Authors: David J. Sugarbaker, MD, Jose J. Norberto, MD, and Raphael Bueno, MD, Division of Thoracic Surgery, Brigham and Women's Hospital, Boston Mass.

Abstract
Methods
Results
Conclusions

Introduction

• Epidemiology

• Presentation and Diagnosis

• Pathogenesis and Histology

• Staging Systems

• Surgery in Trimodality Therapy

• Preoperative Evaluation

• Techniques

  • Pleurectomy/Decortication

  • Extrapleural Pneumonectomy

  • Clinical Experience and Results

Conclusions

Brigham Staging System for Malignant Pleural Mesothelioma.

Steps in Operative Technique for Diffuse Malignant Pleural Mesotheliom.a

• Pleurectomy

• Extrapleural Pneumonectomy

Abstract
Background: Diffuse malignant pleural mesotheliomas (DMPMs) are highly lethal tumors that are becoming more common. Standard management approaches have provided limited effectiveness.

Methods
The literature on management has been revised, and the authors present their data on outcomes for 120 patients treated with an aggressive trimodality approach.

Results
An aggressive trimodality approach including extrapleural pneumonectomy followed by chemoradiation produces low mortality and acceptable morbidity. The five-year survival rate in patients with epithelial histology and negative nodes approaches 40%.

Conclusions
Nodal status and histologic subtype are major predictors for survival in patients with early DMPM. A uniformly accepted staging system would allow comparison of treatment approaches from various institutions. More effective management interventions are required.

[Cancer Control: JMCC 4(4):326-334, 1997. © 1997 Moffitt Cancer Center & Research Institute]

Introduction
Mesotheliomas of the pleural cavity are relatively rare tumors. Generally, two types of pleural tumors can be referred to as mesotheliomas. The less common is the solitary (or localized) fibrous tumor of the pleura, previously known as "benign mesothelioma." This slow-growing, commonly benign, well-circumscribed tumor is pedunculated on a pleural-based pedicle and often is cured by resection. The tumor appears to originate from submesothelial rather than mesothelial or epithelial cells.[1] The more common variety is the diffuse malignant pleural mesothelioma (DMPM), a true mesothelial malignancy that is locally aggressive, invasive, and almost universally fatal. This multicentric tumor infiltrates the pleural space, results in a pleural effusion, and mechanically compresses the surrounding structures. Though distant metastatic lesions may be seen in up to 30% of cases in autopsy series, most patients die of locoregional invasion and compression of vital structures. The median survival for patients with DMPM is between four and 12 months, depending on the stage at presentation.

Epidemiology
In the United States, 2,000 to 3,000 patients are diagnosed with DMPM each year, representing a 50% increase in the number of cases over the last decade. This increase probably reflects the long latency period between the asbestos exposure in the 1940s to 1960s and the clinical manifestation of DMPM.[7­9] The appearance of a new etiologic factor (eg, SV40-contaminated polio vaccines) is also a possible reason for the increase. Women are less likely to be affected than men, possibly due to womenís scarce asbestos exposure resulting from different employment patterns. The disease is most common in the sixth decade of life.

Presentation and Diagnosis
The majority of the patients (60% to 90%) present with dyspnea and chest discomfort.[3] The dyspnea is usually caused by an expanding pleural effusion that eventually becomes loculated. Inevitably, the pleural space fills with tumor that invades and compresses all the adjacent structures and thus limits lung expansion. The chest discomfort is usually dull and nonspecific at presentation. Once the chest wall and intercostal nerves are invaded by tumor, the pain is more localized and severe, which indicates advanced disease. Less common symptoms include fever, night sweats, cough, malaise, and weight loss.

In cases of advanced disease, the patient may present with ascites, cachexia, or chest and abdominal wall deformity. Thrombocytosis is a relatively common finding and may be associated with a poorer prognosis.[10] Other associated paraneoplastic abnormalities include hypoglycemia, hypercalcemia, thrombocytosis, pulmonary embolism, autoimmune hemolytic anemia, hypercoagulability, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These complications are extremely rare.

Physical examination reveals diminished breath sounds on the affected side due to the effusion and atelectasis. In advanced disease, palpation of a chest wall mass is an indication of thoracic wall invasion. Abdominal fullness also may be present. Such transdiaphragmatic invasion often results in ascites and renders the tumor unresectable. Bowel obstruction is observed in 30% of the patients once transdiaphragmatic invasion has occurred.

