Original Paper Respiration 1992;59:129-135
L. Tammilehtoa P. Maasiltaa S. Kostiainerth P. Appelqvisth L.R. Holstic K. Mattsona Departments of Pulmonary Medicine, Thoracic and Cardiovascular Surgery and Radiotherapy and Oncology, Helsinki University Central Hospital, Helsinki, Finland
Key Words Asbestos exposure Malignant mesothelioma, symptoms Prognostic factors
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma: A Retrospective Analysis of Sixty-Five Patients
Abstract This report is an analysis of the medical records of 83 patients registered bctween I960 and 1980 at Helsinki University Central Hospital as having malignant pleural mesothelioma. 65 of 83 patients had histologically confirmed ma lignant mesothelioma, and are the focus of this analysis. The remaining 18 (22%) patients were excluded because malignant mesothelioma was only con firmed cytologically, or because the primary tumor was not a mesothelioma. The ratio of men to women was 2:1.30 of 65 (46%) patients were not known or not likely to have been exposed to asbestos. The main symptoms at presenta tion were dyspnea, cough, chest pain, fatigue and weight loss. The median sur vival from diagnosis was 12 months, and from the onset of symptoms 18 months. Clinical stage and performance status were significant prognostic fac tors. Hematogenous metastases were present at autopsy in most cases. Disease and performance status therefore need to be well established and documented in clinical trials involving mesothelioma.
Introduction
Received: November 4, 1991 Accepted after revision: April 14. 1992
The diagnosis of diffuse pleural mesothelioma is often delayed: either because the symptoms are nonspecific, e.g. chest pain, dyspnea and dry cough, or because mesothe lioma is relatively rarely diagnosed from pleural fluid cy tology and/or needle biopsy alone. An erroneous diag nosis of metastatic adenocarcinoma may be made [5]. The mesothelioma tumor is resistant to chemotherapy and radiotherapy. There is no standard treatment. Radical surgical removal of the tumor is often impossible because
Lauri Tammilehto. MD Department of Pulmonary Medicine Helsinki University Central 1lospital Haartmaninkatu 4 SF-4X)290 Helsinki (Finland)
© 1992S. Karger AG.Basel 0025-7931/92,4)593-0129 $ 2.75/0
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The number of cases of mesothelioma in men in creased by 12% per year between 1973 and 1980 in the United States [1] as a result of the widespread industrial use of asbestos prior to 1975. The same trend has been noted in other industrialized countries [2, 3]. Because there is a latent period of up to 40 years from asbestos ex posure to the development of clinical disease, a significant increase in the incidence of mesothelioma is expected dur ing the coming decades [4],
Table 1. Symptoms at initial presentation for 65 patients with pleural mesothelioma
Symptom
Dyspnea Cough Chest pain Fatigue and weight loss Fever Hemoptysis Palpitation Asymptomatic1
Patients n
%
25 24 23 10 4 1 1 5
38 37 35 15 6 2 2 8
1 Chance finding on chest X-ray.
Treatment given in this series is described in the results section. There were no formal protocols before 1980. Patients were referred to the D epartments of Thoracic Surgery, Pulmonary Medicine or Ra diotherapy and Oncology by chance. Statistical Analysis Statistical analysis was carried out using the SAS statistical soft ware package [10]. Cumulative survival rates were calculated using the product-limit method. The variables selected for analysis were those which might be expected to influence survival from the time of diagnosis, the dependent variable. A Cox proportional hazards re gression model was used to investigate the effects of various factors on survival.
Results Patient Characteristics
Patients and Methods From 1960 to 1980, a total of 83 patients were registered at the Helsinki University Central Hospital as having malignant pleural mesothelioma. In 65 cases (78%) the diagnoses were based on histo logical specimens. Clinical stage, according to the system modified by Butchart et at. [7], was determined retrospectively on the basis of clin ical and surgical findings described in the patients’ records. Because computerized axial tomography was not available as a routine proce dure at that time, disease status was often estimated according to the method proposed by Dimitrow and McMahon [8]: the patients were grouped according to whether the longest diameter of the greatest tumor bulk was equal to or greater than 5 cm, or smaller. Occupational histories were taken from the patients’ records. As bestos exposure was classified into three categories according to the following guide-lines: definite or probable exposure (group 1). pa tients employed in asbestos mining, manufacture of asbestos prod ucts, the asbestos cement industry, asbestos insulation, demolition of old buildings, shipyards, the construction industry, or metal work shops; possible exposure (group 2), patients in occupations liable to dust exposure such as mining, power plant operation, transportation or the paper and pulp industry, and unlikely/unknown exposure (group 3), patients employed in occupations having no evident liabil ity to asbestos exposure [9].
