Understanding Gastroesophageal Cancer: Insights and Implications

Introduction

Gastroesophageal cancers are a group of malignancies that include cancers of the esophagus, the gastroesophageal junction, and the stomach. These cancers are known for their aggressive nature and diverse molecular biology, which can sometimes overlap, posing a significant global health burden. Considered the fourth most common type of gastrointestinal cancer, it is associated with high mortality. Histologically, it is divided into two main types: Squamous Cell Carcinoma and Adenocarcinoma [1].

1. Global Burden of Gastroesophageal Cancer

Globally, gastroesophageal cancer is the fifth most common malignancy and the fourth leading cause of cancer-related death. The global burden of this disease is projected to increase by 62% by the year 2040 [2]. In India, it places a considerable strain on the healthcare system, with 60,222 new cases reported annually, making it the sixth most common cancer in the country.

Symptoms of Gastroesophageal Cancer

The symptoms of gastroesophageal cancer can be subtle and are often mistaken for other conditions, which can delay diagnosis.

• Persistent Heartburn: Frequent and ongoing discomfort often prompts individuals to seek medical advice.

• Indigestion: This non-specific symptom can mask more serious underlying issues.

• Dysphagia: Difficulty swallowing, which may worsen over time.

• Chest Pain: Pain that can mimic cardiac conditions, complicating the initial diagnosis.

• Unintentional Weight Loss: A significant and concerning indicator of potential malignancy.

Esophageal cancer can grow rapidly. Because the esophagus is flexible and can expand around a growing tumour, symptoms may not appear until the cancer has spread to distant organs [3].

Diagnosis of Gastroesophageal Cancer

Several diagnostic procedures are used to identify and stage gastroesophageal cancer:

• Barium Swallow Study: In this study, the patient swallows a liquid containing barium, which coats the lining of the esophagus. X-ray images are then taken to visualize the anatomy and identify any abnormalities.

• Upper Gastrointestinal (UGI) Endoscopy: This invasive procedure is the gold standard for diagnosis. It allows a direct view of the upper gastrointestinal tract, and crucially, enables the collection of tissue samples (biopsies) from any suspicious masses, growths, or areas of metaplasia for histological examination.

• Endoscopic Ultrasound (EUS): EUS provides detailed insights into the depth of tumour invasion and lymph node involvement. It can accurately determine tumour size, locate nearby lymph nodes, and even allow for biopsy of those nodes to assess lymphatic spread.

• CT and PET Scans: Computed Tomography (CT) and Positron Emission Tomography (PET) scans help healthcare professionals determine the extent of the tumour and detect metastasis, which is crucial for staging the cancer and planning the appropriate treatment.

Causes and Risk Factors

A risk factor is anything that increases the chance of developing a disease. Different cancers have different risk factors, which can be categorized as modifiable or non-modifiable. It's important to note that having a risk factor does not mean an individual will get the disease, and some people may develop the disease without any known risk factors [4].

• Age: The risk of developing gastroesophageal cancer increases significantly after the age of 55 [4].

• Sex: Men are more likely to develop gastroesophageal cancer than women [4].

• Tobacco: The use of tobacco in any form is a major risk factor [4].

• Alcohol: Excessive alcohol consumption increases the permeability of the gastroesophageal mucosa, which can enhance the absorption of carcinogens [4].

• Gastroesophageal Reflux Disease (GERD): In this common condition, stomach acid flows back into the lower esophagus. Individuals with chronic, frequent symptoms of GERD have an increased risk of gastroesophageal cancer [4].

• Barrett's Esophagus: Long-term exposure of the lower esophagus to stomach acid can cause the normal squamous cells to change into glandular cells, a process called trans differentiation [5]. This condition, known as Barrett's esophagus, is a significant risk factor as these glandular cells are more prone to dysplasia (pre-cancerous changes) and subsequently, adenocarcinoma [4].

• Achalasia: Also known as esophageal achalasia or achalasia cardia, this is a swallowing disorder where the muscles in the esophagus do not contract properly, and the lower esophageal sphincter fails to relax. This leads to food retention in the esophagus, and if left untreated, increases the risk of developing esophageal cancer [6].

