Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung

  • Serdar Altinay
  • Jasna Metovic
  • Federica Massa
  • Gaia Gatti
  • Paola Cassoni
  • Giorgio Vittorio Scagliotti
  • Marco VolanteEmail author
  • Mauro Papotti
Original Article


Spread through air spaces (STAS) have been recently recognized as a prognostic factor for adenocarcinoma and squamous cell carcinoma of the lung. Pulmonary neuroendocrine neoplasms (NENs) include tumors with different morphology and a heterogeneous clinical behavior. Among atypical carcinoids (ACs), new prognostic factors able to refine prognosis are needed. In the present study, a retrospective series of 91 surgically resected ACs was investigated, in parallel with 191 control cases of typical carcinoids (TCs) and of high-grade small- and large-cell neuroendocrine carcinomas, to assess the presence and potential prognostic role of STAS. STAS was defined by the presence of neoplastic nests or single cells in air spaces beyond the tumor edge. Clinicopathological parameters and survival were correlated by univariate and multivariate analyses. STAS was identified in 48% of ACs (44/91) compared to 20.5% of TCs and 71–88% of high-grade large- and small-cell carcinomas in the control group. In the carcinoid group, presence of STAS was significantly correlated with unfavorable parameters, such as high tumor stage, positive nodal status, high Ki-67 index, presence of angioinvasion, and with adverse disease outcome, shorter overall survival, and time to progression. In conclusion, the presence of STAS is an additional relevant adverse prognostic factor in pulmonary AC that currently has the most unpredictable outcome and the most controversial treatment strategy.


Lung Atypical carcinoid Neuroendocrine neoplasm Spread through air spaces (STAS) Prognosis 



Study conception and design: MP. Data collection: SA, JM, FM, GG, PC, GVS, MV, MP. Analysis and interpretation of data: MP, MV, SA, JM, MV. Drafting of manuscript: MP, MV, SA, JM. Critical revision: SA, JM, FM, GG, PC, GVS, MV, MP. All the authors gave final approval for publication. The author MV takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.


This study was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan), grant #IG19238 to MV. JM is a PhD fellow at the University of Turin.

Compliance with ethical standards

The study was approved by the local ethical committee (Department of Oncology at San Luigi Hospital, number 17975/2015).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2019_2596_MOESM1_ESM.pdf (137 kb)
Supplementary Fig 1 Histopathologic pitfalls mimicking STAS. A1/A2: mildly atypical alveolar macrophages resemble clusters of neoplastic cells. B1/B2: Chromogranin nicely highlights strongly reactive cells within STAS, but also shows some weak positivity in alveolar macrophages, as a result of passive absorption. (A1/A2: H&E staining; B1/B2: Chromogranin A immunohistochemistry; original magnification A1, B1: 100x; A2,B2: 200x) (PDF 136 kb)
428_2019_2596_MOESM2_ESM.pdf (112 kb)
Supplementary Fig 2 Kaplan Meier curves showing a significant increased risk of death in the group with 4–5 score value (p < 0.001) (PDF 112 kb)
428_2019_2596_MOESM3_ESM.pdf (365 kb)
Supplementary Fig 3 Kaplan Meier curves of overall survival analysis performed in the TC group, only. Both single cells invasion (p = 0.016) and STAS (p = 0.045) are significantly associated with shorter survival (PDF 365 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Serdar Altinay
    • 1
  • Jasna Metovic
    • 2
  • Federica Massa
    • 2
  • Gaia Gatti
    • 2
  • Paola Cassoni
    • 3
  • Giorgio Vittorio Scagliotti
    • 2
  • Marco Volante
    • 2
    Email author
  • Mauro Papotti
    • 2
  1. 1.Division of PathologyUniversity of Health Sciences, Dr. Sadi Konuk Training and Research HospitalIstanbulTurkey
  2. 2.Pathology Division of the Department of OncologyUniversity of TurinTorinoItaly
  3. 3.Pathology Division of the Department of Medical SciencesUniversity of TurinTurinItaly

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