HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joseph Zacharias George P. Ladas Peter Goldstraw Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zacharias, J. Articles by Goldstraw, P. Search for Related Content PubMed PubMed Citation Articles by Zacharias, J. Articles by Goldstraw, P. Related Collections Lung - cancer

Ann Thorac Surg 2003;75:348-352
© 2003 The Society of Thoracic Surgeons

---

Original article: general thoracic

Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection

^a Department of aThoracic Surgery and bHistopathology, Royal Brompton Hospital, London, United Kingdom

Accepted for publication July 26, 2002.

* Address reprint requests to Mr Goldstraw, Department of Thoracic Surgery, Royal Brompton Hospital, Sydney St, London SW3 6NP, United Kingdom.
e-mail: p.goldstraw{at}rbh.nthames.nhs.uk

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) and large cell carcinoma with neuroendocrine morphology of the lung are both currently classified as subtypes of large cell carcinomas according to the World Health Organization IASLC classification system for lung and pleural tumors. Prognosis is reported as similar to that of small cell carcinomas. There is no consensus on management of this subset and adjuvant chemotherapy is recommended by some for early stage LCNEC to impact long-term prognosis. We retrospectively reviewed a cohort of patients at our institution who had this type of tumor to determine factors that might influence survival.

METHODS: Twenty-one cases of LCNEC and large cell carcinoma with neuroendocrine morphology were identified in the files of the Royal Brompton Hospital between 1986 and 1999. All patient data were reviewed, and complete follow-up was achieved with 20 of these patients.

RESULTS: Of the 21 patients identified, 20 underwent resection with systematic nodal dissection in 18. There was no in-hospital mortality. Of those patients fully staged by systematic nodal dissection, 9 were stage I, 5 were stage II and 4 were stage III. Median follow-up was 25 months (range, 2 to 120 months). At the time of review, 11 patients were alive and free of disease. One patient was alive and free of disease when lost to follow-up. Nine patients had died, 7 related and 2 unrelated to disease. The 5-year actuarial survival for the entire group was 47%. The actuarial survival of accurately staged, stage I patients at 5 years was 88%. The actuarial survival of patients in stage II and III was 28% at 5 years.

CONCLUSIONS: LCNEC and large cell carcinoma with neuroendocrine morphology are aggressive tumors, but patients with completely resected disease after systematic nodal dissection have a better prognosis than previously described. Patients with more advanced disease have a poor prognosis.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The prognostic relevance of classifying neuroendocrine tumors in the lung has changed significantly since Travis and colleagues [1] introduced the concept of large cell neuroendocrine carcinoma (LCNEC) as a subgroup of neuroendocrine tumors. LCNEC, being distinguishable from typical carcinoids, atypical carcinoidsm and small cell carcinoma. This is supported by later studies [2, 3], confirming that prognosis varies between the different subgroups, and also that such a classification system is reproducible [4]. However in 1999 the World Health Organization IASLC classification of lung and pleural tumors classified large cell neuroendocrine carcinoma on morphologic grounds as a type of large cell carcinoma, recognizing LCNECs as tumors with both neuroendocrine morphology and immunohistochemical evidence of neuroendocrine differentiation. Those tumors with neuroendocrine morphology that lack immunohistochemical evidence of neuroendocrine differentiation are termed large cell carcinomas with neuroendocrine morphology (LCCNM) [5]. Prognostic data on LCNECs are limited and most series are small [1, 2, 6], despite collections of cases from multiple institutions [3] with even less data on the clinical relevance of subclassification as LCCNM [7]. Use of the term large cell carcinoma with neuroendocrine features has been suggested to encompass both these tumor types as clinical behavior is similar [7]. The purpose of this study was to report our experience of these tumors, in particular to assess the importance of such classification in relation to prognosis.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
A retrospective review of resection specimens from nonsmall cell tumors with neuroendocrine morphology was undertaken from the case records of the Royal Brompton Hospital between 1986 and 1999. Twenty-five cases showed morphologic evidence of neuroendocrine differentiation as described by Travis and colleagues [1]. Of these, 9 had previously been classified as atypical carcinoids, but a mitotic count of greater than 10 per 2 mm² led to reclassification as either LCNEC or LCCNM. Three cases were rejected because they were mixed tumors with the second component as small cell carcinoma. A fourth case was rejected because no material was available for immunohistochemical analysis. An immunohistochemical panel comprising CD56 (dilution 1:100 Novocastra; UK), chromogranin (dilution 1/20; Dako; UK), and synaptophysin (dilution 1/100; Dako; UK) was subsequently applied to look for immunohistochemical evidence of neuroendocrine differentiation with subsequent subdivision into either LCNEC (neuroendocrine marker positive) or LCCNM (neuroendocrine marker negative).

