Prognostic Impact of Intra-Alveolar
Tumour Spread in Lung Cancer
Arne Warth
Institut of Pathology
Spread Through Air Spaces (STAS)
- 261 stage I-II adenocarcinomas
- 58 with tumor islands
- 203 without tumor islands
Definition of tumor islands:
„A tumor island was defined as an isolated, large collection of tumor cells present within
alveolar spaces that lacked well-demarcated micropapillary configuration. The island was
located at the periphery of the lesion and was separated from the main tumor by at least a
few alveoli“
Association of tumor islands
with clinico-pathological
characteristics
STAS
Prognostic Impact and Association
with Clinico-Pathological
Characteristics
411 stage I
adenocarcinomas
Tumor STAS was defined as
tumor cells – micropapillary
structures, solid nests, or single
cells – spreading within air
spaces beyond the edge of the
main tumor.
569 resected adenocarcinomas
stage I-IV
STAS was defined as a detachment of
tumor cell clusters (> 5 cells) beyond
the edge of the main tumor
- Limited STAS: < 3 alveoli away from
main tumor
- Extensive STAS: > 3 alveoli away
from main tumor
In multivariate analysis STAS was a pattern-independend prognosticator but not a
stage-independend prognosticator
318 stage I adenocarcinomas
Definition of STAS
Tumor cell clusters lying freely within the
alveolar space at a distance of at least 0.5 mm
from the main tumor.
Interaction of STAS with solid and micropapillary
predominant pattern
Prasad Adusumilli, MSKCC
The prognostic impact of STAS is in
the range of high grade
histological pattern
International study including >2000 stage I adenocarcinomas from 5 countries
Summary
STAS (including tumor islands)
- Is present in 15%-50% of all adenocarcinomas (different definitions and cohorts).
- Is significantly associated with males, smoking, high grade histological pattern, higher
nuclear grade, lympho-vascular and pleural invasion, higher tumor stage/tumor size,
lymph node and distant metastasis, KRAS and BRAF mutations.
- Is significantly associated with poor overall and disease-free survival, in some studies
independend of the histological pattern and stage.
- Adds significant prognostic information to the predominant histological pattern.
- Is significantly associated with local recurrence following wedge resections.
Late Breaking News: STAS in Squamous Cell Carcinomas
445 cases, stage I-III
STAS = tumor cell nests beyond the
main tumor edge (even in the first
alveolar layer)
STAS in squamous cell carcinomas
was associated with:
- p-stage
- Lymphatic and vascular invasion
- Necrosis
- Large nuclear diameter
- Increased mitosis
- High Ki-67 labeling index
J Thorac Oncol, in press
STAS
Fact or Artifact?
STAS vs. STAKS (Spread Through A
Knife Surface)
Adenocarcinoma with intraalveolar cell clusters
Open lung biopsy of an ILD patient with an intraalveolar
fragment of loose bronchiolar epithelium.
Data of a multicentre
study to be presented
at the 17th WCLC in
Vienna, Dec. 4-7 2016
If STAS is only an artifact, how can we
explain the significant association with
prognosis and recurrence?
Other explanations?
- Significant association of STAS with lymphovascular
invasion  local recurrence?
- STAS was an independent risk factor from vascular and
lymphatic invasion (Kadota et al. 2015; Shiono and
Yanagawa 2016).
- All cases with local recurrence at the surgical stump had
STAS (Shiono and Yanagawa 2016).
STAS = Spread Through A Surgeon?
Intraoperative tumor cell detachment
 recurrence at the surgical stump?
Images provided by H. Hoffmann, Thoracic Hospital Heidelberg
STAS = Spread Through A Surgeon?
VATS
Lobectomy
-
How long can tumor cells survive within alveolar spaces?
- Starvation of tumor cells in culture: >12 h
- Intraalveolar survival of macrophages (e.g. DIP)
Perspectives
- More precise definition of STAS: Number of cells/cell clusters, distance to tumor
edge
> One cell cluster beyond the main tumor edge?
> No need to separate STAS from tumor islands.
- Further studies on the prognostic impact and associations to clinicopathological
characteristics are needed.
- Further studies concerning STAKS: Type of resection, surgical method, type of
dissection/used knifes/fixation/time points, …
- Reliable detection of STAS in frozen sections?  limited resections
- Integration into the TNM System?  pT2a, pN1, L1, V0, PL1, pn0, STAS+
Thank you