The document summarizes information about gastric cancer including its location in the stomach, classification, risk factors, diagnosis, staging, and management. Some key points are: - Gastric cancer develops through a sequence of changes called the Correa cascade triggered by H. pylori infection and other environmental factors. - Classification includes anatomical staging, histological subtypes, and molecular markers which guide treatment and prognosis. - Risk increases with age, smoking, diet, and genetic conditions. Screening occurs in high-risk areas like Japan. - Diagnosis is by endoscopy and biopsy. Staging involves blood tests, imaging, and endoscopic ultrasound. - Treatment depends on stage but may include surgery,

1. Yahya Berke DEMIREL
Odessa National Medical University
1st Group
5th Course

2. • The stomach is a muscular organ that is part of the gastrointestinal (GI) tract. It is
located at the distal end of the oesophagus beyond the gastro-oesophageal junction
(GOJ). The stomach is essential for digestion.
• The stomach is divided into five anatomical components known at the cardia, fundus,
body, antrum and pylorus. The pylorus marks the entry into the duodenum and the
whole stomach is composed of columnar epithelium. For more information see our
notes on gastrointestinal physiology.
• Over 90% of gastric cancers are adenocarcinoma, which is historically divided into two
histological subtypes known as intestinal and diffuse (based on Lauren criteria):
• Intestinal-type: most common, gland-forming. Further divided into papillary, tubular or
mucinous adenocarcinomas.
• Diffuse-type: less common, composed of discohesive cells. Classically signet cells see
on histology. Can lead to extensive infiltration of the stomach and more likely to have a
familial element.

3. Epidemiology
• The incidence of gastric cancer is highly variable depending on the geographical
location.
• Across the world, gastric cancer is the fourth most common malignancy. The
highest incidence of gastric cancer is found in Eastern Asia (e.g. Korea, Japan),
Eastern Europe, and Central and Latin America. The lowest incidence is found
in North America, Europe and Africa. In fact, due to the high incidence Japan
has a gastric cancer screening programme.
• Gastric cancer is more common in older people with >50% of patients in the UK
being over 75 years old. It is more common in men and strongly linked to
environmental factors (discussed in aetiology).
• In the UK, the overall incidence of gastric cancer has been declining, although
there has been an increase in adenocarcinomas affecting the gastric cardia,
which lies just below the GOJ.

4. Classification
• Gastric cancer may be classified based on anatomy, histology, disease extent or
molecular markers.
• These classifications broadly apply to gastric adenocarcinomas, which are the most
prevalent gastric cancer seen in >90% of cases.
• Anatomical
• This is the universally accepted classification of gastric cancer, which is based on
the tumour, node, metastasis (TNM) classification used for all cancers.
• Gastric cancers can be staged according to the size of the tumour, number of nodes
involved and presence of distant metastasis. In 2017, further clarification was made on
how best to classify cancers affecting the GOJ.
• If an upper GI cancer involves the GOJ, it may be classified and treated as an
oesophageal or gastric cancer:
• Epicentre of the tumour ≤2 cm from the GOJ: oesophageal cancer
• Epicentre of the tumour >2cm from the GOJ: gastric cancer

5. • Histological
• Traditionally, gastric cancer was classified based on the Lauren criteria (1965) into two
histological subtypes:
• Intestinal: more commonly seen in males, older ages and better prognosis
• Diffuse: equal sex prevalence, seen in younger patients, worse prognosis.
• These subtypes have very different clinical, pathological and molecular features. If diffuse
gastric cancer involves a major portion, or all of the stomach, it may be referred to as linitis
plastica or ‘leather bottle stomach’.
• More recently, the World Health Organisation (WHO) classified gastric cancers based on
defined histological subtypes, which include:
• Papillary, tubular and mucinous adenocarcinoma: these correlate with the intestinal type
based on the Lauren criteria
• Signet-ring cell and other poorly cohesive carcinomas: these correlate with the diffuse type
based on the Lauren criteria