130
Tammilehto/Maasilta/Kostiainen/ Appelqvist/Holsti/Mattson
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma
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of the peculiar and characteristic growth pattern. The prognosis is poor, most patients dying within 18 months of diagnosis [6]. We have carried out this retrospective analysis of all the cases of pleural malignant mesothelioma diagnosed at our institution between 1960 and 1980 in order to evaluate the effectiveness of past treatment policies at the Helsinki University Central Hospital, and the prognostic signifi cance of some clinical features.
There were 43 men (66%) and 22 women (34%). The mean age for the men was 54 years (range 20-73) and for the women 55 years (range 24-79). Histopathological sub typing was available for 53 patients; a majority of the tu mors, 32 of 53 (60%), were of the epithelial type. Accord ing to Butchart’s staging system, 42% (25 of 59) of the pa tients had stage-I disease, 49% had stage-II, 3% had stage-III and 5% had stage-IV disease at the time of histo logical diagnosis. Data on the greatest diameter of the tu mor bulk, according to the Dimitrow system, were avail able for 32 patients (49%). Performance status at the time of diagnosis, according to WHO criteria, was evaluable in 56 patients (86%). 51% of the patients for whom a smoking history was available (24 of 47) were smokers at the time of diagnosis; of the remainder 13% were exsmokers and 36% nonsmokers. 13 patients (20%) were rated as having defi nite or probable exposure to asbestos, 22 (33%) possible exposure and 30 (47%) were not known or were unlikely to have been exposed. Chest X-ray findings at presentation were a unilateral pleural effusion involving the right side in 31 cases, and the left side in 20. Bilateral effusion was present in 1 case. Af ter the removal of pleural fluid, most chest X-rays showed pleural thickening and nodularity, especially in the lower part of the pleural space. In 1 patient, spontaneous pneu mothorax was found before biopsy. In 3 cases the chest ra diograph showed a solitary, circumscribed, homogeneous lesion. Histological diagnosis was based on needle biopsy specimens (12 patients); surgical biopsy specimens of su perficially infiltrative tumor (3 patients); thoracoscopy specimens (1 patient); autopsy findings (3 patients) or specimens obtained at thoracotomy (46 patients). Cytological examination of the pleural fluid gave a diagnosis of
Table 2. Median survival of patients with malignant pleural mesothelioma (n =
Survival, months
log-rank test
Wilcoxon test
65) by prognostic factors
median
range
P
P
Disease stage1 1 Il-IV
25 34
20 7
3-86 0-61
0.0007
0.0009
Tumor diameter2 1
38 18
20 5
3-86 0-13
0.0001
0.0001
43 22
8 20
0-86 0-65
0.0160
0.0253
46 19
17 7
2-86 0-20
0.0002
0.0018
Radiotherapy Yes No
40 25
14 6
0-86 0-61
0.0186
0.0183
Chemotherapy Yes No
32 33
20 6
0-86 0-65
0.0232
0.0010
Diagnostic delay3 ¿ 6 months > 6 months or asymptomatic Surgery Yes4 No
1 Butchart et al. [7]. 2 The maximum tumor diameter [8], 3 Delay between first symptom and histological diagnosis. 4 26 diagnostic thoracotomies; 15 palliative operations; 5 radical operations.