The notes of these patients were reviewed and clinical data comprising sex, age, symptoms at presentation, preoperative staging investigations, type of resection, postoperative staging, morbidity and mortality, and follow-up details were collected.

Statistical analysis
Statistical analysis was carried out on the follow-up details using an SPSS package (SPSS Inc, Chicago, IL). We used the Kaplan-Meier survival curves for calculating actuarial survival of the accurately staged patients (n = 18 patients). We also compared actuarial survival between patients (n = 9 patients) proven to be in Stage I by systematic nodal dissection (SND) and patients (n = 11 patients) not in stage I. Actuarial survival was also compared between the LCNEC group (15 patients) and those classified as LCCNM (6 patients). We used the log rank test to see if the survival was significantly different between the groups.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Pathology
The pathologic data are presented in Table 1. Of the 21 tumors, 15 patients showed immunohistochemical evidence of neuroendocrine differentiation and were classified as LCNEC, with the remainder classified as LCCNM. Mitotic counts ranged form 21 to 140 (average, 66) per 2 mm². Extensive necrosis was present in 20 of 21 patients. The architecture was either solid islands of tumor with peripheral palisading or cribriform.

All 21 patients proceeded to thoracotomy. One patient was found to be unresectable at the time of operation because of the involvement of mediastinal structures. Of the remaining 20 patients, 2 underwent pneumonectomy, 16 had lobectomy, 1 had a segmental resection, and 1 had a wedge resection. Eighteen patients had systematic nodal dissection at the time of resection. Two patients were operated on before the practice of regular systematic nodal dissection, although they did not have lymph node sampling. Data are summarized in Table 1.

Of the 21 patients identified, 18 patients were considered to have been accurately staged by their preoperative and intraoperative evaluation. The TNM details are given in Table 1. Stage distribution using the 1997 TNM system for classification of lung cancers [8] showed 1 patient at stage Ia, 8 patients at stage Ib, 0 at stage IIa, 5 at stage IIb, 2 at stage IIIa, and 2 at stage IIIb. Two patients who did not have any lymph node sampling were considered to be inaccurately staged and were not included in the initial survival calculations.

Follow-up data
The follow-up for this group ranged from 1.5 months to 120 months. The median follow-up time was 25 months. One patient was lost to follow-up at 37 months, at which time he was alive and disease free. Of the 20 with complete follow-ups 11 were alive and disease free, 7 were dead from their disease, and 2 had died from other causes. The Kaplan-Meier survival curve for the 18 accurately staged patients with complete resection was 47% at 5 years as shown in Figure 1. Patients not having SND were included in the second calculation that looked at a difference between recurrence-free survival in patients with accurate early stage disease (stage Ia and Ib; 9 of 20) compared with patients in other stages (11 of 20), and found a significant difference in survival (Fig 2). Actuarial survival of patients with pathologic diagnosis of LCCNM and LCNEC were found to be similar at 63% and 52%, respectively (Fig 3). The log rank test was used to look for significance between the groups.

View larger version (10K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival estimates for all 18 accurately staged patients with large cell neuroendocrine carcinoma.

View larger version (14K): [in this window] [in a new window]   Fig 2. Disease-free survival for 9 early stage patients (stage Ia & Ib) with large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology compared with 11 patients with non-early stage disease (log rank test = significant; p = 0.0075). (SND = systematic nodal dissection.)

View larger version (14K): [in this window] [in a new window]   Fig 3. Kaplan-Meier survival estimates for all patients comparing survival between large cell neuroendocrine carcinoma (LCNEC) (15 patients) and large cell carcinoma with neuroendocrine morphology (LCCNM) (6 patients). (Log rank test = not significant; p = 0.54.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The World Health Organization IASLC (International Association for Staging of Lung Cancer) classification of lung and pleural tumors have recently classified LCNEC as a subgroup of large cell carcinoma on the basis of morphologic and immunohistochemical evidence of neuroendocrine differentiation. Those showing morphologic evidence of neuroendocrine differentiation, but with negative immunohistochemistry are classified as LCCNM [4]. However, the prognostic significance of recognizing subgroups of large cell carcinomas with neuroendocrine features has yet to be proven with some groups showing a prognosis similar to that of other nonsmall cell lung cancers [9], whereas others findings showed a worse prognosis in those with neuroendocrine features [10]. Most series relate to LCNEC series, which show the prognosis lies between that of an atypical carcinoid and small cell carcinoma, although much closer to that of small cell lung cancer (SCLC) [2, 3, 5, 6]. In terms of the pathology, the histologic findings are similar to those seen in other series.

