Adult Chest Surgery

Chapter 99. Overview 

Tumors of the pleura are most commonly secondary to metastases. Primary pleural tumors are quite uncommon and thus pose a diagnostic and therapeutic dilemma to the thoracic surgeon. The most common primary tumor of the pleura is malignant pleural mesothelioma (MPM). There has been improvement in the survival of these patients but owing to the complexity and spectrum of treatment options, diagnosis and management of patients with MPM remain a difficult task for the thoracic surgeon. In contrast, malignant pleural effusions (MPEs) are one of the most common problems a thoracic surgeon will see. Timely diagnosis as well as optimal treatment is crucial for the palliation of the patient with advanced disease.

ANATOMY/PHYSIOLOGY OF THE PLEURA

The anatomy and physiology of the pleura and pleural space are described and illustrated in Chap. 106. Briefly, each lobe of the lung is covered by a thin double-layered sac called the pleura that covers the lung and lines the chest wall, diaphragm, and mediastinum (Fig. 99-1). The internal surface of the sac is called the visceral layer, and it lies adjacent to the lung surface; the external surface is known as the parietal pleura, and it lies adjacent to the chest wall, diaphragm, and mediastinum. Each pleural membrane is composed of five distinct layers (Fig. 99-2; see also Chap. 109). The internal-most layer consists of a monolayer of mesothelial cells, and the space between is defined as the pleural space. The lymphatic drainage of the pleural space depends on the subpleural lymphatic networks of both the parietal and visceral pleurae (Fig. 99-3).

Figure 99-1.

 

Cross-sectional anatomy of the thorax, with attention to the relationship between the parietal and visceral pleura, as well as the chest wall, lung, and mediastinum. A. Coronal view. B. Axial view

 

Figure 99-2.

 

Histologic layers of the parietal and visceral pleurae. Note the presence of stomata only in the parietal pleura.

 

Figure 99-3.

 

Illustration depicting subpleural lymphatics and drainage pathways to the mediastinal and internal mammary chains. A. Parietal pleura. B. Visceral pleura.

MALIGNANT PLEURAL MESOTHELIOMA

Primary pleural malignancies are very rare tumors (Table 99-1). MPM is the most common primary pleural tumor. Approximately 2000–3000 new cases occur annually in the United States.Exposure to asbestos has long been linked to the development of MPM.Despite the widespread ban on asbestos use since the early 1970s, the incidence of MPM has increased steadily since the 1960s and is not expected to peak until 2020.Diagnosis of MPM is often delayed, resulting in a poor prognosis. With the acceptance of multimodality therapy, better outcomes have been reported, especially in a subset of patients with favorable prognostic factors. MPM remains a difficult and complex disease for the thoracic surgeon to manage.

Table 99-1. Malignant Primary Pleural Tumors

Mesothelioma

Malignant fibrous histiocytoma

Liposarcoma

Leiomyosarcoma

Rhabdomyosarcoma

Squamous cell carcinoma of the pleura

Lymphoma

Melanoma

Chondrosarcoma

Mesodermoma

Small cell carcinoma of the pleura

 

Epidemiology

The incidence of MPM is expected to peak in Western countries by 2020 as a consequence of industrial regulations limiting the use of asbestos, which began in England in the 1930s, followed by the United States in the 1970s. However, the mining and use of asbestos have continued in many Eastern and Southern nations of the hemisphere, and the expected duration of the mesothelioma epidemic in some of these regions is unknown.In this country, males born in the 1930s and 1940s are in the highest risk cohort. Most of the cases of MPM are attributable to asbestos fibers.Several studies have suggested that perhaps 85% of male cases of mesothelioma are directly attributable to asbestos. The remaining cases are likely related to paraoccupational exposures (through family contact) and nonasbestos causes. These nonasbestos causes include radiation, nonasbestos fibers, and perhaps exposure to simian virus 40 (SV40).6,7 There have been many case reports and series implicating the role of asbestos in the development of MPM, but the landmark epidemiologic studies were reported in the 1960s from South Africa and Australia.2,8,9 These papers definitively linked asbestos exposure to the development of MPM.

The mechanism of asbestos carcinogenesis is thought to involve the generation of free radicals by asbestos fibers that damage DNA.10 The type of asbestos fiber may indicate its genotoxicity.Asbestos fibers can be classified as either amphibole or serpentine. Amphibole fibers tend to be narrow and straight, and serpentine fibers tend to be larger. Chrysolite "white" asbestos accounts for most of the asbestos produced today. It may be contaminated with "brown" asbestos, such as tremolite and amosite. In exposed individuals, these fibers migrate through the lymphatics and accumulate in the interstitial spaces and subpleural regions. It is the amphibole asbestos, specifically crocidolite, that is more clearly associated with MPM, although there is evidence that both long and short fibers have carcinogenic potential.

Not all cases of MPM are owing to asbestos. Other silicate fibers with properties similar to asbestos, such as a diameter less than 0.25 m and length greater than 5.0 m, also may lead to the development of MPM. An example includes erionite, a silicate found in the volcano deposits in Turkey. Other causative agents include radiation exposure, chronic inflammation, and genetic susceptibility. The role of SV40 remains controversial. SV40 is a monkey virus that contaminated polio vaccines in the 1950s. SV40-like fragments have been reported in approximately 60% of patients with MPM.Some have suggested that SV40 may act in concert with asbestos to cause DNA damage. Of note, smoking is not a risk factor for MPM.