treated as tuberculosis or nonspecific pleuritis in 13 cases. The median delay from first symptom to diagnosis was 9 months (range 0-51) in this group of patients. Treatment Offered to Patients
For 46 patients, surgery consisted of diagnostic thora cotomy (26 patients), pleurectomy (15 patients); or pneumectomy and excision of all macroscopically visible tumor tissue from the ipsilateral pericardium and/or diaphragm (5 patients). Patients with large effusions clearly benefited from the palliative surgical intervention, in that dyspnea diminished. Local radiotherapy using small lung-sparing volumes, was employed in 40 cases; in 32 of these the application was postoperative. The total dose to the tumor was ^5,000 cGy (mean 5,370, range 5,000-6,000) in 27 cases, and
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malignant mesothelioma in 6 of 32 cases (19%), and histo logical examination of needle biopsy specimens of the af fected pleura revealed malignant mesothelioma in 12 of 28 cases (43%). Symptoms from the patients’ clinical histories are shown in table 1. Dyspnea was reported as the first symp tom in 25 cases, cough in 24 cases and chest pain in 23 cases. The median duration of symptoms before diagnosis was 3 months (range 0-51). Five asymptomatic patients having diffuse pleural mesothelioma were discovered by chance through routine chest X-rays. One patient had bacteriologically confirmed pleural tu berculosis concomitantly with histologically confirmed malignant mesothelioma. Three patients had histories of active pulmonary tuberculosis. Before the diagnosis of mesothelioma was confirmed, the disease had been
Fig. 1- Survival after the diagnosis of malignant pleural mesothe lioma (n = 65).
Fig. 3. Performance status and survival after the diagnosis of ma lignant pleural mesothelioma, a = WHO I (n = 38); b = WHO > I (n = 18).
eluding cyclophosphamide, 5-fluorouracil, vincristine, doxorubicin and DTIC intercalated with local therapies. In 18 cases 30-45 mg of thiotepa was instilled into the pleu ral cavity once a month to decrease pleural effusion. From the retrospective evaluation this method seemed to be less effective than pleurectomy. Survival
Fig. 2. Clinical stage and survival after the diagnosis of malignant pleural mesothelioma, a = Stage I (n = 25); b = stage II, III and IV (n = 34).
1 (WHO). For the 64 patients who had died by the time of the analysis, the cause of death was established on the basis of clinical features in 46 cases and on the basis of autopsy findings in 18 cases. One patient died of pericardial tam ponade as a result of extension of the tumor through the pericardium. The spread of the disease as recorded at au topsy is shown in table 3. Hematogenous métastasés were present in 13 patients (72%), and extrathoracic lymph node métastasés in 5 patients (28%).
134
method is not used more routinely. The definitive role of surgery in the management of mesothelioma remains open. The effectiveness of other treatment modalities ra diotherapy, chemotherapy and/or combined modality treatment cannot be evaluated in this retrospective analy sis, where treatment decisions were made without refer ence to a protocol, and they likewise remain unclear [5, 25]. Although it used to be believed that mesothelioma spreads mainly by direct extension, hematogenous metastases are frequently found at autopsy. The liver, adrenal glands and kidneys are the organs most frequently in volved [13]. In our series of 18 autopsies, direct extension to the pericardium, contralateral lung or pleura, chest wall or peritoneum were observed in 14 cases (78%). Hemato genous metastases to the liver, bone, adrenal gland, kidney or brain were observed in 13 cases (72%). This supports the view that mesothelioma is a systemic disease, and that treatment should take this into account. Our results confirm the common experience [11] that there is a considerable delay on the part of doctors and/or patients before the start of active treatment. Since treat ment decisions and results depend directly on the extent of the disease at diagnosis, accurate assessment of clinical stage is essential. Based on our experience, from a pro spective study involving 100 patients with pleural meso thelioma (unpublished data), we strongly recommend the routine use of CT scanning in the diagnosis of patients who may have mesothelioma. Thoracoscopy and thora cotomy should be performed at an early stage for patients with undefined pleurisy, especially in cases where there is an occupational history of asbestos exposure. Large multi-center prospective studies are urgently needed to elucidate further the natural history and opti mal treatment for this highly malignant neoplasm.
