Malignant Mesothelioma - Clinical Tree

Summary of Key Points

Development of malignant mesothelioma is usually associated with asbestos exposure.
The most common genetic alterations in mesothelioma are deletion of CDKN2A/ARF , inactivation of NF2 , and mutation or deletion in BAP1.
The eighth edition of the American Joint Commission on Cancer/Union for International Cancer Control staging manual has altered the T and N components for staging from the previous edition.
Clinical, imaging, and serum biomarkers can contribute to prognostication in pleural mesothelioma.
First-line palliative chemotherapy is cisplatin (or carboplatin) with pemetrexed; appropriate patients may benefit from the addition of bevacizumab.
There is no standard second-line chemotherapy for pleural mesothelioma although reintroduction of a pemetrexed-containing regimen, or the use of vinorelbine or gemcitabine, would be considered reasonable.
Optimal surgical management of malignant pleural mesothelioma remains controversial.
Immunotherapies including mesothelin-targeted agents and immune checkpoint inhibitors have shown promising efficacy in mesothelioma but further research is required before these are adopted as standard therapy.

All mesothelioma tumors originate from the lining of the pleural cavity, the lung, the pericardium, and the abdominal cavity, including the tunica vaginalis. After transformation of the mesothelium or peritoneum, subtypes of mesothelioma can develop. Malignant mesothelioma (MM) occurs most frequently on one side of the thorax (Malignant Pleural Mesothelioma [MPM]—80%) with the remainder occurring in the abdomen as malignant peritoneal mesothelioma. Although the World Health Organization classification distinguishes three main histologic subtypes of mesothelioma, epithelioid (60%), sarcomatoid (10% to 15%), and biphasic (25% to 30%), there are different subtypes of the epithelioid histology. These subtypes include the papillary, pleomorphic, tubulopapillary, and small cell type. However, these subtypes are not standardly reported.

The main cause of MPM is the exposure to asbestos fibers, which was first described by Wagner et al. Other causes of mesothelioma are endemic erionite exposure in Turkey, ionizing radiation, and chronic inflammation in the pleura. Unlike the case with lung cancer, cigarette smoking does not play a role in the development of MPM. MPM is one of the best-known occupational diseases and it is more likely to develop in men than in women (90% vs. 10%), primarily as a result of its association with mining and processing of asbestos fibers. Given the long latency period of 30 to 50 years, the prevalence of mesothelioma is expected to peak for the next decade. Regulations against handling and mining asbestos in Western Europe and the United States were put in place in the 1990s. It is expected that the disease will be increasingly encountered in third-world countries because of the lack of legislation and increased export to these countries.

Biology of Malignant Pleural Mesothelioma

Considerable progress has been made in understanding the molecular basis of mesothelioma, which has, in turn, led to an abundance of preclinical studies translating these discoveries to treatment.

Some people with mesothelioma have no history of asbestos exposure or prior radiotherapy. In the case of peritoneal mesothelioma, many patients are teenagers or young adults. Good evidence now exists that at least in some people there may be a genetic basis for developing mesothelioma, which could lead to mesothelioma by itself or cause some individuals to be susceptible to asbestos carcinogenesis. Cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF) , neurofibromatosis type 2 (NF2) , and BRCA1-associated protein 1 (BAP1) are the most frequently mutated tumor suppressor genes in mesothelioma.

Cyclin-Dependent Kinase Inhibitor 2A/Alternative Reading Frame

CDKN2A/ARF is the most frequently inactivated tumor suppressor gene in malignant mesothelioma and encodes two important cell cycle regulatory proteins, p16 (INK4A) and, in an alternative reading frame, p14 (ARF) . p16, a cyclin-dependent kinase (CDK) inhibitor, blocks phosphorylation of retinoblastoma protein, and p14 (ARF) blocks murine double minute 2 (MDM2) , thus resulting in a positive regulation of p53. Homozygous deletion of CDKN2A/ARF thus results in inactivation of two major tumor suppressing pathways, retinoblastoma protein and p53.

CDKN2A deletion is found in about 70% of primary tumors and nearly all mesothelioma cell lines.

Neurofibromatosis Type 2

The NF2 gene encodes a tumor suppressor protein Merlin, a member of the band 4.1 family of cytoskeletal linker proteins. Inactivating NF2 mutations are found in 35% to 40% of MPMs. The mechanisms of Merlin-mediated tumor suppression are not well defined. Merlin mediates contact-dependent inhibition of cell proliferation in normal cells, primarily through inhibition of mammalian target of rapamycin (mTOR) in an AKT-independent manner. mTOR activity is aberrantly upregulated in the absence of Merlin, leading to increased cell proliferation.