The peak incidence of MPM is in the sixth decade of life. Males are affected more often than females (5:1), with incidences of 14 cases per million for males and 3 cases per million for females. A latency period of between 15 and 50 years, with an average of 32 years, explains why the incidence of MPM has been increasing and is not expected to peak until 2020 in the United States and Europe.

Pathology

MPM arises from multipotent mesothelioma cells in the parietal pleura.11 Diagnosis can be difficult and is often confused with metastatic adenocarcinoma. Light microscopic examination of hematoxylin-eosin stains, immunohistochemistry, and electron microscopy may be used for definitive diagnosis. It is crucial to obtain a satisfactory amount of pleural soft tissue to allow for appropriate examination. The gross appearance of MPM is often a gray, firm, or myxoid tumor (Fig. 99-4). There is characteristic extensive involvement of both parietal and visceral surfaces by tumor. MPM may be classified into four subcategories: epithelioid, sarcomatoid, biphasic (or mixed), and undifferentiated (see Chap. 9).

Figure 99-4.

 

Gross surgical specimen of a malignant pleural mesothelioma. (Courtesy of Dr. Kemp H. Kernstine.)

EPITHELIOID MESOTHELIOMA

The major diagnostic dilemma in the diagnosis of epithelial mesothelioma is the differentiation between it and metastatic adenocarcinoma of the lung because these entities share similar clinical characteristics on presentation (e.g., unilateral malignant pleural effusion). The immunohistochemical stains used primarily at the Brigham and Women's Hospital include antibodies to calretinin (see Fig. 9-15); keratin antibody AE1/AE3, a product of Wilms' tumor susceptibility gene 1 (WT1) (see Fig. 9-16); CEA; Leu-M1; and TTF1. Antibodies to calretinin appear to stain most epithelioid mesotheliomas, whereas most adenocarcinomas are negative or only weakly positive. Keratin antibody AE1/AE3 is reactive in mesothelioma and adenocarcinoma. Negativity essentially excludes mesothelioma, as well as melanoma and lymphoma. The antibody to WT1 is positive in epithelial mesothelioma and negative in adenocarcinoma, except kidney and ovary. CEA and Leu-M1 are both usually positive in adenocarcinomas but usually negative or only weakly positive in epithelial mesothelioma. Finally, TTF is positive in thyroid and lung adenocarcinomas and negative in others. If the diagnosis is still in question after immunohistochemistry, electron microscopy may be helpful. Typically, cells have well-developed desmosomal junctions, tonofilaments, and long, thin, curved and branched microvilli. Recently, Gordon and colleagues have developed a gene expression ratio technique using methods in genetic microarray analysis.12 This diagnostic test yields a definitive diagnosis of mesothelioma versus adenocarcinoma of the lung and has a reported accuracy rate of 99%.

SARCOMATOID MESOTHELIOMA

Sarcomatoid mesothelioma typically is composed of spindle-shaped cells arranged in sheets. Nuclear pleomorphism and mitotic activity are usually present. Multinucleated giant cells are present occasionally. Their histochemistry is remarkable for strong keratin reactivity.

To be classified as a biphasic mesothelioma, the tissue must be composed of at least 10% epithelial and sarcomatoid components. Undifferentiated mesothelioma is even more uncommon and poorly described.

Clinical Presentation

The symptoms of MPM are nonspecific. Dyspnea is the most common symptom, usually attributable to a pleural effusion or encasement of the lung by tumor. Chest pain is the next most common symptom. Cough, anorexia, weight loss, hemoptysis, and fever also may be present. On physical examination, decreased breath sounds and dullness to percussion may be identified. Decreased chest wall excursion also may be evident in advanced disease. There may be chest wall masses, especially at previous biopsy sites. Lymphadenopathy may be present in the cervical and supraclavicular regions. Paraneoplastic syndromes such as autoimmune hemolytic anemia, hypercalcemia, hypoglycemia, syndrome of inappropriate antidiuretic hormone secretion, and hypercoagulability also may be present.

Radiologic Investigations

In the initial stages, MPM may present as a pleural effusion, subtle pleural thickening, or a discrete pleural-based mass. With advanced disease, a thick, confluent pleural rind develops with encasement of the lung. In addition, mediastinal adenopathy, chest wall invasion, pericardial invasion, or transdiaphragmatic extension may be evident. CT scan with IV contrast material usually is the first test obtained for evaluating the extent of disease. CT scanning is readily available and provides useful anatomic information. MRI and PET scanning can be used to complement CT scanning, especially in patients in whom resectability is in question. MRI with different pulse sequences and gadolinium-based contrast material can improve the detection of tumor extension into chest wall or diaphragm. PET scanning is very useful in the detection of possible nodal involvement and occult metastases. Correlation of all imaging modalities provides the maximal amount of preoperative staging information (see Chap. 3).

