Diagnosis: Diffuse, mixed epithelial and sarcomatous malignant mesothelioma, pleura

Follow-up: The patient remains stable 7 months following surgery. Pleural fluid has not reaccumulated. Asbestos exposure occurred during his 45-year career as a painter in boiler rooms where asbestos was being applied. He described a dusty environment. The latent period from onset of exposure to the onset of pleural effusion was 58 years.


Diffuse Malignant Mesotheliomas (DMM)

Introduction & Epidemiology: The association of asbestos and mesothelioma was first described in South Africa in 1960 [1] and then re-explored 30 years later [2]. Now, about 3000 DMMs occur each year in the United States [3]. The peak incidence is in persons 50 to 70 years old; about 7% of cases are diagnosed before age 40 [4]. Men predominate (1.8 to 12: 1) [4-6]. The low ratio of M:F is in patients without asbestos exposure [4], but since the '60s, the M:F ratio has climbed progressively in asbestos-exposed individuals [6,7]. Occupational exposure to asbestos is considered to be the cause of most cases [5], but domestic contact with an asbestos worker may also cause the disease [4,8]. The latent period from onset of asbestos exposure to death averages 41 y (range 15-67 y) [6]. Percentages of asbestos-related mesotheliomas vary widely, and other causes have been sought [9]. A few cases are caused by radiation. These occur in a younger age group, and the latent period from radiation to diagnosis of mesothelioma is almost always over 10 years [10]. The occurrence of familial cases suggests a genetic susceptibility [11]. Other possible causes include zeolites, another type of fibrous silicate mineral found in lungs of, and building materials used by, Turkish mesothelioma patients [9]. Chronic pleuropulmonary inflammation is another potential cause [9]. Smoking is not a risk factor in any group.

Types of asbestos: Asbestos is a commercial term for a number of silicate minerals that have an asbestiform habit (fibrous form) as well as a massive or rock-like form. The asbestiform minerals are chrysotile and the amphiboles, which include crocidolite, amosite, tremolite/actinolite, and anthophyllite. The asbestiform habit is an elongate crystal or aggregate of crystals that have parallel sides and a length to width ratio greater than 3. Their commercial uses are related to their flexibility, tensile strength, and fire resistance [9]. The risk of mesothelioma depends on the type of fiber inhaled. It is high for crocidolite and apparently somewhat less for chrysotile [12,13].

Clinical features: Symptoms of DMM are non-specific: chest pain, dyspnea, weight loss, night sweats, pneumothorax, or chest wall mass. About 1/3 of cases present with pleural effusion and dyspnea without pain and 1/3 present with chest pain without effusion [6]. Radiographically, there may be unilateral pleural effusion, pleural thickening, or a mass. The associated fluid is an exudate that may be bloody [12]. Metastases, although usually subclinical, are found in over 50% of cases at autopsy. Sites include lung, lymph nodes, kidneys, adrenals, bone, heart, thyroid, pancreas, liver, and brain [6,12,14]. Recently, clinical, occupational, and pathological features of these tumors have been summarized for a large group of patients.

Diagnosis: DMMs may be difficult to differentiate from inflammation or other neoplasms. Usually a large thoracoscopic or open biopsy is required to evaluate the histologic pattern and to use for special studies. Cytologic examination or tissue from a cutting needle biopsy can sometimes yield a diagnosis, but Cope needle biopsies are usually inadequate. If malignancy is a consideration at the time of biopsy, some tissue should be put into glutaraldehyde fixative in the operating room for electron microscopy. H&E staining alone may suggest the diagnosis, but it requires confirmation by one or more special studies including stains for mucin, immunohistochemical stains, or electron microscopy.

Pain or tumor growth along the incision line occurs in around 20% of needle biopsies, but in up to 40% of open biopsies [12]. A recent study indicated that such seeding can be prevented by local post-operative radiation [15].