A thorough radiologic evaluation is performed to determine the stage of tumor and to help in the design of therapy. Posteroanterior and lateral chest radiograph, computed axial tomography scan of the chest and upper abdomen and, in some centers, magnetic resonance imaging (MRI) of the chest constitute the requisite staging and evaluation. The chest radiograph typically reveals a pleural effusion with or without pleural calcifications. In our institution, we routinely obtain a computed tomography scan and MRI of the chest and upper abdomen. These studies allow greater accuracy in determining whether tumor has surpassed the confines of the ipsilateral pleural space.[11] Radiologic criteria of unresectability include invasion of mediastinal structures, transdiaphragmatic involvement, and metastatic disease. Examination of the sagittal sections of the involved chest by MRI allows for a sensitive determination of mediastinal and diaphragmatic invasion.

We have also found two-dimensional echocardiography (2D ECHO) to be useful in searching for pericardial effusions and tumor infiltration through the pericardium. This modality is also helpful in determining whether the patientís baseline myocardial function and pulmonary artery pressure will allow an aggressive resection.

The pleural effusion may be examined via thoracentesis. The pleural effusion associated with mesothelioma is usually yellow and thus different from the blood-containing effusion that is characteristic of adenocarcinoma. A diagnosis of DMPM is rarely possible by cytology because malignant cells are seldom seen in these effusions; when they are present, it is often difficult to correctly identify the malignancy. Therefore, to establish a definite diagnosis, it is usually necessary to perform a pleural biopsy. The closed pleural biopsy, widely used in the past, is helpful only when the results are positive. Negative pleural biopsies should be interpreted with caution and, if clinically suspicious, should be followed by open biopsies. Thoracoscopy or pleuroscopy, therefore, is the best approach to obtain pleural tissues in patients with suspected mesothelioma. In this manner, generous biopsies of the involved areas in the pleura are obtained, and frozen section analysis can confirm that the material is sufficient for final diagnosis. Thoracentesis, pleuroscopy, and thoracoscopy should all be performed through strategically placed incisions because mesothelioma cells can easily seed the tracts of the incisions used for the diagnostic biopsy. We usually place one or, at most, two thoracoscopy ports on the patient's chest in an area that will be included in a subsequent resection. Planning avoids recurrence in the port sites. In cases of obliterated pleural space where a thoracoscope cannot be inserted, an open pleural biopsy is performed.

Pathogenesis and Histology
The earliest pathologic findings are small nodules that are present in parietal pleura. The tumor crosses the pleural space to involve the visceral pleura, coalesces, and replaces the pleural space. As the tumor mass becomes locally advanced, it constricts the underlying normal pulmonary parenchyma. Late in the disease process, the tumor invades the pericardium and mediastinum and may metastasize elsewhere. Patient death is usually caused by compression of the heart and the lung.

DMPM derives from mesothelial stem cells that are, by definition, pluripotential. The cells differentiate into epithelial or mesenchymal elements. It is common to find both cell types in the same tumor specimen. The dominant histology classifies DMPM as having epithelial (50%), sarcomatous (35%), and mixed (15%) histologic groups. This histologic classification has prognostic implications. Several studies have demonstrated that epithelial-type mesothelioma has a better prognosis than the sarcomatous and mixed types.[12,13]

The histopathologic diagnosis of mesothelioma can be difficult. Common diagnostic dilemmas for the pathologist include differentiation between adenocarcinoma and tubulopapillary mesothelioma (Table 1),[14] between reactive mesothelial hyperplasia and early mesothelioma, and between desmoplastic mesothelioma and benign pleuritis or plaquing. Use of immunochemistry stains by an experienced pathologist who has access to sufficient fresh and formalin-fixed tissue will optimize results.

Staging Systems
DMPM appears to be a heterogeneous disease with different patient survival statistics reported by various authors. Characteristics such as young age, female gender, epithelial subtype, normal platelet count, uninvolved lymph nodes, and absence of pain have been associated with longer survival, but the lack of consensus on a uniform staging system prevents a valid comparison of patients from various institutions. An essential factor in any analysis of disease requires a solid staging scheme that allows the clinician to categorize patients in homogeneous groups with established survival curves to permit evaluation of therapy.

Several staging systems for DMPM have been presented. Developed in 1976, the Butchart staging system[15] was based on a series of 29 patients who were treated with extrapleural pneumonectomy (EPP). The four stages indicate tumor, lymph node location (either inside or outside of the chest), and blood-borne metastases. It does not address tumor burden. This scheme was used because of its simplicity, but the association of stage with survival was unclear, and the staging system is now obsolete.

Chahinian[16] was the first to apply the variables of tumor (T), lymph node (N), and metastasis (M) to DMPM staging in the early 1980s. However, this staging system does not correctly separate resectable and unresectable patients and is not useful in predicting patient survival. The major drawback with any TNM classification system in DMPM is the difficulty in quantifying the T stage, especially early in the disease, in any surgically and prognostically meaningful terms.

