Mesothelioma Metastases - Asbestos Exposure, Asbestos Fibers

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At the University of South Alabama Medical Center (USAMC), 161 autopsies for asbestosis were done from February 1989 through July 1994. Of those autopsies, 22 cases of mesothelioma were diagnosed based on gross and histologic findings. The majority of these tumors involved other viscera by direct extension and/or metastases. These postmortem examinations provided an opportunity to determine distribution of metastases and staining characteristics of primary mesothelioma compared to tissue involved by metastases and/or direct extension.

MATERIALS AND METHODS

From February 1989 through July 1994, 161 autopsies for asbestosis were done at the USAMC. All were requested by families of the deceased because of a history of asbestos exposure and, in many cases, a clinical history of asbestosis. Of the 22 cases with mesothelioma, 15 were complete autopsies and 7 were limited to the thoracic cavity. Three had been embalmed before autopsy.

Demographic data, including occupational history and smoking history, were reviewed. The presence or absence of pleural and/or diaphragmatic plaques and lung fibrosis and ferruginous body counts on sections were recorded for each case. Lung tissue was digested and ferruginous bodies were counted as previously reported.8,9 Fibrosis was reported as previously described. No lung tissue was available for digestion in one case.

Formalin-fixed tissue from each primary mesothelioma and tissue from a metastasis (or area involved by direct extension) were stained with the following: carcinoembryonic antigen (CEA), low-molecular-weight keratin (LMWK), high-molecular-weight keratin (HMWK), Leu-M1, Ber-EP4, periodic acidñSchiff (PAS) with diastase,10 alcian blue,11 and alcian blue after hyaluronidase12 (Table 1). Blocks of tissue were not available for one case (Case 4). One case (Case 22) involved only the lung and pleura with no metastases or direct extension.

RESULTS

Demographic data were as follows: mean age, 68 years (range, 38 to 88 years); black:white patient ratio, 4:18; male:female patient ratio, 21:1. The majority had exposure to asbestos while working in the shipyards or on ships (Table 2). Jobs included pipe fitter, boilermaker, carpenter, welder, plumber, tacker, shipfitter, electrician, and longshoreman. Complete, detailed histories of occupational exposure could not be supplied by family members in all cases, but all patients had a clinical history of exposure to asbestos. In 13 cases, the duration of occupational exposure to asbestos was known. The majority (85%) were exposed for 20 or more years .Of the 13 cases with smoking history available, 11 (85%) were smokers.

Pleural and/or diaphragmatic plaques were present in 20 of the 22 cases (91%). Fifty percent of the cases (11 cases) had mild interstitial fibrosis. Seven cases (32%) had ferruginous bodies identified on hematoxylin- eosinñstained sections. Two more cases had ferruginous bodies identified on iron-stained sections at the time of autopsy. Eighty-one percent (17 of 21 cases) had >10 ferruginous bodies per slide after tissue digestion .Two cases had no ferruginous bodies after tissue digestion.

The mesotheliomas encased the right lung in 10 cases and the left lung in 11 cases. One case of peritoneal mesothelioma was also studied. Seventeen mesotheliomas were biphasic, and five had only an epithelial component. Widespread metastases and/or direct tumor extension of the pleural mesotheliomas were present .In one case (Case 10), the tumor involved the mucosal surface of the gastrointestinal tract. Other malignancies included two adenocarcinomas of the prostate, one adenocarcinoma of the lung, and one Waldenströmís macroglobulinemia. One patient had a history of Alzheimerís disease and Parkinsonís disease.

Results of immunohistochemical staining of primary mesothelioma and metastases were similar, with positivity for LMWK and negativity for CEA, Leu-M1, and Ber-EP4 (Tables 4, 5). Occasional areas of necrosis were positive (false-positive) for CEA. Results for HMWK were variable. Results of staining with alcian blue with and without hyaluronidase were highly variable. Of the primary mesotheliomas, 5 of 21 stained positively with alcian blue, and none stained positively with alcian blue after hyaluronidase. Of the metastases, 4 of 20 stained positively with alcian blue, and none stained positively with alcian blue after hyaluronidase. Of the primary mesotheliomas, none of the 22 reacted positively to PAS with diastase. Of the 20 metastases, none reacted positively to PAS with diastase.

DISCUSSION

Mesothelioma is often associated with asbestos exposure, which has usually been occupational. Shipyards and numerous industries have used asbestos, thus exposing employees.4 In 1971, the Occupational Safety and Health Administration regulated asbestos use and handling. Due to the long latency period between exposure and diagnosis of mesothelioma,5 new cases continue to appear. In 1986, an estimated 1,500 new cases were diagnosed in the United States.13 In a study of 19 patients with mesothelioma,14 the mean age was 57.8 ± 11.5 years. Demographic data of the patients in our study are consistent with those previously described. The mean age was 68 years, and the majority were men occupationally exposed to asbestos in shipyards or related industries.

