Mesothelioma (from page 1)

Differential Diagnosis. The diagnosis of epithelial mesothelioma and adenocarcinoma was based on macroscopic, histologic, histochemical, immunohistochemical and ultrastructural features. Like Otis, et al., we used the ultrastructural features as the "gold standard" for the diagnosis of epithelial mesothelioma. The most important ultrastructural feature for diagnosing epithelial mesothelioma is long, thin, "bushy" cell surface microvilli (Figure A) that characteristically have length:width ratios of 15 or greater, and which are not covered by a fuzzy glycocalyx that usually coats the surface of pulmonary adenocarcinoma microvilli. Other frequent ultrastructural features of epithelial mesotheliomas include: (1) abundant tonofilaments circumferentially oriented around the nucleus; (2) short profiles of rough endoplasmic reticulum that are often oriented around the nucleus; (3) cytoplasmic aggregates of glycogen; (4) large and often frequent desmosomes that connect the neoplastic cells to each other; (5) lack of intracellular membrane-enclosed mucin granules, and (6) microvillous-matrix association.

Conclusions. The following conclusions can be made from results presented in this study: (1) Mucin positive epithelial mesotheliomas are not uncommon. In our experience approximately 5% of well- to moderately well-differentiated epithelial mesotheliomas show focal mucin staining. (2) In most cases, mucicarmine and alcian blue staining is eradicated or reduced in intensity by pretreatment of the tissue with hyaluronidase. This finding suggests that hyaluronic acid is responsible for the positive mucicarmine staining reaction. (3) PAS-d positive epithelial mesotheliomas are less frequent than mucicarmine and alcian blue positive mesotheliomas, and pretreatment with hyaluronidase eradicates or reduces PAS-d staining in some cases. (4) Rare cases of mucicarmine, PAS-d and alcian blue positive epithelial mesotheliomas exist that are not affected by pretreatment with hyaluronidase. (5) The ultrastructural correlate of the mucicarmine, PAS-d and alcian blue staining, is an extracellular medium-electron-dense material that represents the secretory product (proteoglycan/hyaluronic acid) of these cells. (6) The apparent intracellular positive mucicarmine, alcian blue and PAS-d staining correlates ultrastructurally with intracellular "neolumens" that contain the secreted proteoglycan-hyaluronic acid. (7) Hyaluronic acid, hyaluronic acid-proteoglycan complexes, or other types of proteoglycan frequently aggregate or crystallize, forming fern-like structures (Figure B) and tubular crystalloid structures that have an electron microscopic appearance that we have observed almost exclusively in epithelial mesotheliomas. (8) A few epithelial mesotheliomas show focal immunostaining with a polyclonal antibody against carcinoembryonic antigen. Fewer epithelial mesotheliomas show focal immunostaining for LeuM1, and with the B72.3 antibody. The positive immunostaining for CEA, LeuM1 and B72.3 has been reported to be eradicated or decreased in intensity by pretreatment with hyaluronidase, suggesting that hyaluronic acid may be responsible for the positive reaction. (9) Pulmonary adenocarcinomas that show intracellular mucicarmine and PAS-d positive staining are also alcian blue positive (pH 1.0 and 2.5). This histochemical staining is resistant to hyaluronidase pretreatment of the tissue sections. (10) Unlike epithelial mesotheliomas, mucicarmine, PAS-d and alcian blue-positive pulmonary adenocarcinomas contain intracellular mucin granules that can be demonstrated ultrastructurally (Figure B). (11) Some pulmonary adenocarcinomas form intracellular "neolumens". The microvilli that project into the neolumens are usually short to medium length, and are covered by a fuzzy glycocalyx (Figure C). Only rarely are the microvilli of pulmonary adenocarcinomas long and sinuous, and when they are, they are usually covered by a fuzzy glycocalyx. (12). Many pulmonary adenocarcinomas contain glycocalyceal bodies (Figures D) and other secretory products (mucin) in their intracellular neolumens and glandular lumens. This secretory product does not look like proteoglycan-hyaluronic acid complexes, and is usually displaced by the glycocalyx covering the microvilli. Occasionally the secretory product may crystallize, but the crystallized material does not have the same appearance as crystallized hyaluronic acid-proteoglycan.