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An overview of squamous cell and adenocarcinoma of the esophagus.

Esophageal carcinoma, also known as esophageal cancer, is a malignant tumor of the esophagus. Squamous cell and adenocarcinomas are clinically relevant.

What is esophageal carcinoma?

Definition: Esophageal carcinoma is a cancer of the esophagus that is often diagnosed late. Histologically, there are two main types of tissue: adenocarcinoma and squamous cell carcinoma. The most common risk factors include nicotine and alcohol. Esophageal carcinoma usually causes symptoms relatively late. Indicative symptoms include dysphagia and a feeling of retrosternal pressure. The diagnosis is made endoscopically by means of oesophagogastroduodenoscopy and oesophageal open-swallow examination. Patients with esophageal carcinoma should receive interdisciplinary treatment. The usual multimodal treatment methods include resection of the tumor as well as (combined) radio- and chemotherapy. Personalized treatment approaches are available for tumours at the oesophagogastric junction. In the worst case, for example in the case of distant metastases and multiple comorbidities, a palliative treatment concept is usually the only remaining option. The prognosis of esophageal carcinoma depends on the extent of the tumor.

Epidemiology : Squamous cell carcinoma is the most common type of esophageal cancer worldwide. In the so-called "Asian esophageal cancer belt", an incidence of up to 100/100,000 inhabitants is reached. In the industrialized countries of Europe, North America and Australia, however, adenocarcinomas are becoming increasingly common. They now account for around 40 to 50 percent of all malignant esophageal neoplasms; in Western Europe, this figure is as high as 50 to 60 percent. The increase is attributed to the rise in risk factors, including obesity and a high-fat diet.

What are the causes of adenocarcinomas?

Adenocarcinomas are almost always caused by Barrett's esophagus as a result of gastroesophageal reflux disease (GERD). More than 90 percent of them are localized in the distal third of the oesophagus at the oesophagogastric junction (AEG carcinoma). Adenocarcinoma usually grows as a polypous papillary tumor and infiltrates neighboring organs at an early stage. In contrast to squamous cell carcinoma, which usually grows wall-infiltrating, clinically relevant lumen narrowing occurs late. Locoregional lymph node metastases occur earlier and more frequently in adenocarcinoma than in squamous cell carcinoma.

What are the causes of squamous cell carcinoma?

In most cases, squamous cell carcinomas are caused by exposure to noxious substances such as nicotine and alcohol. Approximately every second tumor develops in the middle section of the esophagus. The remaining squamous cell carcinomas are distributed along the entire esophagus. Squamous cell carcinomas are often associated with a second carcinoma, especially pharyngeal tumors.

What are the risk factors for the development of adenocarcinomas?

The risk of developing esophageal carcinoma is influenced by various factors. For both entities, the negative influence of nicotine is considered certain. The following risk factors are known for adenocarcinomas:

What are risk factors for the development of squamous cell carcinoma?

Typical risk factors for squamous cell carcinoma are

  • Nicotine and alcohol consumption (if more than 80 mg of alcohol is consumed per day, the risk increases 18-fold; if 20 mg of nicotine is consumed daily, the risk increases by a factor of 44)
  • Consumption of very hot food and drinks
  • Underweight
  • Malnutrition (especially low consumption of fruit and vegetables)
  • male gender
  • Howel-Evans syndrome (tylosis palmaris et plantaris): autosomal dominant dys/hyperkeratosis of feet and hands
  • esophageal achalasia
  • Stenosis after chemical burns with alkalis or acids
  • Radiotherapy in the neck/thorax area (dose-dependent)
  • synchronous and metachronous tumors in the head and neck area or the lungs

What is the pathogenesis of esophageal carcinoma?

