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Malignant Mesothelioma of the Pleura

      Malignant mesothelioma of the pleura most commonly occurs in persons with a heavy occupational exposure to asbestos. Some patients, however, have no such history of exposure. Clinical features include initial complaints of nonpleuritic chest pain and dyspnea. The most frequent roentgenographic finding is a unilateral pleural effusion. Thrombocytosis and elevated erythrocyte sedimentation rates are common. Pleural effusions are typically exudates, are often hemorrhagic, and are usually insufficient for diagnosing mesothelioma based on cytology alone. Even pleural biopsy may not produce enough tissue to enable the pathologist to make a firm diagnosis. Thoracotomy and open biopsy will confirm the diagnosis in most cases. Pathologic distinction from metastatic adenocarcinoma may be difficult even after the use of special stains and electron microscopy. Clinical deterioration is primarily attributable to local spread of tumor. Several factors seem to predict prolonged survival: (1) epithelial histologic subtype, (2) performance score, (3) age of the patient at the time of diagnosis, and (4) absence of chest pain. Surgical treatment, chemotherapy, and irradiation, alone or in combination, have been used for malignant mesothelioma. Except for the palliative effect of irradiation, most treatment protocols have not altered the dismal median survival of approximately 11 months seen in untreated patients with malignant mesothelioma.
      The incidence of malignant mesothelioma of the pleura is increasing at a rate of 13% per year in American men.
      • Spirtas R
      • Beebe GW
      • Connelly RR
      • Wright WE
      • Peters JM
      • Sherwin RP
      • Henderson BE
      • Stark A
      • Kovasznay BM
      • Davies JNP
      • Vianna NJ
      • Keehn RJ
      • Ortega LG
      • Hochholzer L
      • Wagner JC
      Recent trends in mesothelioma incidence in the United States.
      In addition, although formerly seen predominantly in men employed in high-asbestos-exposure occupations, malignant mesothelioma is beginning to occur more frequently in women and in those with no history of work-related exposure to asbestos.
      • Wolf KM
      • Piotrowski ZH
      • Engel JD
      • Bekeris LG
      • Palacios E
      • Fisher KA
      Malignant mesothelioma with occupational and environmental asbestos exposure in an Illinois community hospital.
      Despite the application of multiple therapeutic approaches, the poor prognosis has not been altered since the initial descriptions of mesothelioma. In this review, we summarize our current understanding of malignant mesothelioma.

      HISTORICAL BACKGROUND

      One of the first clues leading to the eventual link between asbestos and mesothelioma was the observation that tumors occurred more frequently in coastal cities than elsewhere.
      • Glatzel H
      Zur Geographie des Pleuracarcinoms.
      Subsequently, investigations in South African coal miners confirmed that exposure to asbestos was associated with an increased incidence of mesothelioma.
      • Wagner JC
      • Sleggs CA
      • Marchand P
      Diffuse pleural mesothelioma and asbestos exposure in the north western Cape Province.
      This observation, made in 1960, has been confirmed in numerous studies.
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      • Selikoff IJ
      • Churg J
      • Hammond EC
      Relation between exposure to asbestos and mesothelioma.
      • Whitwell F
      • Rawcliffe RM
      Diffuse malignant pleural mesothelioma and asbestos exposure.
      Although malignant mesothelioma probably was initially described before 1900,
      • Wagner E
      Das tuberkelahnliche Lymphadenom.
      it was not well recognized until 1960.
      • Wagner JC
      • Sleggs CA
      • Marchand P
      Diffuse pleural mesothelioma and asbestos exposure in the north western Cape Province.
      Localized fibrous mesothelioma is unrelated to exposure to asbestos and is discussed only briefly in this report, primarily to illustrate features that distinguish it from diffuse malignant mesothelioma. Three reviews of localized fibrous mesothelioma have been published recently.
      • Briselli M
      • Mark EJ
      • Dickersin GR
      Solitary fibrous tumors of the pleura: eight new cases and review of 360 cases in the literature.
      • Okike N
      • Bernatz PE
      • Woolner LB
      Localized mesothelioma of the pleura: benign and malignant variants.
      • Dalton WT
      • Zolliker AS
      • McCaughey WTE
      • Jacques J
      • Kannerstein M
      Localized primary tumors of the pleura: an analysis of 40 cases.

