gastric%20cancer
GASTRIC CANCER
Treatment Guideline Chart
Gastric cancer is the cancer originating in the esophagus, esophagogastric junction and stomach.
Most of gastric cancers are adenocarcinomas, subdivided according to histological appearances into diffuse (undifferentiated) and intestinal (well differentiated) types.
It is the 4th most common cancer and the 2nd most common cause of cancer-related deaths worldwide.
Most common sites of gastric cancer are the proximal lesser curvature, cardia and esophagogastric junction.

Gastric%20cancer Diagnosis

Staging

  • To ensure that patients are appropriately selected for treatment interventions, a careful cancer tumor staging is essential
  • The most common sites of distant spread of gastric cancer are the liver, the peritoneum and distal lymph nodes
    • Less common sites are the lungs and brain
  • A minimum of 15 examined lymph nodes is recommended for adequate staging
  • Tumor size, perineural or lymphovascular invasion and the nodal status have been shown to be stronger predictors of survival
  • There are 2 major classifications being used:
    • American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC)
    •  Japanese classification is more elaborate and is based on anatomic involvement, particularly the lymph node stations

Tumor, Nodes and Metastases (TNM) System (8th Edition of AJCC/UICC guidelines)

Primary tumor
Tx Tumor size cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ; intraepithelial tumor has no lamina propria invasion
T1a Tumor invades lamina propria or muscularis mucosa
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures
Also includes tumors that are extending into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures (that include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine and retroperitoneum)
Regional Lymph Node (LN) Evaluation
  Nx   Regional lymph node (LN) cannot be assessed
N0 No regional lymph node (LN) metastasis
N1 Metastases in one to two regional lymph nodes
N2 Metastases in three to six regional lymph nodes
N3 Metastases in seven or more regional lymph nodes
N3a Metastases in seven to fifteen regional lymph nodes
N3b Metastases in sixteen or more regional lymph nodes
Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis present or positive peritoneal cytology
Histologic Grade (G)
  Gx   Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated, undifferentiated
Clinical Staging
  Stage 0   Tis N0 M0
Stage I T1 N0 M0
T2 N0 M0
Stage IIA T1 N1, N2, N3 M0
T2 N1, N2, N3 M0
Stage IIB T4a N0 M0
Stage III T3 N1, N2, N3 M0
T4a N1, N2, N3 M0
  Stage IVA   T4b Any N M0
  Stage IVB   Any T Any N M0
Pathological Staging
  Stage 0   Tis N0 M0
Stage IA T1 N0 M0
Stage IB
T1 N1 M0
T2 N0 M0
Stage IIA T1 N2 M0
T2 N1 M0
T3 N0 M0
Stage IIB  T1 N3a M0 
T2 N2 M0 
T3 N1 M0 
T4a N0 M0 
T4a N0 M0 
Stage IIIA T2 N3a M0 
T3 N2 M0 
T4a N1 or N2 M0 
T4b N0 M0 
Stage IIIB  T3 N3b M0
T3 N3b M0 
T3 N3a M0
T4a N3a M0 
T4b N1 or N2 M0 
  Stage IIIC   T3 N3b M0
  T4a N3b M0
  T4b N3a or N3b M0
  Stage IV   Any T Any N M1

Japanese Classification of Gastric Carcinoma (Japanese Gastric Cancer Association)

Clinical Classification

  • It is used after pretreatment assessment in order to decide if surgery is an appropriate treatment option
  • Essential in the selection of treatment selection and evaluation of therapeutic options
  • Derived from physical examination (PE), imaging studies, endoscopic, laparoscopic and surgical findings, biopsy, cytology, biochemical and biological investigations

Pathological Classification

  • Provides prognostic information
  • Helps in deciding if additional therapy is needed
  • Derived from histological examination of surgically or endoscopically resected specimens; peritoneal lavage cytology

Histological Classification of Gastric Tumors

  • Histological tumor findings are recorded in the following order: Tumor location, macroscopic type, size, histological type, depth of invasion, cancer-stroma relationship, pattern of infiltration, lymphatic invasion, venous invasion, lymph node metastasis, and resection margins

