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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Carcinoma of the esophagus and gastro-esophageal junction

.

Department of Thoracic Surgery, University of Leuven, Belgium

Epidemiology – etiology – pathology

Adenocarcinoma of the esophagus and the gastro-esophageal junction is reportedly the fasted rising malignancy.

Esophageal carcinoma is ranking ninth in the list of most common cancers in the world. Esophageal carcinoma is a disease of the mid to late adulthood. It's late mortality is high with only 8% of patients surviving more than five years with a median survival of nine months. There are no differences in survival chances according to sex, racial background and histological type.

There is a marked variation in incidence, more than for any other tumor, according to sex, geographical area, racial and economical background. The annual age adjusted incidence rate amongst males is varying from less than 5 cases per 100,000 inhabitants amongst whites in the U.S. to up to 12.5 per 100,000 in some regions of France (Normandy) and even more than 100 cases per 100,000 in parts of China (Linxian) or the Kaspian part of Iran. In most countries, esophageal carcinoma is twice- to four times more frequent in men as compared to women. Squamous cell carcinoma is five times as frequent in blacks as compared to Kaukasians. Today a clear rising incidence is noticed in parts of the world where this condition used to be rather occasional in the past e.g. Germany, Denmark and former Sovjet Union countries. This probably relates to an increased alcohol consumption. In Germany the cumulative risk has quadrupled in five yearly birth cohorts between 1915 and 1940. On the contrary there is a clear decreasing trend in Finland with an incidence in mortality decreasing about 10% every five years in both sexes.

Also patterns of incidence of histological subtypes are showing some changes squamous cell carcinoma seemingly decreasing while on the other hand a sharp and fast increase of adenocarcinoma is noticed mainly in the Western World.

In Burgundy (France) the incidence of squamous cell carcinoma remained stable between 1976 and 1983 but the incidence of adenocarcinomas sharply rized from 5.6% between 1976 and 1987, up to 20.1% in 1991 until 1993. In Norway the yearly increase of incidence of adenocarcinoma is estimated at 17% for the male population and 14% for the female population between 1983 and 1992. The increase of incidence of adenocarcinoma is estimated faster and bigger than for any other carcinoma over the last two decades and is currently estimated at a rise between 5 to 10% per year during the 1980 decade.

Heavy smoking and drinking are considered as the two main risk factors to develop a squamous cell carcinoma. More than 95% of the patients with a squamous cell carcinoma are smokers and there is an increase with both the number of cigarettes smoked per day and the duration of smoking.

Carotenoids, vitamins C and E may be involved as preventives of esophageal carcinogenesis. Randomized trials in China indicate that a supplement of these micro-elements significantly decreases mortality caused by esophageal carcinoma as compared to a population deprived of these supplements in their diet.

Genetic predisposition is unusual. However 95% of patients with congenital palmar and plantar keratosis (tylosis) may develop esophageal carcinoma before age 65.

Other predisposing conditions to esophageal carcinoma are: chronic inflammation (reflux?), achalasia, caustic injury and Plummer-Vinson syndrome. Little is known about the role of viruses (papilloma virus) which may be involved as agents favoring the progression from dysplasia to invasive carcinoma.

Adenocarcinoma may also be related to smoking and alcohol abuse, but to a lesser extend than squamous cell carcinoma. Most adenocarcinomas (from 20% to 80%) seem to arise from specialized columnar metaplastic epithelium (Barrett). It is now accepted that the cancer risk is mostly related to the intestinal type of metaplasia with a 5% chance of apparition of cancer within 5 years. Esophageal carcinoma is considered to be the consequence of an accumulation of different mutations in different suppressor genes and protooncogenes. There is evidence of multiple chromosomal defects and deletions (13 Q, 5 Q, 18 Q, 3 P, 9 P, 17 Q). Often significant aneuploidy is noticed. P53 mutation seems to be an early event in the progression towards esophageal carcinoma. P53 is over-expressed in a wide spectrum of pathologic changes from metaplasia to low grade dysplasia, high grade dysplasia and invasive carcinoma both for adenocarcinoma and squamous cell carcinoma. In Barrett metaplasia a clear correlation exists between overexpression of P53 and malignant degeneration. Such an overexpression preceeds aneuploidy.

