1 Surgical Oncology 7 (1999) 5}12 Review Malignant pleural mesothelioma: a problematic review Thomas L. Moskal*, John D. Urschel, Timothy M. Anderson, Joseph G. Antkowiak, Hiroshi Takita- Division of Surgical Oncology and Department of Thoracic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buwalo, New York, USA Abstract Malignant pleural mesothelioma is a rare tumor that has been di$cult to study. Because of disappointing treatment results, malignant pleural mesothelioma has remained an area of active research and development. A clinicopathologic review is performed in light of several problematic issues involving diagnosis, staging, natural history, and treatment. Multimodality treatment with surgery followed by adjuvant local and systemic therapy remains the most optimal therapy. Many controversial issues still exist in the treatment of malignant pleural mesothelioma. In the ensuing years newer staging systems, better preoperative staging, newer experimental therapies, and the localization of patients at expert centers will undoubtedly have an impact on disease management Published by Elsevier Science Ltd. All rights reserved. Keywords: Mesothelioma; Pleural neoplasm; Lung neoplasm 1. Introduction Malignant mesothelioma is a rare tumor a!ecting a variety of mesodermally derived tissues in the body. Pleura is the most commonly a!ected site followed by peritoneum, pericardium, and tunica vaginalis testes. This review will focus on malignant pleural mesothelioma. Etiologic factors, natural history, possible therapeutic options as well as future directions in the management of malignant pleural mesothelioma will be overviewed. Multiple controversial issues exist concerning the diagnosis, staging, and treatment of malignant pleural mesothelioma, and contemporary solutions to these issues will be discussed. Responses to primary therapies are strikingly disappointing making malignant pleural mesothelioma an important disease in the study of innovative oncological therapies. *Corresponding author: North Shore Surgical Oncology Associates. 600 Northern Boulevard, Great Neck, New York 11021, Tel.: # ; fax: # Reprint requests should be addressed to Dr Hiroshi Takita, Department of Thoracic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Bu!alo, New York, 14263, USA. Tel.: # ; fax: # Epidemiology Malignant pleural mesothelioma (MPM) did not become a clinical entity until "rst reported by Wagner in 1960 when he described 33 cases of malignant pleural mesothelioma . It is a rare disease with 2000 cases occurring annually in the United States . This combination of low incidence in a recently discovered disease has made the study of MPM di$cult. Clinical information stems mostly from single institution case series with small numbers of patients. Signi"cant clinical work has been completed in other rare malignancies, such as sarcoma and Wilm's tumor, utilizing well designed prospective, randomized, multi-institutional trials. Such study design techniques will have to be extrapolated to MPM research. When malignant pleural mesothelioma was described in the 1960s the majority of cases were in asbestos mine workers. Soon after, epidemiologic studies "rmly established asbestos as the primary etiologic factor for malignant pleural mesothelioma . Asbestos is the commercial name for hydrated magnesium silicate "bers. These "bers possess high tensile strength, high stability and high thermal resistant properties. These attractive properties along with its inexpensive price have made asbestos a commonly used manufacturing material. There is a long latent period of 20}50 yr prior to /99/$ - see front matter 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S ( 9 8 ) X
2 6 T.L. Moskal et al. / Surgical Oncology 7 (1999) 5}12 developing MPM after exposure . Sixty to 80% of patients with MPM have a history of exposure to asbestos . Occupations at risk include miners, railroad workers, shipyard workers, construction workers, plumbers, and carpenters. Other possible etiologic factors for MPM include sporadic cases, passive or occult exposure to asbestos, exposure to radiation, exposure to other industrial "bers such as zeolite, exposure to beryllium and tuberculosis [4, 5]. Legislation has been implemented in the United States to minimize occupational and environmental asbestos exposure since the early 1970s. However, worldwide asbestos use has been underregulated and one can only conclude that the incidence of pleural mesothelioma will continue to rise. 3. Patient characteristics A recent review of 40 patients at Roswell Park Cancer Institute (RPCI) revealed the following patient characteristics. Median age was 59 yr; age range was from 21 to 77 yr. Male patients outnumbered female patients in a ratio of 3.4 : 1. Right sided lesions predominated over left sided lesions in a ratio of 2.6 : 1. Seventy-eight percent of patients had a history of exposure to asbestos. In this same series, presenting symptoms included dyspnea in 50%, chest pain in 33%, and cough in 23%; 15% of lesions were asymptomatic. Less frequently seen symptoms were chest wall mass and weight loss, each seen 3% of the time. Fig. 1. Chest X-ray of patient with left sided pleural mesothelioma with moderate pleural e!usion. 