Primary Tumors of the Pleura: Mesothelioma

Primary benign and malignant tumors of the pleura are rare, and they include solitary fibrous tumor, adenomatoid tumor, pleural desmoid tumors, calcifying fibrous pseudotumor, and malignant pleural mesothelioma (MPM).1,2 For clinicians, the most frequent differential diagnosis is solitary fibrous tumor versus MPM. Solitary fibrous tumors of the pleura are significantly less common than MPM and are not associated with asbestos exposure.³ Solitary fibrous tumors are generally asymptomatic at the time of diagnosis, and the radiographic features are a well-circumscribed, peripheral mass that abuts the pleural surface, frequently attached by a pedicle.⁴ Approximately 10% to 20% of solitary fibrous tumors are classified as malignant; malignant tumors are characterized by mitoses, necrosis, atypia, and hypercellularity.⁴ Radiographically malignant solitary fibrous tumors compared to benign tumors tend to be larger and are associated with increased likelihood of being positive on positron emission tomography (PET).^5,6 Patients with malignant solitary fibrous tumors tend to have a higher recurrence rate and worse survival.^7–10 The primary treatment for solitary fibrous tumors is complete surgical resection if feasible.^12–12 Because of the rarity of solitary fibrous tumors, it is difficult to define the natural history and the optimal management, but postoperative radiation and chemotherapy are not standard therapies. The primary focus of this section will be on MPM because that is the most common pleura malignancy.

Epidemiology

The association between MPM and asbestos exposure has been well established for decades; in the mid-20th-century, commercial uses for asbestos were developed, which led to increased occupational exposure of asbestos. Common sites of occupational exposure were in asbestos mines, shipyards, cement factories, or work with insulation. Asbestos refers to six fibrous silicate minerals found widely throughout the world, and is divided into two categories based on the chemical composition and crystalline structure13,14: a serpentine form (ie, chrysotile) and a thin, rodlike form (ie, amphiboles, including crocidolite, amosite, anthophyllite, tremolite, and actinolyte).¹⁵ The association of the amphibole form and MPM is well established, but the association between the serpentine form and MPM is a matter of debate.¹³ The long latency period between asbestos exposure and the development of MPM can make identification of the type, amount, and duration of asbestos exposure difficult. There does not appear to be a linear relationship between exposure and risk of developing MPM, and it appears that prolonged exposure is required in order to develop MPM. This is important for workers who had sporadic or limited exposure.¹³ A higher rate of MPM has been observed among family members of workers with occupational exposure caused by secondary exposure from clothes and close contact.^16,17 Some patients with MPM will not report a known asbestos exposure, so the absence of a history of asbestos exposure should not eliminate MPM from the differential diagnosis.¹⁸ Other less common etiologic agents associated with MPM include prior radiation therapy, diagnostic use of thorium dioxide (Thorotrast), mineral fibers with similar properties (e.g., erionite), and potentially simian virus 40.¹⁹ In the United States, the incidence of MPM is estimated to be 2000 to 3000 cases per year and it appears to be rising, which is related to not only increased asbestos exposure a generation ago but also improved recognition.^20,21

Despite the clear association between asbestos exposure and MPM, only a minority of people with significant exposure develop MPM (~5%), and the identification of MPM clusters within certain families raises the question about influence of genetics in carcinogenesis.¹⁴ A study of a MPM epidemic in Cappadocia, Turkey, and the United States revealed that the risk of developing MPM is transmitted in certain high-risk families, suggesting a genetic predisposition to erionite carcinogenesis.²² A high incidence of MPM in some families in the United States has been linked to germline mutations of the BAP1 gene.²³ BAP1 somatic mutations have been identified in 25% of sporadic MPM as well.^23,24 BAP1 appears to regulate deubiquitination during the DNA damage response and the cell cycle, and mutations that affect the deubiquitination of BAP1 or the nuclear localization reduce the tumor suppressor activity of BAP1.²⁵ Other potential mechanisms of carcinogenesis include direct mechanical interference of asbestos fibers with chromosome segregation during mitosis or the generation of oxidants by macrophages attempting to digest asbestos fibers.^28–28 The presence of asbestos causes inflammation, and the chronic inflammation associated with the asbestos fibers contributes to the process of carcinogenesis.^14,29,30 The mechanism of carcinogenesis from chronic inflammation appears to be related to the cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).^30,31