Most frequent histologic types are squamous cell carcinoma and adenocarcinoma.

The squamous cell carcinoma is presenting mostly in the upper 2/3 of the esophagus. Squamous cell carcinomas tend to be more differentiated. Verrucous carcinoma is a rare variant of a well differentiated squamous cell carcinoma whereas a spindle cell carcinoma is a variant of undifferentiated carcinoma. The latter has to be differentiated from sarcoma or carcinocarcinoma.

Adenocarcinomas arise from glandular epithelioma with a papillar or tubular structure. Most adenocarcinomas arise from Barrett metaplasia or from glandular metaplasia in the esophageal mucosa. Adenocarcinomas mainly arise in the distal third and gastroesophageal junction.

Precancerous lesions: Dysplasia is an epithelial precancerous lesion. Histologically it is characterized by nuclear enlargement and hyperchromaticity with increased mitotic activity.

Squamous cell dysplasia is found preceeding or combining with squamous cell carcinoma. Glandular dysplasia is associated with adenocarcinoma complicating Barrett's esophagus. Dysplasia develops more frequently in the intestinal and in gastric type of metaplasia. Increasing grades of dysplasia from low to severe appear to be associated with an increasing risk of cancer. High grade dysplasia is described as carcinoma in situ. Its natural history is not well defined since either no apparent progression to carcinoma or progression to invasive carcinoma during a follow-up of 2 to 46 months have been decribed.

In resection specimens from patients with high grade dysplasia in up to 50% of the cases invasive associated micro-invasive carcinoma will be found. This is the reason why resection is considered as the treatment of choice in patients presenting with high grade dysplasia.

Diagnosis

Early stage cancer has no typical symptoms. Symptoms of advanced cancers of the esophagus and gastroesophageal junction are non specific and mostly correlate with the presence of a mass causing a difficult transit of the bolus. Therefore dysphagia is the common symptom being painful (odynophagia) in a number of cases. Regurgitation and sialorrhea are frequent as the mass causes esophageal obstruction. Weight loss is mostly due to interference with diet habits. In advanced stage carcinoma weight loss is the result of toxicity from the tumor.

Bronchopneumopathy can be associated either with regurgitation and aspiration can be indicative of the presence of a tracheo-esophageal fistula. Dysphonia is indicating direct invasion of the recurrent nerve.

Clinial examination in patients with carcinoma of the esophagus or G.E. junction is usually negative. In advanced cases supraclavicular or cervical adenopathy can be discovered by palpation.

In case of a suggestive history, especially when presenting dysphagia, diagnosis needs to be confirmed. Barium swallow and/or endoscopy are the first examinations. Barium swallow is helpful in evaluating the topography in relation to important structures in the chest and allows easy identification of the tumor level in relation to the carina as this may have important consequences towards therapy especially surgical access.

Barium swallow usually shows an irregular lined mass.

Endoscopy allows direct visualization of the tumor allowing biopsy. Vital colorations using Lugol or Toluidine blue are helpful to guide biopsy or cytologic specimens in cases of early carcinoma increasing diagnostic accuracy.

Staging and classification

Oncologic evaluation (clinical staging)

Staging is performed according to the UICC and TNM classification, 1997 edition. In this staging system the esophagus is topographically subdivided in tumors of the cervical esophagus, tumors of the proximal third of the esophagus i.e. from the clavicula to the bifurcation of the trachea, tumors of the mid esophagus starting from the tracheal bifurcation down to half the distance to the GE junction, tumors of the distal esophagus starting from halfway down of the distance between the tracheal bifurcation and the GE junction.

Tumors of the gastroesophageal junction (-GEJ) are classified as gastric cancers. However their natural behavior and their therapeutic modalities are similar to tumors of the esophagus.

Therefore tumors of the GEJ will be further treated in this chapter together as one entity with esophageal carcinomas.

Clinical staging (especially lymphnode staging) is inaccurate, both by over- and understaging, in 20 to 30% of the cases. This inaccuracy may jeopardize the value of some therapeutic strategies.

