable (associated with diffuse subtype), and chromosomally unstable. • Pathogenesis Cascade: ◦ Esophageal Adenocarcinoma: Chronic reflux esophagitis → Barrett's esophagus (glandular gastric type mucosa) → Dysplasia → Adenocarcinoma. ◦ Gastric Cancer: H. pylori infection → Chronic inflammation → Atrophic gastritis → Intestinal metaplasia → Dysplasia → Adenocarcinoma. ◦ Diffuse Type: Arises via CDH1 mutation leading to loss of cell adhesion.
4. CLINICAL FEATURES¶
• Esophageal Cancer Symptoms: ◦ Dysphagia/Odynophagia: Most common; usually not perceived until substantial obstruction occurs. ◦ Other: Hematemesis, melena, anorexia, weight loss, fatigue, and shortness of breath (if anemia is present). ◦ Note: In young patients, symptoms may be mistaken for benign illnesses, leading to advanced stages at diagnosis. • Gastric Cancer Symptoms: ◦ Vague upper abdominal discomfort; hematemesis or melena; anorexia and early satiety; unexplained weight loss. ◦ GEJ Cancers: May present with dysphagia or odynophagia. ◦ Anemia: Often due to occult bleeding. • Physical Examination Findings: ◦ Virchow's node: Left supraclavicular adenopathy. ◦ Sister Mary Joseph nodule: Periumbilical mass. ◦ Blumer's shelf: Pelvic mass on rectal exam. ◦ Krukenberg tumor: Ovarian mass. ◦ Other: Ascites, palpable lymphadenopathy, or hepatomegaly.
5. DIFFERENTIAL DIAGNOSIS¶
• Dysphagia: ◦ Esophageal Cancer: Progressive dysphagia, weight loss, anemia. ◦ Achalasia: Dysphagia to solids/liquids, regurgitation; no initial weight loss. ◦ Peptic Stricture: History of GERD; responds to acid suppression. ◦ Eosinophilic Esophagitis: Food impaction, atopy history. • Gastric Mass/Anemia: ◦ Gastric Cancer: Weight loss, early satiety, positive H. pylori. ◦ Gastric Ulcer: Pain relieved by food (duodenal) or worsened by food (gastric); responds to PPIs. ◦ GIST: Subepithelial mass; may bleed. ◦ Lymphoma: B symptoms, lymphadenopathy.
6. INVESTIGATIONS & DIAGNOSIS¶
- Endoscopy and Biopsy: Standard for diagnosis; biopsy determines histology.
- EUS (Endoscopic Ultrasonography): Determines depth of penetration (T stage) and regional lymph node involvement; AI may assist analysis.
- Bronchoscopy: For mid/upper esophagus tumors to rule out tracheobronchial tree invasion. → Invasion rules out surgical intervention with curative intent.
- Laparoscopy: For GEJ tumors to assess peritoneal involvement if T stage is advanced.
- Imaging: ◦ CT: Assess for metastatic disease. ◦ FDG-PET/CT: Assess for metastasis; serial scans guide therapy changes (FDG avidity >4 SUV max indicates aggressive disease).
- Cytology: Peritoneal cavity washing if no visible metastases; → Positive cytology rules out curative resection.
- Molecular Diagnostics: ◦ NGS: Most efficient for genomic analysis; required for all metastatic patients (requires adequate tumor cellularity). ◦ PD-L1: Assessed by IHC to guide immune modulation therapy. ◦ HER2/ERBB2: Assessed by IHC/FISH/NGS to guide trastuzumab-based therapy. ◦ MSI/dMMR: Assessed by IHC/NGS to guide immune therapy. ◦ Claudin 18.2: Assessed by IHC; guides use of zolbetuximab (investigational).
Molecular Diagnostics Table Summary¶
Table 85-3 highlights the following: • Esophageal SCC: PD-L1 (IHC) → Immunomodulation. • Esophageal Adeno/GEJ: HER2 (IHC/FISH/NGS) → Trastuzumab; trastuzumab-deruxtecan; dMMRP/MSI (IHC/NGS) → Immunomodulation. • Gastric Adeno: Claudin 18.2 (IHC) → Zolbetuximab.