      EPIDEMIOLOGIC FEATURES

      Approximately two-thirds of the patients with diffuse malignant pleural mesothelioma are between the ages of 50 and 70 years.
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.
      Rarely, the tumor occurs in children.
      • Grundy GW
      • Miller RW
      Malignant mesothelioma in childhood: report of 13 cases.
      The incidence of malignant mesothelioma is 2 to 6 times higher in men than in women. Wives of men employed in asbestos-related work also have an increased incidence of mesothelioma.
      • Vianna NJ
      • Polan AK
      Non-occupational exposure to asbestos and malignant mesothelioma in females.
      The incidence of malignant mesothelioma in populations considered minimally exposed to asbestos was estimated at one case per million per year in Canada between 1959 and 1968.
      • McDonald AD
      • Harper A
      • El Attar OA
      • McDonald JC
      Epidemiology of primary malignant mesothelial tumors in Canada.
      Industrialized countries have an increased incidence, and the highest incidence occurs among persons with heavy occupational exposure to asbestos (for example, shipyard workers and insulators). Data from more than 40,000 autopsies performed in various countries show the rate of occurrence of malignant mesothelioma to range from 0.02 to 0.7%;
      • Shearin Jr, JC
      • Jackson D
      Malignant pleural mesothelioma: report of 19 cases.
      the highest rate was found in Hamburg, a shipbuilding center. One study estimated that a mesothelioma will develop in approximately 2% of workers exposed to one asbestos fiber per cubic centimeter for 50 years.
      • Peto J
      The hygiene standard for chrysotile asbestos.
      Among a population of asbestos insulation workers from the United States and Canada, 8% of deaths were due to mesothelioma during a decade of observation.
      • Selikoff IJ
      • Hammond EC
      • Seidman H
      Latency of asbestos disease among insulation workers in the United States and Canada.
      These studies reinforce the association of malignant mesothelioma with exposure to asbestos. This relationship has several interesting features. The latency period between the first exposure and the diagnosis of tumor usually ranges from 30 to 45 years.
      • Selikoff IJ
      • Hammond EC
      • Seidman H
      Latency of asbestos disease among insulation workers in the United States and Canada.
      The different types of asbestos, including crocidolite, amosite, tremolite, chrysotile, and anthophyllite, are not equally hazardous. (Table 1) summarizes the risk of mesothelioma that accompanies exposure to each type of asbestos fiber and the settings in which such exposure might occur. The likelihood of developing mesothelioma depends in part on the physical characteristics of the fibers inhaled. Fibers with the greatest length-to-diameter ratio are the most carcinogenic.
      • Jaurand M-C
      • Fleury J
      • Monchaux G
      • Nebut M
      • Bignon J
      Pleural carcinogenic potency of mineral fibers (asbestos, attapulgite) and their cytotoxicity on cultured cells.
      • Wagner JC
      • Berry G
      • Timbrell V
      Mesotheliomata in rats after inoculation with asbestos and other materials.
      The epidemiologic data presented in (Table 1) confirm this finding, inasmuch as crocidolite, amosite, and tremolite all tend to have high length-to-diameter ratios.
      • Hillerdal G
      Malignant mesothelioma 1982: review of 4710 published cases.
      Table 1Types of Asbestos Fibers: Environmental Exposure and Carcinogenicity
      TypeExposureMesothelioma carcinogenicity
      Crocidolite
      • Miners (South Africa)
      • Factory workers
      High
      Amosite
      • Miners
      • Insulators
      • Factory workers
      High
      Tremolite
      • Environmental (Greece)
      • As a contaminant in chrysotile
      High (?)
      Chrysotile
      • Miners (North America)
      • Insulators
      • Factory workers
      Low
      AnthophylliteMiners (Finland)None
      The epidemiologic data linking crocidolite and amosite with an increased incidence of mesothelioma are widely accepted.
      • Wagner JC
      • Sleggs CA
      • Marchand P
      Diffuse pleural mesothelioma and asbestos exposure in the north western Cape Province.
      • Selikoff IJ
      • Hammond EC
      • Seidman H
      Latency of asbestos disease among insulation workers in the United States and Canada.
      In comparison, the carcinogenicity of chrysotile is not as great, and increased risk seems to be limited to those directly exposed to chrysotile mine dust.
      • Nicholson WJ
      • Selikoff IJ
      • Seidman H
      • Lilis R
      • Formby P
      Long-term mortality experience of chrysotile miners and millers in Thetford Mines, Quebec.
      • Churg A
      Chrysotile, tremolite, and malignant mesothelioma in man.
      A localized area in Greece with a death rate from mesothelioma of 1% represents a rare instance of exposure to pure tremolite asbestos.
      • Langer AM
      • Nolan RP
      • Constantopoulos SH
      • Moutsopoulos HM
      Association of metsovo lung and pleural mesothelioma with exposure to tremolite-containing whitewash.
      Occupational exposure to tremolite alone is rare, but tremolite may contaminate chrysotile asbestos and account for some of the cases of mesothelioma reported in workers exposed to chrysotile.
      • Churg A
      Chrysotile, tremolite, and malignant mesothelioma in man.
      No case of mesothelioma has been reported to date among Finnish miners exposed to anthophyllite asbestos.
      • Huuskonen MS
      • Ahlman K
      • Mattsson T
      • Tossavainen A
      Asbestos disease in Finland.
      Studies vary in estimated percentages of patients with malignant mesothelioma who have well-substantiated antecedent exposure to asbestos. Some of this variation may be due to geographic differences: studies from the eastern coast of the United States,
      • Borow M
      • Conston A
      • Livornese L
      • Schalet N
      Mesothelioma following exposure to asbestos: a review of 72 cases.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      Great Britain,
      • Edge JR
      • Choudhury SL
      Malignant mesothelioma of the pleura in Barrow-in-Furness.
      • Dorward AJ
      • Stack BHR
      Diffuse malignant pleural mesothelioma in Glasgow.
      and South Africa
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      all reported exposure in 80% or more of the described cases. Studies from the midwestern United States
      • Wolf KM
      • Piotrowski ZH
      • Engel JD
      • Bekeris LG
      • Palacios E
      • Fisher KA
      Malignant mesothelioma with occupational and environmental asbestos exposure in an Illinois community hospital.
      • Oels HC
      • Harrison Jr, EG
      • Carr DT
      • Bernatz PE
      Diffuse malignant mesothelioma of the pleura: a review of 37 cases.
      • Vogelzang NJ
      • Schultz SM
      • Iannucci AM
      • Kennedy BJ
      Malignant mesothelioma: the University of Minnesota experience.
      confirmed exposure to asbestos in less than 50% of cases. The possibility that exposure to nonasbestos minerals or other factors promote formation of tumors in patients with no occupational exposure to asbestos is confounded by the observation that more than 90% of urban dwellers harbor asbestos mineral fibers in their lungs.
      • Mollo F
      • Andrion A
      • Bellis D
      • Bertoldo E
      Screening of autopsy populations for previous occupational exposure to asbestos.
      In addition, residential proximity to primary asbestos manufacturing plants may be a major risk factor. A recent review from a community hospital showed that although less than half the patients with malignant mesothelioma had occupational exposure to asbestos, 84% lived within 2 miles of an asbestos-producing plant.
      • Wolf KM
      • Piotrowski ZH
      • Engel JD
      • Bekeris LG
      • Palacios E
      • Fisher KA
      Malignant mesothelioma with occupational and environmental asbestos exposure in an Illinois community hospital.
      The role of such environmental exposures remains controversial.
      Other risk factors such as irradiation,
      • Stock RJ
      • Fu YS
      • Carter JR
      Malignant peritoneal mesothelioma following radiotherapy for seminoma of the testis.
      exposure to beryllium,
      • Gold C
      A primary mesothelioma involving the rectovaginal septum and associated with beryllium.
      and viral illness
      • Chabot JF
      • Beard D
      • Langlois AJ
      • Beard JW
      Mesotheliomas of peritoneum, epicardium, and pericardium induced by strain MC29 avian leukosis virus.
      have been reported, but further studies must be conducted to establish their clinical significance. Cigarette smoking, by increasing the likelihood of death from bronchogenic carcinoma, may actually lower the risk of death from mesothelioma among asbestos-exposed workers who smoke.
      • Tagnon I
      • Blot WJ
      • Stroube RB
      • Day NE
      • Morris LE
      • Peace BB
      • Fraumeni Jr, JF
      Mesothelioma associated with the shipbuilding industry in coastal Virginia.
      The incidence of malignant mesothelioma in the United States has increased most substantially in white men older than 50 years of age at the time of diagnosis. This trend is unlikely to be due to increased recognition of the condition by clinicians and pathologists but rather supports the conclusion that a group exposed to high levels of asbestos in the 1940s and 1950s is reaching the end of a prolonged latency period.

