Oesophageal and gastroesophageal junction (GEJ) malignancy is the fastest growing cancer in the Western population. This together with the deadly nature of the disease has attracted increased attention from doctors and researchers alike. The increasing incidence has been primarily attributed to the increase in rates of obesity that in turn causes increased gastroesophageal reflux disease leading to Barrett’s oesophagus and eventually adenocarcinoma of the oesophagus especially at the GEJ. We discuss the epidemiology, risk factors and the management of GEJ tumours.
Oesophageal and gastroesophageal junction (GEJ) malignancy is the fastest growing cancer in the Western population, especially in United States of America (USA), rising by 6-fold annually on the background of declining rates of most other cancers[
The definition of GEJ cancers has been an area of controversy and disagreement and have in the past been considered either a gastric or oesophageal cancer as they lie in between the two. GEJ tumours also go by many other names including distal oesophageal cancers, proximal gastric cancers and cancers of cardia. This has led to discrepancies in the literature regarding the classification, pathophysiology, surgical approach and prognosis. The most widely accepted definition for GEJ cancer is that proposed by Siewert
The importance of accurate and reproducible definition of GEJ cancer is important as the tumour biology, management is different and importantly the prognosis is considered worse than that of oesophageal and gastric cancer. Even within GEJ tumours there is marked heterogeneity, Siewert Type II and III are known to have better prognosis than Siewert I[
GEJ tumour incidence has dramatically increased in Western population and the distal oesophageal cancer type is the dominant oesophageal cancer type in the USA. Similarly, the rates of proximal gastric cancer have increased while that of distal gastric cancer has dropped. The rates of GEJ tumours has increased between 4%-10% every year in USA since 1976[
The etiology of GEJ tumours is still unclear. Much of its alarming rise has been blamed on increasing trends of obesity and GERD. This is likely to explain the rise in Siewert I tumours, which arise from areas of intestinal metaplasia in the distal oesophagus contributed by chronic GERD due to obesity. However, it is still unclear if metaplasia is due to acid reflux or bile reflux into oesophagus. Analysis of oesophageal fluid in patients with GERD found that they contain 10 times more bile than normal controls[
Increasing rates of GERD due to acid or bile irritation does not explain the rise in Siewert Type II and III tumours. An analysis of GEJ tumours by Siewert
Obesity has been consistently implicated as a risk factor for development of GEJ. Apart from the mechanical pathway resulting in increased reflux, there maybe independent inflammatory and hormonal mediators. An Australian study, showed that obesity in combination with frequent reflux were risk factors for development of GEJ tumours than either acting alone suggesting that synergistic as opposed to additive effects was most likely[
Infection with
Smoking has been found to have a strong association with GEJ tumours. A pooled analysis of multiple primary studies from the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON)[
The other factors found to be associated with GEJ tumours include alcohol intake, intake of highly processed meat diet while intake of high fibre diet and medications such as non-steroidal anti-inflammatory drugs are thought to confer a protective effect[
Management of GEJ tumours is challenging as they involve two contiguous organs and also straddle the thoracic cavity and abdominal cavity via hiatal opening.
Management of GEJ cancers depends on the stage of the tumour. For early tumours there is a role for endoscopic submucosal dissection (ESD) but advanced tumours require multimodality treatment including surgery.
With the development of the Insulated-tip diathermic knife (IT-knife) in late 1990 and subsequent development of the ESD technique in 2003, the endoscopic management of early gastrointestinal tumours including early gastric cancer and early esophageal cancer became feasible and popular[
There are various surgical strategies for management of GEJ cancers. They include esophagectomy with partial gastrectomy or extended total gastrectomy with or without thoracotomy. Individualization of the surgical strategy and adherence to sound oncological principles with aims of radical lymphadenectomy with negative margins for the resectable GEJ tumours is key in attaining good outcomes. Tumour location as per Siewert Classification and location of enlarged lymph nodes are critical factors in determining the surgical strategy.