T staging

T staging and particular presence or absence of infiltration into surrounding structures e.g. tracheal-bronchial tree, vertebrae, major blood vessels is mainly evaluated by CT scan and echo-endoscopy (EUS).

Accuracy of CT in assessing tumor infiltration in the aorta is about 80%. When esophageal contact exceeds 90° of the aortic circumference over a distance of more than two images invasion is likely. Also the loss of the triangular fat plane between esophagus, aorta and spine is helpful to assess invasion of the descending aorta. CT is less accurate in assessing infiltration of the pericardium because of the lack of a fat plane between esophagus and pericardium. Suspicion of invasion of the tracheo-bronchial tree is based on displacement or indentation of the posterior wall of either the trachea or bronchus. Accuracy of CT here is 75%.

Endoscopic ultrasonography (EUS) is a more accurate technique in defining the T parameter.

Nevertheless a margin of error both false positive and false negative is still around 20 to 30% in the early T1 T2 tumors. Moreover in T1 tumors it is important to discriminate between the T1a (intramucosal) and T1b (submucosal) infiltration. Indeed in the T1b tumors the likelihood of lymphnode invasion is approximately 10 to 15% contraindicating non surgical therapies such mucosectomy or laser ablation. A frequency of 20 megahertz is required to discriminate between these structures. The accuracy of EUS in the diagnosis of infiltration to adjacent anatomical structures is around 80% provided an ability to pass the tumor. The inability to pass a tumor or stenosis ranges between 20 and 40% which of course also restricts the possibility of assessing not only tumors but also lymphnode invasion.

Esophageal dilatation prior to EUS is not recommended because of the risk of perforation estimated at 30 to 70%.

Tracheo-bronchoscopy is recommended to detect either direct infiltration of the tumor or a second primary tumor especially in tumors located in the proximal part of the esophagus. In tumors of the hypopharynx and the cervical esophagus the incidence of a second primary tumor is estimated at 10 to 15%.

N staging

Occasionally cervical nodes can be diagnosed by clinical examination (supraclavicular and cervical lymphnodes). CT accuracy in diagnosing invasion of mediastinal lymphnodes is about 60%. The CT criterion for an abnormal node is a transverse axis of 10 mm or greater. In such cases overstaging is to be taken in consideration. EUS accuracy for positive lymphnode detection is about 70 to 80%. However EUS has a tendency to overestimate histologic involvement (sensitivity 90%, specificity 60%). As a result of these difficulties there is a growing interest for minimal invasive techniques such as thoracoscopy and laparoscopy in the pretreatment staging of esophageal carcinoma. However because of the rather chaotic pattern of lymphnode metastasis theoretically both laparoscopic and thoracoscopic staging will be required which is rather time consuming and probably rather a (too?) invasive staging methodology.

M staging

Chest X-ray, liver ultrasound, ultrasound of the neck, CT of the chest and abdomen are performed in order to detect visceral metastasis and distal lymphnode metastasis. More recently PET scan (Positron Emission Tomography) has been introduced offering additional possibilities in detecting occult visceral organ metastasis and distant lymphnode metastasis.

Assessing resectability

One of the final goals of staging is to evaluate the possibility of a complete so called R0 resection that is removal of microscopic and macroscopic tumor which is an important prognostic indicator. Indeed leaving behind the microscopic (R1) or macroscopic (R2) tumor precludes any chance of curative treatment. As a general rule it is accepted that for supracarinal tumors complete resection is feasable in T1 T2 tumors and for tumors located below the carina T1, T2 and T3 tumors. However because of the difficulties in obtaining accurate clinical staging and especially the tendency to overstage T and N careful interpretation of clinical staging remains mandatory and no patient should be denied possibility of any treatment with curative option.

Medical assessment

Careful assessment of medical operability is mandatory since complete resection offers the best chances for curative option. Patients with esophageal cancer are often heavy smokers suffering from chronic obstructive or restrictive pulmonary diseases and also often heavy alcoholic drinkers with the potential for liver cirrhosis. Cardiovascular and pulmonary evaluation as well as hepatic and renal function and the state of nutrition should all be examined routinely. According to the individual findings supplementary specific investigations e.g. stress ECG may be indicated. Portal hypertension generally represents a contraindication for surgery. Age in itself is not a contraindication for surgical treatment. In such patients careful assessment of biological parameters will determine the operative risk.