Our results support the findings of Iyoda and colleagues [7] who found no difference in the clinical behavior between LCCNM and LCNEC (Fig 3). However, we also found that the accurately staged patients in stage 1 (9 of 18) had a 3-year survival of 88% (n = 6), maintained at 5 years (n = 4). In the group that did not have SND or complete resection in an advanced stage, the 3-year survival rate was 28% (Fig 2). These data contrast with other published series (eg, Dressler and colleagues showed a poor prognosis similar to that of small cell lung cancers with an overall 5-year survival of 18% [2]). In this study, patients with stage I disease showed 5-year survival of 20% (n = 17), whereas stage I survival was 33% (n = 13) in a Spanish multicenter study [3]. For patients with stage II or III disease in the Spanish study, none survived longer than 18 months after resection, whereas in our study those patients with advanced disease had a 3-year survival of 28% (Fig 2).

The markedly better survival in our series may be caused by several factors. First, it is possible that stage migration accounted for the markedly superior survival results in our series. SND was performed in 18 of 21 patients, and it is known to provide improved staging at thoracotomy. The IASLC recommends SND for all cancer resections [11]. There is no mention of the exact extent of mediastinal nodal dissection in the other series that have published long-term follow-up in LCNEC [2–4, 6, 10]. Therefore potential understaging in the absence of SND may have an effect on prognostic data. Although not investigated in a randomized fashion, evidence from other studies of neuroendocrine lung cancers suggests SND to be of benefit. Martini and colleagues [12] showed excellent results after complete resection and SND with bronchial carcinoids with lymph node involvement. Shepherd and colleagues [13] also found that micrometastases are very likely in SCLCs, as clinical TNM stage correlated with final pathologic stage in less than 50% of patients if SND was carried out, and there was an apparent survival advantage in the accurately staged group. Finally, recent evidence suggests a possible independent survival benefit from SND in other forms of nonsmall cell lung cancer with lymph node metastasis [14].

Second, survival in our series may have been influenced by the extent of complete anatomical resections. In previously published trials the extent of wedge resections in the LCNEC group was up to 30% [2, 4], and this may have had an adverse effect on outcome. Two patients in our study were excluded from the initial survival calculations as no lymph node sampling was undertaken. Both these patients were considered preoperatively to be stage I but had died within 18 months of the resection from recurrence of disease. This may reflect other comorbid factors, which mitigated against SND and the extent of resection in this small subgroup. Despite this we believe that the outcome is markedly better in the group with anatomical resection and SND justifies this approach.

Besides, our series had far fewer patients with locally advanced stage when compared with the group presented by Rusch and colleagues [6]. In their study, 52% of patients were in stage IIIa, and this would have skewed the prognosis. We had 50% of our patients in stage I, which was comparable with other published trials [2, 3]. A 25% pickup of asymptomatic patients could have helped the high incidence of early stage tumors in our series.

Because of the neuroendocrine phenotype and the aggressive nature of the disease, postoperative chemotherapy or radiotherapy has been used in all studies published about LCNEC. The group receiving adjuvant chemotherapy or radiotherapy ranged from 40% to 60% in the published trials. There did not appear to be a survival advantage in the adjuvant therapy group in any of the trials [2–4, 6]. No standardized treatment protocol was followed. There is a suspicion that these tumors are chemotherapy resistant. Lai and colleagues [15] did find a majority of lung cancers with neuroendocrine markers to demonstrate the multi-drug resistance gene (MDR1) expression, which suggests the presence of chemotherapy resistance to the tumor. Due to the lack of clear advantages of adjuvant therapy postoperatively, a majority of our patients were not considered for postoperative chemotherapy or radiotherapy. In our series only one patient in stage I received elective postoperative chemotherapy and he was alive and well at 37 months. A recent publication by Iyoda and colleagues [16] showed a comparable survival of Stage I patients with LCNEC at 62% more than 5 years. They found that in a subgroup of 5 patients who had stage I disease and adjuvant chemotherapy, survival was 100% at 5 years. In patients not in stage I, survival with and without adjuvant chemotherapy was comparable at less than 20% at more than 5 years. In view of the small numbers in all the published groups, the question of adjuvant chemotherapy has not been adequately answered. On the evidence of our series we believe that complete resection and SND is the best treatment for early stage LCNEC and LCCNM.

