Abstract
OBJECTIVE To retrospectively evaluate the prognostic factors for advanced thymic carcinoma.
METHODS The data from 45 patients with advanced thymic carcinoma were retrospectively analyzed according to Masaoka stage criteria. There were 29 Stage III patients and 16 Stage IV patients (13 Stage IVA patients and 3 Stage IVB patients). According to the World Heath Organization Histological Criteria (2004), 25 cases were identified as low-grade and 20 cases were identified as high-grade. All diagnoses were confirmed by biopsy. Five patients underwent gross total resection, 21 patients underwent subtotal resection and 19 patients underwent biopsy alone. Forty-two patients received radiotherapy with a median dose of 60 Gy, and 37 patients underwent conventional radiotherapy, including local irradiation and expanded irradiation. Local irradiation volume covered the primary tumor bed and approximately 1-2 cm2 surrounding the tumor (according to preoperative imaging). Expanded irradiation volume covered the full mediastinal and pericardium areas (with or without prophylactic irradiation in the supraclavicular area). Five cases received stereotactic radiotherapy. Thirty-one patients were also treated with chemotherapeutics, including Cisplatin, VP-16, Endoxan, 5-FU and taxol.
RESULTS The median follow-up period was 59 months. The overall 3-year survival rate was 57.8%, and the median survival was 45 months. Univariate statistical analysis showed that the histological subtype and Masaoka stage were prognostic factors. The 3-year survival rate was 61.9% in patients treated with gross total resection and 55.0% in those who underwent biopsy only. The 3-year survival rate was 59.5% in patients treated with conventional radiotherapy and 80% in those treated with stereotactic radiotherapy. The 3-year survival rate was 64.5% in patients treated with simultaneous chemotherapy and 42.9% in patients treated without simultaneous chemotherapy (P > 0.05). Chemotherapy in combination with radiation treatment and surgery achieved better outcomes for Stage IV patients than radiation treatment and surgery without chemotherapy (P < 0.05).
CONCLUSION For patients with Stage III and IV thymic carcinoma, complete resection and postoperative radiotherapy or fractionated stereotactic radiotherapy constitute the best treatment solution. Chemotherapy can also be used in combination to improve prognosis. For patients with Stage IV thymic carcinoma, chemotherapy is necessary.
keywords
Introduction
Thymic carcinoma, originated in thymic epithelial cells, accounted for 2.7% of all mediastinal tumor and 6% of primary anterior mediastinal tumor. In 1977, Shimosato et al.[1] analyzed 8 cases of squamous cell carcinoma of thymoma and presented the concept of thymic carcinoma. The malignant biological behavior of thymic carcinoma is different from thymoma in histopathology and its incidence has been increased in recent years. We studied the pathologically confirmed prognosis of 45 cases with thymic carcinoma, and aimed at raising the awareness of the disease and providing clinical reference.
Materials and Methods
Selection criteria based on patient history
The selected cases were consistent with the following criteria: i) Thymic carcinoma had been pathologically confirmed. ii) All cases were in Masaoka Stage III or IV. iii) Clinical data and follow-up data were complete. iv) There was no history of other malignancies.
Clinical data
From January 1992 to August 2003, 58 patients were diagnosed as thymic carcinoma and treated in our hospital. Forty-five of them were chosen for our research. This group of patients had an age ranged from 17 to 71 and the median age was 49 years old. In the cases, 33 were male and 12 female, with a male-female ratio of 2.75:1. Chest pain and tightness as main symptoms were present in 18 cases, coughing or shortness of breath in 15 cases, shoulder pain or back pain in 4 cases, and the superior vena cava syndrome in 3 cases. Three cases had myasthenia gravis and 2 cases were found to be asymptomatic upon examination. Pathological types were as follows: low-grade 25 cases (18 cases of squamous cell carcinoma, 3 cases of mucoepidermoid carcinoma and 4 cases of basaloid carcinoma), 20 patients with high-grade (6 cases of lymphoepitheloid carcinoma, 9 cases of undifferentiated carcinoma, 2 cases of clear-cell carcinom, 1 case of small cell carcinoma, and 2 cases of carcinoma sarcomatodes). In the 45 cases, 29 cases were in Stage III and 16 cases in Stage IV according to Masaoka stage classification.
Treatment methods
Surgery
Surgical operation was performed in the 45 patients. Five patients received total resection; 21 received subtotal resection, and only 19 received biopsy (The patients with biopsy alone were listed in the surgical treatment based on previous overseas literature).
Radiation therapy
With the exception of three cases, all other patients received radiation therapy.