      CLINICAL FEATURES

      The gradual onset of chest pain is the most common (60%) initial manifestation in most series of patients with diffuse malignant mesothelioma.
      • Vogelzang NJ
      • Schultz SM
      • Iannucci AM
      • Kennedy BJ
      Malignant mesothelioma: the University of Minnesota experience.
      • Antman KH
      • Blum RH
      • Greenberger JS
      • Flowerdew G
      • Skarin AT
      • Canellos GP
      Multimodality therapy for malignant mesothelioma based on a study of natural history.
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      This pain is typically nonpleuritic. Dyspnea is the next most frequent respiratory complaint (40%). Fever, chills, sweats, or weakness and malaise have been reported in a considerable number of patients. Cough is relatively uncommon (10%). A small percentage of patients have an acute onset of severe pain and dyspnea, usually related to either hemothorax or spontaneous pneumothorax.
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      Most patients have experienced symptoms for at least 2 months before diagnosis, and as many as a fourth of the patients have had symptoms for 6 months or longer.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      Rarely, diagnostic evaluation is initiated on the basis of abnormal findings on a chest roentgenogram in an otherwise asymptomatic patient. This type of presentation would be expected to be more common in screening programs of persons with exposure to high levels of asbestos. Most patients with peritoneal mesothelioma complain of abdominal pain and increasing abdominal girth.
      Other than dullness to percussion and decreased breath sounds, due to either pleural effusion or involvement by tumor, physical examination is unrevealing. Occasionally, metastatic disease is suspected on the basis of the presence of lymphadenopathy (15%) or hepatomegaly (10%). Clubbing is seen in up to 20% of patients with localized fibrous mesothelioma and more frequently in those with large benign tumors,
      • Okike N
      • Bernatz PE
      • Woolner LB
      Localized mesothelioma of the pleura: benign and malignant variants.
      but it is found in less than 10% of patients with diffuse malignant mesothelioma.
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.

      RADIOLOGIC FINDINGS

      The most common chest x-ray finding in patients with malignant mesothelioma is a unilateral pleural effusion; the incidence varies from 30 to 95%.
      • Vogelzang NJ
      • Schultz SM
      • Iannucci AM
      • Kennedy BJ
      Malignant mesothelioma: the University of Minnesota experience.
      • Antman KH
      • Blum RH
      • Greenberger JS
      • Flowerdew G
      • Skarin AT
      • Canellos GP
      Multimodality therapy for malignant mesothelioma based on a study of natural history.
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      • Solomon A
      Radiological features of diffuse mesothelioma.
      • Wechsler RJ
      • Rao VM
      • Steiner RM
      The radiology of thoracic malignant mesothelioma.
      • Krumhaar D
      • Lange S
      • Hartmann C
      • Anhuth D
      Follow-up study of 100 malignant pleural mesotheliomas.
      A mediastinal shift toward the affected side, even in the presence of a large amount of fluid, should suggest the possible presence of mesothelioma. Most reported series describe a small number of patients with mesothelioma who have bilateral pleural effusions; thus, this finding should not be used as evidence against the diagnosis.
      Pleural thickening is present on more than 50% of chest roentgenograms in patients with malignant mesothelioma, but occasionally it is obscured by effusion and will not become evident until thoracentesis has been performed. Diffuse pleural thickening may also be seen in patients with asbestosis, tuberculosis, fungal disease, metastatic cancer, or lymphoma. Lobulation is a feature thought to be highly suggestive of mesothelioma. On the initial chest roentgenogram, less than 25% of patients with malignant mesothelioma have distinct multiple pleural masses without effusions, and even fewer have a solitary pleural mass. Benign pleural plaques, with or without calcifications, may be an accompanying finding. Metastatic pulmonary nodules are commonly found at autopsy,
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      but chest x-ray evidence of lung nodules is uncommon (in less than 15% of patients in most reports). Ipsilateral hilar enlargement is occasionally noted and most often signifies mediastinal pleural involvement rather than metastatic nodal spread. Rib destruction can be present, most often in patients who have far-advanced and bulky tumors.
      Other imaging modalities are helpful in a variety of situations. Ultrasound scanning is useful for distinguishing pleural effusions from pleural masses. Although gallium scanning has been reported to disclose abnormalities in 88% of patients with malignant mesothelioma,
      • Wolk RB
      Gallium-67 scanning in the evaluation of mesothelioma.
      it is being replaced by computed tomography for staging of mesothelioma. Computed tomography can more clearly delineate the extent of involvement of mesothelioma but, like isotope scans, does not distinguish mesothelioma from metastatic adenocarcinoma.
      • Alexander E
      • Clark RA
      • Colley DP
      • Mitchell SE
      CT of malignant pleural mesothelioma.
      One of the most valuable functions of computed tomographic scanning is to assist the surgeon in selecting optimal biopsy sites.

      LABORATORY DATA

      Serum chemistries, hemoglobin concentration, and leukocyte counts are typically normal at the time of diagnosis of malignant mesothelioma. Thrombocytosis (more than 400,000 platelets/mm3) was noted in 90% of patients in one series.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      The erythrocyte sedimentation rate can exceed 100 mm in 1 hour.
      Laboratory features of pleural fluid obtained from patients with mesothelioma have been well described,
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      but they are not diagnostic. Half the effusions are bloody. Most are exudates with a specific gravity of more than 1.021, a protein concentration of more than 3.4 g/dl, and elevated lactate dehydrogenase.
      • Taryle DA
      • Lakshminarayan S
      • Sahn SA
      Pleural mesotheliomas—an analysis of 18 cases and review of the literature.
      The glucose concentration is variable but tends to decrease in inverse proportion to the number of cancer cells present. In one series, malignant cells were found in the pleural fluid in only 32% of patients,
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      and the diagnosis of mesothelioma was based solely on the cytologic findings in 10%. Most pathologists prefer a tissue biopsy specimen for diagnosing mesothelioma. A high level of hyaluronic acid in the pleural fluid is found more commonly in mesothelioma than in other processes, and mesothelioma can be suspected with levels in excess of 50 ng/liter. In most patients with a highly suspected diagnosis of mesothelioma, a tissue biopsy is necessary to establish the diagnosis.

