EASC is a very rare disease and accounts for approximately 1% of all cases of primary esophageal cancer [1,2,3,4,5,6]. The biological behavior and treatment of EASC have not been well studied to date. Most of the previous studies on the disease were case reports [8,9,10,11,12,13,14,15] and only a few series with small patient numbers have been reported to date [7, 16,17,18,19]. Recently, four large series of this rare disease have been reported [3,4,5,6]. However, all the data in these studies were obtained from public databases in the United States. As the patients were treated in various hospitals and the histological examination was conducted by various experts, misclassification bias might exist. Moreover, most of the patients enrolled in these studies did not undergo surgical resection, and detailed treatment information was not available for most of the patients, so specific treatment recommendations might not be drawn from these studies. Furthermore, the clinicopathological features of esophageal cancer, including the histology, tumor location, and age distribution, vary widely between patients in Eastern and Western countries. Lastly, the etiologic factors for esophageal cancer were also quite different between patients in Eastern and Western countries. The major risk factors for esophageal cancer in western countries were history of smoking, BMI above the lowest quartile, history of gastro-esophageal reflux, and low fruit and vegetable consumption [20]. However, history of smoking, alcohol consumption, drinking beverages at high temperatures, and poor nutritional status accounted for most of the esophageal cancer in eastern countries [20]. We think that more data on this rare disease from Eastern countries patients should be analyzed.

In the current study, we evaluated data from 56 patients with EASC who underwent esophagectomy from a single center and compared the clinicopathological features and prognosis of these patients with those of ESCC patients who underwent esophagectomy at the same time. All patients selected surgical resection as their initial treatment. All resection specimens were re-examined by an expert pathologist (Dr. Xiao-long Wei) to avoid misclassification bias. The homogeneity in histopathology and treatment may give us a more reliable understanding of this rare disease.

Due to the small volume of biopsy specimens from esophagoscopies, it is difficult to obtain an accurate pathological diagnosis before surgery [7, 16,17,18,19]. In this study, although 43 patients underwent esophagoscopic biopsy before treatment, only 1 patient (2.3%) was diagnosed with EASC, and all the other patients were misdiagnosed with ESCC. Ni et al. [17] reported that 92.1% (35/38) of patients were misdiagnosed with ESCC or others in preoperative esophagoscopic biopsy. Zhang et al. [16] reported that only 2 of the 18 patients (11.1%) were diagnosed with EASC in preoperative esophagoscopic biopsy, while 13 patients (72.2%) were misdiagnosed with ESCC and 3 patients (16.7%) were misdiagnosed with esophageal adenocarcinoma (EAC). One reason for the high rate of misdiagnosis may be that the squamous cell carcinoma component was mainly found in the epithelium, while the adenocarcinoma component mainly occurred in the submucosal gland or even deeper portion, which was difficult to be obtained from esophagoscopic biopsy [17]. So, most of these patients were misdiagnosed as ESCC in preoperative esophagoscopic biopsy. The other reason may be that the squamous and mucinous containing components are separate in adenosquamous carcinoma [1]. As the biopsy specimens from esophagoscopies were very small, it might be difficult to observe these two components simultaneously in these small specimens. The diagnosis of these carcinomas often requires resection specimens [2].

Data from the USA showed that the demographics and clinicopathological features of EASC were more similar to those of EAC than to those of ESCC [3,4,5,6]. For example, the male:female ratio was similar between EASC and EAC (approximately 6:1) but was significantly higher than that of ESCC (approximately 2:1) [3,4,5,6]. Nearly 70% of EASC was found in the lower third of the esophagus, which was similar to that of EAC but was significantly higher than the 30% for ESCC [3,4,5,6].. However, our data showed that the demographics and clinicopathological features of patients with EASC in China were different from those of patients with EASC in Western countries but were similar to those of patients with ESCC in China. Most of the EASC and ESCC cases were located in the middle third of the esophagus in this study, while only 17.9% of EASC and 16.5% of ESCC cases were located in the lower third of the esophagus (P = 0.737). Moreover, the male:female ratio was similar between EASC and ESCC (both approximately 3:1, P = 0.660). Furthermore, the mean age of patients with EASC at diagnosis in this study was 59.7 years, lower than that of approximately 66 years for patients with EASC in Western countries [3,4,5,6]. The differences in demographics and clinicopathological features of EASC between Eastern and Western countries patients may contribute to the different pathogenesis or tumor biology of this disease in different areas. We think that more data should be collected to investigate the potential differences in EASC between Eastern and Western countries patients.

Esophagectomy with lymphadenectomy is still the most important treatment for esophageal carcinoma, while neoadjuvant chemoradiotherapy is recommended for locally advanced disease [21]. Gamboa et al. [6] found that 20% of patients with EASC who received preoperative chemoradiotherapy had a pathologically complete response, which was similar to that of patients with EAC, and recommended that EASC should be treated more like EAC rather than ESCC. However, as it is difficult to obtain an accurate pathological diagnosis in preoperative esophagoscopic biopsy, most of these patients received surgical resection directly and received an accurate diagnosis from the resection specimens. It is reasonable to evaluate the value of postoperative adjuvant therapy in these patients. Our study showed that adjuvant chemotherapy was an independent predictor for patients with EASC after resection. Patients who received adjuvant chemotherapy had significantly better survival than patients who did not receive adjuvant chemotherapy. However, adjuvant radiotherapy did not improve survival for patients with EASC after resection.

Because of the rarity of EASC, the prognosis of this disease is still controversial. Most of the previous studies showed that EASC might be more aggressive than ESCC [4, 5, 7, 16]. However, Yendamuri et al. [3] reported that the survival was equivalent between patients with EASC and ESCC, but 32.7% of patients with EASC underwent surgical resection in their study, while only 15.9% of patients with ESCC underwent surgical resection. Yachida et al. [18] even found that EASC had a better prognosis than ESCC; however, half of the patients (9/18) in their cohort had T1 disease. Our previous study showed that the prognosis of EASC was similar to that of poorly differentiated ESCC but was significantly poorer than that of well- or moderately differentiated ESCC [7]. However, none of the previous studies matched the clinicopathological characteristics of patients with EASC and ESCC before survival analysis, which might contributed to these inconsistent results. In the current studies, we used PSM analysis to balance the baseline characteristics between patients with EASC and ESCC before survival analysis, and our results that the prognosis of EASC was similar to ESCC might be more reliable than previous studies.

Our study still has some limitations. First, it is a retrospective study from a single center, which may undermine its power. Second, the patient number in some subgroups was small, which limited its statistical power. Third, many other prognostic factors, such as the lymphovascular invasion, has been known to be a poor prognostic factor for many cancers. However, we did not recorded the information of these factors in this study. However, as there are few studies enrolling patients from Eastern countries concerned with this rare disease, our results may still provide us with a better understanding of this disease.

In conclusion, EASC is a rare disease and is easily misdiagnosed in esophagoscopic biopsy. The demographics and clinicopathological features may be different between patients with EASC from Eastern and Western countries. The prognosis of EASC was similar to that ESCC. Postoperative adjuvant chemotherapy may improve the survival of patients with EASC after esophagectomy. Further studies are needed to evaluate our findings and investigate a multidisciplinary treatment strategy for EASC.

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