Endoscopic therapy of esophageal premalignancy and early malignancy

Esophageal adenocarcinoma (EAC) is an often deadly cancer with a rising incidence in Western countries. Chronic gastroesophageal reflux disease is associated with the metaplastic transformation of normal squamous epithelium to premalignant specialized intestinal metaplasia within the esophagus (Barrett's esophagus). Barrett's esophagus may progress to low-grade dysplasia (LGD), high-grade dysplasia (HGD), or even EAC. Although nondysplastic Barrett's esophagus progresses to EAC at a rate of 0.5% per year, rates of progression for true LGD and HGD are significantly higher. Treatment is mandatory for HGD and may be appropriate in select patients with nondysplastic Barrett's esophagus and many with LGD. Thus, accurate pathologic assessment is necessary before considering endoscopic therapy. Previously, only esophagectomy was offered to patients with HGD or EAC. However, esophagectomy has significant morbidity and mortality, and therefore endoscopic therapies have been advocated for early Barrett's neoplasia. These methods include endoscopic mucosal resection (EMR) and ablative techniques. Ablation techniques include argon plasma coagulation, multipolar electrocoagulation, laser therapy, photodynamic therapy, radiofrequency ablation, and cryotherapy. Of these, radiofrequency ablation has experienced the greatest adoption for the treatment of dysplastic Barrett's esophagus because of excellent published outcomes. The use of EMR to resect suspicious areas or raised lesions is mandatory to provide histology. In contrast, ablation techniques such as radiofrequency ablation have been shown to effectively eradicate large areas of dysplastic tissue with relative ease but do not allow for histologic assessment of the treated area. Combination EMR with radiofrequency ablation is thus advocated to resect visible lesions via EMR (providing histology) and ablate the remainder of the Barrett's esophagus. As always, the appropriate treatment is best determined after careful discussion with patients in a multidisciplinary environment. However, endoscopic therapy offers an attractive alternative to esophagectomy for early Barrett's neoplasia.     

Optical detection and eradication of dysplastic Barrett's esophagus

Dysplastic Barrett's esophagus is a condition that offers multiple diagnostic and therapeutic challenges. The diagnosis of dysplasia within Barrett's esophagus currently relies on periodic endoscopic surveillance with multiple biopsies, a methodology limited by random sampling error, inconsistent histopathologic interpretation and delay in diagnosis. Optical spectroscopic and imaging techniques have the potential to identify dysplastic or early neoplastic lesions in real-time. These diagnostic modalities are needed to enhance the endoscopic surveillance of Barrett's esophagus in the future as well as help to define lesions for endoscopic therapy. Esophagectomy has been the standard of care for Barrett's esophagus with high-grade dysplasia although it is a procedure associated with significant morbidity and mortality. Minimally invasive endoscopic ablative therapies are attractive and less morbid alternatives to esophagectomy, with promising results obtained from the use of light-activated drugs (i.e., photodynamic therapy). The combination of novel optical diagnostic techniques and therapies will provide the endoscopist with much needed tools that can considerably enhance the management of patients with Barrett's esophagus. This article reviews the current status and future prospects of optical-based modalities for diagnosis and therapy of dysplastic Barrett's esophagus.     

Clinicopathological and immunohistochemical study of cancer arising from Barrett's esophagus.

In Japan, Barrett's esophageal cancer is a very rare disease. We examined clinicopathologically and immunohistologically 4 patients with Barrett's esophageal cancer who underwent surgical resection in our department. Barrett's esophageal mucosa was classified into 3 types for detailed observation. Specialized columnar epithelium (SCE) remained on the orifice side of carcinoma, and progression to adenocarcinoma was observed in some dysplastic glands. positive findings were detected on p53 immunohistochemical staining, and the ki-67 labeling index was higher than other types. SCE-type Barrett's esophagus may be a precancerous lesion arising prior to the development of adenocarcinoma.     

