1.      Introduction

China has a high incidence of esophageal cancer, with the 2008 global cancer statistics showing that the incidence of esophageal cancer in China was the 4th highest in the world [1]. Previously, primary Small Cell Carcinoma of the esophagus (SCEC) was considered to be a rare disease. By 1999, China had reported 174 cases [2], with an incidence rate of 0.7-5.1% among all primary esophageal malignancies in a given period. However, since the year 2000, the incidence of SCEC in China has been increasing gradually with the development of pathological diagnosis techniques. In this study, we retrospectively analyzed the clinical manifestations, treatments and prognosis of SCEC to make inferences about the future development of small cell carcinoma of the esophagus.

2.      Materials and Methods

Articles were identified and collected from the China Digital Library CNKI, which is a database of full-text Chinese publications. The original articles, appearing between January 2000 and December 2012, were identified using the terms “esophagus” and “Small cell carcinoma of the esophagus”. We selected all eligible patients from these documents and recorded parameters such as age, gender, tumor site, histology (pure or mixed), tumor stage (TNM stage), treatment and follow-up. Treatments included surgery, preoperative neoadjuvant chemotherapy, postoperative chemotherapy, postoperative radiotherapy and postoperative adjuvant radiotherapy + chemotherapy. The histological criteria for pulmonary small cell carcinoma prepared by the World Health Organization (WHO, sixth edition) were used, and both sole small cell and mixed cell types were considered. Disease stages were presented according to the 2002 American Joint Committee on Cancer (AJCC) TNM staging system for esophageal cancer [3].

3.      Statistical Analyses

We computed the mean standard deviation of the continuous variables and the differences were compared using the Kruskal–Wallis test. A comparison of the survival curves was conducted using the Kaplan–Meier method and differences were compared using the log-rank test. The Cox proportional hazards model with stepwise regression was used for multivariate analysis. Statistical significance was defined as a p value of less than 0.05.

4.      Results

A total of 51 articles (1456 reported cases) on SCEC were published during the selected period in China [4-52], of which 19 articles reported 55,167 cases of esophageal cancer [4,5,10,21,23-25,28,30,31,35,41,42,48-53]. SCEC accounted for 1.14% of esophageal cancer during this period (630/55167).

The reported cases ranged throughout the 17 Chinese provinces (Figure 1) and were distributed in Middle-Eastern China. Traditionally, a high incidence of esophageal cancer has been found in the following areas: China Taihang Mountains, the Qinling ministry area, the Dabie Mountain area, northern Sichuan, Fujian, the Guangdong Chaozhou-Shantou area and northern Jiangsu [53]. All reported cases of esophageal small cell carcinoma were found in these areas. The gender statistics (n=1405) included 1017 males and 388 females, with a male to female ratio of 2.4:1. The age of the cases ranged from 26 to 85 years, with the average age being 57.39±3.697 years.

Previous studies showed clinical symptoms similar to squamous cell carcinoma, with the most common first symptoms being progressive dysphagia and anorexia. Other symptoms included chest pain and pain on swallowing and a small number of patients could have a hoarse voice and weight loss.

The tumor characteristics are summarized in Table 1. In three cases (0.22%), the tumors were found in the cervical segment of the esophagus. The tumors were located in the upper third of the thoracic esophagus in 136 cases (10.04%), in the mid-esophagus in 796 cases (58.79%) and in the lower thoracic segment in 419 cases (30.95%). The exact size of the tumor was measured in 1354 cases, with the average length being 5.24±0.83 cm. All patients (n=1456) were pathologically diagnosed with small cell carcinoma of the esophagus, and the specimens were classified as sole SCEC in 1,317 cases (90.45%, 1317/1456) and mixed carcinoma of the esophagus in 119 cases (8.17%, 119/1456). Of the 119 cases, there were 81 with squamous cell carcinoma predominance, 22 with adenocarcinoma and 16 with Adenosquamous carcinoma. 293 patients (20.12%) underwent preoperative endoscopy biopsy to confirm the diagnosis.

According to the 2002 AJCC TNM staging system, of the 824-TNM staged patients, 62 were in stage I (7.52%, 62/824), 227 were in stage IIa (27.55%), 107 were in stage IIb (12.99%), 313 were in stage III (37.99%) and 115 were in stage IV (13.96%).

