Treatment and prognosis of primary esophageal small cell carcinoma

[Chinese Journal of Cancer 28:3, 254-258; March 2009]; 2009 Landes Bioscience Clinical Research Paper Treatment and prognosis of primary esophageal small cell carcinoma A report of 151 cases Yan Song, 1 Lv-Hua Wang, 2 Jie He 3 and Jin-Wan Wang 1, * 1 Department of Medical Oncology; 2 Department of Radiation Oncology; 3 Department of Thoracic Surgery; Cancer Hospital; Chinese Academy of Medical Sciences; Beijing P.R. China. Key words: esophageal neoplasm, small cell carcinoma, combined therapy, prognosis Background and Objective: The treatment and prognosis of primary esophageal small cell carcinoma (PESC), an uncommon esophageal malignant tumor, have seldom been reported. This study was to analyze the clinical characteristics, treatment and prognosis of PESC. Methods: Clinical data of 151 patients treated in Cancer Hospital, Chinese Academy of Medical Sciences, from 1982 to 2007 were reviewed. The median age of the patients was 59 years. According to VALSG criteria, 138 patients had limited disease (LD), 13 had extensive disease (ED). Patients received surgery, chemotherapy and/or radiotherapy. The survival rate was calculated by the Kaplan-Meier method and the log-rank test using SPSS 13.0 software. Results: The 6, 12, 24, 36 and 60-month survival rates of these patients were 86.6%, 56.7%, 24.8%, 17.4% and 12.0%, respectively. The clinical stage and blood vessel invasion were independent prognostic factors of PESC. The median survival time of LD patients was longer in those undergoing combined therapy (12.3 months) than in those undergoing local treatment alone (surgery or radiotherapy). Conclusions: PESC is a malignant tumor with early metastasis and poor prognosis. Combined therapy based on chemotherapy may improve the short term survival of PESC patients. Primary esophageal small cell carcinoma (PESC) is a rare malignant tumor. It was first reported by Mckeown et al. in 1952. 1 This disease has the characteristics of high malignancy, local recurrence, high metastatic rate, and short survival time. We retrospectively analyzed the clinical data of 151 cases of PESC to investigate clinical features, treatment approaches, and prognostic outcomes of this disease. *Correspondence to: Jin-Wan Wang; Department of Medical Oncology; Cancer Hospital; Chinese Academy of Medical Sciences; Beijing 100021 P.R. China; Tel.: 86.10.87788842; Fax: 86.10.87788842; Email: jwwang@csco.org.cn Submitted: 07/28/08; Revised: 09/16/08; Accepted: 10/12/08 This paper was translated into English from its original publication in Chinese. Translated by: Beijing Xinglin Meditrans Center (http://www.58medtrans.com) and Hua He on 02/20/09. The original Chinese version of this paper is published in: Ai Zheng (Chinese Journal of Cancer), 28(3); http://www.cjcsysu.cn/cn/article.asp?id=15237 Previously published online as a Chinese Journal of Cancer E-publication: http://www.landesbioscience.com/journals/cjc/article/8653 Patients and Methods Clinical data. In total 151 patients with PESC from April 1982 to July 2007 were admitted at Cancer Institute & Hospital of Chinese Academy of Medical Sciences, among which 114 were males and 37 were females, with a medium age of 59 years (33 to 82 years). Two cases were at the cervical segment of the esophagus, 15 cases were at the upper thoracic segment, 95 cases were at the midthoracic segment, and 39 cases were at the lower thoracic segment. Based on the X-ray manifestations, the patients were classified into the followings: 73 cases of the medullar type, 45 cases of the mushroom type, six cases of the ulcer type, 12 cases of the luminal type, and 15 cases of the plague type at the early stage. The medium length of lesions was 5.5 cm (0.5 to 11.0 cm), where 48.8% cases had lesions less than or equal to 5 cm and 51.2% had lesions greater than 5 cm. Initial symptoms of patients included difficulty swallowing (86.1%), chest and back pain (32.5%), pain swallowing (23.2%), posterior sternal discomfort (14.6%), and hoarse voice (2.6). Based on the TNM staging proposed by AJCC in 2002, 16 cases are at stage I, 21 cases at stage IIa, 23 cases at stage IIb, 66 cases at stage III, and 25 cases at stage IV. According to the classification of Veterans Administration Lung Cancer Study Group, 138 cases were classified as limited disease (LD) and 13 cases as extensive disease (ED). All cases were pathologically confirmed as PESC, among which 138 cases were simple small cell carcinoma and 13 cases were small cell carcinoma containing a component of squamous cell carcinoma. Immunohistochemical analysis showed that 88.6% patients had positive neural specific enolase (NSE), 74.4% had positive synaptic protein (Syn), and 60.5% had chromogranin A (CgA). Seventy-seven patients of simple small cell carcinoma had preoperative pathological results from esophagoscopy, in which 26 cases were small cell carcinoma, 22 cases were poorly differentiated squamous cell carcinoma, 20 cases were poorly differentiated carcinoma, and tumor tissues were not found in nine cases. Treatment. Among 138 patients classified as LD, 98 underwent radical surgical resection, eight received palliative surgical resection, four had chemotherapy alone, 13 underwent radiotherapy alone, and 15 had combined treatment with radiotherapy and chemotherapy. After radical surgery, 42 patients received adjunctive chemotherapy, three patients received adjunctive radiotherapy, 254 Chinese Journal of Cancer 2009; Vol. 28 Issue 3