Staging: Because different therapeutic options are now available for patients, staging procedures have been refined. In a newly-proposed TNM system, T1 to T3 tumors are potentially resectable. Node and metastatic designations are the same as for lung cancer [16].

Pathology--Gross features: The surgeon may encounter non-specific inflammatory granulations; multiple nodules or masses (5 mm-10 cm), sometimes described as grape-like; or diffuse thickening [15]. Solitary masses are usually tumors of another type (e.g., solitary fibrous tumor of pleura).

Microscopic features: Tumors may be composed of epithelial cells, spindled cells, or a mixture. Epithelial tumors grow as sheets or nests of polygonal cells; form glands, tubules, or microcysts lined by cuboid to columnar epithelium; or cover papillary projections. Tumor cells are distinct from the benign stroma. These patterns resemble carcinomas.

Spindle-celled tumors are composed of sheets of elongate cells without an identifiable benign stroma. Tumors with both epithelial and sarcomatous components are termed dimorphic tumors. Dimorphic pleural tumors are likely to be mesotheliomas because most metastatic tumors have a monomorphic (epithelial or spindled) growth pattern.

Summary of Polymorphous Pathologic Features of DMM

Gross Features:

Microscopic Features:

Diagnostic strategies for the pathologist: These tumors have a varied appearance that mimics other diseases, both benign and malignant. Diagnostic dilemmas include [18]:

Features of malignancy include cytologic atypia, invasion of lung parenchyma or chest wall, and absence of a heavy inflammatory infiltrate. Necrosis, especially bland necrosis, is a useful feature of malignancy in spindled tumors [19]. The pathologist must first decide whether or not malignancy is present. Special stains are of no proven value in this regard. Once a diagnosis of malignancy is made, special stains are of use in determining whether it is a mesothelioma or a metastasis.

Special studies include histochemical and immunoperoxidase stains and electron microscopy. Experience with both the performance and the interpretation of these tests is important.

Differential diagnosis: Metastatic tumor of any type, but especially metastatic lung cancer, can mimic DMM. If the primary tumor is in the lung and metastasis diffusely involves the pleura, the tumor is called a pseudomesotheliomatous carcinoma of the lung [20]. In this case the primary tumor is usually a peripheral adenocarcinoma. Metastatic spindled carcinomas (of lung, kidney) can also resemble DMM [18]. Diffuse pleural fibrosis can also mimic DMM radiographically and clinically with pain, dyspnea, and effusion [21]. Certain sarcomas, including synovial sarcoma [22], malignant fibrous histiocytoma, rhabdomyosarcoma [18], pseudomesotheliomatous angiosarcoma [23], extraskeletal myxoid chondrosarcoma [24], and smooth muscle tumors [25], can look like DMM. Solitary fibrous tumors of the pleura are occasionally malignant, but they are not related to asbestos and do not stain for keratin. However, a few otherwise typical localized malignant mesotheliomas have been described [26].

Remember: The diagnosis of DMM rests on the concordance of:

Pathogenesis: The following hypothesis has some support. The normal flow of fluid in the pleura is from the visceral layer to pores in the parietal layer that lead to lymphatics. In persons exposed to black pigment, the tissue around the pores is black. If black tissue around the pore is examined in asbestos workers, amphibole fibers are found in greater concentration than in the surrounding, non-pigmented pleura. Taken in conjunction with thoracoscopic observations that tumor may occur on the parietal pleura alone but never on the visceral pleural alone, these studies suggest that tumor begins around the pores where amphibole fibers accumulate [27].

Prognosis: The median survival after diagnosis depends on stage (stage IA 32.7 mo, stage IB 7 mo, stage III/IV 1-9 mo) [16,28]. Patients with epithelial tumors have a somewhat better prognosis than those with sarcomatous or mixed tumors. The favorable prognostic importance of negative nodal status and epithelial histology has been described in 52 patients undergoing multimodality treatment (extrapleural pneumonectomy, chemotherapy, and radiotherapy) [29].

Further follow-up

The National Cancer Institute has other useful information.

