Oesophageal Carcinoma

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— oesophageal cancer usually presents with progressive dysphagia initially for solids and ultimately liquids. Investigation is by endoscopy and biopsy, and chest X-ray to detect any enlargement of the heart, mediastinal lymph nodes or lung lesion that may be causing extrinsic compression. For biopsy-proven cancer, staging for local and distant disease includes endoluminal ultrasound (tumour depth and nodal spread), computed tomographic (CT) scan chest and abdomen and positron emission tomographic (PET) scan. Treatment may be palliative (radiotherapy, stent) in bulky high-stage disease, or curative in intent with earlier lesions. The latter may involve neoadjuvant radio-/chemotherapy to downstage the tumour and then surgery, or surgery alone. Choice of operative procedure depends on the general health of the patient, the tumour site and extent, the choice of planned oesophageal substitute (stomach, jejunum, colon) and preference of the surgeon. Ideally, longitudinal clearance margins of 5-10cm should be achieved. Transthoracic or transdiaphragmatic hiatal approaches are available, with the latter particularly suitable for localized distal oesophageal lesions and resulting in less operative morbidity than thoracotomy.

— biopsy/partial oesophagectomy/total thoracic oesophagectomy (TTO)/ oesophagectomy with limited gastrectomy/oesophagogastrectomy.

— procedure: transthoracic or transhiatal.

— number of fragments/length of oesophagus and proximal stomach (cm). Measurements are better assessed on the fresh specimen as formalin fixation causes up to 30% contraction. The external surface is also inspected for the presence of adventitial fat, lateral mediastinal pleura and distally abdominal peritoneum.



— mid/lower oesophagus/oesophagogastric junction/cardia. Tumour is considered oesophageal if >50% of its mucosal bulk or epicentre is

Oesophagus Mid
Figure 1-1. Oesophagus. |W

above the oesophagogastric junction as defined by internal or external landmarks, i.e. where the tubular oesophagus ends and the saccular stomach begins. Equally, adjacent oesophageal Barrett's metaplasia or mucosal dysplasia indicates an oesophageal lesion, and gastric mucosal dysplasia a gastric tumour. — distances (cm) to the proximal and distal resection limits and the oesophagogastric junction. The junction can vary in location or be obscured by tumour and anatomically distal oesophagus has an external layer of adventitia or abdominal peritoneum whereas proximal stomach is oriented to serosa. Distinction is important as the TNM staging and mode of spread differ. Tumours involving the junction are classified as either Siewert I (distal oesophagus growing down), II (truly junctional) or III (gastric cardia growing up). Siewert

I is staged as oesophageal under TNM rules, Siewert II and III as gastric. In addition, squamous cell, small cell and undifferentiated carcinomas involving the junction are regarded as oesophageal in origin.


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

— superficial carcinoma is often small (<2-3 cm long) but advanced carcinoma frequently involves long segments of oesophagus.


— polypoid: spindle cell carcinoma with good prognosis.

— warty/verrucous: verrucous carcinoma.

— nodular/plaque: superficial carcinoma (the gross and endoscopic appearances may be classified similar to that of early gastric cancer; see Chapter 2).

— fungating/stricture/ulcerated/infiltrative: usual types.

— regression and scarring post neoadjuvant chemo-/radiotherapy.


— circumscribed/irregular.

Other pathology

— fistula/perforation either spontaneous, post adjuvant therapy or post endoscopy.

— diverticulum.

— Barrett's metaplasia: velvety mucosa distinct from the pale squamous mucosa and proximal to the junction.



— distal oesophagus/oesophagogastric junction on the basis of specialized enteric-type Barrett's metaplasia and dysplasia. The incidence of this tumour has greatly increased (x3-5 in the last 20 years). Various suggested factors are heredity, improved socio-economic conditions with obesity from a Western diet rich in processed foods, antibiotic eradication of acid-suppressing pangastric cag-A (cytotoxin-associated gene product)-positive Helicobacter pylori with restoration of gastric acidity and increased gastro-oesophageal reflux disease, proton pump inhibitor therapy and bile reflux. Most are tubular or papillary and of intestinal type, some are signet ring cell or mucinous. Prognosis is poor as presentation is at a late stage, typically with per-ineural invasion.