Tammilehto/Maasilta/Kostiainen/ Appelqvist/Holsti/Mattson
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma
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cording to the Dimitrow system [8] were available for only 32 (49%) patients. These data could not therefore be used for multivariate analyses on survival. Most centers now use computerized axial tomography for routine staging, and as one of several diagnostic tools [18,19, 20]. We used a rough grouping into two classes by perform ance status, WHO ^1 and WHO > 1. 38 (68%) patients had a good performance status. Nonspecific symptoms and good performance status are typical of malignant mesothelioma. This is one explanation for diagnostic de lays by patients and doctors [5], The frequency of malignant mesothelioma in patients exposed to asbestos ranges from 8% in areas lacking heavy asbestos-using industry, to 80% in areas having shipyards or asbestos mines [12,21]. There is one shipyard, and many other industries where asbestos exposure is possible, in the catchment area of the Helsinki University Central Hospi tal. From their occupational histories, 53% of our patients can be presumed to have had some exposure to asbestos. Prospective analysis in the same catchment area gives much the same figure (51%) for 100 patients (unpublished data). Early clinical stage, female gender, absence of chest pain, epithelial subtype, duration of symptoms > 6 months, age < 50 years, good performance status, absence of asbestos exposure, chemotherapy and surgery have been reported as favorable prognostic factors in mesothe lioma [22,23]. In our study, good prognosis was associated with clinical stage I, maximum tumor diameter 6 months or asymptomatic, and treatment with surgery, radiotherapy and chemotherapy. In some series a longer survival time has been associated with the epithelial subtype [13]. However, the histological subtype was not a positive prognostic factor for our pa tients. One explanation could be that pathological subtyp ing was not routinely performed until the latter part of the study period. The treatment of choice for diffuse malignant pleural mesothelioma is controversial. Pleurectomy has been re ported to give survival rates of 10-37% for 2 years and 3.5-10% for 5 years [7, 24], However, radical surgical re moval of all tumor tissue is seldom possible. In our study pleuropneumonectomy, including excision of all macroscopically visible tumor tissue, was performed in only 5 pa tients (they survived 17, 20, 54 and 86 months from histo logical diagnosis, and 1 patient was still alive 126 months after diagnosis). Butchart et al. [7] also associated good survival times with radical surgery. A higher than normal risk of operative mortality is probably the reason that this
References 10 SAS/STAT User’s Guide: Version 6, ed 4. vol 2. Cary. SAS Institute, 1990. 11 Brenner J. Sordillo PP, Magill GB, Golbey RB: Malignant mesothelioma of the pleura. Review of 123 patients. Cancer 1982;49:2431-2435. 12 Achatzy R, Beba W, Ritschler R. W öm H, Wählers B. Macha HN, Morgan JA: The diag nosis, therapy and prognosis of diffuse malig nant mesothelioma. Eur J Cardiothorac Surg 1989;3:445-448. 13 van Gelder T, Hoogsteden HC, Versnel MA, van Hezik EJ, Vandenbroucke JP, Planteydt HT: Malignant pleural mesothelioma in the southwestern part of the Netherlands. Eur R espirJ 1989;2:981-984. 14 Jones JSP, LundC, Planteydt HT (eds): Colour Atlas of Mesothelioma. Lancaster, Commis sion of the European Communities, 1985. 15 Elmes PC, Simpson MJC: The clinical aspects of mesothelioma. Q J Med 1976;45:427-449. 16 Sherman ME, Mark EJ: Effusion cytology in the diagnosis of malignant epitheloid and biphasic pleural mesothelioma. Arch Pathol Lab 1990;414:845-851. 17 Adams VI, Unni KK. Muhm JR, Jett JR, IIstrup DM, Bernatz PE: Diffuse malignant mesothelioma of pleura diagnosis and survival in 92 cases. Cancer 1986;58:1540-1551. 18 Leung AN, Muller NL, Miller RR: CT in differ ential diagnosis of diffuse pleural disease. AJR 1990;154:487-492.