4. Diagnosis A typical chest X-ray (Fig. 1) of a patient with MPM demonstrates a moderate pleural e!usion. A typical computed tomographic (CT) scan (Fig. 2) in a patient with MPM demonstrates di!use pleural thickening in the chest. In the RPCI series radiographic "ndings included a pleural e!usion in 77%, a combination of pleural e!usion and pleural-based mass in 8%, and a solitary pleural mass in 15%. During the "rst three decades of MPM research, the histologic diagnosis was very di$cult to make. It was often impossible to di!erentiate malignant pleural mesothelioma from adenocarcinoma. Because of these interpretative di$culties, the early literature must be scrutinized. In the 1980s electron microscopy became the gold standard for histologic diagnosis. In the 1990s immunohistochemical staining has made histologic diagnosis even easier. By way of a body of immunohistochemical stains (see Table 1), the accurate diagnosis of MPM and di!erentiation from adenocarcinoma is now possible . Periodic acid Schi! stain with diastase digestion, mucicarmine, carcino-embryonic antigen and Fig. 2. CT scan of patient with left sided pleural mesothelioma with di!use pleural thickening. leukocyte M1 antibody staining seem to be the most useful. There are three main histologic subtypes for MPM. In the RPCI series the epithelial subtype was the most commonly seen accounting for 62%. The biphasic subtype accounted for 25%, whereas the sarcomatous subtype was least frequently seen accounting for 13%.
3 T.L. Moskal et al. / Surgical Oncology 7 (1999) 5}12 7 Table 1 Immunohistochemical staining Stain Mesothelioma Adenocarcinoma PAS #/! # DPAS! # Hyaluronic acid #/!!/# Mucicarmine! # Keratin # # CEA! # Leu-M1! # Vimentin #/!!/# PAS, periodic acid shi!; DPAS, diastase digested PAS; CEA, carcinoembryonic antigen; Leu-M1, leukocyte M1 antibody. In the RPCI series diagnosis was achieved by thoracentesis in 2%, percutaneous biopsy in 13%, open thoracotomy biopsy in 35%, and video assisted thoracoscopic biopsy in 50%. In 1993, Boutin reviewed 188 consecutive patients comparing thoracentesis, CT guided "ne needle aspiration biopsy and thoracoscopic assisted biopsy as diagnostic tools in MPM . Although thoracentesis was performed in the majority of patients for their pleural e!usions, it was only useful 26% of the time. CT guided "ne needle aspiration biopsy was useful 21% of the time. Finally, thoracoscopic assisted biopsy was most useful in obtaining a diagnosis in 98% of patients. Ultimately, as percutaneous biopsy instrumentation and immunohistochemistry improve, the feasibility of CT scan guided percutaneous biopsy will increase as a diagnostic tool. Scott in 1995 achieved diagnostic accuracy of 93% in 42 patients and Metintas in 1995 achieved diagnostic accuracy of 83% in 30 patients undergoing CT guided percutaneous biopsy for MPM [7, 8]. A problem with invasive histologic sampling in the diagnosis of MPM is the potential for malignant tract seeding which can be seen in 19% of patients . In 1995 Boutin studied the role of radiation therapy to decrease disease seeding from diagnostic procedures in 40 patients undergoing video assisted thoracoscopic biopsy. For the 20 patients without radiation therapy treatment to their biopsy tract, eight of those patients developed tract seeding. For the 20 patients treated with local radiation to their biopsy tract, none of those patients developed tract seeding. Commonly found laboratory abnormalities in pleural mesothelioma include elevations in platelet counts and liver function tests. Consistent elevations are not seen although in some studies elevated platelet counts were signi"cant prognostic factors [10, 11]. In the RPCI series 35% of patients had platelet counts greater than and 23% had nonspeci"c elevations in lactate dehydrogenase and alkaline phosphatase. Preoperative platelet count was a signi"cant prognostic factor only on univariate analysis in this series. 