Behaviour and survival of high-grade neuroendocrine carcinomas of the lung

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Behaviour and survival of high-grade

neuroendocrine carcinomas of the lung

J.M. Naranjo Go

´mez

a,

*

, J.J. Go

´mez Roma

´n

b

a

Department of Thoracic Surgery, Hospital Universitario Marque´s de Valdecilla, Servicio de Cirugı´a Tora´cica, Avda. de Valdecilla 25, 39008 Santander (Cantabria), Spain

b

Department of Pathology, Hospital Universitario Marque´s de Valdecilla, Avda. de Valdecilla 25, 39008 Santander (Cantabria), Spain

Received 29 May 2009; accepted 9 August 2010

KEYWORDS Lung cancer; Survival analysis; Neuroendocrine lung carcinomas Summary

Introduction: Large-cell neuroendocrine carcinoma is an aggressive variant of large-cell carci-noma of the lung, which has poor survival in most series, resembling that of small-cell lung carcinoma. We report our retrospective assessment of surgically-resected cases of both tumours.

Methods: 33 large-cell neuroendocrine carcinomas and 16 peripheral small-cell lung carci-nomas were reassessed retrospectively. Survival rates of both tumours in surgically-resected cases were calculated and compared using KaplaneMeier survival curves and Log Rank test, respectively.

Results: In large-cell neuroendocrine carcinomas, there were 25 patients with pathologic stage I, 4 with pathologic stage II and 4 with pathologic stage III. In small-cell lung carcinomas, there were 6 patients with pathologic stage I, 3 with pathologic stage II and 7 with pathologic stage III. 12% of large-cell neuroendocrine carcinomas and 62.5% of small-cell lung carcinomas were of advanced disease. The mean follow-up was 89 months. The actuarial survival for the 2 groups was not significantly different.

Conclusion: Large-cell neuroendocrine carcinomas of the lung have poor prognosis even in early stages, with survival rates similar to that of small-cell lung carcinomas.

ª 2010 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.:þ34942202520; fax: þ34942202520

E-mail addresses:jomanago1@hotmail.com(J.M. Naranjo Go´mez),apagrj@humv.es(J.J. Go´mez Roma´n). a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r m e d

0954-6111/$ - see front matterª 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2010.08.007

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Summary

In this paper, we compare a series of surgically-resected large-cell neuroendocrine carcinomas with another series of surgically-resected small-cell lung carcinomas. We have found a more advanced pathologic stage of the disease in the second group but without actuarial survival differences.

Introduction

Neuroendocrine lung neoplasms are a group of tumours that share some morphological and biochemical characteristics, such as the presence of dense cytoplasmic granules and the ability to synthesise neuropeptides. In 1980, pulmonary neuroendocrine tumours were categorised as typical carci-noids, atypical carcinoids and small-cell lung carcinomas (SCLC).1 However, some authors indicated that a fourth category may exist between atypical carcinoids and SCLC in prognosis.2,3In 1991, Travis and colleagues4proposed a new category for large-cell neuroendocrine carcinoma (LCNEC) and reported that its prognosis fell between atypical carci-noids and SCLC. In 1999, the World Health Organization5 classified LCNEC as a variant of large-cell carcinoma. Its cytologic features are identical to those of non-small-cell carcinomas, but in addition, these tumour cells are positive for neuroendocrine markers (chromogranin and synapto-physin) or have neuroendocrine granules that are detected by electron microscope. In 2004, Travis6 proposed a new classification for neuroendocrine tumours with LCNEC and SCLC among the high-grade malignity entities.

LCNEC is classified as a variant of large-cell carcinomas. Although there is a report7that referred to the prognosis of

patients with LCNEC as being the same as those with large-cell carcinomas, most8e17 revealed that patients with

LCNEC had poorer prognoses, with 5-year survival rates of 15%e57%, and with clinical and biological features resem-bling those of SCLC. This contrasts with the results of Travis,4who reported a prognosis between that of atypical carcinoids and SCLC.

The purpose of this study is to report our experience with resected LCNEC and peripheral SCLC, and in particular to assess the differences between both regarding prognosis.

