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Fig. 1.18 TP53 immunoreactivity in squamous cell carcinoma of the oesophagus.

Fig. 1.19 Immunoreactivity for epidermal growth factor receptor (EGFR) in oesophageal squamous cell carcinoma.

finding {935}. Therefore, the determination of DNA ploidy is currently not considered to improve the prognostic information provided by the TNM system {1055}. Extent of resection. The frequency of locoregional recurrence is negatively correlated with the distance of the primary tumour to the proximal resection margin and possibly to preoperative chemotherapy {1890, 1027}. Molecular factors

The TP53 gene is mutated in 35% to 80%

Fig. 1.19 Immunoreactivity for epidermal growth factor receptor (EGFR) in oesophageal squamous cell carcinoma.

of oesophageal SCC {1266}. Whereas some studies Indicated a negative prognostic Influence of p53 protein accumulation in cancer cell nuclei {1743, 277}, others did not observe any prognostic value of either immunoexpression or TP53 mutation {2014, 1661, 1008, 779, 319}. Other potential prognostic factors include growth factors and their receptors {927}, oncogenes, including c-erbB-2 and int-2 {778}, cell cycle regulators {1748, 1297}, tumour suppressor genes {1886}, redox

Fig. 1.20 Fluorescence in situ hybridisation demonstrating cyclin D1 in squamous carcinoma cells.

defence system components, e.g., metal-lothionein and heat shock proteins {897}, and matrix proteinases {1303, 1947, 2155}. Alterations of these factors in oesophageal SCC may enhance tumour cell proliferation, invasiveness, and metastatic potential, and thus may be associated with survival. However, none of the factors tested so far has entered clinical practice.

Multiple LOH

Amplification of CMYC, EGFR, CYCLIND1, HST1.

Overexpression of CYCLIN D1 LOH at 3p21; LOH at 9p31

TP53 mutations

TP53 mutations

Normal oesophagus

Oesophagitis

Low-grade intraepithelial neoplasia

High-grade intraepithelial neoplasia

Invasive SCC

Fig. 1.21 Putative sequence of genetic alterations in the development of squamous cell carcinoma of the oesophagus.

Normal oesophagus

Oesophagitis

Low-grade intraepithelial neoplasia

High-grade intraepithelial neoplasia

Invasive SCC

Fig. 1.21 Putative sequence of genetic alterations in the development of squamous cell carcinoma of the oesophagus.

Adenocarcinoma of the oesophagus

M. Werner R. Lambert

J.F. Flejou G. Keller

Definition

A malignant epithelial tumour of the oesophagus with glandular differentiation arising predominantly from Barrett mucosa in the lower third of the oesophagus. Infrequently, adenocarcinoma originates from heterotopic gastric mucosa in the upper oesophagus, or from mucosal and submucosal glands.

ICD-O Code 8140/3

Epidemiology

In industrialized countries, the incidence and prevalence of adenocarcinoma of the oesophagus has risen dramatically {1827}. Population based studies in the U.S.A. and several European countries indicate that the incidence of oeso-phageal adenocarcinoma has doubled between the early 1970s to the late 1980s and continues to increase at a rate of about 5% to 10% per year {152, 153, 370, 405, 1496}. This is paralleled by rising rates of adenocarcinoma of the gastric cardia and of subcardial gastric carcinoma. It has been estimated that the rate of increase of oesophageal and oesophagogastric junction adenocarci-noma in the U.S.A. during the past decade surpassed that of any other type of cancer {152}. In the mid 1990s the incidence of oesophageal adenocarcino-ma has been estimated between 1 and 4 per 100,000 per year in the U.S.A. and several European countries and thus approaches or exceeds that of squa-mous cell oesophageal cancer in these regions. In Asia and Africa, adenocarci-noma of the oesophagus is an uncommon finding, but increasing rates are also reported from these areas. In addition to the rise in incidence, ade-nocarcinoma of the oesophagus and of the oesophagogastric junction share some epidemiological characteristics that clearly distinguish them from squa-mous cell oesophageal carcinoma and adenocarcinoma of the distal stomach. These include a high preponderance for the male sex (male:female ratio 7:1), a higher incidence among whites and an average age at the time of diagnosis of around 65 years {1756}.

