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Ann Thorac Surg 1999;68:227-231
© 1999 The Society of Thoracic Surgeons

Original Articles

Prognostic factors and results after surgical treatment of primary sarcomas of the lung

Jean-François Régnard, MDa, Philippe Icard, MDa, Lionel Guibert, MDa, Vincent Thomas de Montpreville, MDb, Pierre Magdeleinat, MDa, Philippe Levasseur, MDa

a Department of Thoracic Surgery, Marie Lannelongue Hospital, Le Plessis Robinson, France
b Department of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France

Address reprint requests to Dr Régnard, Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, 133 avenue de la résistance, Le Plessis Robinson 92350, France


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Primary sarcoma of the lung is a rare tumor. Our purpose was to study survival after resection and prognostic factors, which have been rarely reported.

Methods. In a 24-year period, we performed 20 complete resections and three exploratory thoracotomies only for primary lung sarcomas. One patient declined operation. Mean diameter of resected tumors was 9 cm (range, 4 to 18 cm). There were eight stage IB, eight stage IIB, one stage IIIA, and three stage IIIB. Sixty percent of patients with resected tumors received adjuvant therapy. Age, sex, resectability, tumor size, histologic cell type, stage, and adjuvant therapy were analyzed as predictors of survival.

Results. No postoperative deaths occurred. All 4 patients who had no resection died within 15 months. The 5- and 10-year actuarial survival after complete resection was 48%. The 5- and 10-year actuarial survival in stage IB was 83%, whereas the 4-year actuarial survival in stage IIB was 30% (p < 0.05). Complete resection and stage of disease were the sole significant prognostic factors.

Conclusions. Complete resection of primary sarcoma of the lung, when feasible, can achieve prolonged survival, although almost half of the patients died of metastasis within 2 years of operation. Adjuvant therapy needs to be investigated.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Primary sarcoma of the lung is a rare tumor, accounting for 0.013% to 0.4% of all lung malignancies [1, 2], and it has been estimated that there are 500 carcinomas for every sarcoma of the lung [3]. Because of the rarity of this tumor, experiences with its treatment, particularly with its surgical resection, are uncommon [1, 4–6]. The purpose of this study was to report the survival rates and prognostic factors of 24 patients who were treated in our department.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
In a 24-year period (1973 to 1997), 24 patients with primary sarcoma of the lung were consecutively treated in our thoracic department. There were 16 men and 8 women, with a mean age of 48 years (range, 14 to 73 years). Twenty patients presented with thoracic symptoms such as hemoptysis in eight cases, cough in six, chest pain in five, and hemopneumothorax in one, with associated systemic symptoms in six cases, such as fatigue, malaise, fever, or weight loss. Four patients had no symptoms, and their lesions were detected by routine chest roentgenogram. Nine patients (37.5%) were smokers. All lesions were solitary masses. The mean diameter of tumors was 9 cm (range, 4 to 18 cm). Eleven sarcomas involved the right lung and 13 the left lung. Preoperative diagnosis of malignant tumor was established in 13 patients by biopsy specimen taken through flexible bronchoscopy, with a correct preoperative diagnosis of sarcoma in nine of these 13 cases. In 15 cases (62.5%), no diagnosis of sarcoma was obtained until operation, and all these patients were operated on because of a suspected preoperative diagnosis of lung carcinoma.

Treatment
One patient declined operation, despite a relatively localized tumor (patient 3, Table 1), and 23 patients were operated on. Exploratory thoracotomy only was the sole available procedure in 3 patients because of extensive mediastinal invasion precluding resection. Twenty patients (83%) had complete resection of their tumors (Table 1). These resections included 13 lobectomies with extension to the chest wall in six cases and to the pericardium and the phrenic nerve in one case, and seven pneumonectomies with extension to the pericardium in five cases, and to the left atrium in one case. Twelve of the 20 (60%) patients who had complete resection received adjuvant therapy (radiotherapy in 5 patients, chemotherapy in 5, both treatments in 2).


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  		Table 1. Patient Characteristics