19 Aberie DR: CT fills vital role in study of as bestos-related disease. Diagn Imaging 1988; 10:106-111. 20 Shephard KE, Oliver LC, Kazemi H: Diffuse malignant pleural mesothelioma in an urban hospital: Clinical spectrum and trend in inci dence over time. Am J Ind Med I989;16:373383. 21 McDonald JC: Health implications of environ mental exposure to asbestos. Environ Health Perspect 1985;62:319-328. 22 Spirtas R. Connelly RR, Tucker MA: Survival patterns for malignant mesothelioma: The SEER experience. Int J Cancer 1988:41:525530. 23 Amman K, Shamin R, Ryan L. el al: Malignant mesothelioma. Prognostic variables in a regis try of 180 patients, the Dana-Farber Cancer In stitute and Brigham and Women's Hospital ex perience over 2 decades 1965—1985. J Clin On col 1988;6:147-153. 24 Shemin RJ: Surgical treatment of pleuromcsothelioma; in Antman K, Aisner J (eds): Asbe stos Related Malignancies. New York, Grune & Stratton, 1986, pp 323-337. 25 Alberts AS. Falkson F. Goedhals L, Vorobiof DA, Van Dcr Mcrwe CA: Malignant pleural mesothelioma: A disease unaffected by current therapeutic measures. J Clin Oncol 1988:6:527535.
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1 Spirtas R, Beebe GW, Connelly RR, et al: Re cent trends in mesothelioma incidence in the United States. Am J Ind Med 1986;9:397-407. 2 Hulks G, Thomas J, Waclawski H: Malignant pleural mesothelioma in western Glasgow in 1980-6. Thorax 1989;44:496-500. 3 Ferguson D: Malignant mesothelioma: The ris ing epidemic. Med J Aust 1989:150:233-235. 4 Nicholson WJ, Perkel G, Selikoff U: Occupa tional exposure to asbestos: Population at risk and projected mortality 1980-2030. Am J Ind Med 1982;3:259-311. 5 Amman KH: Asbestos-related malignancy. CRC Crit Rev Oncol Hemal 1987;6:287-309.' 6 Gibbs AR: Role of asbestos and other fibers in the development of diffuse malignant mesothe lioma. Thorax 1990;45:649-654. 7 Butchart EG, Ashcroft T, Barnsley WC, Hol den MP: Pleuropncumonectomy in the man agement of diffuse malignant mesothelioma of the pleura. Thorax 1976;31:15-24. 8 Dimitrow NV. McMahon S: Presentation, diag nostic methods, staging, and natural history of malignant mesothelioma; in Amman K, Aisner J (eds): Asbestos-Related Malignancy. New York, Grune & Stratton, 1986, pp 225-238. 9 Tuomi T, Huuskonen MS, Tammilchto L, Vanhala E, Virtamo M: Occupational exposure to asbestos as evaluated from work histories and analysis of lung tissues from patients with mesothelioma. Br J Ind Med 1991:48:48-52.
L. Tammilehtoa P. Maasiltaa S. Kostiainerth P. Appelqvisth L.R. Holstic K. Mattsona Departments of Pulmonary Medicine, Thoracic and Cardiovascular Surgery and Radiotherapy and Oncology, Helsinki University Central Hospital, Helsinki, Finland
Key Words Asbestos exposure Malignant mesothelioma, symptoms Prognostic factors
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma: A Retrospective Analysis of Sixty-Five Patients
Abstract This report is an analysis of the medical records of 83 patients registered bctween I960 and 1980 at Helsinki University Central Hospital as having malignant pleural mesothelioma. 65 of 83 patients had histologically confirmed ma lignant mesothelioma, and are the focus of this analysis. The remaining 18 (22%) patients were excluded because malignant mesothelioma was only con firmed cytologically, or because the primary tumor was not a mesothelioma. The ratio of men to women was 2:1.30 of 65 (46%) patients were not known or not likely to have been exposed to asbestos. The main symptoms at presenta tion were dyspnea, cough, chest pain, fatigue and weight loss. The median sur vival from diagnosis was 12 months, and from the onset of symptoms 18 months. Clinical stage and performance status were significant prognostic fac tors. Hematogenous metastases were present at autopsy in most cases. Disease and performance status therefore need to be well established and documented in clinical trials involving mesothelioma.