Clinical Presentation

The most common presenting symptoms for patients with MPM are shortness of breath, dyspnea on exertion, and chest wall pain or discomfort. Other less common symptoms include fever of unknown origin, sweats, weight loss, and a decline in performance status.³² Many times patients have symptoms for months prior to presenting to a medical professional. On physical examination, decreased breath sounds on auscultation or dullness to percussion may be present. Frequently, a chest x-ray is performed and this reveals a pleural effusion and/or opacification in one hemithorax. There are no specific laboratory abnormalities or tumor markers diagnostic of MPM, although it has been associated with thrombocytosis.³³

A thoracentesis is frequently performed to alleviate the patient’s symptoms, and it is part of the initial evaluation. A cytologic analysis of the pleural fluid is frequently performed; however, pleural effusion cytology is not reliable. Diagnostic cytologic criteria have not been established and invasion cannot be assessed on the specimen.36–36 Evidence of invasion into the subpleural adipose tissue is the most reliable indicator of malignancy.^34,37 Thus, if there is clinical suspicion of MPM, a pleural effusion cytology negative for malignancy is not sufficient to eliminate MPM from the differential. Many times, a thoracoscopic biopsy is required, and if the tumor is surgically resectable the thoracoscopic port should be placed within the line of a potential thoracotomy so the area can be excised at the time of thoracotomy; this is to help prevent seeding/recurrence at the port site, which has been reported.

A number of prognostic markers have been identified including performance status, histology, presence or absence of chest pain, younger age, and normal platelet count.32,33,38–41 Many of these factors were identified from retrospective analyses that included small numbers of patients. The European Organization for Research and Treatment of Cancer (EORTC) performed a multivariate analysis and found poor prognosis to be associated with poor performance status, a high white blood cell count, a probable/possible histologic diagnosis of MPM (compared to definite diagnosis), male gender, and sarcomatous histologic subtype.⁴² On the basis of these five factors, patients were divided into a good prognosis group (1-year survival rate of 40%, 95% confidence interval [CI] = 30% to 50%), and a poor prognosis group (1-year survival rate of 12%, 95% CI = 4% to 20%). This model was validated based on independent clinical trials.⁴³ An analysis of a phase III trial also validated the EORTC prognostic index and identified pain and appetite loss as independent prognostic factors.⁴⁴ The prognostic index is useful to assist in the interpretation of phase II trials and may assist the clinician in estimating the prognosis for clinical decision making.

Pathology

The four subtypes of MPM according to the World Health Organization (WHO) are as follows: epithelioid, sarcomatous, biphasic epithelial (also referred to as mixed), and desmoplastic.⁴⁵ The epithelioid type is the most common and has a better prognosis compared to the other types. It can be difficult to distinguish MPM from reactive mesothelial hyperplasia, non–small cell lung cancer (NSCLC) with adenocarcinoma histology, and metastatic adenocarcinoma. Unfortunately, no single immunohistochemistry (IHC) stain can differentiate MPM from NSCLC with adenocarcinoma histology, and a panel of IHC stains is frequently used. One practice is to test for two markers that are positive in MPM (e.g., cytokeratin AE1/AE3, keratins [e.g., CK 5/6, CK 7], calretinin, Wilms tumor 1 [WT-1; nuclear staining], D2-40) as well as two that are negative for MPM (e.g., carcinoembryonic antigen [CEA] and thyroid transcription factor 1 [TTF-1]) (Table 73-1).⁴⁶

Table 73-1

Histochemistry Studies to Distinguish NSCLC and MPM⁴⁶

Stain	Adenocarcinoma	MPM
Cytokeratin AE1/AE3
Keratins
Calretinin
WT-1
D2 40
CEA
TTF-1

NSCLC, non–small cell lung cancer; WT-1, Wilms tumor; CEA, carcinoembryonic antigen; TTF-1, thyroid transcription factor