Conventional radiation therapy
Thirty-seven patients received conventional radiotherapy, radiotherapy and surgery at a median interval of 40 days (10-150 days). The median dose was 58 Gy (45-70 Gy) and conventional segmentation was 1.8-2.0 Gy/time. Co-60 irradiation was administrated in 8 cases, 6-MV accelerator X-ray irradiation in 24 cases, 6-MV accelerator X-ray and electron irradiation in 5 cases. Irradiation included local irradiation and expanded irradiation. Local irradiation volume included the primary tumor bed with approximately 1-2 cm2 (according to preoperative imaging). Expanded irradiation volume included the full of mediastinum and pericardium (with or without irradiation prevention of the supraclavicular area). Local irradiation was performed on 14 patients and expanded exposure on 23 patients.
Stereotactic radiotherapy
Stereotactic radiotherapy was received by 5 cases. Here the patient was fitted with a vacuum suction device for SCT positioning which has a CT positioning chip marking the target. This minimizes the dose received by vital organs such as heart, lung, spinal cord and esophagus. Volume histograms showed that the high dose regions (80%-100% isodose lines) received 4-6 Gy, qod, a total of 8-10 times. The total dose was 65-70 Gy.
Chemical therapy
Thirty-one patients received different periods and different cycles (2-6 cycles) of chemotherapy before and after receiving radiation therapy, 21 cases of Stage III and 10 cases of Stage IV. Chemotherapy drugs included cisplatin, VP-16, cyclophosphamide, 5-fluorouracil and paclitaxel.
Statistical analysis
The overall survival was calculated from the start of treatment, including biopsy, by the Kaplan-Meier parametric estimation. Differences between the groups were analyzed by using the Log rank test, and the value of P < 0.05 was considered as statistically significant.
Results
Follow-up
The follow-up ended in August 17, 2003 with 2 cases lost and follow-up rate was 95.6%, and the median follow-up duration was 59 months.
Survival
So far, there are six cases of survival, and the overall 3-year survival rate was 57.8%. The median survival time was 45 months (Table 1).
Results of univariate analysis of different prognostic factors
Thirty-one of 45 cases adopted chemotherapy, of which Stage III made up 19 cases, and 12 cases in Stage IV. The 3-year survival rate and the median survival time were 84.2%, 56 months for Stage III and 33.3%, 29 months for Stage IV. Of the 14 cases without chemotherapy, 10 were in Stage III and 4 in Stage IV. The three-year survival rate and the median survival time were 60.0%, 45 months for Stage III and 0%, 16 months for Stage IV. In Stage III, the comparison between the chemotherapy group and non-chemotherapy group did not have statistical significance (P < 0.05), but in Stage IV, it showed a significant difference in the prognosis (P < 0.05). In the conventional radiation therapy and stereotactic radiation therapy groups, the survival rates for the 3-year and the median survival time were 59.5%, 44 months and 80%, 54 months, respectively. It had statistical significance (P < 0.05). However, the efficiency needs further ascertainment since the number of the cases is less.
Results of treatment
At the end of the follow-up, 37 cases were dead, 2 cases were lost and 6 cases survived. 10 patients died of local recurrence. Distant metastases occurred in 18 cases. The cause of death was unknown in 5 cases. Both local recurrence and distant metastasis occurred in 4 cases. The cases with distant metastasis accounted for 59.5% of the total death cases. Pleura and pericardium are the main locations for recurrence.
Discussion
Clinically, thymic carcinoma is a rare malignancy, more common in males of 40-60 years old. Its main clinical manifestations are chest tightness, chest pain, cough, expectoration, fatigue and weight loss, all of which are similar to that of thymoma. Some patients without any symptoms may be found in physical examination inadvertently. A minority may have merged chest syndrome.
Preoperative diagnosis of thymic carcinoma relies mainly on chest CT and chest radiography often shows to have mediastinal mass density without calcification, a serious encroachment of the surrounding organs, and the disappeared fat space. But these signs are not diagnostic for malignant thymoma. Comparatively, malignant thymoma is rare and associated with autoimmune disease, while pleural metastasis of primary and distant metastasis are more commonly seen.