Of the 1,153 patients studied, 961 received surgical resection, including 147 with a sole operation, 36 received preoperative neoadjuvant chemotherapy, 100 were treated with postoperative adjuvant radiotherapy, 511 were treated with adjuvant chemotherapy and 167 were treated with postoperative chemotherapy combined with radiotherapy.

In the 1,153 patients studied, the median survival time was 13.42±4.05 months. The median survival time for the preoperative neoadjuvant chemotherapy patients was 12.85±3.10 months, for the sole surgery patients was 13.38±4.64 months, for the postoperative adjuvant-chemotherapy patients was 14.94±5.15 months and for the postoperative adjuvant radiotherapy with chemotherapy patients was 12.49±3.08 months. Table 2 shows a detailed univariate analysis of the median survival rate in SCEC patients.

The average overall one-, two-, three- and five-year survival rates for the 1153 patients were 52.05%, 25.21%, 18.62% and 7.27%, respectively, for the 36 patients who received preoperative chemotherapy were 56.20%, 28.62%, 17.40% and 9.07%, respectively, for the 147 patients who received sole surgery were 53.23%, 26.69%, 18.79% and 7.5%, respectively, for the 100 patients who received postoperative radiotherapy were 39.43%, 26.48%, 16.56% and 6.17%, respectively, for the 511 patients who received postoperative adjuvant chemotherapy were 52.60%, 28.55%, 18.94% and 6.78%, respectively and for the 167 patients who received postoperative adjuvant radiotherapy with chemotherapy were 51.17%, 27.62%, 13.85% and 7.91%, respectively. However, there were no statistically significant differences between the different treatment methods (p＞0.05) (Figure 2,3).

The survival rate of patients with different stages of SCEC by univariate analysis (Table 3) showed that the SCEC tumor stage was related to the patient survival rate. Stage I patients had a median survival rate of 15.62±3.40 months. The one-, two-, three- and five-year survival rates for the 62 stage I patients were 87.57%, 65.08%, 41.53% and 7.39%, respectively, for the 227 stage IIa patients were 59.21%, 41.95%, 39.34% and 6.0%, respectively, for the 107 stage IIb patients were 59.98%, 28.35%, 15.04% and 0, respectively, for the 313 stage III patients were 39.1%, 14.46%, 12.57% and 0, respectively, and for the 115 stage IV patients were 38.62%, 19.35%, 14.11% and 0, respectively. There were significant differences between the survival rates of patients at the different stages (p＜0.05) (Figure 4,5).

5.      Discussion

Over the past decade, the number of reported cases of esophageal small cell carcinoma has increased in China, but the overall incidence rate has remained stable. The incidence of esophageal small cell carcinoma within all esophageal malignancies was 1.14%. American authors have reported an incidence of 0.05 to 2.4% [54]. In this report, the regions in which cases of small cell carcinoma of the esophagus were reported were consistent with the areas of China in which a high incidence of esophageal cancer have been traditionally reported. Viewed from the geographical distribution of cases, these regions have had the fastest growing economy over the past 30 years. SCECs and the incidence of esophageal squamous carcinoma were positively correlated. In the past few decades, the incidence of esophageal squamous cell carcinomas in western countries has been stable or declining [55], while the incidence of esophageal adenocarcinoma has been rapidly increasing. According to the Zeng [56], prediction of trends in incidence of esophageal cancer in China, from 1998 to 2007, the

incidence of esophageal squamous cell carcinoma was declining overall. In the cities, the annual standardized incidence rate decreased to 2.1% in men and 7.5% in women. This shows that the basic trend of the incidence of esophageal squamous cell carcinoma in China was in line with that in Western countries, but that there was a lack of a large-scale epidemiological survey of esophageal small cell carcinoma in China. It is not yet certain whether the increase in literature reported cases represents the true incidence of the disease and it is difficult to use statistical results to truly reflect the overall incidence.