Surgical treatment

The aim of the treatment is definite cure. There is a consensus that in potentially resectable tumors surgery is the first choice. Lymphnode status seems to be the most important prognostic factor with involvement in 30 to 80% of reported series. In more than 40% of the recurrences lymphnodes are involved. As a result two attitudes towards the extent of resection and lymphadenectomy evolved.

There are those who state that lymphnode involvement equals by definition systemic disease thus claiming that it is useless to make efforts to perform wide peritumoral resections and lymphadenectomy to improve survival. Standard technique typical for this approach is transhiatal stripping and the use of gastric tube for reconstruction. Other authors believe that the radical en bloc esophagectomy had beneficial effect on cure rate even in cases of lymphnode involvement. When adding meticulous extended lymphadenectomy all these efforts are aiming at a so-called R0 situation i.e. no residual microscopic of macroscopic tumor because either R1 (microscopic) or R2 (macroscopic) residual tumor leaves the patient with virtually no chances for cure.

Beside efforts to perform peritumoral resection as wide as possible experience learns that carcinoma of the esophagus and GEJ have a tendency to extend submucosally in the longitudinal axis. Many patients present with multicentric localizations (skip lesions). In order to decrease the risk of anastomotic recurrences most authors today agree on performing a subtotal esophagectomy for carcinoma of the esophagus and many advocate the same procedure for tumors of the GEJ. For the same oncologic reasons resection of the lesser curvature of the stomach is advocated to obtain a negative distal section plane and to resect potentially positive lymphnodes at the level of the lesser curvature. For tumors extending more than 5 cm towards the stomach as a rule a total gastrectomy will be performed.

Lymphadenectomy consists in removing lymphnodes along the left gastric artery, coeliac axis, splenic artery up to the splenic hilum (especially in tumors of the GEJ) and along the common hepatic artery up to the level of the portal vein. This is called compartment D2 lymphadenectomy in analogy with lymphadenectomy in gastric cancer. In the mediastinum a distinction is made between standard lymphadenectomy and more extended lymphadenectomies. In the standard lymphadenectomy para-esophageal, peritumoral and subcarinal lymphnodes are removed. In the more extended lymphadenectomies also the lymphnodes in the aortopulmonary window, along both main stem bronchi and along the left recurrent nerve and the area arround the brachio-cephalic trunc and right recurrent nerve are removed. Mostly influenced by Japanese authors more attention has been paid recently to the so-called three-field lymphadenectomy. Beside the lymphadenectomy in the abdomen and the mediastinum a Ushape incision is made in the neck allowing a bilateral cervical lymphadenectomy. Lymphnodes along the trachea, both recurrent nerves, along the carotid vessels as well as deep lateral lymphnodes of the neck will be removed.

The most important factor in the surgical treatment is the completeness of resection (R0). There is indirect evidence that more extended resection and lymphadenectomy result in a beneficial effect in outcome.

Over recent years there is a clear tendency in a number of centers of excellency to perform more radical resections and lymphadenectomies. However there is no clear consensus about the extend of resection and lymphadenectomy in relation to tumor localization. As a general rule in tumors located above the carina a three field lymphadenectomy is proposed. Indeed many authors consider in these tumors cervical lymphnode involvement still being regional lymphnode metastasis (N1) rather than distant lymphnode metastasis (M+LY). It is accepted that in such cases cervical bilateral lymphadenectomy is having a potential beneficial effect on survival. For tumors of the distal third of the esophagus and GEJ two-field lymphadenectomy is the rule. Cervical lymphnode involvement is considered as distant lymphnode metastasis i.e. stage IV disease and therefore no beneficial effect on survival is to be expected by adding bilateral cervical lymphadenectomy. However some authors advocate three-field lymphadenectomy claiming not only optimal staging but also better disease free survival and possibly cure rate. However controversy persist mainly due the lack of prospective randomized studies.