6. Linitis Plastica seen at endoscopy

7. • Early versus advanced
• Classifying gastric cancers based on whether they are ‘early’ or ‘advanced’
refers to the extent of spread through the stomach wall, which includes the
mucosa, submucosa, muscularis externa and serosa.
• Early: cancer confined to the mucosa or submucosa. May or may not be
associated with lymph node involvement. Much better prognosis (>90% five-
year survival). Further divided based on Paris classification of superficial GI
lesions.
• Advanced: cancer invades the muscularis and beyond. Much worse prognosis
with five year survival ≤60%. May be associated with lymph node and distant
metastasis. Described using Borrmann’s classification into four subtypes.
• Type IV advanced gastric cancer based on Borrmann’s classification is similar to
diffuse gastric cancer with a linitis plastica appearance.

8. • Molecular
• Modern molecular techniques have allowed sequencing of gastric cancers and better
understanding of the genetic mutations associated with different tumour types.
• Gastric cancers are highly heterogeneous with numerous somatic mutations (i.e.
occurring in the tumour) that differ significantly between individuals. TP53, also known
as the 'guardian of the genome’ because of its crucial role in the cell cycle is the most
commonly identified mutation.
• Identifying molecular abnormalities has different clinical implications:
• Guide treatment: identification of HER2 positive tumours may be treated with
trastuzumab (blocks the HER2 receptor).
• Determine prognosis: certain mutations are associated with more unstable tumours and
worse prognosis.
• Suggest hereditary aggregation: mutations in CDH1 are linked to hereditary diffuse
gastric cancer.

9. Etiology
• The gram negative bacterium Helicobacter pylori has a significant role in the
aetiology of gastric cancer.
• Gastric cancer is a very heterogeneous condition, which is influenced by a
variety of environmental, infectious, and patient-related factors (e.g. genetics).
• Environmental
• Smoking and diet are important environmental risk factors for gastric cancer
formation
• Smoking: increase risk of gastritis, peptic ulcers and malignancy
• High salt intake: risk combined with presence of H. pylori infection. Thought to
directly damage mucosa.
• Inadequate intake of fruit and vegetables
• Meat consumption: only possible link

10. • Infectious
• Helicobacter pylori is a gram negative spiral bacterium, which colonises the
stomach. It has been implicated in up to 89% of non-cardia gastric cancers.
• H. pylori infection usually begins in childhood, although the precise mechanism
for acquirement and transmission of the organism is not fully understood. It
causes both acute and chronic inflammation that promotes abnormal cellular
growth, genetic mutations, and dysplasia (discussed in pathophysiology).
• One of the main proteins involved in its pathogenies is CagA, which is an
oncogenic protein that can disrupt epithelial intercellular junctions, increase cell
proliferation, reduce apoptosis, and promote formation of adenocarcinomas
• Other infections linked to gastric cancer include Epstein-Barr virus (EBV).

12. • Patient-related factors
• Patient-related factors include genetic polymorphisms (i.e. unique mutations that
increase risk of gastric cancer), pernicious anaemia (autoantibodies directed
against parietal cells leading to vitamin B12 deficiency) and Menetrier's disease
(rare condition associated with overgrowth of glandular mucous cells).
• In addition, some genetic mutations can be inherited in an autosomal dominant
pattern leading to a very high risk of gastric cancer including hereditary diffuse
gastric cancer (HDGC).

13. Hereditary diffuse gastric cancer
• HDGC is a diffuse type of gastric cancer most commonly due to an inherited
mutation in CDH1.
• HDGC is inherited in an autosomal dominant pattern. The lifetime risk of gastric
cancer is 70% in men and 56% in women. The median age at diagnosis is 38
years old.
• The majority of cases are due to a pathogenic mutations in the CDH1 gene. This
is needed for formation of cadherins, which are important in cell-to-cell
interaction. Other genetic mutations have been linked to HDGC.
• Patients with known HDGC are usually recommend prophylactic total
gastrectomy due to the high risk of cancer. In addition, there is an increased risk
of lobular breast cancer.