A revised TNM staging scheme was proposed in 1990 by the International Union Against Cancer (UICC).[17] While the definitions of the T categories are more precise than those in the Chahinian system, the degree of tumor infiltration beyond the preresectional extension is not appropriately described. In a malignancy such as mesothelioma in which tumor usually spreads locally, the T category must account for the degree of tumor infiltration and for tumor resectability. In the UICC staging scheme, the T variable remains imprecise. The nodal scheme is also a potential pitfall. The same nodal designations used in the UICC lung cancer staging system are applied in this DMPM system. However, in reality, this tumor is more pleural than hilar, and it behaves differently from lung cancer in lymphatic drainage, thus making the nodal category (N) potentially unreliable. The application of the M category is of limited value because many patients die of persistent local disease. Thus, the UICC system has major limitations.

The most recent TNM-based system was created by the International Mesothelioma Interest Group (IMIG) in June 1994 at the Seventh World Conference of the International Association for the Study of Lung Cancer (Table 2).[18] By incorporating recent prognostic data on T and N status, the IMIG system provides both a more detailed description of the T status and a better delineation of subtle differences (eg, parietal vs visceral pleural involvement). It uses the same N and M categories as the lung cancer TNM-based system. This system, which has been validated on retrospective data, will probably require revision. The Brigham staging system was introduced after analyzing the first 52 patients treated with trimodality therapy at the Dana-Farber Cancer Institute/Brigham and Women's Hospital Thoracic Oncology Program.[12] This staging scheme allows four stages and considers resectability and nodal status (Table 3). Patients with stage I disease have resectable tumors with no affected lymph nodes. Stage II refers to resectable tumors accompanied by positive lymph nodes. Stage III includes tumors that are unresectable due to local extension into mediastinal structures or through the confines of the diaphragm. Stage IV describes metastatic disease at presentation. Fig 1 demonstrates the Kaplan-Meier curves in which survival of 120 patients was stratified according to stage.[13] (PLEASE SEE HARD COPY OF JOURNAL FOR FIG 1.)

Surgery in Trimodality Therapy
Radiotherapy, chemotherapy, and surgery have been used in single- and bi-modality therapy for mesothelioma, but the impact on local control and survival has been poor.[19­23] Surgery, as EPP or pleurectomy, may allow palliation.[22,23] Attempts at palliation provided by radiotherapy have been moderately successful at best,[19,20] and the impact of chemotherapy on palliation has been poor. Most single agents are relatively ineffective. A combination of cyclophosphamide, doxorubicin, and cisplatin has provided response rates of 20% to 30%.[21]

The lack of any curative single modality therapy for mesothelioma has led our group and others to evaluate an aggressive trimodal approach to this malignancy. Our current treatment regimen consists of a cytoreductive operation followed by chemotherapy and radiotherapy. This approach maximizes the beneficial effects and minimizes the adverse effects of adjuvant therapy. The two surgical techniques that are currently employed in cytoreduction are pleurectomy/decortication and EPP. These two procedures have not been directly compared in prospective randomized trials. Each surgical technique has advantages and disadvantages. The advantages of pleurectomy/decortication are its low morbidity (25%)[24] and mortality (2%).[18] Thus, this operation can be performed in patients with a less favorable cardiorespiratory status than that required for EPP. However, pleurectomy/decortication may not be feasible if the pleural space is thoroughly obliterated by tumor growth, and the amount of postoperative radiotherapy delivered to the chest cavity is limited due to the presence of the lung parenchyma and the risk of development of postradiation pneumonitis. Furthermore, the local control of disease achieved by pleurectomy may not be efficient,[25] although the addition of external beam radiation with or without intraoperative brachytherapy may minimize local recurrence. The cytoreduction achieved by the procedure is not as effective as the reduction achieved with EPP. Adequate debulking of tumor in the fissure or near the hilum is also difficult and hazardous.

Some surgeons favor pleurectomy/decortication as the primary procedure for cytoreduction in DMPM. Rusch et al[26] and others added intrapleural chemotherapy with cisplatin and mitomycin postoperatively. At our institute, we attempt to proceed with EPP in all eligible patients and generally perform a pleurectomy only in those patients who are unable to withstand the rigors of EPP.

EPP in the setting of trimodality therapy has several advantages. First, obliteration of the pleural space by tumor does not preclude EPP because the entire pleural envelope is removed en bloc. Also, radiation pneumonitis following surgery is not a concern because the lung has been resected and a higher total radiation dose might be feasible. Most importantly, EPP has been associated with longer than average median survival rates (21 months in some series). However, this apparent benefit could reflect earlier disease stages rather than an effort of the intervention.