CT scanning is the primary imaging modality for diagnosis and staging, as well as for monitoring the therapeutic response of MPM.13 Findings suggestive of MPM on CT scan include unilateral pleural effusion, pleural thickening, and nodularity. There may be circumferential growth resulting in encasement of the lung with a thick rindlike appearance. With encasement of the entire lung, the hemithorax may be constricted and contracted with ipsilateral mediastinal shift, narrowed intercostal spaces, and elevation of the ipsilateral diaphragm. Chest wall invasion may present as invasion of the intercostal muscles with or without bone destruction. Tumor also may be found growing along previous chest tube or biopsy sites. Tumor may invade the mediastinum and involve organs or vascular structures. Presence of a soft tissue mass that abuts a vascular structure for greater than 50% of its circumference is a strong predictor of invasion. Transpericardial and transdiaphragmatic extension also may be detected. CT scan may identify pulmonary nodules or masses and enlarged mediastinal lymph nodes. Most common CT manifestations include pleural thickening (92%), thickening of interlobar fissure (86%), pleural effusion (74%), pleural calcifications (20%), contraction of involved hemithorax (42%), and contralateral mediastinal shift (14%).14 CT findings of circumferential pleural rind, mediastinal pleural involvement, and pleural thickening greater than 1 cm are highly sensitive and specific for mesothelioma.15

MRI can be a useful adjunct to CT scanning by providing additional information about chest wall invasion and transdiaphragmatic extension. MPM enhances with the use of gadolinium-based contrast material, aiding in the discrimination between tumor and normal tissue. Relative to adjacent chest wall muscle, MPM is typically iso- or slightly hyperintense on T1-weighted images and moderately hyperintense on T2-weighted images. MRI is superior to CT scan in identifying endothoracic fascia invasion and diaphragm invasion.16 MRI is indicated for patients with questionable areas of chest wall invasion or transdiaphragmatic extension or for patients in whom CT scan with IV iodinated contrast material is contraindicated.

PET scanning is another modality that is a useful adjunct to CT scanning. The standard uptake value of MPM has been found to be significantly higher than that of benign pleural lesions such as pleuritis and asbestos-related pleural thickening.17 PET scanning also has been found to have increased accuracy for the detection of mediastinal nodal metastases,17 as well as occult extrathoracic metastases.18 PET scanning may provide prognostic information as well. Higher fluorodeoxyglucose uptake was found to be associated with significantly shorter survival time.19 Correlation of all imaging modalities can provide the maximal amount of preoperative staging information.

Diagnosis

Tissue diagnosis can be obtained by a variety of different methods. Pleural fluid cytology only yields the diagnosis of mesothelioma in 30–50% of patients. Furthermore, because of the limited size of the specimen, immunohistochemistry and electron microscopy cannot be performed. Neither cytologic analysis of pleural fluid nor needle aspiration biopsy of the pleura is usually diagnostic because it is extremely difficult to distinguish between cells of MPM, metastatic adenocarcinoma, and severe atypia.

Percutaneous pleural biopsy is not much better at a diagnostic yield of only 33%, but when percutaneous biopsy is combined with imaging, the diagnostic yield is much higher. CT-guided core needle biopsy was found to be accurate in 83.3% of patients.20 Image-guided core needle biopsy was compared with thoracoscopy and thoracotomy for the diagnosis of MPM. Core needle biopsy was found to be 86% sensitive compared with 94% for thoracoscopy and 100% for thoracotomy.21 Because of the superior rate of detection, as well as the amount of tissue returned, thoracoscopic pleural biopsy is the preferred approach. If the pleural space is fused, an open pleural biopsy may be required. Regardless of the method of biopsy, the location of the incision needs to be planned carefully to permit subsequent resection based on the high rate of tumor seeding. Some of the specimen should be delivered fresh to the pathology department for electron microscopic preparation.

Serum markers such as osteopontin have been developed and approved for commercial use. Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The biologic function of mesothelin is not known. A blood test for soluble mesothelin-related proteins can be used to identify people with mesothelioma and to monitor progression of the disease. More patients with mesothelioma have raised concentrations of soluble mesothelin-related proteins than do those with other cancers or other inflammatory lung or pleural diseases. Soluble mesothelin-related protein concentrations also correlate with the size of the tumor and increase during tumor progression.

Osteopontin is overexpressed in a number of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, melanoma, and mesothelioma. Osteopontin and mesothelin are serum markers that have shown some promise in the diagnosis and prognosis of MPM. Serum levels of osteopontin were increased in patients with MPM, but did not distinguish those with MPM from those with metastatic pleural carcinoma. Both osteopontin and mesothelin were found on univariate analysis to be predictive of prognosis.22

Staging

INVASIVE STAGING

Although N2 disease has been shown by many to portend a poor prognosis, the benefit of mediastinoscopy is not as clear. In a univariate analysis, N2 disease was significant but mediastinoscopy was not in its impact on survival.23 The sensitivity, specificity, and accuracy of cervical mediastinoscopy was found to be 80%, 100%, and 93% compared with 60%, 71%, and 67% for CT scan. Mediastinoscopy failed to detect 21% of patients with positive intrathoracic lymph nodes.24 Critics of mediastinoscopy cite inaccessibility of the mediastinoscope to regions of N2 disease, such as the prevascular, anteroposterior window, paraesophageal, internal mammary, and anterior diaphragmatic regions. Despite this, given the relatively low risk and ease of the procedure, most thoracic surgeons would advise cervical mediastinoscopy prior to surgical resection.

Some groups have advocated extended surgical staging involving thoracoscopy and/or laparoscopy. In one study, peritoneal disease was discovered in 9.2% of patients.24

We routinely perform cervical mediastinoscopy, and those with N2 disease go on to receive induction chemotherapy. Laparoscopy is reserved for those with preoperative imaging suggestive of transperitoneal spread.