Methods

A total of 38 large-cell neuroendocrine carcinomas of the lung and 23 peripheral small-cell lung carcinomas were selected from surgical specimens of the Surgical Pathology archives of the Hospital Universitario Marques de Valdecilla (Santander, Spain). These surgical specimens were obtained from patients who underwent surgery from 1988 to 2005, and were reviewed by two experienced and inde-pendent pathologists to verify the correct pathological diagnosis, as described by Travis and colleagues: a mitotic count of greater than 10 per 2 square millimetres.4 No distinction was made between neuroendocrine differenti-ation and neuroendocrine morphology, because no prog-nosis difference was found in other studies.7,18Five LCNEC

cases and seven SCLC were rejected because these were widespread tumours (patients had simply undergone

surgery for pathologic diagnosis), or resection was less than lobectomy, due to functional limitations. Thus, 33 LCNEC and 16 peripheral SCLC, all early clinical stage and completely resected tumours, remained for study. Clinical charts were retrospectively studied in order to collect data about epidemiology, manifestations, method of diagnosis, clinical stage, treatment, pathologic stage, surgical complications and follow-up details. When necessary, patients or their families were telephoned if some piece of information was not available on the clinical chart. InTable 1, some of these aspects are shown.

Statistical analysis

For the statistical analysis we used an SPSS package (SPSS Inc, Chicago, IL). We used the KaplaneMeier survival curves for calculating actuarial survivals and the Log Rank test to see if the survivals were significantly different between LCNEC and SCLC. In the survival analysis, the event measured was death related to neoplastic disease.

This study requires no approval by the ethical committee as it is a retrospective study and no patient names have been revealed.

Results

Pathology

In the LCNEC group, 3 pneumonectomies and 30 lobectomies were performed. Stage distribution (Table 2) according to the 1997 TNM system for classification of lung cancers19 showed 25 patients with pathologic stage I disease (6 T1N0, 19 T2N0), 4 with pathologic stage II (3 T3N0, 1 T2N1) and 4 with pathologic stage IIIa (1 T1N2, 3 T2N2). In the clinical evaluation, no patient had N2 disease.

In the peripheral SCLC group, 5 pneumonectomies and 11 lobectomies were performed. In this group there were 6 patients with pathologic stage I disease (3 T1N0, 3 T2N0), 3 with pathologic stage II (1 T1N1, 2 T2N1), and 7 with pathologic stage IIIa (1 T1N2, 4 T2N2, 2 T3N2) (Table 2). In the clinical evaluation no patient had N1 or N2 disease.

In all patients, the clinical evaluation was a thorax e upper abdomen CT and a PET-TAC. Peripheral negative cases underwent resection without additional mediastinal exploration. Patients with a positive PET-TAC exploration or central tumours underwent EBUS, and if negative, media-stinoscopy (both explorations are regarded as surgically-explored mediastinum inTable 1).

Clinical data

All of the 33 patients with LCNEC and the 16 patients with SCLC were males, and there were no females in these groups. The average age at presentation was 64.91 in the LCNEC group and 61.68 in the SCLC group. Both groups were comparable for other prognostic factors, such as perfor-mance status or clinical manifestations. Of the anatomically resected tumours, 30 were located on the right side and 19 on the left side. At the time of presentation, 28 were asymp-tomatic and the tumour was found incidentally on a chest

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X-ray exam. In the other 21 patients, symptoms included: 16 haemoptysis, none of which was massive; 2 chest pain, both with involvement of the chest wall; 2 non-productive persistent cough; and one LamberteEaton syndrome in

a patient with SCLC. There was no correlation between asymptomatic or symptomatic presentation and pathological stage, although the presentation of the unique case of LamberteEaton syndrome in an N2 SCLC and the 3 patients

Table 1 General patient characteristics.