      DIAGNOSIS

      Among patients with mesothelioma, a needle biopsy specimen of the pleura is usually insufficient to make the diagnosis. Because of its small size, it was considered diagnostic in only 25% of cases in one series
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.
      and 39% in another.
      • Prakash UBS
      • Reiman HM
      Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases.
      Needle biopsy often fails to provide enough tissue to enable the pathologist to exclude reactive mesothelial proliferations confidently. In addition, needle biopsy does not permit gross inspection and palpation of the pleura, both of which may be helpful in establishing the diffuse nature of malignant mesothelioma and in choosing optimal tissue sampling sites. Finally, one study showed that biopsy needle channels can be invaded by tumor tissue in as many as 20% of cases.
      • Dorward AJ
      • Stack BHR
      Diffuse malignant pleural mesothelioma in Glasgow.
      At one time, an autopsy was considered necessary for confirmation of the diagnosis of mesothelioma in order to exclude the possibility of metastatic lesions from another site, but open biopsy is now generally considered sufficient in the appropriate clinical setting. In patients suspected of having a mesothelioma (that is, those in whom other entities such as metastatic adenocarcinoma are still possible), open biopsy confirms a mesothelioma approximately 60% of the time.
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      In autopsy-proven mesothelioma, previous thoracotomy and biopsy established the diagnosis in 90% of cases.
      • Ryan CJ
      • Rodgers RF
      • Unni KK
      • Hepper NGG
      The outcome of patients with pleural effusion of indeterminate cause at thoracotomy.
      Unfortunately, in as many as 40% of patients diagnosed in this fashion, intractable pain develops along the incision line,
      • Shearin Jr, JC
      • Jackson D
      Malignant pleural mesothelioma: report of 19 cases.
      and metastatic lesions may occur in the thoracotomy wound.
      • Edge JR
      • Choudhury SL
      Malignant mesothelioma of the pleura in Barrow-in-Furness.
      Although a history of exposure to asbestos is important when the pathogenesis of mesothelioma is considered, it is not a feature that should influence the histologic diagnosis because those persons exposed to asbestos also may have other tumors that involve the pleura (notably, bronchogenic carcinomas), and epidemiologic data have confirmed that primary lung carcinomas occur more frequently than mesotheliomas among the asbestos-exposed population.
      • Selikoff IJ
      • Hammond EC
      • Seidman H
      Mortality experience of insulation workers in the United States and Canada, 1943–1976.