Barrett's esophageal cancer

Barrett's esophageal cancer is defined as carcinoma developing in Barrett's esophagus. The esophagogastric junction is located at the distal end of a network of fine longitudinal vessels, and the columnar epithelium existing above it is Barrett's mucosa. Barrett's mucosa, especially specialized columnar epithelium is considered as precancerous lesion, and malignant potential is examined in various ways. For the surveillance of malignant lesions from Barrett's esophagus, periodic endoscopic examination is necessary with chromoendoscopy or magnifying endoscopy. Treatment strategies are EMR and other endoscopic treatment for mucosal cancer, and surgical treatment for submucosal and advanced cancer. Several surgical modalities are employed depending on the stage of cancerous progression, the location of the cancer in Barrett's esophagus, and the length of Barrett's esophagus. There remain many unexplained problems in Barrett's esophagus and Barrett's cancer.     

Barretts carcinoma in a 25-year-old man with point mutation of the p53 tumor suppressor gene

Barrett's esophagus is a recognized risk factor for adenocarcinoma of the esophagus. Dysplasia in Barrett's epithelium is considered a precursor to malignancy. Several tumor suppressor genes, including p53, have recently been implicated in the pathogenesis of esophageal adenocarcinoma. However, the interval between the development of Barrett's esophagus, dysplasia, and frank malignancy is usually very long. A case of adenocarcinoma of the esophagus arising from Barrett's esophagus in a 25-year-old man is discussed. Point mutation in exon 8 of p53 was discovered in this patient's tumor and surrounding dysplastic Barrett's mucosa. To our knowledge, this is the youngest reported case of Barrett's-associated esophageal adenocarcinoma in the medical literature. It suggests that acquired somatic mutations in tumor suppressor genes may occur early in life and that these mutations may contribute to the development of dysplasia and cancer in Barrett's esophagus.     

Barrett's esophageal adenocarcinoma

Barrett's esophageal adenocarcinoma arises in Barrett's epithelium, which is grouped with gastro-esophageal reflux disease (GERD). Although the incidence of esophageal adenocarcinoma is very low in eastern countries, including Japan, it has been increasing markedly and is similar to that of squamous cell carcinoma in the western countries. Surveillance, endoscopic treatment, and chemoprevention using COX-2 inhibitors have recently been developed for dysplasia or mucosal cancer in Barrett's esophagus. Barrett's esophageal adenocarcinoma is diagnosed by endoscopy and by biopsy specimens pathologically. Surgical resection has been a mainstream treatment but definitive or neoadjuvant chemoradiotherapy has recently been performed.     

Histopathological classification of esophageal carcinomas

Esophageal carcinomas are steadily rising worldwide; they rank sixth among tumors. Adenocarcinoma is the most common histological type in Western countries while squamous carcinoma is more common in the developing countries. Both types are preceded by pre-neoplastic lesions rappresented by Barrett's esophagus for adenocarcinoma and low and high grade dysplasia for squamous carcinoma. Some continuity exists between dysplastic lesions and frankly invasive tumors. Moreover rare hystological types have been described. The surgical pathologist plays an important role in evaluating small endoscopic biopsies as well as in examining surgical specimens from esophagectomy. In the former case the role is exclusively diagnostic while in the latter surgical radicality, cancer stage and outcomes of neoadjuvant therapies are assessed. All these data are crucial not only for prognosis but also for therapy planning.     

Clinical use of p53 in Barrett's esophagus.

Barrett's esophagus is an established precursor to esophageal adenocarcinoma. Whereas most patients with Barrett's esophagus do not progress to adenocarcinoma, patients with progression have a poor prognosis. Current management strategies use frequent endoscopic surveillance and multiple nontargeted biopsies. This approach, however, may miss dysplastic areas. Furthermore, given the relatively high prevalence of Barrett's esophagus but low incidence of progression, this invasive and expensive approach has not been shown to be cost-effective. Thus, there is intense interest in using biomarkers to identify patients at increased risk of progressing to adenocarcinoma. This has included examination of mutations in the tumor suppressor gene, p53. In this report, we discuss the biology of p53 and the incidence of p53 mutations in Barrett's esophagus and review relevant studies regarding the ability of p53 to predict neoplastic progression. Additionally, we report our results of the expression of p53 by immunohistochemistry in a group of 18 patients that have undergone endoscopic esophageal mucosal resection for dysplasia. Although the presence of a p53 mutation increases the risk of neoplastic progression, the absence of this mutation does not abrogate the risk. Continuing efforts, therefore, are needed to define and prospectively validate a panel of biomarkers to risk-stratify patients with Barrett's esophagus. Determination of p53 mutational status may ultimately be a component of such a panel.     