PROGNOSTIC FEATURES

Various prognostic features have been identified on univariate and multivariate analyses. Those include histology, gender, smoking, asbestos exposure, laterality, surgical resection, American Joint Commission on Cancer clinical stage,25 and symptoms.26 Six prognostic features were identified in 337 patients treated by the Cancer and Leukemia Group B, including pleural involvement, lactate dehydrogenase > 500 IU/L, poor performance status, chest pain, platelets > 400,000/L, and nonepithelial histology, which along with increasing age older than 75 years jointly predicted poor survival on multivariate analysis.27

The European Organization for Research and Treatment of Cancer performed a similar analysis on 204 patients. On multivariate analysis, poor prognosis was associated with a poor performance status, a high white blood cell count, a probable/possible histologic diagnosis of mesothelioma, male gender, and having a sarcomatoid histologic subtype.28

STAGING SYSTEMS

Lack of a uniformly accepted staging system for MPM has hampered cross-study comparison of ongoing clinical protocols. Multiple staging systems have been proposed. Butchart and colleagues were the first to propose a system in 1976.29 Unfortunately, it did not do well in correlating stage with prognosis. The two most used staging systems include the International Mesothelioma Interest Group tumor-node-metastasis system,25 which is related to clinical experience with lung cancer, and the revised Brigham and Women's Hospital surgical staging system, which was designed as a prognostic indicator for patients treated with surgery.30,31 The International Mesothelioma Interest Group tumor-node-metastasis staging system for MPM has been endorsed by the American Joint Commission on Cancer (Table 99-2).

Table 99-2. New International Staging System for Diffuse Malignant Pleural Mesothelioma

Stage

Definition

Tl

T1a Tumor limited to the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura

 

  No involvement of the visceral pleura

 

T1b Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura

 

  Scattered foci of tumor also involving the visceral pleura

T2

Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral) with at least one of the following features:

 

·   involvement of diaphragmatic muscle

·   confluent visceral pleural tumor (including the fissures) or extension of tumor from visceral pleura into the underlying pulmonary parenchyma

 

T3

Describes locally advanced but potentially resectable tumor

 

Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral) with at least one of the following features:

 

·   involvement of the endothoracic fascia

·   extension into the mediastinal fat

·   solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall

·   nontransmural involvement of the pericardium

 

T4

Describes locally advanced technically unresectable tumor

 

Tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral) 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 contralateral pleura

·   direct extension of tumor to one or more 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

 

N—Lymph nodes

NX

Regional lymph nodes cannot be assessed

NO

No regional lymph node metastases

Nl

Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes

N2

Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes

N3

Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral, or contralateral supraclavicular lymph nodes

M—Metastases

MX

Presence of distant metastases cannot be assessed

MO

No distant metastasis

Ml

Distant metastasis present

 

From ref 25.

The revised Brigham and Women's Hospital surgical staging system for MPM considers resectability, tumor histology, and nodal status and includes four stages. Stage I corresponds to disease confined within the capsule of the ipsilateral parietal pleura without adenopathy. Lung, pericardium, diaphragm, or chest wall disease must be limited to previous biopsy sites. Stage II is the same as stage I with positive resection margins and/or positive intrapleural lymph nodes. In stage III, there is local extension of disease into chest wall or mediastinum, into the heart, through the diaphragm or peritoneum, with or without extrapleural lymph node involvement. Stage IV corresponds to the presence of distant metastatic disease (Table 99-3).

Table 99-3. The Revised Brigham Staging System for Malignant Pleural Mesothelioma

Stage

Definition

I

Disease confined to within the capsule of the parietal pleura; ipsilateral pleura, lung, pericardium, diaphragm, or chest wall disease limited to previous biopsy sites

II

All of stage I with positive intrathoracic (N1 or N2) lymph nodes

III

Local extension of disease into chest wall or mediastinum, heart, or through the diaphragm and peritoneum, with or without extrathoracic or contralateral (N1) lymph node involvement

IV

Distant metastatic disease

 

Treatment

MPM has shown to be an aggressive disease that is very difficult to treat and has consistently poor long-term results. Initially, because of poor responses to therapy, many had considered palliative or symptomatic treatment to be the standard of care. Pleurodesis, with talc or other sclerosing agents, was found to improve quality of life, with a median survival between 6 and 9 months.

SINGLE-MODALITY THERAPY

As more experience was gained in the management this disease and newer chemotherapeutic agents became available, more treatment options arose. Various single-agent chemotherapy trials have shown response rates of between 15% and 20%, with overall median survivals not significantly improved over palliative treatment. Multiagent chemotherapeutic regimens have shown promise. In phase II trials, some multiagent regimens produced response rates of greater than 40%. A landmark phase III trial in 448 patients by Vogelzang and colleagues compared cisplatin alone versus cisplatin and pemetrexed. Response rates were superior in the combination group (41.3% versus 16.7%, p < 0.0001) as was overall median survival (12.1% versus 9.3%, p = 0.02).32 Another phase III trial comparing cisplatin with cisplatin and raltitrexed (another antifolate) produced similar improvement in overall median survival, although the result was of borderline statistical significance.33

The experience with surgical treatment alone was disappointing. The primary two types of surgical procedures carried out for MPM include parietal and visceral pleurectomy and decortication (P/D) and extrapleural pneumonectomy (EPP).

Parietal and visceral P/D entails resection of the parietal pleura with or without resection of the pericardium and diaphragm (see Chap. 102). The visceral pleura is also removed, allowing for the lung to be decorticated and fully expand. Proponents of this approach highlight the low mortality associated with this procedure (1–2%) in larger centers. Postoperative morbidity includes persistent air leaks, pneumonia, empyema, and hemorrhage. A number of different studies report median survivals of between 9 and 20 months. Detractors of this approach note the difficulty in removing all gross disease, especially on the visceral pleura, resulting in incomplete resection.