Adenocarcinomas: In principle, adenocarcinomas in the area of the esophagus can develop from persistent cylindrical epithelial islands, but also from intraesophageal mucous glands and the heterotopic gastric mucosa. The majority of all adenocarcinomas develop on the basis of a reflux-related change in the distal oesophagus, so-called preneoplastic Barrett's metaplasia. This can be detected in more than 80 percent of patients with esophageal adenocarcinomas. In Barrett's oesophagus, the normal squamous epithelium of the distal section of the oesophagus is replaced by an intestinalized epithelium consisting of monolayered cylindrical epithelium with goblet cells. The malignancy develops sequentially in multi-stage processes from low-grade to high-grade intraepithelial neoplasia (IEN) to invasive adenocarcinoma. In the course of this metaplasia-dysplasia-carcinoma sequence, there is

  • increasing genomic instability with abnormalities in the cell cycle
  • aneuploid cell fractions
  • Mutations in a number of oncogenes and tumor suppressor genes
  • reduced expression of cell adhesion molecules

Squamous cell carcinomas: Squamous cell carcinomas are usually caused by initial mechanical damage to the oesophageal mucosa, sometimes in combination with toxic carcinogenic substances. The carcinogens are also responsible for secondary squamous cell carcinomas in the head and neck area or in the lungs. Pathogenetically, the inactivation of the tumor suppressor gene p53 plays a decisive role. This change, which is detected in up to 55 percent of all patients with oesophageal squamous cell carcinoma, causes a transformation of the cylindrical epithelium into cylindrical epithelial dysplasia. The tumor suppressor genes p16 and the fragile histidine triad gene (FHIT gene) as well as the amplification/overexpression of cyclin D1 also contribute to tumor progression in esophageal squamous cell carcinoma. Inactivation of p16 causes, among other things, uncontrolled cell proliferation. The FHIT gene is particularly susceptible to the effects of chemical carcinogens. Overexpression of cyclin D1 is associated with an increased number of lymph node metastases, high tumor proliferation rates, an unfavorable prognosis and a poor chemotherapeutic response.

What is the localization and morphology of esophageal carcinoma?

Depending on the location, a distinction is made between cervical, intrathoracic and gastroesophageal junction carcinomas or AEG carcinomas; histopathologically, a distinction is made primarily between epithelial tumors and non-epithelial tumors.

Epithelial esophageal malignancies include

  • Adenocarcinomas
  • Squamous cell carcinomas
  • adenosquamous carcinomas
  • Mucoepidermoid carcinomas
  • adenoid-cystic carcinomas
  • small cell carcinomas
  • undifferentiated carcinomas
  • pseudosarcomatous carcinomas

Non-epithelial or mesenchymal malignant esophageal tumors are

  • Kaposi's sarcoma
  • Leiomyosarcoma

Morphologically, they are classified as:

  • Carcinoma in situ (CIS): macroscopically visible as raised or flat epithelial thickening or as sunken thinning of the mucosal epithelium, either whitish (leukoplakia), reddish (erythroplasia) or unchanged (occult), occurrence solitary in 10-20% of cases and multiple in 80-90% of cases
  • polypous carcinoma: most common at around 60%, often early tumor stage; transition to ulcerated form possible in the course of the disease, with or without wall infiltration
  • ulcerative carcinoma: around 25% of cases, irregularly limited hemorrhagic ulcer with wall-like raised edges
  • diffuse infiltrating carcinoma: around 15% of cases, infiltration extending far into the adjacent esophageal wall and tracheobronchial tract, very aggressive carcinoma with poor prognosis
  • varicose carcinoma: resembles oesophageal varices endoscopically and radiographically

What are the symptoms of esophageal cancer?

esophageal carcinomas usually only become symptomatic at a late stage. Dysphagia is the classic leading symptom - albeit usually at an advanced stage with a lumen narrowing of more than 50 percent. Those affected often feel food particles sticking (first dry/solid, later also mushy/liquid food), forcing them to make repeated swallowing movements.

Further findings complete the clinical picture:

  • Regurgitation of undigested food
  • retrosternal discomfort (pain, feeling of pressure, burning sensation)
  • Feeling of fullness
  • Nausea
  • Vomiting
  • Cough and hoarseness (with infiltration of the recurrent laryngeal nerve)
  • Pseudohypersalivation (with complete obstruction of the oesophageal lumen)
  • Hematemesis and melena (as a sign of gastrointestinal bleeding)
  • Lymphadenopathy, especially cervical
  • recurrent aspiration/pneumonia
  • early feeling of fullness
  • Inappetence
  • Weight loss up to tumor cachexia

Metastasis from esophageal carcinoma?

