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Am J Pathol. 1985 Nov; 121(2): 235–247.
PMCID: PMC1888049

The intermediate filament cytoskeleton of malignant mesotheliomas and its diagnostic significance.


The intermediate filament cytoskeleton of epithelial, biphasic, and fibrous malignant pleural mesotheliomas was studied by immunohistochemistry and gel electrophoresis. The results were compared with data similarly obtained from lung adenocarcinomas. All mesotheliomas immunostained with various monoclonal and polyclonal antibodies against cytokeratins. By double immunofluorescence microscopy, coexpression of cytokeratins and vimentin was found in the fusiform cells of biphasic and fibrous mesotheliomas. As determined by two-dimensional gel electrophoresis, lung adenocarcinomas exclusively expressed Cytokeratins 7, 8, 18, and 19, and the same polypeptides were found in the fibrous mesotheliomas. These four cytokeratins were also found in the epithelial and biphasic mesotheliomas, most of which, however, also expressed, additional cytokeratins, such as the basic Polypeptide 5 and, in some cases, Cytokeratins 4, 6, 14, and 17. The results demonstrate the epithelial nature of all types of malignant mesotheliomas and thus justify their classification as carcinomas. When epithelial morphology is evident, the pattern of cytokeratin expression is usually more complex, as indicated by the synthesis, in addition to the "simple epithelial" pattern (7, 8, 18, and 19), of certain cytokeratin polypeptides which hitherto have been presumed to be typical of stratified epithelia. This cytokeratin complexity and the coexpression of vimentin and cytokeratins in certain forms of mesotheliomas indicate that these tumors are a clearly distinct and complex group of carcinomas. Their special cytoskeletal filament protein expression should prove useful in differentiating mesotheliomas from other carcinomas, particularly from adenocarcinomas growing in the lung.

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  • Bolen JW, Thorning D. Mesotheliomas: a light- and electron-microscopical study concerning histogenetic relationships between the epithelial and the mesenchymal variants. Am J Surg Pathol. 1980 Oct;4(5):451–464. [PubMed]
  • Warhol MJ, Hickey WF, Corson JM. Malignant mesothelioma: ultrastructural distinction from adenocarcinoma. Am J Surg Pathol. 1982 Jun;6(4):307–314. [PubMed]
  • Pascal RR, Mesa-Tejada R, Bennett SJ, Garces A, Fenoglio CM. Carcinoembryonic antigen: immunohistologic identification in invasive and intraepithelial carcinomas of the lung. Arch Pathol Lab Med. 1977 Nov;101(11):568–571. [PubMed]
  • Singh G, Whiteside TL, Dekker A. Immunodiagnosis of mesothelioma: use of antimesothelial cell serum in an indirect immunofluorescence assay. Cancer. 1979 Jun;43(6):2288–2296. [PubMed]
  • Wang NS, Huang SN, Gold P. Absence of carcinoembryonic antigen-like material in mesothelioma: an immunohistochemical differentiation from other lung cancers. Cancer. 1979 Sep;44(3):937–943. [PubMed]
  • Corson JM, Pinkus GS. Mesothelioma: profile of keratin proteins and carcinoembryonic antigen: an immunoperoxidase study of 20 cases and comparison with pulmonary adenocarcinomas. Am J Pathol. 1982 Jul;108(1):80–88. [PMC free article] [PubMed]
  • Kwee WS, Veldhuizen RW, Golding RP, Mullink H, Stam J, Donner R, Boon ME. Histologic distinction between malignant mesothelioma, benign pleural lesion and carcinoma metastasis. Evaluation of the application of morphometry combined with histochemistry and immunostaining. Virchows Arch A Pathol Anat Histol. 1982;397(3):287–299. [PubMed]