Staging

The natural history of MPM is growth along the pleural surfaces of the thoracic cavity and invasion of the surrounding lung tissue, followed by transdiaphragmatic extension, peritoneal spread, and metastatic disease. The staging system provides an estimate of the prognosis, and an assessment if the tumor is potentially resectable. A number of different staging systems have been used,47,48 and there has been a lack of a consensus on the optimal staging system. The tumor, nodal, and metastasis (TNM) staging system is often used (Table 73-2).⁴⁹ Computed tomography (CT) is the standard staging procedure. An assessment of the mediastinal lymph nodes is critical for assessment of staging and for potential resection, and the staging tests frequently used are CT, fluorodeoxyglucose positron emission tomography (FDG-PET), CT-PET, and mediastinoscopy. A recent systemic review of the imaging modalities revealed that FDG-PET was superior to CT scan, but inferior to CT/FDG-PET, in terms diagnostic specificity, sensitivity, and staging.⁵⁰ The mean standardized uptake value was statistically higher in malignant compared to benign disease, and PET-CT had a higher sensitivity for detection of lymph node involvement. PET or PET-CT also has the ability to detect extrathoracic disease, and approximately 10% to 25% of patients will have distant disease detected with PET scanning.^51,52 Transdiaphragmatic extension is a contraindication to surgical resection, and some centers perform peritoneal lavage or laparoscopy. In one study, the use of peritoneal lavage prior to surgical resection demonstrated transdiaphragmatic invasion of the peritoneal cavity or peritoneal metastases in approximately 10% of patients.⁵³ The role of cervical mediastinoscopy is undetermined, but may be of value for patients being considered for surgical resection. A recent retrospective review revealed that patients without mediastinal involvement had a significantly better survival compared to patients with mediastinal disease.⁵⁴ Noninvasive tests improve the staging, in particular, to increase the detection of patients with metastatic disease and to assist in the selection of the optimal site to biopsy; however, definitive staging requires surgical resection and pathological examination of the specimen.

Surgical Evaluation and Resection

As mentioned previously, the majority of patients present with a large pleural effusion and, on imaging, pleural studding.55,56 In these patients, thoracentesis and pleural biopsy is the initial step in making a diagnosis. Thoracentesis is able to provide a diagnosis of MPM in 33% to 84% of cases. Other modalities to assist in establishing a diagnosis includes the use of a Cope or Abrams needle. This is effective in 30% to 50% of cases.⁵⁷

Thoracoscopy is an essential tool to aid in the diagnosis and management of MPM. This is especially helpful in patients with large pleural effusions with no appreciable mass on imaging. With thoracoscopy, the surgeon is able to directly visualize the entire thorax space. This includes evaluation of the visceral and parietal pleura and chest wall. In addition, mediastinal structures including pericardium and mediastinal lymph nodes can be directly evaluated to aid in determining the extent of future resection. Lastly, the diaphragm can be inspected from the thoracic side to determine the extent of disease. If on imaging or during thoracoscopy there is diaphragmatic involvement, laparoscopy must be strongly considered.⁵⁸ At the time of thoracoscopy, ample biopsies of abnormal pleura can be performed directly. In addition, if contralateral thoracic involvement of MPM is suspected, thoracoscopic approaches can be used to aid in confirming the diagnosis.

After determining the extent of disease, the patient must be evaluated medically to determine suitability for resection and to help guide the type of resection required. An echocardiogram is performed to assess cardiac function and, in particular, to evaluate if there is any right heart dysfunction. If extrapleural pneumonectomy (EPP) is performed, this creates pulmonary hypertension and some degree of right heart strain. Preoperative cardiac imaging will help assess whether the patient can tolerate this insult on the heart. In addition, duplex imaging of the lower extremities has been found to be of assistance in identifying patients with deep vein thrombosis (DVT) to prevent the often lethal complication of pulmonary embolism in a pneumonectomy patient.⁵⁹ For patients identified to have a DVT preoperatively, treatment with anticoagulation and, if appropriate, placement of an inferior vena cava (IVC) filter is highly recommended.

