Gastric Carcinoma

1. GROSS DESCRIPTION

Specimen

— gastric cancer can present with anaemia, weight loss or dyspeptic symptoms. Investigation is by endoscopy with biopsy. Staging for local and distant disease includes ELUS (endoluminal ultrasound: tumour depth and nodal spread), CT scan chest, abdomen and pelvis, PET scan and peritoneal laparoscopy with cytological washings and biopsy. Non-regional disease is an indicator for palliative treatment including chemotherapy, and surgery if there is anatomical dysfunction, e.g. extensive ulceration and bleeding or gastric outlet obstruction. Curative intent surgery can be localized [e.g. endoscopic mucosal resection (EMR)] or radical, the extent of the latter depending on the patient's age, fitness, tumour type, stage and location.

— cytological brushing, washing or aspirate/biopsy/ partial (proximal or distal) or total gastrectomy/oesophagogastrectomy/lymphadenectomy ± omentectomy.

— length (cm) along greater curvature.

— length (cm) of oesophagus and duodenum.

Tumour

Site

— distal oesophagus/cardia/fundus/corpus/antrum/pylorus/duodenum.

— lesser curve/greater curve.

— anterior/posterior.

Antrum (50%) and lesser curve (15%) are traditionally the most frequent sites. However, the incidence of distal gastric carcinoma is decreasing while that of the proximal stomach and cardia is markedly increasing. This is in part due to eradication of Helicobacter pylori infection and loss of its acid suppression effect and more reflux changes. It presents at a more advanced stage than equivalent-size distal lesions with a worse prognosis and similarities in behaviour to distal oesophageal adenocar-cinoma. Adenocarcinomas involving the oesophagogastric junction are TNM staged as either oesophageal (Siewert I: distal oesophagus coming

Anatomical subsites:

1. Cardia

2. Fundus

3. Corpus

4. Antrum

5. Pylorus

down) or gastric (Siewert II: junctional, Siewert III: gastric cardia going up).

— multifocal 6%: in particular early gastric cancer and lymphoma. Size

— length x width x depth (cm) or maximum dimension (cm). Appearance

— polypoid/plaque/ulcerated/infiltrative/mucoid/linitis plastica/scirrhous/ fleshy.

Advanced (muscle invasive) gastric cancer is classified macroscopically according to Borrmann type as:

I polypoid II fungating

III ulcerated

IV infiltrative.

Types I, II/III and IV tend to correspond to tubulo/papillary, intestinal and signet ring cell (linitis plastica) adenocarcinoma, respectively, although there is overlap between the categories. Polypoid/ulcerated tumours are regarded as being of better prognosis than infiltrative cancers.

Edge

— circumscribed/irregular. 2. HISTOLOGICAL TYPE

An amalgam of the WHO and Lauren* classifications is used

Adenocarcinoma

*intestinal 50% antrum

*diffuse 20% body of stomach, young or old patients *mixed 25% *solid 5%

Intestinal carcinomas have tubuloacinar (common), papillary or mucinous (colloid) patterns, form polypoid or ulcerative lesions with expansile margins and are associated with atrophic gastritis, intestinal metaplasia and dysplasia. By definition tubular adenocarcinoma is well differentiated and may be difficult to diagnose due to wide separation of glands in a non-desmoplastic stroma. Undermining of structures can be helpful, e.g. muscularis mucosae or oesophagogastric junction squamous epithelium. Equally, papillary adenocarcinoma is exophytic with well-differentiated epithelial fronds supported by fine fibrovascular stroma. Biopsies may only sample its surface component and distinction from high-grade dysplasia can be problematic. Its endoscopic and ELUS/CT appearances and sharp demarcation from adjacent mucosa must be taken into account. The definition of a mucinous adenocarcinoma, whether glandular, colloid or signet ring cell, requires mucin production in >50% of the tumour area or cells.

Diffuse carcinomas comprise single cells with signet ring or granular cytoplasmic appearances and form linitis plastica with infiltrating margins. A point of origin from dysplasia is often difficult to demonstrate and the tumour emanates from the mid-mucosal proliferative zone (from non-metaplastic foveolar or mucous neck cells), or deep lamina propria invading submucosa, muscularis, serosa and into the peritoneal cavity. The cells do not express the adhesion protein E-cadherin. A minority (8-10%) of gastric cancers are hereditary and in a young patient occult presentation with an inherited autosomal dominant diffuse gastric cancer should be considered. Alternatively, intestinal gastric cancer can develop in a young patient as part of the hereditary non-polyposis colon cancer syndrome (HNPCC).

