Lect 4-gastric tumors

GASTRIC CANCER Gastric cancer is the second most common fatal cancer in the world with high frequency in Japan. (after lung cancer) The disease presents most commonly in the 5 th and 6 th decades of life and affect males twice as often as females. Contn…

Gastric Cancer Epidemiology Forth common types of cancer Second most common cancer related death Geographic variations (ten times) Continuing decline Primarily a decline of distal GC (2000) (2000)

TUMORS The gastrointestinal tract tumors arising from the mucosa predominate over mesenchymal tumors. Parenchyma is a term used to describe a bulk of a substance and it is the functional part of an organ in the body. This is in contrast to the stroma, which refers to the structural tissue of organs, being exactly, connective tissues.

 The cause of the disease multistep process but several predisposing factors attributed to cause the disease : a. Environment e. Atrophic gastritis b. Diet f. Chronic gastric ulcer c. Heredity g. Adenomatous polyps d. Achlorhydria i. H. Pyloric colonisation

Gastric Cancer Environmental factors H. pylori Genetic factors Etiological Factors of Gastric Cancer Precancerous changes

TYPES OF GASTRIC CANCER: A . Benign Tumours B . Malignant Tumours

 The benign groups includes:- 1. Non-neoplastic gastric polyps 2. Adenomas 3. Neoplastic gastric polyps 4. Smooth muscles tumours benign (Leiomyomas) 5 . Polyposis Syndrome (eg:- Polyposis coli, Juvenile polyps and P.J. Syndrome) 6. Other benign tumours are fibromas, neurofibromas, aberrat pancreas and angiomas.

Gastric Tumors These are broadly classified into polyps and carcinoma. Gastric Polyps The term "polyp" is applied to any nodule or mass that projects above the level of the surrounding mucosa. Occasionally, a lipoma or leiomyoma arising in the wall of the stomach may protrude from under the mucosa to produce an apparent polypoid lesion. However, the use of the term "polyp" in the gastrointestinal tract is generally restricted to mass lesions arising in the mucosa.

Hyperplastic polyps arise from an exuberant reparative response to chronic mucosal damage and hence are composed of a hyperplastic mucosal epithelium and an inflamed edematous stroma . They are not true neoplasms. Fundic gland polyps are small collections of dilated corpus-type glands thought to be small hamartomas. On the other hand, the less common adenomas contain dysplastic epithelium . As with colonic adenomas, adenomas are true neoplasms. MORPHOLOGY

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Histoology Histopathology report of a gastric polyp should comment on the following: Histological features of the polyp: Presence of cystic dilatation Lining epithelium of the cyst Presence of muscle fibres in the lamina propria Inflammatory inflltrate ( Eg. presence of eosinophils). Presence of muscle fibres in the lamina propria. Presence or absence of dysplasia or malignancy in case of Neoplastic.

PATHOLOGY OF GASTRIC (MALIGNANT) TUMOURS:  The gastric cancer may arise in the antrum (50%), the gastric body (30%), the fundus or oesophago-gastric juntion (20%).

 Types of Malignant Tumours : a. Adenocarcinoma b. Leiomyosarcoma c. Lymphomas d. Carcinoid Tumours

Pathohistologic classification Histology Adenocarcinoma 90% Lymphoma 5% Stromal 2% Carcinoid <1% Metastasis <1% Adenosquamous/squamous <1% Miscellaneous <1%

 Early Gastric Cancer: Defined as cancer which is confined to the mucosa and submucosa regardless of lymph nodes status.  Advanced Gastric Cancer : Defined as tumor that has involved the muscularis propria of the stomach wall .

1. Polypoid or Proliferative 2. Ulcerating 3. Ulcerating/Infiltrating 4. Diffuse Infiltrating (Linnitus- Plastica)  The macroscopic forms of gastric cancers are classified by (Bormann classification) into:-

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Pathogenesis Vast majority are adenocarcinomas Arise on background of chronic gastritis, intestinal metaplasia, dysplasia Most cases advanced at presentation

Pathogenesis The major factors thought to affect the genesis of this form of cancer are Environmental. Risk factors for the increasingly more common diffuse carcinoma are largely unknown, although germ-line mutations in E-cadherin leading to an autosomal dominant inheritance of diffuse gastric carcinoma. E-cadherin (epithelial) , also known as CDH1 , is a human gene . CDH1 has also been designated as

Chronic gastritis associated with H. pylori infection remains a major risk factor for gastric carcinoma. A recent prospective study from Japan has underscored the relationship between H. pylori infection and gastric cancer. The risk is particularly high in those with chronic gastritis limited to the gastric antrum. These patients develop severe gastric atrophy, intestinal metaplasia, and ultimately dysplasia and cancer. Perhaps chronic inflammation generates DNA-damaging free radicals, and the resulting mutations lead to hyperproliferation that is not balanced by apoptosis. Much remains to be known.