Patients fit for surgery must have a Karnofsky performance status greater than 70 and have normal kidney and hepatic function. In addition, their room air Pco₂ must be less than 45 mm Hg, Po₂ greater than 65 mm Hg, and an ejection fraction of 45% or greater. In addition, in accordance with the American College of Chest Physicians (ACCP) guidelines, patients should have a forced expiratory volume in the first second (FEV₁) greater than 2 L or have a predicted postoperative (PPO) FEV₁ of greater than 800 mL. Those patients with an FEV₁ less than 2 L should undergo quantitative perfusion scan to determine their exact PPO FEV₁.⁶⁰ Patients with PPO FEV₁ of less than 800 mL may be candidates for pleurectomy and decortication (P/D) rather than EPP.

The primary goal of surgery in the multimodality treatment of MPM is to achieve maximum cytoreduction of the tumor. With MPM, this is defined as an R1 resection.⁶¹ Despite the effectiveness of chemotherapy and radiotherapy, surgical therapy remains the foundation of potential curative treatment for MPM. The secondary objective of surgery is to improve symptoms. This includes evacuation of the pleural effusion and pulmonary decortication of an entrapped lung, which improves pain related to chest wall invasion of the MPM. There are three operations that are typically used in the treatment of MPM. These include EPP, P/D, and palliative limited pleurectomy.

EPP involves en bloc resection of the pleura, lung, pericardium, and diaphragm. The steps involved with this procedure have been described previously⁶² and include

P/D involves attempts at complete resection of gross pleural disease without resection of the lung parenchyma. During this procedure, resection of the pericardium and diaphragm may be required and therefore require reconstruction, similar to the techniques used for EPP. Mediastinal lymphadenectomy is also performed. Again, the main difference between P/D and EPP involved the pulmonary resection. The mortality for this procedure is 1.8% to 4%,63,64 yet there is less morbidity as a result of preservation of the pulmonary parenchyma.

The decision to perform EPP or P/D is dependent on several factors and should be made by a thoracic surgeon who is experienced in managing MPM. Each patient when undergoing surgical resection for MPM should be physiologically prepared to undergo either procedure. The decision as to which procedure is appropriate depends on the bulk of disease at the time of surgery. If minimal disease is encountered (T1) then P/D is appropriate. If the patient has involvement of visceral pleura, then EPP is the procedure of choice to give the patient a macroscopic complete resection. If the patient has diffuse disease, including chest wall involvement, performing an EPP will still leave the patient with gross residual disease and is not appropriate for this disease process. Therefore, the decision to perform EPP or P/D should be an intraoperative choice depending on the magnitude of disease. Again, the surgical goal in MPM is to provide the patient with a macroscopically complete resection (R1) with the procedure that will be of least morbidity and mortality for the patient.

Chemotherapy

For a prolonged period of time, there was doubt about the efficacy of chemotherapy in unresectable MPM and it is only recently that palliative chemotherapy has been accepted. The goals of chemotherapy are to reduce disease related symptoms, maintain or improve quality of life, and extend overall survival (OS). In general, for patients to be considered chemotherapy candidates, they should be ambulatory (ie, an Eastern Cooperative Oncology Group [ECOG] performance status [PS] of 0 to 2 or a Karnofsky PS of ≥70), have adequate organ function, and not have significant co-morbidities. One challenge when attempting to assess the activity of chemotherapy is that assessment of radiographic response by the commonly used Response Evaluation Criteria in Solid Tumors (RECIST) is difficult given the radiographic appearance and growth pattern of MPM.⁶⁵ Consequently, many physicians use a modified RECIST using the sum of six unidimensional measurements of pleural thickness in order to reduce intra- and interobserver variability.⁶⁶ The modified RECIST may be particularly useful when assessing the activity of novel agents.

The standard first-line therapy for MPM is a platinum agent (e.g., cisplatin or carboplatin) with an antifolate agent (e.g., pemetrexed or raltitrexed), based on two phase III clinical trials.67,68 A phase III trial by Vogelzang et al. compared cisplatin alone and with pemetrexed in chemotherapy-naïve patients who were not eligible for surgical resection (n = 456).⁶⁷ Patients assigned to the combination arm compared to the cisplatin alone arm experienced a superior overall response rate (ORR), median time to progression, and OS (Table 73-3). A phase III trial of the EORTC compared cisplatin alone to cisplatin and raltitrexed in chemotherapy-naïve patients (n = 250).⁶⁸ Patients assigned to the combination experienced a numerically higher ORR and longer progression-free survival (PFS), and a statistically significant longer OS. No difference in health-related quality of life was observed between the two arms.