  • Whitaker D, Sterrett GF, Shilkin KB. Detection of tissue CEA-like substance as an aid in the differential diagnosis of malignant mesothelioma. Pathology. 1982 Jul;14(3):255–258. [PubMed]
  • Said JW, Nash G, Tepper G, Banks-Schlegel S. Keratin proteins and carcinoembryonic antigen in lung carcinoma: an immunoperoxidase study of fifty-four cases, with ultrastructural correlations. Hum Pathol. 1983 Jan;14(1):70–76. [PubMed]
  • Walts AE, Said JW, Banks-Schlegel S. Keratin and carcinoembryonic antigen in exfoliated mesothelial and malignant cells: an immunoperoxidase study. Am J Clin Pathol. 1983 Nov;80(5):671–676. [PubMed]
  • Walts AE, Said JW, Shintaku IP, Sassoon AF, Banks-Schlegel S. Keratins of different molecular weight in exfoliated mesothelial and adenocarcinoma cells--an aid to cell identification. Am J Clin Pathol. 1984 Apr;81(4):442–446. [PubMed]
  • Holden J, Churg A. Immunohistochemical staining for keratin and carcinoembryonic antigen in the diagnosis of malignant mesothelioma. Am J Surg Pathol. 1984 Apr;8(4):277–279. [PubMed]
  • Loosli H, Hurlimann J. Immunohistological study of malignant diffuse mesotheliomas of the pleura. Histopathology. 1984 Sep;8(5):793–803. [PubMed]
  • Warhol MJ. The ultrastructural localization of keratin proteins and carcinoembryonic antigen in malignant mesotheliomas. Am J Pathol. 1984 Sep;116(3):385–390. [PMC free article] [PubMed]
  • Bannasch P, Zerban H, Schmid E, Franke WW. Liver tumors distinguished by immunofluorescence microscopy with antibodies to proteins of intermediate-sized filaments. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4948–4952. [PMC free article] [PubMed]
  • Battifora H, Sun TT, Bahu RM, Rao S. The use of antikeratin antiserum as a diagnostic tool: thymoma versus lymphoma. Hum Pathol. 1980 Nov;11(6):635–641. [PubMed]
  • Schlegel R, Banks-Schlegel S, McLeod JA, Pinkus GS. Immunoperoxidase localization of keratin in human neoplasms: a preliminary survey. Am J Pathol. 1980 Oct;101(1):41–49. [PMC free article] [PubMed]
  • Gabbiani G, Kapanci Y, Barazzone P, Franke WW. Immunochemical identification of intermediate-sized filaments in human neoplastic cells. A diagnostic aid for the surgical pathologist. Am J Pathol. 1981 Sep;104(3):206–216. [PMC free article] [PubMed]
  • Osborn M, Weber K. Tumor diagnosis by intermediate filament typing: a novel tool for surgical pathology. Lab Invest. 1983 Apr;48(4):372–394. [PubMed]
  • Franke WW, Schmid E, Osborn M, Weber K. Different intermediate-sized filaments distinguished by immunofluorescence microscopy. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5034–5038. [PMC free article] [PubMed]
  • Franke WW, Weber K, Osborn M, Schmid E, Freudenstein C. Antibody to prekeratin. Decoration of tonofilament like arrays in various cells of epithelial character. Exp Cell Res. 1978 Oct 15;116(2):429–445. [PubMed]
  • Franke WW, Appelhans B, Schmid E, Freudenstein C, Osborn M, Weber K. Identification and characterization of epithelial cells in mammalian tissues by immunofluorescence microscopy using antibodies to prekeratin. Differentiation. 1979;15(1):7–25. [PubMed]
  • Franke WW, Schmid E, Weber K, Osborn M. HeLa cells contain intermediate-sized filaments of the prekeratin type. Exp Cell Res. 1979 Jan;118(1):95–109. [PubMed]
  • Sun TT, Green H. Immunofluorescent staining of keratin fibers in cultured cells. Cell. 1978 Jul;14(3):469–476. [PubMed]
