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Fig. 3.13 Signet-ring cell carcinomas. A Overview showing Infiltration of the lamina propria. B Dispersed signet-ring cells. C Accumulation of neoplastic signet ring cells in the mucosa. D Alcian green positive signet-ring cells expanding the lamina propria in this Movat stain.

Fig. 3.13 Signet-ring cell carcinomas. A Overview showing Infiltration of the lamina propria. B Dispersed signet-ring cells. C Accumulation of neoplastic signet ring cells in the mucosa. D Alcian green positive signet-ring cells expanding the lamina propria in this Movat stain.

Fig. 3.15 Hepatoid variant of gastric carcinoma.

Fig. 3.16 Gastric choriocarcinoma composed of syncytiotrophoblastic and cytotrophoblastic cells next to thin-walled vascular structures. A Papillary carcinoma component is adjacent to the choriocarcinoma. B High magnification of the choriocarcinoma.

or no gland formation. The cells usually appear round and small, either arranged as single cells or clustered in abortive, lacy gland-like or reticular formations. These tumours resemble those classified as signet-ring cell tumours in the WHO classification. The mitotic rate is lower in diffuse carcinomas than in intestinal tumours. Small amounts of interstitial mucin may be present. Desmoplasia is more pronounced and associated inflammation is less evident in diffuse cancers than in the intestinal carcinomas.

Rare variants

Several other carcinomas exist that are not an integral part of the Laurén or WHO classifications.

Adenosquamous carcinoma

This lesion combines an adenocarcino-ma and squamous cell carcinoma; neither quantitatively prevails. Transitions exist between both components. A tumour with a distinct boundary between the two components may represent a collision tumour Tumours containing discrete foci of benign-appearing squa-mous metaplasia are termed adenocarcinomas with squamous differentiation (synonymous with adenoacanthoma).

Squamous cell carcinoma

Pure squamous cell carcinomas develop rarely in the stomach; they resemble squamous cell carcinomas arising elsewhere in the body.

Undifferentiated carcinoma

These lesions lack any differentiated features beyond an epithelial phenotype (e.g. cytokeratin expression). They fall into the indeterminate group of Laurén's scheme. Further analysis of this heterogeneous group using histochemical methods may allow their separation into other types.

Other rare tumours include mixed adeno-carcinoma-carcinoid (mixed exocrine-endocrine carcinoma), small cell carcinoma, parietal cell carcinoma, cho-riocarcinoma, endodermal sinus tumour, embryonal carcinoma, Paneth cell rich-adenocarcinoma and hepatoid adenocar-cinoma.

Fig. 3.17 A, B Adenocarcinoma, poorly differentiated. These two lesions show both intestinal and diffuse components (Lauren classification).

Early gastric cancer

Early gastric cancer (EGC) is a carcinoma limited to the mucosa or the mucosa and submucosa, regardless of nodal status. Countries in which asymptomatic patients are screened have a high incidence of EGCs ranging from 30-50% {1410, 908, 718}, contrasting with a smaller fraction of 16-24% {620, 253, 627} in Western countries. The follow-up of dysplastic lesions does appear to increase the prevalence of EGC. The cost effectiveness of such an integrated

Fig. 3.18 Tubular adenocarcinoma. A Well differentiated; intramucosal invasion. B Moderately differentiated. C Poorly differentiated.

endoscopic/biopsy approach remains to be evaluated {1634, 1638}. Histologically, most subtypes of carcinoma occur in EGC in either pure or mixed forms. Elevated carcinomas with papillary, granular or nodular patterns and a red colour are more often well or moderately differentiated, tubular or papillary tumours with intestinal features; sometimes a preexisting adenoma is recognizable. Flat, depressed, poorly differentiated carcinomas may contain residual or regenerative mucosal islands. Ulcerated lesions are either intestinal or diffuse cancers. Adenocarcinoma limited to the mucosal thickness has also been divided into small mucosal (< 4cm=SM) and superficial (> 4cm=SUPER) {950}. Both of them may be strictly confined at the mucosal level (small mucosal M and superficial M) or focally infiltrate the sub-mucosa (small mucosal SM and superficial SM). In the penetrating variant, (including two sub-

Fig. 3.19 A, B Tubular adenocarcinoma, well differentiated.

categories: PenA and PenB) the invasion of the submucosa is more extensive than in the two above-mentioned variants. PenA is defined by a pushing margin, and is less frequent than PenB, which penetrates muscularis mucosae at multiple sites.

The prognosis is worse in PenA carcinomas (in contrast to adenocarcinomas of the colon, where a pushing margin is associated with a better prognosis). The coexistence of more than one of the described patterns results in the mixed variant {950}.

Stromal reactions

The four common stromal responses to gastric carcinoma are marked desmo-plasia, lymphocytic infiltrates, stromal eosinophilia and a granulomatous response. The granulomatous reaction is characterized by the presence of single and confluent small sarcoid-like granulomas, often accompanied by a moderately intense mononuclear cell infiltrate. The lymphoid response is associated with an improved survival.

Grading

Well differentiated: An adenocarcinoma with well-formed glands, often resembling metaplastic intestinal epithelium. Moderately differentiated: An adenocarcinoma intermediate between well differentiated and poorly differentiated. Poorly differentiated: An adenocarcino-ma composed of highly irregular glands that are recognized with difficulty, or single cells that remain isolated or are arranged in small or large clusters with mucin secretions or acinar structures. They may also be graded as low-grade (well and moderately differentiated) or high-grade (poorly differentiated). Note that this grading system applies primarily to tubular carcinomas. Other types of gastric carcinoma are not graded.