• Tylosis: This rare, inherited condition causes hyperkeratosis (thickening) of the skin on the hands and feet. Individuals with tylosis have a very high risk of developing small growths (papilloma’s) in the esophagus and must be monitored closely for the development of esophageal cancer [7].

• Plummer-Vinson Syndrome: This syndrome is characterized by a triad of iron-deficiency anaemia, upper esophageal webs, and dysphagia. Food can become trapped in these webs, causing chronic irritation that can lead to esophageal cancer [8].

• Obesity and Lack of Physical Activity: Both obesity and a sedentary lifestyle are linked to an increased risk of gastroesophageal cancer.

• Classification of Gastroesophageal Cancer

  1. Histopathological Classification

Based on the cell type, gastroesophageal cancers are primarily classified into two types:

1. Adenocarcinoma: These cancers arise from glandular cells, often forming papillary or tubular structures. Most adenocarcinomas in the esophagus develop from Barrett's metaplasia in the distal third of the esophagus and the gastroesophageal junction [9]. This is the dominant type of gastroesophageal cancer in Western countries. While its incidence is rising, it is not currently the dominant type in India.

2. Squamous Cell Carcinoma: This is the most common type of esophageal cancer worldwide. It originates in the thin, flat cells (squamous cells) that line the surface of the upper and middle parts of the esophagus [10]. It remains the dominant type in India, with smoking being a major risk factor.

3. Siewert Classification

The Siewert-Stein classification is used specifically for adenocarcinomas of the esophagogastric junction (EGJ) to guide surgical planning.

• Type I: Adenocarcinoma of the distal esophagus with the tumour's center located 1-5 cm above the anatomical gastroesophageal junction.

• Type II: True adenocarcinoma of the cardia, where the tumour's center is between 1 cm above and 2 cm below the gastroesophageal junction.

• Type III: Subcardial gastric carcinoma where the tumour's center is 2-5 cm below the gastroesophageal junction, infiltrating the EGJ from below.

Adenocarcinomas classified as Siewert Type II are generally associated with the worst prognosis [10].

3. Treatment Options

4. Endoscopic Resection: This minimally invasive approach is suitable for early-stage cancers and can be performed using two techniques: Endoscopic Mucosal Resection (EMR) or Endoscopic Submucosal Dissection (ESD). When a complete resection is achieved, the long-term prognosis is excellent [11].

5. Surgical Resection: Various surgical techniques are employed, including esophagectomy, gastrectomy, or combined approaches, often involving the removal of nearby lymph nodes (lymph node dissection).

6. Chemotherapy: Chemotherapy plays a crucial role and can be administered in several ways [12]:

   • Neoadjuvant Chemotherapy: Given before surgery to shrink the tumour.

   • Perioperative Chemotherapy: Given both before and after surgery.

   • Definitive Chemotherapy: Used as the primary treatment, often combined with radiation.

   • Adjuvant (Post-operative) Chemotherapy: Given after surgery to eliminate any remaining cancer cells.

   • Palliative Chemotherapy: Used for metastatic disease when surgery is not an option, to control symptoms and prolong life.

7. Targeted Therapy: These newer treatments focus on specific molecular characteristics of the tumour. Given the high morbidity and mortality associated with traditional treatments, targeted therapies offer a more precise approach with potentially fewer severe side effects. Examples include [13]:

   • Cetuximab and Bevacizumab: Target the Epidermal Growth Factor Receptor (EGFR).

   • Trastuzumab: A monoclonal antibody targeting the Human Epidermal Growth Factor Receptor 2 (HER2). It is FDA-approved as a first-line treatment for patients with HER2-positive metastatic gastroesophageal cancer.

8. Role of Ayurveda in Management

Ayurveda, a traditional system of medicine, may play a significant role in cancer management. Some studies suggest that Ayurvedic treatments can provide symptomatic relief, help in reducing tumor size [14], inhibit tumor growth [15], and potentially reduce the metastatic activity of cancer. Unlike modern chemotherapy, Ayurvedic treatments are generally associated with fewer severe side effects. Further rigorous scientific research is essential to validate and understand the role of Ayurveda in the integrated management of cancer.

5. Case Presentation

A 70-year-old male presented with a 2–3-month history of progressively worsening heartburn, chest pain, dysphagia, and generalized weakness. This was associated with significant weight loss and intermittent vomiting.

