Natural History and Staging of Malignant Mesothelioma

associated with either karyotypic alterations or minor mutational changes in the cell genetic makeup. ••·a Given the concurrent occurrence of mutation~ and the production of growth substances in a localized area of the pleura, one might envision a multistage series of events whereby genetically damaged cells are stimulated to proliferate. Were this process to continue over an extended time, neoplastic transformation could occur in the mesothelial progenitor cells in the lining layers of the peritoneal and pleural cavities. Although this hypothesis most probably cannot l>e proved definitively, it is a plausible explanation for carcinogenesis consistent with all of the experimental and epidemiologic evidence existing today. Accepting the validity of this notion, we might then consider the epidemiologic evidence further. As indicated above, amphibole asbestos types are retained in the lungs for indefinite periods and tend to accumulate adjacent to and in the pleural tissue. In contrast, chrysotile fibers break down into subfibrils in lung tissue due to the leaching effect of body fluids.• These subfibrils deteriorate or dissolve further and are then eliminated by the lymphatic system of the lungs and the mucociliary escalator system of the airways. A number of studies of human lungs have shown that chrysotile does not accumulate in inordinate quantities in the lungs of occupationally exposed individuals. Epidemiologic evidence suggests that the likelihood of an individual's developing a mesothelioma relates proportionately to the length of their life. One might speculate that an individual encumbered by a burden of amphibole asbestos might invariably develop a mesothelioma were he to live long enough. This is, of course, a hypothesis that cannot be proved, but it argues strongly for the initiation of deliberate efforts to develop prophylactic approaches to reverse the course of the neoplastic events which might invariably occur in amphibole-exposed individuals. Clearly, therapeutic research efforts and interventions in the future might reasonably focus on means whereby the macrophage and its products might be altered in such a way that the mesothelioma would not be inevitable. REFERENCES 1 Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 1960; 17:260 2 Stanton MF, Wrench C. Mechanisms of mesothelioma induction with asbestos and fibrous glass. JNCI 1978; 48:797 3 Whitwell F, Rawcliffe RM. Diffuse malignant pleural mesothelioma and asbestos exposure. Thorax 1971; 26:6-22 4 Sheers, G. Mesothelioma rislcs in a naval dockyard. Arch Environ Health 1980; 35:276-82 5 SelikofFIJ, Hammond EC, Seidman H. Mortality experience of insulation workers in the United States and Canada 1943-1976. Ann NY Acad Sci 1979; 330:91-116 6 Mancuso TF. Mesothelioma among machinists in railroad and other industries. Am J Ind Med 1983; 4:501-13 7 Berry G, Newhouse ML, Antonis P. Combined effect of asbestos and smolcing on mortality from lung cancer and mesothelioma in factory workers. Br J Ind Med 1985; 42:12-18 8 Lilienfield DE, Mandel JS, Coin P, Schuman LM. Projection of asbestos-related diseases in the United States, 1985-2009 I. Cancer. Br J Ind Med 1988; 45:283-91 9 Walker AM, Loughlin JE, Friedlander ER, Rothman KJ, Dreyer NA. Projections of asbestos-related disease 1~2009. J Occup