EPP is a procedure that involves the en bloc resection of the lung, parietal and visceral pleurae, pericardium, and ipsilateral hemidiaphragm (see Chap. 103). It was used initially in the treatment of tuberculous empyema but was adapted for use in the setting of MPM in the 1970s. The perioperative mortality was high (30%) in these initial experiences but, over the past decade, has dropped to as low as 3.8% in large, specialized centers. Postoperative morbidity remains high, ranging from 30-60%. The most common of these complications is arrhythmia, as well as pneumonia, empyema, and respiratory failure. In a variety of different settings, overall median survival has ranged from 9 to 19 months.

Many have suggested that one approach is superior to another, but no prospective, randomized trial has been carried out. In truth, it is likely that comparison of the two approaches is not justified because they represent two appropriate interventions for different stages of disease. P/D may be more appropriate for the patients with limited cardiopulmonary reserve or early-stage disease, whereas EPP may be more appropriate for younger patients with good cardiopulmonary reserve and more bulky disease.

Regardless of the approach, the experience with surgery without adjuvant therapy was disappointing. This led to the use of surgery combined with chemotherapy and/or radiation.

MULTIMODALITY THERAPY

Multimodality therapy employs surgery along with chemotherapy and/or radiation. Various combinations have been used. Because of the lack of standardization in the treatment of MPM, it is difficult to compare different studies.

Sugarbaker and colleagues at the Brigham and Women's Hospital reported on 183 patients with MPM who underwent EPP followed by chemotherapy and radiation.30 Perioperative mortality was 3.8% (7 of 183). Postoperative morbidity occurred in 50%. A total of 176 patients underwent adjuvant chemotherapy after a period of 4–6 weeks following surgery. This treatment was followed by hemithoracic radiation for a cumulative dose of up to 54 Gy. Median survival was 19 months, with 2- and 5-year survival rates of 38% and 15%. Subset analysis identified three prognostic variables that were associated with improved survival: epithelial cell type, negative resection margins, and negative extrapleural lymph nodes. Those with all three prognostic variables had a remarkable 51-month median survival. Baldini and colleagues from the Dana Farber Cancer Institute reported on 46 patients with a mean follow-up of 18 months.34 Disease recurrence was seen in 25 patients (54%). Locoregional recurrence occurred in 35%, abdominal recurrence in 26%, and contralateral chest recurrence in 17%.

A number of other centers have reported their experience with multimodality therapy, with various permutations, proving that it is a feasible approach. Among the various permutations is the use of neoadjuvant chemotherapy, intracavitary chemotherapy, and intensity-modulated radiation therapy (IMRT).

With the excitement generated by the neoadjuvant chemotherapy experience in lung cancer, it was not long before this approach was brought to the treatment of MPM. A number of single- and multicenter trials have been completed with induction multiagent chemotherapy followed by surgery followed by postoperative radiation (Table 99-4). Median survivals ranging from 19 to 25.5 months have been reported.

Table 99-4. Neoadjuvant Chemotherapy Followed by Surgery

Study

Year

n

Chemotherapy

Surgery

Overall Survival (mos)

Chemo + Surgery Survival (mos)

Weder40

2004

19

Cisplatin + gemcitabine

EPP

23

NR

Flores41

2006

19

Cisplatin + gemcitabine

EPP

19

33.5

Krug42

2007

72

Cisplatin + pemetrexed

EPP

16.6

NR

Weder43

2007

61

Cisplatin + gemcitabine

EPP

19.8

23

Rea44

2007

21

Carboplatin + gemcitabine

EPP

25.5

27.5

 

Another novel approach in the treatment of mesothelioma has been the use of intrapleural or intracavitary chemotherapy (Table 99-5). Theoretically, intracavitary chemotherapy has the advantage of achieving high local drug concentrations with less systemic toxicity. Some have added hyperthermia, which further aids in the uptake of chemotherapy and destruction of tumor cells (see Chap. 104). The approach has been evaluated with both P/D and EPP. Median survivals have ranged from 9 to 18 months. Certain subsets, such as epithelial histology, have had median survivals of 26 months.

Table 99-5. Surgery with Intracavitary/Intrapleural Chemotherapy

Study

Year

Sample

Surgery

Chemotherapy

Median Survival (mos)

Rusch45

1994

28

P/D

Cisplatin

18.3

 

 

 

 

Mitomycin

 

Rice46

1994

19

9 P/D

Cisplatin

13

 

 

 

10 EPP

Mitomycin

 

Lee47

1995

15

P/D

Cisplatin

11.5

(epithelial 12)

 

 

 

 

Arabaside

 

Sauter48

1995

13

P/D

Cisplatin

9

 

 

 

 

Arabaside

 

Colleoni49

1996

20

P/D

Cisplatin

11.5

 

 

 

 

Arabaside

 

Yellin50

2001

4

EPP

Cisplatin

3 alive at 2 years

Aziz51

2002

51

EPP

Carboplatin

35 (versus 10 mos for EPP alone)

Moneusse52

2003

17

P/D

Cisplatin

Overall: 18

 

 

 

 

Mitomycin

T1/2: 41.3

 

 

 

 

 

T3/4: 6

van Ruth53

2003

20

12 P/D

Cisplatin

11

 

 

 

8 EPP

Doxorubicin

 

Richards54

2006

44

P/D

Cisplatin

Overall: 9.3

 

 

 

 

 

Epithelial: 19

 

 

 

 

 

High-dose: 18

 

 

 

 

 

Epi + HD: 26

Lucchi55

2007

49

P/D

IL-2

Overall: 26

 

 

 

 

Epidoxorubicin

Stage II: 31

 

 

 

 

 

Stage III: 21

Zellos56

2009

42

29 EPP

Cisplatin with amifostine cytoprotection

Overall: 17.1

 

 

 

 

 

Resected: 20

 

Other intrapleural therapies have been investigated, including immunomodulating agents such as interleukin 2 and photodynamic therapy (see Chap. 105).