Currently, the mortality (5%) and morbidity (22%; major complications: 12.5%) are much lower in specialized centers than those reported in the older series.[13,15] Nevertheless, the complication rates following EPP are higher than those following pleurectomy. Another disadvantage of EPP is that the patient must have enough physiologic reserve and adequate cardiac function to tolerate an EPP.

Preoperative Evaluation
The goal of preoperative evaluation is to determine the technical resectability and the ability of the patient to withstand the trimodality therapy. The patient is considered resectable if the tumor is confined to one pleural space without invasion of the mediastinum or any transdiaphragmatic tumor infiltration.

Systematic history is obtained and a physical examination is performed. Premorbid conditions are identified preoperatively because trimodality therapy may worsen any underlying medical condition. We obtain pulmonary function tests, exercise oximetry, arterial blood gas analysis, and occasionally a quantitative ventilation perfusion scan in order to evaluate the respiratory physiological reserve. A 2D ECHO provides a baseline functional evaluation to rule out unsuspected intracardiac abnormalities or pulmonary hypertension as well as baseline cardiac

function prior to the adjuvant therapy. A 2D ECHO is also used to screen for pericardial tumor involvement. The physiologic exclusion criteria include ejection fraction of less than 45%, predicted postoperative FEV1 of less than one liter, inadequate ventilatory function (PaCO2 above 45 mm Hg), and PO2 of less than 65 mm Hg. A chest MRI is obtained to determine the extent of the tumor and to ensure that it is confined to one side only without transdiaphragmatic or mediastinal involvement. If questionable, a laparoscopy or contralateral thoracoscopy with biopsies is performed.

Techniques

Pleurectomy/Decortication
The goal of this procedure is to debulk tumor mass while preserving the underlying normal lung parenchyma. The surgical specimen consists of the parietal pleura and visceral pleura and may or may not include a pericardial or diaphragmatic portion. This operation is performed under general anesthesia and one lung ventilation. Following induction, the patient is placed in the appropriate lateral decubitus position. A posterolateral thoracotomy is performed followed by a meticulous dissection to remove all gross tumor while preserving the lung. The technical steps of this operation are included in Table 4.

The postoperative care centers on analgesia, pulmonary toilet, chest tube care, and ambulation. A pleurectomy may result in some operative blood loss and a large air leak early on. The chest tube output and the air leak usually decrease in the first few postoperative days. Patient-controlled analgesia or, preferably, epidural analgesia is used to control incisional pain. Adequate analgesia facilitates ambulation and pulmonary toilet. Incentive spirometry is important in keeping the lung expanded and avoiding atelectasis. Keeping the lung fully expanded is also necessary to decrease the bleeding from the raw areas. We find that early ambulation is important to both pulmonary toilet and the prevention of deep venous thrombosis. We also routinely use pneumatic compression boots and low-dose subcutaneous heparin to reduce the risk of deep venous thrombosis and pulmonary embolus.

Extrapleural Pneumonectomy
This technique maximizes surgical cytoreduction. The specimen consists of parietal and viscera pleura, pericardial portion, diaphragmatic portion, and the entire lung. The procedure is performed under general anesthesia with double-lumen endotracheal intubation (Table 4). The en bloc resection is accomplished via an extended thoracotomy incision [27]The diaphragmatic and pericardial defects are repaired with prosthetic patches.

As in the postoperative care described for decortication/pleurectomy, attention is paid to adequate analgesia, pulmonary toilet, strict fluid balance, early ambulation, and deep venous thrombosis prophylaxis. Bronchoscopy is liberally used in clearing thick secretions in patients with poor cough. Close attention to fluid balance is crucial since volume overload can lead to hypoxemia. We recommend fluid restriction to one liter per day in the first three to five days and diuresis as needed to maintain a negative fluid balance and improve oxygen saturation.

Clinical Experience and Results
At our center, patients with mesothelioma are preoperatively evaluated by a multidisciplinary team of clinicians and allied health professionals. Clinical stage, premorbid conditions, resectability, and physiologic status are determined. The inclusion criteria for our preferred trimodality therapy includes adequate cardiac, hepatic, and renal function, sufficient pulmonary reserve to undergo EPP, resectable tumor by radiologic parameters, and Karnofsky performance status greater than 70.