A comparative cytopathologic and histologic study of atypia, dysplasia, and adenocarcinoma in Barrett's esophagus.

As a potentially premalignant condition, Barrett's esophagus has stimulated controversy over the need for surveillance of glandular dysplasia and early carcinoma. This prompted the authors to review their experience with endoscopic cytologic brushings and biopsies from patients with Barrett's esophagus. The authors reviewed 65 consecutive specimens from 42 patients with Barrett's esophagus in which both the concurrently obtained esophageal cytologic brushings and companion biopsy specimens were available. In addition, esophagogastrectomy specimens from 9 nine these patients were reviewed. Cytologic and histologic specimens were assigned to one of four diagnostic categories, based on specifically defined criteria: simple Barrett's esophagus with or without inflammatory atypia; dysplasia; adenocarcinoma; or suspicious for dysplasia or carcinoma. Simple Barrett's esophagus was diagnosed in 38 cytologic brushings and 44 biopsy specimens, dysplasia in 4 brushings and 7 biopsy specimens, and carcinoma in 14 brushings and 10 biopsy specimens. Nine brushings and three biopsy specimens were suspicious. In 13 cases, brushings revealed a higher grade lesion than did histology; in 5 cases, biopsy specimens showed a higher grade lesion. Agreement between the two occurred in 72% (47/65) of all specimens. Accuracy was confirmed in the histologic examinations of the resection specimens. The authors conclude that specific criteria, when consistently applied, allow accurate cytologic diagnoses of epithelial changes in Barrett's esophagus. The use of esophageal brush cytology and biopsy specimens provides two complementary techniques, which detect a greater number of serious lesions than either technique alone.     

内镜切除治疗在早期食管癌和贲门癌及其癌前病变中的应用价值

目的 评价内镜套帽法切除早期食管癌、贲门癌及癌前病变的长期疗效和应用价值.方法 采用内镜套帽法切除早期食管癌、贲门癌及癌前病变147例(154个病灶),其中早期食管癌64例(69个病灶),癌前病变45例(47个病灶),病灶直径3～40 nm,平均(14.8±6.1)mm;早期贲门癌23例,癌前病变15例(均为单灶),病灶直径5～25 mm,平均(8.2±4.3)mm.全组病例均经病理证实.结果 全组有139个病灶被完全切除,完全切除率为90.3%.食管和贲门病灶的完全切除率均与病灶大小有关,病灶越大,完全切除率越低(P=0.001和P=0.014).147例患者中,内镜随访不足3年者66例,3～5年者31例,5～10年者43例,10年以上者7例.全组死亡11例,其中肿瘤复发死亡1例.早期食管癌和贲门痈的5年生存率分别为96.2%和100.0%.本组有5例(3.4%)患者发生术中出血,1例(0.7%)患者发生狭窄,无穿孔发生.结论 内镜黏膜切除治疗早期食管癌和贲门癌,符合其生物学特点,可达到传统手术治疗相同的长期疗效,亦适用于重度不典型增生的治疗.     

Adenocarcinoma in Barrett's esophagus following total resection of the gastric remnant: a case report.

We report a case of adenocarcinoma in Barrett's esophagus following a total resection of the gastric remnant. A 52-year-old man had undergone a distal gastrectomy for gastric cancer at 33 years of age and a total resection of the gastric remnant for local recurrence of the gastric cancer at 35 years of age. Repeated endoscopic examinations revealed the sequence of reflux esophagitis and Barrett's esophagus. Furthermore, adenocarcinoma in Barrett's esophagus was detected in December, 1989. A subtotal esophagectomy was performed in January, 1990. The elevated lesion in the lower esophagus showed coarse lobulation and measured 7.4 x 3.2 cm. The histologic type was that of well-differentiated adenocarcinoma, with the invasion limited to the muscularis mucosae without lymph node involvement. Severe dysplasia was seen adjacent to the definite carcinoma. The case supports the acquired theory of pathogenesis for Barrett's esophagus and suggests that reflux esophagitis after total gastrectomy may result in a dysplasia-carcinoma sequence.     