Introduction
Received: November 4, 1991 Accepted after revision: April 14. 1992
The diagnosis of diffuse pleural mesothelioma is often delayed: either because the symptoms are nonspecific, e.g. chest pain, dyspnea and dry cough, or because mesothe lioma is relatively rarely diagnosed from pleural fluid cy tology and/or needle biopsy alone. An erroneous diag nosis of metastatic adenocarcinoma may be made [5]. The mesothelioma tumor is resistant to chemotherapy and radiotherapy. There is no standard treatment. Radical surgical removal of the tumor is often impossible because
Lauri Tammilehto. MD Department of Pulmonary Medicine Helsinki University Central 1lospital Haartmaninkatu 4 SF-4X)290 Helsinki (Finland)
© 1992S. Karger AG.Basel 0025-7931/92,4)593-0129 $ 2.75/0
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The number of cases of mesothelioma in men in creased by 12% per year between 1973 and 1980 in the United States [1] as a result of the widespread industrial use of asbestos prior to 1975. The same trend has been noted in other industrialized countries [2, 3]. Because there is a latent period of up to 40 years from asbestos ex posure to the development of clinical disease, a significant increase in the incidence of mesothelioma is expected dur ing the coming decades [4],
Table 1. Symptoms at initial presentation for 65 patients with pleural mesothelioma
Symptom
Dyspnea Cough Chest pain Fatigue and weight loss Fever Hemoptysis Palpitation Asymptomatic1
Patients n
%
25 24 23 10 4 1 1 5
38 37 35 15 6 2 2 8
1 Chance finding on chest X-ray.
Treatment given in this series is described in the results section. There were no formal protocols before 1980. Patients were referred to the D epartments of Thoracic Surgery, Pulmonary Medicine or Ra diotherapy and Oncology by chance. Statistical Analysis Statistical analysis was carried out using the SAS statistical soft ware package [10]. Cumulative survival rates were calculated using the product-limit method. The variables selected for analysis were those which might be expected to influence survival from the time of diagnosis, the dependent variable. A Cox proportional hazards re gression model was used to investigate the effects of various factors on survival.
Results Patient Characteristics
Patients and Methods From 1960 to 1980, a total of 83 patients were registered at the Helsinki University Central Hospital as having malignant pleural mesothelioma. In 65 cases (78%) the diagnoses were based on histo logical specimens. Clinical stage, according to the system modified by Butchart et at. [7], was determined retrospectively on the basis of clin ical and surgical findings described in the patients’ records. Because computerized axial tomography was not available as a routine proce dure at that time, disease status was often estimated according to the method proposed by Dimitrow and McMahon [8]: the patients were grouped according to whether the longest diameter of the greatest tumor bulk was equal to or greater than 5 cm, or smaller. Occupational histories were taken from the patients’ records. As bestos exposure was classified into three categories according to the following guide-lines: definite or probable exposure (group 1). pa tients employed in asbestos mining, manufacture of asbestos prod ucts, the asbestos cement industry, asbestos insulation, demolition of old buildings, shipyards, the construction industry, or metal work shops; possible exposure (group 2), patients in occupations liable to dust exposure such as mining, power plant operation, transportation or the paper and pulp industry, and unlikely/unknown exposure (group 3), patients employed in occupations having no evident liabil ity to asbestos exposure [9].
130
Tammilehto/Maasilta/Kostiainen/ Appelqvist/Holsti/Mattson
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma
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of the peculiar and characteristic growth pattern. The prognosis is poor, most patients dying within 18 months of diagnosis [6]. We have carried out this retrospective analysis of all the cases of pleural malignant mesothelioma diagnosed at our institution between 1960 and 1980 in order to evaluate the effectiveness of past treatment policies at the Helsinki University Central Hospital, and the prognostic signifi cance of some clinical features.