 
Tumor characteristics
All specimens were systematically reviewed by a pathologist who used immunohistochemical analysis, and patients with sarcomatoïd lung cancer and carcinosarcomas (three cases) were excluded. For histologic classification, the basic criteria and nomenclature used were those applied in the revised World Health Organization classification of soft tissue tumors [7]. In most cases, the histologic type was decided on the basis of hematoxylin and eosin stained slides and of various immunohistochemical stains. In some cases, special stains were used, including trichrome, reticulin, periodic acid-Schiff with and without diastase and alcian blue. Immunohistochemical examinations were done with the following primary antibodies used at the indicated dilution: mouse monoclonal anti-human desmin (Dako; dilution 1/25; Dako, Trappes, France), monoclonal mouse anti-human epithelial membrane antigen (Dako; dilution 1/50), mouse monoclonal anti-human muscle actin HHF-35 (Dako; dilution 1/25), monoclonal mouse anti-vimentin (Dako; dilution 1/5), rabbit anti-cow S-100 protein (Dako; dilution 1/200), monoclonal mouse anti-cytokeratin (KL1 Dako; dilution 1/50), rabbit anti-human neuron-specific enolase (Dako; dilution 1/50), monoclonal mouse anti-human melanoma (HMB-45) (Dako; dilution 1/10), mouse monoclonal anti-human CD 34 (Immunotech; dilution 1/25; Roissy CDG, France), and rabbit polyclonal anti-F VIII (Dako; dilution 1/100). Histologic diagnosis was fibrosarcoma in 10 patients, malignant fibrous histiocytoma in 4, angiosarcoma in 2, leiomyosarcoma in 3, synovial sarcoma in 3, and Ewing sarcoma in 2. In these last five cases, the diagnosis of primary sarcoma of the lung was made because most of the tumor was located in the lung and because the patients had no histories of other primary sarcomas.

Tumors were scored in three grades according to the classification of the French Federation of Cancer Centers, reported by Coindre and associates [8], with the score based on tumor differentiation, mitosis count, and necrosis. No tumors were scored in grade 1, and 20 tumors were classified in the highest grade of malignancy, ie, grade III, and four in grade II.

According to the recently revised TNM classification for lung cancers [9], the 20 resected tumors were classified as follows: eight stage IB (eight T2N0), eight stage IIB (seven T3N0, one T2N1), one stage IIIA (one T3N2), and 3 stage IIIB (two T4N1, one T4N2).

Statistical analysis
All patients were followed up either until death or the completion of the study (May 1998). All deaths were attributed to malignancy. Sex, age, resectability, tumor size (less than or greater than 5 cm), histologic cell type, stage, and adjuvant treatment were analyzed as predictors of survival. Survival rates were obtained according to the actuarial method derived from the Kaplan-Meier method [10], and survival differences between subgroups were compared with the log-rank test. A p value less than 0.05 was considered to be significant.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
There were no operative deaths. All 4 patients who did not have complete resection died within 15 months (median survival, 14 months). Ten of the 20 patients who had complete resection died of cancer, 9 of them within 2 years of operation and one 11 years after the operation. The site of metastases was the brain in three cases, the lung in one case, the brain and the lung in two cases, the bone in one case, and disseminated in three cases. Only one of these patients had an associated local recurrence. Ten patients are currently alive, 9 of them free of disease and the remaining one (patient 19) with disseminated bone and pulmonary metastases. However among the 9 patients currently alive, 2 patients had reoperation for complete resection of a localized metastasis, in the adrenal gland in one instance (patient 12) and in the pleural space in the other instance (patient 14). The overall actuarial 5-year survival rate was 42%. The 1-, 5-, and 10-year actuarial survival rates for the 20 patients who had complete resection were 67%, 48%, and 48%, respectively, which was significantly higher (p < 0.001) than that of the 4 patients who did not have resection, who demonstrated 1- and 2-year survival rates of 75% and 0%, respectively (Fig 1). As indicated in Figure 2, the only factor significantly influencing survival after complete resection was the stage of disease. The actuarial 5- and 10-year survival rate in stage IB was 83%, whereas the actuarial 3- and 4-year survival in stage IIB was 30%, with no patient alive for 5 years at the completion of the study (p < 0.05). The sole patient with stage IIIA disease (patient 13) died of brain metastases 2 months after the operation. Two of the three patients with stage IIIB disease died within 5 months and 8 months after the operation and the remaining one is still alive 19 months after operation. When studying the influence of T and N factors independently, there was a significant difference in survival between T2 and T3 tumors (p = 0.01). In contrast, no significant difference in survival was observed between N0 and N1 disease, with only five cases of positive nodes (three N1 and two N2) for comparison. Other factors such as sex, age, tumor size (less than or greater than 5 cm), histologic subtype, and adjuvant therapy did not influence survival.



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  		Fig 1. Actuarial survival of patients with primary lung sarcomas who had resection or no resection. Numbers in parentheses indicate patients at risk.

 


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  		Fig 2. Actuarial survival of patients with stage IB and stage IIB primary lung sarcomas. Numbers in parentheses indicate patients at risk.