References

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3. Aisner J. Current approach to malignant mesothelioma of the pleura. Chest 1995; 107:332S-344S.

4. Kane M, Chahinian A, Holland J. Malignant mesothelioma in young adults. Cancer 1990; 65:1449-1455.

5. Gibbs A, Griffiths D, Pooley F, Jones J. Comparison of fibre types and size distributions in lung tissues of paraoccupational and occupational cases of malignant mesothelioma. Br J Indust Med 1990; 47:621-626.

6. Yates D, Corrin B, Stidolph P, Browne K. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases. Thorax 1997; 52:507-512.

7. Connelly R, Spirtas R, Myers M, Percy C, Fraumeni Jr J. Demographic patterns for mesothelioma in the United States. JNCI 1987; 78:1053-1060.

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13. Smith A, Wright C. Chrysotile asbestos is the main cause of pleural mesothelioma. Am J Ind Med 1996; 30:252-266.

14. Roberts G. Distant visceral metastases in pleural mesothelioma. Thorax 1976; 70:246-250.

15. Boutin C, Rey F. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: diagnosis. Cancer 1993; 72:389-393.

16. Patz Jr E, Rusch V, Heelan R. The proposed new international TNM staging system for malignant pleural mesothelioma: application to imaging. AJR 1996; 166:323-327.

17.Yousem S, Hochholzer L. Malignant mesotheliomas with osseous and cartilaginous differentiation. Arch Pathol Lab Med 1987; 111:62-66.

18. McCaughey W, Colby T, Battifora H, Churg A, Corson J, Greenberg S, Grimes M, et al. Diagnosis of diffuse malignant mesothelioma: experience of a US/Canadian mesothelioma panel. Mod Pathol 1991; 4:342-353.

19. Wilson G, Hasleton P, Chatterjee A. Desmoplastic malignant mesothelioma: a review of 17 cases. J Clin Pathol 1992; 45:295-298.

20. Koss M, Travis W, Moran C, Hochholzer L. Pseudomesotheliomatous adenocarcinoma: a reappraisal. Sem Diagn Pathol 1992; 9:117-123.

21. Yates D, Browne K, Stidolph P, Neville E. Asbestos-related bilateral diffuse pleural thickening: natural history of radiographic and lung function abnormalities. Am J Respir Crit Care Med 1996; 153:301-306.

22. Gaertner E, Zeren E, Fleming M, Colby T, Travis W. Biphasic synovial sarcomas arising in the pleural cavity. A clinicopathologic study of five cases. Am J Surg Pathol 1996; 20:36-45.

23. Falconieri G, Bussani R, Mirra M, Zanella M. Pseudomesotheliomatous angiosarcoma: a pleuropulmonary lesion simulating malignant pleural mesothelioma. Histopathology 1997; 30:419-424.

24. Goetz S, Robinson R, Landas S. Extraskeletal myxoid chondrosarcoma of the pleura. Report of a case clinically simulating mesothelioma. Am J Clin Pathol 1992; 97:498-502.

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26. Crotty T, Myers J, Katzenstein A-L, Tazelaar H, Swensen S, Churg A. Localized malignant mesothelioma. A clinicopathologic and flow cytometric study. Am J Surg Pathol 1994; 18:357-363.

27. Boutin C, Dumortier P, Rey F, Viallat J, De Vuyst P. Black spots concentrate oncogenic asbestos fibers in the parietal pleura. Thoracoscopic and mineralogic study. Am J Respir Crit Care Med 1996; 153:444-449.

28. Boutin C, Rey F, Gouvernet J, Viallat J, Astoul P, Ledoray V. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 2: Prognosis and staging. Cancer 1993; 72:394-404.

29. Sugarbaker D, Strauss G, Lynch T, Richards W, Mentzer S, Lee T, Corson J, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993; 11:1172-1178.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Copyright 1997 by Martha L. Warnock. All rights reserved.

Last revised 9/23/00

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