The pattern and frequency of lymph node metastasis differ according to the epicenter of the tumour location and histology[
Regardless of the Siewert classification, the majority of the junctional tumours metastasise to the perigastric/abdominal regional lymph nodes[
Siewert type I tumours are considered as lower esophageal tumours with potential lymph node metastasis to mediastinal and abdominal lymph nodes. Subtotal esophagectomy with partial gastrectomy is considered to be a superior approach for type 1 tumours. Siewert type 3 tumours are considered proximal gastric cancer with potential lymph node metastasis to lower mediastinal and abdominal lymph nodes. Extended total gastrectomy with distal esophagectomy is considered more appropriate for type 3 tumour[
Siewert type II tumours are true junctional tumours and choice of surgical approach is controversial. In a retrospective study comparing transmediastinal esophagectomy with partial gastrectomy and extended total gastrectomy with transhiatal distal esophagectomy, it was demonstrated that the latter was associated with fewer post-operative morbidity and mortality without any difference in survival[
There were two phase III randomized control trials which compared two operative strategies for GEJ cancers[
In the Japanese JCOG 9502 trial, patients with Siewert II and III cancers were assigned to either transhiatal approach (TH) or left thoracoabdominal approach (LTA)[
Complete R0 resection of GEJ tumours is key to achieving good survival outcomes. Systematic review and meta-analysis of fourteen studies involving 2433 patients with oesophageal cancer who had undergone oesophagectomy showed that circumferential resection margin (CRM) involvement was associated with significantly higher 5-year mortality rate (OR 2.05, 95%CI: 1.41-2.99;
There are few options for reconstruction after resection of GEJ tumours. For Type II and Type III tumours, after extended total gastrectomy and distal esophagectomy the reconstruction is usually done with Roux-En-Y esophago-jejunostomy. For Type I tumours, combined transabdominal and transthroaic approach is required to perform enbloc eosophagectomy and proximal gastrectomy together with 2 field lymphadenectomy. The other available option is a left throacoabdominal approach with intrathoracic anastomosis know as Sweet esophagectomy. The stomach is used as a conduit to perform intrathoracic oesophagogastrostomy for reconstruction. In some patients, if gastric conduit is unsuitable, due to previous surgery, the jejunum and colon are both possible conduit options.
Evidence suggests that transthoracic approach with radical lymphadenectomy may be an oncologically superior operation with better long-term survival with the downsides of increased operative morbidity and mortality especially pulmonary complications. Minimally invasive approaches may be a promising alternative with decreased post-operative complications without compromising the radicality of the surgery. The current evidence suggests the potential benefits for minimally invasive esophagectomy approach to GEJ tumours include smaller incisions, less intraoperative blood loss fewer postoperative complications, shorter admission to the intensive care unit and overall hospital stay, better preservation of postoperative pulmonary function and equivalent quality of lymph node dissections[
Multimodality treatment strategies in locally advanced GEJ tumours (T2 and higher or node positive) result in improved outcomes. These strategies include neoadjuvant and adjuvant chemotherapy with or without radiation therapy in addition to surgery. The multimodality treatment has now become the standard of care for advanced GEJ cancers. However, the best approach to multimodality treatment for GEJ cancers is not established yet as GEJ tumours represent only a small subset of cohort in most of clinical trials[
Adjuvant chemoradiotherapy is one possible option for patients with GEJ tumours who didn’t receive the preoperative treatment with survival benefit demonstrated in US intergroup 0116 trial[
Neoadjuvant or perioperative chemotherapy with or without radiation therapy have proven to be effective in improving survival. The MAGIC trial compared patients who underwent surgery alone to surgery plus perioperative chemotherapy (3 cycles of preoperative and 3 cycles of postoperative epirubicin, cisplatin and infusional flurouracil)[
The Dutch Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS) trial included 22%of patients with GEJ cancers and compared the effectiveness of neoadjuvant chemoradiation over surgery alone[
The Preoperative therapy in Esophagogastric adenocarcinoma Trial (POET) was the only trial which compared neoadjuvant chemotherapy versus chemoradiotherapy in locally advanced GEJ adenocarcinoma[
A meta-analysis including 24 studies concluded that there was strong evidence for survival benefit of neoadjuvant chemoradiotherapy or chemotherapy over surgery alone in patients with esophageal carcinoma including GEJ cancers[
The management of GEJ junction tumours is challenging and there is no one-size-fit-all strategy. The endoscopic option can be considered for early tumours especially for those patients with high risk for surgery. The surgical approach for advanced GEJ cancers should be tailored according to the histological subtype, extent of oesophageal and/or gastric invasion, clinical and radiological lymph node involvement, achievement of negative resection margins with R0 resection as well as achievement of safe anastomosis for reconstruction. Minimally invasive approach is promising especially in experienced hands however more data on long-term oncological results is needed.
Multimodality treatment is superior to surgery alone in locally advanced resectable GEJ tumours. The advantages of neoadjuvant or perioperative treatment are downstaging of tumour, reducing the risk of recurrence, improving rates of R0 resection and improving outcomes after complete resection. At present, there is no global consensus on the optimal multimodality management of GEJ tumours. Further studies are needed to explore the optimal treatment strategy including surgical approach, sequence and regimen of multimodality management .
Oo AM and Ahmed S contributed equally to literature search and writing of manuscript.
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The authors declared that there are no conflicts of interest.
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© The Author(s) 2019.