Minimally Invasive Esophagectomy for Esophageal Cancer: A Western Perspective




BACKGROUND



Listen





“The history of esophageal surgery is the tale of men repeatedly losing to a stronger adversary yet persisting in this unequal struggle until the nature of the problems became apparent and the war was won.1’’




The evolution of esophagectomy techniques has been wrought with challenges that have demanded resilience on the part of both surgeons and their patients. Beginning with the first successful esophagectomy by Torek in 1913, a variety of open approaches, esophageal substitutes, and anastomotic techniques have evolved from decades of wrestling with the principal challenges with esophagectomy outcomes: (1) low 5-year survival rates (approximately 20% in some series), (2) high perioperative mortality rates (which can exceed 20%),2 and (3) high morbidity rates (which can exceed 50%).3



The advent of minimally invasive surgery paved the way for foregut surgeons to explore the potential benefit of a minimally invasive esophagectomy (MIE) to reduce the morbidity of laparotomies and thoracotomies without compromising oncologic outcomes.




EPIDEMIOLOGY



Listen




Esophageal carcinoma is the eighth most common cancer worldwide. In 2008, the estimated worldwide incidence was 484,000.4 Although esophageal squamous cell carcinoma remains the preponderate histological subtype worldwide, esophageal adenocarcinoma has become the predominant histological subtype in many Western countries. In fact, the incidence of esophageal adenocarinoma is rising at an epidemic rate in the United States. Since 1975, the incidence of esophageal adenocarcinoma in the United States has risen more than sixfold, faster than any other malignancy.5 The risk factors for, pathology of, and the surgical approach to these two most common histological subtypes are distinct.



A number of potential risk factors have been reported for squamous cell carcinoma of the esophagus (Table 88-1).69 The importance of each of these risk factors varies across geographic regions, based on cultural and environmental factors. In the United States, it has been estimated that alcohol and smoking (which have a synergistic effect on one another) and diets low in fruits and vegetables account for 90% of cases.10 In contrast, alcohol consumption is rare in the high incident region of Northern China and therefore is not a significant risk factor.8 Unique dietary factors (i.e., nitrate consumption in smoked and pickled foods, mycotoxin contamination of food products, vitamin and mineral deficiencies ([i.e., vitamins A, B2, C, and E; selenium, zinc, and calcium] in underdeveloped countries, betel quid consumption in Southeast Asia, mate consumption in South America, etc.) play a more important role in particular regions outside of the United States.7,8




TABLE 88-1:

Risk Factors for Esophageal Carcinoma





Various risk factors have also been reported for adenocarcinoma of the esophagus (Table 88-1).7,1113 In the United States, nearly 80% of esophageal adenocarcinoma cases are due to gastroesophageal reflux disease (GERD), tobacco abuse, obesity, and low dietary intake of fruit and vegetables.10



GERD is a well-established, dose-dependent risk factor for the development of esophageal adenocarcinoma.10,14 As compared with patients without GERD symptoms, a recent meta-analysis of five studies demonstrated that patients with at least weekly symptoms had a nearly fivefold increase in the odds (odds ratio [OR], 4.92; 95% confidence interval [CI], 3.90 to 6.22) for developing adenocarcinoma; daily symptoms increase the odds more than sevenfold (OR, 7.40; 95% CI, 4.94 to 11.10).14 However, it should be noted that 40% of patients with esophageal adenocarcinoma do not experience reflux symptoms.15