Pt Age Sex Stage PD FEV1 Resect Sympt DM SEM

1 63 M T1N1 SCLC 75% LN No BB Y 2 60 M N2 SCLC 80% LUL No BB N 3 62 M T2N0 LCNC 92% LUL No CTGB N 4 60 M T2N0 LCNC 102% LN Hem CTGB Y 5 56 M N2 LCNC 66% RLL No BB N 6 69 M T1N0 SCLC 93% LUL Hem IB Y 7 58 M N2 SCLC 82% RLL No BB N 8 66 M T2N0 LCNC 70% LLL No BB Y 9 59 M T1N0 LCNC 69% RUL No CTGB N 10 70 M T2N0 LCNC 104% RN Hem BB Y 11 55 M T2N1 SCLC 82% LLL No CTGB N 12 54 M T2N0 LCNC 93% RUL No SC Y 13 60 M T3N0 LCNC 97% RUL Pain CTGB N 14 61 M T2N0 LCNC 63% LLL No BB Y 15 45 M N2 LCNC 100% LN Cough CTGB Y 16 72 M T2N0 LCNC 90% RUL No IB N 17 73 M T2N0 LCNC 92% RUL Hem BB N 18 63 M T2N0 LCNC 99% LUL No SC Y 19 61 M T2N0 LCNC 94% LLL No BB Y 20 58 M T1N0 SCLC 88% LUL Hem IB Y 21 74 M T1N0 LCNC 90% RLL Hem CTGB N 22 61 M T3N0 LCNC 98% RUL Pain CTGB N 23 61 M N2 SCLC 99% RN No IB Y 24 69 M T2N0 LCNC 101% RLL No BB Y 25 57 M N2 SCLC 100% RLL LE BB N 26 64 M T2N0 LCNC 98% RUL Hem SC N 27 74 M T1N0 LCNC 83% LLL No IB Y 28 62 M T2N0 LCNC 86% RLL Hem BB Y 29 65 M T2N0 SCLC 90% RUL No BB Y 30 49 M T2N0 LCNC 105% RUL No CTGB Y 31 70 M T1N0 SCLC 78% RLL No CTGB Y 32 59 M N2 LCNC 99% RUL Hem BB N 33 65 M T1N0 LCNC 88% RLL Cough IB N 34 70 M T2N0 LCNC 54% RLL No SC Y 35 64 M N2 SCLC 67% LN Hem BB Y 36 58 M N2 SCLC 90% RLL No CTGB N 37 67 M T1N0 LCNC 95% RLL No IB N 38 64 M T2N1 SCLC 84% LN Hem BB Y 39 71 M T3N0 LCNC 97% RUL Hem CTGB Y 40 68 M T1N0 LCNC 85% LUL No BB N 41 63 M T2N0 LCNC 96% RLL Hem SC N 42 65 M T2N0 LCNC 75% RUL No BB Y 43 67 M N2 LCNC 59% LLL Hem IB N 44 62 M N2 SCLC 88% LN Hem CTGB Y 45 79 M T2N1 LCNC 96% LUL No CTGB N 46 73 M T2N0 LCNC 77% RUL Hem BB Y 47 59 M T2N0 SCLC 84% RUL No BB Y 48 64 M T2N0 SCLC 89% RLL No BB N 49 80 M T2N0 LCNC 91% RLL No BB Y

PtZ Patient; PD Z Pathological diagnosis; Resect Z resection; Sympt Z symptoms; M Z male; SCLC Z small-cell lung carcinoma; LCNCZ large-cell neuroendocrine carcinoma; RUL Z right upper lobectomy; LUL Z left upper lobectomy; RLL Z right lower lobec-tomy; LLLZ left lower lobectomy; LN Z left pneumonectomy; RN Z right pneumonectomy; Hem Z haemoptysis; LE Z Lambert Eaton; DMZ diagnosis method; SEM Z surgical exploration of the mediastinum; Y Z yes; N]No.

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with pain in the T3N0 cases should be noted. In the LCNEC group, non-small-cell lung carcinoma diagnosis was deter-mined with bronchoscopic biopsy in 13 patients, with computed tomography-guided biopsy in 10 patients, with sputum cytology in 5 patients and with intraoperative biopsy in another 5 patients. None of these patients had been diagnosed as LCNEC before referral. Regarding SCLC, diag-nosis was suggested with bronchoscopic biopsy in 9 patients, with computed tomography-guided biopsy in 4 patients and with intraoperative biopsy in another 3 patients. All of them were peripheral tumours.

All 49 patients proceeded to thoracotomy and were anatomically resected, 8 with pneumonectomy and 41 with lobectomy. Each patient had systematic nodal dissection at the time of resection. In the LCNEC group, no patient under-went induction chemotherapy. No patient with T3N0 disease underwent adjuvant therapy because the tumour was completely resected. The N1 and N2 positive patients under-went cisplatin-based adjuvant chemotherapy. T2 N0 cases were not treated with chemotherapy because at that time it was not considered for that stage. All patients with SCLC underwent cisplatin-based adjuvant chemotherapy, medias-tinum radiotherapy and prophylactic cranial irradiation.

