Upper Gastrointestinal Tract Cancers¶
Chapter 85 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Esophageal, gastric, and small bowel cancers are among the most common and lethal malignancies globally, with significant geographic and demographic variations in incidence.
- HER2-positive and PD-L1-expressing tumors benefit from targeted therapies like trastuzumab, pembrolizumab, and ADCs (e.g., trastuzumab deruxtecan).
- Genomic profiling (e.g., HER2/ERBB2 amplification, MSI/MMRP status) is critical for guiding systemic therapy and prognosis.
- Staging systems (AJCC cTNM, pTNM, ypTNM) and molecular subtypes (e.g., intestinal vs. diffuse gastric cancer) influence treatment decisions.
- Multimodal approaches (surgery, chemotherapy, radiation, immunotherapy) are standard for resectable cancers, while palliative strategies focus on symptom management.
1. DEFINITION & OVERVIEW¶
Upper gastrointestinal tract cancers include esophageal, gastric, and small bowel malignancies. Esophageal cancer has two main subtypes: squamous cell carcinoma (SCC) and adenocarcinoma. Gastric cancer is classified as intestinal or diffuse subtype based on histology. Small bowel cancers include neuroendocrine tumors (NETs), adenocarcinomas, lymphomas, and GISTs. These cancers are associated with high mortality and require multidisciplinary management.
Table 85-1 AJCC Prognostic Stage Groups for Esophageal Cancer Using cTNM (Pretreatment)¶
| TNM | CLINICAL STAGE | PRESENTING AT THIS STAGE | SQUAMOUS | ADENOCARCINOM A |
|---|---|---|---|---|
| cTis, N0, M0 | 0 | 1.2% | 75% | 82% |
| cT1-2, N0, M0 | I | 17% | 75% | 78% |
| cT1-2, N1-3, M0 | IIA | 7% | 53% | 50% |
| cT3-4a, N0, M0 | IIB | 13% | 40% | 40% |
| cT3-4a, N1-3, M0 | III | 31% | 25% | 25% |
| cT4b, any N, M0 | IVA | 17% | 21% | |
| cAny T, any N, M1 | IVB | 5% | 10% | 18% |
Table 85-2 Staging System for Gastric Carcinomaa¶
| 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 | |
| IA | T1N0M0 | Node negative; invasion of lamina propria or submucosa | 7 | ||
| IB | T2N0M0 | Node negative; invasion of muscularis propria | 10 | 44 | |
| IIA | T1N1M0 | Node positive; invasion beyond mucosa but within wall | 17 | ||
| IIIA | T2N2M0 | Node positive; invasion of muscularis propria or through wall | 21 | 15 | |
| IIIB | T4N0-1M0 | Node negative; adherence to surrounding tissue | 14 | ||
| IIIC | T4N2-3M0 | >3 nodes positive; invasion of serosa or adjacent structures | |||
| IV | T4N2M0 | Node positive; adherence to surrounding tissue | 30 | 3 |
1.1 Subtopic¶
Esophageal cancer is more common in Asia, the Normandy coast, and Middle Eastern countries. Gastric cancer incidence has decreased globally but remains high in certain regions. Small bowel cancers are rare but include NETs, which are the most common type.
2. EPIDEMIOLOGY¶
Esophageal cancer has a global incidence of ~604,100 new cases/year, with higher rates in Asia, Normandy, and Middle Eastern countries. Gastric cancer incidence has decreased in Western countries but increased in GEJ adenocarcinomas. Small bowel cancers account for ~3% of gastrointestinal tumors. Risk factors include alcohol/tobacco use, obesity, H. pylori infection, and inherited syndromes (e.g., Lynch syndrome).
2.1 Subtopic¶
Early-onset gastrointestinal malignancies (EOGI) have increased in incidence, particularly in younger patients. H. pylori infection is a major driver for gastric cancer, with ~10–15% of patients having successful eradication leading to reduced cancer risk.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Esophageal SCC is linked to alcohol/tobacco use, hot beverages, and Plummer-Vinson syndrome. Adenocarcinoma is associated with Barrett’s esophagus and reflux. Gastric cancer is driven by H. pylori infection, genetic mutations (e.g., CDH1, TP53), and chronic inflammation. Small bowel cancers include NETs (linked to cKIT/PDGFRA mutations) and adenocarcinomas (associated with Lynch syndrome).
3.1 Subtopic¶
Genomic alterations in gastric cancer include HER2/ERBB2 amplification, MSI/MMRP status, and Claudin 18.2 overexpression. Esophageal adenocarcinoma is linked to Barrett’s esophagus and EBV infection. Small bowel NETs are driven by cKIT/PDGFRA mutations.
