IMAGING OF MESOTHELIOMA

Introduction

Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm that is refractory to current therapies and associated with poor prognosis. The disease originates in pleural mesothelial cells and progresses locally along the pleural reflections until it encases the lungs and mediastinum, ultimately causing death. MPM has been designated as a worldwide epidemic, which is predicted to peak in the next decade (2015–2019) in most Western countries Patients with mesothelioma have an average survival of 7–12 months; however, trimodality therapy with cytoreductive surgery followed by radiotherapy and chemotherapy can prolong survival  The three distinct histologic subtypes – epithelial, sarcomatoid (sarcomatous), and mixed (biphasic) – cannot be distinguished by imaging. Even though contrast-enhanced CT is the preferred technique for evaluating suspected malignant pleural disease, histological sampling and immunohistocytochemistry can only reliably

diagnose MPM. The complex morphology and growth pattern of MPM make it an imaging enigma. This chapter aims to highlight the practical aspects of imaging of MPM with an emphasis on guiding management.

Patterns of Presentation and Imaging Features

MPM has varied and nonspecific imaging appearances ranging from pleural effusion, focal pleural thickening, diffuse circumferential pleural thickening, pleural nodularity to pleural masses. Calcified and noncalcified bilateral pleural plaques coexist with pleural thickening. Pleural thickening can be focal or circumferential

and extends along the mediastinal, diaphragmatic surface of the pleura and along fissures. Nodal involvement and contiguous invasion of adjacent chest wall and direct intra-diaphragmatic extension can be seen in later stages. Contralateral disease can be in the form of pleural effusion or pulmonary nodules. Brain and osseous metastases can be seen in later stages, as well. The constellation of findings ranges from unilateral pleural effusion, circumferential nodular pleural thickening, pleural masses, and invasion of adjacent structures, to adenopathy, osseous, pulmonary and distant metastases in the later stages. Pleural thickening and/or effusions also represent early presentation and are nonspecific without histological confirmation. Rind-like circumferential pleural thickening is seen as the disease progresses, with the disease process often starting from the diaphragmatic surface of the pleura extending upward. Apical involvement is considered a bad prognostic factor and is seen in later stages. Volume loss and mediastinal shift can be seen secondary to encasement of the lung. Sixty percent of the time the disease is seen on the right and is only bilateral in 10% cases. Biphasic and sarcomatoid subtypes have more aggressive behavior and can present with distant and osseous metastases in early stages of the disease.

Preoperative Evaluation of MPM
MPM patients are considered surgical candidates if the disease is confined to the ipsilateral hemithorax and there is no evidence of spread to mediastinal lymph nodes (N = 0) or distant metastases (M = 0). Current methods for predicting resectability of patients undergoing extrapleural pneumonectomy for macroscopic complete resection of MPM are limited. Despite improvements in diagnostic imaging over several decades, the proportion of patients who are unable to complete resection after thoracotomy remains high at 25%  Using current methods of preoperative evaluation for patients with malignant pleural mesothelioma, evidence of local invasion of contiguous structures, transdiaphragmatic or transmediastinal invasion, and diffuse chest wall invasion are clear indicators of unresectability. Computed tomography (CT) is the mainstay in preoperative evaluation and is complemented by magnetic resonance imaging and 18F-FDG positron tomography Plain radiography plays a limited role due to varied and nonspecific appearances ranging from pleural effusion to lobulated pleural thickening and pleural masses. Pleural plaques, the hallmark of asbestos exposure, further limit evaluation on radiographs and can potentially obscure contralateral involvement and can obscure pulmonary nodules. CT continues to be the initial and primary modality for diagnosis, staging, and monitoringof therapeutic response in MPM [25]. Even though CT can easily depict the overall extent of

the pleural abnormality, early chest wall invasion, peritoneal involvement, and lymph node metastases can be challenging even on a contrast- enhanced CT scan. Subtle transdiaphragmatic extension can also be difficult to identify on CT.
CT image data can also be effectively reconstructed in three-dimensional planes to yield multi-planar reformats and volume rendered images to simulate the anatomical detail for surgical planning. Three-dimensional (3-D) volume rendered images are increasingly becoming popular to show association with adjacent structures and encasement or encroachment of vascular structures by the tumor [13, 15]. Maximum intensity projections depict the course of vessels encased by the pleural rind and are helpful during
surgery. The 3-D images are intuitive and provide the surgeons an overview of the tumor in vitro, thereby aiding the surgeons during resection. These images also provide patients an overview and extent of their disease during management discussions.
Furthermore, volumetric assessment of MPM can be easily acquired by serially segmenting the tumor using Hounsfield thresholding. Tumor and lung volumes can be generated and have been proven to be prognostically significant.
Ultrasound has a limited role in diagnosis and management of MPM; however, the fluid attenuation of the tumor provides a diagnostic window for the ultrasound, thus enabling ultrasound-guided biopsy and thoracentesis, thereby improving the diagnostic yield of pleural biopsy . MRI is superior to CT both in the differentiation of malignant from benign pleural disease due to its superior signal-to-noise ratio and is the modality of choice in the assessment of chest wall and diaphragmatic invasion by MPM. Dynamic contrast-enhanced (DCE) MRI is a promising technique and has the ability to correlate histology and pathology(Giesel 2008).