Surgical access differs strongly from center to center reflecting the complexity of the pathology and the individual experience in each center. When using transthoracic approach right sided thoracotomy is performed for supracarinal tumors to allow optimal lymphadenectomy in the upper mediastinum and along the left recurrent nerve and the brachio-cephalic trunc. After closing the chest, the intervention is continued through laparotomy and cervicotomy. A right sided thoracotomy can be used as well for tumors located in the distal esophagus although many authors prefer for these tumors as well as for tumors of the GEJ a left sided approach. Through left thoracotomy including transsection of the costal margin and an incision at the periphery of the diaphragm an excellent access is obtained on both superior abdomen compartment and posterior mediastinum. After closure of the chest the intervention finishes through a left cervical incision.

Restoration of continuity: Today most authors prefer stomach to restore continuity. After resection of the lesser curvature usually a long gastric tube is easily fashioned allowing cervical esophagogastrostomy. Also in tumors of the GEJ because of longitudinal submucosal spread and distant skip lesions subtotal esophagectomy is to be preferred above intrathoracic anastomosis. On the contrary when tumors are extending downwards on to the stomach over more than 5 cm total gastrectomy is preferred usually performing a reconstruction using Roux-en-Y intrathoracic esophagojejunostomy or a long colonsegment interposition in case subtotal esophagectomy is felt to be necessary.

In patients who already underwent in the past a major gastric surgery e.g. Billroth II colon interposition is used to restore continuity.

When not considering radical resection and lymphadenectomy blind esophagectomy can be performed through laparotomy and cervical incision. The esophagus is progressively mobilized from both proximal and distal end. After full mobilization the esophagus is extirpated and the gastric tube is brought up through the posterior mediastinal route into the cervical incision. A cervical esophagogastrostomy completes the intervention. This method is considered to be less invasive because avoiding thoracotomy. However the incidence of postoperative pulmonary complications seems to be as frequent as through the open transthoracic route. As a result there is an increasing interest for minimal invasive surgical techniques either through video-assisted thoracoscopic surgery (VATS) and/or laparoscopy. Preliminary results until now are not showing a clear benefit in terms of postoperative mortality or morbidity. Little is known about the oncologic results. Consequently minimal invasive surgery in the treatment of carcinoma of the esophagus and GEJ remains strictly investigational.

Results of primary surgery

Approximately one in three patients will be cured after primary esophagectomy. Esophagectomy with curative options (R0 resection) results in over 40% 5-year survival.

Over the last two decades important improvements in surgical techniques and peri- and postoperative management have been resulting in a significant decrease of postoperative mortality and morbidity. Today postoperative mortality in centers with large experience is below 5%. Postoperative morbidity is mainly caused by pulmonary complications (infection, atelectasis) in about 25% of the patients. Anastomotic leaks occur in 5 to 10% but rarely results in fatal septic complications especially if anastomosis is performed in the neck. Overall five-year survival both for squamous cell carcinoma as well as far adenocarcinoma is about 30% According to multivariate analysis most important prognostic indicators are pathologic staging and lymphnode involvement. In early stage I carcinoma five-year survival reaches 90%. In stage II 50 to 60%. Five-year survival in stage III is between 10 to 15%. In lymphnode negative patients five-year survival is between 60 and 65%. In case of lymphnode involvement 10 to 15%. R0 complete resections result in five-year survivals between 40 to 50%. Even in an advanced stage III provided a complete Ro resection has been performed five-year survival is to be estimated at 20%. In Barrett carcinoma several authors have published a five-year survival exceeding 50%. These more favorable survival curves are probably related to a number of patients that where under endoscopic surveillance for Barrett metaplasia resulting in a earlier diagnosis. The majority of such patients at the time of degeneration present with an early stage I and II carcinoma. On the contrary patients presenting themselves with carcinoma at the time of their first medical visit will have positive lymphnodes in about 75%. These findings highlights the importance of a regular follow-up including multiple biopsies in patients with Barrett metaplasia.

Many authors have stressed when reporting their results the beneficial effect of extended lymphadenectomies as compared to the results after standard esophagectomy including tumor free survival as well cure rate. Also for adenocarcinomas of the GEJ five-year survival of approximately 30% have been reported by several authors and even in the presence of intrathoracic lymphnode involvement five-year survival exceeding 10% is to be expected. These surgical results together with other epidemiologic and biologic findings suggest that tumors of the GEJ behave similarly to tumors of the tubular esophagus rather than behaving like tumors of the stomach. Therefore several authors advocate to treat GEJ tumors in the same way as tumors of the esophagus and prefer to stage them rather as esophageal carcinomas than gastric carcinomas.