BAP1

Up to 60% of mesotheliomas have BAP1 alterations, which include, among others, homozygous deletions of partial or entire BAP1 and sequence-level mutations. BAP1 is located on chromosome 3p21.1, which is also deleted in several human malignancies. Germline BAP1 mutations were described in 2011 in mesothelioma families in which BAP1 mutation carriers had an exceptionally high incidence of malignancies, including mesothelioma and uveal melanoma. These malignancies did not develop in family members who did not carry germline BAP1 mutations. BAP1 is a nuclear protein that enhances BRCA1-mediated inhibition of breast cancer cell proliferation, acting as a tumor suppressor in the BRCA1 growth control pathway and regulating proliferation by deubiquitinating host cell factor. BAP1 influences a wide array of cellular functions, and its depletion induces significant changes in the expression of many genes that control various cellular pathways.

Diagnosis

Diagnosis of mesothelioma may be achieved by cytologic analysis of pleural effusions sampled by thoracentesis, blind pleural biopsy, computed tomography (CT)-directed fine-needle aspiration or core biopsy, and, increasingly more commonly, via pleuroscopy. However, in a considerable number of cases, evaluations of specimens obtained by these less invasive modalities are inconclusive, necessitating surgical biopsy. Video-assisted thoracoscopic surgery (VATS) is the preferred method for surgical diagnosis of MPM ( Fig. 53.1 ). VATS allows large tissue samples to be obtained from multiple areas of the thoracic cavity, an important consideration, given the considerable tumor heterogeneity within individual mesothelioma tumors. Multiple separate biopsies by VATS increases the likelihood of accurately determining histologic subtype. VATS can also be used to identify whether the tumor involves the visceral pleura as well as the parietal pleura, although this distinction is no longer required for staging with the updated American Joint Commission on Cancer (AJCC)/Union for International Cancer Control (UICC) eighth edition guidelines. VATS is otherwise of limited use for assessment of tumor or node stage. Although VATS is most easily performed in patients with a large effusive component, occasionally tumor burden is such that VATS is impossible due to fusion of the visceral and parietal pleurae and, in such instances, a small, 2-cm cutdown can usually allow access to the underlying pleural tumor under direct vision. A further merit of VATS is that it allows talc pleurodesis to be done at the time of tissue diagnosis, which often obviates the need for additional palliative procedures. Pleurodesis does not influence the ability to perform subsequent cytoreductive surgery (pleurectomy/decortication [PD] or extrapleural pneumonectomy [EPP]). Talc will cause fluorodeoxyglucose (FDG) activity in the pleural distribution and in mediastinal lymph nodes on positron emission tomography (PET) imaging. For this reason, initial staging with PET should be performed before talc pleurodesis.

Fig. 53.1, (A) Computed tomography (CT) image of a male patient with a pleural effusion and minimal pleural thickening. (B) Image from video-assisted thorascopic surgery shows multiple nodules on chest wall at the level of the CT image. (B) The lung is partly collapsed and shows no involvement.

Thoracotomy is to be avoided as a diagnostic method as it not only causes the patient unnecessary trauma but also hampers the performance of subsequent cytoreductive surgery due to disruption of tissue planes and risks iatrogenic tumor invasion of the chest wall.

Staging

The AJCC/International Mesothelioma Interest Group staging system is based primarily on pathologic data and is, therefore, of limited use when applied to clinical staging of this disease. Many of the factors that contribute to stage assignment, such as involvement of the pericardium, lung, and diaphragm; involvement of the endothoracic fascia; and lymph node metastases, for example, simply are not possible to determine accurately with current imaging technology. The staging system has recently undergone revision based on an international multicenter prospective data collection of detailed staging information and component descriptors ( Table 53.1 ). The revision for the eighth edition AJCC/UICC staging system has made a number of important changes, including collapsing T1a and T1b into T1 and revising nodal staging such that any ipsilateral mediastinal involved lymph nodes are all included as N1 disease, whereas nodes previously categorized as N3 and reclassified as N2. PET is useful for identifying occult distant metastatic disease (present in up to 25% of cases), but it is inaccurate for determining T and N stage.