Med 1983; 25:409-25 10 Craighead JE. Current pathogenetic concepts of diffuse malignant mesothelioma. Hum Pathol1987; 18:544-57 11 Churg A, Wiggs B, Depaoli L, Kampe B, Stevens B. Lung asbestos content in chrysotile workers with mesothelioma. Am Rev Respir Dis 1984; 130:1042-45 12 Churg A. Chrysotile, tremolite, and malignant man. Chest 1988; 93:621-37 13 McDonald AD, McDonald JC. Mesothelioma after crocidolite exposure during gas mask manufacture. Environ Res 1978; 17:340-46 14 Case BW, Sebastien P. Environmental and occupational exposures to chrysotile asbestos: a comparative microanalytic study. Arch Environ Health 1987; 42:185-90 15 Jackson JH, Schraufstatter IU, Hyslop PA, et al. Role of oxidants in DNA damage. Hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke. J Clin Invest 1987; 80:1090-95 16 Hansen K, Mossman BT. Generation of superoxide (OJ from alveolar macrophages exposed to asbestiform and nonfibrous particles. Cancer Res 1987; 47:1681-86 17 Case BW, Ip MPC, Padilla M, Kleinerman J. Asbestos effects on superoxide production. An in vitro study of hamster alveolar macrophages. Environ Res 1986; 39:299-306 18 Goodglick LA, Kane AB. Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. Cancer Res 1986; 46:5558-66 19 Lemaire I, Beaudoin H, MasseS, Grondin C. Alveolar macrophage stimulation oflung fibroblast growth in asbestos-induced pulmonary fibrosis. Am J Pathol1986; 122:205-11 20 Brody AR, Overby LH. Incorporation of tritiated thymidine by epithelial and interstitial cells in bronchio~alveolar regions of asbestos-exposed rats. Am J Pathol1989; 134:133-40 21 Palekar LD, Eyre JF, Most BM, Coffin DL. Metaphase and anaphase analysis of V79 cells exposed to erionite, UICC chrysotile and UICC crocidolite. Carcinogenesis 1987; 8:553-60 22 Achard S, Perderiset M, Jaurand M-e. Sister chromatid exchanges in rat pleural mesothelial cells treated with crocidolite, attapulgite, or benzo 3-4 pyrene. Br J Ind Med 1987; 44:281-83 23 AppelJD, FasyTM, KohtzDS, KohtzJD,JohnsonEM. Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA. Proc Natl Acad Sci 1988; 85:7670-74 24 Libbus BL, Craighead JE. Chromosomal translocations with specific breakpoints in asbestos-induced rat mesotheliomas. Cancer Res 1988; 48:6455-61 25 Libbus BL, Craighead JE. Specific chromosomal changes characterize most abestos-induced mesotheliomas in rats. 4th International Worlcshop NATO. Effects of Mineral Dusts on Cells, Quebec, September 21-23, 1988 26 Wagner JC, Berry G, Pooley FD. Mesotheliomas and asbestos type in asbestos textile workers: a study of lung contents. Br Med J 1982; 285:603-06

Natural History and Staging of Malignant Mesothelioma Kanm H. Antman, M.D. •

P

NATURAL HISTORY

atients with malignant pleural mesothelioma, characteristically aged 50 to 80 years (median 60), 1 first seek medical attention for dyspnea, nonpleuritic chest wall pain, or both.u The ratio of men to women is 2-5:1, presumably *Associate Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston. CHEST I 98 I 1 I JULY, 1989 I Supplement

838

reflecting workplace exposure. When first seen, most will have a large, freely mobile, unilateral pleural effusion on chest x-ray film. Approximately 60% of patients present with right-sided primary lesions and fewer than 5% with bilateral involvement. Occasional patients are asymptomatic, with an effusion found incidentally on chest x-ray film taken for another indication. Pleural plaques or interstitial fibrosis are visible on the chest x-ray films in only about 20% of patients with pleural mesothelioma despite a history of asbestos contact in 50-70%. However, calcifications can be documented on CT scan in almost half4 and at autopsy in up to 87%. Loss oflung volume is frequently documented on CT scan at presentation....,. With more advanced disease, scoliosis develops, with contracture of the ipsilateral hemithorax apparent on chest x-ray film. Symptoms of dyspnea and chest pain can be controlled initially by repeated thoracocenteses and minor narcotics. Pleurodesis to control fluid accumulation is generally unsuccessful and renders any subsequent surgical resection technically more difficult. As the tumor obliterates the pleural space, fluid eventually becomes loculated or disappears, 9 and dyspnea increases out of proportion to chest x-ray findings or tests of pulmonary function. Because hypoxia results from shunting of blood through a poorly aerated lung, therapeutic oxygen is of little use. Mesothelioma tends to be locally invasive. Painful masses, which generally arise in sites of prior thoracocentesis, chest tube drainage, or thoracotomy, develop in about 10% of patients and can sometimes be managed with radiotherapy.1·9·10 Direct extension to ribs, esophagus, vertebra, nerves, and the superior vena cava cause pain, dysphagia, cord compression, bracheal plexopathy, Horner's syndrome, Table 1- Prognostic Variable. Median Survival Characteristic (N=180) Age <20 20-40 40-60 >60 Performance status 0-1 1 >1 Sex Men Women Smoker

+

Chest pain Stage 1 2-3 4 Histology Epithelial Sarcoma Mixed

%

Mo.