Size and Number of Lesions

  • 2 greatest dimensions should be recorded for each lesion
  • If there are multiple lesions, the most advanced T category (or the largest lesion where the T stage is identical) is classified

Tumor Location

  • 3 portions of the stomach
    • U - upper third
    • M - middle third
    • L - lower third
    • E - esophagus
    • D - duodenum
    • EGJ - esophagogastric junction (border between the esophageal and gastric muscles)
  • Clinically, tumor location is often expressed as: Cardia, fundus, body, incisura and antrum

Macroscopic Types of Gastric Tumors

  • Gross tumor morphology is categorized as either superficial or advanced type
  • Superficial type is typical of T1 tumors while T2-4 tumors usually manifest advanced types
  • Type 0 - Typical of T1 tumors (superficial)
    • Type 0-I - Polypoid tumors (protruding)
    • Type 0-II - Tumors with or without minimal elevation or depression relative to the surrounding mucosa (superficial)
    • Type 0-IIa - Slightly elevated tumors (superficial elevated)
    • Type 0-IIb - Tumors without elevation or depression (superficial flat)
    • Type 0-IIc - Slightly depressed tumors (superficial depressed)
    • Type 0-III - Tumors with deep depression (excavated)
  • Type 1 - Polypoid tumors sharply demarcated from the surrounding mucosa (mass)
  • Type 2 - Ulcerated tumors with raised margins surrounded by a thickened gastric wall with clear margins (ulcerative)
  • Type 3 - Ulcerated tumors with raised margins surrounded by thickened gastric wall without clear margins (infiltrative ulcerative)
  • Type 4  - Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear (diffuse infiltrative)
  • Type 5 - Tumors that cannot be classified into any of the above types (unclassifiable)

Histological Types of Gastric Tumors 

Benign Epithelial Tumor

  • Adenoma

Malignant Epithelial Tumor (Common Type)

  • Papillary adenocarcinoma (pap)
  • Tubular adenocarcinoma (tub)
    • Well-differentiated (tub1)
    • Moderately differentiated (tub2)
  • Poorly differentiated adenocarcinoma (por)
    • Solid type (por1)
    • Non-solid type (por2)
  • Signet-ring cell carcinoma (sig)
  • Mucinous adenocarcinoma (muc)

Malignant Epithelial Tumor (Special Type)

  • Carcinoid tumor
  • Endocrine carcinoma
  • Carcinoma with lymphoid stroma
  • Hepatoid adenocarcinoma
  • Adenosquamous carcinoma
  • Squamous cell carcinoma
  • Undifferentiated carcinoma
  • Miscellaneous carcinoma

Non-epithelial Tumor

  • Gastrointestinal stromal tumor (GIST)
  • Smooth muscle tumor
  • Neurogenic tumor
  • Miscellaneous non-epithelial tumors

Lymphoma (B-cell Lymphoma)

  • MALT (mucosa-associated lymphoid tissue) lymphoma
  • Follicular lymphoma
  • Mantle cell lymphoma
  • Diffuse large B-cell lymphoma
  • Other B-cell lymphomas 

Lymphoma (T-cell Lymphoma)

Lymphoma (Other Lymphomas)

Metastatic Tumor

Tumor-like Lesion

  • Hyperplastic polyp
  • Fundic gland polyp
  • Heterotopic submucosal gland
  • Heterotopic pancreas
  • Inflammatory fibroid polyp (IFP)

Gastrointestinal Polyposis

  • Familial polyposis coli, Peutz-Jeghers syndrome, juvenile polyposis, Cowden’s disease

Depth of Tumor Invasion

  • TX - Unknown depth of tumor
  • T0 - No evidence of primary tumor
  • T1- Tumor confined to the mucosa (M) or submucosa (SM)
    • T1a - Tumor confined to the mucosa (M) 
    • T1b - Tumor confined to the submucosa (SM)
  •  T2 - Tumor invades the muscularis propria (MP)