The development of IMRT is another novel therapy being investigated in MPM. IMRT is used to deliver dose distributions that conform to the complicated convex and concave target volumes, such as the chest. Rice and colleagues at the MD Anderson Cancer Center published a study of 63 patients who received IMRT (median dose 45 Gy) following EPP with curative intent.35 Chemotherapy was not administered routinely. For patients who received IMRT, median overall survival was 14.2 months. Only 3 patients (5%) had recurrence within the irradiated field.35 There is, however, a concern about the treatment-related toxicity, which can be higher than the operative mortality.

The treatment of MPM continues to evolve with the addition of novel therapies and approaches. There is still considerable work that needs to be done, but over the past several decades, median survivals have improved from 6 to 9 months to 20 months or better in certain subgroups.36

MALIGNANT PLEURAL EFFUSIONS

MPEs can be defined as pleural effusions that contain malignant cells. MPEs are common problems encountered by thoracic surgeons. Patients with a variety of malignancies, including lung, breast, ovarian, stomach, and lymphoma, may develop MPE. Unfortunately, its development signifies advanced disease, often with a poor prognosis. Management varies from observation to tube drainage to pleurodesis to surgery. The correct choice depends on individual patient circumstances. Treatment options include observation only in asymptomatic patients, pleurodesis, and multimodality therapy, including pleurectomy.

Presentation

Approximately 75% of patients with MPEs are symptomatic, with dyspnea (96%) being the most common complaint.37 Other symptoms may include nonproductive cough, chest pain or discomfort, or other symptoms of advanced malignancy such as malaise and decreased energy.

Physical examination may identify increased respiratory rate or work of breathing, dullness to percussion, and decreased air entry on the affected side. Egophony and tactile fremitus also may be present. In addition, there may be other signs of advanced malignancy, including lymphadenopathy and weight loss.

Pathogenesis

The development of an MPE can be attributed to at least three different mechanisms. Tumor seeding of the parietal pleura may interfere with pleural fluid resorption and lead to the accumulation of fluids in the pleural space. The inflammatory response to the tumor may result in increased capillary permeability as well as "leakage" of fluid from the interstitial space to the pleural space. Finally, blockage of the lymphatics between the parietal pleura and the mediastinal lymph nodes may result in the development of MPE.

Diagnosis

The diagnosis of MPE is important for a number of reasons. First, accurate diagnosis not only permits proper staging of the patient's cancer but also provides a clue to the patient's prognosis. In most malignancies, the presence of an MPE indicates metastatic disease and a poor prognosis, with survival often less than 6 months. In lung cancer, the presence of an MPE is currently classified as T4 (stage IIIB), but the anticipated revision to the tumor-node-metastasis staging system may change the designation of MPE from a T4 descriptor to an M1a descriptor based on the dismal survival of patients with lung cancer and MPE. Exceptions to this rule are patients with breast cancer or lymphoma. With systemic chemotherapy, survival may range from several months to years for those with a good treatment response. Establishing a diagnosis is also necessary to distinguish MPE from a paramalignant effusion. Paramalignant effusion, as coined by Sahn,38 denotes a pleural effusion in a patient with a known malignancy, but the effusion is cytologically negative. Such an effusion may be present in a patient with an endobronchial lesion that causes atelectasis and a reactive effusion. Therefore, it is essential to diagnosis an MPE accurately for both prognostic and treatment reasons.

The most common form of invasive diagnostic intervention is thoracentesis (see Chap. 100). While a serosanguineous or sanguineous effusion is more likely to be malignant, even serous effusions can contain malignant cells. Pleural fluid should be sent for cell count, pH, glucose, lactate dehydrogenase, total protein, and cytology. The presence of greater than 100,000 red blood cells per microliter in the absence of trauma is suspicious for malignancy.39 Although usually associated with infection, a low pH is found in approximately a third of MPEs. The ratios of lactate dehydrogenase and total protein in the pleural fluid and serum can distinguish between an exudative and transudative effusion. MPEs typically are exudative (although 5% may be transudative) and must be differentiated from other exudative effusions such as in empyema, tuberculous pleurisy, and pulmonary embolism. Finally, pleural fluid cytology has a diagnostic accuracy ranging from approximately 66% to as high as 90% if repeated on three separate occasions. The variation in accuracy likely depends on the cytopathologist, extent of pleural involvement, and primary tumor.