      PATHOLOGIC FEATURES

      Localized fibrous mesotheliomas (so-called benign mesotheliomas) are probably mesenchymal tumors derived from submesothelial mesenchymal cells rather than tumors of the mesothelial lining cells.
      • Dalton WT
      • Zolliker AS
      • McCaughey WTE
      • Jacques J
      • Kannerstein M
      Localized primary tumors of the pleura: an analysis of 40 cases.
      • Dervan PA
      • Tobin B
      • O'Connor M
      Solitary (localized) fibrous mesothelioma: evidence against mesothelial cell origin.
      They are single masses
      • Briselli M
      • Mark EJ
      • Dickersin GR
      Solitary fibrous tumors of the pleura: eight new cases and review of 360 cases in the literature.
      • Okike N
      • Bernatz PE
      • Woolner LB
      Localized mesothelioma of the pleura: benign and malignant variants.
      • Dalton WT
      • Zolliker AS
      • McCaughey WTE
      • Jacques J
      • Kannerstein M
      Localized primary tumors of the pleura: an analysis of 40 cases.
      • Dervan PA
      • Tobin B
      • O'Connor M
      Solitary (localized) fibrous mesothelioma: evidence against mesothelial cell origin.
      (rarely multiple) usually attached by a pedicle to the visceral pleura. Histologically, they are composed of spindle cells with intervening dense collagen, and most of these lesions are histologically benign, lacking mitotic figures and cellular anaplasia.
      Diffuse malignant mesotheliomas typically involve the pleura or peritoneum as a uniform tumorous thickening; multiple nodules and plaques also can be present. They are divided into three histologic groups: epithelial (50%), sarcomatous (fibrosarcomatous and desmoplastic, 20%), and the biphasic type, which includes both patterns (30%).
      • Roggli VL
      • Kolbeck J
      • Sanfilippo F
      • Shelburne JD
      Pathology of human mesothelioma: etiologic and diagnostic considerations.
      In the epithelial variant, the tumor cells grow in tubular, cordlike, papillary, or sheetlike patterns. Relative cytologic uniformity is evident, and pronounced cellular atypia is unusual. Sarcomatous mesotheliomas manifest a variety of patterns, including fascicles of plump spindle cells and a more desmoplastic variant with abundant intercellular deposition of collagen, within which tumor cells sometimes grow in a storiform pattern. Biphasic mesotheliomas have a combination of the epithelial and sarcomatous growth patterns.
      Occasionally, distinguishing malignant mesothelioma from reactive mesothelial proliferation is difficult on small tissue samples.
      • Herbert A
      • Gallagher PJ
      Pleural biopsy in the diagnosis of malignant mesothelioma.
      With adequate biopsy material, however, the distinction can be made. Reactive mesothelial proliferations leave gaping clefts in a background of organizing pleuritis or sheets of mesothelial cells without supporting stroma growing in the pleural space. In contrast, mesotheliomas manifest small infiltrative nests of mesothelial cells with stromal reaction, and when the cells grow in sheets, a supporting stromal network can be identified.
      Distinguishing mesothelioma from carcinoma metastatic to the pleura remains a major problem ((Table 2)) because no specific stain or test identifies a mesothelioma cell and only some carcinomas have intracellular mucin that is diagnostic of adenocarcinoma. Some problem cases can be separated on routine slides stained with hematoxylin and eosin in the appropriate clinical setting, such as a known history of carcinoma. Stains for mucin are the next step, and if neutral mucin is identified in the tumor cells, a diagnosis of adenocarcinoma is secure. Unfortunately, not all carcinomas have intracellular mucin, and one may then resort to immunoperoxidase studies, although these are not entirely specific.
      • Herbert A
      • Gallagher PJ
      Pleural biopsy in the diagnosis of malignant mesothelioma.
      • Ghosh AK
      • Gatter KC
      • Dunnill MS
      • Mason DY
      Immunohistological staining of reactive mesothelium, mesothelioma, and lung carcinoma with a panel of monoclonal antibodies.
      • Bolen JW
      • Hammar SP
      • McNutt MA
      Reactive and neoplastic serosal tissue: a light-microscopic, ultrastructural, and immunocytochemical study.
      • Strickler JG
      • Herndier BG
      • Rouse RV
      Immunohistochemical staining in malignant mesotheliomas.
      • Sheibani K
      • Battifora H
      • Burke JS
      Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas.
      • Marshall RJ
      • Herbert A
      • Braye SG
      • Jones DB
      Use of antibodies to carcinoembryonic antigen and human milk fat globule to distinguish carcinoma, mesothelioma, and reactive mesothelium.
      • Blobel GA
      • Moll R
      • Franke WW
      • Kayser KW
      • Gould VE
      The intermediate filament cytoskeleton of malignant mesotheliomas and its diagnostic significance.
      • Battifora H
      • Kopinski MI
      Distinction of mesothelioma from adenocarcinoma: an immunohistochemical approach.
      • Corson JM
      • Pinkus GS
      Mesothelioma: profile of keratin proteins and carcinoembryonic antigen; an immunoperoxidase study of 20 cases and comparison with pulmonary adenocarcinomas.
      • Otis CN
      • Carter D
      • Cole S
      • Battifora H
      Immunohistochemical evaluation of pleural mesothelioma and pulmonary adenocarcinoma: a bi-institutional study of 47 cases.
      • Szpak CA
      • Johnston WW
      • Roggli V
      • Kolbeck J
      • Lottich SC
      • Vollmer R
      • Thor A
      • Schlom J
      The diagnostic distinction between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by a monoclonal antibody (B72.3).
      • Donna A
      • Betta PG
      • Bellingeri D
      • Marchesini A
      New marker for mesothelioma: an immunoperoxidase study.
      Finally, with use of electron microscopy, certain ultrastructural features (particularly long microvilli on the cell surface and prominent tonofibrils) may support a diagnosis of mesothelioma.
      • Roggli VL
      • Kolbeck J
      • Sanfilippo F
      • Shelburne JD
      Pathology of human mesothelioma: etiologic and diagnostic considerations.
      • Ghosh AK
      • Gatter KC
      • Dunnill MS
      • Mason DY
      Immunohistological staining of reactive mesothelium, mesothelioma, and lung carcinoma with a panel of monoclonal antibodies.
      • Stoebner P
      • Bernaudin JF
      • Nebut M
      • Basset F
      Contribution of electron microscopy to the diagnosis of pleural mesothelioma.
      Without optimal fixation, however, electron microscopy is difficult. Several recently described monoclonal antibodies may facilitate accurate distinction on even small specimens such as those obtained at closed pleural biopsy,
      • Lee I
      • Radosevich JA
      • Chejfec G
      • Ma Y
      • Warren WH
      • Rosen ST
      • Gould VE
      Malignant mesotheliomas: improved differential diagnosis from lung adenocarcinomas using monoclonal antibodies 44–3A6 and 624A12.
      • Anderson TM
      • Holmes EC
      • Kosaka CJ
      • Cheng L
      • Saxton RE
      Monoclonal antibodies to human malignant mesothelioma.
      but further confirmation is necessary. In summary, a portion of cases can be unequivocally diagnosed as metastatic adenocarcinoma based on the presence of intracellular mucin, but the rest of the cases are diagnosed on the basis of historical, clinical, histologic, histochemical, immunohistochemical, and electron microscopic data, which are variably supportive of one diagnosis over the other but not absolutely specific.
      Table 2Mesothelioma Versus Adenocarcinoma: Immunocytochemical Results
      A summary of currently available immunohistochemical stains adapted from results in references 51–62.
      StainMesotheliomaAdenocarcinoma
      CytokeratinUsually positiveUsually positive
      Carcinoembryonic antigenRarely positiveOften positive
      Leu M1Rarely positiveOften positive
      Epithelial membrane antigenMay be positive
      Incidence and type of positivity may vary among series.
      Often positive
      B72.3Rarely positiveOften positive
      * A summary of currently available immunohistochemical stains adapted from results in references 51–62.
      Incidence and type of positivity may vary among series.
      Distinguishing sarcomatous mesothelioma from pleural fibrosis can be extremely difficult. Sarcomatous mesotheliomas, particularly the desmoplastic variant, can be deceptively bland in their appearance. Invasion into muscle of the chest wall is a helpful diagnostic feature. Both pleural fibrosis and sarcomatous mesotheliomas may be associated with keratin-positive spindle cells in the fibrous tissue; thus, immunoperoxidase staining is not a helpful distinguishing feature. In the occasional case in which a soft tissue sarcoma of the chest wall is being considered, the presence of keratin-positive cells in the tumor supports a diagnosis of mesothelioma.
      The stage of the tumor may have an influence on prognosis and therefore merits discussion. The most commonly used staging system for mesothelioma is that introduced by Butchart and associates
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.
      in 1976 and later modified by Antman
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.
      ((Table 3)). Computed tomography of both the chest and the abdomen should allow fairly accurate premortem staging. It remains questionable whether the information gained from such studies will alter the natural history of mesothelioma regardless of the therapy used.
      Table 3Staging of Malignant Mesothelioma
      Modified from Butchart and associates.
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.
      By permission.
      StageDescription
      IConfined to ipsilateral pleura and lung or to peritoneal cavity
      IIInvolving chest wall, mediastinum, pericardium, or contralateral pleura
      IIIInvolving both thorax and abdomen or lymph nodes outside the chest or abdomen
      IVDistant blood-borne metastatic lesions

