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Eur J Cardiothorac Surg 2002;22:701-707
© 2002 Elsevier Science NL

Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance

^a Department of Thoracic Surgery, University of Torino, 3, Via Genova, 10126 Turin, Italy
^b Department of Pathology, University of Torino, 3, Via Genova, 10126 Turin, Italy

Received 4 September 2001; received in revised form 2 August 2002; accepted 5 August 2002.

* Corresponding author. Tel.: +39-11-633-5919; fax: +39-11-696-0170
e-mail: enrico.ruffini{at}unito.it

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objective: To analyze and compare clinico-pathologic characteristics and survival between lung tumors with mixed histologic pattern and our population of resected lung tumors with single histology in the same period. Methods: From January 1993 to December 1999, 1158 patients received resection for lung tumors. Of these, 59 (5.1%) presented a mixed histologic pattern on the surgical specimen. There were 48 men and 11 women (mean age 64 years, range 43–79). Three groups of tumors were identified: adenosquamous carcinoma, combined neuroendocrine+non-neuroendocrine carcinoma (NNEC) and biphasic tumors (epithelial+mesenchymal malignant components) represented by carcinosarcoma and blastoma. The combined neuroendocrine tumors were further divided in small cell lung carcinoma (SCLC)+large cell neuroendocrine carcinoma (LCNEC)/NNEC and other neuroendocrine tumors/NNEC. Clinico-pathologic characteristics, pTNM and survival were analyzed and compared to our population of resected lung tumors with single histology. Results: There were 33 adenosquamous carcinomas, 19 combined SCLC+LCNEC/NNEC, two other neuroendocrine tumors/NNEC and five biphasic tumors (three carcinosarcomas and two blastomas). Among adenosquamous carcinomas, high cell grading (G2 or G3), advanced stage (IIIa or higher) and intratumoral perineural invasion were significantly more evident than in the single histology population. Among combined neuroendocrine/NNEC, high cell grading (G3) and intratumoral vascular invasion were significantly more evident than in the single histology population. Among biphasic tumors, all were at early stages and showed high cell grading (G3). Three-year survival rates were 46% in the single histology group, 28% in the adenosquamous group and 21% in the combined SCLC+LCNEC/NNEC. The difference among the three groups was significant (P=0.013). Median survival of biphasic tumors was 19 months (range 8–37). Conclusions: Lung tumors with mixed histologic pattern are rare tumors. Adenosquamous carcinoma and combined SCLC+LCNEC/NNEC present a more aggressive clinico-pathologic behaviour and reduced survival as compared to the single histology population of resected lung tumors.

Key Words: Mixed lung tumors • Combined lung tumors • Biphasic tumors • Adenosquamous carcinoma • Neuroendocrine tumors • Carcinosarcoma • Blastoma

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Primary lung cancers can be categorized into four groups according to World Health Organization (WHO) guidelines [1]: these include squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma. In addition to these, there is the heterogeneous group of neuroendocrine tumors of the lung which are currently classified according to Travis et al. [2] and WHO guidelines [1] in typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma.

On several occasions, lung tumors may present a mixed histologic pattern, and these neoplasms have been referred to with various terms as combined or mixed tumors. Few surgical studies have been published investigating clinical, pathologic and prognostic significance of the presence of a dual histologic component on patients submitted to resection for lung tumors.

In the present study we analyzed our patient population of resected pulmonary neoplasms who presented an association of two histologic types on the resected specimen and we investigated the clinico-pathologic characteristics of these tumors and their prognostic significance as compared to the population of resected patients with lung neoplasm and single histology in the same period.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
2.1. Total population
From January 1993 to December 1999 a total of 1237 patients received operation with curative intent for bronchogenic carcinoma. Seventy-nine patients received exploratory thoracotomy and were excluded from the study. The remaining 1158 patients received curative resection of the tumor and were analyzed for the presence of two histologic types on the resected specimen. There were 984 men and 174 women ranging in age from 24 to 82 years with a mean age of 63 years.

Preoperative mediastinal lymphnodal sampling by means of mediastinoscopy or anterior parasternal mediastinotomy were performed selectively in case of enlarged (>1.5 cm) mediastinal lymphnodes at computed tomography scan.

The types of operation performed included 95 sublobar resections, 830 lobectomies, 43 bilobectomies, and 190 pneumonectomies.