Since most people who have been exposed to asbestos are smokers,4 it follows that most people with mesothelioma are smokers. As expected, in our study 85% of the people with known smoking history were smokers. However, cigarette smoking is not considered a factor in the development of mesothelioma.15,16

Pleural plaques are present at autopsy in greater than 80% of people with exposure to asbestos.4 Not surprisingly, most diffuse pleural mesotheliomas are associated with plaques.7 As predicted, the majority (91%) of people in our study had plaques.

Roggli et al17 studied lung asbestos content in 25 cases of mesothelioma. They hypothesized that no threshold burden of asbestos fibers is needed to produce mesothelioma. Mesothelioma occurs in some people with low exposure.18,19 Other reports have suggested that a dose-response relationship exists.20,21 Tuomi et al22 studied lung asbestos content from 23 people with mesothelioma and correlated the findings with occupational history of asbestos exposure. They determined that asbestos burden correlates with work exposure. In their study, 78% (18 of 23) were exposed at work, based on history or asbestos content. In those authorsí opinion, a history of exposure to asbestos is medicolegally significant even if low concentrations of asbestos fibers are identified. In our study, 91% of cases had ferruginous bodies in sections or digested specimens. In 2 cases, no ferruginous bodies were identified in sections or after tissue digestion. Other cases of mesothelioma without identified ferruginous bodies have been reported.22

Histologic classification of mesotheliomas includes the following: epithelial, sarcomatoid, mixed (biphasic), transitional, desmoplastic, and localized fibrous tumor of the pleura.7 Epithelial mesotheliomas are the most common type. Biphasic mesotheliomas contain regions with an epithelial pattern and regions with a sarcomatous pattern. Tumors tend to be variable in their histologic pattern. As pointed out by Hammar,7 the more tumor available for examination, the more variation will be seen. In our study, the majority of mesotheliomas (17 cases; 77%) were biphasic. Five cases (23%) had only an epithelial pattern.

As discussed by Hammar,7 diffuse mesotheliomas encase the lung and can encase mediastinal structures. The esophagus, trachea, heart, and great vessels may become involved by tumor. Lung parenchymal invasion is common. Metastases may occur in lymph nodes associated with the hilum and mediastinum, as well as in the lung parenchyma. Because of the direct involvement of structures by the tumor, areas involved by direct extension are sometimes difficult to distinguish from those that are truly metastases.7 In our study, areas involved by direct extension and/or metastases were numerous (Table 3). Distant metastases were documented in numerous sites including omentum, stomach, intestine, mesentery, adrenal glands, vertebral column, ovary, kidneys, liver, pancreas, and spleen. In 7 cases, autopsy was limited to the thoracic cavity, so distant metastases in those cases could not be documented.

Autopsy cases with diagnostic mesothelioma on gross and histologic examination may not require an extensive immunopanel; biopsy material, however, can be much more challenging. As shown in our study, mesothelioma can involve multiple sites, such as the lymph nodes or subcutaneous tissue. Thus, areas involved by metastatic mesothelioma or by direct extension of the tumor may be biopsied instead of the pleura. Since mesothelioma is rare and metastases are infrequent, no studies comparing the immunohistochemical staining of primary mesotheliomas and metastases have been previously reported. The number of cases of mesothelioma with metastases at USAMC provided an unusual opportunity to evaluate their staining characteristics.

Primary mesotheliomas and metastases stained similarly, showing negativity for CEA, Leu-M1, Ber-EP4, and PAS with diastase and showing positivity for LMWK (Tables 4, 5). Studies have shown that the majority of mesotheliomas are negative for CEA,23-29 Leu-M1,24,30-34 and Ber-EP4.35 Most epithelial mesotheliomas stain positively for LMWK and HMWK.7,24,31 Staining reactions for HMWK, however, have been mixed in sarcomatous and biphasic mesotheliomas.7 Since 17 of the 22 cases of mesothelioma in our study were biphasic, the low positivity rate for HMWK is not unexpected.

Twenty percent of epithelial mesotheliomas produce hyaluronic acid, a highly acidic mucosubstance.7 Alcian blue, with and without hyaluronidase, has been used to determine if staining is due to hyaluronic acid. Despite their historical importance, the stains are often not reliable. Bedrossian et al36(p) stated that alcian blue stains before and after hyaluronidase ìare not reliable if the tissue has remained in the fixative over 48 hours.î Since the tissue in our study was formalin-fixed and paraffin-embedded as long as 5 years before this study, it is not known how long each tissue specimen was in formalin. Therefore, it is not surprising that the staining was not consistent.

References

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