One clinical question is whether carboplatin can be substituted for cisplatin, but data from randomized trials investigating this question are not available. However, retrospective data from a large expanded access program is available; the selection of carboplatin or cisplatin was based on physician’s selection. The International Extended Access Program was a multicenter, nonrandomized study that enrolled chemotherapy-naïve patients; patients could receive pemetrexed with cisplatin (n = 843) or carboplatin (n = 861).⁶⁹ The ORR, median time to progression, and 1-year survival rates were similar (Table 73-3). Regarding safety, patients receiving cisplatin/pemetrexed experienced a higher rate of grade 3 or 4 neutropenia (36.1% vs 23.9%) and a lower rate of grade 3 or 4 anemia (7.2% vs 14.3%) and thrombocytopenia (5.0% vs 14.3%). Other phase I or II trials have revealed a similar efficacy to carboplatin and pemetrexed.^70,71 These data suggest that the cisplatin or carboplatin in combination with pemetrexed have similar efficacy, and carboplatin may be substituted for cisplatin in patients who have a relative or absolute contraindication to cisplatin.

A phase III trial compared active symptom control (ASC) alone, defined as treatment with steroids, analgesic drugs, bronchodilators, palliative radiotherapy, to ASC plus mitomycin, vinblastine, and cisplatin (MVP), or ASC plus weekly vinorelbine.⁷² The primary end point was OS, and the trial was designed to enroll 840 patients to detect a 3-month difference in OS. The trial design was changed because of slow accrual, and the ASC was compared to ASC plus chemotherapy in a two-arm design with the ability to detect an improvement from a median OS of 9 months with ASC to 12 months with ASC plus chemotherapy (5% significance level, 76% power, and 420 total patients). A significant difference in ASC compared to ASC plus chemotherapy was not detected (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.72 to 1.10, P = 0.29, median OS = 7.6 and 8.5 months, respectively). An exploratory analysis suggested a survival benefit with the addition of vinorelbine, but there was no evidence of survival benefit with MVP. These results are provocative, but interpretation is difficult because survival in the chemotherapy arm was poor, the changes in the study design and the chemotherapy used does not reflect current standards. The OS of the ASC provides an estimated survival for patients who elect not to pursue chemotherapy.

All patients experience disease progression, and many patients will be candidates for further chemotherapy. Currently, there is no defined standard of care for second-line therapy, and numerous single-arm, phase II trials have been performed of single agent or combination in the second-line setting.⁷³ Some of these trials have demonstrated activity in terms of response, but none have been promising enough to warrant a phase III trial. Single agent vinorelbine and in combination with cisplatin has demonstrated activity, and would be considered a reasonable choice.^74,75 The combination of cisplatin or carboplatin and gemcitabine may be a reasonable choice in the appropriate patient, and outside the context of a clinical trial.^76,77 The activity of single agent gemcitabine appears to be limited,^78,79 and the combination of gemcitabine and pemetrexed does not appear to have greater activity than single agent pemetrexed.⁸⁰