For small cell carcinoma of the esophagus, our current understanding is that SCEC is characterized by high malignancy, distant metastasis and poor prognosis. For small cell carcinoma of the esophagus, X-ray imaging and endoscopy clinical symptoms are similar to those observed in esophageal squamous carcinoma and adenocarcinoma. Hence, it is necessary to rely on histological diagnosis, as the preoperative diagnosis rate is not high. In our group, the preoperative diagnostic rate of the patients was 20.12%, which is higher than other literature reports where most patients were pathologically confirmed to have squamous cell carcinoma or poorly differentiated cell carcinoma by preoperative esophagoscopy biopsy. The main reason for this difference is that a small amount of tissue was selected for the endoscopic biopsy, which could limit the diagnosis of complex small cell carcinomas and make it difficult to differentiate between SCEC and poorly differentiated squamous cell carcinoma. Because the pathological diagnosis of some patients before surgery is not accurate, the effect of the combined treatment is not ideal. Hence, improving the preoperative diagnostic rate is a problem to be solved in the future.

The risk factors of esophageal small cell carcinoma are unclear, and whether smoking, alcohol consumption and environmental and dietary changes increase its incidence needs further study. Mixed small cell carcinoma of the esophagus was present in 8.17% of the patients in this group. For 796 cases (58.79%), the tumors were located in the mid-esophagus and for 419 cases (30.95%), they were located in the lower thoracic segment. In only three cases (0.22%), the tumors were found in the cervical segment of the esophagus, as reported by Casas et al.^[54]. A leading hypothesis is that SCEC could originate from a pluripotent stem cell of the endoderm, which could differentiate into squamous cell carcinoma and adenocarcinoma or small cell carcinoma due to the stimulation of different carcinogenic agents [57]. However, the specific cause is not known and also something to figure out in the future. Small cell neuroendocrine carcinoma-derived markers, NSE, Syn and CgA, are expressed at high levels [58]. Results can be combined with endoscopy in pathological diagnosis and immunohistochemistry test results to improve the accuracy of diagnosis.

For small cell carcinoma of the esophagus, the best treatments are still unknown. Currently, the recommended treatment is a plastin-like drug based chemotherapy treatment. Casas’ [54] retrospective analysis of 199 cases of small cell carcinoma of the esophagus showed that treatment with chemotherapy resulted in a survival benefit in patients with limited stages and that comprehensive treatment was better than a single treatment. To accept the prognosis of a patients’ sole surgery is not ideal, as transfers tend to occur within a short period of time after surgery. This is similar to our study, which showed that postoperative adjuvant chemotherapy prolonged the median survival rate (14.94±5.15 months) more than other treatments. However, the effects of the different treatments on the five-year survival rate were not statistically significant. Furthermore, surgery combined with chemotherapy for early stage patients is still preferred, while chemotherapy combined with radiotherapy in the treatment of advanced cases is currently a more agreeable treatment option. Currently, there is no prospective, randomized controlled study of the treatment options and guidelines of small cell carcinoma of the esophagus. Walker et al. [59] also believed that surgery was the best means of local control, but the system has been combined with chemotherapy treatment. In China, patients with small cell carcinoma of the esophagus are often already at an advanced stage; therefore, the choice of systemic treatments is necessary. Attar et al. [60] found a 90% incidence of metastases in the liver, 25% in the lungs and 1% in the brain by autopsy of small cell carcinoma of the esophagus. Mandrd et al. [61] studied 23 autopsy cases of small cell carcinoma of the esophagus and found 91% metastasis in the lymph nodes and 87% in the visceral organs. Thus, small cell carcinoma of the esophagus should be considered a systemic disease, and it is necessary to implement systemic chemotherapy to treat it. However, the survival rate of the patients receiving chemotherapy is not high; therefore, in these patients, after chemotherapy is used to achieve systemic control, radiotherapy or surgery should be performed to achieve local control. Our study showed that the tumor stage affected the prognosis of SCEC, with higher rates of the five-year survival in patients with stage I or IIa disease. Therefore, early detection and early treatment is the key to improving overall survival.