Classically, esophageal carcinomas metastasize:

  • Lymphogenous: early; primarily to regional lymph nodes along the esophageal wall, later - depending on the location of the tumor - to paraesophageal, cervical, paratracheal, parabronchial, hilar, gastric and celiac lymph node areas. Compared to oesophageal squamous cell carcinoma, lymph node metastases develop later in adenocarcinoma.
  • infiltrative: relatively early; infiltrations mainly in the trachea and vertebral body
  • hematogenous: late, distant metastases are found in proximal carcinomas (upper half of the esophagus) primarily in the lungs and pleura, in distal malignancies (lower half of the esophagus) and AEG tumors in the liver. Metastases in other organs or the skeletal system are usually only observed at a very late stage.

Diagnosis of esophageal carcinoma?

An initial indication of the diagnosis of esophageal carcinoma is provided by the patient's medical history and clinical examination. In the case of adenocarcinomas, there is often a long history of reflux, and in the case of squamous cell carcinomas, a long history of alcohol consumption. This is followed by imaging procedures, especially endoscopies (including biopsies) and computer tomography (CT).

Endoscopic procedures

All patients with new onset of dysphagia, gastrointestinal bleeding, recurrent aspiration, repeated vomiting, dyspepsia, unintentional weight loss and/or inappetence should be endoscopically examined at an early stage. The standard procedure here is oesophagogastroduodenoscopy (OGD).

To detect dysplasia and early neoplastic lesions in patients with an increased risk of oesophageal carcinoma (e.g. alcohol and/or nicotine abuse and patients with a history of oro-/nasopharyngeal squamous cell carcinoma), chromoendoscopy (e.g. acetic acid staining) is used.(e.g. acetic acid staining, Lugol's solution) or virtual chromoendoscopy are recommended.

Chromoendoscopy:

The latest generation of virtual chromoendoscopies includes iScan which is offered as standard at Vivomed. In these procedures, the oesophageal mucosa is viewed with a high-resolution video endoscope that highlights mucosal features using selective color filter techniques. In this way, macroscopically invisible changes can be predicted histologically.

Further imaging:

Endosonography and high-resolution computed tomography (CT) of the mediastinum are used to further clarify the positional relationship between the oesophageal carcinoma and the tracheobronchial tract as well as the depth extension.

Staging

The prognosis of esophageal carcinoma correlates clearly with the TNM stage. Precise, pre-therapeutic sectional image staging is therefore mandatory.

Suitable methods are

  • Abdominal ultrasonography (B-scan ultrasonography as the preferred initial procedure)
  • contrast-enhanced endosonography (CEUS)
  • CT scans of the thorax and abdomen: Multidetector CT (MDCT) of the neck/thorax and abdomen is recommended for primary staging in patients with a newly diagnosed esophageal carcinoma; to improve T-staging, always with wall distension (primarily negative oral contrast medium). In addition to negative contrasting, intravenous administration of iodinated contrast medium is mandatory. If CT is not possible, an MRI is indicated
  • flexible bronchoscopy with biopsy if necessary
  • diagnostic laparoscopy if necessary (especially for the detection of liver metastasis and peritoneal carcinomatosis in AEG carcinomas)
  • Positron emission tomography (PET) for locally advanced tumors
  • skeletal scintigraphy if necessary

Therapy

the type and extent of treatment for esophageal carcinoma should be discussed and decided on an interdisciplinary basis. Depending on the time of diagnosis and tumor classification or staging, the treatment concept is determined in a so-called tumor conference. In principle, a choice should be made between curative and palliative treatment approaches. The decisive factors here are

  • patient-related characteristics such as general condition and comorbidities
  • tumor-specific characteristics such as tumor extent and metastasis (TNM stage)
  • Histological findings
  • Localization of the tumour
  • Patient preference

Prerequisites for curative therapy are

  • no distant metastasis
  • locally less advanced mass
  • sufficient general and nutritional condition
  • satisfactory cardiopulmonary sufficiency

The following options are available for curative primary treatment:

  • endoscopic resection (ER) for early carcinomas using endoscopic submucosal resection (ESD).
  • surgery alone
  • Combination of neoadjuvant preoperative radiochemotherapy plus surgery
  • radiochemotherapy alone

The palliative concept includes, among other things

  • Stent implantation or intraluminal thermal ablation
  • palliative polychemotherapy
  • Trastuzumab antibody therapy for HER2 expression
  • palliative brachytherapy
  • Analgesia
  • Ensuring nutritional intake

Endoscopic resection

Endoscopic tumor resection (ER) is achieved using the latest standard with endoscopic submucosal dissection (ESD). ESD involves targeted resection of the tumor under visualization, which cannot be achieved using old suction techniques or EMR with a snare.