  • Sun TT, Shih C, Green H. Keratin cytoskeletons in epithelial cells of internal organs. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2813–2817. [PMC free article] [PubMed]
  • Holthöfer H, Miettinen A, Paasivuo R, Lehto VP, Linder E, Alfthan O, Virtanen I. Cellular origin and differentiation of renal carcinomas. A fluorescence microscopic study with kidney-specific antibodies, antiintermediate filament antibodies, and lectins. Lab Invest. 1983 Sep;49(3):317–326. [PubMed]
  • Vogel AM, Gown AM, Caughlan J, Haas JE, Beckwith JB. Rhabdoid tumors of the kidney contain mesenchymal specific and epithelial specific intermediate filament proteins. Lab Invest. 1984 Feb;50(2):232–238. [PubMed]
  • Krepler R, Denk H, Artlieb U, Moll R. Immunocytochemistry of intermediate filament proteins present in pleomorphic adenomas of the human parotid gland: characterization of different cell types in the same tumor. Differentiation. 1982 May;21(3):191–199. [PubMed]
  • Ramaekers FC, Haag D, Kant A, Moesker O, Jap PH, Vooijs GP. Coexpression of keratin- and vimentin-type intermediate filaments in human metastatic carcinoma cells. Proc Natl Acad Sci U S A. 1983 May;80(9):2618–2622. [PMC free article] [PubMed]
  • Franke WW, Schmid E, Breitkreutz D, Lüder M, Boukamp P, Fusenig NE, Osborn M, Weber K. Simultaneous expression of two different types of intermediate sized filaments in mouse keratinocytes proliferating in vitro. Differentiation. 1979;14(1-2):35–50. [PubMed]
  • Franke WW, Schmid E, Winter S, Osborn M, Weber K. Widespread occurrence of intermediate-sized filaments of the vimentin-type in cultured cells from diverse vertebrates. Exp Cell Res. 1979 Oct 1;123(1):25–46. [PubMed]
  • Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. [PubMed]
  • Denk H, Krepler R, Lackinger E, Artlieb U, Franke WW. Biochemical and immunocytochemical analysis of the intermediate filament cytoskeleton in human hepatocellular carcinomas and in hepatic neoplastic nodules of mice. Lab Invest. 1982 Jun;46(6):584–596. [PubMed]
  • Moll R, Krepler R, Franke WW. Complex cytokeratin polypeptide patterns observed in certain human carcinomas. Differentiation. 1983;23(3):256–269. [PubMed]
  • Moll R, Levy R, Czernobilsky B, Hohlweg-Majert P, Dallenbach-Hellweg G, Franke WW. Cytokeratins of normal epithelia and some neoplasms of the female genital tract. Lab Invest. 1983 Nov;49(5):599–610. [PubMed]
  • Nagle RB, McDaniel KM, Clark VA, Payne CM. The use of antikeratin antibodies in the diagnosis of human neoplasms. Am J Clin Pathol. 1983 Apr;79(4):458–466. [PubMed]
  • Kahn HJ, Huang SN, Hanna WM, Baumal R, Phillips MJ. Immunohistochemical localization of epidermal and Mallory body cytokeratin in undifferentiated epithelial tumors. Comparison with ultrastructural features. Am J Clin Pathol. 1984 Feb;81(2):184–191. [PubMed]
  • Bejui-Thivolet F, Patricot LM, Vauzelle JL, Viac J. Keratins in malignant mesotheliomas and pleural adenocarcinomas: comparative immunohistochemical analysis with polyclonal and monoclonal antibodies. Pathol Res Pract. 1984 Sep;179(1):67–73. [PubMed]
  • LaRocca PJ, Rheinwald JG. Coexpression of simple epithelial keratins and vimentin by human mesothelium and mesothelioma in vivo and in culture. Cancer Res. 1984 Jul;44(7):2991–2999. [PubMed]
  • Blobel GA, Moll R, Franke WW, Vogt-Moykopf I. Cytokeratins in normal lung and lung carcinomas. I. Adenocarcinomas, squamous cell carcinomas and cultured cell lines. Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;45(4):407–429. [PubMed]
