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Adenocarcinoma

Fig. 2.03 Pathogenetic pathways operative in the evolution of oesophageal and gastric carcinoma. Intestinal metaplasia is a common precursor lesion that may result from gastro-oesophageal reflux disease (GERD) or chronic H. pylori infection.

Table 2.01

Features of intestinal metaplasia in the oesophagus and stomach.

Stomach Oesophagus

H. pylori association Yes No

GERD association No Yes

Usual type of metaplasia Complete Incomplete

Barrett cytokeratin pattern No Yes

Cancer risk Lower Higher

Clinical features

Common presenting symptoms for patients with adenocarcinomas of the oesophagogastric junction include dys-phagia, weight loss, and abdominal pain. Early cancers, and the metaplastic and dysplastic lesions that spawn them, usually cause no symptoms. Consequently symptomatic patients usually have advanced, incurable disease. Oesophago-gastric junction tumours are discovered at an early stage during endoscopic surveillance in patients known to have Barrett oesophagus.

Endoscopy and imaging

The diagnosis of cancer at the oesopha-gogastric junction is typically established by endoscopic examination with biopsy. Endoscopy. The distal oesophagus should be examined carefully for evidence of intestinal metaplasia (Barrett oesophagus), and biopsy specimens of the metaplastic epithelium should be taken to determine whether the tumour is oesophageal in origin. The finding of intestinal metaplasia with dysplastic features above an OG junction tumour is strong evidence that the cancer began in the oesophagus. The location of the tumour in reference to the landmarks shown in Figure 2.01 should be noted. The proximal stomach is examined carefully, preferably by retroversion of the endoscope, to determine the gastric extent of the tumour. Early tumours may be polypoid, but flat lesions are more frequent. These flat lesions may appear depressed, elevated, or completely flush with the surrounding mucosa {1010}. Mucosal hyperplasia immediately distal to the squamo-columnar junction, occurs in carditis and can, without biopsy sampling, be mistaken for an elevated neoplastic lesion. In advanced adenocarci noma, the tumour is often polypoid and circumferential. Tight stenoses can be difficult to explore endoscopically and dangerous to dilate, especially when there is tortuosity.

Endoscopic ultrasonography is the modality of choice for tumour staging, and accuracy can be improved even further by using high frequency (20 or 30 MHz) miniprobes {669}. Endosonogra-phy accurately identifies the depth of tumour invasion and regional lymph node involvement in approximately 77% and 78% of cases, respectively {1301}. Endosonography is also useful in assessing the proximal extent of submu-cosal tumour invasion in the oesophagus. Endosonographic study of the wall of the oesophagus reveals 3 hyperechoic layers that are separated by 2 hypo-echoic layers. The inner (1st) and external (3rd) hyperechoic layers correspond to the interfaces of the wall with the gut lumen and surrounding tissues, respectively. The intermediate (2nd) hypere-choic layer corresponds to the submu-cosa. The inner (1st) and outer (2nd)

Fig. 2.04 Endoscopic ultrasonograph demonstrating adenocarcinoma at the oesophagogastric junction (CA) with deep infiltration and several lymph node metastases (arrows).

hypoechoic layers represent part of the muscularis mucosae and the muscularis propria, respectively. Computed tomography is necessary to detect distant thoracic and abdominal metastases.

Barium swallow has a limited role as a diagnostic test for cancer at the oeso-phagogastric junction {1058, 1180} but may be helpful in the analysis of malignant stenoses that are too narrow to be traversed by the endoscope.