5. Staging Since 1970, there have been "ve staging sytems for MPM, making interpretation and comparison of studies di$cult. As the natural history of MPM is further clari"- ed, the staging systems are evolving to incorporate this newer information. The Butchart system is the initial staging system described in 1970 . This four stage system is still used by some today. In the late 1980s and early 1990s the International Union Against Cancer proposed a tumor, node, and metastasis (TNM) staging system. In the 1998 American Joint Committee on Cancer TNM staging system T stage is de"ned as T1 (pleural), T2 (beyond pleura), T3 (chest wall or mediastinal organ invasion), and T4 (direct extension outside of the chest); while nodal disease is de"ned in a similar manner to lung cancers with N1 (hilar), N2 (mediastinal), and N3 (contralateral or supraclavicular) . These are then grouped into four stages with stage I having no nodal involvement. In 1996, the International Mesothelioma Interest Group introduced a newer TNM Staging system taking into account emerging T and N status prognostic factors . In this system T1a (parietal pleura) and T1b (visceral pleura) further separate stage I into stage IA and IB, and stage II now also has no nodal involvement. Clinical staging has been di$cult in pleural mesothelioma. CT scan radiologic imaging has been the most e$cacious test, yet accuracy rates are low. In the RPCI series preoperative CT scanning determined stage correctly in only 30% of the patients. Magnetic resonance imaging (MRI) and positron emission tomographic (PET) scanning are being studied as alternative imaging techniques with mixed results. The roles of mediastinoscopy and thoracoscopy are also being de"ned. Pathologic staging is di$cult in part because resections are often performed piecemeal. Analysis of specimens requires a dedicated surgical and pathology team for proper stage determination. As the need to select patients for di!erent treatment regimens arises, the development of a de"nitive staging system and better preoperative assessment will become necessary. 6. Natural history The natural history of MPM involves a di!use local process a!ecting the pleural surfaces. Lung, diaphragm, pericardium, and mediastinum are invaded resulting in increasing pleural e!usion and lung parenchymal trapping. Patients develop progressive symptoms of dyspnea, cough and chest wall pain. Death usually occurs from respiratory failure. In 1989 Ru$e clearly described the metastatic potential of malignant pleural mesothelioma . He reviewed 92 autopsies and in 49% of the patients distant
4 8 T.L. Moskal et al. / Surgical Oncology 7 (1999) 5}12 metastases were found in the liver, contralateral lung, adrenal gland, kidney, bone and pancreas. Recent reports reveal that two-thirds of patients recur locally and 50}75% at distant sites after treatment. In 1997 King published an autopsy series in which 10 out of 15 patients (67%) had distant metastasis to omentum, stomach, intestine, mesentery, adrenal gland, ovary, pancreas, kidney, liver, spleen, and vertebrae . Sixty seven percent of patients also had recurrence in the contralateral lung. In 1997 Baldini showed that in 46 patients treated with trimodality therapy local recurrence occurred in 35% and distant recurrence in 51% . Initial treatment of pleural mesothelioma consisted of local therapy only. From the described natural history it is clear that treatment options need to address both local and systemic disease. Treatment options for MPM include supportive care, surgery, chemotherapy, radiation therapy, multimodality therapy, photodynamic therapy, intrapleural therapy, immunotherapy, and experimental therapies. 7. Primary single modality therapy Supportive care in the treatment of MPM involves thoracentesis and pleurodesis to control pleural e!usions and dyspnea. Analgesia is also used to control the severe chest wall pain that is often seen. In 1989 Ru$e reviewed 176 patients treated with supportive care, and his median survival was 6.8 months . A controversial issue in the treatment of MPM with surgery is the exact extent of surgery. There is an ongoing debate comparing pleurectomy with extrapleural pneumonectomy. Pleurectomy is associated with lower morbidity and mortality, and preservation of pulmonary function. Extrapleural pneumonectomy is associated with higher morbidity and mortality, a more complete resection of the tumor, and easier feasibility to deliver postoperative radiation therapy. Table 2 includes several series showing the mortality for pleurectomy ranging from 0 to 3.7% [17}20] and for extrapleural pneumonectomy ranging from 5 to 15% [11, 21}23]. In 1996 Sugarbaker, with the largest series of patients, has decreased the contemporary mortality for extrapleural pneumonectomy to 5%. Radiation therapy, as a single modality therapy for MPM, has disappointing results. In 1973 Eshuege treated 14 patients with doses ranging from 35 to 75 gray and observed a median survival of 15 months . In 1981 Gordon treated 27 patients with doses ranging from 10 to 56 gray and observed a median survival of 11.5 months . In 1988 Alberts treated 13 patients with 40 to 80 gray and observed a median survival of 7.8 