TABLE 53.1

IASLC Mesothelioma Staging Project: TNM Definitions ^∗

Stage	Definition
Primary Tumor (T)
TX	Primary tumor cannot be assessed
TO	No evidence of primary tumor
T1	Tumor imited to the ipsilateral parietal± visceral ± mediastinal± diaphragmatic pleura
T2	Tumorinvolving each of theipsi ateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: involvement of diaphragmatic muscle extension of tumor from visceral pleura into the underlying pulmonary parenchyma
T3	Describeslocally advanced but potentially resectable tumor. Tumor involving all of theipsilaterat pleuralsurfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: involvement of the endothoracic fascia extension into the mediastinal fat solitary, completely resectabte focus of tumor extendinginto the soft tissues of the chest wall nontransmurat involvement of the pericardium
T4	Describes locally advanced technically unresectable tumor. Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following features: diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction direct transdiaphragmatic extension of tumor to the peritoneum direct extension of tumor to the contralaterat pleura direct extension of tumor to mediastinal organs direct extension of tumor into the spine tumor extending through to the internal surface of the pericardium with or without a pericardial effusion, or tumor involving the myocardium

Regional Lymph Nodes (N)
NX	Regional lymph nodes cannot be assessed
NO	No regional lymph node metastases
N1	Metastases in the ipsilateral bronchoputmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal lymph nodes) lymph nodes
N2	Metastases in the contralateral mediastinal, ipsilaterat, or contralateral supraclavicutar lymph nodes

Distant Metastasis (M)
MO	No distant metastasis
Ml	Distant metastasis present

IASLC Mesothelioma Staging Project: Stage Grouping Changes
	NO		N1 /N2	N1	N3	N2
Stage	Seventh Edition	Eighth Edition	Seventh Edition	Eighth Edition	Seventh Edition	Eighth Edition
Tl	I (A, B)	IA	Ill		IV	IIIB
T2	II	IB	III		IV	IIIB
T3		IB	Ill	lllA	IV	IIIB
T4	IV	IIIB	IV	IIIB	IV	IIIB
M1	IV	IV	IV	IV	IV	IV

∗ Modified from Rusch VW, Chansky K, Kindler HL, Nowak AK, Pass HI, Rice DC, et al. IASLC Staging and Prognostic Factors Committee, advisory boards, and participating institutions.The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma. J Thorac Oncol. 2016;11(12):2112-2119.

Laparoscopy and Thoracoscopy

Extension of the tumor through the diaphragm into the peritoneal cavity or dissemination to the contralateral side can occur, which will influence the staging and treatment options. Rice et al. reported on 109 patients who had routine laparoscopy before planned EPP and found nine (8.3%) patients with transdiaphragmatic extension of tumor and one (0.9%) with diffuse peritoneal carcinomatosis. Alvarez et al. performed thoracoscopic examination of the contralateral side and found contralateral chest involvement in three (10%) of 30 patients from a selected group.

Mediastinal Evaluation

Lymph node metastases occur in approximately 50% of patients with MPM undergoing multimodality therapy and portends a poor prognosis. Current imaging modalities are inaccurate for defining N stage, and, therefore, cervical mediastinoscopy has been advocated for pretreatment staging of MPM. The sensitivity, specificity, and accuracy for cervical mediastinoscopy have been reported by two groups and vary from 60% to 80%, 71% to 100%, and 67% to 93%, respectively.

Endobronchial ultrasound (EBUS)- and endoscopic ultrasound (EUS)-guided fine-needle aspiration of mediastinal lymph nodes have been highly effective for staging nonsmall cell lung cancer. Rice et al. compared 50 consecutive patients with mesothelioma who had staging cervical mediastinoscopy with 38 patients who had staging EBUS. Sensitivity and negative-predictive value were 28% and 49%, respectively, for cervical mediastinoscopy, and 59% and 57%, respectively, for EBUS. Furthermore, 11 patients had EUS preoperatively, and metastases were found in the infradiaphragmatic nodes in five patients. Tournoy et al. performed EUS and fine-needle aspiration in 32 patients with presumed early-stage mesothelioma and identified N2 metastases in four patients (12.5%). In 17 patients who subsequently had extrapleural pneumonectomy, one false-negative result (4.7%) was found. Some centers now prefer to stage the mediastinum by combined EBUC and EUS before entering a patient into a multimodality trial.

Biomarkers

Biomarkers have the potential to play a key role in current oncology practice. They can be used in diagnosis (screening), measurement of response, and follow-up. The requisites that apply for biomarkers are technical reproducibility, validation, and clinical relevance. Diagnostic biomarkers can underpin screening programs and early detection in high-risk individuals, can help to direct diagnostic procedures, and can provide support for cytologic or histologic diagnoses. Biomarkers can be predictive for a response or can be prognostic. Predictive biomarkers can assist with treatment selection, in particular drug therapy. Biomarkers of response can accelerate drug development through surrogate end point and provide guidance during routine patient care. Prognostic biomarkers can give patients and clinicians valuable information, in addition to their use as stratification factors in clinical trials. Biomarkers can involve blood measurements (plasma or serum) or molecular genetics or can be based on imaging.