ESD is clearly superior to EMR, especially for larger lesions. ESD achieves better results in terms of R0 resection and local recurrence, especially for squamous cell carcinomas.

If high-grade intraepithelial neoplasia or a mucosal carcinoma (L0, V0, no ulcerations, grading G1/G2, infiltration depth 1000ym) is detected in the squamous epithelium, endoscopic en bloc resection should be attempted. In addition to treatment, this also ensures staging of the lesion with regard to depth of infiltration.

Squamous cell carcinomas

Criteria in favor of endoscopic resection for esophageal squamous cell carcinoma:

  • Grading ≤ G2
  • no invasion of lymphatic vessels (L0) and/or veins (V0)
  • no ulceration

Adenocarcinomas

Criteria in favor of endoscopic resection for esophageal adenocarcinomas:

  • Depth of invasion < 500 µm
  • Diameter of the mass < 20 mm
  • L0 and/or V0
  • tumor-free basal or lateral resection margin
  • no ulceration
  • no higher differentiation (G1/G2)

Following a successful neoplasia resection in Barrett's esophagus, the remaining non-neoplastic Barrett's mucosa should be thermally ablated. This reduces the risk of further metachronous neoplasia. Common methods are:

  • Radio-frequency ablation (RFA), especially for long-segment Barrett's esophagus
  • APC ablation (argon plasma coagulation), especially for short-segment Barrett's oesophagus

Procedure for local recurrence: A local recurrence confined to the mucosa (crT1a cN0 cM0) following endoscopic resection of a mucosal carcinoma in Barrett's esophagus can be treated again endoscopically. If an R0 resection cannot be achieved, a surgical procedure is more suitable.

Follow-up care: After successful endoscopic intervention of a high-grade intraepithelial neoplasia or early carcinoma, regular follow-up endoscopies are recommended; initially after three months, then every six months for two years and then every year.

Surgical therapy

With the exception of carcinomas limited purely to the mucosa (T1a, N0, M0), which can be completely resected R0 endoscopically, surgical resection with curative intent is the standard procedure for all potentially resectable esophageal carcinomas in the middle and distal third of the esophagus. In order to achieve an R0 resection, a safety margin of 3 to 4 cm proximally and distally must be maintained.

Surgery should always be considered if one of the following is present:

  • Lymphatic (L1) or venous invasion (V1)
  • Poor degree of differentiation (≥ G3)
  • deep submucosal infiltration (≥ 500 μm)

Surgical treatment should be performed in clinics with a high number of cases. The aim of surgical resection for squamous cell and adenocarcinomas is the complete removal of the tumor and the regional lymph nodes. If possible, minimally invasive procedures should be preferred to open surgical interventions.

Surgical therapy is indicated in:

  • Tumor stage T2
  • Tumor stages T3 and T4 or in N+, M0 after neoadjuvant chemotherapy (adenocarcinoma) or radiochemotherapy (squamous cell carcinoma), provided operability and resectability are given

Surgical method

The choice of surgical method depends on the tumour location:

  • Carcinomas in the distal and mid-thoracic section of the esophagus (incl. AEG Siewert type I): transthoracic subtotal esophagectomy with resection of the proximal stomach, gastric pull-up and intrathoracic anastomosis
  • Carcinomas in the esophagogastric junction Siewert type II: total gastrectomy with distal esophageal resection or transthoracic subtotal esophagectomy; alternatively transhiatal abdomino-cervical subtotal esophagectomy
  • Carcinomas of the esophagogastric junction Siewert type III: total extended gastrectomy with distal esophagectomy. In the case of advanced infiltration, esophagogastrectomy if necessaryCarcinomas in the upper thoracic esophageal segment: subtotal esophagectomy with extension of the safety distance to the oralthoracic squamous cell carcinomas: transthoracic esophageal dissection
  • Squamous cell carcinomas in the cervical oesophagus: carefully weigh up surgery versus radiochemotherapy; in the case of a surgical procedure, total oesophagectomy or cervical oesophageal resection via a cervical approach with upper sternotomy, reconstruction through free jejunum interposition

The regional lymph nodes are also removed during the operation. The extent depends on the location of the primary tumor. A distinction is made between three fields of lymphadenectomy: abdominal, thoracic and cervical. Two-field lymphadenectomy is standard.