months . These survivals are not much better than treatment with supportive care. Table 2 Mortality for pleurectomy and pneumonectomy Study Year n Surgery Mortality (%) Hilaris  Pleurectomy 0 Rusch  Pleurectomy 3.7 Lee  Pleurectomy 0 Colleoni  Pleurectomy 0 DaValle  Pneumonectomy 9.1 Ru$e  Pneumonectomy 13 Rusch  Pneumonectomy 15 Sugarbaker  Pneumonectomy 5 Single agent chemotherapy as a primary single modality therapy for MPM has disappointing results. The responses are low, ranging from 0 to 37%, and the most e$cacious agents seem to be cisplatin, mitomycin C and doxorubicin [27, 28]. Multiple agent chemotherapy for the treatment of MPM also has disappointing results. Responses are slightly better ranging from 0 to 44% [27, 28]. In 1993, the Cancer and Leukemia Group B published its results comparing two di!erent multiple drug regimens . There were 26% responses for a combination of cisplatin and mitomycin C, and 14% responses for a combination of doxorubicin and cisplatin. In 1996 Huncharek compared the results of the treatments with di!erent single modality therapies . In his supportive care group (n"26), median survival was 4.5 months; for surgery alone (n"17), it was 5.0 months; for radiation alone (n"4) 11.5 months; and for chemotherapy (n"11) it was 6.0 months. Interestingly, 21 patients were also treated with multimodality therapy consisting of surgery followed by adjuvant chemotherapy with a superior survival of 23.9 months. 8. Multimodality therapy Many series have shown the potential bene"t of multimodality therapy increasing survival in MPM (see Table 3). In many of these series the staging is variable and because of these selection biases study comparisons must be done cautiously. The combination of chemotherapy and radiation therapy demonstrates median survivals ranging from 7.9 to 11 months [26, 31, 32]. In 1988 Alberts, utilizing a combination of radiation therapy and doxorubicin in 10 patients, had improved median survival of 22.6 months . The combination of surgery followed by systemic chemotherapy, followed by radiation therapy remains an attractive treatment because of its availability at most medical centers [21, 23, 33]. In 1992 Mattson had an
5 T.L. Moskal et al. / Surgical Oncology 7 (1999) 5}12 9 Table 3 Multimodality therapy Study Treatment Year n Median survival (months) OS (2 yr) (%) Chahinian  C, XRT NA Sino!  C, XRT NA Alberts * C, XRT NA Alberts * C, XRT NA Alberts * C, XRT NA Alberts * C, XRT NA Mattson  S, C, XRT DaValle  S, C, XRT Sugarbaker  S, C, XRT Hilaris  S, B, XRT Lee  S, IPC Rusch  S, IPC, C Rice  S, IPC, C Sauter  S, IPC, C Colleoni  S, IPC, C OS, overall survival; C, systemic chemotherapy; XRT, external beam radiation therapy; S, surgery; B, brachytherapy; IPC, intrapleural chemotherapy; and NA, not available. *Di!erent chemotherapeutic agents. overall survival at 2 yr of 20 %, but this was an inconsistent study in that the adjuvant chemotherapy was comprised of various combinations of seven di!erent chemotherapeutic agents . In 1994 DaValle had an overall survival of 23%, but this was also an inconsistent study in that only 52% of patients had adjuvant chemotherapy . In 1996 Sugarbaker had an overall survival at 2 yr of 45% utilizing a regimen of cyclophosphamide, doxorubicin and cisplatin . In 1983 Hilaris looked at surgery followed by brachytherapy, followed by radiation therapy in 41 patients, demonstrating a median survival of 21 months and overall survival at 2 yr of 40% . In 1995 Lee looked at surgery followed by intrapleural chemotherapy utilizing cisplatin and cytosine arabinoside in 15 patients, revealing median survival of 11.5 months and overall survival at 2 yr of 16% . Several series have looked at the combination of surgery followed by intrapleural chemotherapy, followed by systemic chemotherapy [18, 20, 35, 36]. In 1994 Rusch had overall survival at 2 yr of 40% utilizing a regimen of intrapleural cisplatin and mitomycin C followed by systemic cisplatin and mitomycin C . In 1994 Rice utilizing a similar regimen demonstrated 2 yr overall survival of 25% . In 1995 Sauter looked at intrapleural cisplatin followed by cytosine arabinoside, followed by intravenous cisplatin and mitomycin C with overall survival at 2 yr of 15% . In 1996 Colleoni utilized intrapleural cisplatin and cytosine arabinoside followed by systemic epirubicin and mitomycin C with overall survival at 2 yr of 34% . 