Adenocarcinoma variants

Hepatoid carcinoma: glandular and hepatocellular differentiation with marked vascular invasion and poor prognosis. ±AFP (alphafetoprotein) immunoexpression, polyclonal carcinoembryonic antigen (CEA) positive.

Parietal cell carcinoma: rare. Solid sheets of cells with eosinophilic granular cytoplasm.

Medullary carcinoma (syn. lymphoepithelial carcinoma): circumscribed with a dense lymphoplasmacytic infiltrate, regular vesicular nuclei and small nucleoli.

77% 5-year survival and associated with Epstein-Barr virus infection and HNPCC.

Adenosquamous carcinoma and squamous cell carcinoma

— rare: need keratinization and intercellular bridges. Vascular invasion and aggressive.

pTis pT1 pT2

a pTis pT1 pT2

Early gastric cancer = pT1± nodal disease. Intramural extension to the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites including the stomach.

Figure 2.2. Gastric carcinoma. [OS!

Undifferentiated carcinoma

— cytokeratin positive but no histological differentiation features.

Neuroendocrine carcinoma

— carcinoid, small cell/large cell carcinoma.

Lymphoma

— low/high-grade MALToma.

— less commonly: diffuse large B-cell lymphoma, follicle centre cell lymphoma, mantle cell lymphoma, T-cell lymphoma.

Metastatic carcinoma

— direct spread: pancreas, oesophagus, transverse colon.

— distant spread: small cell carcinoma lung, malignant melanoma, breast, kidney, choriocarcinoma, ovary.

— metastatic infiltrating lobular carcinoma of breast can mimic signet ring cell carcinoma of stomach and a known clinical history of a previous breast primary is crucial to the diagnosis. Breast cancer may also be ER/PR/GCDFP-15/cytokeratin 7 positive and cytokeratin 20 negative. Note that a significant minority of gastric adenocarcinomas may also be oestrogen receptor positive.

3. DIFFERENTIATION

Well/moderate/poor/undifferentiated, or Grade 1/2/3/4.

For adenocarcinoma based on the percentage tumour gland formation (well/G1 >95%: moderate/G2 50-95%: poor/G3 <50%).

Undifferentiated gastric carcinoma (grade 4) shows no glandular differentiation and requires positive cytokeratin stains to distinguish it from lymphoma or sarcoma. Signet ring cell carcinoma is regarded as poorly differentiated (grade 3) and small cell carcinoma as undifferentiated (grade 4).

Goseki grade—based on mucin secretion and tubule formation:

I tubules well differentiated, mucin-poor

II tubules well differentiated, mucin-rich

III tubules poorly differentiated, mucin-poor

IV tubules poorly differentiated, mucin-rich.

Well-differentiated (tubule-rich) mucin-poor cancers have better (50-80%) 5-year survival rates than moderately or poorly differentiated (tubule-poor) mucin-rich tumours (18-46%).

4. EXTENT OF LOCAL TUMOUR SPREAD

Border: pushing/infiltrative.

Well-circumscribed tumours have longer patient survival than infiltrating cancers (except in early gastric cancer). Lymphocytic reaction: prominent/sparse.

Gastric cancer is considered as either early (pT1) or advanced (>pT2) as there is prognostic discrepancy between these two levels of invasion.

The TNM classification applies only to carcinomas.

pTis carcinoma in situ: intraepithelial tumour without invasion of the lamina propria pT1 tumour invades lamina propria or submucosa* pT2 tumour invades muscularis propria or subserosa or lesser/greater omenta a. muscularis propria b. subserosa or omentum pT3 tumour penetrates serosa (visceral peritoneum) without invasion of adjacent structures pT4 tumour invades adjacent structures (spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, retroperitoneum).

The lesser omentum includes the gastrocolic and gastrohepatic ligaments and involvement of their peritoneal covering constitutes pT3 disease. There is decreased post surgical 5-year survival for pT2b versus pT2a cancer. Discontinuous greater omental tumour nodules are classified as metastatic disease (pM1).

Intramural extension to the oesophagus or duodenum is classified by the depth of greatest invasion in any of these sites.

