gastric cancer

Gastric TumorsBy

Dr. Haytham M. FayedAssistant professor of surgical oncology

Alexandria Faculty of Medicine

BLOOD SUPPLY

Lymphatic drainage

Lymphatic drainageLymph node stations draining the stomach

according to the Japanese Research Society for Gastric

Cancer. Stations 3 to 6 are

commonly removed with D1 gastrectomy. Stations 1, 2, and 7 to

12 are commonly removed with D2

gastrectomy

Lymphatic drainage

Adenocarcinoma

Adenocarcinoma

• Carcinoma of the stomach is a major cause of cancer mortality worldwide.

• Its prognosis tends to be poor, with cure rates little better than 5–10 per cent,

• although better results are obtained in Japan, where the disease is common. Gastric cancer is actually an eminently curable disease provided that it is detected at an appropriate stage and treated adequately.

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• It rarely disseminates widely before it has involved the lymph nodes and, therefore, there is an opportunity to cure the disease prior to dissemination. Early diagnosis is therefore the key to success with this disease.

• Unfortunately, the late presentation of many cases is the cause of the poor overall survival figures.

• The only treatment modality able to cure the disease is SURGICAL RESECTION

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• IncidenceThere are marked variations in the incidence of gastric cancer worldwide. In the UK, it is approximately 15/100 000 per year, in the USA 10/100 000 per year and in Eastern Europe 40/100 000 per year.

In Japan, the disease is much more common, with an incidence of approximately 70/100 000 per year, and there are small geographical areas in China where the incidence is double that in Japan.

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• Incidence

• The disease affects men disproportionately, with more than 60% of new cases occurring in men.

• It is a disease of older individuals, with peak incidence in the seventh decade of life.

• Worldwide, gastric cancer is the fourth most common cancer and the second leading cause of cancer death.

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Aetiology• Diet and Drugs• Helicobacter pylori• Epstein-Barr Virus• Genetic Factors• Premalignant Conditions of the Stomach

PolypsAtrophic GastritisIntestinal MetaplasiaBenign Gastric UlcerGastric Remnant CancerMénétrier’s disease

The Genetic Landscape of Gastric Cancer

• The molecular profile of gastric cancer is heterogeneous, partly due to different classification systems being used, and also because most analyses have considered a very limited number of cases


The Cancer Genome Atlas (TCGA) project point to a new four molecular classification of gastric cancers:

(i) Gastric cancers positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1 and PD-L2;

(ii) Microsatellite unstable gastric cancers, which show elevated mutation rates; (iii) Genomically stable gastric cancers, which are enriched for the diffuse histological

variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and

(iv) Gastric cancers with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases


Specific Genomic Aberrations in Gastric Cancer• TP53• MUC6• ARID1A


Pathways Frequently Harboring Driver Mutations

• Adherens Pathway: Gastric cancer driver mutations identified within the genes of this pathway include CDH1, CTNNB1, CTNNA1, and RHOA.

• Wnt Pathway—(CTNNB1, RNF43): The Wnt signal transduction pathway is a highly conserved signaling cascade mediating fundamental cellular and biologic processes including growth, development, polarity, and organogenesis

• TGF-β Pathway Multiple TGF-β family genes demonstrate mutations in primary human GC, implicating them as possible drivers in gastric carcinogenesis. These include TGFBR2, SMAD4, and ELF 3


• METcMET is a receptor tyrosine kinase whose endogenous ligand is hepatocyte growth factor (HGF). This proto-oncogene is activated in a variety of human cancers, including approximately 10 % of human gastric carcinomas.

• HER2Human epidermal growth factor receptor 2 (HER2) is overexpressed in several types of human cancers, and has become a well-established player in the pathogenesis of up to 54% of gastric carcinomas.

HER2 is well recognized as a proto-oncogene, as its amplification results in overexpression of the HER2 RTK protein, which promotes cell proliferation and survival, properties promoting malignant transformation.

In addition to being found on the cell membrane, HER2 receptors have also been localized to the cellular nucleus, functioning as transcription factors for proto-oncogenes such as cyclin D1

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Pathology:Dysplasia It is generally accepted that gastric dysplasia is the universal precursor to gastric adenocarcinoma.

Patients with severe dysplasia should be considered for gastric resection if the abnormality is widespread or multifocal, or EMR if the severe dysplasia is localized.