6.      Conclusion

The risk factors for esophageal cancer include age, smoking, drinking, esophageal reflux disease, human papillomavirus infection, eating pickled foods, trace elements and vitamin deficiency. As the Chinese diet and lifestyle change, it is expected that the incidence of esophageal small cell carcinoma will increase. However, the direct link between the environment and changes in diet structure and the increase in incidence of SCEC still needs to be further researched. The goal is to reduce the mortality due to small cell carcinoma of the esophagus. Therefore, to cure the disease, it is necessary to improve the environment and food safety and to eliminate possible risk factors in the high incidence areas. Early detection and early treatment are the most effective measures with which to improve the five-year survival rate, so future efforts need to focus on finding new tumor markers and new diagnostics. Currently, targeted drug research and research on the development of small cell carcinoma and small cell carcinoma of the esophagus gene polymorphisms is lacking. To sum up, we need to improve the detection level of small cell carcinoma of the esophagus and the ability of patients to choose feasible individualized treatments and discover new drugs in order to really improve the survival rate of small cell carcinoma of the esophagus patients.

7.      Acknowledgement

Supported by One Hundred Person Project of The Hebei Province (Project number: E2016100001)

Figure 1:Regional distribution of small cell carcinoma of esophagus in China.

Figure 2:Survival Curves of Treatment with Primary Esophageal Small Cell Carcinoma.

Figure 3: Univariate Analyses for the Treatment of Patients with Primary Esophageal Small Cell Carcinoma.

Figure 4:TNM Stage Survival Curve of 824 PESC Patients.

Figure 5: Survival Curve of 824 Patients with Primary Esophageal Small Cell Carcinoma.

Table1: Characteristics of Study Patients.

Table 2: Univariate Analyses for the Treatment of Patients with Primary Esophageal Small Cell Carcinoma.

Table 3: Univariate analyses for the TNM stage of patients with primary esophageal small cell carcinoma.