Lamina propria Muscularis mucosae


Muscularis propria

Adventitia pTis pTI

Superficial (early) oesophageal cancer = pTI + nodal disease. D = tumour distance (mm) to the circumferential radial margin (CRM) of excision of the adventitia.

Figure 1.2. Oesophageal carcinoma. pA|

Oesophagus Pathology Adenocarcinoma

Squamous cell carcinoma

— usually moderately differentiated keratinizing.

— verrucous: exophytic and keratotic with a pushing deep margin of cytologically bland bulbous processes. Slow growing but anecdotally may become more aggressive, especially after radiation.

— basaloid: poor prognosis and aggressive. Deeply invasive nested pattern of palisaded basaloid cells with central necrosis, atypia and mitoses. Often admixed with usual squamous carcinoma.

Spindle cell/sarcomatoid carcinoma (polypoid carcinoma/carcinosarcoma)

— a spindle cell squamous carcinoma that undergoes varying degrees of stromal mesenchymal differentiation.

Adenosquamous carcinoma

— mixed differentiation, aggressive.

Undifferentiated carcinoma

— no distinct squamous or glandular differentiation features and a highgrade lesion.

— in poorly differentiated lesions adenocarcinoma may be CK7/CAM5.2 positive and squamous cancer negative for these markers. Characterization is of use as squamous cancers are often more responsive to adjuvant therapy and can be associated with synchronous or metachronous upper aerodigestive tract tumours.

Mucoepidermoid/adenoid cystic carcinoma

— of oesophageal submucosal duct origin. Tendency to local recurrence and metastases in 50%.

Small cell carcinoma

— primary or secondary from lung, or as part of a mixed differentiation oesophageal cancer. Poor prognosis. Distinguish from poorly differentiated basaloid squamous cell or adenocarcinoma by chromo-granin/synaptophysin/CD56 and paranuclear dot CAM5.2 expression.

Malignant melanoma

— primary or secondary. Primary requires adjacent mucosal junctional atypia. Comprises 0.1% of oesophageal malignancy—polypoid, ulcerated, satellite nodules, pigment, poor prognosis.

Metastatic carcinoma

— direct spread: stomach, thyroid, hypopharynx, bronchus and lung

— distant spread: breast, malignant melanoma.


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

— influence on prognosis is uncertain unless the tumour is anaplastic, e.g. undifferentiated carcinoma, small cell carcinoma or basaloid carcinoma.

— for squamous cancers differentiation features are keratinization and intercellular bridges, and for adenocarcinomas the percentage tumour gland formation (well/G1 >95%: moderate/G2 50-95%: poor/G3 <50%). Undifferentiated carcinomas cannot be categorized as either squa-mous cell or adenocarcinoma and are classified as Grade 4 (as is small cell carcinoma).

— heterogeneity of differentiation within individual tumours is not uncommon.


Border: pushing/infiltrative. Lymphocytic reaction: prominent/sparse.

Depth (cm) and distance (mm) to the nearest painted perioesophageal circumferential resection margin.

Superficial or "early" squamous carcinoma of the oesophagus is defined as intraepithelial or invasive squamous carcinoma confined to the mucosa or submucosa, with or without lymph node spread (pTis, pT1) and is of more favourable prognosis than the usual muscle invasive deep or "advanced" carcinoma (60-90% 5-year survival rates versus 5-10%). Carcinoma invading submucosa does less well (35% nodal metastases, 55% 5-year survival) than that confined to the mucosa alone (88% 5-year survival irrespective of nodal status). Depth of invasion is the most important prognostic indicator on multivariate analysis and requires histological assessment as there is variable correlation with gross, radiological and endoscopic appearances. Note that on biopsy distinction between dysplastic glands or squamous epithelium abutting an irregular muscularis mucosae and true invasion can be difficult: look for single cells and nests of infiltration (± a desmoplastic stromal reaction). The edge of a well-differentiated adenocarcinoma may manifest as mildly atypical glands devoid of stromal reaction but undermining oesophageal squamous epithelium. However, the pitfall of treatment-related squamous re-epithelialization overlying Barrett's mucosa (± dysplasia) must also be borne in mind.

The TNM classification applies only to carcinomas.

pTis carcinoma in situ pT1 tumour invades lamina propria or submucosa*

pT2 tumour invades muscularis propria pT3 tumour invades adventitia pT4 tumour invades adjacent structures."'

