Chinese Medical Journal 2007;120(5):355-358
Management of primary small cell carcinoma of the esophagus

SUN Ke-lin,  HE Jie,  CHENG Gui-yu,  CHAI Li-xun

SUN Ke-lin (Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China)

HE Jie (Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China)

CHENG Gui-yu (Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China)

CHAI Li-xun (Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China)

Correspondence to:SUN Ke-lin,Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China (Tel: 86-10-87788909. Fax:86-10-67793015. E-mail:kelin.sun. md@sohu.com)
Keywords
esophagus; small cell carcinoma; surgery
Abstract

Background  Primary small cell carcinoma of the esophagus is rare. Although surgery is successful in eradicating local tumor, the five-year survival rate of patients with primary small cell carcinoma of the esophagus after resection is lower than that of patients with primary squamous cell carcinoma of the esophagus. The purpose of this study was to analyze the clinical manifestations, pathological features and treatment of primary small cell carcinoma of the esophagus.
Methods  A total of 73 patients with primary small cell carcinoma of the esophagus who had been treated by surgery from 1984 to 2003 were analyzed retrospectively.
Results  In this series, the overall resection rate was 94.5% (69/73) , the radical resection rate 89.0% (65/73) and the operative mortality 1.4% (1/73). The 1-, 3- and 5-year survival rates of patients were 50.7%, 13.7% and 8.2%, respectively.
Conclusions  Primary small cell carcinoma of the esophagus is rare with a poor prognosis. Surgical resection is the leading method for patients with stage I or II primary small cell carcinoma of the esophagus. Postoperative chemotherapy is beneficial to these patients. The patients of stage III or IV should be given chemotherapy and radiation therapy.

Primary small cell carcinoma of the esophagus (PSCE), characterized by high malignancy, poor prognosis and distant metastasis, is rarely seen with an incidence rate of 0.05%-7.6% among esophageal cancers in a given period.1 From 1984 to 2003, 73 patients with primary small cell carcinoma of the esophagus underwent surgical resection in our hospital and were confirmed pathologically. In this report we retrospectively analyzed the clinical manifestations, pathological features and treatment of primary small cell carcinoma of the esophagus.

METHODS

Patients
Of the 73 patients, 57 were men and 16 women (3.6:1). Their age ranged from 40 to 70 years with a median age of 57. All patients were subjected to barium meal examination and 36 received esophagoscopy preoperatively. For cytological examination, esophageal abrasive balloon was used preoperatively in 28 patients.

The 73 patients underwent surgical resection, including cervical esophagogastrostomy through left neck and left thoracic incisions (7 patients), cervical esophagogas- trostomy through left neck, right thoracic and median abdominal incisions (3), intrathoracic esophagogas- trostomy through left thoracic and median abdominal incisions due to the previous subtotal gastrectomy (1), and intrathoracic anastomosis through routine approach of left posterolateral incision (62).

In the 73 patients, only 13 received simple surgery and the other 60 received chemotherapy after operation, a regimen comprising carboplatin+etoposide (CE) or cyclophosphmide + vincristine + mitomycin + etoposide (COMVP) or cyclophosphmide+doxorubicin+cisplatin (CAP). Three patients received preoperative chemotherapy, and 8 postoperative radiotherapy.

Statistical analysis
The data were expressed as mean±standard deviation (SD). Statistical analysis was conducted with SPSS 10.0. The chi-square test was performed. A P value < 0.05 was considered statistically significant.

RESULTS

The tumor was found at the cervical segment of the esophagus in 1 patient (1.4%), at the upper third of the thoracic esophagus in 11 (15.1%), at the middle in 45 (61.6%), and at the lower third in 16 (21.9%). The length of lesions ranged from 1 to 15 cm. Similar to those of esophageal squamous cell carcinoma, the clinical manifestations included progressive dysphagia, chest pain and weight loss.

Lower diagnostic rates of 41.7% (15/36) and 35.7% (10/28) were given by esophagoscopy and esophageal abrasive cytologic examination, respectively. Twenty- three patients were diagnosed as having PSCE preoperatively with a diagnostic rate of 31.5%. According to the UICC standards in 1997,2 10 patients were in stage I, 13 in stage IIa, 10 in stage IIb, 39 in stage III (53.4%), and 1 in stage IV. Thirty-three patients in stage I and II accounted for 45.2%. Sixty-five patients underwent radical resection, 4 palliative operation, and 4 explorative operation because the tumor was irremovable. The resection rate and radical resection rate were 94.5% and 89.0%, respectively.