p

2 14 33 50

7 26 15 13

.001

72 15

31 32 7

.001

15 14

.01

64 22 40

23 38

.01

24

.01

62 34 4

16 17 32

.01

61 13 23

17 7 13

.04

8 76

24

Table !-Independent Prognoatic Variable. DFCI Mt. Sinai (N=69) Sex Stage Symptoms Primary

Histology Age Performance

1980(N=40)

1987 (N = 180)

Women 1 >6mo

>6mo* No chest pain Peritoneal Epithelial <50 0-1

Pleural Epithelial <65 0-1

*Duration prior to diagnosis.

or superior vena cava syndromes, respectively. 2 Debilitating fevers with no documented source of infection accompanied by significant weight loss and a poor performance status are common. Clotting abnormalities including disseminated intravascular coagulation, thromboses of extremities, thrombophlebitis, pulmonary emboli, and Comb's positive hemolytic anemia have been observed in up to 20% of patients with peritoneal mesothelioma, 11 resulting in significant morbidity and mortality perioperatively and in patients with advanced or uncontrolled tumor. Table 3-Staging Schemas* Butchart et al 1• I Ipsilateral pleura, lung, pericardium, diaphragm II Invading chest wall or mediastinum: esophagus, heart, opposite pleura, or + Lymph nodes within the chest III Through diaphragm to peritoneum or involving the opposite pleura, or + Lymph nodes outside the chest IV Distant blood-borne metastases Dlmitrov and McMahon11 I Ipsilateral pleura ± effusion a. Longest diameter <5 em b. Longest diameter >5 em II Ipsilateral pleura + endothoracic fascia/lung III Ipsilateral pleura, endothoracic fascia, chest wall, lung, or pericardium IV Hilar or mediastinal lymph nodes, opposite pleura, or extrathoracic site. Mattson1• I Ipsilateral pleura and lung II Chest wall, mediastinum or pericardium, contralateral lung or pleura III Extrathoracic extension (a) Nodes outside chest (b) Through diaphragmatic to peritoneum IV Distant metastases Chabinian et al 17 NO MO T1 I MO T1-2 N1 II MO T2 NO MO N0-3 III T3 M1 N0-3 IV T4 *T Primary tumor; T1 ipsilateral pleura only; T2 superficial (diaphragm, thoracic fascia, ipsilateral lung, fissures); T3 deep local (chest wall beyond endothoracic fascia); T4 extensive direct (opposite pleura, peritoneum, retroperitoneum); N lymph nodes; NO - lymph nodes; N1 + ipsilateral hilar nodes; N2 + mediastinal nodes; N3 + contralateral hilar nodes; M metastases; MO none; M1 blood-borne or lymphatic. 5th World

eom-nce on Lung

cancer

Patients generally die of respiratory failure after a median survival of 6-18 months in various series (range: weeks to 16 years). Inanition and small bowel obstruction from direct extension through the diaphragm develop in about one third. Cardiac complications of pericardia! or myocardial involvement result in a smaller percentage of deaths. 2 Younger age, ts-13 0-1 performance status, epithelial histology, lack of chest pain at diagnosis, and therapy with pleuropneumonectomy and chemotherapy12•13 are associated with a significantly longer survival {Tables 1 and 2). STAGING