Diagnostic Biomarkers

The development of robust diagnostic serum biomarkers for mesothelioma is important, as exposure to the etiologic agent is often known. A population with heavy asbestos exposure would be rational participants in a screening program. The availability of a blood-based biomarker would facilitate early detection and treatment. The most important candidate diagnostic serum biomarkers are mesothelin (serum mesothelin-related protein), osteopontin, and fibulin-3. Elevated levels of mesothelin are highly specific, unless patients have concurrent renal failure, and add to the diagnostic certainty or direct additional investigations when a diagnosis of mesothelioma is suspected. However, mesothelin lacks sensitivity at the time of diagnosis, thus limiting its use in screening. Osteopontin does not perform as well as mesothelin. In 2012, Pass et al. reported on fibulin-3 as a blood and effusion biomarker. Plasma levels of fibulin-3 were significantly higher for patients with mesothelioma than in people exposed to asbestos without mesothelioma, with a sensitivity of 100% and specificity of 94% reported. Effusion levels of fibulin-3 were also significantly higher in effusions from mesothelioma than from other etiologies; nevertheless, these findings should be further validated before translation to practice. Carcinoembryogenic antigen is a well-known marker that will not be elevated in case of a MPM. It can be used for quick screening for other tumor types with pleural dissemination.

Prognostic Biomarkers

A number of simple prognostic biomarkers have been well established in the literature for MPM. At pathologic diagnosis, a diagnosis of sarcomatoid or nonepithelioid subtypes of mesothelioma is uniformly associated with poor prognosis. The same large retrospective series, mostly based on collections of clinical trial data, has also validated readily available laboratory parameters, including low hemoglobin, thrombocytosis, high white blood cell count, and elevated serum lactate dehydrogenase level as poor prognostic indicators. In 2010, Kao et al. proposed and independently validated an elevated neutrophil-to-lymphocyte ratio as a poor prognostic indicator; however, the patient groups used were heterogeneous and relatively small, and others have been unable to confirm these findings. High serum vascular endothelial growth factor (VEGF) levels have been found to correlate with poor prognosis and advanced stage of disease. A recent publication used a Classification and Regression Tree analysis to group patients into prognostic categories at diagnosis, deriving four prognostic groupings with median survivals ranging from 7.5 months (risk group 4) to 34 months (risk group 1) using readily available clinical indicators including weight loss, hemoglobin level, performance status, histology, and albumin level.

Considering prognostic serum biomarkers more specific to mesothelioma, mesothelin levels at diagnosis may also be prognostic; however, mesothelin levels appear to reflect tumor bulk, as the addition of tumor bulk metrics to the model eliminates the significance of serum mesothelin. No strong evidence exists that serum osteopontin is useful in prognostication, although lower tissue expression of osteopontin may be associated with longer survival and plasma osteopontin as well as mesothelin were found to increase prognostic accuracy in combination with the EORTC and CALGB mesothleioma prognostic indices.

Many candidate tumor molecular and histologic prognostic markers have been reported (phosphatase and tensin homolog, VEGF expression, fibroblast growth factor 2, cyclooxygenase-2, platelet-derived growth factor, epidermal growth factor receptor, epithelial-to-mesenchymal transition, osteopontin, and c-MET expression); however, at the time of publication, none has been sufficiently validated to be entered into routine clinical use worldwide. The anticipation is that the extensive molecular profiling and characterization efforts proceeding worldwide will identify new molecular prognostic biomarkers that will translate to routine clinical practice in addition to providing potential molecular targets for therapy.

Prognostic Imaging Biomarkers

In addition to providing anatomic staging information regarding the sites of disease involvement, a substantial body of evidence indicates that the bulk of tumor as demonstrated on imaging and metabolic characteristics of tumor may be prognostic biomarkers. Tumor volume as measured by CT is a prognostic indicator, but it can be challenging to implement automated volumetric measurements due to the difficulty of distinguishing tumor from pleural fluid and atelectasis. Quantitative parameters from FDG-PET may be simpler to implement reproducibly and with less manual input. FDG-PET has consistently shown prognostic value in MPM, although the appropriate metric for quantitative assessment remains the subject of debate. A higher maximum standardized uptake value (SUV) is a poor prognostic indicator. However, the inclusion of volumetric parameters may also be important, with the concepts of total lesion glycolysis or total glycolytic volume incorporating both SUV and a measure of lesion volume and performing better than SUV alone in studies incorporating both measures.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here