On the resected specimen, histologic types and the following pathologic characteristics were analyzed with light microscopic and immunohistochemical techniques: cell differentiation (grading G1 through G3), intratumoral vascular invasion, intratumoral perineural invasion, peritumoral lymphocytic infiltrate, visceral, parietal and mediastinal pleural involvement, the presence of in situ carcinoma, pTNM according to the 1997 revised TNM staging system [3].

2.2. Patients with mixed histologic pattern
Patients with squamous or glandular tumours associated with large cell components were excluded since the large cell population often represents a poorly differentiated aspects of the primary histotype. Pleomorphic carcinoma, carcinoma with spindle cell and giant cell carcinoma were also excluded since the pleomorphic, spindle cells and giant cells components may be considered as different aspects of the primary histotype.

The patients who presented two histologic types on the resected specimen were divided into three groups (Table 1).

1. Adenosquamous carcinoma: include the presence of both squamous and glandular malignant components as defined by the 1999 WHO classification [1].
   
2. Combined tumors: include the association of neuroendocrine tumors and non-neuroendocrine lung carcinoma (NNEC); a further distinction includes small cell lung carcinoma (SCLC) or large cells neuroendocrine carcinoma (LCNEC)/NNEC and other neuroendocrine tumors (typical or atypical carcinoid)/NNEC.
   
3. Biphasic tumors: include neoplasms with an associated epithelial and mesenchymal malignant growth pattern and include carcinosarcoma and blastoma.
   

A probability value less than 5% (P<0.05) was regarded as significant.

Data were analyzed with the use of STATISTICA 1999 edition software (Statsoft, Tulsa, OK).

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Overall, 59 resected pulmonary tumors presented the association of two histologic types. The prevalence of this condition was 5.1% out of our total population of resected lung tumors (59/1158).

There were 48 men and 11 women with a mean age of 64 years (range 43–79 years).

In all patients in whom a cytologic or histologic diagnosis was obtained before resection, the pathologist's response was that of undifferentiated carcinoma or non-small cell lung carcinoma.

The population of patients with the association of two histologic types was analyzed according to the three histologic groups, adenosquamous, combined and biphasic.

3.1. Adenosquamous tumors group
Thirty-three patients presented with an adenosquamous carcinoma. The prevalence of this tumor was 2.8% out of our total population of resected lung tumors. The clinical characteristics of the adenosquamous group are shown in Table 2, along with a comparison between the adenosquamous group and our single histology population of resected lung tumors patients in the same period.

Sex, mean age and type of resection did not differ between the two groups. All adenosquamous tumors showed a moderate or poor cell differentiation (G2 or G3 grading). Mean tumor size was 4 cm (range 2–11 cm). A significantly higher prevalence of advanced stages (IIIa through IV) was observed in the adenosquamous group (P=0.0001) as compared to the single histology population.

Among the light microscopic pathologic characteristics examined, only intratumoral perineural invasion was significantly more evident in the adenosquamous group (Table 3) (P=0.02).

Fig. 1 shows comparison of survival rates among the adenosquamous group, the combined SCLC+LCNEC/NNEC group and our single histology population of resected lung tumors patients in the same period.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Comparison of survival curves among the patients with adenosquamous carcinoma (N=33), combined SCLC or LCNEC/NNEC (N=19) and the single histology population of resected lung tumors (N=1099). P=0.013. Patients at risk at 3-year: adenosquamous, 1; combined SCLC or LCNEC/NNEC, 1; single histology, 489.

Pattern of relapse was investigated in the two groups. Among 33 adenosquamous carcinoma, 20 patients died (14 with distant metastases and six with local relapse). Five out of 13 patients are alive at follow-up with recurrence (three distant and two local). Among 19 combined SCLC or LCNEC/NNEC, ten patients died, eight with distant metastases and two with local relapse. Six out of nine patients are alive at follow-up with recurrence (four distant and two local).

Among the five patients with biphasic tumors, one patient was lost to follow-up, one patient died after 2 years (distant metastases were recorded 11 months earlier) and three patients are alive and disease-free after 8, 14, and 37 months; median survival was 19 months.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
In the present study we report our experience on operated lung tumors which presented a mixed histologic pattern on the resected specimen. We classified these tumors into three groups, adenosquamous, combined neuroendocrine and biphasic.

Adenosquamous tumors include the presence of both squamous and glandular malignant components.

Combined tumors include a combination of a neuroendocrine tumor and either a squamous cell carcinoma or adenocarcinoma.

Biphasic tumors include the presence of both epithelial and mesenchymal malignant components.