14. Pathophysiology
• Gastric cancer is a heterogeneous condition associated with numerous genetic
alterations.
• The development of any cancer is based on the acquirement of sequential
mutations that allow a cell to proliferate uncontrollably. By itself, uncontrolled
proliferation is not sufficient for cancer development. Malignant cells must
develop mechanisms to support their growth, resist cell death and invade
normal tissue. These adaptations occur over years and some cancers have very
classic sequences of events.

15. • Correa’s cascade
• The Correa cascade describes the classic sequence of histological lesions for
the most common gastric cancer: intestinal type adenocarcinoma. It was first
described in 1975, but later linked with infection by H. pylori following its
identification as a cause of gastritis in 1983.
• The sequence progresses from normal gastric mucosa to gastric dysplasia,
which is high-risk of developing invasive carcinoma:
1. Normal gastric mucosa
2. Chronic non-atrophic gastritis
3. Chronic atrophic gastritis (CAG)
4. Intestinal metaplasia
5. Dysplasia

17. Clinical features
• Patients with gastric cancer may be asymptomatic or present with non-specific
symptoms.
• Symptoms
• Constitutional symptoms: fevers, anorexia, lethargy, weight loss
• Dysphagia: if involvement of gastric cardia
• Indigestion
• Dyspepsia
• Nausea/vomiting
• Haematemesis/melaena
• Post-prandial fullness

18. • Signs
• Usually absent unless late presentation with distant spread
• Pallor
• Cachexia
• Lymphadenopathy
• Virchow node: left supraclavicular node
• Metastatic lesions
• Hepatomegaly
• Sister Mary Joseph nodule: periumbilical metastasis

19. • Paraneoplastic syndromes
• These refer to the non-metastatic manifestations of malignancy.
• Acanthosis nigricans: velvety hyperpigmentation of the skin, usually in skin folds (e.g.
axilla)
• Dermatomyositis: inflammatory myopathy characterised by a helicotropic rash (purple rash
around the eyes) and Gottron's papules (red areas over the knuckles).
• Erythema gyratum repens: erythematous rash with an annular (ring-shaped) appearance.
Usually involves limbs and trunk.
• Gastric outlet obstruction (GOO)
• GOO occurs when there is obstruction to emptying of the stomach at the pylorus. This may
occur due to a fibrotic stricture of obstructing tumour.
• Classic features include early satiety, abdominal fullness, nausea, vomiting, weight loss.
On auscultation of the stomach there may be a succussion splash (sloshing sound heard
on patient movement due to a full stomach).

20. Gastric Adenocarcinoma Upper Gastrointestinal
Cancer

21. Suspected cancer referral
• Early recognition and diagnosis is essential to improve mortality.
• The NICE (NG12) guideline outlines recommendations for the referral of suspected
cancer cases including upper gastrointestinal cancers. Below details the recommended
referral for suspected gastric cancer.
• Urgent (two week wait) referral
• This means referring a patient for appropriate investigations (e.g. gastroscopy) for
suspected gastric cancer within two weeks. It is usually combined with a clinic
appointment and CT imaging.
• Upper abdominal mass consistent with gastric cancer, OR
• Dysphagia, OR
• > 55 years with weight loss and one of the following:
• Upper abdominal pain
• Reflux
• Dyspepsia

22. • Non-urgent referral
• This means referral for a non-urgent gastroscopy to assess for gastric pathology. Usually
performed within 6 weeks.
• Haematemesis, OR
• > 55 years with treatment resistant dyspepsia, OR
• > 55 years with upper abdominal pain and anaemia, OR
• Thrombocytosis with one of the following:
• Nausea/vomiting
• Weight loss
• Reflux
• Dyspepsia
• Upper abdominal pain
• Nausea/vomiting with one of the following:
• Weight loss
• Reflux
• Dyspepsia
• Upper abdominal pain
• NOTE: Upper and lower gastrointestinal (GI) investigations should also be considered to
investigate for GI malignancy (inc. gastric cancer) in all postmenopausal female and male patients
where IDA has been confirmed unless there is a history of significant overt non-GI blood
loss. British Society of Gastroenterology guidelines 2011.

