• Clinical science

Gastric cancer

Abstract

Gastric cancer refers to neoplasms in the stomach, including cancers of the esophagogastric junction. The incidence is declining in the United States and Europe, while it is rising in Japan and South Korea. Gastric cancer is associated with several risk factors (e.g., consumption of foods high in nitrates, increased alcohol and nicotine intake, Helicobacter pylori infection). In its early stages, the disease is often asymptomatic or accompanied by nonspecific symptoms (e.g., epigastric discomfort, postprandial fullness, or nausea). Late-stage disease may present with gastric outlet obstruction (mechanical obstruction of the pyloric canal), leading to weight loss and vomiting. Biopsy during endoscopy confirms the diagnosis. Adenocarcinomas are the most common form of gastric cancer. Treatment includes endoscopic or surgical resection. Depending on staging, chemotherapy may be indicated before or after surgery (neoadjuvant or adjuvant chemotherapy), or as a palliative therapy.

Epidemiology

  • Sex: >
  • Peak incidence: 70 years
  • Geographical distribution: strong regional differences
    • High incidence in South Korea and Japan
    • Declining incidence in the United States and Europe


References:[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Exogenous risk factors
    • Diet rich in nitrates and/or salts (e.g., dried, preserved food)
    • Alcohol and nicotine use
    • Low socioeconomic status
    • Obesity (for cancers of the gastroesophageal junction)
  • Endogenous risk factors

References:[1][3][4][5][6]

Classification

TNM classification of gastric cancer

TNM Extent
Tis Carcinoma in situ: without invasion of basal membrane. No metastatic spread!
T1 Limited to mucosa (T1a) and submucosa (T1b) (does not penetrate the muscularis propria): T1 = early gastric cancer (metastatic spread possible!)
T2 Penetration of muscularis propria
T3 Penetration of subserosa
T4 Penetration of serosa (T4a), including penetration of adjacent structures (T4b)
N1 1–2 regional lymph nodes
N2 3–6 regional lymph nodes
N3 ≥ 7 regional lymph nodes (N3a: 7–15 lymph nodes, N3b: > 15 lymph nodes)
M1 Distant metastases, peritoneal carcinomatosis

Siewert classification of adenocarcinoma of the esophagogastric junction

This classification was proposed by Siewert and is applied in clinical practice.

Type Localization Comments and surgical approaches

Siewert type I

Center of the tumor located 1–5 cm above the z-line (associated with Barrett mucosa)
Siewert type II Center of the tumor located 1 cm above or 2 cm below the z-line (true carcinoma of the cardia)
  • Surgical approach: transhiatal extended gastrectomy
Siewert type III Center of the tumor located 2–5 cm below the z-line (proximal gastric cancer diffused to cardia)

References:[7][8]

Clinical features

Gastric cancer is often asymptomatic. Early signs are nonspecific and often go unnoticed. At later stages the following symptoms may occur:

Subtypes and variants

Metastatic Disease

Stages

UICC classification (Union for International Cancer Control)

UICC stage TNM classification of gastric cancer
Stage 0 Tis (Carcinoma in situ)
Stage IA T1 N0 M0
Stage IB T1 N1 M0
T2 N0 M0
Stage II T1 N2 M0
T2 N1 M0
T3 N0 M0
Stage IIIA T2 N2 M0
T3 N1 M0
T4 N0 M0
Stage IIIB T3 N2 M0
Stage IV T1-T3 N3 M0
T4 N1-3 M0
Tx Nx M1 (any distant metastases)

References:[7]

Diagnostics

Diagnostic procedures

  • Upper endoscopy with biopsy (best initial test) : Biopsy confirms the diagnosis
  • Barium upper GI series may be considered and would show loss of intestinal folds and stenosis

Laboratory test

Staging

  • Abdominal ultrasound
  • Endosonography
  • Abdominal and pelvic CT-scan using intravenous and oral contrast; sufficient oral contrast is required to fill the stomach
  • Thoracic CT-scan
  • Diagnostic laparoscopy

Staging of gastric cancer is essential to determine the correct treatment options. When first diagnosed with gastric cancer, ∼ 70% of patients already show metastatic spread to the lymph nodes!