Endoscopic assessment and management of early esophageal adenocarcinoma

Esophageal carcinoma affects more than 450000 people worldwide and the incidence is rapidly increasing. In the United States and Europe, esophageal adenocarcinoma has superseded esophageal squamous cell carcinoma in its incidence. Esophageal cancer has a high mortality rates secondary to the late presentation of most patients at advanced stages. Endoscopic screening is recommended for patients with multiple risk factors for cancer in Barrett’s esophagus. These risk factors include chronic gastroesophageal reflux disease, hiatal hernia, advanced age, male sex, white race, cigarette smoking, and obesity. The annual risk of esophageal cancer is approximately 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia. Twenty percent of all esophageal adenocarcinoma in the United States is early stage with disease confined to the mucosa or submucosa. The significant morbidity and mortality of esophagectomy make endoscopic treatment an attractive option. The American Gastroenterological Association recommends endoscopic eradication therapy for patients with high-grade dysplasia. Endoscopic modalities for treatment of early esophageal adenocarcinoma include endoscopic resection techniques and endoscopic ablative techniques such as radiofrequency ablation, photodynamic therapy and cryoablation. Endoscopic therapy should be precluded to patients with no evidence of lymphovascular invasion. Local tumor recurrence is low after endoscopic therapy and is predicted by poor differentiation of tumor, positive lymph node and submucosal invasion. Surgical resection should be offered to patients with deep submucosal invasion.     

内镜下黏膜切除术联合氩离子血浆凝固术治疗早期食管癌及其癌前病变

[目的]探讨内镜下黏膜切除术（endoscopic mucosal resection,EMR）联合氩离子血浆凝固术（Argon plasma coagulation,APC）在食管癌高发区治疗早期食管癌及其癌前病变的意义。[方法]应用透明帽法对食管癌高发区普查中发现的84例早期食管癌及食管癌前病变行EMR治疗,并联合应用APC治疗残留及复发病灶。术后2、6个月进行内镜复查。[结果]2004～2008年间共有84例患者成功行EMR,治疗成功率为100%。并发症：术中出血3例,术后出血2例,经内镜下治疗或保守治疗均成功止血;无一例穿孔、狭窄等并发症发生。随访：84例中,5例早期食管癌,49例原位癌/重度不典型增生术后半年随访时对原切除部位行内镜下活检,病理诊断5例重度不典型增生、8例中度不典型增生和19例轻度不典型增生,均内镜下APC治疗。平均随访21个月,无一例复发。[结论]应用透明帽法内镜下黏膜切除联合氩离子凝固术治疗早期食管癌及其癌前病变是食管癌二级预防的有效方法。     

Platelet 12-lipoxygenase and stem cells in Barrett's esophagus

Esophageal adenocarcinoma has shown a significant increase in incidence in recent years. It is thought that the development of gastroesophageal reflux disease (GERD), followed by columnar-lined esophagus and the development of dysplasia, leads to invasive adenocarcinoma. The exact pathogenesis of this process, the diagnosis and differentiation of the metaplastic and dysplastic esophageal lesions have yet to be determined. The purpose of this immunohistochemical study was to investigate the expression of pro-tumorigenic enzyme platelet 12-lipoxygenase (p12LOX) using two new available antibodies in non-dysplastic and dysplastic Barrett's esophagus. The stem cell markers nestin, CD117 and CD44, were then evaluated. The comparative group included GERD carditis, gastric intestinal metaplasia and colorectal adenoma. The overexpression of p12LOX detected by two specific antibodies in the non-dysplastic and dysplastic Barrett's mucosa clearly demonstrated that this enzyme plays an important role in the development of esophageal adenocarcinoma.     

