Elsevier

Lung Cancer

Volume 123, September 2018, Pages 107-111
Lung Cancer

Review
Pulmonary loose tumor tissue fragments and spread through air spaces (STAS): Invasive pattern or artifact? A critical review

https://doi.org/10.1016/j.lungcan.2018.07.017Get rights and content

Highlights

  • Pulmonary loose tumor tissue fragments is called “spread through air spaces, STAS’’.

  • Recent data demonstrate that loose tissue fragments are a tissue handling artifact.

  • Loose tissue fragments often reveal the presence of a high-grade neoplasm.

  • High grade neoplasm explains the (inconsistent) association with poor prognosis.

  • Inclusion of STAS in the 2015 WHO classification was premature and erroneous.

Abstract

The concept of loose tumor tissue fragments as a pattern of invasion in lung carcinoma has recently been proposed and is included in the 2015 WHO fascicle on the classification of lung tumors, so-called “spread through airs paces” or STAS. This inclusion is controversial, as there are significant data to support that this histologic finding represents an artifact of tissue handling and processing rather than a pattern of invasion. These data are summarized in this review.

These data are summarized in this review and support the conclusion that the inclusion of STAS in the WHO classification for lung cancer as a pattern of invasion was premature and erroneous. In our opinion, these tumor cell clusters or loose cells appear to be simply an artifact, although one which may or may not pinpoint to a high-grade tumor with discohesive cells and adverse prognosis.

Introduction

The concept of loose tumor tissue fragments as a pattern of invasion in lung carcinoma has recently been proposed and is included in the 2015 WHO fascicle on the classification of lung tumors, so-called ‘spread through air spaces” or STAS [1]. This inclusion is controversial, as there are significant data to support that this histologic finding represents an artifact of tissue handling and processing rather than a pattern of invasion.

An extraneous tissue contaminant on a histologic slide is a very well-known phenomenon for pathologists and is called a floater. This can be a source of potential diagnostic error and occurs in approximately 1.2% of prepared slides [2]. Since at least half of these contaminants are not derived from the same patient sample [3], many of them are recognized as artifacts on morphological grounds alone. Moreover, in patients’ samples many of these contaminants are easily recognized as irrelevant, most likely produced by the biopsy procedure passing through other tissues, for instance when fragments of colonic mucosa are seen in prostate biopsies or fragments of skin are present in breast biopsies. In addition, many of these aberrant tissue fragments lie on top of the tissue to be examined, above the tissue plane of the slide, and therefore are also easily recognizable as an artifact.

“Displacement of loose tumor tissue fragments” in organs other than the lung have been described in the colon [4], uterus [5,6], and thyroid [7]. In these cases, the tumor is occasionally displaced into vascular structures during biopsy procedures, surgical manipulation, or pathologic gross processing.

We question the validity of the inclusion of the presence of loose tumor fragments as an invasive pattern in lung cancer.

In this review, we will submit the data on loose tumor fragments in the lung and will examine whether this histologic finding should be considered an invasive pattern, a useful prognostic artifact, or simply an artifact.

Section snippets

The road of loose tissue fragments to STAS

Loose tissue fragments in the lung have been recognized by pathologists for a long time and have been interpreted by many as an artifact. The first study adding importance to the phenomenon of ‘loose tumor fragments’ was that by Onozato and colleagues [8] in 2013, adding a prognostic relevance to loose fragments. Prior to this however in the 1990′s the concept of aerogenic spread of what was previously called bronchioloalveolar carcinoma already existed [9]. While this concept uses the term

The prognostic argument in favor of STAS

The claimed relevance of STAS seems to be supported by the presence of loose tumor fragments and tumor cells, which, irrespective of their numbers, were frequently significantly associated with adverse clinicopathological features. The published studies and the types of clinicopathologic factors associated with STAS are summarized in Table 2. The presence of STAS has been found to be associated with lymphovascular-, vascular- and pleural invasion as well as with criteria for higher histological

The alternative explanation for ‘loose fragments’

In vivo spread of tumor cells in oncologic surgery is a well-known phenomenon and therefore the general approach is to avoid cutting through a tumor, as if this occurs, the whole field of operation is then considered to be contaminated. In a model system, the chance of tumor recurrence was instrument dependent [28]. In medicine, tumor contamination of a biopsy path with subsequent outgrowth of the tumor along that path is seen in different tumor types such as NSCLC [[29], [30], [31], [32], [33]

Mimickers of ‘loose tissue fragments’

Yet other explanations of 2-dimensional representations of loose tissue fragments are i) poor fixation and ii) collapse of certain adenocarcinoma subtypes.

In pulmonary specimens subjected to a delay in fixation resulting in poor fixation, the bronchial epithelium frequently detaches from the underlying basement membrane and can be displaced by handling, with displacement occurring into the adjacent alveolar spaces. This phenomenon is well known, especially in autopsy specimens, but may also

How to explain the association of ‘loose tumor fragments’ with poor prognosis?

A plausible biological explanation for the association of loose tumor fragments with poor prognosis is that disruption of tumor cells is simply seen in poorly differentiated, highly discohesive tumors. It has been postulated that such poorly differentiated discohesive tumors have fewer intercellular adhesions between tumor cells, such as in micropapillary adenocarcinomas and poorly differentiated squamous cell carcinomas [[42], [43], [44], [45]]. Interestingly, in micropapillary carcinoma

Conflict of interest

All authors declare that they have no any conflict of interest.

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