The location of gastric carcinomas within the stomach is as follows: pylorus and antrum, 50% to 60%; cardia, 25%; and the remainder in the body and fundus. The lesser curvature is involved in about 40% and the greater curvature in 12%. Thus, a favored location is the lesser curvature of the antropyloric region . Although less frequent, an ulcerative lesion on the greater curvature is more likely to be malignant. Gastric carcinoma is classified on the basis of depth of invasion, macroscopic growth pattern, and histologic subtype. MORPHOLOGY

The morphologic feature having the greatest impact on clinical outcome is the depth of invasion. Early gastric carcinoma is defined as a lesion confined to the mucosa and submucosa, regardless of the presence or absence of perigastric lymph node metastases. I. Protruded IIA. Superficial-elevated IIB. Superficial-flat IIC. Superficial-depressed III. Excavated Advanced gastric carcinoma is a neoplasm that has extended below the submucosa into the muscular wall and has perhaps spread more widely. I. Polypoid or fungating II. Excavating III. Ulcerated and infiltrating IV. Infiltrating (diffuse thickening) Gastric mucosal dysplasia is the presumed precursor lesion of early gastric cancer, which then in turn progresses to "advanced" lesions.

Ulcerative gastric carcinoma. The ulcer is large with irregular, heaped-up margins. There is extensive excavation of the gastric mucosa with a necrotic gray area in the deepest portion. Compare with the benign peptic ulcer The three macroscopic growth patterns of gastric carcinoma, which may be evident at both the early and advanced stages, are (1) Exophytic, with protrusion of a tumor mass into the lumen; (2) flat or depressed, in which there is no obvious tumor mass within the mucosa; and (3) Excavated, whereby a shallow or deeply erosive crater is present in the wall of the stomach.

Exophytic tumors may contain portions of an adenoma. Flat or depressed malignancy presents only as regional effacement of the normal surface mucosal pattern. Excavated cancers may mimic, in size and appearance, chronic peptic ulcers, although more advanced cases exhibit heaped-up margins . Uncommonly, a broad region of the gastric wall, or the entire stomach, is extensively infiltrated by malignancy. The rigid and thickened stomach is termed a leather bottle stomach, or linitis plastica; metastatic carcinoma from the breast and lung may generate a similar picture.

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The Histologic appearances of gastric cancer have been variously subclassified, but the two most important types are the intestinal type and diffuse type . The intestinal variant is composed of malignant cells forming neoplastic intestinal glands resembling those of colonic adenocarcinoma. The diffuse variant is composed of gastric-type mucous cells that generally do not form glands but rather permeate the mucosa and wall as scattered individual " signet-ring" cells or small clusters in an "infiltrative" growth pattern. Histologic appearances

Microscopy Intestinal type (forms glands – like cancers of colon and oesophagus) Diffuse type – dissociated tumour cells often containing a mucinous “blob” – signet ring cells

Histopathology Adenocarcinomas tend to aggressively invade the gastric wall, infiltrating the muscularis mucosae , the submucosa, and thence the muscularis propria. Intestinal type adenocarcinoma tumor cells describe irregular tubular structures , harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighboring mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated. chronic atrophic gastritis , retained glandular structure, little invasiveness, and a sharp margin.

Histopathology Diffuse type adenocarcinoma (mucinous, colloid, linitis plastica, leather-bottle stomach) Tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid (optically "empty" spaces). Margins that appear clear It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus to the periphery- " signet-ring cell ". 08/19/11

08/19/11 Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. According to Lauren classification, gastric adenocarcinoma may be: intestinal type, diffuse type and mixed type

Whatever the histologic variant, all gastric carcinomas eventually penetrate the wall to involve the serosa , spread to regional and more distant lymph nodes, and metastasize widely. For obscure reasons, the earliest lymph node metastasis may sometimes involve a supraclavicular lymph node (Virchow's node). Another somewhat unusual mode of intraperitoneal spread in females is to both the ovaries, giving rise to the so-called Krukenberg tumor 08/19/11 Free template from www.brainybetty.com

Gastric cancer. A, Intestinal type demonstrating gland formation by malignant cells, which are invading the muscular wall of the stomach. (H & E.) B, Diffuse type demonstrating individual red, mucin-containing malignant cells in the lamina propria of an intact mucosa. (Mucicarmine stain.)