  • Gigi O, Geiger B, Eshhar Z, Moll R, Schmid E, Winter S, Schiller DL, Franke WW. Detection of a cytokeratin determinant common to diverse epithelial cells by a broadly cross-reacting monoclonal antibody. EMBO J. 1982;1(11):1429–1437. [PMC free article] [PubMed]
  • Franke WW, Schmid E, Freudenstein C, Appelhans B, Osborn M, Weber K, Keenan TW. Intermediate-sized filaments of the prekeratin type in myoepithelial cells. J Cell Biol. 1980 Mar;84(3):633–654. [PMC free article] [PubMed]
  • Franke WW, Schiller DL, Moll R, Winter S, Schmid E, Engelbrecht I, Denk H, Krepler R, Platzer B. Diversity of cytokeratins. Differentiation specific expression of cytokeratin polypeptides in epithelial cells and tissues. J Mol Biol. 1981 Dec 25;153(4):933–959. [PubMed]
  • Debus E, Weber K, Osborn M. Monoclonal cytokeratin antibodies that distinguish simple from stratified squamous epithelia: characterization on human tissues. EMBO J. 1982;1(12):1641–1647. [PMC free article] [PubMed]
  • Debus E, Moll R, Franke WW, Weber K, Osborn M. Immunohistochemical distinction of human carcinomas by cytokeratin typing with monoclonal antibodies. Am J Pathol. 1984 Jan;114(1):121–130. [PMC free article] [PubMed]
  • Osborn M, Debus E, Weber K. Monoclonal antibodies specific for vimentin. Eur J Cell Biol. 1984 May;34(1):137–143. [PubMed]
  • Moll R, Franke WW, Volc-Platzer B, Krepler R. Different keratin polypeptides in epidermis and other epithelia of human skin: a specific cytokeratin of molecular weight 46,000 in epithelia of the pilosebaceous tract and basal cell epitheliomas. J Cell Biol. 1982 Oct;95(1):285–295. [PMC free article] [PubMed]
  • O'Farrell PZ, Goodman HM, O'Farrell PH. High resolution two-dimensional electrophoresis of basic as well as acidic proteins. Cell. 1977 Dec;12(4):1133–1141. [PubMed]
  • Oakley BR, Kirsch DR, Morris NR. A simplified ultrasensitive silver stain for detecting proteins in polyacrylamide gels. Anal Biochem. 1980 Jul 1;105(2):361–363. [PubMed]
  • Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. [PMC free article] [PubMed]
  • Kaetzel CS, Mather IH, Bruder G, Madara PJ. Characterization of a monoclonal antibody to bovine xanthine oxidase. Biochem J. 1984 May 1;219(3):917–925. [PMC free article] [PubMed]
  • Schlegel R, Banks-Schlegel S, Pinkus GS. Immunohistochemical localization of keratin in normal human tissues. Lab Invest. 1980 Jan;42(1):91–96. [PubMed]
  • Ramaekers F, Huysmans A, Moesker O, Kant A, Jap P, Herman C, Vooijs P. Monoclonal antibody to keratin filaments, specific for glandular epithelia and their tumors. Use in surgical pathology. Lab Invest. 1983 Sep;49(3):353–361. [PubMed]
  • Franke WW, Denk H, Kalt R, Schmid E. Biochemical and immunological identification of cytokeratin proteins present in hepatocytes of mammalian liver tissue. Exp Cell Res. 1981 Feb;131(2):299–318. [PubMed]
  • Quinlan RA, Cohlberg JA, Schiller DL, Hatzfeld M, Franke WW. Heterotypic tetramer (A2D2) complexes of non-epidermal keratins isolated from cytoskeletons of rat hepatocytes and hepatoma cells. J Mol Biol. 1984 Sep 15;178(2):365–388. [PubMed]
  • Blobel GA, Gould VE, Moll R, Lee I, Huszar M, Geiger B, Franke WW. Coexpression of neuroendocrine markers and epithelial cytoskeletal proteins in bronchopulmonary neuroendocrine neoplasms. Lab Invest. 1985 Jan;52(1):39–51. [PubMed]