Other diagnostic options include percutaneous, thoracoscopic, and open pleural biopsy. Percutaneous (closed) pleural biopsy yields disappointing results likely owing to the blind nature of the procedure and sampling error. Diagnostic accuracy is approximately 40%. Thoracoscopic pleural biopsy permits direct visualization of the visceral and parietal pleura and therefore guided biopsies (see Chap. 101). Diagnostic accuracy is at least 90% and higher if several specimens are taken. Although this is an operative procedure requiring general anesthesia, morbidity and mortality are low. A thoracoscopic pleural biopsy is a good option in a patient with an effusion suspicious for malignancy despite repeated negative pleural fluid cytology. Open pleural biopsy generally is reserved for situations in which thoracoscopic biopsy is not possible because of a fused pleural space.

SUMMARY

Diffuse MPM is extremely rare, even though it is the most common primary pleural tumor. Many thoracic surgeons will never see a case of MPM in an entire career. MPE is a common problem in patients with various malignancies, and it is important for the thoracic surgeon to be able to diagnosis and manage these patients optimally. Although usually a poor prognosis, management may lead to better palliation of symptoms and improved patient comfort.

EDITOR'S COMMENT

MPM remains a challenging disease from diagnosis and staging to management. Stage and type specific treatment is lacking and randomized studies are difficult to complete given the rarity of the disease and lack of accurate preoperative staging. Clearly, this disease should be treated only at specialized centers that treat large numbers of cases in order to improve outcomes and expand knowledge of this disease.

–LZ

REFERENCES

1. Price B: Analysis of current trends in United States mesothelioma incidence. Am J Epidemiol 145:211–8, 1997. [PubMed: 9012593]

2. Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 17:260–71, 1960. [PubMed: 13782506]

3. Singhal S, Kaiser LR: Malignant mesothelioma: Options for management. Surg Clin North Am 82:797–831, 2002. [PubMed: 12472131]

4. Zellos L, Christiani DC: Epidemiology, biologic behavior, and natural history of mesothelioma. Thorac Surg Clin 14:469–77, 2004. [PubMed: 15559053]

5. Godleski JJ: Role of asbestos in etiology of malignant pleural mesothelioma. Thorac Surg Clin 14:479–87, 2004. [PubMed: 15559054]

6. Pass HI, Bocchetta M, Carbone M: Evidence of an important role for SV40 in mesothelioma. Thorac Surg Clin 14:489–95, 2004. [PubMed: 15559055]

7. Shah KV: Causality of mesothelioma: SV40 question. Thorac Surg Clin 14:497–504. 

8. Selikoff IJ, Churg J, Hammond EC: Asbestos exposure and neoplasia. JAMA 188:22–6, 1964. [PubMed: 14107207]

9. Armstrong BK, de Klerk NH, Musk AW, Hobbs MS: Mortality in miners and millers of crocidolite in western Australia. Br J Ind Med 45:5–13, 1988. [PubMed: 2829959]

10. Kane A: Mechanisms of mineral fibre carcinogenesis. In Kane AB, Bofetta P, Saracci R (eds): Mechanism of Fiber Carcinogenesis. Lyon, France, IARC Scientific Publications, 1996.

11. Corson JM: Pathology of mesothelioma. Thorac Surg Clin 14:447–60, 2004. [PubMed: 15559051]

12. Gordon GJ, Jensen RV, Hsiao LL, et al: Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma. Cancer Res 62:4963–7, 2002. [PubMed: 12208747]

13. Mujoomdar A, Kukreja J, Sugarbaker D: Primary pleural and chest wall tumors. In Crapo JD (ed): Bone's Atlas of Pulmonary Medicine. Philadelphia, Current Medicine, 2008.

14. Kawashima A, Libshitz HI: Malignant pleural mesothelioma: CT manifestations in 50 cases. AJR 155:965–9, 1990. [PubMed: 2120965]

15. Metintas M, Ucgun I, Elbek O, et al: Computed tomography features in malignant pleural mesothelioma and other commonly seen pleural diseases. Eur J Radiol 41:1–9, 2002. [PubMed: 11750145]

16. Heelan RT, Rusch VW, Begg CB, et al: Staging of malignant pleural mesothelioma: Comparison of CT and MR imaging. AJR 172:1039–47, 1999. [PubMed: 10587144]

17. Benard F, Sterman D, Smith RJ, et al: Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest 114:713–22, 1998. [PubMed: 9743156]

18. Schneider DB, Clary-Macy C, Challa S, et al: Positron emission tomography with 18F-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma. J Thorac Cardiovasc Surg120:128–33, 2000. [PubMed: 10884665]

19. Ng DC, Hain SF, O'Doherty MJ, Dussek J: Prognostic value of FDG PET imaging in malignant pleural mesothelioma. J Nucl Med 41:1443–4, 2000. [PubMed: 10945542]

20. Metintas M, Ozdemir N, Isiksoy S, et al: CT-guided pleural needle biopsy in the diagnosis of malignant mesothelioma. J Comput Assist Tomogr 19:370–4, 1995. [PubMed: 7790544]

21. Agarwal PP, Seely JM, Matzinger FR, et al: Pleural mesothelioma: Sensitivity and incidence of needle track seeding after image-guided biopsy versus surgical biopsy. Radiology 241:589–94, 2006. [PubMed: 17005770]

22. Goh YW, Danczak SM, Lim TK, White JM: Manifestations of the Alder-Rickert reaction in the structures of bicyclo[2.2.2]octadiene and bicyclo[2.2.2]octene derivatives. J Org Chem 72:2929–35, 2007. [PubMed: 17371072]

23. de Perrot M, Uy K, Anraku M, et al: Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 133:111–6, 2007. 