Screening diagnosis and staging of esophageal cancer

In geographic areas where there is a high risk of esophageal cancer, analysis of cells obtained from the esophagus has been used effectively to detect early lesions. This has been demonstrated on a large scale in studies from China. Using abrasive balloon cytology techniques, 75% of the cancers detected were early lesions, where the 5-year survival after resection was in the range of 90%. Endoscopic followup studies indicate that dysplastic changes in the esophageal mucosa are a common precursor to malignancy. In many cases, the time course from dysplasia to carcinoma in situ to early invasive cancer may take place over many years, allowing a reasonable amount of time for screening. In low-incidence areas, such as the United States, most esophageal cancers are related to the excessive use of tobacco and alcohol. These factors are too common and the incidence of the disease too low, however, to justify screening on this basis. There are smaller groups at higher risk where selective screening by endoscopy with cytology and biopsy is recommended, usually every 1 to 3 years. These include patients with longstanding achalasia, lye strictures, and Plummer- Vinson syndrome. Patients with cancers of the head and neck region and patients with celiac disease may also be considered to be at increased risk. Tylosis is a rare inherited disease with a very high risk of esophageal cancer. There is an increased incidence of adenocarcinoma of the esophagus with Barrett's epithelium, and once identified such patients should be kept under endoscopic surveillance. The finding of severe dysplasia in any of these groups would indicate a shorter screening interval. Most patients with symptoms referable to the esophagus are first tested by barium esophagram. If negative, with persistent symptoms or if a suspicious lesion is identified, endoscopy with cytology and biopsy is recommended. Staging of the cancer is based on the size of the cancer both longitudinally and circumferentially and the presence of extraesophageal spread. At the present time, CT is the best noninvasive method for judging the extent of the cancer. Performance and nutritional status are also determinants of prognosis and should be considered in planning treatment.     

Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors (VEGF)-A, -C and -D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma (EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma (SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and -D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.     

Cost‐effectiveness of treatment and endoscopic surveillance of precancerous lesions to prevent gastric cancer

BACKGROUND:

Although surveillance for Barrett esophagus and other gastrointestinal precancerous conditions is recommended, no analogous guidelines exist for gastric lesions. The objective of this study was to estimate the clinical benefits and cost‐effectiveness of treatment and endoscopic surveillance to prevent gastric cancer.

METHODS:

The authors developed a state‐transition decision model for a cohort of US men with a recent incidental diagnosis of gastric precancerous lesions (dysplasia, intestinal metaplasia, or atrophy). Strategies included 1) no surveillance or treatment and 2) referral for surveillance and treatment, and varied by surveillance frequency (none, every 10 years, every 5 years, or every year) and treatment modality for dysplastic and cancerous lesions (surgery or endoscopic mucosal resection [EMR]). The term “post‐treatment surveillance” was restricted to surveillance of individuals after treatment. Data were based on published literature and databases. Outcomes included lifetime gastric cancer risk, quality‐adjusted life expectancy, lifetime costs, and incremental cost‐effectiveness ratios.

RESULTS:

For a cohort of men with dysplasia aged 50 years, the lifetime gastric cancer risk was 5.9%. EMR with annual surveillance reduced the lifetime cancer risk by 90% and cost $39,800 per quality‐adjusted life year (QALY). Addition of post‐treatment surveillance every 10 years provided little incremental benefit (～5%) but cost >$1 million per QALY. Results were most sensitive to surgical risks and the proportion of lesions completely removed with EMR. For intestinal metaplasia, surveillance every 10 years reduced lifetime cancer risk by 61% and cost $544,500 per QALY.

CONCLUSIONS:

EMR with surveillance every 1 to 5 years for gastric dysplasia was promising for secondary cancer prevention and had a cost‐effectiveness ratio that would be considered attractive in the United States. Endoscopic surveillance of less advanced lesions did not appear to be cost‐effective, except possibly for immigrants from high‐risk countries. Cancer 2010. © 2010 American Cancer Society.     