References:[9][10][11][12]

Pathology

  • Adenocarcinoma (90% of cases)
    • Typically localized, exophytic lesion +/- ulceration
    • Arise from glandular cells in the stomach; usually located on the lesser curvature of the stomach
  • Signet ring cell carcinoma
    • Diffuse growth
    • Multiple signet ring cells = round cells filled with mucin, with a flat nucleus in the cell periphery
  • Less common

Lauren classification of gastric adenocarcinoma

  • Intestinal type (∼ 50% of cases): polypoid, glandular formation; expanding (not infiltrative) growth pattern; clear border
  • Diffuse type (∼ 40% of cases): infiltrative growth and diffuse spread in the gastric wall, no clear border
  • Mixed type (∼ 10% of cases)

References:[9]

Differential diagnoses

The differential diagnoses listed here are not exhaustive.

Treatment

Principles of treatment

  • Exact therapy, which may be either curative or palliative , depends on staging and the type of tumor.

Endoscopic resection of superficial gastric cancer

  • Curative treatment: up to T1a (N0M0) → endoscopic resection
    • En bloc resection using endoscopic mucosal resection (= EMR) or endoscopic submucosal dissection (= ESD)
    • Local recurrence (up to T1a) may be resected endoscopically.

Surgery (stage-adapted)

  • T1b and more (NxM0): surgical resection with curative intent (if operable and resectable)
  • Radical gastrectomy and D2 lymphadenectomy (operative standard)
    • Resection of the lesser and greater omentum and radical lymphadenectomy of compartments I (perigastric lymph nodes along the greater and lesser curvature of the stomach) and II (lymph nodes along the left gastric artery, common hepatic artery, splenic artery, celiac trunk, and along the vessels in hepatoduodenal ligament)
    • Splenectomy only in the case of pathological lymph nodes in the splenic hilus and/or a carcinoma of the greater curvature infiltrating the spleen
    • Diffuse type (Lauren classification) requires 8 cm proximal safety margin; intestinal type requires 5 cm
    • Roux-en-Y gastric bypass
      • The surgeon separates the proximal jejunum from the duodenum and creates an end-to-end anastomosis of the jejunum with the remaining part of the stomach (gastrojejunostomy), or in the case of a total gastrectomy, with the esophagus (esophagojejunostomy).
      • Duodenal stump is connected distally with the jejunum using an end-to-side anastomosis.
      • Advantage: The stomach is more protected against bile reflux and consequent complications, such as ventricular ulcer and anastomotic recurrent gastric cancer.
    • Extended in the case of cardia carcinoma EGJ Siewert type II and III: abdominothoracic resection of the distal esophagus and cardia, intrathoracic anastomosis by gastric pull-up
  • Alternative: subtotal gastrectomy
    • Carcinoma of the lower third of the stomach or intestinal carcinoma of the middle third of the stomach
    • Subtotal gastrectomy (4/5 resection) with lymphadenectomy
  • No R0 resection: curative reresection aiming at R0, neoadjuvant chemotherapy may complement the treatment

Perioperative management

  • Brief explanation: combination of neoadjuvant and adjuvant radiochemotherapy in curative intent
    • In particular, preoperative chemotherapy is essential to downsize the tumor and make it resectable.

Palliative treatment

  • Indication: distant metastases; advanced tumor stage with unresectable cancer ; functionally inoperable patients
  • Potential treatment options: Usual palliative measures (e.g., analgesic treatment); in addition chemotherapy, medical management of cancer and/or surgical management may be depending on the patient's general condition
    • Chemotherapy and medical management of cancer
      • Patients with a good ECOG performance status (ECOG 0-2) may particularly benefit from chemotherapy and medical management, as these measures may prolong life and improve the quality of life.
    • Surgical management
      • Surgical or endoscopic management of gastrointestinal obstruction
      • Partial gastrectomies may be used in exceptional cases

References:[13]

Complications

Malignant acanthosis nigricans

  • A paraneoplastic syndrome seen in adenocarcinomas of GI origin, especially in gastric adenocarcinoma
  • Pathophysiology: caused by exogenous transforming growth factor TGF-α and epidermal growth factor (GF)
  • Clinical findings
    • Brown to black, intertriginous and/or nuchal hyperpigmentation that can turn into itching, papillomatous, poorly-defined efflorescence
    • Rapid growth and verrucous or papulous surface helps to differentiate it from benign acanthosis nigricans
    • Localization: axilla, groin, neck

Malignant acanthosis nigricans always requires further diagnostic measures to look for malignancy!