Aetiology

Barrett oesophagus

The epidemiological features of adeno-carcinoma of the distal oesophagus and oesophagogastric junction match those of patients with known intestinal metaplasia in the distal oesophagus, i.e. Barrett oesophagus {1605, 1827}, which has been identified as the single most important precursor lesion and risk factor for adenocarcinoma of the distal oesophagus, irrespective of the length of the segment with intestinal metaplasia. Intestinal metaplasia of the oesophagus develops when the normal squamous oesophageal epithelium is replaced by columnar epithelium during the process of healing after repetitive injury to the oesophageal mucosa, typically associated with gastro-oesophageal reflux disease {1798, 1799}.

Intestinal metaplasia can be detected in more than 80% of patients with adenocarcinoma of the distal oesophagus. {1756, 1824}. A series of prospective endoscop-ic surveillance studies in patients with known intestinal metaplasia of the distal oesophagus has shown an incidence of oesophageal adenocarcinoma in the order of 1/100 years of follow up {1799}. This translates into a life-time risk for oesophageal adenocarcinoma of about 10% in these patients. The length of the oesophageal segment with intestinal metaplasia, and the presence of ulcerations and strictures have been implicated as further risk factors for the development of oesophageal adenocarcinoma by some authors, but this has not been confirmed by others {1799, 1797, 1827}. The biological significance of so-called ultrashort Barrett oesophagus or intestinal metaplasia just beneath a normal Z line has yet to be fully clarified {1325}. Whether adenocarcinoma of the gastric cardia or subcardial gastric cancer is also related to foci of intestinal metapla sia at or immediately below the gastric cardia {715, 1797, 1722} is discussed in the chapter on adenocarcinoma of the oesophagogstric junction. Despite the broad advocation of endoscopic surveillance in patients with known Barrett oesophagus, more than 50% of patients with oesophageal adenocarcinoma still have locally advanced or metastatic disease at the time of presentation {1826}. Chronic gastro-oesophageal reflux is the usual underlying cause of the repetitive mucosal injury and also provides an abnormal environment during the healing process that predisposes to intestinal metaplasia {1799}. Data from Sweden have shown an odds ratio of 7.7 for oeso-phageal adenocarcinoma in persons with recurrent reflux symptoms, as compared with persons without such symptoms {1002, 1001}.

The more frequent, more severe, and longer-lasting the symptoms of reflux, the greater the risk. Among persons with long-standing and severe symptoms of reflux, the odds ratio for oesophageal adenocarcinoma was 43.5. Based on these data a strong and probably causal relation between gastro-oesophageal reflux, one of the most common benign disorders of the digestive tract, and oesophageal adenocarcinoma has been postulated.

Factors predisposing for the development of Barrett oesophagus and subsequent adenocarcinoma in patients with gastro-oesophageal reflux disease include a markedly increased oesophageal exposure time to refluxed gastric and duodenal contents due to a defective barrier function of the lower oesophageal sphincter and ineffective clearance function of the tubular oesophagus {1823, 1827}. Experimental and clinical data indicate that combined oesophageal exposure to gastric acid and duodenal contents (bile acids and pancreatic enzymes) appears to be more detrimental than isolated exposure to gastric juice or duodenal contents alone {1241, 1825}. Combined reflux is thought to increase cancer risk by promoting cellular proliferation, and by exposing the oesophageal epithelium to potentially genotoxic gastric and intestinal contents, e.g. nitrosamines {1825}.

Tobacco

Smoking has been identified as another major risk factor for oesophageal adeno-carcinoma and may account for as much as 40% of cases through an early stage carcinogenic effect {562, 2204}.

Obesity

In a Swedish population-based case control study, obesity was also associated with an increased risk for oesophageal adenocarcinoma. In this study the adjusted odds ratio was 7.6 among persons in the highest body mass index (BMI) quar-tile compared with persons in the lowest. Obese persons (BMI > 30 kg/m2) had an odds ratio of 16.2 as compared with the leanest persons (persons with a BMI < 22 kg/m2) {1002}. The pathogenetic basis of the association with obesity remains to be elucidated {310}.