Management of Barrett's esophagus

Barrett's esophagus represents replacement of normal distal esophageal squamous epithelium with specialized columnar epithelium containing goblet cells. Typically arising in the setting of chronic gastroesophageal reflux disease, the presence of Barrett's esophagus carries a 50- to 100-fold increased risk of developing esophageal cancer. Risk factors include male sex, smoking history, obesity, Caucasian ethnicity, age > 50 and > 5-year history of reflux symptoms. Aggressive medical or surgical antireflux therapy may ameliorate symptoms, but have not yet been proven to affect the risk of developing esophageal adenocarcinoma in randomized trials. Although dysplasia is an imperfect biomarker for the development of subsequent malignancy, random sampling of esophageal tissue for dysplasia remains the clinical standard. There have been no studies to establish that endoscopic screening/surveillance programs decrease the rates of death from cancer. Fit patients with Barrett's esophagus and high-grade dysplasia should undergo esophagectomy to prevent the risk of developing esophageal adenocarcinoma. For non-operative candidates, endoscopic ablative approaches may represent a reasonable therapeutic alternative.     

Technology insight: ablative techniques for Barrett's esophagus--current and emerging trends

New mucosal ablative techniques that can be used in the esophagus have emerged over the past two decades. These techniques have been develop primarily to treat the precursors of esophageal adenocarcinoma: dyspla, in Barrett's esophagus and early esophageal cancer. Although high-grade dysplasia and early stage cancer can be treated with esophagectomy, the inherent morbidity and mortality of esophageal adenocarcinoma and the morbidities, difficulties, costs and limitations of the current technology mean that there has been a significant increase in interest and research regarding alternative treatments such as ablative techniques. At this stage it is not clear which of the numerous endoscopic ablative techniques available---photodynamic therapy, laser therapy, multipolar electrocoagulation, argon plasma coagulation, endoscopic mucosal resection, radiofrequency ablation or cryotherapy--will emerge as superior. In addition, it has yet to be determined whether the risks associated with ablation therapy are less than the risk of Barrett's esophagus progressing to cancer. Whether ablation therapy eliminates o significantly reduces the risk of cancer, eliminates the need for surveillance endoscopy, or is cost-effective, also remains to be seen. Comparative triads that are now underway should help to answer these questions.     

Treatment of Barrett’s esophagus with high-grade dysplasia

The incidence of esophageal adenocarcinoma is increasing in the USA, now accounting for at least 4% of US cancer-related deaths. Barrett’s esophagus is the main risk factor for the development of esophageal adenocarcinoma. The annual incidence of development of adenocarcinoma in Barrett’s esophagus is approximately 0.5% per year, representing at least a 30–40-fold increase in risk from the general population. High-grade dysplasia is known to be the most important risk factor for progression to adenocarcinoma. Traditionally, esophagectomy has been the standard treatment for Barrett’s esophagus with high-grade dysplasia. This practice is supported by studies revealing unexpected adenocarcinoma in 29–50% of esophageal resection specimens for high-grade dysplasia. In addition, esophagectomy employed prior to tumor invasion of the muscularis mucosa results in 5-year survival rates in excess of 80%. Although esophagectomy can result in improved survival rates for early-stage cancer, it is accompanied by significant morbidity and mortality. Recently, more accurate methods of surveillance and advances in endoscopic therapies have allowed scientists and clinicians to develop treatment strategies with lower morbidity for high-grade dysplasia. Early data suggests that carefully selected patients with high-grade dysplasia can be managed safely with endoscopic therapy, with outcomes comparable to surgery, but with less morbidity. This is an especially attractive approach for patients that either cannot tolerate or decline surgical esophagectomy. For patients that are surgical candidates, high-volume centers have demonstrated improved morbidity and mortality rates for esophagectomy. The addition of laparoscopic esophagectomy adds a less invasive surgical resection to the treatment armanentarium. Esophagectomy will remain the gold-standard treatment of Barrett’s esophagus with high-grade dysplasia until clinical research validates the role of endoscopic therapies. Current treatment strategies for Barrett’s esophagus with high-grade dysplasia will be reviewed.