24. Schouwink JH, Kool LS, Rutgers EJ, et al: The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg75:1715–8; discussion 1718–9, 2003. 

25. Rusch VW: A proposed new international TNM staging system for malignant pleural mesothelioma: From the International Mesothelioma Interest Group. Chest 108:1122–8, 1995. [PubMed: 7555126]

26. Flores RM, Zakowski M, Venkatraman E, et al: Prognostic factors in the treatment of malignant pleural mesothelioma at a large tertiary referral center. J Thorac Oncol 2:957–65, 2007. [PubMed: 17909360]

27. Herndon JE, Green MR, Chahinian AP, et al: Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 113:723–31, 1998. [PubMed: 9515850]

28. Curran D, Sahmoud T, Therasse P, et al: Prognostic factors in patients with pleural mesothelioma: The European Organization for Research and Treatment of Cancer experience. J Clin Oncol 16:145–52, 1998. [PubMed: 9440736]

29. Butchart EG, Ashcroft T, Barnsley WC, Holden MP: Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: Experience with 29 patients. Thorax 31:15–24, 1976. [PubMed: 1257933]

30. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al: Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg 117:54–63; discussion 65, 1999. 

31. Paul S, Neragi-Miandoab S, Jaklitsch MT: Preoperative assessment and therapeutic options for patients with malignant pleural mesothelioma. Thorac Surg Clin 14:505–16, 2004. [PubMed: 15559057]

32. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–44, 2003. [PubMed: 12860938]

33. van Meerbeeck J, Gaafar R, Manegold C, et al: Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An intergroup study of the European Organization for Research and Treatment of Cancer. J Clin Oncol 23:6881–9, 2005. 

34. Baldini EH, Recht A, Strauss GM, et al: Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 63:334–8, 1997. [PubMed: 9033296]

35. Rice DC, Stevens CW, Correa AM, et al: Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 84:1685–92; discussion 1692–3, 2007. 

36. Kjellstrom T, Smartt P: Increased mesothelioma incidence in New Zealand: The asbestos-cancer epidemic has started. NZ Med J 113:485–90, 2000. [PubMed: 11198540]

37. Chernow B, Sahn SA: Carcinomatous involvement of the pleura: An analysis of 96 patients. Am J Med 63:695–702, 1977. [PubMed: 930945]

38. Sahn SA: Malignant pleural effusions. Clin Chest Med 6:113–25, 1985. [PubMed: 2988851]

39. Light RW, Erozan YS, Ball WC Jr: Cells in pleural fluid: Their value in differential diagnosis. Arch Intern Med 132:854–60, 1973. [PubMed: 4757257]

40. Weder W, Kestenholz P, Taverna C, et al: Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22:3451–7, 2004. [PubMed: 15337794]

41. Flores RM, Krug LM, Rosenzweig KE, et al: Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: A phase II trial. J Thorac Oncol 1:289–95, 2006. [PubMed: 17409872]

42. Krug L, Pass H, Rusch V, et al: A multicenter US trial of neoadjuvant pemetrexed plus cisplatin (PC) followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT) for stage I-III malignant pleural mesothelioma (MPM). J Clin Oncol Suppl 7561, 2007. 

43. Weder W, Stahel RA, Bernhard J, et al: Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 18:1196–202, 2007. [PubMed: 17429100]

44. Rea F, Marulli G, Bortolotti L, et al: Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and results. Lung Cancer57:89–95, 2007. [PubMed: 17403553]

45. Rusch V, Saltz L, Venkatraman E, et al: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12:1156–63, 1994. [PubMed: 8201377]

46. Rice TW, Adelstein DJ, Kirby TJ, et al: Aggressive multimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 58:24–9, 1994. [PubMed: 7518666]

47. Lee JD, Perez S, Wang HJ, et al: Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: The UCLA experience. J Surg Oncol 60:262–7, 1995. [PubMed: 8551737]

48. Sauter ER, Langer C, Coia LR, et al: Optimal management of malignant mesothelioma after subtotal pleurectomy: Revisiting the role of intrapleural chemotherapy and postoperative radiation. J Surg Oncol 60:100–5, 1995. [PubMed: 7564374]

49. Colleoni M, Sartori F, Calabro F, et al: Surgery followed by intracavitary plus systemic chemotherapy in malignant pleural mesothelioma. Tumori 82:53–6, 1996. [PubMed: 8623505]

50. Yellin A, Simansky DA, Paley M, Refaely Y: Hyperthermic pleural perfusion with cisplatin: Early clinical experience. Cancer 92:2197–203, 2001. [PubMed: 11596038]

51. Aziz T, Jilaihawi A, Prakash D: The management of malignant pleural mesothelioma: Single-centre experience in 10 years. Eur J Cardiothorac Surg 22:298–305, 2002. [PubMed: 12142203]

52. Monneuse O, Beaujard AC, Guibert B, et al: Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies. Br J Cancer 88:1839–43, 2003. [PubMed: 12799624]

53. van Ruth S, Baas P, Haas RL, et al: Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 10:176–82, 2003. 

54. Richards WG, Zellos L, Bueno R, et al: Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J Clin Oncol 24:1561–7, 2006. [PubMed: 16575008]

55. Lucchi M, Chella A, Melfi F, et al: Four-modality therapy in malignant pleural mesothelioma: A phase II study. J Thorac Oncol 2:237–42, 2007. [PubMed: 17410047]

56. Zellos L, Richards WG, Capalbo L, et al: A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 137:453–8, 2009. [PubMed: 19185169]



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!