23. Diagnosis
• Gastric cancer is diagnosed using upper GI endoscopy and biopsies of
suspected lesions.
• Gastric cancer may be suspected based on clinical features or incidental finding
on imaging (i.e. thickening of the gastric mucosa). However, definitive diagnosis
is made using upper GI endoscopy, known as gastroscopy.
•
All patients with suspected gastric cancer should undergo gastroscopy to enable
direct visualisation of the gastric mucosa followed by biopsies of suspected
lesions. Biopsies are subsequently sent for histological analysis to see if any
features of malignancy are present.

24. Evidence of early gastric cancer at gastroscopy

25. Investigations
• Bloods
• Full blood count
• Serum iron, transferrin saturation, total iron binding capacity (TIBC)
• Urea & electrolytes
• Liver function tests
• Bone profile
• Clotting screen
• Renal function

26. • Imaging
• CT chest/abdomen/pelvis: patients with suspected gastric cancer undergo CT
imaging to help stage the cancer, which means assessing how locally advanced
it is and looking for distant spread.
• Abdominal ultrasound: may be used to assess for liver metastasis. Usually
superseded by CT.
• PET-CT: offered to patients with potentially resectable disease (i.e. candidates
for surgery) to assess for distant disease not detected by conventional CT.

27. Stomach cancer CT
Stomach cancer CT

28. • Special
• Gastroscopy: principle investigation for diagnosis
• Endoscopic ultrasound (EUS): performed at time of endoscopy. Sometimes
completed to help more accurately stage gastric cancer if it will change
management
• Diagnostic laparoscopy: can be offered to more accurately stage gastric cancer.
Particularly important if the disease is locally advanced but potentially
resectable.
• HER2 testing
• Human epidermal growth factor receptor 2 (HER2) testing should be completed
on patients with metastatic gastric cancer as treatment directed against the
HER2 receptor may be used in treatment regimens.

29. Staging
• Tumour
• TX: Primary tumour cannot be assessed
• T0: No evidence of primary tumour
• Tis: Carcinoma in situ: intraepithelial tumour without invasion of the lamina propria
• T1: Tumour invades lamina propria or submucosa
• T1a: Tumour invades the lamina propria or the muscularis mucosae
• T1b: Tumour invades the submucosa
• T2: Tumour invades the muscularis propria
• T3: Tumour penetrates the subserosal connective tissue without invasion of the
visceral peritoneum or adjacent structures
• T4: Tumour invades the serosa or adjacent structures
• T4a: Tumour invades the serosa
• T4b: Tumour invades adjacent structures

30. • Node
• NX: Regional lymph node(s) cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in 1–2 regional lymph nodes
• N2: Metastasis in 3–6 regional lymph nodes
• N3: Metastasis in 7 or more regional lymph nodes
• Metastasis
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis or positive peritoneal cytology

31. Management
• The management of gastric cancer depends on the extent of cancer and patients
fitness.
• Treatment options
• There are numerous treatment options for the management of gastric cancer:
• Surgery: resection of gastric or gastro-oesophageal tumours (e.g. gastrectomy).
• Endoscopic techniques: mucosal resection or mucosal dissection
• Radiotherapy: use of high energy rays to destroy cancer cells.
• Chemotherapy: use of anti-cancer medications to destroy cancer cells
• Targeted cancer drugs: monoclonal antibodies against certain receptors (e.g. HER2)
• Palliative care: use of chemotherapy or radiotherapy for disease or symptom control
without aiming to cure
• Best supportive care: focus primarily on symptoms and quality of life without systemic
treatments.

