Elsevier

Lung Cancer

Volume 82, Issue 2, November 2013, Pages 190-196
Lung Cancer

Review
Imaging in pleural mesothelioma: A review of the 11th International Conference of the International Mesothelioma Interest Group

https://doi.org/10.1016/j.lungcan.2013.08.005Get rights and content

Abstract

Imaging of malignant pleural mesothelioma (MPM) is essential to the diagnosis, assessment, and monitoring of this disease. The complex morphology and growth pattern of MPM, however, create unique challenges for image acquisition and interpretation. These challenges have captured the attention of investigators around the world, some of whom presented their work at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012. The measurement of tumor thickness on computed tomography (CT) scans is the current standard of care in the assessment of MPM tumor response to therapy; in this context, variability among observers in the measurement task and in the tumor response classification categories derived from such measurements was reported. Alternate CT-based tumor response criteria, specifically direct measurement of tumor volume change and change in lung volume as a surrogate for tumor response, were presented. Dynamic contrast-enhanced CT has a role in other settings, but investigation into its potential use for imaging mesothelioma tumor perfusion only recently has been initiated. Magnetic resonance imaging (MRI) and positron-emission tomography (PET) are important imaging modalities in MPM and complement the information provided by CT. The pointillism sign in diffusion-weighted MRI was reported as a potential parameter for the classification of pleural lesions as benign or malignant, and PET parameters that measure tumor activity and functional tumor volume were presented as indicators of patient prognosis. Also reported was the use of PET/CT in the management of patients who undergo high-dose radiation therapy. Imaging for MPM impacts everything from initial patient diagnosis to the outcomes of clinical trials; iMig 2012 captured this broad range of imaging applications as investigators exploit technology and implement multidisciplinary approaches toward the benefit of MPM patients.

Introduction

Mesothelioma is a malignant neoplastic growth of mesothelial cells that line anatomic cavities, specifically the pleura, peritoneum, pericardium, and tunica vaginalis. Malignant pleural mesothelioma (MPM) is the most common form of this disease and accounts for nearly 75% of cases [1]. An active and committed community of physicians, clinician-scientists, and basic researchers is engaged in understanding the genesis, biology, and biochemical response of mesothelioma to further the development of new treatment strategies. Advances in imaging have played an important role in the development of these strategies. Throughout the history of a mesothelioma patient, imaging plays a key role in diagnosis, pre-treatment assessment, treatment planning, monitoring, and post-treatment surveillance. If treatment involves surgery, imaging is used for pre-surgical planning and post-surgical follow-up; if treatment involves chemotherapy or some form of immunotherapy or targeted therapy, imaging is used for response assessment. The multi-faceted role of imaging has evolved in terms of scope, technical capabilities, and expectations. This paper synthesizes the state of science in imaging of MPM as presented at the 2012 International Conference of the International Mesothelioma Interest Group (iMig 2012) in Boston, Massachusetts, USA, September 2012.

Computed tomography (CT) is the first-line (and the most common) imaging modality for the evaluation of mesothelioma. The concept of “evaluation” traditionally has required qualitative interpretation by a radiologist; the term has taken on a more quantitative connotation as image-based surrogates of tumor burden and tumor response assessment have become necessary and more prevalent. Despite its ubiquitous availability and strong clinical value, CT has limitations. CT captures “form” (i.e., anatomic structure) rather than “function” (i.e., physiology or biological processes). Furthermore, the ability of CT to differentiate subtle differences among soft tissues may not be optimal [2]. Fortunately, complementary (and important) information is available through magnetic resonance (MR) imaging and positron-emission tomography (PET), although these imaging modalities are not always available or financially practical.

MR imaging provides improved anatomic detail due to increased signal-to-noise ratio, resulting in a more reliable depiction of chest wall and trans-diaphragmatic extension of mesothelioma tumor and the ability to distinguish pleural effusion from tumor [3]. Perfusion MR allows for quantification of blood-flow parameters (which have an analog in dynamic contrast-enhanced CT, see Section 5), and newer MR pulse sequences, such as diffusion-weighted magnetic resonance imaging (DW-MRI), have a unique role in the imaging of mesothelioma [4]. DW-MRI also gives rise to the “pointillism sign,” which has demonstrated utility in the non-invasive diagnosis of MPM (see Section 6).