  • Franke WW, Moll R, Mueller H, Schmid E, Kuhn C, Krepler R, Artlieb U, Denk H. Immunocytochemical identification of epithelium-derived human tumors with antibodies to desmosomal plaque proteins. Proc Natl Acad Sci U S A. 1983 Jan;80(2):543–547. [PMC free article] [PubMed]
  • Gould VE, Battifora H. Origin and significance of the basal lamina and some interstitial fibrillar components in epithelial neoplasms. Pathol Annu. 1976;11:353–386. [PubMed]
  • Miettinen M, Virtanen I. Synovial sarcoma--a misnomer. Am J Pathol. 1984 Oct;117(1):18–25. [PMC free article] [PubMed]
  • Schmid E, Schiller DL, Grund C, Stadler J, Franke WW. Tissue type-specific expression of intermediate filament proteins in a cultured epithelial cell line from bovine mammary gland. J Cell Biol. 1983 Jan;96(1):37–50. [PMC free article] [PubMed]
  • Connell ND, Rheinwald JG. Regulation of the cytoskeleton in mesothelial cells: reversible loss of keratin and increase in vimentin during rapid growth in culture. Cell. 1983 Aug;34(1):245–253. [PubMed]
  • Virtanen I, Lehto VP, Lehtonen E, Vartio T, Stenman S, Kurki P, Wager O, Small JV, Dahl D, Badley RA. Expression of intermediate filaments in cultured cells. J Cell Sci. 1981 Aug;50:45–63. [PubMed]
  • Franke WW, Grund C, Jackson BW, Illmensee K. Formation of cytoskeletal elements during mouse embryogenesis. IV. Ultrastructure of primary mesenchymal cells and their cell-cell interactions. Differentiation. 1983;25(2):121–141. [PubMed]
  • Lane EB, Hogan BL, Kurkinen M, Garrels JI. Co-expression of vimentin and cytokeratins in parietal endoderm cells of early mouse embryo. Nature. 1983 Jun 23;303(5919):701–704. [PubMed]
  • Lehtonen E, Lehto VP, Paasivuo R, Virtanen I. Parietal and visceral endoderm differ in their expression of intermediate filaments. EMBO J. 1983;2(7):1023–1028. [PMC free article] [PubMed]
  • Cremer M, Treiss I, Cremer T, Hager D, Franke WW. Characterization of cells of amniotic fluids by immunological identification of intermediate-sized filaments: presence of cells of different tissue origin. Hum Genet. 1981;59(4):373–379. [PubMed]
  • Regauer S, Franke WW, Virtanen I. Intermediate filament cytoskeleton of amnion epithelium and cultured amnion epithelial cells: expression of epidermal cytokeratins in cells of a simple epithelium. J Cell Biol. 1985 Apr;100(4):997–1009. [PMC free article] [PubMed]
  • Czernobilsky B, Moll R, Levy R, Franke WW. Co-expression of cytokeratin and vimentin filaments in mesothelial, granulosa and rete ovarii cells of the human ovary. Eur J Cell Biol. 1985 May;37:175–190. [PubMed]
  • Miettinen M, Franssila K, Lehto VP, Paasivuo R, Virtanen I. Expression of intermediate filament proteins in thyroid gland and thyroid tumors. Lab Invest. 1984 Mar;50(3):262–270. [PubMed]
  • Wu YJ, Parker LM, Binder NE, Beckett MA, Sinard JH, Griffiths CT, Rheinwald JG. The mesothelial keratins: a new family of cytoskeletal proteins identified in cultured mesothelial cells and nonkeratinizing epithelia. Cell. 1982 Dec;31(3 Pt 2):693–703. [PubMed]
  • Sun TT, Eichner R, Nelson WG, Tseng SC, Weiss RA, Jarvinen M, Woodcock-Mitchell J. Keratin classes: molecular markers for different types of epithelial differentiation. J Invest Dermatol. 1983 Jul;81(1 Suppl):109s–115s. [PubMed]
  • Nelson WG, Battifora H, Santana H, Sun TT. Specific keratins as molecular markers for neoplasms with a stratified epithelial origin. Cancer Res. 1984 Apr;44(4):1600–1603. [PubMed]
  • Fuchs E, Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell. 1980 Apr;19(4):1033–1042. [PubMed]

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