In conclusion, this series shows that LCNEC and LCCNM are rare and aggressive tumors. Complete resection with SND is associated with a 47% survival at 5 years for the whole group and an 88% 5-year survival for stage I disease. This is better than what has been reported in previously published series. In the reviewed literature there seems to be conflicting evidence for adjuvant therapy in this group of patients. A multicenter prospective randomized control trial is needed to answer the role of adjuvant chemotherapy in early stage LCNEC and LCCNM. Patients with more advanced disease and those in whom intrathoracic nodal staging has been less reliable have a less favorable prognosis with a 5 year survival of 28%.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We would like to thank Dr Steven Bourke and Therese Small for help with the statistical analysis of the results.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumours of the lung with proposed criteria for large cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15(6):529–53
2. Dresler C.M., Ritter J.H., Patterson G.A., et al. Clinico-pathologic analysis of 40 patients with large cell neuroendocrine carcinoma of the lung. Ann Thorac Surg 1997;63:180-185.[Abstract/Free Full Text]
3. Garcia-Yuste M., Matilla J.M., et al. Prognostic factors in neuroendocrine lung tumors: a Spanish multicentre study. Ann Thorac Surg 2000;70:258-263.[Abstract/Free Full Text]
4. Travis W.D., Gal A.A., Colby T.V., Klimstra D.S., Falk R., Koss M.N. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 1998;29(3):272-279.[Medline]
5. Travis W.D., Corrin B., Shimosato Y., Brambilla E. The histological typing of lung and pleural tumors. WHO/IASLC classification of lung and pleural tumours, 3rd ed Berlin: Springer Verlag, 1999.
6. Rusch V.W., Klimstra D.S., Venkatraman E.S. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg 1996;62:798-810.[Abstract/Free Full Text]
7. Iyoda A, Hiroshima K, Toyozaki T, Haga Y, Fujisawa T, Ohwada H. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001;91(11):1992–2000
8. Mountain C.F. Revisions in the international system for staging lung cancer. Chest 1997;111:1710.[Abstract/Free Full Text]
9. Linnoila R.I., Piantadosi S., Ruckdeschel J.C. Impact of neuroendocrine differentiation in non-small cell lung cancer. The LCSG experience. Chest 1994;106(Suppl):367S-371S.[Abstract/Free Full Text]
10. Cooper W.A., Thourani V.H., Gal A.A., et al. The surgical spectrum of pulmonary neuroendocrine neoplasms. Chest 2001;119:14-18.[Abstract/Free Full Text]
11. Goldstraw P. Report on the International Workshop on Intrathoracic Staging. London, October 1996. Lung Cancer 1997;18:107-111.
12. Martini N., Zaman M.B., Bains M.S., et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994;107:1-6.[Abstract/Free Full Text]
13. Shepherd F.A., et al. Surgical treatment for limited small cell lung cancer. J Thorac Cardiovasc Surg 1991;101:385.[Abstract]
14. Izbicki J.R., Passlick B., Pantel K., et al. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg 1998;227(1):138-144.[Medline]
15. Lai S.-L., Goldstein L.J., Gottesman M.M., et al. MDR1 gene expression in lung cancer. J Natl Cancer Inst 1989;81:1144-1150.[Abstract/Free Full Text]
16. Iyoda A., Hiroshima K., Toyozaki T., et al. Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. Cancer 2001;92:1108-1112.[Medline]

This article has been cited by other articles:

				C. A. Moran, S. Suster, D. Coppola, and M. R. Wick Neuroendocrine Carcinomas of the Lung: A Critical Analysis Am J Clin Pathol, February 1, 2009; 131(2): 206 - 221. [Abstract] [Full Text] [PDF]

				A. Iyoda, K. Hiroshima, Y. Nakatani, and T. Fujisawa Pulmonary Large Cell Neuroendocrine Carcinoma: Its Place in the Spectrum of Pulmonary Carcinoma Ann. Thorac. Surg., August 1, 2007; 84(2): 702 - 707. [Abstract] [Full Text] [PDF]