Tumour spread and staging

According to TNM, in this junction area, carcinomas that are mainly on the gastric side should be classified according to the TNM for gastric tumours, while those predominantly on the oesophageal side should be staged according to the TNM for oesophageal carcinomas {698}. Adenocarcinomas at the oesophago-gastric junction exhibit a great propensity for upward lymphatic spread mainly in the submucosa of the oesophagus. For this reason, intraoperative frozen-section examination of the proximal oesophageal resection margin is recommended. Upward spread can also involve lower mediastinal nodes. Lymphatic spread from the cardia frequently extends downwards to nodes in the oesophagogastric angles and around the left gastric artery and may involve para-coeliac and paraaortic lymph nodes {26, 949}. There are differences in the criteria for stage grouping oesophageal and gastric malignancies, and the pathological staging recommended by the AJCC {1} for lymph node involvement by gastric cancers is not easily adapted for use by endosonographers. Involvement of the coeliac lymph nodes is usually deemed regional disease for gastric cancers, whereas coeliac node involvement is considered distant metastatic disease (M1) for cancers of the thoracic oesophagus. The regional nodes of the OG junction are not well enough defined to stage OG junction cancers properly.

Histopathology

Adenocarcinoma

The vast majority of cancers arising at the cardia are adenocarcinomas {1790}. Histologically, four types are usually distinguished in the WHO classification: papillary, tubular, mucinous, and signetring cell adenocarcinoma. The latter two types are uncommon. The signet-ring

Fig. 2.05 Adenocarcinoma of the proximal stomach ('pylorocardiac type'). A Macroscopic appearance resembles other adenocarcinmomas. B Glands with tall cells, pale cytoplasm, and basal or central nuclei.

type is much less common in the proximal than in the distal stomach, and usually not accompanied by atrophic gastritis {2045}. Well differentiated tubular adenocarcinomas can present considerable diagnostic difficulty as the neoplas-tic tubules may have a deceptively regular appearance and can be readily mistaken for low-grade dysplasia or even hyperplastic glands.

Pylorocardiac carcinoma. Mulligan and Rember {1847} termed lesions resembling normal pyloric glands as 'pylorocardiac carcinomas'. They predominate in the cardiac region and typically have tall epithelial cells with clear or pale cytoplasm and nuclei in a basal or central position. However, this pattern is difficult to distinguish reliably from other gland-forming adenocarcinomas {1847}.

Adenosquamous carcinoma

Of the less common forms of cancers in the oesophagogastric junction region, adenosquamous carcinoma is the one most likely to be encountered. The diagnosis rests on the finding of a mixture of glandular and squamous elements and not merely on the presence of small squamoid foci in an otherwise typical ade-nocarcinoma. The latter is a frequent finding in tumours at this site. Such composite tumours should also be distinguished from the rare mucoepidermoid carcinoma of the oesophagus, which arises from mucous glands and is similar to the salivary gland tumour of that name. Although the term mucoepidermoid has been used synonymously for adenosquamous carci nomas {1476}, the latter are distinguished by increased nuclear pleomorphism, occasional keratin pearls, and the separation of the two components with some areas of purely glandular epithelium and mucin. While in the past there were claims that adenosquamous carcinoma represented a 'collision tumour', it is now generally accepted that this malignancy results from dual differentiation and that it is analogous to other cancers arising at junctional sites in the body (e.g. uterine cervix and anal canal).

Fig. 2.06 Adenocarcinoma of the oesophagogastric junction. pT2 lesion.

Small cell carcinoma can occur at this site. Grading

Adenocarcinomas in the oesophago-gastric junction region can be graded as well, moderately, or poorly differentiated. However, agreement on tumour grading is notoriously poor. Blomjous et al. {151} reported that 3.6% of gastric cardiac cancers were well differentiated, 31% moderately differentiated, and 43% poorly differentiated, but others consider a greater proportion well differentiated, particularly when early carcinomas are included {1271, 1903, 1363}.

Precursor lesions

Intraepithelial neoplasia Interobserver agreement on the grading of intraepithelial neoplasia in the absence of invasion of the lamina propria is poor, particularly in the identification of low-grade changes, and different terms have been applied to identical appearances {1683}. Such differences in nomenclature have been reduced by the widespread acceptance of a new classification that embraces the previously discordant terminology in a unified scheme {1637}.

Intramucosal non-invasive neoplasia can be classified as flat (synonymous with dysplasia) or elevated (synonymous with adenoma); lesions can be low grade or high grade, the latter including lesions previously designated as intraglandular carcinoma. Intestinal metaplasia Putative precancerous lesions other than intraepithelial neoplasia are controversial.