seven patients had integrated therapy with radiochemotherapy, and 46 patients did not receive any adjunctive treatments. After palliative surgery, two patients received chemotherapy, one patient received radiotherapy, and five patients did not receive any tr eatments. Thirteen patients were classified as ED. In four cases who received palliative surgery, only one had chemotherapy afterward, and the rest did not receive any chemotherapy or radiotherapy. Six patients received chemotherapy alone, one patient received radiotherapy alone, and two patients had integrated treatments of chemoradiotherapy. The first choice of chemotherapy regimen was COME (CTX + VCR + MTX + VP-16) before. Since the 90s of the 20 th century, DDP/CBP+VP-16 has been used as the first choice. Second-line chemotherapy drugs include taxane agents, Ifostamide, vinorelbine, and so on. The 60 Co or 6 MV-X-ray linear accelerator was used for radiotherapy, with a medium dosage of 56.0 Gy (38.0Gy-70.0Gy). Intra-thoracic anastomosis with lateral incision at posterior left chest was primarily used for radical surgery. Follow-ups. Patients were followed up until June 2008. The follow-up rate for this study was 91.4%. Thirteen lost patients were assumed death losses. The medium follow-up time was 12.3 months (1.2 months to 190.0 months). Statistical analysis. The survival rate was calculated by the Kaplan-Meier method and the log-rank test using SPSS 13.0 software. The Cox regression model was used for survival analysis. p < 0.05 is considered statistically significant. Results Survival and influential factors for PESC patients. The medium survival of the 151 patients was 10.7 months (1.5 181.0 months). One patient died nine days after surgery due to infection, and one patient died eight days after surgery due to hemorrhage. The 6-, 12-, 24-, 36-, and 60- month survival rates were 86.6%, 56.7%, 24.8%, 17.4%, and 12.0%, respectively (Fig. 1). Singlefactorial analysis of survival rates revealed that clinical stage (inclusive of TNM stage and VALSG stage), lesion length, blood vessel invasion, and postoperative lymphatic metastatic region after radical surgery had significant influences on the survival rate (all p values < 0.05, Table 1). Dietary habit, pathological components, age, sex, lesion location and lesion type had no significant influence on the survival rate (all p values > 0.05). The Cox regression analysis showed that clinical stage and blood vessel invasion were independent influential factors (p = 0.012, p = 0.023, relative degrees of risk were all > 1). Influences of different treatment strategies on the survival. The medium survival period for 47 LD patients receiving local therapy (surgery and/or radiotherapy) was 7.7 months. The other 21 LD patients who were not initially treated by chemotherapy were included into the comprehensive treatment group after relapse. The medium survival period for 91 patients who received chemotherapy- based comprehensive treatment was 12.3 months (Fig. 2). The survival of patients receiving comprehensive treatment was significantly longer than that of those receiving local treatment (p = 0.042). The medium survival period for 46 LD patients who Figure 1. Survival curve of 151 patients with primary esophageal small cell carcinoma (PESC). received radical surgery only was 9.0 months, while that of 52 patients who received adjunctive treatment was 13.4 months (Fig. 3). The survival of patients with adjunctive treatment was significantly longer than that of patients without adjunctive treatment (p = 0.029). The medium survival for four ED patients undergoing local therapy was 7.8 months, while that for nine patients who received comprehensive treatment inclusive of chemotherapy was 8.6 months, without significant difference (p = 0.453). Distant metastases. In 138 cases of LD, 78.9% had distant metastasis during the process of treatments: 48 cases of hepatic metastasis (34.8%), 40 cases of supraclavicular metastasis (29.0%), 28 cases of pulmonary metastasis (20.3%), 22 cases of bone metastasis (15.9%), 20 cases of posterior peritoneal lymphatic metastasis (14.5%), 18 cases of peritoneal lymphatic metastasis (13.0%), 14 cases of cervical lymphatic metastasis (10.1%), 10 cases of subcutaneous metastasis (7.2%), eight cases of axillary lymphatic metastasis (5.8%), and one case each in adrenal glands, brain, bone marrow, pancreas, and thyroid glands. Discussion Undifferentiated small cell carcinoma usually occurs in lungs, while only 5% develop in organs outside the lungs, 2 where PECC is the most common one. The incidence of PECC accounts for approximately 1% to 2.8% of all esophageal carcinoma. 3,4 PECC took up 1.5% of all cases of esophageal malignant tumors in our hospital, which was in accordance to the reported results. Clinical symptoms of PECC, including X-ray manifestations and endoscopic observations, are very similar to those of esophageal squamous cell carcinoma and adenocarcinoma, and thus, PECC can only be diagnosed by pathohistological examination. 5 In this study, patients mainly complained of difficulty swallowing, as well as chest and back pain, which were not typical symptoms. The diagnostic accuracy of preoperative esophagoscopy was only 33.8%, which suggests that more samples should be extracted at esophagoscopy. Some patients were not accurately diagnosed www.landesbioscience.com Chinese Journal of Cancer 255