The true prevalence of lung tumors with mixed histologic pattern is unknown but probably in the range of 2–4%. Our prevalence on a population of 1158 resected lung tumors was 5% (59 patients).

The first group of tumors with mixed histologic pattern is the adenosquamous carcinoma. Although well described in its morphologic, immunohistochemical and ultrastructural aspects, adenosquamous carcinomas have received far less attention in its clinical and prognostic aspects in the recent past.

Naunheim and associates in 1987 [5] reported on 20 patients with adenosquamous carcinoma, and pointed out an aggressive behaviour for this subtype of lung carcinoma; 75% of their patients were at Stage III and only nine patients could receive a surgical treatment. Median survival was 5 months for Stage III disease despite the use of multimodality treatment. Only three out of five patients with Stage I disease were alive and disease-free between 1 and 6 years postoperatively. The authors concluded that adenosquamous carcinoma is a subtype of non-small cell lung carcinoma with an aggressive behaviour and poor survival. Sridhar and associates in 1990 [6] examined clinical features of 127 patients with adenosquamous carcinoma, of whom only 38 received curative resection. The authors emphasized that early stages are infrequent at presentation, and the vast majority of the patients presented with loco-regional or distant spread (Stage IIIa through IV). However, survival rates in the surgically treated patients were similar to those of resected NSCLC. Similar conclusions were reached by Ishida and associates in 1992 [7] on 11 patients who received resection for adenosquamous carcinoma. Their prevalence out of the total population of resected lung carcinoma was 1–2%. More than half of the patients were at advanced stages; nonetheless, 5-year survival rate was 35%, not significantly different from survival of adenocarcinoma and squamous cell carcinoma. The authors of the two studies agree in the conclusion that it is reasonable to treat adenosquamous carcinoma similarly to other NSCLC. The most recent studies on adenosquamous carcinoma were published in 1994 by Hofmann and associates [8] and in 1999 by Hsia and associates [9]: the first reported a 28% 3-year survival rate with no 5-year survivors in a series of 13 patients; the second reported a 22% 5-year survival in a series of 39 patients. The latter observed no significant survival differences between adenosquamous carcinoma, adenocarcinoma and squamous cell carcinoma.

Our results on 33 patients with adenosquamous carcinoma are very similar to the previous studies. Our prevalence out of our total population of resected lung tumors is 2.8%, in the range of that reported by other authors. About 60% of the patients presented at an advanced stage, and light microscopic pathologic examination revealed a significantly higher prevalence of intratumoral perineural invasion as compared to the total population. Despite this morphological and clinical aggressive tendency, a curative resection could be accomplished in all patients. Three-year survival rate was significantly lower than that of the single histology population of resected lung carcinoma. To conclude, adenosquamous carcinoma is an aggressive subtype of lung carcinoma with a distinct tendency to loco-regional and distant spread and poor prognosis.

The second group of lung tumors with mixed histologic pattern include the combined tumors, in which one component is represented by a neuroendocrine tumor.

The recent guidelines from WHO [1] and other series [2,10] including a recent multicenter Spanish study based on analysis of pathologic prognostic factors [11] include categorization of neuroendocrine tumors into four types: typical carcinoid, atypical carcinoid, LCNEC, SCLC. Occasionally, neuroendocrine tumors may be combined with either squamous cell carcinoma or adenocarcinoma (NNEC).

A further distinction should be made between combined SCLC+LCNEC/NNEC and the remaining neuroendocrine combined tumors (typical or atypical carcinoid)/NNEC.

Combined SCLC tumors are rare: the most recent classification of SCLC as proposed by the International Association for the Study of Lung Cancer [12] considers it as one of the three subtypes of SCLC: pure, mixed small/large cell, and combined SCLC. Combined SCLC are SCLC admixed with a component of squamous cell carcinoma and/or adenocarcinoma.

Very few studies exist in the literature regarding clinical and prognostic aspects of patients with combined SCLC. In the clinical practice of pulmonary oncology, it is crucial to know if combined SCLC behaves clinically like pure or mixed SCLC or like pure NSCLC; how the SCLC component affects long-term outcome, and what is the role of surgery for this kind of neoplasm. In 1989 Mangum and associates [13] reported on nine patients with combined SCLC: of these, five had extensive disease and four had limited disease. Surgery was performed in four patients of whom two survived 5 years. The authors conclude that in very selected cases surgery may yield long-term survival in these subgroup of SCLC which should be considered clinically similar to pure SCLC. In a recent report, Hage and associates [14] examined 26 patients with combined SCLC of whom 21 were associated with squamous cell carcinoma, four with adenocarcinoma and one with adenosquamous carcinoma. A total of 42% of the patients were at Stage III. Survival was 31% for pStage I while no 5-year survivors were observed in Stages II and III. The authors conclude that combined SCLC behaves similarly to pure SCLC and surgical resection should be considered in highly selected patients with clinical pretreatment Stage I.