Alcohol

In contrast to squamous cell oesophageal carcinoma, there is no strong relation between alcohol consumption and adenocarcinoma of the oesophagus.

Helicobacter pylori

This infection does not appear to be a predisposing factor for the development of intestinal metaplasia and adenocarci-noma in the distal oesophagus. According to recent studies, gastric H. pylori infection may even exert a protective effect {309}.

Localization

Adenocarcinoma may occur anywhere in a segment lined with columnar metaplastic mucosa (Barrett oesophagus) but develops mostly in its proximal verge. Adenocarcinoma in a short segment of Barrett oesophagus is easily mistaken for adenocarcinoma of the cardia. Since adenocarcinoma originating from the distal oesophagus may infiltrate the gastric cardia and carcinoma of the gastric cardia or subcardial region may grow into the distal oesophagus these entities are frequently difficult to discriminate (see chapter on tumours of the oesopha-gogastric junction). As an exception, ade-nocarcinoma occurs also in the middle or proximal third of the oesophagus, in the

Fig. 1.22 Endoscopic ultrasonograph of Barrett 71 adenocarcinoma. 7he hypoechoic tumour lies between the first and second hyperechoic layers (markers). 7he continuity of the second layer (sub-mucosa) is respected.

latter usually from a congenital islet of het-erotopic columnar mucosa (that is present in up to 10% of the population).

Barrett oesophagus

Symptoms and signs

Barrett oesophagus as the precursor of most adenocarcinomas is clinically silent in up to 90% of cases. The symptomatology of Barrett oesophagus, when present, is that of gastro-oesophageal reflux {1011}. This is the condition where the early stages of neoplasia (intraepithelial and intramucosal neoplasia) should be sought.

Endoscopy

The endoscopic analysis of the squamo-columnar junction aims at the detection of columnar metaplasia in the distal oesophagus. At endoscopy, the squamo-columnar junction (Z-line) is in the thorax, just above the narrowed passage across the diaphragm. The anatomical landmarks in this area are treated in the chapter on tumours of the oesophago-gastric junction.

If the length of the columnar lining in this distal oesophageal segment is > 3 cm, it is termed a long type of Barrett metaplasia. When the length is < 3 cm, it is a short type. Single or multiple finger-like (1-3 cm) protrusions of columnar mucosa are classified as short type. In patients with short segment (< 3 cm) Barrett oesophagus the risk for developing ade-nocarcinoma is reported to be lower compared to those with long segment Barrett oesophagus {1720}. As Barrett oesophagus is restricted to cases with histologically confirmed intestinal metaplasia, adequate tissue sampling is required.

Histopathology

Barrett epithelium is characterized by two different types of cells, i.e. goblet cells and columnar cells, and has also been termed 'specialized', 'distinctive' or Barrett metaplasia. The goblet cells stain positively with Alcian blue at low pH (2.5). The metaplastic epithelium has a flat or villiform surface, and is identical to gastric intestinal metaplasia of the incomplete type (type II or III). Rarely, foci of complete intestinal metaplasia (type I) with absorptive cells and Paneth cells may be found. The mucous glands beneath the surface epithelium and pits may also contain metaplastic epithelium. Recent studies suggest that the columnar metaplasia originates from multipotential cells located in intrinsic oesophageal glands {1429}.

Intraepithelial neoplasia in Barrett oesophagus

Macroscopy

Intraepithelial neoplasia generally has no distinctive gross features, and is detected by systematic sampling of a flat Barrett mucosa {634, 1573}. The area involved is variable, and the presence of multiple dysplastic foci is common {226, 1197}. In some cases, intraepithelial neoplasia presents as one or several nodular masses resembling sessile adenomas. Rare dysplastic lesions have been considered true adenomas, with an expanding but localised growth resulting in a well demarcated interface with the surrounding tissue {1459}.

Microscopy

Epithelial atypia in Barrett mucosa is usually assessed according to the system

Table 1.02

7attern of endoscopic ultrasound in oesophageal cancer. 7here are three hyper- and two hypo-echoic layers; the tumour mass is hypoechoic.