7. MANAGEMENT & TREATMENT¶
- Early-Stage Esophageal (Tis/T1a): → Endoscopic mucosal resection (EMR) or submucosal dissection (ESD).
- Locally Advanced Esophageal: → Combined-modality therapies (chemotherapy + radiation or chemotherapy alone).
- Esophageal SCC Management: → Chemoradiation (CROSS regimen: carboplatin/5-FU or cisplatin/5-FU + radiation) is standard. → Surgery reserved for patients not achieving complete response. → Nivolumab for residual disease after neoadjuvant chemoradiation.
- Esophageal Adenocarcinoma Management: → FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) preferred neoadjuvant systemic therapy. → Trastuzumab added if HER2-positive. → Trastuzumab-deruxtecan for second-line therapy.
- Metastatic Esophageal: → Systemic therapy (chemotherapy + immunotherapy if PD-L1 positive).
- Gastric Cancer Management: → Curable: Surgical removal with R0 resection and regional lymph node resection. → Metastatic/Unresectable: Systemic therapy. ◦ HER2-Positive: Trastuzumab + chemotherapy (or trastuzumab-deruxtecan). ◦ HER1-Negative: Immune-modulating therapy (PD-1 inhibitors) + chemotherapy if PD-L1 positive. ◦ MSI-High/dMMR: Immune therapy alone. ◦ Claudin 18.2 Positive: Zolbetuximab (investigational).
- Supportive Care: → Endoluminal stent for obstruction; enteral nutrition via percutaneous gastrostomy.
- Systemic Agents: → Fluoropyrimidines (Capecitabine, 5-fluorouracil); Platinum (Oxaliplatin, Cisplatin); Taxanes (Docetaxel, Paclitaxel); Anthracyclines (Doxorubicin); Immunotherapy (Nivolumab, Pembrolizumab, Ipilimumab); ADCs (Trastuzumab-deruxtecan, Sacituzumab govitecan); PARP Inhibitors (Olaparib, Taloparib for BRCA).
- Treatment Algorithm: Step 1: Diagnosis/Staging (Endoscopy, EUS, CT, PET) → Step 2: Molecular Testing (HER2, PD-L1, MSI, Claudin 18.2) → Step 3: Selection based on Stage/Biomarkers → Step 4: Response Assessment (Serial FDG-PET/CT, ctDNA) → Step 5: Salvage/Refractory Options (ADCs, Clinical Trials).
8. PROGNOSIS & COMPLICATIONS¶
• Esophageal Cancer Survival: → Varies by stage (Table 85-1). → Metastatic disease treated with palliative intent. • Gastric Cancer Survival: → Varies by stage (Table 85-2). → Microsatellite unstable tumors have best outcome (before immune therapy). → Genomically stable (TCG) and mesenchymal (ACRG) types have worst outcome. • Neoadjuvant Therapy: FLOT improved survival compared to preoperative chemoradiation (CROSS) for adenocarcinoma. • Complications: ◦ Early: Anemia, obstruction, bleeding. ◦ Late: Metastatic disease, cachexia, treatment-related toxicities (neuropathy, myelosuppression, immune-related adverse events).
9. SPECIAL CONSIDERATIONS¶
• Early-Onset GI Cancers (EOGI): → Defined as occurring in patients <50 years of age. → Incidence rising in US. → Note: Symptoms in young patients may be attributed to benign illnesses; surveillance endoscopy not recommended for asymptomatic general population.
Inherited Susceptibility¶
• CDH1 Mutation: Prophylactic gastrectomy option; systemic therapy varies (immune modulation for Lynch, DNA-damaging agents for BRCA). ◦ Lynch Syndrome: Modestly increased risk of gastric/GEJ adenocarcinoma. ◦ BRCA Mutation: Modestly increased risk of gastric/GEJ adenocarcinoma.