Gastric Carcinoma Malignant Normal Gland

Stages Early stage limited in the mucosa and submucosa layers, no matter with or without lymph node metastasis Classified by the Japanese Society for Gastric Cancer <1cm <0.5cm Advanced stage invaded over submucosa According to Bormann’ classification

Gastric adenocarcinoma, intestinal type , infiltrating muscularis propria. (H&E, ob. x10)

Gastric adenocarcinoma, intestinal type . (H&E, ob. X40)

Early gastric carcinoma is generally asymptomatic and can be discovered only by repeated endoscopic examinations in persons at high risk. Advanced carcinoma also may be asymptomatic , but it often first comes to light because of abdominal discomfort or weight loss. Uncommonly, these neoplasms cause dysphagia when they are located in the cardia or obstructive symptoms when they arise in the pyloric canal. The only hope for cure is early detection and surgical removal, because the most important prognostic indicator is stage of the tumor at the time of resection. Clinical Features

Clinical manifestation Signs and Symptoms Early Gastric Cancer Asymptomatic or silent 80% Peptic ulcer symptoms 10% Nausea or vomiting 8% Anorexia 8% Early satiety 5% Abdominal pain 2% Gastrointestinal blood loss <2% Weight loss <2% Dysphagia <1%

Signs and Symptoms Advanced Gastric Cancer Weight loss 60% Abdominal pain 50% Nausea or vomiting 30% Anorexia 30% Dysphagia 25% Gastrointestinal blood loss 20% Early satiety 20% Peptic ulcer symptoms 20% Abdominal mass or fullness 5% Asymptomatic or silent <5% Duration of symptoms Less than 3 month 40% 3-12 months 40% Longer than 12 month 20%

Gastric adenocarcinoma, intestinal type . Tumor cells describe irregular tubular structures, with stratification, multiple lumens surrounded by a reduced stroma ("back to back" aspect). The tumor invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Often it associates intestinal metaplasia in adjacent mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation : well (photo), moderate and poorly differentiate. (H&E, ob. x10)

Spread of gastric carcinoma Local infiltration (through wall of stomach to peritoneum, pancreas etc) Lymphatic – local and regional lymph nodes Blood – liver, lungs Transcoelomic (across peritoneal cavity). Often involves ovaries (esp. signet ring cancer) – Krukenberg tumour.

Less common gastric neoplasms Lymphoma Gastrointestinal stromal tumour (GIST) Neuroendocrine (carcinoid) tumours

Gastric lymphoma Malignant neoplasm of mucosa associated lymphoid tissue (MALT) A (usually) low grade B-cell (marginal cell) lymphoma

Gastric lymphoma (maltoma) Neoplastic cells infiltrate the epithelium (lymphoepithelial lesions) Strongly associated with H. pylori and can be cured by eliminating infection.

Gastrointestinal stromal tumours (GIST) Mesenchymal neoplasms Derived from interstitial cells of Cajal (pacemaker cells controlling peristalsis) Overexpress c-kit oncogene Used as diagnostic aid on tissue A target for therapy with tyrosine kinase inhibitor imatinib (also used in CML)

GIST-spindle cell neoplasm of GI tract

GIST Larger tumours with high mitotic rate tend to behave malignantly Stomach is commonest site

Neuroendocrine tumours Carcinoids are tumours of resident neuroendocrine cells in gastric glands Usually seen in context of chronic atrophic gastritis (driven by gastrin) Clinical behaviour variable

INVESTIGATIONS : A. Upper gastero intestinal endoscopy with multiple biopsy and brush cytology B. Radiology:  CT Scan of the chest and abdomen  USS upper abdomen  Barium meal C. Diagnostic laparoscopy

Treatment Surgical resection EMR = Endoscopic mucosal resection Adjuvant therapy Palliative therapy

TREATMENTS OF GASTRIC CANCER:  Surgery (Early or Advanced Cancer)  Distal tumours which involve the lower ½ (sub-total or partial gasterectomy).  Proximal tumours which involve the fundus, cardia or body (total gasterectomy).

 Chemotherapy for gastric cancer (Pre-operatve & post-operative)  Radiotherapy (Pre-intra & post-operatively)

Lect 4-gastric tumors

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