In many cancers, the development of targeted therapies has revolutionized treatment. Several targeted therapies have been investigated in MPM but these results have been disappointing. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been investigated in phase II trials, and the results do not reveal significant activity.83–83 This is probably due to the absence of EGFR mutations in MPM.⁸⁴ Patients with MPM have elevated vascular endothelial growth factor (VEGF) levels, and thus there is preclinical rationale for investigating bevacizumab, a monoclonal antibody against VEGF. However, a randomized phase II trial of cisplatin and gemcitabine alone and with bevacizumab in chemotherapy-naïve patients did not reveal an improvement in the primary end point of PFS or OS with the addition of bevacizumab.⁸⁵ A randomized phase II/III trial of cisplatin and pemetrexed alone and with bevacizumab is ongoing, and data are available from the phase II component of the trial. The disease control rate was numerically higher in the bevacizumab-containing arm compared to the chemotherapy alone arm, and the rate of grade 3 or 4 toxicities were similar in the two arms. The criteria to proceed to the phase III component of the trial were met.⁸⁶ Phase II trials of multitargeted tyrosine kinase inhibitors have not revealed significant activity and it is unlikely these agents will have a role in MPM.^87–90 A phase III trial compared thalidomide maintenance therapy to observation in patients who did not experience disease progression after four cycles of carboplatin or cisplatin with pemetrexed; a similar PFS and OS were observed in the two arms.⁹¹ Imatinib has demonstrated limited efficacy in MPM as well.^92,93 The indiscriminate investigation of targeted therapy and lack of a well-identified marker to enrich trial enrollment have probably contributed to the lack of success of targeted therapy in MPM.

Radiotherapy

MPM is difficult to treat because of its locally aggressive behavior, and surgical resection has been the cornerstone of curative treatment. Unfortunately, after EPP or P/D, the risk for local recurrence is high, ranging from 30% to 60%.64,98–100 Because the most common site of treatment failure is the ipsilateral hemithorax, the need to optimize local control has provided impetus for evaluation of adjuvant radiotherapy (RT). In fact, in a series of retrospective studies, the use of adjuvant hemithoracic RT after EPP or P/D to the chest cavity has been shown to improve local control and survival.^103–103 Although some believe that MPM is relatively radiation “resistant,” there is in vivo data to suggest that the opposite is true and that MPM cells are actually quite sensitive; however, it is difficult to deliver effective tumoricidal doses of radiation to the pleura without significant toxicity, including death. The target volume is the preoperative extent of the pleural space, which is large, irregular, and close to radiosensitive normal structures and several critical structures, including the lungs, heart, and liver.¹⁰⁴

The role of RT in the modern management of MPM typically falls into one of two main categories—as an integral part of trimodality therapy for early-stage disease and in the palliation of pain in locally advanced/metastatic disease. When used in the definitive setting, we typically use an extended course of RT (4500 to 5040 cGy in 180-cGy fractions) over 5 weeks in the postsurgical setting. When we palliate for pain or to help improve dyspnea, we used a shorter course (e.g., 300 cGy × 10 fractions) and treat only focal areas that we think are responsible for the patients’ symptomatology. The role of RT in the prophylaxis of port-site recurrence is controversial; it is our policy to include the port-sites when we treat with curative intent because it does not add much morbidity and these areas are adjacent to our primary target.

Radiotherapy as a Component of Radical Treatment

Extrapleural Pneumonectomy and Adjuvant Radiotherapy

Much of the data regarding adjuvant RT after EPP is from single institutions and is retrospective in nature, which makes generalization/creation of a standard of care difficult. What is clear from all of the data is that outcomes of patients with this disease are far from optimal and newer combinations of therapy must be studied. Gordon et al. reported on eight patients treated with EPP, RT, and doxorubicin-containing chemotherapy.¹⁰⁵ One patient remained disease free for 2 years, but the other 7 patients recurred locally by 18 months, highlighting the aggressive course of disease.

Rusch et al. retrospectively analyzed 105 patients, looking for factors contributing to poor local control.¹⁰¹ They postulated that the main cause of local failure after surgery and radiation therapy was insufficient radiation dose. As a result, they conducted a phase II trial evaluating an increased dose of RT (54 Gy) following resection (70% had EPP).¹⁰² Of the 54 patients who had an EPP and postoperative RT, 7 patients had a locoregional failure, but only 2 of these patients did not also synchronously have distant metastases. One grade 4 esophageal fistula was observed, but otherwise toxicity was manageable. Chemotherapy was not used in this trial and outcomes may have been better if it had been.

Intensity-Modulated Radiotherapy After EPP

Further attempts at improving local control with radiotherapy after EPP have focused on the use of intensity-modulated radiotherapy (IMRT); IMRT has the flexibility to deliver dose distributions that conform to complicated convex and concave target volumes, while minimizing dose to critical structures in proximity.¹⁰⁶

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