There were 43 men (66%) and 22 women (34%). The mean age for the men was 54 years (range 20-73) and for the women 55 years (range 24-79). Histopathological sub typing was available for 53 patients; a majority of the tu mors, 32 of 53 (60%), were of the epithelial type. Accord ing to Butchart’s staging system, 42% (25 of 59) of the pa tients had stage-I disease, 49% had stage-II, 3% had stage-III and 5% had stage-IV disease at the time of histo logical diagnosis. Data on the greatest diameter of the tu mor bulk, according to the Dimitrow system, were avail able for 32 patients (49%). Performance status at the time of diagnosis, according to WHO criteria, was evaluable in 56 patients (86%). 51% of the patients for whom a smoking history was available (24 of 47) were smokers at the time of diagnosis; of the remainder 13% were exsmokers and 36% nonsmokers. 13 patients (20%) were rated as having defi nite or probable exposure to asbestos, 22 (33%) possible exposure and 30 (47%) were not known or were unlikely to have been exposed. Chest X-ray findings at presentation were a unilateral pleural effusion involving the right side in 31 cases, and the left side in 20. Bilateral effusion was present in 1 case. Af ter the removal of pleural fluid, most chest X-rays showed pleural thickening and nodularity, especially in the lower part of the pleural space. In 1 patient, spontaneous pneu mothorax was found before biopsy. In 3 cases the chest ra diograph showed a solitary, circumscribed, homogeneous lesion. Histological diagnosis was based on needle biopsy specimens (12 patients); surgical biopsy specimens of su perficially infiltrative tumor (3 patients); thoracoscopy specimens (1 patient); autopsy findings (3 patients) or specimens obtained at thoracotomy (46 patients). Cytological examination of the pleural fluid gave a diagnosis of
Table 2. Median survival of patients with malignant pleural mesothelioma (n =
Survival, months
log-rank test
Wilcoxon test
65) by prognostic factors
median
range
P
P
Disease stage1 1 Il-IV
25 34
20 7
3-86 0-61
0.0007
0.0009
Tumor diameter2 1
38 18
20 5
3-86 0-13
0.0001
0.0001
43 22
8 20
0-86 0-65
0.0160
0.0253
46 19
17 7
2-86 0-20
0.0002
0.0018
Radiotherapy Yes No
40 25
14 6
0-86 0-61
0.0186
0.0183
Chemotherapy Yes No
32 33
20 6
0-86 0-65
0.0232
0.0010
Diagnostic delay3 ¿ 6 months > 6 months or asymptomatic Surgery Yes4 No
1 Butchart et al. [7]. 2 The maximum tumor diameter [8], 3 Delay between first symptom and histological diagnosis. 4 26 diagnostic thoracotomies; 15 palliative operations; 5 radical operations.
treated as tuberculosis or nonspecific pleuritis in 13 cases. The median delay from first symptom to diagnosis was 9 months (range 0-51) in this group of patients. Treatment Offered to Patients
For 46 patients, surgery consisted of diagnostic thora cotomy (26 patients), pleurectomy (15 patients); or pneumectomy and excision of all macroscopically visible tumor tissue from the ipsilateral pericardium and/or diaphragm (5 patients). Patients with large effusions clearly benefited from the palliative surgical intervention, in that dyspnea diminished. Local radiotherapy using small lung-sparing volumes, was employed in 40 cases; in 32 of these the application was postoperative. The total dose to the tumor was ^5,000 cGy (mean 5,370, range 5,000-6,000) in 27 cases, and
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malignant mesothelioma in 6 of 32 cases (19%), and histo logical examination of needle biopsy specimens of the af fected pleura revealed malignant mesothelioma in 12 of 28 cases (43%). Symptoms from the patients’ clinical histories are shown in table 1. Dyspnea was reported as the first symp tom in 25 cases, cough in 24 cases and chest pain in 23 cases. The median duration of symptoms before diagnosis was 3 months (range 0-51). Five asymptomatic patients having diffuse pleural mesothelioma were discovered by chance through routine chest X-rays. One patient had bacteriologically confirmed pleural tu berculosis concomitantly with histologically confirmed malignant mesothelioma. Three patients had histories of active pulmonary tuberculosis. Before the diagnosis of mesothelioma was confirmed, the disease had been
Fig. 1- Survival after the diagnosis of malignant pleural mesothe lioma (n = 65).
Fig. 3. Performance status and survival after the diagnosis of ma lignant pleural mesothelioma, a = WHO I (n = 38); b = WHO > I (n = 18).
eluding cyclophosphamide, 5-fluorouracil, vincristine, doxorubicin and DTIC intercalated with local therapies. In 18 cases 30-45 mg of thiotepa was instilled into the pleu ral cavity once a month to decrease pleural effusion. From the retrospective evaluation this method seemed to be less effective than pleurectomy. Survival
Fig. 2. Clinical stage and survival after the diagnosis of malignant pleural mesothelioma, a = Stage I (n = 25); b = stage II, III and IV (n = 34).