Patients with mild dysplasia should be followed with endoscopic biopsy surveillance, and Helicobacter eradication.

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Pathology:Early Gastric Cancer • Defined as adenocarcinoma limited to the mucosa and submucosa of the

stomach, regardless of lymph node status. • Approximately 10% of patients with early gastric cancer will have lymph

node metastases. • There are several types and subtypes of early gastric cancer • Approximately 70% of early gastric cancers are well differentiated, and

30% are poorly differentiated. • The overall cure rate with adequate gastric resection and

lymphadenectomy is 95%. • Small intramucosal lesions can be treated with EMR.

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Pathology:Gross Morphology and Histologic SubtypesThere are four gross forms of gastric cancer: polypoid, fungating, ulcerative, and scirrhous.

In the first two, the bulk of the tumor mass is intraluminal. Polypoid tumors are not ulcerated; fungating tumors are elevated intraluminally, but also ulcerated.

In the latter two gross subtypes, the bulk of the tumor mass is in the wall of the stomach. Ulcerative tumors are self-descriptive; scirrhous tumors infiltrate the entire thickness of the stomach and cover a very large surface area.

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.The Borrmann classification This system was developed in 1926; it remains useful today for the description of endoscopic findings.

This system divides gastric carcinoma into five types, depending on the lesion’s macroscopic appearance

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HistologyThe most important prognostic indicators in gastric cancer are both histologic: lymph node involvement and depth of tumor invasion. Tumor grade (degree of differentiation: well, moderately, or poorly) is also important prognostically.World Health Organization histologic typing of gastric CancerAdenocarcinoma

• Papillary adenocarcinoma• Tubular adenocarcinoma• Mucinous adenocarcinoma• Signet-ring cell carcinoma

Adenosquamous carcinomaSquamous cell carcinomaSmall cell carcinomaUndifferentiated carcinomaOthers

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HistologyLauren classification separates gastric cancers into intestinal type (53%), diffuse type (33%), and unclassified (14%). The Ming classification also is useful and easy to remember, with only two types—expanding (67%) and infiltrative (33%).

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Pathologic Staging

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Clinical Manifestationssymptoms• The most common symptoms are weight loss and decreased

food intake due to anorexia and early satiety. • Abdominal pain (usually not severe and often ignored) also is

common. • Other symptoms include nausea, vomiting, and bloating. • Acute GI bleeding is somewhat unusual (5%), but chronic

occult blood loss is common and manifests as iron deficiency anemia and heme-positive stool.

• Dysphagia is common if the tumor involves the cardia of the stomach.

• Paraneoplastic syndromes such as Trousseau’s syndrome (thrombophlebitis), acanthosis nigricans (hyperpigmentation of the axilla and groin), or peripheral neuropathy are rarely present.

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Clinical ManifestationssignsPhysical examination typically is normal. • Other than signs of weight loss, specific physical

findings usually indicate incurability.• A focused examination in a patient in whom gastric

cancer is a likely part of the differential diagnosis should include an examination of the neck, chest, abdomen, rectum, and pelvis.

• Cervical, supraclavicular (on the left referred to as Virchow’s node), and axillary lymph nodes may be enlarged,

• There may be a metastatic pleural effusion, or aspiration pneumonitis in a patient with vomiting and/or obstruction.

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Clinical ManifestationssignsPhysical examination typically is normal. • An abdominal mass could indicate a large (usually

T4 incurable) primary tumor, liver metastases, or carcinomatosis (including Krukenberg’s tumor of the ovary).

• A palpable umbilical nodule (Sister Joseph’s nodule) is pathognomonic of advanced disease, or there may be evidence on exam of malignant ascites.

• Rectal exam may reveal heme-positive stool and hard nodularity extraluminally and anteriorly, indicating so-called drop metastases, or rectal shelf of Bulmer in the pouch of Douglas.

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Diagnostic Evaluation:

Distinguishing between peptic ulcer and gastric cancer on clinical grounds alone is usually impossible.Patients over the age of 45 years old who have new-onset dyspepsia, as well as all patients with dyspepsia and alarm symptoms (weight loss, recurrent vomiting, dysphagia, evidence of GI bleeding, or anemia) or with a family history of gastric cancer

should have prompt upper endoscopy and biopsy if a mucosal lesion is noted.

