Elsevier

Lung Cancer

Volume 132, June 2019, Pages 141-149
Lung Cancer

Characteristics of 252 patients with bronchopulmonary neuroendocrine tumours treated at the Copenhagen NET Centre of Excellence

https://doi.org/10.1016/j.lungcan.2019.03.013Get rights and content

Highlights

  • Tumour type was the single most potent prognostic factor for survival in BP-NETs.

  • FDG-PET scans were mostly positive in all three subtypes of BP-NETs.

  • LCNEC presented with the lowest 1, 2 and 5 year survival rates.

Abstract

Background

Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC).

Aim

To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded).

Material and methods

Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS.

Results

162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19–89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p < 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p < 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p < 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC.

Conclusion

In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor.

Introduction

Bronchopulmonary neuroendocrine tumours (BP-NETs) represent a group of rare neoplasms with increasing incidence. [[1], [2], [3], [4]] In the 2015 WHO classification the group included low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) [5]. TC includes tumours with a mitotic count of <2/2mm2 and no necrosis, AC a mitotic count of 2–10/2 mm2 and/or tumour necrosis and LCNEC and SCLC a mitotic count >10/2mm2 and abundant necrosis. The SCLC comprises 15% of all lung malignancies, but will not be further addressed in this paper. LCNEC represents 3% whereas bronchopulmonary carcinoids (TC and AC) represent 1%–2% of all new lung cancers. The diagnostic work-up of these tumours has evolved over the past decades with analysis of histological differentiation and new improved methods such as immune staining for neuroendocrine features as diagnostic corner stones [6]. The gold standard of treatment for localized TC and AC is surgical resection, whereas the treatment regimen in advanced disease still remains a field of controversy. Management and treatment of LCNEC is also associated with controversy, which is probably partly due to the heterogeneity of the disease, but the majority of studies have shown that the treatment of LCNEC with chemotherapy mimicking SCLC treatment regime is associated with better survival than treatments used in non-small cell lung cancer [[7], [8], [9]]. The highest mortality is found in high-grade tumours, however advanced disease in low-grade tumours similarly is associated with poor prognosis. Few studies have compared lung carcinoids and LCNEC despite their common histological neuroendocrine features. This study aims to illustrate the similarities and differences amongst TC, AC and LCNEC through a comprehensive evaluation of diagnostic procedures, prognostic factors and overall survival in 252 patients from a single institution.

Section snippets

Patient cohort and preoperative work-up

The study included all patients with TC, AC and LCNEC referred to and treated at the departments of thoracic surgery, oncology, endocrinology and gastrointestinal surgery at the Neuroendocrine Tumour (NET) Centre of Excellence at Rigshospitalet, University of Copenhagen through collection of data from November 2008 to December 2016. All patients with neuroendocrine tumours as well as all patients in need of thoracic surgery from Eastern Denmark (population 2.4 mill.) are referred to and treated

Results

Demographic and clinical features are listed in Table 1. From the prospective NET database we consecutively included 252 patients: 162 patients with TC, 29 patients with AC and 61 patients with LCNEC. The median follow-up time was 48 months (42–54 months) calculated according to the reverse Kaplan Meier method [16]. Median age at diagnosis was 69 (19–89) years. Median age was higher in AC and LCNEC compared to TC (p = 0.046). Gender distribution varied amongst the subtypes with TC and AC

Discussion

In this study of 252 patients the distribution of tumour subtype consisted of 64% with TC, 12% AC and 24% LCNEC. This correlates well with prior studies describing a 10:1 relationship between frequencies of TC and AC and the fact that TC represent approximately 70–80% of neuroendocrine lung tumours [17]. TC presented with centrally located tumours in 58% of patients whereas both AC and LCNEC presented with peripherally located tumours in the majority of patients, 52% and 64% respectively. This

Conclusion

To our knowledge this study is the largest study to analyse and compare diagnostic and prognostic factors in a group of 252 BP-NET patients treated at a single institution.

Our study supports the assumption that the Ki67 index may play an important role as both a diagnostic as well as a prognostic marker together with the mitotic count and amount of necrosis in BP-NETs. Our study suggests that the WHO classification regarding Ki67 in TC tumours may be changed to include proliferation index up to

Conflict of interest

No author of this work had any conflicts of interest. Co-author R.H. Petersen has received speeker fees from Medtronic.

Funding

Danish Cancer Society, Denmark.

References (32)

  • H. Skuladottir et al.

    Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes

    A population-based study in Denmark. Lung Cancer.

    (2002)
  • H. Takei et al.

    Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases

    J. Thorac. Cardiovasc. Surg.

    (2002)
  • G. Pelosi et al.

    Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice

    J. Thorac. Oncol.

    (2014)
  • A.E. Walts et al.

    Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors

    Mod. Pathol.

    (2012)
  • M.B. Beasley et al.

    Pulmonary atypical carcinoid: predictors of survival in 106 cases

    Hum. Pathol.

    (2000)
  • E.M. Tabaksblat et al.

    Diagnosis and treatment of bronchopulmonary neuroendocrine tumours: state of the art

    Acta Oncol. (Madr)

    (2016)
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