      DIFFERENTIAL DIAGNOSIS

      Several entities can cause considerable diagnostic confusion and therefore warrant discussion of their distinguishing features: localized fibrous mesothelioma, benign asbestos-related effusion, rounded atelectasis, and metastatic adenocarcinoma. A summary of the various clinical, radiologic, and pathologic findings in these and other conditions is shown in (Table 4).
      Table 4Features Distinguishing Malignant Mesothelioma From Other Pleural Lesions
      ++ = very common; + = common; +/− = rare; − = not characteristic.
      LesionExposure to asbestosChest painClubbing arthritisSymptomatic at initial examinationPleural mass or massesGrossly bloody pleural effusionMalignant cells in effusionUsual method of diagnosis
      Malignant mesothelioma+++++/−++++/−Pleural biopsy
      Localized fibrous mesothelioma+++++/−
      • Pleural biopsy
      • Resection of lesion
      Benign asbestos-related effusion++++/−+/−+
      • Exclusion of other causes
      • Benign biopsy tissue
      • Spontaneous resolution
      Rounded atelectasis++++
      • Radiographic appearance
      • Resection of “nodule”
      Adenocarcinoma metastatic to the pleura++/−+++++
      • Cytology occasionally
      • Pleural biopsy
      Hyaline pleural plaques++++
      May be calcified.
      Radiographic appearance
      * ++ = very common; + = common; +/− = rare; − = not characteristic.
      May be calcified.
      Localized fibrous mesothelioma has a tendency to occur more often in women than in men (2:1), is not associated with exposure to asbestos, and is often asymptomatic.
      • Antman KH
      Clinical presentation and natural history of benign and malignant mesothelioma.
      Chest pain, dyspnea, and cough occur occasionally. Some patients, particularly those with tumors larger than 7 cm, may have hypertrophic pulmonary osteoarthropathy, a rare occurrence in patients with malignant mesothelioma. The most common radiologic manifestation is a solitary pleural-based mass, and although effusion is much less common (10%) than in malignant mesothelioma, it can occur. These masses are generally encapsulated and amenable to surgical resection.
      Benign asbestos-related effusion is virtually impossible to distinguish from malignant mesothelioma on clinical grounds alone. It occurs in 3 to 7% of asbestos-exposed workers and is typically asymptomatic but can be associated with chest pain in as many as a third of the patients.
      • Epler GR
      • McLoud TC
      • Gaensler EA
      Prevalence and incidence of benign asbestos pleural effusion in the working population.
      Although the condition is usually bilateral, it can be unilateral; thoracentesis will reveal bloody fluid in a third of the cases. The effusion has a mean latency period after initial exposure to asbestos of 34 years, similar to that for mesothelioma,
      • Nicholson WJ
      • Selikoff IJ
      • Seidman H
      • Lilis R
      • Formby P
      Long-term mortality experience of chrysotile miners and millers in Thetford Mines, Quebec.
      but it is the most common asbestos-related abnormality seen during the first 20 years after exposure to asbestos.
      • Epler GR
      • McLoud TC
      • Gaensler EA
      Prevalence and incidence of benign asbestos pleural effusion in the working population.
      It can occur suddenly and may last for months or several years. Continued observation shows resolution or failure to progress, either of which distinguishes it from mesothelioma.
      Rounded atelectasis is a term used to describe a localized fibrous thickening of the pleura that contains entrapped lung. It may be seen in persons with or without heavy exposure to asbestos, and it typically manifests as an asymptomatic mass in the lung; thus, it is primarily a problem of roentgenographic differential diagnosis. Blood vessels supplying this tissue may blur the border and cause a characteristic “comet” sign.
      • Wechsler RJ
      • Rao VM
      • Steiner RM
      The radiology of thoracic malignant mesothelioma.
      If plain films or tomograms fail to establish the diagnosis, computed tomography with use of a contrast agent may be helpful.
      Adenocarcinoma that metastasizes to the pleura was discussed earlier in the section on pathologic features. In addition to the aforementioned conditions, hyaline pleural plaques are usually seen on chest roentgenograms of patients with substantiated exposure to asbestos. They are usually asymptomatic and may be calcified or noncalcified. Histologically, they are hyalinized fibrous tissue lined by normal mesothelial cells.

      NATURAL HISTORY

      Early in its course, malignant mesothelioma may primarily cause recurrent pleural effusions that necessitate repeated therapeutic thoracenteses. As the tumor expands and enlarges, eventually encasing a substantial amount of the surface area of the lung, effusions become less of a management problem. Dyspnea becomes a factor as tumor encasement begins to restrict lung expansion. Local spread to ribs and intercostal nerves is a late occurrence and may precipitate intractable chest wall pain. Oftentimes, this spread may occur without palpable evidence of a tumor on examination or roentgenographic evidence of rib destruction. When tumor cells invade the site of pleural biopsy or thoracotomy scar, palpable tumor masses are detected 80% of the time.
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      The most frequent sites of intrathoracic invasion are the ipsilateral lung, pericardium, diaphragm, mediastinal nodes, contralateral lung, and heart.
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      • Dorward AJ
      • Stack BHR
      Diffuse malignant pleural mesothelioma in Glasgow.
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      • Krumhaar D
      • Lange S
      • Hartmann C
      • Anhuth D
      Follow-up study of 100 malignant pleural mesotheliomas.
      Less often, the trachea, spine, esophagus, or superior vena cava will be involved and cause related symptoms. Death most often results from respiratory failure, but arrhythmias and intestinal obstruction can be fatal when the heart or peritoneum is involved.
      At the time of diagnosis, stage II disease is most common (50%), stages I (18%) and III (28%) are less frequent, and stage IV is very infrequent (4%).
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      Lymphatic spread is uncommon; hematogenous metastatic lesions, however, have been noted in from 20 to 80% of patients with malignant mesothelioma in whom autopsy has been done.
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      • Dorward AJ
      • Stack BHR
      Diffuse malignant pleural mesothelioma in Glasgow.
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      • Krumhaar D
      • Lange S
      • Hartmann C
      • Anhuth D
      Follow-up study of 100 malignant pleural mesotheliomas.
      The most frequently involved organs are the liver, peritoneum, intestines, adrenal glands, and bone. Although commonly found at autopsy, hematogenous spread to these organs is rarely of clinical significance.
      Many investigators have tried to identify factors retrospectively that may predict a more favorable outcome. At least six different studies
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.
      • Mårtensson G
      • Hagmar B
      • Zettergren L
      Diagnosis and prognosis in malignant pleural mesothelioma: a prospective study.

      Antman K, Shamin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Corson J: Malignant mesothelioma: prognostic variables in a registry of 180 patients. J Clin Oncol (in press)

      suggest that epithelial histopathologic features are associated with prolonged survival. In one study,
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      patients with the epithelial subtype had a median survival of 13 months in comparison with 3.6 and 8.4 months for sarcomatous and mixed subtypes, respectively. In addition, patients who have chest wall pain at the time of initial examination have a worse prognosis than cohorts without chest pain.