				A. Iyoda, K. Hiroshima, Y. Moriya, Y. Takiguchi, Y. Sekine, K. Shibuya, T. Iizasa, H. Kimura, Y. Nakatani, and T. Fujisawa Prospective Study of Adjuvant Chemotherapy for Pulmonary Large Cell Neuroendocrine Carcinoma Ann. Thorac. Surg., November 1, 2006; 82(5): 1802 - 1807. [Abstract] [Full Text] [PDF]

				A. Iyoda, K. Hiroshima, Y. Moriya, Y. Sekine, K. Shibuya, T. Iizasa, Y. Nakatani, and T. Fujisawa Prognostic impact of large cell neuroendocrine histology in patients with pathologic stage Ia pulmonary non-small cell carcinoma. J. Thorac. Cardiovasc. Surg., August 1, 2006; 132(2): 312 - 315. [Abstract] [Full Text] [PDF]

				H. Asamura, T. Kameya, Y. Matsuno, M. Noguchi, H. Tada, Y. Ishikawa, T. Yokose, S.-X. Jiang, T. Inoue, K. Nakagawa, et al. Neuroendocrine Neoplasms of the Lung: A Prognostic Spectrum J. Clin. Oncol., January 1, 2006; 24(1): 70 - 76. [Abstract] [Full Text] [PDF]

				G. Rossi, A. Cavazza, A. Marchioni, L. Longo, M. Migaldi, G. Sartori, N. Bigiani, L. Schirosi, C. Casali, U. Morandi, et al. Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFR{alpha}, PDGFR{beta}, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung J. Clin. Oncol., December 1, 2005; 23(34): 8774 - 8785. [Abstract] [Full Text] [PDF]

				E. Lim, Y. K. Yap, B. L. De Stavola, A. G. Nicholson, and P. Goldstraw The impact of stage and cell type on the prognosis of pulmonary neuroendocrine tumors J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 969 - 972. [Abstract] [Full Text] [PDF]

				R. J. Battafarano, F. G. Fernandez, J. Ritter, B. F. Meyers, T. J. Guthrie, J. D. Cooper, and G. A. Patterson Large cell neuroendocrine carcinoma: An aggressive form of non-small cell lung cancer J. Thorac. Cardiovasc. Surg., July 1, 2005; 130(1): 166 - 172. [Abstract] [Full Text] [PDF]

				P. L. Filosso, E. Ruffini, A. Oliaro, O. Rena, C. Casadio, M. Mancuso, D. Turello, R. C. Cristofori, and G. Maggi Large-cell neuroendocrine carcinoma of the lung: A clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide J. Thorac. Cardiovasc. Surg., April 1, 2005; 129(4): 819 - 824. [Abstract] [Full Text] [PDF]

				A. M. Ab' Saber, L. M. Massoni Neto, C. P. Bianchi, B. B. Ctenas, E. R. Parra, E. M. Eher, J. C. Pereira, T. Takagaki, N. H. Yamaguchi, and V. L. Capelozzi Neuroendocrine and biologic features of primary tumors and tissue in pulmonary large cell carcinomas Ann. Thorac. Surg., June 1, 2004; 77(6): 1883 - 1890. [Abstract] [Full Text] [PDF]

				M. Paci, A. Cavazza, V. Annessi, I. Putrino, G. Ferrari, S. De Franco, and G. Sgarbi Large cell neuroendocrine carcinoma of the lung: a 10-year clinicopathologic retrospective study Ann. Thorac. Surg., April 1, 2004; 77(4): 1163 - 1167. [Abstract] [Full Text] [PDF]

				C. Doddoli, F. Barlesi, B. Chetaille, L. Garbe, P. Thomas, R. Giudicelli, and P. Fuentes Large cell neuroendocrine carcinoma of the lung: an aggressive disease potentially treatable with surgery Ann. Thorac. Surg., April 1, 2004; 77(4): 1168 - 1172. [Abstract] [Full Text] [PDF]

				C. Casali, A. Stefani, G. Rossi, M. Migaldi, S. Bettelli, A. Parise, and U. Morandi The prognostic role of c-kit protein expression in resected large cell neuroendocrine carcinoma of the lung Ann. Thorac. Surg., January 1, 2004; 77(1): 247 - 252. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joseph Zacharias George P. Ladas Peter Goldstraw Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zacharias, J. Articles by Goldstraw, P. Search for Related Content PubMed PubMed Citation Articles by Zacharias, J. Articles by Goldstraw, P. Related Collections Lung - cancer