Table 1 Univariate analyses for the prognosis of patients with primary esophageal small cell carcinoma (PESC) a Only PESC patients with limited disease undergoing radical therapy were analyzed. 256 Chinese Journal of Cancer 2009; Vol. 28 Issue 3

Figure 2. Survival curves of PESC patients with limited disease treated by combined therapy or local therapy. Figure 3. Survival curves of PESC patients with limited disease with or without adjunctive therapy. before surgery, this might affect preoperative comprehensive treatments for patients to some extents. Most cases in this study had lesions located in the middle and lower segments of the esophagus (88.7%), in accordance to Casas et al., 6 which may possibly relate to the abundance of Kulchisky cells, also known as APUD cells, in the distal esophagus. Some believe that PECC is originated from primary stem cells in the esophageal membrane and has multipotent capabilities. Therefore, it is sometimes associated with some non-small cell carcinoma components, such as squamous cell carcinoma or adenocarcinoma. 7 According to histological morphology, PECC is classified as the following three types: 1) Oat cell type with tightly and mostly compressed cells; 2) Small round cell type with loosely and dispersedly arranged tumor cells. Nest-like structures are pronounced. 3) Small cell type with either small round cells or oat cells accompanied by the component of squamous cells carcinoma or adenocarcinoma. The oat cell type and small round cell type are simple types whereas the small cell type is a mixed type. In this study, mixed components of small cell carcinoma and squamous cell carcinoma were detected in 8.6% of patients. Neural endocrine markers are highly expressed in small cell carcinoma, such as NSE, Syn, and CgA. 8 Diagnostic accuracy of PECC can be improved based on the combination of esophagoscopic findings and immunohistochemical results. The gross classification of PECC is different from other types of esophageal carcinoma, characterized by significantly increased ratios of the mushroom type and the luminal type. 9 In this study, the mushroom type and the luminal type accounted for approximately 29.8% (45/151) and 7.9% (12/151), respectively, which were both higher than the average levels of 15% and 3%. 10 PECC grows quickly and has strong infiltrative ability. Early lymphatic and blood metastasis can occur. After radical surgery, 66.3% patients were found localized lymphatic metastasis; 78.9% LD patients showed distant metastasis during treatments. Localized lymphatic metastasis is an important influential factor for prognosis (p = 0.003) So far, no prospective randomized trials have been conducted and no standard treatment regimens have been established for PECC. It remains controversy for surgery alone in treating this disease. The survival of LD patients was much longer in those with adjuvant therapy after radical surgery than those without (13.4 months vs. 9 months) (p = 0.029). Although short-term therapeutic effects of surgery and radiotherapy are good, the long-term survival rates are low. Casas et al. 6 claimed that simple and local treatment is the primary reason for poor prognosis of PECC. In this study, the survival rate for LD patients receiving local treatments was only 7.7 months, which was far shorter than 12.3 months reported in patients receiving comprehensive treatments (p = 0.042). Walker et al. 11 recommend that surgery is the best approach for local control of PECC, even though integrated chemotherapy is still required for systemic treatment. PECC patients are usually in the late stage when they are admitted to the hospital and thus, systemic treatment becomes necessary. Attar et al. 12 discovered that the incidence rate of hepatic metastasis for PECC was as high as 90%, the rate of lung metastasis was 25%, and the rate of brain metastasis was 1% through autopsies. Mandrd et al. 13 statistically analyzed 23 autopsies of PECC and found that the lymphatic metastatic rate was 91% and the metastatic rate of internal organs was 87%. In this study, hepatic and pulmonary metastases were most common seen, which were 34.8% and 20.3%, respectively. Therefore, PECC should be considered as a systemic disease, and systemic chemotherapy is required. After the first case of PECC were treated by the EP+CAO regimen, achieved partial remission and survived for nine months 14, chemotherapy, especially along with multiple drugs or radiotherapy, is considered as the first-line therapy. In this study, among eight patients who survived for over five years, six received chemotherapy or other integrated treatments, while the other two who did not undergo chemotherapy were at early stages (T1N0M0 and T2N0M0) and had no high-risk factors. In conclusion, early diagnosis for PECC is difficult. Systemic chemotherapy combined with surgery and radiotherapy can significantly improve the survival of PECC. Random control research www.landesbioscience.com Chinese Journal of Cancer 257

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