Diffuse gastric carcinoma may not elicit a desmoplastic stroma and the depth of mural invasion, which is often extensive and can be characterized by small, inapparent non-mucinous tumour cells in the muscularis propria and adventitia, may be underestimated. Equally, margin status can be incorrectly assessed. Stains [periodic acid-Schiff (PAS) ± diastase, cytokeratins, CEA, epithelial membrane antigen (EMA)] should be used to show its full extent and also to distinguish tumour cells from histio-cytes in both the mucosa and lymph node sinus network.

5. LYMPHOVASCULAR INVASION

Present/absent. Intra-/extratumoral.

Venous, lymphatic and perineural invasion are adverse prognostic factors.

Intestinal gastric adenocarcinoma tends to venous invasion with spread to liver, lung, adrenal glands and bone, whereas diffuse gastric carcinoma favours lymphatic and direct peritoneal spread. Bilateral ovarian metastases from diffuse gastric cancer comprise the majority of Krukenberg tumours. Uterine body and cervix can also be involved by metastatic disease.

6. LYMPH NODES

Site/number/size/number involved/limit node/extracapsular spread.

Regional nodes: perigastric, hepatoduodenal, nodes along the left gastric, common hepatic, splenic and coeliac arteries. Other intra-

*Potential descriptors: pT1a (lamina propria), pT1b (submucosa).

The regional lymph nodes are the perigastric along the lesser (1,3,5) and greater (2,4a,4b,6) curvatures, the nodes located along the left gastric (7), common hepatic (8), splenic (10,11) and coeliac arteries (9) and the hepatoduodenal nodes (12). The regional nodes of the gastrooesophageal junction are the paracardial (1,2), left gastric (7), coeliac (9), diagphragmatic and the lower mediastinal paraoesophageal. Involvement of other intra-abdominal lymph nodes such as retropancreatic, mesenteric and para-aortic is classified as distant metastasis.

Figure 2.3. Stomach: regional lymph nodes. |W

Figure 2.4. Stomach: regional lymph nodes. |W

abdominal lymph nodes are distant metastases (pM1). A regional lym-phadenectomy will ordinarily include a minimum of 15 lymph nodes but numbers depend on the extent of surgery. In a D1 resection only perigastric lymph nodes are excised. In a D2 (radical) gastrectomy there is additional nodal dissection along the hepatic artery, coeliac plexus, greater omentum, gastroplenic omentum, portal vein, splenic artery and retropancreatic area. The surgeon may choose to submit these in separately labelled containers.

pN0 no regional lymph node metastasis pN1 1 to 6 involved regional nodes pN2 7 to 15 involved regional nodes pN3 more than 15 involved regional nodes.

Five-year survival decreases with increasing numbers of involved lymph nodes.

7. EXCISION MARGINS

Distances (mm) to the radial, proximal and distal limits of excision.

Gastric carcinoma (especially diffuse signet ring cell) may show mul-tifocality and submucosal skip lesions. Margins need to be checked histologically even if well away from the main tumour mass on gross examination. Diffuse carcinoma present to within 5 cm of the resection margin has an adverse prognosis. Distal intestinal cancers tend to stop at the pylorus while diffuse carcinoma may involve the first part of the duodenum. Proximal (cardia) tumours often involve distal oesophagus (Siewert III).

The radial margin is the non-peritonealized lesser or greater omental margin closest to the tumour. It can be inspected and inked prior to blocking.

8. OTHER PATHOLOGY

Early gastric cancer (EGC)

Forming 10-15% of gastric cancers in Western countries and limited to the mucosa ± submucosa ± lymph node involvement. The 5-year survival is 85-95% compared with 20-35% for advanced gastric cancer. Designation as EGC is on a resection specimen as endoscopic biopsies are constrained by sampling limitations.

Macroscopic/endoscopic classification of EGC

Type I Type IIa Type IIb Type IIc Type III

protruded raised flat superficial depressed excavated

Mixed types are common. Types I and IIa tend to be well differentiated (tubular, papillary), whereas types IIb, IIc and III also include ulcerated intestinal, poorly differentiated and signet ring tumours, although there is considerable overlap between macroscopic and microscopic appearances.

Lesser curve is the commonest site but 10% are multifocal and require mapping of the resection specimen.

Tumours with lymph node metastases do worse than those without and tend to be large (>5cm-80% positive nodes) or show submucosal invasion (20% positive nodes) rather than being confined to the mucosa (4% positive nodes).