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

'Trachea, bronchi, pleura, lung, pericardium, heart, aorta, vena cava, azygos vein.

About 50% of distal oesophageal carcinomas spread into the proximal stomach with potential for serosal involvement. Junctional and gastric tumour components are regarded as gastric in site for TNM staging.

In cases with post neoadjuvant therapy regression, ypT is determined by the deepest residual viable tumour and not more deeply placed keratin debris where tumour may have been.


Present/absent. Intra-/extratumoral.

The presence of lymphovascular invasion (LVI) is a strong prognostic indicator. In advanced carcinoma lamina propria and submucosal LVI are not infrequent, resulting in carcinomatous emboli several centimetres beyond the gross tumour edge. These skip metastases are not classified separately under TNM. Perineural invasion is also characteristic.


The significance of nodal micrometastases (<2 mm diameter) is uncertain but involvement of lymph nodes, particularly if multiple, is a strong prognostic indicator. Nodal metastases occur early in the disease course and are the commonest cause of treatment failure. Histological assessment is required as specificity of lymph node involvement on endoluminal ultrasound is limited. Involvement of stomach and later liver, lungs and adrenal gland is not infrequent.

Site/number/size/number involved/limit node/extracapsular spread. Regional nodes: cervical oesophagus—cervical/supraclavicular; intrathoracic oesophagus—perioesophageal/subcarinal/mediastinal/perigas-tric excluding coeliac. A mediastinal lymphadenectomy will ordinarily include a minimum of six regional lymph nodes.

pN0 no regional lymph node metastasis pN1 metastasis in regional lymph node(s)* pM1 distant metastasis commonest sites are mediastinum, lung and liver tumour thoracic oesophagus lower M1a coeliac nodes

M1b other distant metastasis upper M1a cervical nodes

M1b other distant metastasis mid M1b distant metastasis including non-regional nodes.


Distances (cm) to the proximal and distal limits of excision.

Distance (mm) to the painted perioesophageal circumferential radial margin. Involvement (tumour present to within 1 mm) is an index of the

^Potential descriptors: pN1a (1-3), pN1b (4-7), pN1c (>7 nodes involved).

Nodal Spread Esophageal Cancer
Figure 1.3. Oesophagus: regional lymph nodes. j[W

degree of tumour spread and extent of surgical resection with potential for local recurrence or residual mediastinal disease.

Oesophageal carcinoma may show multifocality (10-25%), direct or discontinuous submucosal and lymphovascular spread and intramural metastasis (15%). This has obvious implications for examination of resection margins and potential for local recurrence.


Diverticula, achalasia, coeliac disease and Plummer-Vincent syndrome have an increased incidence of oesophageal carcinoma.

Barrett's metaplasia: defined as replacement of the lower oesophageal squamous mucosa by metaplastic glandular epithelium due to gastro-oesophageal reflux disease. The Barrett's segment can be classical (>3cm long) or short (<3cm long) with, in particular, long segment disease having an increased risk of malignancy. Ultra-short segment Barrett's is now regarded as junctional metaplasia, a separate condition related to