1. Ferly J, Shin HR, Bray F, et al. (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893-2917.
2. Liu FS, Liu PH (1997) oncologic pathology [M]. Beijing: Peking University Medical Press (PUMP):680- 681.
3. Greene FL, Page DL, Fleming ID, A Fritz, CM. Balch, et al. (eds) AJCC Cancer Staging Manual. 6th ed. New York: Springer 2002.
4. Wang FM, Shen HB (2001) Diagnosis and treatment of 7 cases of primary small cell carcinoma of the esophagus. Zhejiang Prev Med 13:56
5. Li CT, Zheng BX, Li JM (2005) Clinical analysis of 25 cases with primary small cell carcinoma of esophagus. Chin J Clinic Oncol 32:294-296.
6. Qian PD, Zhu J, Ma DW (2007) Analysis of 26 patients with small cell carcinoma of esophagus and review of the literature. Chinese Clinical Oncology 12:207-210.
7. Wang HD, Qiu Y, Wu W et al. (2008) Clinical observation and surgical treatment of primary small cell carcinoma of esophagus: analysis of 28 cases. Chongqing Medical Journal 37:353-354
8. Shi F, Guo P (2011) Clinical analysis of 30 cases with primary esophageal small cell carcinoma. Henan Journal of Surgery 17:348-349
9. Wang J, Zhang WC, Zhao LJ (2008) Clinical analysis of 35 cases with primary esophageal small cell carcinoma. The 5th Chinese Conference on Oncology(CCO): 536-537
10. Zhao XJ, Liu ZC, Zhao XY et al. (2007) An analysis of treatment and prognosis in 45 cases with small cell esophageal carcinoma. Bulletin of Chinese cancer (Chin) 16:81-82
11. Feng W, Wang Z, Zheng X et al. (2007) Clinical analysis of 67 cases with primary small cell carcinoma of esophagus. Zhejiang Medical Journal (Chin)29:488-489
12. Zou ML, Zuo FX, Xu J (2008) The clinical analysis of 50 cases of primary small cell carcinoma of esophagus. Chinese Journal of Medical Guide (Chin) 10:1167-1168.
13. Yang XH, Wang ZR, Jia XF (2012) 2 cases of esophageal small cell carcinoma. Hebei Medical Journal (Chin) 34:285.
14. Gao LT, Lv CX, Wang JM et al. (2011) Analysis of clinical characteristics and prognosis of primary small cell carcinoma of the esophagus. Journal of Shanghai Jiaotong University (Medical Science) 31: 357-359.
15. Wang Y, Song Y, Xu LP et al. (2008) A Study of Apoptosis Biological Characteristics on Primary Esophageal Small Cell Carcinoma and Small Cell Lung Cancer. Journal of Chinese Cancer (Chin) 17:1067-1069.
16. Yang B, Yue Q, Zhang RS et al. (2011) Surgical treatment for 43 cases with limited disease small-cell esophageal Carcinoma. Shan Xi Med. Journal 40:483-484.
17. Yan YL (2012) Limited disease with primary small cell carcinoma of the esophagus: report of 30 cases. Shandong Medical Journal 52:107.
18. Gu ZH, Liu GC, Zhan YS (2012) Misdiagnosis of Leiomyoma of esophagus small cell carcinoma: analysis of 1 cases. Clinical Gastroenterology Journal 24:325.
19. Miao LL, Fan Y, Huang ZY et al. (2011) The Clinical Features and Prognosis of 90 Cases with Neuroendocrine Carcinoma of the Esophagus. Journal of Chinese Oncology 17: 766-769
20. Huo YY, Jing CP, Zhang Y (2011) Small cell carcinoma of the esophagus: report of 2 cases. Journal of Yanan University (Medical Sciences) 1:72
21. Song Y, Wang LH, He J, Wang JW (2009) Treatment and prognosis of primary esophageal small cell carcinoma：a report of 151 cases. Chinese Journal of Cancer 28:303-307.
22. Wang QM, Zeng JL, Chen YG (2000) Small cell carcinoma of the esophagus: report of 2 cases. Journal of ChuanBei Medical College19:250.
23. Zhang YG, Wang ZS, Chi FS (2006) Clinical analysis of 6 cases of primary esophageal small cell carcinoma. Chinese Journal of Misdiagnosis 6:2781.
24. Liu SQ, Shi XT (2005) Clinical analysis of 11 cases of primary esophageal small cell carcinoma. Shandong Medical Journal 45:8
25. Gong TQ, Jiang YG, Wang RW et al. (2005) Surgical treatment for small cell carcinoma of esophagus. Chongqing Medical Journal34: 532-535.
26. Wu MX, WU MY (2004) X-ray analysis of esophagus small cell carcinoma. Journal of rare and uncommon Diseases 11:13-14
27. Wang XL, Liu S, Wu GX, Meng X, Guo M, et al. (2004) Clinicopathologic observation on small cell carcinoma of the esophagus Chin J Clinic Oncol 31: 65-68.
28. Yan XM, Sun L, Wang S (2009) Primary esophageal small cell carcinoma, a clinicopathological study of 11 cases. Journal of Basic and Clinical Oncology 22:32-33
29. Tian XW, Zhang JG (2006) Analysis of Clinical pathological features of small cell carcinoma of the esophagus. Journal North China Coal Medical College 8:357-358
30. Wang JY, Qu FL, Wang ZP, et al. (2002) Treatment and prognostic analysis of esophageal small cell carcinoma. The Practical Journal of Cancer 17: 69-71
31. Chen XD, DingT, Duan ZH, et al. (2011) Experience of treatment of small cell carcinoma of the esophagus. Proceeding of Clinical Medicine 20: 506-507