Follow-up data

The follow-up for these patients ranged from 26 months to 179 months with a median follow-up time of 89 months. In an LCNEC patient and in another SCLC patient, it was not possible to determine the survival status. Of the remaining 47 patients with complete follow-up, 10 were alive and disease free at the moment of review: 9 LCNEC, at 26 months (stage T1N0), 36 months (stage T1N0 and T2N2), 42 months (stage T2N0), 51 months (stage T2N0), 55 months (stage T1N0), 71 months (stage T2N0), 72 months (stage T2N0) and 143 months (stage T2N0); and 1 SCLC, at 45 months (stage T1N0). Two patients with LCNEC (stage T2N0) had died at 1 and at 55 months of causes other than neoplastic disease. Another 4 patients with SCLC had died at 2 months (stage T2N0), 6 months (stage T2N1), 42 months (stage T1N0) and 127 months (stage T1N0) of causes other than neoplastic disease. All of them were disease-free. The remaining 21 LCNEC patients and 10 SCLC patients had died from recurrence of their disease. These data are summar-ised inTable 3.

In the LCNEC patient group, the overall survival was 70% at 1 year, 46% at 3 years and 42% at 5 years. For the accurately-staged cases, actuarial 5-year survival rate was 53% for the 25 stage I patients (50% for T1N0 stage, 56% for T2N0 stage), 0% for the 4 stage II patients, and 25% for the 4 stage IIIa patients. For non-stage I patients, 5-year survival was 12%. In the SCLC group, overall survival rate was 46% at 1 year and 31% at 3 years, which held true at 5 years. For the accurately-staged cases, actuarial 5-year survival was 60% for the 6 stage I patients, 66% for the 3 stage II patients, and 0% for the 6 stage IIIa patients. For non-stage I patients, the 5-year survival rate was 13%.

The overall actuarial survival rate of both groups was compared and there was no significant survival difference in Log Rank analysis (pZ 0.54) (Fig. 1). When we analysed individual pathological stages (I, II, III and non-stage I) we found no significant differences either (Figs. 2e5).

Discussion

The classification of neuroendocrine lung tumours has been subjected to considerable controversy in the past, resulting in multiple classifications, the latest established in 2004.6

Several entities are included in this spectrum, from the low-grade typical carcinoids to the intermediate-grade atypical carcinoids and the high-grade categories with large-cell neuroendocrine carcinomas (LCNEC) and small-cell lung carcinomas (SCLC). LCNEC differs from typical and atypical carcinoids in terms of its greater quantity of mitosis and abundant necrosis, while it differs from SCLC exclusively in terms of its cytologic characteristics.20These two high-grade tumours are not always easily differentiated by pathologists.21,22 While there is no doubt about the better prognosis of low-grade neuroendocrine tumours in comparison to high-grade neuroendocrine tumours, and of typical carcinoids in comparison to atypical carcinoids, there are several studies revealing a similar prognosis for LCNEC and SCLC.8,10,11,14,15,20 Some authors go even further, suggesting that LCNEC and SCLC be classified into one group, called “high-grade malignant neuroendocrine tumours”.9

In the present study, we have found one difference between the two tumours: both groups of tumours were studied preoperatively in the same way, as previously described, but while 88% of the LCNEC resected had early disease (pathologic stage I or II), only 37% of SCLC did (path-ologic stage I). Authors agree that the role of surgery in peripheral SCLC should be limited to those with stage I disease27. If we assess only mediastinal nodes and exclude hilar ones, 12% of non-N2 LCNEC disease in the clinical eval-uation had mediastinal involvement, contrasting with 44% of SCLC. Both groups were subjected to the same criteria

Table 2 TNM stages. T1N0 T2N0 T1N1 T2N1 T3N0 N2 Total LCNEC 6 19 0 1 3 4 33 SCLC 3 3 1 2 0 7 16 Table 3 Follow-up. LCNEC SCLC Total

Alive without illness 9 (26e143 m): 8 stage I, 1 stage IIIa (36 m) 1 (45 m): stage I 10 Dead due to other illness 2: 1 and 55 m. Stage I 4 (2e127 m): 3 stage I, 1 stage II 6

Dead due to relapse 21 10 31

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to undergo surgical exploration of the mediastinum, and in both groups there were true and false negative cases (1 LCNEC vs. 3 SCLC) cases. Therefore, we can affirm that, according to our results, SCLC have more probabilities than

LCNEC of spreading to the mediastinal nodes without having been detected in the preoperative evaluation. Most N2 cases in both groups did not undergo surgical exploration of the mediastinum. Perhaps every patient should undergo such

Figure 2 KaplaneMeier survival estimates for stage I patients comparing survival between large-cell neuroendocrine carcinoma (continuous line, 25 patients) and small-cell lung carcinoma (discontinuous line, 6 patients) (Log Rank test; p Z 0.49 not significant).