32. • Determining choice
• Surgical resection of gastric cancer is potentially curable. However, patients with
locally advanced disease are high risk of recurrence so a combination of
therapies is needed.
• Operable (early stage): refers to patients with T1 tumours without lymph node
involvement or metastasis. Endoscopic or limited surgical resection may be
suitable
• Operable (advanced stage): refers to patients with >T1N0 tumours. All patients
with stage IB-III gastric cancer may be considered for resection if fit enough.
This needs to be combined with chemotherapy or chemoradiotherpy.
• Non-operable: refers to patients who are not suitable for operative management
or there is evidence of distant spread. Chemotherapy is the main option. A small
proportion may be considered for surgery if significant response.

33. Operable
• The treatment of choice for early disease is surgical or endoscopic resection.
• Operative management is generally considered for patients who are surgical
candidates without evidence of distant spread. Patients with early stage disease
(T1N0) do not require combined management with chemotherapy. However,
those with disease >T1N0 require a combination of treatment options (e.g.
surgery and chemotherapy) due to the risk of recurrence.

34. • Surgery
• Surgical resection involves removal of the whole stomach or only a portion of
the stomach. The remnant stomach or oesophagus is then joined to the
jejunum. Options include:
• Subtotal gastrectomy
• Total gastrectomy
• Oesophago-gastrectomy (if GOJ involvement)
• The choice of surgery depends on the location and size of the tumour and
presence of lymph node involvement. Patients with lymph node involvement will
usually undergo lymph node dissection at the time of surgery.

35. • Endoscopic therapy
• Patients with small, early gastric cancers that are confined to the mucosa may be
considered for endoscopic resection. There are two options:
• Endoscopic mucosal resection (EMR)
• Endoscopic submucosal dissection (ESD): treatment of choice
• Systemic anti-cancer therapy
• The principle anti-cancer therapy in gastric cancer is chemotherapy. Pre-operative
chemotherapy, which includes a combination of platinum/fluoropyrimidine should be
offered to all patients with ≥stage IB resectable gastric cancer.
• If patients undergo surgery before administration of chemotherapy, it should be offered
post-operatively and may be combined with radiotherapy.

36. Non-operable
• Patients with advanced non-operable or metastatic gastric cancer should
be offered chemotherapy if fit enough.
• The principle treatment for metastatic or non-operable gastric cancer
is chemotherapy. This is usually platinum/fluoropyrimidine combinations. Those
who are not fit enough to undergo systemic treatment should undergo best
supportive care, which focuses on symptom control and quality of life.

37. • Systemic anti-cancer therapy
• Chemotherapy forms the principle treatment in patients with metastatic or non-
operable gastric cancer, which improves quality of life and survival.
Chemotherapy combination regimens depend on whether the tumour is HER2
positive.
• HER2-negative advanced/metastatic gastric cancer: double/triple chemotherapy
regimens (e.g. oxaliplatin, 5-Fluorouracil +/- epirubicin)
• HER-2-positive advanced metastatic gastric cancer: Trastuzumab (monoclonal
antibody against HER2-receptor) in combination with platinum/fluoropyrimidine
chemotherapy.
• Newer agents and clinical trials may be available to patients. This depends on
patient co-morbidities, performance status and patient choice.

38. Prognosis
• The five year survival of gastric cancer is poor at ~20%.
• Survival from gastric cancer depends on stage. The five year survival for early
stage disease is almost 90% but only 24% in patients with stage 3 disease. The
overall survival is poor because the disease is usually advanced at presentation
and is more common in elderly patients who are likely to have multiple co-
morbidities.
• Nevertheless, survival from gastric cancer has significantly improved within the
UK over the last 40 years.

39. Prepared by: Yahya Berke DEMIREL
ONMU
1st Group
5th Course