9. Experimental therapy The results of MPM treatment are disappointing with low overall 2-yr survival in most cases and with 5-yr overall survivals approaching 0%. Because of these disappointing treatment results with conventional therapy using combinations of surgery, chemotherapy, and radiation therapy, pleural mesothelioma has become an arena for the implementation of new and emerging therapies such as immunotherapy, gene therapy, and photodynamic therapy . Clinical trials with immunotherapy have centered on cytokine therapy. Vaccine treatments are beginning to enter into human treatment protocols. In 1991 Boutin looked at intrapleural interferon-gamma with low responses of 23% in 22 patients . In 1991 Eggermont looked at interleukin-2 given intrapleurally with responses of 24% in 17 patients . Astoul also looked at interleukin-2 given intrapleurally in 15 patients with response rates of 47% . In 1993 Christmas looked at intravenous interferon-α with responses of 12% in 13 patients . Finally, in 1995 Pass looked at a combination of cisplatin, intravenous interferon-α and tamoxifen in 36 patients with responses of 19% . Gene therapy for the treatment of pleural mesothelioma remains in the early stages of development because of the incomplete understanding of tumor molecular biology and immunology. The main approach has focused on delivery of genes into the tumor cells to generate toxic metabolites. The tumor with the gene is then exposed to the nontoxic substrate to generate the toxic product. The two most common systems are the
6 10 T.L. Moskal et al. / Surgical Oncology 7 (1999) 5}12 bacterial cytosine deaminase gene with the 5-#uorocytosine substrate and the herpes simplex thymidine kinase gene (HSVtk) with the ganciclovir substrate [43, 44]. In 1997 Albeda described a phase I trial with intrapleural gene therapy using the HSVtk gene driven by the Rous sarcoma virus promoter (AdRSVtk) . Photodynamic therapy (PDT) is a surface oriented photochemical induced cytotoxic therapy [46}50]. The technology relies on tumor preferential uptake of agents that when activated by light lead to tumor cytotoxicity. The "rst generation agents have been porphyrin based. In 1990 Feins showed the eradication of mesothelioma tumors implanted in nude mice with PDT therapy . In 1990 Pass showed the clinical feasibility of this trea tment . In 1997, Pass described a phase III trial with surgery and chemo-immunotherapy (cisplatin, interferon-α-2b, and tamoxifen) and PDT in 48 patients demonstrating no bene"t from PDT with both groups having median survivals of 14 months . However, this study accrued only 48 out of the required 88 patients and there were only eight patients with early stage I or II disease. Takita treated 40 patients with a combination of surgery and photodynamic therapy in the RPCI series . For the patients with early stage I and II disease (n"13), median survival of 36 months and overall survival at 2 yr was 61%. However, for patients with stage III and IV disease (n"24), median survival was 10 months and 2 yr overall survival was 0%. For the combined patients (n"37), median survival was 15 months and 2 yr overall survival was 23%. Morbidity was increased for all patients and mortality was increased in patients undergoing pneumonectomy. The addition of systemic therapy to the above regimen is expected to further improve treatment results. E!orts in improving PDT delivery and in developing second generation photosensitizers are actively being pursued [55, 56]. 10. Prognostic indicators Positive prognostic indicators for MPM include epithelial histology [10, 57}62], stage I or II disease [11, 57, 59, 61], negative nodal status , and good performance status [57, 62]. Other less frequently described positive prognostic factors in the literature are female gender [10, 57, 62], young age , normal platelet count [10, 11], long symptom duration , weight loss , normal white blood cell count , and no history of asbestos exposure . In the RPCI series univariate analysis identi"ed stage, completeness of resection, N stage, T stage, histology, platelet count, chest wall muscle invasion, and length of hospital stay as prognostic factors. On multivariate analysis stage, length of hospital stay, PDT dose, and N stage remained prognostic factors. 11. Conclusions Malignant pleural mesothelioma is a rare disease that has been di$cult to study. No standard therapies exist to date. Treatment results are generally disappointing with very few long term survivors. Multimodality therapy with surgery and adjuvant local and systemic therapy seem to give the most favorable outcomes. Aggressive therapy seems most appropriate for patients with early stage I and II disease. This review has touched upon some of the problematic issues in the treatment of malignant pleural mesotheliomas particularly concerning diagnosis, staging, and di$culty with clinical trials. Future directions to help advance malignant pleural mesothelioma treatment will most likely concentrate e!orts on several key points. A uniform staging system must be widely accepted to allow better treatment planning and comparison of outcomes. 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