PET imaging, and more recently PET-CT imaging, has been the subject of much investigation in the diagnosis, restaging, and post-therapy follow-up of mesothelioma. Although discrepant results have been obtained by various groups, the ability of PET to identify the presence of distant metastases emerges as the main strength of this imaging modality. PET continues to provide prognostic information (see Section 7) and assist in tumor response assessment. The reported utility of PET parameters such as SUVmax and SUVmean has varied over time. The parameter total glycolytic volume (TGV) combines SUV data with the spatial distribution of higher SUV pixels and has shown significant correlation with survival [5]. Imaging is a critical component of radiation therapy treatment planning and monitoring, and PET has been shown to play a key role in the management of patients undergoing radiotherapy for MPM (see Section 8).

CT-based tumor response is governed by the RECIST (response evaluation criteria in solid tumors) guidelines, which specify both a tumor measurement protocol and a set of response criteria that convert change in tumor measurements to one of four response categories: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The shortcomings of the RECIST guidelines when applied to the complex morphology and growth pattern of mesothelioma, which often grows as a rind around the pleural surface, led to the development of the modified RECIST guidelines [6]. Modified RECIST changed the measurement protocol from longest tumor diameter to tumor thickness perpendicular to the chest wall or mediastinum and adopted the same response criteria established by RECIST. The practical application of these criteria, and the definition of “measurable disease,” must consider the extent of variability inherent in manual tumor measurements [7] (see Sections 2 Tumor thickness measurement variability, 3 Variability in tumor response evaluation).

Tumor response based on linear measurements is meant to be a surrogate for change in tumor burden [8], [9], which may be better reflected in tumor volume. Since the manual delineation of tumor boundaries is a tedious and time-consuming task, some level of automation is essential for the acquisition of volumetric mesothelioma tumor measurements. Several recent semi-automated methods for volumetric assessment of mesothelioma require manual delineation of structures surrounding the tumor, manual initialization of the tumor boundary, and/or manual correction of the computer output [10], [11], [12]. Tumor volume has been incorporated in the clinical workflow at some institutions and has been used to establish pre-operative prognosis [13].

The ability to obtain mesothelioma tumor volume naturally leads to the notion of volume-based tumor response assessment. Two approaches to “volumetric response” exist: (1) discretize volume change into response categories or (2) maintain the quantitative, continuous volume change data. The most straightforward approach to the definition of volumetric response is to extend the one-dimensional response criteria of RECIST to three dimensions under the assumption of spherical tumor morphology on which RECIST is based. Mesothelioma, however, is not spherical, so the extrapolation of these criteria to three dimensions based on the mathematical relation between diameter and volume of a sphere is not necessarily relevant. The second approach to the definition of volumetric response is to use the actual numeric volume data to obtain data-driven volumetric assessments without grouping patients into response categories [10]; this approach makes possible the incorporation of time-varying tumor volumes to derive response models from the complete history of patients’ CT scans [14] (see Section 4).

Section snippets

Tumor thickness measurement variability

Single time-point unidimensional MPM tumor thickness measurements define measurable disease for clinical trial inclusion and establish the baseline tumor burden, and tumor thickness measurements across multiple time points provide the basis for tumor response assessment. Although modified RECIST [6] adapted the tumor measurement approach of the RECIST guidelines [15] to the unique morphology and growth pattern of MPM, modified RECIST changed neither the tumor response criteria of RECIST nor the

Variability in tumor response evaluation

MPM treatment monitoring is difficult due to the unique growth pattern of this tumor so that unidimensional measurements of the long axis (e.g., RECIST) or even bidimensional measurements (e.g., WHO) seem poorly suited for this task in pharmacological phase II/III trials and routine clinical practice. A number of varying response evaluation guidelines exist, including mesothelioma-specific modified RECIST (tumor thickness at two positions at three separate CT sections for up to 6 target