Thymic carcinoma confirmation depend on histopathological examination. In 1999 WHO developed a classification of thymic epithelial tumors. A Muller-Hermelink classification has been used in the pathological classification in accordance with the epithelial cell morphology and a proportion between the epithelial cells and lymphocytes. Thymoma can be divided into A, AB, B1, B2, B3 and C-type. Type C is thymic carcinoma with obvious cell heterogeneit, and there is a loss of the special structure of the thymus and similarity to other organ cancers. In the classification of thymic carcinoma of WHO (2004), it was divided into squamous cell carcinoma, basal carcinoma, mucoid carcinoma, lymphoepitheloid carcinoma, clear-cell carcinoma, adenocarcinoma and undifferentiated carcinoma. In addition, thymus neuroendocrine carcinoma primarily belongs to the malignant epithelial tumors of the thymus. Typical and atypical carcinoids are well-differentiated carcinoid, while small cell carcinoma and large cell carcinoma of neuroendocrine carcinoma are classified as poorly differentiated carcinoid. Pathological types of thymic carcinoma are generally acknowledged to be one of the prognostic factors. The research of Suster and Rosai[2] has proven that the prognosis of the well-differentiated is better than that of the poorly differentiated. In this study we supported this view. Whether Masaoka stage is an important independent prognostic factor or not is also contentious. Some authors[3] reported that there was a correlation in the prognosis of thymoma between the Masaoka stage and WHO histological type. However, this correlation has not been found in the thymic carcinoma. Blumberg et al.[4] reported Masaoka stage and the prognosis of thymic carcinoma were unrelated. The current law of Masaoka stage is equivalent to Masaoka’s revision[5] enacted in 1981. It was divided into four categories of thymoma: Stage I: encapsuled tumor; Stage II: infiltration of mediastinal fat; Stage III: infiltration of neighboring organs; Stage IVa: pleural or pericardial dissemination; and Stage IVb: lymphatic or hematogenous metastases. Stage I is the non-invasive thymoma, Stage II and others are invasive thymomas. As there is a rapid progression in thymic carcinoma, it is difficult to find Stage I. Forty-five cases of thymic carcinoma in this group are in Stage III and IV. Its 3-year survival rate and median survival time were 75.9%, 54 months and 25.0%, 16 months (P < 0.05). The prognosis for Stage III is better than that for Stage IV.
A specialized standard treatment model for thymic carcinoma remains to be developed. Currently the principles used for thymomas have been extended for application on thymic carcinomas. For thymoma, complete surgical resection should be the first choice of the treatment. The extent of surgical resection is the significant prognostic factor for survival[6,7]. But for complete resection of thymic carcinoma there are disputes over the validity. The research does not support its effectiveness. Because of the biological behavior of thymic carcinoma, proportion of candidates, for whom a complete surgical resection can be adopted, is small. This group was 11.1%, radiotherapy, therefore, becomes an important means of treatment.
In this research, the prognosis of patients receiving radiotherapy appears to be much better than that without (Despite the small number in the radiotherapy group; and the results are not statistically significant). Many studies show that postoperative radiotherapy can reduce local recurrence and increase the survival time of patients (8-11 months). Considering a complete surgical excision generally, the total dose of irradiation should reach 45-50 Gy, and partially resected > 50 Gy. Ogawa et al.[8] reported the treatment results of 40 patients with thymic carcinoma. For patients with completely resected tumors, receiving a dose of 50 Gy in the postoperative radiotherapy, there was no local recurrence case. Some people think that for the entire pleural cavity, a 40-Gy irradiation is effective in the prevention of thymic carcinoma recurrence after complete resection. For some with encroachment of the pleura, mediastinal radiotherapy alone prevents the occurrence of pleural-based recurrence. The role of radiotherapy in the treatment of thymic carcinoma should not be neglected. Nonaka et al.[9] reported the results of 12 cases of thymic carcinoma and found that the pleura and pericardium were the main locations of recurrence. One author also reported that dissemination throughout the pleura was the most common type of failure in all the patients with invasive thymoma who received mediastinal irradiation after complete resection. The main sites for recurrence were pleura and pericardium in our research, which is similar to Tetsuo’s, so we need to develop a new programme to reduce the relapse rate. In this research, 5 patients underwent stereotactic radiotherapy, and the survival rate was significantly higher than conventional radiotherapy. Because of this, for patients with advanced thymic carcinoma stereotactic radiation therapy after surgical resection may increase the survival rate.
The status of chemotherapy in the treatment of thymic carcinoma is not clear. Koizumi et al.[10] reported a group of 8 cases of patients with thymic carcinoma on an ADOC (cisplatin, doxorubicin, vincristine, Cyclophosphamide) program. The clinical efficiency was 75%, and the median survival time was 19 months. In light of the above viewpoint, chemotherapy may play a definite role in the clinical treatment. But in this research between the chemotherapy group and the group of non-chemotherapy, P > 0.05, there was no statistical difference between the groups. But for patients with chemotherapy and non-chemotherapy group in Stage IV, P < 0.05, the prognosis was different.
From the analysis, Masaoka stage and histological type affect the prognosis of patients with advanced thymic carcinoma, and stereotactic radiotherapy treatment efficacy is better than that of conventional radiotherapy. The role of chemotherapy should also be further studied. But patients in Stage IV should receive chemotherapy as more as possible. Radiotherapy and surgery with chemotherapy treatment patterns contribute a lot in the prognosis of patients with thymic carcinoma in Stage III-IV.
- Received May 15, 2008.
- Accepted January 7, 2009.
- Copyright © 2009 by Tianjin Medical University Cancer Institute & Hospital and Springer
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