Helicobacter pylori infection or reflux. An approximate guide is that 10% of patients with hiatus hernia and/or gastro-oesophageal reflux develop Barrett's metaplasia and that 10% of these subsequently have dysplasia or adenocarcinoma with a x 30-40 risk that of the general population, although this may be an overestimate. The specialized intestinal or enteric variant of Barrett's metaplasia is the usual precursor to dysplasia rather than the atrophic gastric fundic or non-specialized cardia types. The biological behaviour of low-grade dysplasia is uncertain with potential for regression after PPI (proton pump inhibitor) treatment or progression. It requires reassessment and if a higher grade lesion is excluded, subsequent 6-monthly endoscopic surveillance. There is a strong (30-40%) association between high-grade dysplasia and concurrent or subsequent adeno-carcinoma, indicating the need for immediate clinicopathological reassessment, short-term follow-up and consideration of surgery. The recognition of significant dysplasia requires confirmation by a second experienced pathologist or positive repeat biopsy. Useful clues to the presence of dysplasia are mucosal villousity and persistence of cytological dys-maturation into the surface epithelium. Observer agreement rates are reasonably high for high-grade dysplasia. However, it is important to distinguish florid regenerative changes in oesophageal squamous and glandular mucosae from dysplasia taking into account erosion, ulceration and the degree of inflammation that is present as well as cytoarchitectural changes, e.g. nuclear enlargement with nucleolar prominence and basal cell hyperplasia. Squamous epithelial regrowth with anti-reflux, laser or photodynamic ablative therapy can produce variably atypical and confusing cytoarchitectural changes, as does chemo-/radiation therapy. Maturation towards the epithelial surface is reassuring. Over-expression of p53 antibody and a high Ki67 proliferation index (especially in the surface epithelium) may help to confirm mucosal dysplasia and its potential for progression to carcinoma in dysplastic Barrett's mucosa, although they are not routinely applicable. It should be noted that the primary diagnosis of Barrett's metaplasia (columnar lined oesophagus) is heavily dependent on the endoscopic findings and site of biopsy, i.e. an origin from the anatomical oesophagus. Pathognomonic histological features are meta-plastic glandular epithelium associated with native oesophageal structures, e.g. submucosal glands or ducts. Glandular mucosa with squamous epithelial islands is also a useful clue. Specialized enteric differentiation is reasonably distinctive, whereas fundic or cardia gastric mucosa is more often associated with hiatus hernia. Surveillance for dysplasia in Barrett's mucosa is recommended as annual or biennial endoscopy with quadran-tic, segmental (every 2 cm) biopsies. Target biopsy of any gross lesion (ulcers, nodules, plaques, strictures) is important, as this is more likely to yield significant pathology.

Field change dysplasia/carcinoma in situ: may be encountered adjacent to or overlying squamous cell carcinoma. A precancerous phase and the biological course of these premalignant changes is uncertain but better established in countries such as China and Japan, where the incidence of oesophageal carcinoma is greater. This has led to the establishment of endoscopic and cytological screening programmes targeted at the early detection of lesions. As with glandular dysplasia, a two-tiered system of low- and high-grade dysplasia is used. Dysplasia is found more frequently overlying and adjacent to superficial than advanced squamous cell carcinoma.

Concurrent squamous cell carcinoma of bronchus and oropharyngo-laryngeal ring has an incidence of 10-15%. Bronchoscopy and upper airways endoscopy should be carried out prior to radical treatment to exclude a lung cancer spreading to involve the oesophagus.

Radio-/chemotherapy necrosis and tumour regression: cell apoptosis, vacuolation and degeneration, necrosis, inflammation, fibrosis, residual aggregates of keratin with a giant cell reaction and perforation may all be seen leaving only residual microscopic tumour. Radiotherapy is the main treatment for extensive squamous carcinoma of the middle third of the oesophagus, and surgery for medically fit patients with locally confined lesions <5 cm in length and cancers of the distal third. Preoperative chemo-/radiotherapy is being increasingly used in an attempt to downstage the tumour and achieve better operative resectability. It is estimated that some 50-60% of tumours show quite marked morphological changes of regression, with squamous carcinoma being more radioresponsive than equally chemoresponsive adenocarcinoma. More sophisticated preoperative staging (e.g. CT/PET scan and endoluminal ultrasound with fine-needle aspiration cytology) is being assessed as a means of predicting those patients likely to benefit from preoperative adjuvant therapy and in selecting patients with locoregional confined disease for resection. Ablative laser therapy and insertion of an expansile metal stent are additional palliative measures for bulky tumour.

Carcinosarcoma: cytokeratin and mesenchymal markers (vimentin, desmin, actin) are helpful in spindle cell/sarcomatoid carcinoma. These tumours show a biphasic spectrum of malignant epithelial (squamous) and mesenchymal (usually sarcoma not otherwise specified, sometimes cartilage, bone, striated muscle) differentiation with either intimate intermingling or juxtaposition of the components that are present in variable amounts (the epithelial component may be microscopic or in situ). Prognosis is intermediate to good because they are exophytic intraluminal lesions which present at a relatively early stage despite their size (50% 5-year survival).

Squamous cell carcinoma is common in the mid-thoracic oesophagus, while Barrett's-related adenocarcinoma is commoner, being the most frequent malignant tumour of the distal oesophagus. The incidence of Barrett's-related adenocarcinoma is markedly increasing, along with that of oesophagogastric junctional lesions.

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  • martin
    What is circumferential resection margin in verrucous carcinoma?
    7 years ago

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