      Antman K, Shamin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Corson J: Malignant mesothelioma: prognostic variables in a registry of 180 patients. J Clin Oncol (in press)

      Other factors such as stage of disease,
      • McCormack PM
      • Nagasaki F
      • Hilaris BS
      • Martini N
      Surgical treatment of pleural mesothelioma.
      performance score,

      Antman K, Shamin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Corson J: Malignant mesothelioma: prognostic variables in a registry of 180 patients. J Clin Oncol (in press)

      • Samson MK
      • Wasser LP
      • Borden EC
      • Wanebo HJ
      • Creech RH
      • Phillips M
      • Baker LH
      Randomized comparison of cyclophosphamide, imidazole carboxamide, and Adriamycin versus cyclophosphamide and Adriamycin in patients with advanced stage malignant mesothelioma: a sarcoma intergroup study.
      and age at diagnosis
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      • Battifora H
      • Kopinski MI
      Distinction of mesothelioma from adenocarcinoma: an immunohistochemical approach.
      apparently correlate with survival also. Evidence about some factors (for example, sex, duration of exposure to asbestos, and duration of symptoms) is insufficient to draw confident conclusions about their predictive value.

      THERAPY

      Therapy for malignant mesothelioma has included three modalities used individually or in combination: operation, irradiation, and chemotherapy. The extent of surgical treatment is based on preoperative goals. Surgical attempts to remove all tumor usually entails pleuropneumonectomy and, occasionally, excision of the ipsilateral hemidiaphragm and pericardium. Palliative surgical intervention, most commonly pleurectomy, is aimed at preventing recurrent effusions and decreasing pain from chest wall involvement. Three monographs focusing on the surgical management of mesothelioma have been published in the past decade.
      • McCormack PM
      • Nagasaki F
      • Hilaris BS
      • Martini N
      Surgical treatment of pleural mesothelioma.
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      The role of surgery in diffuse malignant mesothelioma of the pleura.
      • Kittle CF
      External-beam irradiation, when used in high doses (more than 4,000 cGy), may prolong survival.
      • Hillerdal G
      Malignant mesothelioma 1982: review of 4710 published cases.
      It has also been beneficial for alleviating chest wall pain and reducing pleural effusions.
      • Law MR
      • Gregor A
      • Hodson ME
      • Bloom HJG
      • Turner-Warwick M
      Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients.
      Recently, implantation of radioactive isotopes has been used to increase the dose and reduce the damage to normal tissue. One study suggested that when added to multimodality therapy in patients with limited disease (stage I or II), implantation irradiation prolonged survival.
      • McCormack PM
      • Nagasaki F
      • Hilaris BS
      • Martini N
      Surgical treatment of pleural mesothelioma.
      Chemotherapy is often used in patients with malignant mesothelioma and is occasionally associated with a complete response.
      • Samson MK
      • Wasser LP
      • Borden EC
      • Wanebo HJ
      • Creech RH
      • Phillips M
      • Baker LH
      Randomized comparison of cyclophosphamide, imidazole carboxamide, and Adriamycin versus cyclophosphamide and Adriamycin in patients with advanced stage malignant mesothelioma: a sarcoma intergroup study.
      In 1978, a study by Yap and colleagues
      • Yap B-S
      • Benjamin RS
      • Burgess MA
      • Bodey GP
      The value of Adriamycin in the treatment of diffuse malignant pleural mesothelioma.
      indicated that regimens containing doxorubicin (Adriamycin) seemed to prolong survival in comparison with those without doxorubicin. Since then, most combination chemotherapy programs have incorporated doxorubicin.
      • Jett JR
      • Eagan RT
      Chemotherapy for malignant mesothelioma: CAMEO.
      Recent evidence suggests that mitomycin may be more effective than doxorubicin in the treatment of mesothelioma (Chahinian AP: Unpublished data).
      The precise effect of various methods of intervention on eventual outcome of patients with mesothelioma is difficult to assess. Most claims of therapeutic effectiveness have been based on small, single-center, retrospective, unrandomized studies that used survival time as an endpoint. Drawing sound conclusions from these reports is difficult, for several reasons. First, survival data are often insufficient because of patients “lost to follow-up.” Second, duration of survival can be measured from the onset of symptoms, time of diagnosis, or time of initiation of treatment, and many reports fail to specify which measurement has been used. Consequently, comparison of data from various studies is extremely difficult. Third, because of the lack of randomization and appropriate controls, nontreatment factors (for example, epithelial subtype or stage of disease at diagnosis) can have a major influence on outcome attributed to a particular therapy. Fourth, because patients in retrospective studies often received more than one treatment modality, the independent effect of each therapy used is indeterminable. Finally, pressure to “do something” for patients with mesothelioma has limited the number of studies with an adequate control group consisting of patients who received either no treatment or placebo.
      Despite their inherent limitations, these studies, when reviewed in aggregate, provide a crude estimation of the influence of each therapeutic approach. (Table 5) summarizes the median survival data from 14 previously published studies. Some interesting observations can be made on the basis of this information. The study by Wanebo and co-workers
      • Wanebo HJ
      • Martini N
      • Melamed MR
      • Hilaris B
      • Beattie Jr, EJ
      Pleural mesothelioma.
      demonstrated that when the same treatment (in this case, pleurectomy) was applied to patients with different histopathologic subtypes of lesions, survival time differed considerably (21 versus 11 months). McCormack and associates
      • McCormack PM
      • Nagasaki F
      • Hilaris BS
      • Martini N
      Surgical treatment of pleural mesothelioma.
      showed that treatment efficacy varied appreciably with stage of disease. Patients with stage I or II disease survived 21 months in comparison with 4 months for similarly treated patients with stage III or IV disease. Samson and colleagues
      • Samson MK
      • Wasser LP
      • Borden EC
      • Wanebo HJ
      • Creech RH
      • Phillips M
      • Baker LH
      Randomized comparison of cyclophosphamide, imidazole carboxamide, and Adriamycin versus cyclophosphamide and Adriamycin in patients with advanced stage malignant mesothelioma: a sarcoma intergroup study.