GERD progresses to adenocarcinoma in a step-wise pattern beginning with inflammation of the esophagus (esophagitis). Chronic inflammation can lead to the development of metaplasia of the distal esophagus from the native squamous cell epithelium to columnar-lined intestinal epithelium (Barrett’s esophagus). Some patients with Barrett’s esophagus develop dysplasia, which can progress to invasive carcinoma. The risk of malignant transformation increases with the degree of dysplasia (no dysplasia, 0.1% per year; low-grade dysplasia, 0.51% per year).16 The risk of progression from high-grade dysplasia is high; the incidence of adenocarcinoma in esophagectomy specimens following resection for high-grade dysplasia is 10% to 50%.1721 Due to the potential for sampling error, high-grade dysplasia should be considered analogous to early stage carcinoma. Risk factors for presence of occult carcinoma in patients with high-grade dysplasia include nodular Barrett’s and multilevel high-grade dysplasia.22 Potential factors implicated in the development of Barrett’s esophagus and progression to invasive carcinoma include stem cells,23 cytokine expression (i.e., IL-6, IL-8, and IL-18),2426 gene expression (i.e., CDX2, COX-2, and various signal transducer and transcription factors),2628 and microRNAs.29



There is also a strong association between obesity and esophageal adenocarcinoma. Though a number of studies have demonstrated an association between body mass index (BMI) and esophageal adenocarcinoma,3032 BMI is not an accurate anthropometric marker of obesity. The distribution of obesity is likely more important. In particular, central obesity is a strong risk factor.3335 Various mechanisms have been proposed to explain the association between obesity and the development of adenocarcinoma, including increased insulin resistance (and its associated effect on insulin-like growth factor-1 [IGF-1], which can stimulate cell proliferation and inhibit apoptosis), changes in endogenous sex steroids, altered levels of adipokines (increased levels of leptin, decreased levels of adiponectin, increased levels of PAI-1), and increased levels of proinflammatory cytokines (TNF-α, IL-6, and vascular endothelial growth factor [VEGF]).36,37



There is a marked male predominance in the global rising incidence of esophageal adenocarcinoma (female ratio, 3:1);38 this gender association is even stronger in the United States (male:female ratio, 9:1).39 Although there is a strong male predominance, the incidence of adenocarcinoma is also rising among women.38 The reasons behind this gender disparity are unclear. Postulated mechanisms include increasing severity of reflux disease among men,40 differences in obesity patterns of men (android [central]) and women (gynoid [pear-shape]),33,35 and hormone-related factors.41




MOLECULAR BIOLOGY



Listen




The molecular mechanisms behind esophageal carcinogenesis include mutations in tumor suppressor genes (i.e., Rb, APC, and p53), mutations in oncogenes (i.e., ras and c-myc), upregulation of growth factor receptors (c-erbB-2), upregulation of antiapoptotic genes (i.e., NF-κB and antiapoptotic Bcl-2 proteins), downregulation of genes that are protective against cytotoxic stress (i.e., heat shock proteins), upregulation in telomerase (which can lead to unlimited cell cycle progression), upregulation of angiogenesis promoting genes (i.e., VEGF), and mutations in cell adhesion molecules (which promotes invasion and metastases).



A clinically important oncogene is human epidermal growth factor receptor 2-neu (Her2-neu), which encodes a transmembrane tyrosine kinase receptor that is responsible for cell proliferation, differentiation and survival.42 Unlike other growth factor receptors, it has no known direct ligand. As such, it may be capable of producing a constant effect without the need for active binding to a ligand. Consequently, it may be able to independently induce malignant transformation and tumor growth.42 Though Her2-neu overexpression is more common in esophageal adenocarcinomas (adenocarcinoma, 15% to 30%; squamous cell carcinoma, 4% to 15%), it has a negative impact on survival for both tumor histologies.4345 A meta-analysis of 14 studies of patients with operable esophageal cancer demonstrated that Her-2 expression had a negative impact on survival for both squamous cell carcinoma (OR, 2.99; 95% CI, 1.34 to 6.17) and adenocarcinoma (OR, 1.91; 95% CI, 1.15 to 3.17).46 The clinical importance of Her2-neu is the availability of a targeted therapy (trastuzumab, a monoclonal antibody against Her2), which has been found to confer a survival advantage when used in combination with systemic chemotherapy as compared to systemic chemotherapy alone for patients with advanced adenocarcinomas of the gastroesophageal junction.47