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Sarcomas are mesenchymal tumors that rarely occur in the lung in comparison with some other anatomic sites, such as soft and bone tissues. They originate from the stromal elements of the bronchial or vascular wall or from the interstices of lung parenchyma. They usually expand toward lung parenchyma, giving well-circumscribed but unencapsulated tumors that occasionally expand intrabronchially. However, they rarely invade the bronchial epithelium, leading to exfoliating cells [11]. Dail [12] classified soft-tissue sarcomas originating within the lung into three groups, parenchymal and bronchial-endobronchial sarcomas, sarcomas of large vessel origin, and sarcomas of small vessel origin.

As indicated by Burt and Zakowski [13], prior to 1975 the descriptions of patients with primary sarcoma of the lung were confusing because they included the lymphoproliferative disorders, as in Hochberg and Crastnopol’s report [14], which included 34% lymphomas. However, since 1931, at least 221 true primary lung sarcomas have been reported, generally as case reports [13]. One of the largest series came from the Armed Forces Institute of Pathology, in which 32 primary sarcomas of the lung were reported in 1972 [2]. More recently, three series [4–6] reported 18, 42, and 22 patients with primary lung sarcomas, respectively, collected during periods of 28 years, 62 years, and 32 years, respectively (Table 2). As most malignant mesenchymal tumors of the lung are secondary metastases, a solitary sarcoma of the lung should be considered as primary only if thorough investigation failed to discover a primary lesion elsewhere, metastasizing to the lung through the hematogenous route. However, as emphasized by Nascimento and colleagues [4], most metastatic sarcomas are usually expressed in the lung as multiple nodules, and extrathoracic sarcomas seldom are occult.


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  		Table 2. Resectability and Prognostic Factors in Primary Sarcomas of the Lung

 
Although the diagnosis of sarcoma is primarily a histologic one, some differences between sarcomas and carcinomas can help to predict the diagnosis before operation. In contrast with lung carcinomas, where most patients had previous history of tobacco use, only 37.5% of our patients presenting with sarcomas were smokers. Furthermore, despite the fact that most of our patients presented with large tumors (mean diameter, 9 cm), endobronchial invasion was seen on flexible bronchoscopy in less than 50% of them, allowing a correct preoperative diagnosis of sarcoma in only nine cases (37.5%). Small biopsy specimens are less likely to be representative of the lesion as a whole and can lead to errors in diagnosis and grading, particularly in situations where the pathologist relies more heavily on the pattern of the lesion than on the features of the individual cells, which is often the case in these tumors. Preoperative diagnosis presumably could be obtained more often by transcutaneous core biopsy, although all preoperative biopsy procedures might not yield sufficient material for additional techniques which are necessary in most cases, because all of the major histologic subtypes of non-small cell carcinoma can occasionally show either focal or extensive spindling of neoplastic cells. With various immunohistochemical stains and sometimes with electron microscopic examination, it is now possible to separate epithelial tumors from sarcomas and to determine precisely the subtype of sarcomas. Sarcomas have a typical vimentin-positive staining and an anti-keratine KL1 and an anti-EMA–negative presentation. However, a variety of mesenchymal tumors, such as neural or smooth muscle tumors, can express epithelial markers. Although CD 31 is currently considered to be the most reliable marker for endothelial differentiation, we used FVIII as an endothelial marker in our study because it was the only marker available at that time.

In contrast with other series [2, 4–6], we had no patients with small size sarcomas limited to the endobronchial lumen; those lesions are known to have a better prognosis with generally a good outcome and rare metastases than larger intraparenchymal sarcomas [2, 6, 12]. The smallest tumor size in our series was 4 cm (two cases). In contrast, 28% (5 of 18) of the patients in the series of Nascimento and colleagues [4] had tumors 4 cm or less, and the median diameter of tumor was 4 cm (range, 1.5 to 20 cm) in the series of Janssen and colleagues [6].

In contrast also to the findings of MacCormack and Martini [5], who noted pulmonary sarcoma metastases by the bloodstream but rarely by the lymphatic system, we found that nodal involvement was not so rare, with 25% (five of 20) of our operated cases having positive nodes.

Resectability and survival
Resection is the best option when possible. We obtained a high rate of complete resection (83%) despite a high frequency of large tumors (Table 2). The fact that only 1 patient in our series had a local recurrence led us to believe that we had achieved complete resection of tumors with adequacy in most cases. In our series, the 5- and 10-year actuarial survival after complete resection was 48%. MacCormack and Martini [5] reported a 69% rate of resection with 36% of those patients alive at 5 years. Janssen and colleagues [6] reported a 50% rate of complete resection with 64% of these patients (seven of 11) alive at a mean follow-up time of 13.5 years (range, 3 to 25 years).