Figure 1 KaplaneMeier survival estimates for both groups comparing survival between large-cell neuroendocrine carcinoma (continuous line) and small-cell lung carcinoma (discontinuous line) (Log Rank test; pZ 0.54 not significant).

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exploration before resection, although false negatives do exist.

When survival was analyzed, no statistical differences were found between the groups, either globally or in the different stages. The size of our groups is small, but these findings are similar to what has been described by other authors.8,10,11,14,15,20Because in stages II and IIIa there were

not many cases, we decided to group them, but survival again was similar in both tumours. Surprisingly, and as stated previously, overall survival was similar in both neoplasms, despite there being a higher percentage of cases with stage I disease in the LCNEC group than in the SCLC group. But even in stage I, we found poor survival for LCNEC (53%), as had other authors9,11,12,14e17who describe 5-year survival rates of 27%e

Figure 3 KaplaneMeier survival estimates for stage II patients comparing survival between large-cell neuroendocrine carcinoma (continuous line, 4 patients) and small-cell lung carcinoma (discontinuous line, 3 patients) (Log Rank test; pZ 0.42 not significant).

Figure 4 KaplaneMeier survival estimates for stage III patients comparing survival between large-cell neuroendocrine carcinoma (continuous line, 4 patients) and small-cell lung carcinoma (discontinuous line, 7 patients) (Log Rank test; pZ 0.10 not significant).

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67%. Nevertheless, this is in contrast to what was reported by Zacharias et al.,18who described a survival rate of 88% at 5 years for stage I disease. They explain that complete resec-tion and systematic nodal dissecresec-tion make this outcome possible, although we have followed this same approach, too. Because of the aggressive nature of LCNEC, postoperative chemotherapy or radiotherapy have been used in several studies published about this tumour, and no advantages in survival have been found in any of the trials.15,21,23,24On the other hand, adjuvant chemotherapy is effective for patients with non-small-cell carcinomas25e27and patients with path-ologic stage IB or higher should be likewise treated. There-fore, LCNEC patients in advanced stages should perhaps not be an exception. In a study by Iyoda and colleagues,13they found

a comparable survival of stage I patients with LCNEC at 62% after more than 5 years. In a subgroup of 5 patients who had stage I disease and adjuvant chemotherapy, survival was 100% at 5 years. However, this beneficial effect of adjuvant chemotherapy was not observed in non-stage I patients. Iyoda et al.,17in another study, demonstrated poorer survival rates in pathologic stage IA LCNEC patients when compared to patients with adenocarcinomas or squamous cell carcinomas in the same pathologic stage. Multivariate analysis revealed that LCNEC was a significant negative prognostic factor, so authors concluded that patients with LCNEC, even in stage IA, should have adjuvant therapy, just as patients with SCLC. The effectiveness of prophylactic cranial irradiation for patients with LCNEC is not clear. There are trials for advanced non-SCLC, but up to now it is not a standard option.28However, this improves both overall survival and disease-free survival in patients with SCLC,29 and it could be promising among patients with LCNEC.

In conclusion, we have found a greater propensity towards occult lymphatic cancer spreading during clinical evaluation in peripheral SCLC, when compared to LCNEC. However, this has not translated into poorer survival rates. Patients with resected LCNEC have proved to have survival rates similar to those of patients with resected SCLC, globally and in the different pathologic stages. Even in stage I, patients with LCNEC have poor survival, compa-rable to that published by most authors, and not statisti-cally different from the survival of patients with SCLC in the same stage. This study, however, has an important limita-tion: the small size of our groups. In the review of the literature, the role of adjuvant therapy has not been adequately determined. A multicentre, prospective, rand-omised control trial is necessary to answer this question, especially in stage I, and to clarify the absence of differ-ences in survival between SCLC and LCNEC that we have found.

Conflict of interest statement

None of the authors have any conflict of interest to disclose.

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