Precursor lesions

Gastritis and intestinal metaplasia

Chronic atrophic gastritis and intestinal metaplasia commonly precede and/or accompany intestinal type adenocarci-noma, particularly in high-incidence areas {780}. H. pyloriassociated gastritis is the commonest gastric precursor lesion.

However, autoimmune gastritis also associates with an increased carcinoma risk. If gastritis persists, gastric atrophy occurs followed by intestinal metaplasia, beginning a series of changes that may result in neoplasia, especially of intestinal type cancers. In contrast, diffuse gastric cancers often arise in a stomach lacking atrophic gastritis with intestinal metaplasia.

Fig. 3.20 Intestinal metaplasia. The two glands on the left exhibit complete intestinal metaplasia, others show the incomplete type.

There are two main types of intestinal metaplasia: 'complete' (also designated as 'small intestinal type' or type I), and 'incomplete' (types II and III) {843}. Different mucin expression patterns characterize the metaplasias: complete shows decreased expression of 'gastric' (MUC1, MUC5AC and MUC6) mucins and expression of MUC2, an intestinal mucin. In incomplete intestinal metaplasia, 'gastric' mucins are co-expressed with MUC2 mucin. These findings show that incomplete intestinal metaplasia has a mixed gastric and intestinal phenotype reflecting an aberrant differentiation program not reproducing any normal adult gastrointestinal epithelial phenotype {1574}.

Intraepithelial neoplasia

Intraepithelial neoplasia (dysplasia) arises in either the native gastric or of intestinal-ized gastric epithelia. Pyloric gland adenomais a form of intraepithelial neoplasia arising in the native mucosa {2066, 1885}. In the multi-stage theory of gastric onco-genesis, intraepithelial neoplasia lies between atrophic metaplastic lesions and invasive cancer (Table 3.01). Problems associated with diagnosing gastric intraepithelial neoplasia include the distinction from reactive or regenerative changes associated with active

Fig. 3.21 Reactive gastritis with marked foveolar hyperplasia.

inflammation, and the distinction between intraepithelial and invasive carcinoma {1683, 1025}. Several proposals have been made for the terminology of the morphological spectrum of lesions that lie between non-neoplastic changes and early invasive cancer, including the recent international Padova classification {1636}.

Indefinite for intraepithelial neoplasia Sometimes, doubts arise as to whether a lesion is neoplastic or non-neoplastic (i.e. reactive or regenerative), particularly in small biopsies. In such cases, the dilemma is usually solved by cutting deeper levels of the block, by obtaining additional biopsies, or after removing possible sources of cellular hyperproliferation. One important source of a potentially alarming lesion is the regeneration associated with NSAID-induced injury or superficial erosion/ulceration caused by gastric acid. Cases lacking all the attributes required for a definitive diagnosis of intraepithelial neoplasia may be placed into the category 'indefinite for intraepithelial neoplasia'. In native gastric mucosa, foveolar hyper-proliferation may be indefinite for dyspla-sia, showing irregular and tortuous tubular structures with epithelial mucus depletion, a high nuclear-cytoplasmic ratio and loss of cellular polarity. Large, oval/round, hyperchromatic nuclei associate with prominent mitoses, usually located near the proliferative zone in the mucous neck region.

In intestinal metaplasia, areas indefinite for intraepithelial neoplasia exhibit a hyperproliferative metaplastic epithelium. The glands may appear closely packed, lined by cells with large, hyperchromatic, rounded or elongated, basally located nuclei. Nucleoli are an inconsistent finding. The cyto-architectural alterations tend to decrease from the base of the glands to their superficial portion.

Intraepithelial neoplasia

It has flat, polypoid, or slightly depressed growth patterns; the flat pattern may lack any endoscopic changes on conventional endoscopy, but shows an irregular appearance on dye endoscopy. In Western countries, the term adenoma is applied when the proliferation produces a macroscopic, usually discrete, protruding lesion. However, in Japan, adenomas include all gross types (i.e. flat, elevated and depressed). Gastric adenomas are less common than hyperplastic polyps; overall, they account for approximately 10% of gastric polyps {1843}. They tend to arise in the antrum or mid stomach in areas of intestinal metaplasia. Morphologically, adenomas can be described as tubular (the most common), tubulovillous, or villous; the latter two have also been called papillotubular and papillary. Most have epithelium of intestinal type, but some have gastric foveolar features.

Low-grade intraepithelial neoplasia This lesion shows a slightly modified mucosal architecture, including the presence of tubular structures with budding and branching, papillary enfolding, crypt lengthening with serration, and cystic changes. Glands are lined by enlarged columnar cells with minimal or no mucin. Homogeneously blue vesicular, rounded or ovoid nuclei are usually pseudostrati-fied in the proliferation zone located at the superficial portion of the dysplastic tubules.

High-grade intraepithelial neoplasia There is increasing architectural distortion with glandular crowding and prominent cellular atypia. Tubules can be irregular in shape, with frequent branching and fold-

Fig. 3.22 Tubular adenoma of gastric antrum. Uninvolved pyloric glands below the lesion show cystic dilatation.

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