PATHOLOGY



Listen




Squamous Cell Carcinoma



Squamous cell carcincoma is thought to develop through the progression of precursor lesions (from low-grade dysplasia to high-grade dysplasia to carcinoma in situ). Dysplasia typically has an endoscopic appearance of errythematous, friable, and irregular epithelium.48



While most occur in the middle third (50% to 60% of cases) or upper third (10% to 20% of cases), 20% of squamous cell carcinomas are found in the lower third of the esophagus. At the time of diagnosis, approximately 50% to 80% of patients have regional lymph node metastasis.48,49 Carcinomas originating in the upper third of the esophagus typically metastasize to the cervical and upper mediastinal nodes. Carcinomas originating in the middle or lower third of the esophagus typically metastasize to the lower mediastinal or perigastric nodes; middle esophageal tumors also metastasize to the upper mediastinal lymph nodes.49 Squamous cell carcinomas have a tendency to spread through the wall of the esophagus and can involve contiguous organs.48



Microscopically, squamous cell carcinomas exhibit a wide range of differentiation (defined by the degree of keratinization) even within the same tumor.48



Adenocarcinoma



The majority (95%) of adenocarcinomas develop in a background of Barrett’s esophagus. Rarely, tumors can develop from submucosal glands or heterotopic epithelium.48 Given it’s strong association with Barrett’s esophagus, adenocarcinomas occur almost exclusively in the distal third of the esophagus. At the time of diagnosis, approximately 60% to 70% of patients have regional lymph node metastasis.48,50 The most common sites of nodal metastases are the lesser curve, paracardia, lower periesophageal, and left gastric artery nodes.50,51



Microscopically, differentiation is determined by the percentage of the tumor that is composed of glands (well differentiated, >95%; moderately differentiated, 50% to 95%; poorly differentiated, 5% to 49%).



Given the change in the frequency of the two primary esophageal carcinoma histologies (from squamous cell carcinomas that primarily occupy the upper and middle thirds esophagus to adenocarcinomas with primarily involves the lower third of the esophagus) in the United States, our approach to esophagectomy has evolved.




CLINICAL MANIFESTATIONS



Listen




Unfortunately, most esophageal malignancies remain asymptomatic until the tumor has become quite large. This results in an advanced stage at the time of diagnosis in the majority of patients who were not in a surveillance program for Barrett’s esophagus or other conditions. The most common finding in patients with a new diagnosis of esophageal cancer is dysphagia to solid foods, often accompanied by an unintentional weight loss. Depending on the severity of obstruction, these symptoms may be intermittent and rather subtle at first. Bleeding from the tumor may also be seen, which can result in anemia or in some cases, clinical manifestations of gastrointestinal bleeding (hematemesis or melena).



Symptoms relating to involvement of other organ systems may be the initial finding in some patients. Bone pain due to metastatic disease is seen in some patients at the time of presentation. In patients with bulky tumors of the midesophagus, respiratory symptoms may be seen due to either extrinsic airway compression or direct tumor invasion.




STAGING



Listen




In 2009, the TNM staging system for esophageal cancer underwent significant modifications as a part of a joint effort by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). The new staging system included, among other changes, the separation of stage groupings on the basis of tumor histology. Clinical stage is determined using a combination of imaging studies (typically computed tomography [CT] or positron emission tomography [PET-CT) and minimally invasive diagnostics (upper endoscopy, endoscopic ultrasonography (EUS), flexible bronchoscopy, and staging thoracoscopy/laparoscopy). EUS has become the primary modality for the assessment of T stage. Determination of the level of invasion can readily be made by an experienced endoscopic ultrasonographer. T1 lesions are those which remain confined to the submucosa (1st to 3rd EUS layers). T2 tumors extend into the muscularis propria (4th EUS layer) and T3 tumors through the muscularis propria and into surrounding tissue (5th EUS layer). Invasion of surrounding structures (T4) often cannot be determined solely by EUS and requires either a confirmatory imaging study (such as CT or PET-CT) or an operative exploration. EUS also affords excellent characterization of the periesophageal nodal basins and suspicious nodes may be sampled via fine needle aspiration. Intrathoracic and intraabdominal lymph nodes larger than 1.0 cm in the short axis are considered suggestive of malignancy as are nodes larger than 0.5 cm in the supraclavicular region. Inclusion of a PET-CT can further aid in the identification of potential nodal metastasis. This study also serves as the primary tool for the identification of distant metastasis. Selective use of diagnostic laparoscopy and thoracoscopy may be beneficial to establish the presence of advanced disease prior to the initiation of therapy.