• Diagnostic Outcomes:

  • UGI Endoscopy: Revealed a mass at 40 cm from the incisors, extending into the stomach. The mass had a central depressed ulcer with raised, erythematous, nodular margins, causing narrowing of the lumen.

  • 

    Image 1. : UGI Diagnostic endoscopy report of patient.

  • CECT Abdomen and Pelvis: Showed a well-defined, heterogeneously enhancing, asymmetric circumferential thickening of the gastric fundus and antrum, with a maximal thickness of 3.4 cm.

  • 

    Image 2. CECT Andomen report of same patient.

    

    Image 3. Continuation of CECT report of same patient.

  • Histopathology: Biopsy analysis indicated a poorly differentiated carcinoma. Immunohistochemistry (IHC) was recommended for further evaluation.

• Classification: Siewert Type II (Adenocarcinoma of the Cardia).

• Staging: A subsequent PET-CT scan revealed lung metastasis.

• Treatment Course: The patient was started on chemotherapy at a tertiary care center. Unfortunately, after receiving four cycles, he developed acute respiratory distress syndrome (ARDS) and passed away.

• Conclusion

Gastroesophageal cancer remains a formidable challenge in oncology due to its aggressive nature and frequent late-stage diagnosis. The management landscape is continuously evolving, with advancements in diagnostics, surgical techniques, and systemic therapies like targeted agents improving outcomes for some patients. However, mortality rates remain high, underscoring the urgent need for continued progress. A multidisciplinary approach is essential for optimal patient care. Furthermore, dedicated research is crucial, not only to refine existing treatments but also to explore new frontiers. This includes investigating the potential of complementary systems like Ayurveda through rigorous scientific studies. Validating the role of such traditional practices could lead to better supportive care, improved quality of life, and potentially more effective integrated treatment strategies for patients battling this devastating disease.

References

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2. Thrift AP, Wenker TN, El-Serag HB (2023) Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 20: 338–349.

3. Esophageal Cancer: Symptoms, Causes & Treatment Cleveland Clinic. Available from: https://my.clevelandclinic.org/health/diseases/6137-esophageal-cancer.

4. Esophageal Cancer Risk Factors | Esophagus Cancer Risk Available from: https://www.cancer.org/cancer/types/esophagus-cancer/causes-risks-prevention/risk-factors.html.

5. SHEN C-N, Burke ,Zoë D, and Tosh D (2004) Transdifferentiation, Metaplasia and Tissue Regeneration. Organogenesis 1: 36–44.

6. Achalasia Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/achalasia.

7. Maillefer R, Greydanus M (1999) To B or not to B: is tylosis B truly benign?: Two North American genealogies. The American Journal of Gastroenterology 94: 829–834.

8. Plummer-Vinson syndrome | About the Disease | GARD Available from: https://rarediseases.info.nih.gov/diseases/8259/paterson-kelly-syndrome.

9. Holzheimer RG, Mannick JA (Eds.) (2001) Surgical Treatment: Evidence-Based and Problem-Oriented, Munich, Zuckschwerdt.

10. Esophageal cancer - Symptoms and causes Mayo Clinic. Available from: https://www.mayoclinic.org/diseases-conditions/esophageal-cancer/symptoms-causes/syc-20356084.

11. Noordzij IC, Curvers WL, Schoon EJ (2019) Endoscopic resection for early esophageal carcinoma. Journal of Thoracic Disease 11.

12. Esophageal Cancer Treatment Protocols: Overview, General Recommendations Based on Stage, Neoadjuvant Chemotherapy and Chemoradiotherapy, Resectable Disease (2024).

13. Yang Y-M, Hong P, Xu WW, et al. (2020) Advances in targeted therapy for esophageal cancer. Sig Transduct Target Ther 5: 1–11.

14. - S, Saini S, Patiya A, et al. (2025) Esophageal Squamous Cell Carcinoma: A Case Study Of Success-Ful Ayurvedic Treatment. IAMJ p9: 210–213.

15. Sawarkar PG, Raut D, Bhojarj N, et al. (2024) Management of Carcinoma of Esophagus in Old Patient with Panchagavya Therapy as a Palliative Care-A Case Report. Journal of Pharmacy and Bioallied Sciences 16: S4133.