Cancer Stromal Volume (to be recorded for T1b or deeper tumors)

  • Medullary type (med) - scanty stroma
  • Scirrhous type (sci) - abundant stroma
  • Intermediate type (int) - the quantity of stroma is intermediate between the two above types

Tumor Infiltrative Pattern into the Surrounding Tissues (to be recorded in T1b or deeper tumors)

  • INFa - Tumor displays expanding growth with a distinct border from the surrounding tissue
  • INFb - Tumor shows an intermediate pattern between interferon-a and interferon-c (INFa and INFc)
  • INFc - Tumor displays infiltrative growth with no distinct border with the surrounding tissue

Capillary Invasion

Lymphatic

  • ly0 - No lymphatic invasion
  • ly1 - Minimal lymphatic invasion
  • ly2 - Moderate lymphatic invasion
  • ly3 - Marked lymphatic invasion

Venous

  • v0 - No venous invasion
  • v1 - Minimal venous invasion
  • v2 - Moderate venous invasion
  • v3 - Marked venous invasion

Anatomical Definitions of Lymph Node Stations (LNs) and Lymph Node Regions

  • Lymph node stations 1-12 and 14v are defined as regional gastric lymph nodes
  • Metastasis to any other nodes is classified as distant metastasis (M1)
  • In tumors invading the esophagus, lymph node numbers 19, 20, 110 and 111 are included as regional lymph nodes
  • For carcinomas arising in the remnant stomach with a gastrojejunostomy, jejunal lymph nodes adjacent to the anastomosis are included as regional lymph nodes
    Staging

    1

    Right paracardial lymph node stations (LNs) including those along the first branch of the ascending limb of the left gastric artery
    2 Left paracardial lymph node stations (LNs) including those along the esophagocardiac branch of the left subphrenic artery
    3a Lesser curvature lymph node stations (LNs) along the branches of the left gastric artery
    3b Lesser curvature lymph node stations (LNs) along the 2nd branch and distal part of the right gastric artery
    4sa Left greater curvature lymph node stations (LNs) along the short gastric arteries (perigastric area)
    4sb Left greater curvature lymph node stations (LNs) along the left gastroepiploic artery (perigastric area)
    4d Right greater curvature lymph node stations (LNs) along the 2nd branch and distal part of the right gastroepiploic artery
    5 Suprapyloric lymph node stations (LNs) along the 1st branch and proximal part of the right gastric artery
    6 Infrapyloric lymph node stations (LNs) along the 1st branch and proximal part of the right gastroepiploic artery down to the confluence of the right gastroepiploic vein and the anterior superior pancreatoduodenal vein
    7 Lymph node stations (LNs) along the trunk of left gastric artery between its roots and the origin of its ascending branch
    8a Anterosuperior lymph node stations (LNs) along the common hepatic artery
    8p Posterior lymph node stations (LNs) along the common hepatic artery
    9 Celiac artery lymph node stations (LNs)
    10 Splenic hilar lymph node stations (LNs) including those adjacent to the splenic artery distal to the pancreatic tail, and those on the roots of the short gastric arteries and those along the left gastroepiploic artery proximal to its 1st gastric branch
    11p Proximal splenic artery lymph node stations (LNs) from its origin to halfway between its origin and the pancreatic tail end
    11d Distal splenic artery lymph node stations (LNs) from halfway between its origin and the pancreatic tail end to the end of the pancreatic tail
    12a Hepatoduodenal ligament lymph node stations (LNs) along the proper hepatic artery, in the caudal half between the confluence of the right and left hepatic ducts and the upper border of the pancreas
    12b Hepatoduodenal ligament lymph node stations (LNs) along the bile duct, in the caudal half between the confluence of the right and left hepatic ducts and the upper border of the pancreas
    12p Hepatoduodenal ligament lymph node stations (LNs) along the portal vein in the caudal half between the confluence of the right and left hepatic ducts and the upper border of the pancreas
    13 Lymph node stations (LNs) in the posterior surface of the pancreatic head cranial to the duodenal papilla
    14v Lymph node stations (LNs) along the superior mesenteric vein
    15 Lymph node stations (LNs) along the middle colic vessels
    16a1 Paraaortic lymph node stations (LNs)s in the diaphragmatic aortic hiatus
    16a2 Paraaortic lymph node stations (LNs) between the upper margin of the origin of the celiac artery and the lower border of the left renal vein
    16b1 Paraaortic lymph node stations (LNs) between the lower border of the left renal vein and the upper border of the origin of the inferior mesenteric artery
    16b2 Paraaortic lymph node stations (LNs)between the upper border of the origin of the inferior mesenteric artery and the aortic bifurcation
    17 Lymph node stations (LNs) on the anterior surface of the pancreatic head beneath the pancreatic sheath
    18 Lymph node stations (LNs) along the inferior border of the pancreatic body
    19 Infradiaphragmatic lymph node stations (LNs) predominantly along the subphrenic artery
    20 Paraesophageal lymph node stations (LNs) in the diaphragmatic esophageal hiatus
    110 Paraesophageal lymph node stations (LNs)s in the lower thorax
    111 Supradiaphragmatic lymph node stations (LNs) separate from the esophagus
    112 Posterior mediastinal lymph node stations (LNs) separate from the esophagus and the esophageal hiatus
    Lymph Node Metastasis (N)
    NX Regional lymph nodes 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
       N3a Metastasis in 7-15 regional lymph nodes
       N3b Metastasis in 16 or more regional lymph nodes
    Presence or Absence and Sites of Distant Metastasis (M)
    Mx Distant metastasis status unknown
    M0 No distant metastasis
    M1 Distant metastasis
    Peritoneal Metastasis (P)
    PX Peritoneal metastasis is unknown
    P0 No peritoneal metastasis
    P1 Peritoneal metastasis
    Peritoneal Lavage Cytology (CY)
    CYX Peritoneal cytology not performed
    CY0 Peritoneal cytology negative for carcinoma cells
    CY1 Peritoneal cytology positive for carcinoma cells
    Hepatic Metastasis (H)
    HX Hepatic metastasis is unknown
    H0 No hepatic metastasis
    H1 Hepatic metastasis