Intestinal metaplasia is widely regarded as carrying an increased risk of malignant change, but the frequency at which it is found in the OG junction region (5.3% to 23% of dyspeptic patients) limits its value as a criterion for surveillance {716, 1960, 1800, 2028, 1269}. Some of the variability in the reported prevalence of intestinal metaplasia can be attributed to differences in diagnostic criteria. Some authors accept the finding of columnar cells containing acidic glycoproteins ('columnar blues' in Alcian blue / PAS stained sections) as evidence for intestinal metaplasia {1398}. This staining pattern reflects immature, regenerative cells and is a common finding in biopsy specimens of the cardia in children with GERD. This finding alone is not sufficient to identify intestinal metaplasia; intestinal metaplasia should only be diagnosed if goblet cells are present.

Genetic changes

The best characterized somatic alteration found in tumours of this region are mutations of TP53 which are present in up to 60% of carcinomas of the oesophagogastric junction. In 5 patients who had ade-nocarcinomas at the junction associated with Barrett oesophagus, the same mutation was detected in the tumour and in the surrounding oesophageal intestinal metaplasia, indicating an oesophageal origin. No association has been found between p53 status and tumour stage or subtype. The TP53 alterations noted in tumours at the oesophagogastric junction show a predominance of transition mutations at CpG sites, similar to the pattern seen in adenocarcinomas in Barrett oesophagus {585}. Transitions at CpG dinucleotides in TP53 are generally assumed to result from endogenous mutational mechanism (deamination of 5-methylcytosine) which may be enhanced by oxidative or nitrosative stress. In colon cancers that frequently exhibit CpG mutations, excess nitric oxide production resulting from nitric oxide synthase-2 expression may contribute to the transition from adenoma to carcinoma {51}.

In a study of cancers at the oesophagogastric junction that did not show evidence of associated Barrett oesophagus, the prevalence of TP53 mutations was only 30% {1641}. Overexpression of the MDM2 gene was found frequently in these tumours, suggesting that TP53 may be inactivated either by mutation or by overexpression of the MDM2 gene. Comparative genomic hybridization has been used to compare tumours of the 'gastric cardia' and tumours in Barrett oesophagus. Gains and losses of genetic material were identified at a number of common regions in cancers from both sites {1718}. Common altered regions included chromosome 4q (loci not yet identified), 3p14 (FHIT, RCA1), 5q 14-21 (APC, MCC), 9p21 (MTS1/CDKN2), 14q31-32.1 (TSHR), 16q23, 18q21 (DCC, p15), and 21q21. Minimal overlapping amplified sites were seen at 5p14 (MLV12), 6p12-21.1 (NRASL3), 7p12 (EGFR), 8123-24.1 (MYC), 15q25

(IGF1R), 17q12-21 (ERBB2/HER2-neu), 19q13.1 (TGFB1, BCL3, AKT2), 20p12 (PCNA), and 20q12-13 (MYBL2, PTPN1). The distribution of these imbalances was similar in both groups. However, loss of 14q31-32.1 (TSHR) was significantly more frequent in Barrett-related adeno-carcinomas than in cardiac cancers. Overall, the available genetic data suggests that within cancers of the oesoph-agogastric junction, a subset of tumours is genetically similar to adenocarcinomas in Barrett oesophagus, whereas another subset is genetically distinct from adeno-carcinomas of both the oesophagus and distal stomach {314, 1133}.

Prognosis and predictive factors

There is a significant relationship between grade and prognosis by univariate analysis. For example, Blomjous et al. found that 31% of patients with well or moderately differentiated cardia tumours survived 5 years, whereas the survival for patients with poorly or undifferentiated tumours was only 17% {151}. When T, N, and M status were included in the analysis, however, grade was significantly related to survival only in those patients with negative lymph nodes (53% 5-year survival for well and moderate compared to 21% for poor and undifferentiated tumours).

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