10. KEY PEARLS & CLINICAL TRAPS¶
• Diagnostic Clues (Metastatic Signs): → Virchow's node (Left supraclavicular); Sister Mary Joseph nodule (Periumbilical); Blumer's shelf (Pelvic); Krukenberg tumor (Ovarian). • Risk Factors: → Hot substances (tea, mate) are risk factors for SCC. • Exclusion Criteria (Rule out curative intent): → Tracheal/Bronchial Invasion. → Peritoneal Cytology Positive. → Symptoms in young patients (may be benign).
Reference Tables¶
TABLE 85-1 AJCC Prognostic Stage Groups for Esophageal Cancer Using cTNM (Pretreatment) a TNM cTis, N0, M0 cT1-2, N0…¶
Harrison's 22e, p.643
| 5-YEAR SURVIVAL RATE | ||||
|---|---|---|---|---|
| TNM | CLINICAL STAGE | PRESENTING AT THIS STAGEb,c | SQUAMOUS | ADENOCARCINOMA |
| cTis, N0, M0 | 0 | 1.2% | 75% | 82% |
| I | 17% | 75% | ||
| cT1-2, N1-3, M0 | IIA | 7% | 53% | 50% |
| IIB | 13% | 40% | ||
| cT3-4a, N1-3, M0c | III | 31% | 25% | 25% |
| IVA | 17% | |||
| cAny T, any N, M1 | IVB | 5% | 10% | 18% |
| Survival by ypTNM Staging After Neoadjuvant Chemotherapy | ||||
| ESTIMATED 5-YEAR SURVIVAL RATE | ||||
| TNM | yp STAGE | SQUAMOUS | ADENOCARCINOMA | |
| T1-2, N0, M0 T1, N1, M0 |
I | 46% | 52% | |
| II | 34% | |||
| T4a, N1-3 M0 T4b, any N, M0 T3, N2-3, M0 T2, N3, M0 |
III | 22% | 27% | |
| IV | 10% |
TABLE 85-2 Staging System for Gastric Carcinoma a STAGE 0 IA¶
Harrison's 22e, p.645
| STAGE | TNM | FEATURES | DATA FROM ACS IN THE UNITED STATES |
|
|---|---|---|---|---|
| NO. OF CASES, % |
5-YEAR SURVIVAL, % |
|||
| 0 | TisN0M0 | Node negative; limited to mucosa |
1 | 90 |
| T1N0M0 | Node negative; invasion of lamina propria or submucosa |
7 | ||
| IB | T2N0M0 T1N1M0 |
Node negative; invasion of muscularis propria |
10 | 44 |
| T1N2M0 T2N1M0 T3N0M0 |
Node positive; invasion beyond mucosa but within wall or Node negative; extension through wall |
17 | ||
| IIIA | T2N2M0 T3N1-2M0 |
Node positive; invasion of muscularis propria or through wall |
21 | 15 |
| T4N0-1M0 | Node negative; adherence to surrounding tissue |
14 | ||
| IIIC | T4N2-3M0 | >3 nodes positive; invasion of serosa or adjacent structures |
||
| T3N3M0 | 7 or more positive nodes; penetrates wall without invading serosa or adjacent structures |
|||
| IV | T4N2M0 | Node positive; adherence to surrounding tissue |
30 | 3 |
| or | ||||
| T1-4N0-2M1 | Distant metastases |
TABLE 85-3 Molecular Diagnostics and Genomic Alteration Analyses Help Guide Systemic Therapy¶
Harrison's 22e, p.645
| SITE HISTOLOGY | FACTOR | ASSAY TYPE | THERAPY OPTIONS |
|---|---|---|---|
| Esophageal SCC | PD-L1 | IHC | Immunomodulation |
| PD-L1 | IHC | ||
| Esophageal Adeno GEJ |
ERRB2/HER2 | IHC/FISH/NGS | Trastuzumab; trastuzumab-deruxtecan |
| dMMRP/MSI | IHC/NGS | ||
| Gastric Adeno | Claudin 18.2 | IHC | Zolbetuximaba |