Potentially unresectable T4 tumors

Induction therapy in surgical resectable cancer will be discussed in chapter II. In potentially unresectable T4 tumors induction therapy aims at downstaging and therefore increased resectability. Partial response is seen in up to 50 to 60% and complete response in about 20%.

Especially patients showing at pathological examination complete response in the resected specimen and lymphnodes are clearly benefiting from such multimodality regimens.

Surgical treatment of carcinomas of the hypopharynx and cervical esophagus

The location of the tumor in the immediate vicinity of the cricopharyngeal muscle and larynx on one side and the necessity for an oncologic wide peritumoral resection on the other side will determine whether or not beside an esophagectomy laryngectomy is indicated. In case of limited tumors of the cervical esophagus so-called larynx saving esophagectomy can be attempted. In such cases the dissection of the esophagus can be extended proximally of the cricopharyngeal muscle in such a way that a safe section margin can be obtained. However these interventions are technically delicate and complex mainly because the risk of damaging the recurrent nerves. Moreover the functional results may be compromised because of the difficulties in speech and swallow revalidation. Frequently a temporary if not definitive tracheostomy becomes necessary. In some cases even a subsequent laryngectomy may be become mandatory because of chronic aspiration. In more voluminous tumors pharyngolaryngectomy and transhiatal total esphagectomy are the standard options. This applies to both voluminous tumors of the cervical esophagus as to tumors of the hypopharynx invading the larynx and/or the cricopharyngeal muscle and cervical esophagus. The intervention is completed with the bilateral functional cervical lymphadenectomy. This includes the deep submandibular lymphnodes, the superfical parajugular lymphnodes, paratracheal, periesophageal nodes, the supraclavicular lymphnodes. If possible an attempt is made to preserve the upper pole of the thyroid on its feeding artery. A parathyroid gland can be imbedded in a muscle of the forearm. This avoids the need for postoperative life long thyroid and parathyroid substitution medication. Continuity is restored by using the stomach. This is possible in almost all cases even when very high resection up to the tonsillae is requested. If the gastric tube is too short or in case of previous resectional gastric surgery colon interposition can be used. For small tumors of the hypopharynx more conservative surgery may be indicated. The intervention is such cases can be restricted to pharyngolaryngectomy and segmental resection of the cervical esophagus (if preoperative esophagoscopy did not show any further distant malignant lesion in the esophagus). Reconstruction in such cases can be performed by using free jejunum interposition with microvascular anastomosis in the neck. A disadvantage of this technique according to some others is a more limited speech revalidation.

Functional results, late sequelae

Results of gastroplasty following esophagectomy are excellent to very good in the vast majority of the patients i.e. approximately 85%. However in the first postoperative period a number of undesired side effects are common. Most important side effects are decreased appetite, early satiety because of decreased gastric reservoir, post vagotomy diarrhea. As a consequence many patients will continue to loose weight in the first postoperative period. In most patients after few months weight stabilizes and the majority of the patients will start to gain weight again. A frequent complication especially after cervical esophagogastrostomy is anastomotic (sub) stenosis. Today these strictures are easily dilated and usually a limited number of dilatations is requested. If reflux is thought to contribute to stricture formation PPI's are recommended to solve the problem. In case of intrathoracic anastomosis especially when located below the aortic arch the risk of reflux esophagitis and reflux stenosis (and even Barrett metaplasia) is very high up to 50% after 1 year. Beside oncologic reasons this problem of both acid and biliary reflux esophagitis is another important argument to perform on a systematic base esophagogastrostomy in the neck.

Late postresection sequelae are milk intolerance or dumping, the latter in some cases being very disabling.

Voice restoration after pharyngolaryngo-esophagectomy and gastric pull-up is a major problem for many patients. Voice restoration can be obtained by means of tracheogastric punction and placement of a prosthesis. Many patients however use external electric voice amplificator.

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6982

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