Laboratory Tests

Routine Blood Tests

  • Include complete blood count (CBC), differential count, liver and renal function tests
  • To check for evidence of iron-deficiency anemia
  • To determine appropriate treatment options

Gastroscopic or Surgical Biopsy

  • To diagnose, classify histologically and identify the status of molecular biomarkers eg human epidermal growth factor receptor-2 (HER-2)
  • Multiple (6-8) biopsies using standard-size endoscopy forceps are required to provide sufficient specimen for histologic examination

Immunohistochemistry

  • Most widely used primary test for the assessment of human epidermal growth factor receptor-2 (HER-2) overexpression
  • Evaluates the membranous immunostaining of the tumor cells, including intensity and the extent of staining and percentage of immunoreactive tumor cells, with scores ranging from 0 to 3+
  • Score 0 or 1+ means negative for human epidermal growth factor receptor-2 (HER-2) expression
  • Score 2+ is equivocal and needs to have fluorescence in situ hybridization (FISH) for confirmation

Fluorescence in situ hybridization (FISH)

  •  To verify results of human epidermal growth factor receptor-2 (HER-2) testing that are considered equivocal by immunohistochemistry

Tumor Markers

  • Microsatellite instability (MSI) or mismatch repair (MMR) testing should be considered for patients with locally advanced, recurrent or metastatic gastric cancer
    • Performed only in certified laboratories
  • HER-2 and programmed death ligand 1 (PD-L1) expression is recommended for all patients with gastric adenocarcinoma if metastatic adenocarcinoma is suspected or documented
    • HER-2 testing is recommended if therapy with Trastuzumab is being considered for patients with inoperable locally advanced, recurrent or metastatic gastric adenocarcinoma
    • PD-L1 testing should be considered for patients with locally advanced, recurrent, or metastatic gastric adenocarcinoma and possible candidates for PD-1 inhibitor therapy
  • Neurotrophic tropomysin-related kinase (NTRK) gene fusion testing should be considered for patients who are possible candidates for TRK inhibitor therapy