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PRINCIPLES OF ENDOSCOPIC STAGING AND THERAPY • diagnosis Diagnostic and surveillance endoscopies are performed with the

goal of determining the presence and location of neoplastic disease and to biopsy any suspicious lesion.

Multiple (6–8) biopsies using standard size endoscopy forceps

Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) can be performed in the evaluation of small lesions.

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PRINCIPLES OF ENDOSCOPIC STAGING AND THERAPY STAGING • EUS performed prior to any treatment is important in the initial clinical

staging of gastric cancer.• Careful attention to ultrasound images provides evidence of depth of

tumor invasion (T-category), presence of abnormal or enlarged lymph nodes likely to harbor cancer (N-assessment), and occasionally signs of distant spread, such as lesions in surrounding organs (M-category) or the presence of ascites.6 This is especially important in patients who are being considered for endoscopic resection (EMR or ESD).

• FNA of suspicious lymph nodes should be performed if it can be achieved without traversing an area of primary tumor or major blood vessels, and if it will impact on treatment decisions

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PRINCIPLES OF ENDOSCOPIC STAGING AND THERAPY TREATMENT • EMR or ESD of early-stage gastric cancer can be considered adequate therapy

when the lesion is ≤2 cm in diameter, is shown on histopathology to be well or moderately well differentiated, does not penetrate beyond the superficial submucosa, does not exhibit LVI, and has clear lateral and deep margins.

• En-bloc excision of small gastric lesions by ESD has been shown to be more effective than EMR in curing small early-stage gastric cancer, but requires greater skills and instrumentation to perform and has a significant risk of complications including perforation.

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Indications for Endoscopic Resection

(1) Differentiated (well and/or moderately differentiated and/or papillary adenocarcinoma) histology,

(2) No ulcerative findings and a depth of invasion that is confined to the mucosa (T1a), (3) Tumor diameter ≤ 20 mm, and

(4) Absence of lymphatic-vascular involvement

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PRINCIPLES OF ENDOSCOPIC STAGING AND THERAPY POST-TREATMENT SURVEILLANCE • Endoscopic surveillance following definitive treatment of gastric cancer

requires careful attention to detail for mucosal surface changes, and multiple (4–6) biopsies of any visualized abnormalities. Strictures should be biopsied to rule out neoplastic cause.

• EUS performed in conjunction with endoscopy exams has a high sensitivity for recurrent disease.16 EUS-guided FNA should be performed if suspicious lymph nodes or areas of wall thickening are seen.

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Treatment:

Surgical resection is the only curative treatment for gastric cancer and most patients with clinically resectable locoregional disease should have gastric resection.

Complete resection with adequate margins (4 cm or greater) is widely considered as a standard goal, whereas the type of resection (subtotal vs. total gastrectomy) along with extent of lymph node dissection remains a subject of controversy. Obvious exceptions include patients who cannot tolerate an abdominal operation, and patients with overwhelming metastatic disease.

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Treatment:

The goal of curative surgical treatment is resection of all tumor (i.e., R0 resection). Thus, all margins (proximal, distal, and radial) should be negative and an adequate lymphadenectomy performed.

More than 15 resected lymph nodes are required for adequate staging.

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Treatment:Extent of gastrectomy:The standard operation for distal gastric cancer is radical subtotal gastrectomy. Unless required for R0 resection, total gastrectomy confers no additional survival benefit and may have adverse nutritional or quality-of-life consequences, and higher peri-operative morbidity and mortality.

Gastrectomy and reconstruction

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Treatment:Extent of gastrectomy:

Total gastrectomy with Roux-en-Y esophagojejunostomy may be required for R0 resection, and may be the best operation for patients with proximal gastric adenocarcinoma.

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Treatment:Extent of lymphadenectomy:According to the type of gastrectomy, the definition of extent of lymphadectomy is different.

D1 lymphadenectomy in distal gastrectomy requires the dissection of the stations 1, 3, 4sb, 4d, 5, 6, 7.

Furthermore, additional resection of stations 8a, 9, 11p and 12a is needed for D2 lymphadenectomy.

LymphadenectomyD0, D1, D2,

LymphadenectomyD0, D1, D2

• Lymph node dissection may be classified as D0, D1, or D2 depending on the extent of lymph nodes removed at the time of gastrectomy. D0 refers to incomplete resection of N1 lymph nodes.