4. CLINICAL FEATURES¶
Common symptoms include dysphagia, odynophagia, hematemesis, and weight loss. Anemia from GI bleeding may present with fatigue. Early-onset cancers (EOGI) often present with non-specific symptoms. Gastric lymphomas may mimic adenocarcinoma with symptoms like abdominal pain and bleeding.
4.1 Subtopic¶
Esophageal adenocarcinoma presents with dysphagia and weight loss. Gastric cancer may present with vague upper abdominal discomfort or anemia. Small bowel tumors may cause obstruction, bleeding, or intussusception.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include benign esophageal strictures, GERD, peptic ulcers, and gastric lymphomas. For small bowel tumors, differential diagnoses include Crohn’s disease, diverticulitis, and benign neoplasms. Endoscopic biopsy and imaging are critical for distinction.
5.1 Subtopic¶
Esophageal SCC must be differentiated from Barrett’s esophagus or esophageal varices. Gastric lymphomas must be distinguished from adenocarcinoma using immunohistochemistry and molecular testing.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic workup includes upper endoscopy with biopsy, EUS, CT, FDG-PET/CT, and molecular testing (e.g., HER2/ERBB2, MSI/MMRP, PD-L1). Biomarkers like CEA and CA19-9 are nonspecific but useful for monitoring. Staging systems (AJCC cTNM, pTNM) guide treatment decisions.
6.1 Subtopic¶
For esophageal cancer, FDG-PET/CT is preferred over CT for metastatic detection. Gastric cancer staging includes EUS for depth of invasion and lymph node assessment. Small bowel tumors may require capsule endoscopy or enteroscopy.
7. MANAGEMENT & TREATMENT¶
Curative treatment for resectable cancers includes surgery (e.g., subtotal gastrectomy, esophagectomy) with neoadjuvant chemotherapy. Adjuvant therapy (e.g., FLOT, chemotherapy + immunotherapy) improves survival. Palliative options include stenting, radiation, and systemic therapy (e.g., trastuzumab, pembrolizumab).
Table 85-3 Molecular Diagnostics and Genomic Alteration Analyses Help Guide Systemic Therapy¶
| SITE HISTOLOGY | FACTOR | ASSAY TYPE | THERAPY OPTIONS |
|---|---|---|---|
| Esophageal SCC | PD-L1 | IHC | Immunomodulation |
| Esophageal Adeno/GEJ | ERRB2/HER2 | IHC/FISH/NGS | Trastuzumab; trastuzumab-deruxtecan |
| Esophageal Adeno/GEJ | dMMRP/MSI | IHC/NGS | Immunomodulation |
| Gastric Adeno | Claudin 18.2 | IHC | Zolbetuximab |
7.1 Subtopic¶
HER2-positive cancers benefit from trastuzumab-based therapy. MSI-high tumors respond to immune checkpoint inhibitors (e.g., pembrolizumab). Small bowel NETs are treated with somatostatin analogs and PRRT. GISTs use imatinib or avapritinib.
8. PROGNOSIS & COMPLICATIONS¶
5-year survival rates for esophageal cancer range from 5–75% depending on stage. Gastric cancer survival is ~30% for stage IV. Complications include metastasis, peritoneal seeding, and cachexia. Early detection and molecular profiling improve outcomes.
8.1 Subtopic¶
Metastatic disease (stage IV) has poor prognosis, with median survival of 12–15 months. Peritoneal metastasis is common in diffuse-type gastric cancer and limits curative options.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Avoid chemotherapy during the first trimester. Pediatric patients may have distinct genetic profiles (e.g., CDH1 mutations). Elderly patients require dose adjustments for chemotherapy. Inherited syndromes (e.g., Lynch syndrome) increase cancer risk and require genetic counseling.
9.1 Subtopic¶
Lynch syndrome increases risk of gastric and colorectal cancers. CDH1 mutations are linked to diffuse-type gastric cancer and lobular breast cancer. H. pylori eradication is recommended for at-risk patients.
10. KEY POINTS & CLINICAL PEARLS¶
- Esophageal and gastric cancers are highly lethal; early detection and molecular profiling are critical. 2. HER2/ERBB2 and PD-L1 status guide targeted therapies. 3. Staging systems (AJCC cTNM, pTNM) determine treatment options. 4. Multimodal therapy (surgery + chemotherapy) improves survival for resectable cancers. 5. Palliative care focuses on symptom management and quality of life.