Tumor volume and lung volume as markers of patient response

While the majority of clinical image-based response assessment in MPM is performed using the modified RECIST measurement technique with changes classified according to the standard RECIST criteria, changes in three-dimensional disease bulk may be more directly related to therapeutic response. Moreover, it is reasonable to expect that increases in disease volume will result in corresponding decreases in the aerated lung volume. A study presented at iMig 2012 by Labby and colleagues investigated

Dynamic contrast-enhanced CT

Dynamic contrast-enhanced (DCE) CT is an imaging modality that combines the structural information of standard CT with functional hemodynamic information. DCE-CT imaging captures repeated views of a fixed anatomic location over some several-minute duration of time as the injected contrast courses through the body. At iMig 2012 Labby and colleagues reported on an ongoing prospective pilot study to assess the viability of DCE-CT as an imaging modality for patients with MPM and to investigate

Diagnostic impact of pointillism sign in diffusion-weighted imaging

Since 2009, Coolen et al. have been evaluating the potential role of magnetic resonance imaging (MRI) in the diagnosis and staging of MPM by combining anatomic MRI sequences with diffusion and perfusion sequences at a magnetic field strength of 3 T [25]. In a prospective study presented at iMig 2012, this group reported two radiologic parameters, namely the “shrinking lung” sign (i.e., volume loss of the affected lung) and the newly introduced sign of pointillism (i.e., speckled hyperintensities

PET-based survival prediction

MPM has a poor prognosis despite multimodal therapy; nevertheless, variation in survival exists among patients. Prognostic information, therefore, is potentially valuable in patient management, particularly in the context of clinical trials when patients can be stratified according to risk. 2-[18F]fluoro-2-deoxy-d-glucose PET combined with CT (18F-FDG PET/CT) measures metabolic tumor activity and has the potential to predict aggressiveness of MPM and, hence, predict prognosis.

Klabatsa and

PET-based management of radiotherapy

Feigen and colleagues have implemented a clinical program of high-dose radiotherapy for selected patients with localized MPM and incompletely resected disease, relying on PET/CT scans to differentiate viable tumor from postoperative changes and radiation fibrosis and identify targets for higher doses within a larger radiation field. PET scans were performed with planning, 3 months post-radiotherapy, and whenever further intervention was under consideration. At iMig 2012 this group reported

Discussion

Imaging continues to play an important role in the diagnosis, evaluation, and management of mesothelioma. CT remains the primary imaging modality in these settings, but researchers continue to strive to understand the limitations of CT while simultaneously seeking to advance the utility of this modality. The CT-based modified RECIST tumor response guidelines that have become the standard clinical tool for the evaluation of tumor burden and response to therapy remain more reliable than other

Conflict of interest

SGA receives royalties and licensing fees through The University of Chicago for computer-aided diagnosis technology. SGA is grateful for funding from The University of Chicago Comprehensive Cancer Center, the Raine Medical Research Foundation, and the Cancer Council Western Australia.

ZEL is grateful for funding from the Paul C. Hodges Society of the Department of Radiology at The University of Chicago, The University of Chicago Comprehensive Cancer Center, the Raine Medical Research Foundation,

Acknowledgments

The authors gratefully acknowledge the International Mesothelioma Interest Group (iMig) and all those who contributed to the 11th International Conference in Boston, Massachusetts, co-chaired by Raphael Bueno, M.D., and David J. Sugarbaker, M.D. SGA would like to thank Anna K. Nowak, MBBS FRACP, Ph.D., and Roslyn J. Francis, MBBS FRACP, Ph.D. ZEL would like to thank William F. Sensakovic, Ph.D., Hedy L. Kindler, M.D., Christopher Straus, M.D., Jennifer Shouldis, R.N., and Anna K. Nowak, MBBS

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