MRI not only confirms the CT findings such as diffuse pleural thickening and pleural effusion, but is superior in delineating contiguous invasion of adjacent structures. MPM has intermediate to slightly high signal intensity on T1-weighted images (T1-WI) and moderately high signal intensity on T2-weighted images (T2-WI) as compared to adjacent chest wall musculature and shows moderate enhancement after administration of gadolinium. MRI has a higher sensitivity and specificity to CT in detecting early chest wall and subdiaphragmatic involvement. Linear enhancing foci in the chest wall depicting sites of previous biopsy, thoracotomy, or chest tube tracts are also relatively more easily seen on MRI than on CT.


Postoperative Evaluation
Curative treatment for MPM is with extrapleural pneumonectomy. Localized disease or minimal disease is treated with local resection or radical pleurectomy or pleural decortication. Radiographs are used to follow patients postoperatively, reserving CT for evaluating complications.
After pneumonectomy, the pneumonectomy space fills up with fluid, generally at the rate of one intercostal space per 7 days, and can be
monitored by serial radiographs. Controlled filling of the pneumonectomy space helps control mediastinal shift [35]. Rapid filling of the pneumonectomy space is worrisome and is of concern for hemorrhage within the pneumonectomy space or a Chyle leak. Slow filling of the pneumonectomy space or decreasing fluid
level is worrisome for a bronchopleural fistula, or leakage of fluid into the abdomen along the diaphragmatic reconstruction, both these scenarios are secondary to infection
MDCT with the help of multi-planar reformats and 3-D imaging can help delineate the BPF. The data can also be interpolated to provide measurements for personalized stents . Ventilation scans can help delineate a tiny central BPF. Marsupialization of the pneumonectomy space and Clagette window creation are the treatments of choice for a central BPF. The pneumonectomy space is opened and cleaned and packed with antibiotic soaked packing in an attempt to heal the infection and then the cavity is closed and packed with a muscle flap, generally the latissimus dorsi or the omentum.
CT and PET 18F-Fluorodeoxyglucose scans are also used to identify and biopsy possible sites of recurrence. Another complication seen especially with a left-sided pneumonectomy is herniation of stomach along the medial aspect of the pneumonectomy space. Plain radiographs are the best at depicting the herniation of the gastric bubble above the gortex reconstruction, usually seen on the first postoperative radiograph.
Post-pneumonectomy syndrome, another rare complication, can also be assessed by CT. The left main stem bronchus gets stretched over the vertebral body due to severe mediastinal shift to the right postpneumonectomy . The mediastinal shift can be corrected by putting in a saline-filled implant into the pneumonectomy space, with an aim to displacing the mediastinal structure. MR is a very useful modality when Chyle leak is suspected and helps in identifying the site of leak and the thoracic duct prior to embolization. Recurrence and/or progressive metastatic disease are generally evaluated by contrast-enhanced CT scan. Multiple patterns of recurrence are seen mostly as enlarging soft tissue masses along the resection margins, ascites, and peritoneal thickening, which is a manifestation of intra-abdominal disease, new pulmonary nodules, and increasing size of mediastinal nodes. FDG/ PET is very useful in restaging and also monitoring response to therapy.
Post-radical pleurectomy, the granulation tissue along resection margins can be irregular and nodular, thus often raising concern for recurrence; however, serial FDG/PET can help distinguish between the two by semiquantitative evaluation of tracer uptake. Tumor will show progressive increase in uptake of tracer as opposed to granulation tumor, which slowly, over a period of time, will either regress or remain stable.


Future Directions
Dynamic contrast-enhanced MRI can be used to map the heterogeneity of microcirculation in MPM and can be used to predict therapeuticresponse and stratify survival. The development of such a quantitative technique will bring new measures essential to the diagnosis and management of patients with MPM, and will enable an objective assessment of new pharmacologic agents and serve as a possible tumor biomarker enabling prediction of outcomes. Diffusion MRI, combined with DCE MRI, can be a powerful tool. ADC maps derived by plotting intensity from multiple b values can be used to measure tumor cellularity. However, these techniques need to be validated and studied before they can be adapted into clinical practice.



Summary
Imaging plays a key role in diagnosis, management, and follow-up of patients with MPM. CT is the primary diagnostic modality in diagnosis, staging, and posttreatment management of MPM. MRI and PET provide additional and complementary information to CT. Optimization of current MR protocols will provide more efficient and valuable MR applications and potentially serve as an imaging biomarker. Larger population studies and correlation of imaging to pathology and genomic profiles can help improve survival.