T1 The 2nd hyperechoic layer

(submucosa) is continuous

T2 The 2nd hyperechoic layer

(submucosa) is interrupted The 3rd hyperechoic layer (adventitia) is continuous

T3 The 3rd hyperechoic layer

(aventitia) is interrupted

T4 The hypoechoic tumour is continuous with adjacent structures

E*

Fig. 1.23 Barrett oesophagus. A Haphazardly arranged glands (right) adjacent to hyperplastic squamous epithelium (left). B Goblet cells and columnar cells form vil-lus-like structures over chronically inflamed stroma. There is no intraepithelial neoplasia.

devised for atypia in ulcerative colitis, namely: negative, positive or indefinite for intraepithelial neoplasia. If intra-epithelial neoplasia is present, it should be classified as low-grade (synonymous with mild or moderate dysplasia) or highgrade (synonymous with severe dyspla-sia and carcinoma in situ) {1582, 1685}. The criteria used to grade intraepithelial neoplasia comprise cytological and architectural features {75}.

Negative for intraepithelial neoplasia

Usually, the lamina propria of Barrett mucosa contains a mild accompanying inflammatory infiltrate of mononuclear cells. There may be mild reactive changes with enlarged, hyperchromatic nuclei, prominence of nucleoli, and occasional mild stratification in the lower portion of the glands. However, towards the surface there is maturation of the epithelium with few or no abnormalities. These changes meet the criteria of atypia negative for intraepithelial neoplasia, and can usually be separated from low-grade intraepithelial neoplasia. Atypia indefinite for intraepithelial neoplasia. One of the major challenges for the pathologist in Barrett oesophagus is the differentiation of intraepithelial neo-plasia from reactive or regenerative epithelial changes. This is particularly difficult, sometimes even impossible, if

Fig. 1.24 Barrett oesophagus with low-grade intraepithelial neoplasia on the left and high-grade on the right. Note the numerous goblet cells showing a clear cytoplasmic mucous vacuole indenting the adjacent nucleus.

erosions or ulcerations are present {1055}. In areas adjacent to erosions and ulcerations, the metaplastic epithelium may display villiform hyperplasia of the surface foveolae with cytological atypia and architectural disturbances. These abnormalities are usually milder than those observed in intraepithelial neoplasia. There is a normal expansion of the basal replication zone in regenerative epithelium versus intraepithelial neopla-sia, where the proliferation shifts to more superficial portions of the gland {738}. If there is doubt as to whether reactive and regenerative changes or intraepithelial neoplasia is present in a biopsy, the category atypia indefinite for intraepithelial neoplasia is appropriate and a repeat biopsy after reflux control by medical acid suppression or anti-reflux therapy is indicated.

Low-grade and high-grade intraepithelial neoplasia. Intraepithelial neoplasia in Barrett metaplastic mucosa is defined as a neoplastic process limited to the epithelium {1582}. Its prevalence in Barrett mucosa is approximately 10%, and it develops only in the intestinal type metaplastic epithelium. Cytological abnormalities typically extend to the surface of the mucosa. In low-grade intraepithelial neoplasia, there is decreased mucus secretion, nuclear pseudostratification confined to the lower half of the glandular epithelium, occasional mitosis, mild pleomorphism, and minimal architectural changes. High-grade intraepithelial neoplasia shows marked pleomorphism and decrease of mucus secretion, frequent mitosis, nuclear stratification extending

Fig. 1.25 High-grade intraepithelial neoplasia in Barrett oesophagus. A Marked degree of stratification with nuclei being present throughout the thickness of the epithelium. Foci of cribriform, back-to-back glands. B Highly atypical cells lining tubular structures.

to the upper part of the cells and glands, and marked architectural aberrations. The most severe architectural changes consist of a cribriform pattern that is a feature of high-grade intraepithelial neo-plasia as long as the basement membrane of the neoplastic glands has not been disrupted. The diagnostic reproducibility of intraepithelial neoplasia is far from perfect; significant interobserver variation exists {1572}.