Contrary to pure and mixed small cell/large cell SCLC, combined SCLC or LCNEC/NNEC represent a unique group of patients to be considered for surgery, in whom the diagnosis of the SCLC or LCNEC component is frequently made after resection and represents an unexpected finding following surgery for bronchogenic carcinoma. This occurred in more than half of the patients in the series of Hage and in all our patients. Nonetheless, in our series one-third of the patients were at Stage III, and in about 40% of the cases pneumonectomy was required to achieve a curative resection. Light microscopic pathologic examination revealed a strong prevalence of intratumoral vascular invasion. Three-year survival was 21% and we observed no 5-year survivors.

Our results therefore, in accordance to other authors’ experience, indicate that in combined SCLC or LCNEC/NNEC the SCLC and LCNEC components strongly influence outcome: combined SCLC even if diagnosed postoperatively carries a poor prognosis and survival rates are more similar to pure SCLC than to non-small cell carcinoma. The role of adjuvant chemotherapy is still under debate and needs to be clarified.

The combined carcinoid (typical or atypical)/NNEC tumors are exceedingly rare. Only scattered reports exist in the literature on this association [15]. They may be associated with either squamous cell carcinoma or adenocarcinoma. Our two patients (one typical carcinoid and one atypical carcinoid) were at early stage and both were peripheral tumors who could be resected with a lobectomy. Both are alive and disease-free 2 and 6 years after surgery.

The third group of lung tumors with mixed histologic pattern includes the biphasic tumors, in which there is an admixture of malignant epithelial and mesenchymal growth pattern. Two histologic entities have been described, carcinosarcoma and blastoma. Biphasic tumors are extremely rare [16] and together comprise less than 2% of all lung neoplasms [17,18]. The most comprehensive review on these tumors is the report of Berho and associates in 1995 [19] who discussed the histologic, clinical and prognostic aspects of carcinosarcoma and blastoma.

Carcinosarcomas are aggressive tumors with a tendency to a rapid loco-regional and distant spread [20]. Surgery is the treatment of choice, although survival is poor, and less than 10% of the patients survive 2 years. Blastoma are tumors in which the glandular or mesenchymal malignant component is primitive or embryonal in appearance: these are aggressive tumors with rapid growth and intra or extrathoracic spread and their primary treatment is surgical.

Our series of biphasic tumors comprises three carcinosarcomas and two blastomas. All patients were at early stages (I and II). Two patients with carcinosarcoma are alive and disease-free after 7 and 14 months (one was lost to follow-up). Of the two patients with blastoma one died after 24 months and one is alive and disease-free after 37 months. Although limited, results from our series of patients with biphasic lung tumors confirm other authors’ experience.

In conclusion, lung tumors with mixed histologic pattern are a rare occurrence. Very often, the dual histology is not known preoperatively and becomes evident on the resected specimen. Adenosquamous carcinomas are at advanced stages at presentation, show an aggressive histologic behaviour, and have survival rates significantly lower than the single histology group. Combined SCLC or LCNEC/NNEC show clinical, histologic and prognostic characteristics which are more similar to pure SCLC than non-small cell carcinoma. Biphasic tumors are usually aggressive tumors, although in very selected cases occasional long-term survivors may be observed following resection.

	Footnotes

 
Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Dr J. Hasse (Freiburg, Germany): In those cases with a mixed histology, did the metastatic lymph nodes, there were some, reflect the mixed histology as well, or was the histology of the metastases different from the primary tumor?

Dr Ruffini: No. Usually in the metastatic nodes the histology was pure, not mixed.

Dr Hasse: With a predominance of the small cell component probably?

Dr Ruffini: Yes, probably, because of the high aggressiveness of the tumor in the combined group.

Dr P. Thomas (Marseille, France): Did you perform a multivariate analysis to weight the prognostic significance of this particular histologic pattern in comparison with those of lymph node involvement and blood vessel invasion?

Dr Ruffini: No, we did not perform a multivariate analysis because the three groups are heterogenous. So I don't think it would make any sense to do a multivariate analysis.

	References

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