• D1 involves gastrectomy and the removal of the involved proximal or distal part of the stomach or the entire stomach (distal or total resection), including the greater and lesser omental lymph nodes (which would be the right and left cardiac lymph nodes, along lesser and greater curvature, and suprapyloric along the right gastric artery and infra pyloric area).

• D2 involves D1 plus the removal of all the nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery.

• The technical aspects of performing a D2 lymph node dissection require a significant degree of training and expertise.

SURGICAL FINDINGS

Separation of the greater omentum and the anterior two leaflets of the transverse mesocolon.

The dissection was carried onto the pancreas taking the pancreatic capsule with the specimen

Mid colic ves

Go & ant 2 leaf of tmc

panc

Rt gep ves

Duodenal trasection

Dissection of the celiac trunk and its tributaries

Greater omentum

spleenstomach

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Treatment:Radiation therapy for Gastric Cancer:

RT (preoperative, postoperative, or palliative) can be an integral part of treatment for gastric cancer. In general, Siewert I and II tumors should be managed with RT guidelines applicable to esophageal and EGJ cancers.

Depending on the clinical situation, Siewert III tumors may be more appropriately managed with RT guidelines applicable to either esophageal and EGJ cancers or gastric cancer.

These recommendations may be modified depending on the location of the bulk of the tumor..

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Treatment:Radiation therapy for Gastric Cancer:

Radiation therapy (RT) has been assessed in randomized trials in both the preoperative and postoperative setting in patients with resectable gastric cancer.

In the trial of Zhang and colleagues randomized 370 patients to preoperative RT or surgery alone. There was a significant improvement in survival with preoperative RT (30% vs. 20%, P = .0094). Resection rates were also higher in the preoperative RT arm (89.5%) compared to surgery alone (79%), suggesting that preoperative RT improves local control and survival.

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Treatment:

The value of preoperative chemoradiation therapy for patients with resectable gastric cancer remains uncertain and is the subject of an ongoing international prospective phase III randomized trial.

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Treatment:

Postoperative Chemotherapy Postoperative chemotherapy following complete resection has not been associated with a significant survival benefit in patients with gastric cancer.

In the randomized trial conducted by Japan Clinical Oncology Group (JCOG 8801), curative surgery alone was associated with very good survival rates in patients with T1 cancer.

However, two recent, large, Asian, randomized, phase III studies (ACTS GC trial and CLASSIC trial) have documented survival benefit for postoperative chemotherapy after curative D2 lymph node dissection in patients with gastric cancer

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Treatment:

Postoperative Chemotherapy

The ACTS GC trial in Japan and The CLASSIC trial (conducted in South Korea, China, and Taiwan) support the use of postoperative chemotherapy after curative surgery with D2 lymph node dissection in patients with resectable gastric cancer.

However, it should be noted that the benefit of this approach following a D1 or D0 lymph node dissection has not been documented in randomized clinical trials. Thus, postoperative chemoradiation remains an effective treatment of choice for this group of patients

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Treatment:

Targeted Therapies Trastuzumab and ramucirumab are the 2 targeted therapies approved for the treatment of advanced or metastatic gastric cancer.trastuzumab in combination with chemotherapy as a new standard of care for patients with HER2-positive advanced or metastatic gastric and EGJ adenocarcinoma. However, the benefit of trastuzumab was limited only to patients with a tumor score of IHC 3 + or IHC 2+ and FISH positive. There was no significant survival benefit for patients whose tumors were IHC 0 or 1+ and FISH positive.

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Treatment:

Targeted Therapies Trastuzumab and ramucirumab are the 2 targeted therapies approved for the treatment of advanced or metastatic gastric cancer.Ramucirumab, a VEGFR 2 antibody, has shown promising results in the treatment of patients with previously treated advanced or metastatic gastric or EGJ cancers in phase III clinical trials.

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Treatment:

Unresectable Locally Advanced, Recurrent or Metastatic Disease Palliative therapy (systemic therapy, clinical trial, or best supportive care) is recommended for patients with unresectable locally advanced, recurrent or metastatic gastric cancer.

Surgery should be considered as an option for resectable locoregional recurrence in medically fit patients.

Thank you

gastric cancer

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