Reconstruction

If possible, resection and reconstruction should be performed at the same time. In patients with limited functional capacity or questionable vascularization of the prepared gastric interposition, a two-stage reconstruction may be advisable. The method of choice after a subtotal esophagectomy is gastric pull-up. Colonic interposition is the procedure of second choice, particularly in patients who have undergone previous gastric surgery. If the vascular anatomy is very favorable, the jejunum can be used as an interposition. After a total gastrectomy with distal esophageal resection, continuity is usually restored with a Roux-Y jejunum sling and an end-to-side esophagojejunostomy transhiatally in the lower mediastinum.

Procedure for distant metastases

In the presence of distant metastases, esophagectomy and simultaneous resection do not provide a prognostic advantage. Therefore, esophagectomy is not recommended in the case of a preoperative M1 situation. If a previously unknown, very limited distant metastasis (lung or liver) is detected intraoperatively, it can be removed together with the primary tumor.

Procedure for local recurrence

In the case of an isolated local recurrence after curative surgery, an interdisciplinary tumor conference should be held to discuss re-operability and resectability - or alternatively radiochemotherapy. Radiochemotherapy is an option for isolated local recurrences or lymph node metastases of squamous cell carcinoma of the esophagus, provided that no preoperative or postoperative radiotherapy has been performed in the recurrence area and there is sufficient normal tissue tolerance. Radiochemotherapy is also an option for isolated local recurrences of esophageal adenocarcinomas.

Nutritional medicine

The nutritional care of patients with esophageal cancer is an integral part of oncological treatment. The influence of nutritional status on the postoperative complication rate has been described in detail. Nutritional counseling is recommended during neoadjuvant therapy - regardless of nutritional status. Patients with pronounced malnutrition and high metabolic risk should receive preoperative nutritional therapy, even if the operation has to be postponed. The intake of oral nutritional supplements helps to cover energy requirements and should be recommended to all patients, regardless of their nutritional status. Nutritional status (including dietary advice) should be monitored during the first six months after surgery. Supplementation of the oral energy supply with drinking solution or tube feeding may sometimes be advisable.

What is the prognosis for esophageal cancer?

Despite therapeutic advances in recent years, the prognosis for esophageal cancer remains unfavorable. This is mainly due to the lack of early symptoms, the usually late diagnosis and the frequent comorbidities and the resulting limited functional operability. The prognosis correlates directly with the local tumor infiltration depth and the degree of lymphatic seeding. With tumor resection alone, five-year survival is around 15 to 25 percent. The 10-year survival rates are 40 percent for Barrett's carcinoma and 20 percent for squamous cell carcinoma.

Prognostic factors are:

  • Location of the primary tumor: The higher the location of the carcinoma, the worse the prognosis.
  • Tumor size: The greater the length and depth of growth, the worse the prognosis.
  • Growth type: Polypous and pedunculated squamous cell carcinomas have a better prognosis than stenosing and ulcerative forms.
  • Number of affected lymph nodes
  • TNM stage
  • Depth of invasion and histological findings
  • Time of the operation
  • intra- and postoperative complications
  • therapy regimen used

What prophylaxis is available to prevent esophageal cancer?

In Switzerland, there are neither general screening examinations nor a simple test for the early detection of esophageal cancer. However, if Barrett's metaplasia is diagnosed endoscopically, regular follow-up endoscopies are recommended. Patients with frequent reflux and/or heartburn should also consult a doctor.

The current S3 guideline on oesophageal cancer does not currently recommend primary prophylaxis with medication. There is also no recommendation for dietary supplements such as beta-carotene, vitamins A, C, E and selenium. However, a balanced diet with a high proportion of fruit and vegetables plus regular physical activity can help to reduce the risk of oesophageal cancer. It is also helpful to avoid alcohol and nicotine as well as very hot food and drinks.

Some studies show a positive association between the consumption of red meat or meat products and oesophageal squamous cell carcinoma, others with adenocarcinoma. Due to the inconclusive data available to date, it is not yet possible to make any generally binding prevention recommendations.