      studied only patients with stage II to IV disease and found poor survival (7 months) after administration of a chemotherapeutic regimen that contained doxorubicin. In other studies in which similar chemotherapeutic regimens were used, significantly longer median survival times (13 to 19 months) were achieved, but many patients with stage I disease were included. Clearly, interstudy differences in survival could easily be attributable to differences in patient characteristics alone.
      Table 5Summary of Survival Times After Various Treatments in Patients With Malignant Mesothelioma
      Median duration of survival (mo) with use of various treatments
      NT = no treatment; PP = pleuropneumonectomy; P = pleurectomy or palliative resection; XRT = external-beam irradiation; IRT = implantation radiation therapy; AC = Adriamycin-containing chemotherapy; NAC = non-Adriamycin chemotherapy; M = multimodality including surgical therapy, irradiation, and chemotherapy.
      ReferenceNo. of patientsNTPPPXRTIRTACNACM
      Wanebo et al,
      • Wanebo HJ
      • Martini N
      • Melamed MR
      • Hilaris B
      • Beattie Jr, EJ
      Pleural mesothelioma.
      1976
      Patients were divided into those with epithelial (N = 39) and those with mixed (N = 27) histopathologic findings, and results are shown for each group.
      39218
      27119
      Elmes & Simpson,
      • Elmes PC
      • Simpson MJC
      The clinical aspects of mesothelioma.
      1976
      18412161417
      Butchart et al,
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.
      1976
      2910
      DeLaria et al,
      • DeLaria GA
      • Jensik R
      • Faber LP
      • Kittle CF
      Surgical management of malignant mesothelioma.
      1978
      1115
      Yap et al,
      • Yap B-S
      • Benjamin RS
      • Burgess MA
      • Bodey GP
      The value of Adriamycin in the treatment of diffuse malignant pleural mesothelioma.
      1978
      36146
      Antman et al,
      • Antman KH
      • Blum RH
      • Greenberger JS
      • Flowerdew G
      • Skarin AT
      • Canellos GP
      Multimodality therapy for malignant mesothelioma based on a study of natural history.
      1980
      4049915
      McCormack et al,
      • McCormack PM
      • Nagasaki F
      • Hilaris BS
      • Martini N
      Surgical treatment of pleural mesothelioma.
      1982
      Patients were divided into those with stage I or II disease (N = 51) and those with stage III or IV disease (N = 25), and results are shown for each group.
      512116
      2547
      Chahinian et al,
      • Chahinian AP
      • Pajak TF
      • Holland JF
      • Norton L
      • Ambinder RM
      • Mandel EM
      Diffuse malignant mesothelioma.
      1982
      6918131013
      Solomons,
      • Solomons K
      Malignant mesothelioma—clinical and epidemiological features: a report of 80 cases.
      1984
      899
      Law et al,
      • Law MR
      • Gregor A
      • Hodson ME
      • Bloom HJG
      • Turner-Warwick M
      Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients.
      1984
      11618201819
      Vogelzang et al,
      • Vogelzang NJ
      • Schultz SM
      • Iannucci AM
      • Kennedy BJ
      Malignant mesothelioma: the University of Minnesota experience.
      1984
      3116716
      Krumhaar et al,
      • Krumhaar D
      • Lange S
      • Hartmann C
      • Anhuth D
      Follow-up study of 100 malignant pleural mesotheliomas.
      1985
      1008
      Adams et al,
      • Adams VI
      • Unni KK
      • Muhm JR
      • Jett JR
      • Ilstrup DM
      • Bernatz PE
      Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases.
      1986
      9211
      Samson et al,
      • Samson MK
      • Wasser LP
      • Borden EC
      • Wanebo HJ
      • Creech RH
      • Phillips M
      • Baker LH
      Randomized comparison of cyclophosphamide, imidazole carboxamide, and Adriamycin versus cyclophosphamide and Adriamycin in patients with advanced stage malignant mesothelioma: a sarcoma intergroup study.
      1987
      767
      Mean of median survivals11.314.814.810.612.514.010.012.0
      * NT = no treatment; PP = pleuropneumonectomy; P = pleurectomy or palliative resection; XRT = external-beam irradiation; IRT = implantation radiation therapy; AC = Adriamycin-containing chemotherapy; NAC = non-Adriamycin chemotherapy; M = multimodality including surgical therapy, irradiation, and chemotherapy.
      Patients were divided into those with epithelial (N = 39) and those with mixed (N = 27) histopathologic findings, and results are shown for each group.
      Patients were divided into those with stage I or II disease (N = 51) and those with stage III or IV disease (N = 25), and results are shown for each group.
      The study by Law and co-workers
      • Law MR
      • Gregor A
      • Hodson ME
      • Bloom HJG
      • Turner-Warwick M
      Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients.
      was noteworthy for its inclusion of a sizable “no treatment” control group. In addition, it was prospective, and the patient composition of the various treatment groups was similar. The results of this study confirmed that none of the three treatments (chemotherapy containing doxorubicin, megavoltage radiotherapy, or nonradical operation) prolonged survival. These results parallel the cumulative mean survival data shown in (Table 5), which also failed to demonstrate significant prolongation of survival by any treatment.
      In summary, none of the treatments used in patients with malignant mesothelioma has extended the median duration of survival beyond 24 months. When the toxicity that accompanies nonsurgical therapy and the 10 to 30% operative mortality associated with radical surgical treatment are considered,
      • Butchart EG
      • Ashcroft T
      • Barnsley WC
      • Holden MP
      Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura.
      a case could be made for withholding treatment unless the intent is palliation.

      CONCLUSION

      Malignant mesothelioma of the pleura is increasing in incidence in the United States and is beginning to be seen more often in persons without clear-cut occupational exposure to asbestos. The clinical features of dyspnea and chest pain accompanied by pleural thickening with or without effusion have been well described. The pathologic diagnosis usually necessitates acquisition of a generous specimen; thus, open pleural biopsy is necessary in most cases. Unfortunately, this procedure may be complicated by spread of tumor to the incision site and may thereby contribute to chest wall pain. For pathologic distinction from metastatic adenocarcinoma, special stains, electron microscopy, or immunohistochemical analysis may help in select cases. Once malignant mesothelioma has been diagnosed, the usual course is rapid progression to death, usually from local spread, within 2 years. Patients with the epithelial subtype and stage I disease survive longer. Despite numerous studies in which various therapeutic modalities have been assessed, it remains questionable whether any treatment substantially alters the grave prognosis.

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