Patients undergo an EPP as the debulking procedure followed by adjuvant chemotherapy and radiotherapy (two cycles of chemotherapy and radiotherapy and concurrent radiotherapy, then two more cycles of chemotherapy). We currently use carboplatin plus paclitaxel for adjuvant

chemotherapy. Patients receive two cycles of 200 mg/m2 of paclitaxel three weeks apart by continuous intravenous infusion (three-hour) and carboplatin AUC (area under the curve) level 6. External beam radiation is then given with concurrent, weekly administration of 60 mg/m2 of paclitaxel, followed by two cycles of paclitaxel (repeat of initial cycles, 200 mg/m2 intravenous infusion, three-hour) and carboplatin (AUC level 6). In our original series,[13] the chemotherapy regimen consisted of 50 to 60 mg/m2 of doxorubicin, 600 mg/m2 of cyclophosphamide, and 70 mg/m2 of cisplatin. The change in chemotherapy approach was due to the encouraging preliminary data on carboplatin plus paclitaxel[28] and to avoid cardiac complications from doxorubicin.

Radiation is typically given to the entire hemithorax and mediastinum. The borders are the first thoracic vertebral body superiorly, 1.5 cm lateral to the chest wall laterally, approximately 2.5 cm from the edge of the vertebral body to cover the mediastinum medially and 1 cm below the diaphragmatic reflection of the pleura inferiorly (the inferior border is determined by the inferior-most extent of the contralateral intact lung). The hemithorax is treated to 30 Gy in 1.5 daily fractions. If there are localized positive margins or positive lymph nodes, these areas are treated to 2 Gy fractions to a cumulative dose of approximately 54 Gy. The incision and chest tube sites are covered with bolus and included in the treatment field.

A cohort of 120 patients were treated with this trimodality protocol in the period between 1980 to 1995.[13] The morbidity rate was 22%, and the mortality rate was 5%. The survival at two and five years was 45% and 22%, respectively, with 21 months as the overall median survival.[13] A combination of epithelial histology and absence of malignancy in the mediastinal and/or hilar lymph nodes was associated with the best survival outcome. In this particular group (epithelial histology and negative nodes), the two- and five-year survival rates were 74% and 39%, respectively, whereas the subgroup with epithelial tumors and positive lymph nodes had two- and five-year survival rates of 52% and 10%, respectively .[13] Sarcomatous histology was associated with poor prognosis as noted by the two-year survival of 20% and absence of survival at five years).[13] The presence of tumor-involved margins and partial tumor infiltration of the diaphragm did not affect survival. This observation supports our hypothesis that chemoradiation helps in the eradication of the residual microscopic tumor. Survival by stage (Brigham stage) is demonstrated in Fig 1. Survival was 22 months for stage I, 17 months for stage II, and 11 months for stage III.

Conclusions
Mesothelioma is increasing in frequency and presents many diagnostic and management challenges. An optimal universal staging system is still awaiting definition and validation. Prognosis is best for patients with localized disease and epithelial histology. Surgical techniques including pleurectomy/decortication and EPP can result in a major debulking of disease, and studies are ongoing to determine if the addition of chemotherapy and radiation has an impact on survival. Several new investigational approaches are now being tested, including intrapleural interferon gamma, photodynamic therapy, immunotherapy, and gene therapy.

Appreciation is expressed to Mary S. Visciano for editorial assistance.

Address reprint requests to Dr Sugarbaker at the Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Brigham Staging System for Malignant Pleural Mesothelioma

Staging

Definition

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

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

3. Local extension of disease into chest wall or mediastinum, heart, or through diaphragm, peritoneum; with our without extrathoracic or contralateral (N3) lymph node involvement

4. Distant metastatic disease

Note: Butchart stage II and III[15] patients are combined into stage III. Stage I represents resectable patients with negative nodes. Stage II patients are resectable but have positive nodal status. From Sugarbaker DJ, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol.

1993:11:1172-1178. Reprinted with permission.[12]

Steps in Operative Technique for Diffuse Malignant Pleural Mesothelioma

Pleurectomy

1. Incision and exposure of parietal pleura

2. Dissection of parietal pleura from endothoracic fascia, diaphragm, and mediastinum*

3. Incision of the parietal pleura and exposure of the visceral pleura

4. Decortication of the visceral pleura

5. Reconstruction

Extrapleural Pneumonectomy

1. Incision and exposure of parietal pleura

2. Dissection of parietal pleura from endothoracic fascia, diaphragm, and mediastinum*

3. Control and division of pulmonary vessels, subcarinal node dissection, staple main stem bronchus

4. En bloc resection of lung, pleura, pericardium, and diaphragm

5. Reconstruction of diaphragm pericardium

*** POSTED JUNE 17, 1998 ***