PROGNOSIS



Listen




Surgical resection affords the best opportunity for durable control of esophageal malignancies. Resection may be chosen as a single therapy in the setting of less advanced local tumors (T1 or T2) without evidence of regional lymphatic (N0) or distant (M0) disease. Surgical resection may be combined with either chemotherapy or chemoradiotherapy in a multimodality fashion in the setting of locally advanced malignancies. The overall survival for patients with esophageal cancer remains poor with a median survival of 23 months from the time of diagnosis. Five-year survival ranges from 5% to 12% overall. However, there is a wide range with upward of 80% 5-year survival in patients with early-stage disease, 24% in those with local disease, 12% in the setting of locoregional disease, and as low as 2% in those patients with metastasis at diagnosis. Demographic factors associated with a poor prognosis are advanced age, African American race, and tumor location within the lower esophagus. Prognosis is more favorable in patients who display a biological response to chemotherapy as demonstrated on final pathologic examination following resection or a decrease in signal uptake value (SUV) on PET scan (>35%). Treatment in a high volume center has also been demonstrated to improve outcome.




DIAGNOSTIC EVALUATION



Listen




History and Physical Examination



The focused history and physical examination should carefully assess specific cancer risk factors including the patient’s smoking history, history of GERD, personal or family history of cancer, occupational exposures, or other environmental exposures. Presenting symptoms commonly relate to dysphagia, unintentional weight loss, anemia, or upper GI bleeding.



Laboratory Studies



Traditional preoperative laboratory studies are ordered in the course of routine patient evaluation including a complete blood count, serum electrolytes, coagulation studies, and an assessment of nutritional status (albumin and prealbumin).



UPPER ENDOSCOPY


Upper GI endoscopy serves a critical role in the evaluation of the esophageal cancer patient. The study provides a direct evaluation of the extent of the tumor (or other pathology) and biopsies of the lesion can be obtained for histopathologic evaluation, which is often useful in selecting a proper chemotherapy regimen.





  • Assessment of the length of preserved proximal esophagus to allow for planning of the location of proximal resection margin/anastomotic site.



  • Assessment of the extent of gastric involvement and determination of the suitability of the stomach for use as a conduit in reconstruction.




BARIUM ESOPHAGOGRAM




  • Delineation of tumor anatomy.



  • Assessment of the degree of obstruction.




ENDOSCOPIC ULTRASONOGRAPHY




  • Determination of ultrasonographic depth of invasion and more accurate T staging.



  • Visualization of periesophageal lymph nodes with the potential for biopsy of suspicious nodes to provide an accurate N stage preoperatively.



  • May be unable to pass the scope in patients with larger tumors.




CT-PET




  • Evaluation for metastatic disease, especially useful in evaluation of celiac and perigastric lymph nodes not seen by EUS.




PULMONARY FUNCTION TESTING




  • Assessment of the suitability of the patient for thoracoscopy and the ability to tolerate single lung ventilation.


Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Jan 6, 2019 | Posted by in ONCOLOGY | Comments Off on Minimally Invasive Esophagectomy for Esophageal Cancer: A Western Perspective

Full access? Get Clinical Tree

Get Clinical Tree app for offline access