Two prognostic paradoxes contrast with advanced gastric carcinoma:

1. diffuse-type EGC has a better prognosis than intestinal-type EGC due to vascular spread in the latter, and

2. EGC with a broad, expansile deep margin destroying muscularis mucosae (pen A) is more aggressive than EGC with an irregular infiltrating margin fenestrating the muscle (pen B). The tendency for pen A tumours to progress to advanced carcinoma is thought to relate to higher DNA aneuploidy rates. Pen A tumours form a minority (10%) of EGC but have higher rates of lymphovascular invasion, lymph node metastases (25%) and lower 10-year survival rates (65%),

3. i.e. well-differentiated cancers with a pushing margin do worse than poorly differentiated tumours with an infiltrating margin.

Treatment is usually by partial gastrectomy, but after appropriate clin-icopathological staging local excision by endoscopic mucosal resection is possible. Risk factors predictive of nodal metastases and the need for further surgery are: size >3 cm, surface ulceration (>50%), poor differentiation, deep submucosal invasion, lymphovascular invasion and incomplete excision with deep margin involvement.

Predisposing lesions

Gastritis*: ± Helicobacter pylori (HP): (cresyl violet, Giemsa, Warthin-Starry stains; can assume a coccoid rather than spiral form in resections). HP-positive patients have a x 3-6 increased cancer risk, especially those with the cytotoxic (cag-A) genotype of HP.

Intestinal metaplasia*: type Ilb/III (sulphomucin rich)—high iron diamine alcian blue or Gomori's aldehyde fuchsin alcian blue stains—the large intestinal variant of metaplasia is more strongly associated with mucosal dysplasia and intestinal pattern gastric adenocarcinoma. Mucin subtyping is not routinely done as it is not considered a sufficiently strong predictive factor, although the extent of intestinal metaplasia is broadly indicative.

^Classified and semi-quantitatively graded (none/mild/moderate/marked) using the Sydney classification. It classifies and grades chronic gastritis based on an assessment of histological (neutrophils, chronic inflammation, atrophy, intestinal metaplasia), topographical (antral/corpus predominant or pangastritis) and aetiological (HP, drugs) factors.

Table 2.1 Vienna Consensus Classification of gastrointestinal neoplasia Category Neoplasia/dysplasia

1 Negative

2 Indefinite

3 Non-invasive low grade

— low-grade adenoma/dysplasia

4 Non-invasive high grade

— 4.1 high-grade adenoma/dysplasia

— 4.2 non-invasive carcinoma (carcinoma in situ)

— 4.3 suspicious of invasive carcinoma

5 Invasive—either intramucosal*, submucosal or beyond

*A more recent proposed modification suggests categorizing intramucosal carcinoma as 4.4 as these subcategories show poor intra-/inter observer reproducibility and all require at least endoscopic or surgical local resection. Choice of procedure will depend on the lesion size, depth of invasion (as assessed by endoscopy, radiology and endoscopic ultrasound), histological grade and general features (age, fitness).

Atrophy*: ± pernicious anaemia with gastric parietal cell and intrinsic factor antibodies. 10-20% develop carcinoma.

Dysplasia: low/high-grade, either in flat (commonest), sessile or polypoid mucosa, and in metaplastic (intestinal) or non-metaplastic (gastric fove-olar) mucosa. Gastrointestinal epithelial neoplasia is assessed according to the Vienna Consensus Classification (Table 2.1).

There is a strong (30-80%) association between high-grade dysplasia and adenocarcinoma either concurrently or within 1-2 years of diagnosis. Distinction between high-grade dysplasia/carcinoma in situ and lamina propria invasion can be difficult. In Europe and the USA there needs to be invasion of the lamina propria before the term (intramucosal) carcinoma is used, i.e. both cytological and architectural derangement. Eastern hemisphere pathologists require less stringent criteria. Diagnosis of dysplasia in a biopsy should be followed by reassessment with multiple biopsies to exclude concurrent carcinoma. Dye spraying can facilitate endoscopic identification. Imaging, e.g. endoluminal ultrasound, may help define a mass or infiltrative lesion. If this is absent, flat low-grade dysplasia may be monitored endoscopically while polypoid low-grade dysplasia and high-grade dysplasia in flat or polypoid mucosa should be considered for either local endoscopic or formal surgical resection. Care must be taken to distinguish dysplasia from regenerative change in inflammation and ulceration and reactive gastropathy, e.g. foveolar hyperplasia in bile reflux and drug ingestion (non-steroidal anti-inflammatory drugs, aspirin). Lack of surface epithelial maturation, budding/branching and cystically dilated deep glands are useful pointers to dysplasia.

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