The present study showed that the prognostic influence of the American Joint Committee on Cancer/Union International Contre le Cancer (AJCC/UICC) staging system for lung cancers when applied to primary pulmonary sarcomas. The 5-year actuarial survival rate was 83% in stage IB, which is significantly better than survival for more advanced stages of disease. We found that the influence of the tumor extent was dominant in comparison with the influence of the nodal status, however, only 5 patients in this series had positive nodes, which makes difficult any comparison.

The survival of patients who were deemed inoperable or who did not undergo resection was poor, with all of them dying within 2 years, in our series and others [5, 6]. In the study by MacCormack and Martini [5], radiation therapy had no effect on survival. In cases of incomplete resection, whether adjuvant therapy prolongs survival remains questionable. Multiple drug therapy was attempted in incomplete resection by Janssen and colleagues [6], with rare prolonged survival.

Prognostic factors
Size
In our series, because no tumor was less than 4 cm, a size which has been of prognostic value in the literature [6], we could not study the influence of this factor. However, we did not find any difference in survival between patients with sarcomas less than or greater than 5 cm in diameter. The influence of the size on prognostic has been debated. For MacCormack and Martini [5], size (less than or greater 5 cm) did not influence survival (p = 0.2), whereas sizes larger than 4 cm for Janssen and colleagues [6] and larger than 5 cm for Nascimento and associates [4] indicated poor prognosis. In the series of Nascimento and associates [4], all 11 patients with sarcomas of 5 cm or larger died, most of them with intrathoracic recurrence, and in the series of Janssen and colleagues [6], the median survival for patients with tumors larger than 4 cm was only 23 months.

Grade
In our study, most tumors were high-grade malignancies, unlike sarcomas occurring in other sites. Because none of our patients had a low-grade sarcoma, with no cases of small and limited endobronchial form, we could not study the influence of tumor grade. In the literature [6, 12, 13], sarcomas with low-grade malignancy have been considered to have a better prognosis than those with a higher grade. Although no large series of small and limited endobronchial tumors has been reported, it seems that these tumors, which are generally easy to resect radically, correlate with low grade and with long-term survival [2, 4]. However, in our study, unlike other sarcoma sites, low- versus high-grade malignancy did not play such an important part in the prognostic factors.

Histologic form
Similar to other studies [1, 2, 4–6], we did not find any prognostic significance from the histologic type of sarcoma, but because of the small number of patients in all series and the difficulties in arranging subgroups, we must be careful before jumping to definitive conclusions.

Finally, in our experience, only complete resection and low stage of primary lung sarcoma favorably influenced survival. Because almost half the patients we treated died of metastasis within 2 years of operation, multiple drug therapy needs to be investigated for improving survival.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Martini N., Hajdu S.I., Beattie E.J. Primary sarcoma of the lung. J Thorac Cardiovasc Surg 1971;61:33-38.[Medline]
  2. Guccion J.G., Rosen S.H. Bronchopulmonary leiomyosarcoma and fibrosarcoma. Cancer 1972;30:836-847.[Medline]
  3. Iverson L. Bronchopulmonary sarcoma. J Thorac Surg 1954;27:130-148.
  4. Nascimento A.G., Unni K.U., Bernatz P.E. Sarcomas of the lung. Mayo Clin Proc 1982;57:355-359.[Medline]
  5. McCormack PM, Martini N. Primary sarcomas and lymphomas of the lung. In: Martini N, Vogt-Moykopf I, eds. Thoracic surgery: frontiers and uncommon neoplasms. Vol. 5. St. Louis: CV Mosby, 1989:261–83.
  6. Jansen J.P., Mulder J.J.S., Wagenaar S.S., Elbers H.R., Van den Bosch J.M. Primary sarcoma of the lung. Ann Thorac Surg 1994;58:1151-1155.[Abstract]
  7. Weiss S.W. Histological typing of soft tissue tumours, 2nd ed. Berlin, Heidelberg: Springer-Verlag, 1994.
  8. Coindre J.M., Trojani M., Contesso G., et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 1986;58:306-309.[Medline]
  9. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  10. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-481.
  11. Shields T.W., Robinson P.G. Benign and less common malignant tumors of the lung. In: Shields T.W., ed. General thoracic surgery. New York: Lea & Febiger, 1989:935-950.
  12. Dail D.H. Uncommon tumors. In: Dail D.H., Hammar S.P., eds. Pulmonary pathology. New York: Springer-Verlag, 1987:928-941.
  13. Burt M., Zakowski M. Rare primary malignant neoplasms. In: Pearson F.G., Deslauriers J., Ginsberg R.J., McKneally N.F., Urschel H.C., eds. Thoracic surgery. New York: Churchill Livingston, 1995:808-826.
  14. Hochberg L.A., Crastnopol P. Primary sarcoma of the bronchus and lung. Arch Surg 1955;73:74-98.
Accepted for publication February 9, 1999.




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