32. Xie SQ, Yin ZC (2005) Small cell carcinoma of the esophagus: a clinicopathologic and immunohistochemical observation. Journal of Medical Forum 26:70
33. Chen QB, Wang HB, Zhang R, et al. (2007) The clinical analysis on small cell carcinoma of the esophagus. The Practical Journal of Cancer 22:91-93
34. Chen LB, Huang H, Zhu H (2002) Clinical analysis of six cases of small cell carcinoma of the esophagus. Academic Journal of Second Military Medical University 23:1090　
35. Li HS, Chen YB, Lin HT (2002) Imaging diagnosis of small cell carcinoma of esophagus: analysis of 45 cases. Chinese Journal of Misdiagnosis 2:455
36. Liu Y, Cao J, Zhang YL, et al. (2011) VP-16/DDP combination as a first line regimen for esophageal small cell carcinoma. Cancer Research on prevention and treatment 38:1423-1425
37. Zhang J, Gu LJ, Feng WN, et al. (2005) Primary esophageal small cell carcinoma: 1 case report. Guangdong Medical Journal 26:1485
38. Li H, Yie ZB, Lou GY (2003) Primary esophageal small cell carcinoma: 2 case report. Chin J Oncol 25:129
39. Cao GX, Jiang ZX (2011) Clinical analysis of 15 cases of primary small cell carcinoma of the esophagus. Journal of Modern medicine and health 27:3231-3232
40. Zhao JM, Ding D, Liu FC, et al. (2005) Diagnosis and treatment of primary esophageal small cell carcinoma: a report of 19 cases. Cancer Research and Clinic 17:116-117
41. Zong PJ (2010) Clinical pathological analysis of 23 cases with primary esophageal small cell carcinoma. Pathology Branch of the Chinese Medical Association 2010 Annual Conference Collection of papers: 150
42. Fan XS, Wang Y, Li SP, et al. (2007) Clinical analysis of 23 cases with primary esophageal small cell carcinoma. Chinese Journal of Clinical Oncology and Rehabilitation l14:544-545.
43. Li H, Liu SG, Liu XB, et al. (2009) Prognostic analysis of forty seven patients with primary esophageal small cell carcinoma. Tumor 29:180-183
44. Zhou T, Liu XS, Li BS, et al. (2006) Clinical analysis of 56 cases with primary esophageal small cell carcinoma. Shandong Medical Journal 46:27
45. Huang YX, Liu SY (2011) Clinical analysis of 61 cases with primary esophageal small cell carcinoma. Fujian Medical Journal 33:14-16
46. Meng XP, Sun HJ, Yuan NY, et al. (2006) Clinical characteristics and treatment of primary small cell carcinoma of the esophagus. Hainan Medical Journal 17:88-89
47. Li BQ, Wang GQ, Zhai Y, et al. (2003) Diagnosis and treatment of primary small-cell carcinoma of the esophagus (Clinical analysis of 61 cases). Chin J Clinic Oncol 30:742-744
48. Zhao HF, Zhao XJ, Tang P, et al. (2007) Clinical analysis of 67 cases with primary esophageal small cell carcinoma. Journal of Tianjin Medical University 13: 387-389
49. Zhao WP, Chen R, Duan YZ, et al. (2009) Clinical and pathological analysis of primary esophageal small cell carcinoma. Modern Oncology 117: 660-662
50. Jiang F, Chen XZ, Ma SL. (2005) Clinical analysis of primary small cell carcinoma of the esophagus. Chinese Journal of Clinical Oncology and Rehabilitation 12: 549-550
51. Han GD, Zhou Ming, Li HS, et al. (2006) The clinical features of primary esophageal small cell carcinoma and comprehensive treatment. International Medicine & Health Guidance News 12: 8-9
52. Mei XY, Xu MQ, Wei DZ, et al. (2009) Surgical treatment and clinicopathologic observation of primary esophageal small cell carcinoma. Anhui Medical Journal 30:631-633
53. Chen XP (2012) Surgery 2nd Beijing: People's Medical Publishing House (PMPH): 444-449
54. Casas F, Ferrer F, Farrus B, et al. (1997) Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis．Cancer80:1366-1372.
55. Cook MB, Chow WH, Devesa SS. (2009) Esophageal cancer incidence in the United States by race, sex, and histologic type, 1977-2005. Br J Cancer101:855-859.
56. Zeng HM, Zheng RS, Zhang SW, et al. (2012) Trend analysis and prediction for esophageal cancer in China. Chin J Prev: 46
57. Nishimaki T, Suzuki T, Nakagawa S, Watanabe K, Aizawa K, et al. (1997) Tumor spread and outcome of treatment in primary esophagus small cell carcinoma．J SurgOncol64:130-134.
58. Fukunaga Y, Hirata S, Tanimara S, et al. (2002) Superficial undifferentiated small cell carcinoma of the esophagus showing an interesting growing pattern in the histology. Hepatogastroenterology47:429-432.
59. Walker SJ, Steel A, Cullen MH (1989) Treatment of esophageal small cell carcinoma by combined chemotherapy and surgical resection: report of two cases and review of published cases. Thorax44:751-752.
60. Ken-ichiMafune, Yoichi Tanaka, KaiyoTakubo, Nobuyuki Uchida, ShugoAkazawa, et al. (1993) Small cell carcinoma of the esophagus.Report of three cases and review of the literature. Recent Advances in Diseases of the Esophagus1029-1038.
61. Mandard AM, Chasle J, Marnay J,Villedieu B, Bianco C, et al. (1981) Autopsy findings in 111 cases of esophageal cancer. Cancer. 48:329-335.