Adenocarcinoma

Symptoms and signs

Dysphagia is often the first symptom of advanced adenocarcinoma in the oesophagus. This may be associated with retrosternal or epigastric pain or cachexia.

Endoscopy

The endoscopic pattern of the early tumour stages may be that of a small polypoid adenomatous-like lesion, but more often it is flat, depressed, elevated or occult {1011, 1009}. Areas with high

Fig. 1.26 Mucinous adenocarcinoma arising in Barrett oesophagus. Large mucinous lakes extend throughout the oesophageal wall.

grade intraepithelial neoplasia are often multicentric and occult. Therefore a systematic tissue sampling has been recommended when no abnormality is evident macroscopically {483}. The usual pattern of advanced adenocarcinoma at endoscopy is that of an axial, and often tight, stenosis in the distal third of the oesophagus; with a polypoid tumour bleeding occurs at contact.

Radiology

This approach is still proposed in the primary diagnosis of oesophageal cancer when endoscopic access is not easily available {1058}. Today, barium studies are helpful mostly for the analysis of stenotic segments; they are less efficient than endoscopy for the detection of flat abnormalities. Computerised tomography will detect distant thoracic and abdominal metastases.

Endoscopic ultrasonography

At high frequency, some specificities in the echoic pattern of the mucosa and submucosa of the columnar lined oesophagus are displayed. However, the procedure is only suitable for the staging of tumours previously detected at endo-scopy; the tumour is hypoechoic. Lymph nodes adjacent to the oesophageal wall can also be visualised by this technique {1614}.

Macroscopy

The majority of primary adenocarcino-mas of the oesophagus arise in the lower third of the oesophagus within a segment of Barrett mucosa {1055}. Adjacent to the tumour, the typical salmon-pink mucosa of Barrett oesophagus may be evident, especially in early carcinomas. In the early stages, the gross findings of Barrett adenocarcinoma may be subtle with irregular mucosal bumps or small plaques. At the time of diagnosis, most tumours are advanced with deep infiltration of the oesophageal wall. The advanced carcinomas are predominantly flat and ulcerated with only one third having a polypoid or fungating appearance. Occasionally, multifocal tumours

Fig. 1.27 Highly infiltrative adenocarcinoma in Barrett oesophagus (pT3), with extension into the cardia.

Fig. 1.28 Adenocarcinoma, tubular type. A Well differentiated, B moderately differentiated and C poorly differentiated.

Fig. 1.28 Adenocarcinoma, tubular type. A Well differentiated, B moderately differentiated and C poorly differentiated.

may be present {1055, 1770}. The rare adenocarcinomas arising independently of Barrett oesophagus from ectopic gastric glands and oesophageal glands display predominantly ulceration and polypoid gross features, respectively. These tumours are also found in the upper and middle third of the oesophagus {265, 1204}, but are rare.

Histopathology

Adenocarcinomas arising in the setting of Barrett oesophagus are typically papillary and/or tubular. A few tumours are of the diffuse type and show rare glandular formations, and sometimes signet ring cells {1458, 1770}. Differentiation may produce endocrine cells, Paneth cells and squamous epithelium. Mucinous adenocarcinomas, i.e. tumours with more than 50% of the lesion consisting of mucin, also occur.

Grading

Most adenocarcinomas arising from Barrett mucosa are well or moderately differentiated {1458}, and display well formed tubular or papillary structures.

The well differentiated tumours may pose a diagnostic problem in biopsy specimens because the infiltrating component may be difficult to recognize as invasive {1055} since Barrett mucosa often has irregular dispersed glands. Glandular structures are only slightly formed in poorly differentiated adenocarcinomas and absent in undifferentiated tumours. Small cell carcinoma may show foci of glandular differentiation. It is discussed in the chapter on endocrine neoplasms of the oesophagus.