While multiple staging systems for malignant mesothelioma have been published {'lllble 3), 1....7 none reproducibly predicts survival with statistical significance. Obstructive spirometric changes are unrelated to mesothelioma or asbestosis. 18 Pulmonary function tests may document restrictive lung disease resulting from encasement of the lung and assess the feasibility of pneumonectomy. A Cf scan of the primary to assess the extent of disease is indicated if treatment is contemplated. 4 The role of magnetic resonance imaging has not yet been evaluated. While bone, brain, and liver metastases, or extension into other serosal surfaces are found at autopsy in more than half of patients, in the absence of symptoms or laboratory abnormalities, clinically relevant metastases are sufficiently uncommon at presentation to render extensive baseline evaluation nonproductive. lf the initial diagnostic biopsy is equivocal, additional diagnostic studies may be useful to locate an occult primary adenocarcinoma or to document tumor in locations rarely involved by mesothelioma. 1• 22 A markedly elevated serum CEA suggests a diagnosis other than mesothelioma. REFERENCES 1 Anbnan KH. Clinical presentation and natural history of benign and malignant mesothelioma. Semin Oncol1981; 8:313 2 Anbnan KH, Blum R, Greenberger J, et al. Multimodality therapy for mesothelioma based on a study of natural history. Am J Med 1980; 68:356 3 Anbnan KH. Malignant mesothelioma. N Eng) J Med 1980; 303:200 4 Grant DC, Seltzer SE, Anbnan KH, et al. Computer tomography of malignant pleural mesothelioma. J Com put Assist Tomogr 1983; 7:626 5 Alexander E, Clark RA, Colley DP, et al. CT of malignant pleural mesothelioma. AJR 1981; 137:287 6 Cohen BA, Efremidis A, Chahinian AP, et al. Computer tomography of the chest of diffuse malignant pleural mesothelioma. Am Rev Respir Dis 1981; 123:131 7 Kreel L. Computed tomography in mesothelioma. Semin Oncol 1981; 8:302 8 Mirvis S, Dutcher JP, Haney PJ, et al. CT of malignant pleural mesothelioma. AJR 1983; 140:665 9 Elmes PC, Simpson M. The clinical aspects of mesothelioma. QJ Med 1976; 45:427 10 Gordon W, Anbnan K, Greenberger J, ~ichselbaum R, Chaft'ey J. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Bioi Phys 1982; 8:19 11 Anbnan K, Pomfret E, Aisner J, et al. Peritoneal mesothelioma: natural history and response to chemotherapy. J Clin Oncol 1983; 1:386 12 Anbnan K, Shemin R, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-

13

14

15

16 17

18 19

20

Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985 Chahinian AP, Pajak T, Holland J, et al. Diffuse malignant mesothelioma: prospective evaluation of69 patients. Ann Intern Med 1982; 96:746 Butchart EG, Ashcroft T, Bamsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: experience with 29 patients. Thorax 1976; 31:15 Dimitrov Nv, McMahon S. Presentation, diagnostic methods, staging, and natural history of malignant mesothelioma. In: Anbnan K, Aisner J, eds. Asbestos related malignancy. New York: Grune & Stratton, 1986 Mattson K. Natural history and clinical staging of malignant mesothelioma. Environ J Respir Dis 1982; 63(suppl124):87 Chahinian AP, Pajak T, Holland J, et al. Diffuse malignant mesothelioma: prospective evaluation of69 patients. Ann Intern Med 1982; 96:746-55 Weill H. Asbestos-associated diseases: science, public policy and litigation. Chest 1983; 84:601-08 Kannerstein M, McCaughey WTE, ChurgJ, et al. A critique of the criteria for the diagnosis of diffuse malignant mesothelioma. Mt Sinai J Med 1977; 44:485 Kannerstein M, Churg J, Magner D. Histochemistry in the diagnosis of malignant mesothelioma. Ann Clin Lab Sci 1973;

3:207

21 Kannerstein M, ChurgJ. Peritoneal mesothelioma. Hum Pathol 1977; 8:83 22 McDonald AD, Magner D, Eyssen G. Primary malignant mesothelial tumors in Canada, 1960-1968. Cancer 1973; 31:869

Therapeutic Approach to Malignant Mesothelioma Joseph Aisner, M.D.*

mesothelioma is a relatively rare tumor which M alignant has received considerable interest because of its

association with asbestos exposure in the workplace and in the environment. 1 There is a sharply rising incidence of this tumor due, in part, to the increased use of asbestos beginning during WWII. There has thus been a considerable population exposed to asbestos who are at increased risk of developing malignant mesothelioma and other asbestosrelated diseases. Nevertheless, clinical data defining the optimal management of this disease are only beginning to develop. There remains considerable disagreement about the appropriate application of individual or combined modality treatments. In the past because of the difficulties in establishing the diagnosis, mesotheliomas presented late with obliteration of the pleura and considerable deterioration of patient characteristics so that therapies had little or no impact upon survival. As a result of public and medical awareness, patients present with earlier disease, allowing for many treatment opportunities. Review of patient demographics, treatment, and outcome using multivariate analysis showed that before 1980, the significant prognostic factors for outcome included: female sex, early stage, and long duration of symptoms. Treatment could not be shown to be an *Professor of Medicine and Oncology, University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore. Reprint requeat8: Dr. ~~nWerlity of Mat'flland Cancer Center, 22 South Creene Street, tsammore 212of CHEST I 98 I 1 I JULY, 1888 I Supplement

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