One patient (1.4%) died from postoperative hemoptysis. Of the 72 patients who had recovered, 67 (93.1%) were followed up. Postoperative complications included anastomotic fistula (2 patients), anastomotic stenosis (2), pulmonary infection (1), phlebitis of the lower extremities (1), gastric fistula (1), and cardiac arrhythmia (1). The incidence rate of operative complication was 11.0% (8/73). The 1-, 3- and 5-year survival rates of this series were 50.7%, 13.7%, and 8.2% respectively. The 1-, 3- and 5-year survival rates of patients in stage I and II were 75.8%, 30.3%, and 18.2%, respectively; in contrast to 30.0%, 0%, and 0% of patients in stage III and IV, respectively. There were significant differences between patients of stage I, II and stage III, IV (Table 1). Fifty patients had lymph node metastasis, and their 1-, 3- and 5-year survival rates were 38.0% (19/50), 8.0% (4/50), 4.0% (2/50), respectively. The 1-, 3- and 5-year survival rates of patients without lymph node metastasis were 72.7% (16/22), 27.3% (6/22), 18.2% (4/22), respectively. Significant differences were noted between the patients with and without lymph node metastasis (Table 2).


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Table 1. TNM staging of PSCE patients and survival rates in different stage


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Table 2. Survival rates of patients with or without lymph node metastasis

DISCUSSION

Undifferentiated small cell carcinoma occurs mainly in the lung, accounting for 10%-20% of lung cancers. In recent years, small cell carcinoma has also been found in the esophagus, gastrointestinal tract, pancreas, bladder, cervix and skin.

Two cases of primary small cell carcinoma of the esophagus were first reported in 1952. Since then many consecutive cases have been reported, but few large series of cases either in China or other countries. In recent years, the incidence of the tumor increases gradually with the development of pathologically diagnostic techniques in northern China. Wang et al3 reported 47 cases of PSCE in 1999, Li et al4 reported 61 in 2003, and Zhao et al5 reported 19 in 2005. The data suggested that the progress of clinical and pathological techniques resulted in more cases of PSCE diagnosed.

Clinical characteristic and diagnosis
Although our patients were in limited stage preoperatively, one patient had hepatic metastasis and underwent explorative operation. Clinical symptoms of PSCE were similar to those of squamous carcinoma of the esophagus, and no significant specificity was seen in imaging and esophagoscopy. Preoperative imaging or esophagoscopy of PSCE showed early occurrence of dysphagia, quick progression of symptoms, and lymph node or distant metastasis in early stage. PSCE predominantly occurs in men at the age of 40-70 years. Its major symptoms are progressive dysphagia, retrosternal pain and loss of body weight. A few patients may have hoarse voice, alimentary tract hemorrhage, etc. The lesion is located frequently at the middle and lower segments of the esophagus, which may be associated with major precursor uptake and decarboxylation cells in the mucosa of the middle and lower segments of the esophagus.6 In our group, most lesions were located at the middle segment of the esophagus, followed by the lower segment, which is similar to the report of Li et al.4 Lymphatic and hematogenous metastasis in early stage of PSCE patients is characterized by fast progression and strong invasion. Fifty (68.5%) of the patients in this group were pathologically confirmed to have lymph node metastasis postoperatively, which plays an important role in prognosis. The survival rate of patients with lymph node metastasis was significantly lower than that of those without lymph node metastasis. This finding is the same as in patients with squamous cell.7 Visceral metastasis is frequently in the liver, lung and bone, and hepatic metastasis is predominent. The rate of hepatic metastasis was 34.2%.7 The clinical features of PSCE are basically identical to those of squamous cell carcinoma, and the diagnosis of this disease is depended on patho-histological findings. Cytological examination by esophageal abrasive balloon is economic, easy and convenient, but the positive rate was as low as 35.7% (10/28) in our group. Hence the diagnosis of PSCE can not be dependent exclusively on the result of cytological study, and endoscopic biopsy is also optional before treatment. Additionally, PSCE can be diagnosed by punch biopsy under a endoscope. Because of a small amount of picked tissues, this method is limited in the diagnosis of complex small cell carcinoma and sometime it is difficult to differentiate PSCE from poorly differentiated squamous cell carcinoma. In our group, 19 patients (26.0%) were pathologically diagnosed as having poorly differentiated squamous cell carcinoma preoperatively but small cell carcinoma mixed with poorly differentiated squamouse cell carcinoma postoperatively. Therefore, more tissues and multipoint biopsy should be done under an endoscope to make a correct diagnosis.