Postgastrectomy syndromes

Related to resorption

Related to anastomosis

  • Small intestinal bacterial overgrowth (SIBO)
  • Efferent loop syndrome
    • Only an acute abdomen would be an immediate surgical indication, otherwise, watch and wait
    • Kinking or anastomotic narrowing of the efferent loop → emesis, feeling of fullness
  • Afferent loop syndrome
    • Biliary and pancreatic obstruction due to stenosis, kinking, or incorrect anastomosis of the afferent loop → chyme enters the afferent loop instead of the efferent loop → loss of appetite, feeling of fullness, bilious vomiting with subsequent relief of nausea
    • Surgical treatment

Related to motility

  • Dumping syndrome: rapid gastric emptying due to either defective gastric reservoir function or pyloric emptying mechanism, or anomalous postsurgery gastric motor function.
    • Early dumping
      • Cause: rapid emptying of undiluted chyme into the small intestine caused by a dysfunctional or bypassed pyloric sphincter
      • Clinical features
        • Appears within 15–30 minutes after ingestion of a meal
        • Symptoms may include nausea, vomiting, diarrhea, and cramps, as well as vasomotor symptoms such as sweating, flushing, and palpitations.
      • Management
        • Dietary modifications: Small meals that include a combination of complex carbohydrates and foods rich in protein and fat to cover protein and energy requirements are preferable.
        • 30–60 min of rest in the supine position after meals
        • Beta-blockers may be helpful.
        • Often spontaneous improvement after a couple of months
    • Late dumping
      • Cause: postprandial hypoglycemia; dysfunctional pyloric sphincterchyme containing glucose immediately reaches the small intestine → glucose is quickly resorbed → hyperglycemia → excessive release of insulinhypoglycemia and release of catecholamines
      • Treatment
        1. Dietary modifications
        2. Octreotide and surgery are second and third-line therapies
    • Prevention: Constructing an esophagojejunostomy with a pouch may prevent dumping syndromes as it creates a useful reservoir. Therefore, this procedure is becoming more common.

Suspect late dumping syndrome in a patient with previous gastric surgery and hypoglycemia!

Remnant carcinoma is a complication associated with the remnant stomach. Follow-up is important!References:[14][15][16]

We list the most important complications. The selection is not exhaustive.

Follow-up

  • Regular follow-ups after curative treatment are recommended, i.e. every 3–6 months in the first year, and yearly thereafter.
  • There are no standard recommendations, but the following approach is often employed:
    • Patient history and clinical examination
      • Identify postoperative dysfunctions, signs, symptoms, and clinical findings indicating local recurrence
      • Evaluate nutritional status to prevent weight loss and identify malnutrition and hypovitaminosis at an early stage
      • Identify psychosocial stress to patients and relatives → provide support
    • Laboratory tests: blood count, iron levels, serum transferrin, transferrin saturation, vitamin B12, tumor marker (if elevated preoperatively or if previous levels are available for comparison)
    • Abdominal ultrasound: evidence of recurrence or metasteses
    • If recurrence is suspected during follow-up: symptom-oriented restaging

Rehabilitation

  • Following gastrectomy, rehabilitation (ideally in specialized centers) is recommended.
  • Specific treatment of usually neglected aspects of the disease:
    • Nutrition counseling and training on gastrointestinal dysfunctions following (surgical) treatment
    • Identify and treat psychosocial aspects to prevent psychiatric consequences
    • Physical therapy and sports (to regain resilience in the management of everyday tasks)
  • To ensure appropriate care, geriatric patients may be treated in specific rehabilitation centers.

Prognosis

  • Since there are no early signs, gastric cancer is often diagnosed very late. At diagnosis, 60% of cancers have already reached an advanced stage that does not allow for curative treatment.
    • Early gastric cancer has the best prognosis (T1, M0, N0, 5-year survival rate 90–95%).
    • Distant metastases or peritoneal carcinomatosis dramatically worsen the prognosis and are lethal most of the time.
      • 5-year survival rate of stage III is 30%, and of stage IV is 5%.
    • Even if the cancer is resectable at UICC-stage II and above, the prognosis is not satisfactory: 5-year survival is less than 50%.