Tumour spread and staging

Adenocarcinomas spread first locally and infiltrate the oesophageal wall. Distal spread to the stomach may occur. Extension through the oesophageal wall into adventitial tissue, and then into adjacent organs or tissues is similar to squa-mous cell carcinoma. Common sites of local spread comprise the mediastinum, tracheobronchial tree, lung, aorta, pericardium, heart and spine {1055, 1789}. Barrett associated adenocarcinoma metastasizes to para-oesophageal and paracardial lymph nodes, those of the lesser curvature of the stomach and the celiac nodes. Distant metastases occur late. The TNM classification used for SCC is applicable to Barrett adenocarcinoma and provides prognostically significant data {1945}.

Other carcinomas

Adenosquamous carcinoma (ICD-O code: 8560/3)

This carcinoma has a significant squa-mous carcinomatous component that is intermingled with a tubular adenocarci-noma.

Mucoepidermoid carcinoma (ICD-O code: 8430/3)

This rare carcinoma shows an intimate mixture of squamous cells, mucus secreting cells and cells of an intermediate type.

Adenoid cystic carcinoma (ICD-O code: 8200/3)

This neoplasm is also infrequent and believed to arise, like the mucoepider-moid variant, from oesophageal glands {265, 2066}. Both lesions tend to be of salivary gland type, and small tumours may be confined to the submucosa. However, the ordinary oesophageal ade-nocarcinoma can also arise from ectopic gastric glands, or oesophageal glands {1204, 1055}.

Genetic susceptibility

Several lines of evidence suggest that there is a genetic susceptibility to oesophageal adenocarcinoma arising from Barrett oesophagus. The almost exclusive occurrence of Barrett oesophagus in whites and its strong male predominance hint at the involvement of genetic factors {1605}. Several reports describe familial clustering of Barrett oesophagus, adeno-carcinoma and reflux symptoms in up to three generations, with some families showing an autosomal dominant pattern of inheritance with nearly complete pene-trance {470, 480, 482, 569, 861, 1537, 1610, 1959}. Although shared dietary or environmental factors in these families could play a role, the earlier age of onset of Barrett in some families suggests the influence of genetic factors {861}. The molecular factors that determine this genetic susceptibility are largely unknown and linkage analysis in families has not been reported. Recently, an association between a variant of the GSTP1 (glutathione S-transferase P1) gene and Barrett oesophagus and adenocarcino-ma has been demonstrated {1994}. GSTs are responsible for the detoxification of various carcinogens, and inherited differences in carcinogen detoxification capacity may contribute to the development of Barrett epithelium and adenocar-cinoma.

Genetics

In Barrett oesophagus a variety of molecular genetic changes has been correlated with the metaplasia-dysplasia-carci-noma sequence (Fig. 1.21) {2091}. Prospective follow-up of lesions biopsied at endoscopy show that alterations in TP53 and CDKN2A occur at early stages {112, 1337}.

TP53. In high-grade intraepithelial neo-plasia a prevalence of TP53 mutations of approximately 60% is found, similar to adenocarcinoma {789}. Mutation in one allele is often accompanied by loss of the other (17p 13.1). Mutations occur in diploid cells and precede aneuploidy. The pattern of mutations differs significantly from that in squamous cell carcinomas. This is particularly evident for the high frequency of G:C>A:T transition mutations, which prevail in adenocarcino-mas but are infrequent in SCC (Fig. 1.17). CDKN2A. Alterations of CDKN2A, a locus on 9p21 encoding two distinct tumour suppressors, p16 and p19arf

Fig. 1.29 Adenoid cystic carcinoma showing typical cribriform pattern resembling its salivary gland counterpart.

include hypermethylation of the p16 promotor and, more rarely, mutations and LOH {948}.

FHIT. Among other early changes in the premalignant stages of metaplasia are alterations of the transcripts of FHIT, a presumptive tumour suppressor gene spanning the common fragile site FRA3B {1222}.

LOH and gene amplification. A number of other loci are altered relatively late during the development of adenocarcinoma, with no obligate sequence of events. Prevalent changes (> 50%) include LOH on chromosomes 4 (long arm) and 5 (several loci including APC) and amplification of ERBB2 {1266, 1264}. Phenotypic changes in Barrett oesopha

Table 1.03

Genes and proteins involved in carcinogenesis in Barrett oesophagus.

Table 1.03

Genes and proteins involved in carcinogenesis in Barrett oesophagus.

Factor

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