1 (WHO). For the 64 patients who had died by the time of the analysis, the cause of death was established on the basis of clinical features in 46 cases and on the basis of autopsy findings in 18 cases. One patient died of pericardial tam ponade as a result of extension of the tumor through the pericardium. The spread of the disease as recorded at au topsy is shown in table 3. Hematogenous métastasés were present in 13 patients (72%), and extrathoracic lymph node métastasés in 5 patients (28%).
134
method is not used more routinely. The definitive role of surgery in the management of mesothelioma remains open. The effectiveness of other treatment modalities ra diotherapy, chemotherapy and/or combined modality treatment cannot be evaluated in this retrospective analy sis, where treatment decisions were made without refer ence to a protocol, and they likewise remain unclear [5, 25]. Although it used to be believed that mesothelioma spreads mainly by direct extension, hematogenous metastases are frequently found at autopsy. The liver, adrenal glands and kidneys are the organs most frequently in volved [13]. In our series of 18 autopsies, direct extension to the pericardium, contralateral lung or pleura, chest wall or peritoneum were observed in 14 cases (78%). Hemato genous metastases to the liver, bone, adrenal gland, kidney or brain were observed in 13 cases (72%). This supports the view that mesothelioma is a systemic disease, and that treatment should take this into account. Our results confirm the common experience [11] that there is a considerable delay on the part of doctors and/or patients before the start of active treatment. Since treat ment decisions and results depend directly on the extent of the disease at diagnosis, accurate assessment of clinical stage is essential. Based on our experience, from a pro spective study involving 100 patients with pleural meso thelioma (unpublished data), we strongly recommend the routine use of CT scanning in the diagnosis of patients who may have mesothelioma. Thoracoscopy and thora cotomy should be performed at an early stage for patients with undefined pleurisy, especially in cases where there is an occupational history of asbestos exposure. Large multi-center prospective studies are urgently needed to elucidate further the natural history and opti mal treatment for this highly malignant neoplasm.
Tammilehto/Maasilta/Kostiainen/ Appelqvist/Holsti/Mattson
Diagnosis and Prognostic Factors in Malignant Pleural Mesothelioma
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cording to the Dimitrow system [8] were available for only 32 (49%) patients. These data could not therefore be used for multivariate analyses on survival. Most centers now use computerized axial tomography for routine staging, and as one of several diagnostic tools [18,19, 20]. We used a rough grouping into two classes by perform ance status, WHO ^1 and WHO > 1. 38 (68%) patients had a good performance status. Nonspecific symptoms and good performance status are typical of malignant mesothelioma. This is one explanation for diagnostic de lays by patients and doctors [5], The frequency of malignant mesothelioma in patients exposed to asbestos ranges from 8% in areas lacking heavy asbestos-using industry, to 80% in areas having shipyards or asbestos mines [12,21]. There is one shipyard, and many other industries where asbestos exposure is possible, in the catchment area of the Helsinki University Central Hospi tal. From their occupational histories, 53% of our patients can be presumed to have had some exposure to asbestos. Prospective analysis in the same catchment area gives much the same figure (51%) for 100 patients (unpublished data). Early clinical stage, female gender, absence of chest pain, epithelial subtype, duration of symptoms > 6 months, age < 50 years, good performance status, absence of asbestos exposure, chemotherapy and surgery have been reported as favorable prognostic factors in mesothe lioma [22,23]. In our study, good prognosis was associated with clinical stage I, maximum tumor diameter 6 months or asymptomatic, and treatment with surgery, radiotherapy and chemotherapy. In some series a longer survival time has been associated with the epithelial subtype [13]. However, the histological subtype was not a positive prognostic factor for our pa tients. One explanation could be that pathological subtyp ing was not routinely performed until the latter part of the study period. The treatment of choice for diffuse malignant pleural mesothelioma is controversial. Pleurectomy has been re ported to give survival rates of 10-37% for 2 years and 3.5-10% for 5 years [7, 24], However, radical surgical re moval of all tumor tissue is seldom possible. In our study pleuropneumonectomy, including excision of all macroscopically visible tumor tissue, was performed in only 5 pa tients (they survived 17, 20, 54 and 86 months from histo logical diagnosis, and 1 patient was still alive 126 months after diagnosis). Butchart et al. [7] also associated good survival times with radical surgery. A higher than normal risk of operative mortality is probably the reason that this
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