Histological origin and pathological features
At present, there are two viewpoints on the histological origin of PSCE. One is that PSCE originates from neuroendocrine cells of the submucosal gland or stratum basal, i.e. the major precursor uptake and decarboxylation cells, as confirmed histologically. The other is that PSCE originates from multipotential stem cells of the endoderm. Most of these cells may be differentiated into squamous cell carcinoma and some differentiated into adenocarcinoma or small cell carcinoma. This is due to the diversity of morphological, immunohistological and electron microscopic features of PSCE,in addition to the coexistence of PSCE with squamous cell carcinoma and (or) adenocarcinoma. Ugras et al8 found the transition between small cell carcinoma and squamous cell carcinoma in complicated small cell carcinoma of the esophagus, proving that PSCE is originated from multipotential stem cells. In the present study, 38.4% cases of small cell carcinoma with squamouse cell carcinoma or adenocarcinoma confirmed postoperatively by pathological examination, support the latter viewpoint. That may be why the diagnostic rate of cytological examination with esophageal abrasive balloon or with biopsy by esophagoscopy is much lower. The major macropathologic types of the specimen of PSCE include mushroom type and intraluminal type.9 In this series the two types accounted for 30.1% (22/73) and 26.0% (19/73), respectively, totalling 56.1%, which is similar to the results reported elsewhere.

Treatment and prognosis
There is no agreement on the therapy of PSCE due to its lower incidence rate and limited knowledge on the disease. It is commonly thought that surgical resection and radiotherapy have good therapeutic effects on PSCE in short term, but long-term survival rate of patients is still low. Mcfadden et al10 reported that the average survival time of 29 PSCE cases received surgical resection alone was only 8 months. Nemoto et al11 reported the median survival time of 20 PSCE patients who had received radiotherapy alone was only 5 months. With increasing recognition of biological behavior of PSCE and the therapeutic mode of small cell carcinoma of the lung, chemotherapy plays a more important role in the combined therapy of PSCE. In our series, the 4 patients who survived more than 10 years had received postoperative chemotherapy. In addition, the therapy of PSCE is related to the staging and typing of tumor, which is similar to small cell lung cancer. In the present study, there were significant differences in the 1-, 3- and 5-year survival rates between patients in stage I/II and in stage III/IV. Although the patients in stage III/IV all received surgical resection combined with chemotherapy, none could survive more than 3 years. Since early metastasis is frequent in PSCE and chemotherapy has a high remission rate, the consensus on therapy of PSCE is that despite limited stage or extensive stage, systemic chemotherapy plays an essential role in the therapy of PSCE. However not all PSCE cases are sensitive to chemotherapy. Nichols et al12 reported that 50% of patients with PSCE were insensitive to chemotherapy, and Nishimaki et al13 also reported that chemotherapy with single drug can not prolong the survival.

According to the report,14 patients with longer survival usually had received combined therapy including surgical resection, and those without combined therapy seldomly survived more than 2 years. In the 6 patients who survived over 5 years in our series, 5 in stage I/II received combined therapy and only 1 received surgical resection alone. Medgyesy et al15 reported that in the postoperative specimen of 8 PSCE cases who had received postoperative radiotherapy and chemotherapy, residual small cell carcinoma was found in 2 patients, residual squamous cell carcinoma in 1, and residual adenocarcinoma in 1. Therefore, it is recommended that the treatment of PSCE in limited stage should include systemic therapy combined with surgical resection. Pantraidya et al16 thought that surgical resection combined with chemotherapy was the best way to treat of PSCE.

In short, PSCE is a tumor characterized by high malignancy and early metastasis. The systemic chemotherapy plays a major role in the therapy of PSCE as a systemic disease. In addition, surgical resection also plays an important role in the treatment of PSCE as a disease with the major symptom of dysphagia. Because of the lower incidence rate of PSCE, it is hard to conduct a randomized controlled trial so as to find a new therapeutic strategy. Systemic therapy based on chemotherapy combined with surgery may be an effective approach for the treatment of PSCE in stage I/II, but the outcome of surgery on PSCE in stage III needs further study.

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