Imaging

Upper Endoscopy

  • Also called esophagogastroduodenoscopy (EGD)
  • Gastric cancer appears like an ulcer, a mushroom-shaped or protruding mass or diffuse, flat, thickened areas of mucosa known as linitis plastica
  • Performed to determine the presence and location of gastric cancer and to biopsy any suspicious lesions

Endoscopic Ultrasound

  • To determine the depth of the tumor invasions (T and N stages), although it is less useful in antral tumors
  • Provides an accurate initial clinical staging of locoregional gastric cancer
  • Preferred modality if early-stage cancer is suspected or to determine early versus locally advanced disease
  • To identify perigastric lymph nodes and presence of malignant or inflammatory lymph nodes
    • These nodes appear as enlarged, hypoechoic (dark), homogenous, well-circumscribed, rounded structures
  • To diagnose submucosal tumor and to differentiate potentially malignant lesions, endoscopic ultrasound with fine needle aspiration biopsy is done

Laparoscopic Staging with Peritoneal Washings for Cytology

  • To exclude metastatic disease involving the diaphragm/peritoneum
  • Indicated for patients with clinical stages ≥T1b gastric cancers
  • Recommended for evaluation of peritoneal spread when surgery or chemoradiation is being considered for patients with unresectable locoregional cancer
  • Recommended in patients receiving preoperative therapy
  • May be useful in patients with T3 and/or N+ gastric cancers who are being considered for surgical resection without preoperative therapy
  • Peritoneal fluid cytology testing may help to improve staging through identification of occult carcinomatosis
  • Positive peritoneal cytology is:
    • Associated with poor prognosis
    • An independent predictor for identifying patients who are at higher risk for recurrence following curative resection
  • Laparoscopic lavage cytology is also very useful to identify subset of patients with distant metastasis (M1) disease who are unlikely to benefit from resection alone

Positron Emission Tomography (PET) Scan

  • In some cases, it improves detection of occult metastatic disease

Positron Emission Tomography/Computed Tomography (PET/CT) Scans

  • Computed tomography (CT) scan is routinely used for preoperative staging
  • CT scans of the chest, abdomen and pelvis are recommended for all gastric cancer patients to evaluate for metastases
  • To predict response to preoperative chemotherapy as well as in the evaluation of recurrent gastric cancer

Evaluation of Performance Status

  • Eastern Cooperative Oncology Group (ECOG) performance status scale and Karnofsky performance status may be used to assess functional status of patients with cancer
  • Patients with ECOG performance score ≥3 or Karnofsky performance score <60% should be offered palliative or best supportive care only
  • Chemoradiation for locally unresectable tumors without previous therapy or systemic therapy in addition to palliative or best supportive care may be offered to patients with ECOG performance score ≤2 or Karnofsky performance score ≥60%

ECOG Performance Status

0 - Fully active; no performance without restriction

1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg office work, light household chores)

2 - Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about >50% of waking hours

3 - Capable of only limited selfcare; confined to bed or chair >50% of waking hours

4 - Completely disabled; cannot carry on any selfcare; totally confined to bed or chair

Karnofsky Performance Status

100 - Normal, no complaints, no evidence of disease

90 - Able to carry on normal activity; minor signs and symptoms of disease

80 - Normal activity with effort, some signs and symptoms of disease

70 - Cares for self but unable to carry on normal activity or to do active work

60 - Requires occasional assistance but is able to care for most personal needs

50 - Requires considerable assistance and frequent medical care

40 - Disabled; special care and assistance

30 - Severely disabled; hospitalization is indicated although death not imminent

20 - Very ill; hospitalization and active supportive care necessary

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