Introduction 1 1 1 1 1 2008 2007 2007 2007 2007 Fig. 1 a red b red green c arrowhead d black arrowhead white arrowhead  1952 1986 2007 1976 1978 1981 1982b 1982 1982 1982b 1990 1992 1992a b 1995 1998 2002 2003 2006 2005 1988a 1999 2001 2004 2005 2007 2006 2006 1 1 genes KRT1 KRT2 KRT3 2006 2 Fig. 2 a arrow b 2006  Table 1 2006  1982b 1990 KRT”) KRT20 2004 2007 1982 2 1990 1 1 2004 2007 2007 2004 2007 http://www.interfil.org 2007 2007 2003 2000 2000 2003b 2006 2000 2003a 2006 2007 2007 1990 1994 1994 1998 2002b 2004 2007 1999 2004 2007 Human keratins and their expression patterns 2 3 Table 2 Characteristic expression patterns of typical keratins in selected human normal epithelial tissues  Keratins of simple epithelia Keratins of stratified epithelia Type II keratins: K8 K7  K5  K6  K1 K2 K4 Type I keratins: K18 K19 K10 K14 K15 K16 K17 K10 K9 K13 a All cells          b All cells K7 and K19 in all cells  Sparse cells   Sparse cells   K4 heterogeneously in pancreatic ducts Gastrointestinal epithelia All cells K19 in all cells c       K4 heterogeneously in luminal cells; K13 in sparse luminal cells Respiratory epithelium Predominantly luminal cells K7 in luminal cells; K19 in all cells  Predominantly basal cells  K6 in basal cells Predominantly basal cells    Urothelium All cells K7 and K19 in all cells Luminal (umbrella) cells Basal cells   Few basal cells   K13 in all basal and intermediate cells Non-keratinizing stratified squamous epithelia Some basal cells K19 in many basal cells  Basal cell layer (predominantly) Basal cells layer Suprabasal compartment  At some sites focal expression in suprabasal cells  Suprabasal compartment Epidermis    Predominantly basal cell layer Basal cell layer   Suprabasal compartment d  5 6 a b c d Table 3 Characteristic expression patterns of typical keratins in selected human carcinomas  1998 2002b filled circle open dotted circle open circle a b c d e Simple (one-layered) epithelia K8/K18: primary keratins of simple epithelial cells 1981 1982b 2003 1980 1988 1988 1993 1985 1987 1987 1989 1989 1989 1993 1995 1988 1989 1991 2007 2007 2007 2003 2000 2003b 2000 2003a 2006 2001 2002 2006 2007 2007 2003a 2004 2004 2007 1984 1991 1984 1996 2007 1999 2004 2007 K7/K19: secondary keratins of simple epithelial cells Apart from K8/K18, keratins K7 and K19 are “additional” (secondary) and also widely distributed simple-epithelial keratins which are frequently but not always co-expressed. They typically occur as a keratin pair in simple ductal epithelia such as bile and pancreatic ducts (“ductal-type” keratins). However, in several epithelia lacking K7 such as intestinal epithelium, the type I keratin K19 must form a pair with the sole type II keratin K8. 1986 1989 1985 1986 1986 1999 2000 2004 1991 1989 1998 1989 1993 1988 2006 3 2004 2007 1982b 1990 1988 2002 2004 1991 3 3 1992 1993b 2000 2002b 2002 1998 2005 1992 1993b 2000 2002b 2002 2006 Fig. 3 a b − + c d left d right e f a d b c e f  K20: keratin of gastrointestinal epithelium, urothelium, and Merkel cells i t 1982b 1990 3 3 1993b 3 1992 1995 2004 2003 2006 1992 1993 1992 3 1992 1993b 1995 2000 2002b 2006 3 1992 1995 2000 − + 3 1996 1998 1998 2005 2006 2007 1999 Stratified epithelia K5/K14: major keratins of basal keratinocytes 1982b 4 1980 2007 1990 1989 Fig. 4 a b c d e f a b c e f  1989 1990 1989 1995 2002 2004 2004 1991 4 1982b 1989 1998 2002a b 4 4 + − 1998 2002a + − 1989 1998 2006 4 1998 2002a 2002b 2000 2002 2003 K15: basal keratinocyte keratin and hair follicle stem cell “marker” 1982b c 1988 1993a 1995 1999 4 1995 1999 1995 1999 1998 1999 1993a 2001 2008 1999 2000 1 1999 1999 2000 2001 1999 K6/K16: keratins of hyperproliferative keratinocytes inducible in “activated” epidermis 1982b c 2005 1998 2005 2007 1988b 2004 2004 1982b 1982b 2005 2005 2006 1995 2003 2005 1995 1998 1995 1984 1996 2001 2000 2000 2001 2001 2002 2003 1995 2004 Thus, K6/K16 are constitutive keratins of stratified epithelia built up by keratinocytes of relatively high proliferative state such as mucosal tissues, palmoplantar epidermis, and certain skin appendages. On the other hand, they are “stress-inducible” keratins in interfollicular epidermis, being rapidly switched on e.g. after injury and UV-irradiation or being present also in inflammation and in hyperproliferative disorders. 5 1995 2005 2006 2003 2005 2005 Fig. 5 a a′ b b′′ lc igd idd sdr ied/ac asterisks sb ss sg sc gl c d d′′ arrows e f Bars  1991 1992 1982b 1998 4 1993 1991 1998 K17: keratin of basal/myoepithelial cells and inducible in “activated” keratinocytes 1982c 1982b 1983 1989 1989 1992 1982c 1998 2005 2006 2006 2000 2004 1993a 1982a 1984 1996 2003 2006 2005 2002 2006 2004 2004 2005 1982b 1983 2002b 1987 1999 1993 1998 2002b 1998 K1/K10: major keratins of keratinocyte differentiation and keratinization 4 1980 1982b 1982 1984 1987 1988 1 1999 2004 2004 2007 2004 2004 2004 1992 1996 1998 5 2005 1989 1998 1998 4 1991 K9: palmoplantar epidermal differentiation keratin 1987 1993 1987 1998 1994 1994 2004 1993 2005 2006 2008 1998 1999 2007 1971 2008 K2: keratin of highly differentiated, advanced epidermal keratinocytes 1 1992a 2004 2005 2006 2008 K3/K12: keratins of the corneal epithelium 1986 2002 1997 2004 1996 1992b 1993 K4/K13: keratins of mucosal stratified squamous epithelial cells 1982b 1985 1986 1986 1988b 1986 1993 2004 1989 1998 1998 1988b 1998 1992 1993 1998 1998 K76, K77: keratins with very special expression sites 1992b 5 2005 2005 5 2008 5 K25, K26, K27, K28, K71, K72, K73, K74, K75: hair follicle-specific epithelial keratins 2005 2006 2007 1992a b 1998 6 1998 1998 2005 2003 2007 2005 2004 2007 2002 2001 Fig. 6 a cl med b c icu IRS d cu e f co g co dp ORS h i 2006  1 1 6 6 6 2002 2003 2006 2005 6 2006 2007 2007 2004 2006 K31, K32, K33a, K33b, K34, K35, K36, K37, K38, K39, K40, K81, K82, K83, K84, K85, K86: keratins of the hair fiber (hair keratins) 1953 1959 1965 1968 2006 1986 1988a b 2004 2005 1999 2001 2007 2005 2006 1 1999 2001 2007 2005 2006 1 1999 2001 2006 1 6 1999 2001 2007 2005 2007 6 6 6 2005 2007 2005 6 2004 2007 1988b 1997 2007 2006 2007 1988a 1997 2001 2004 2006 2004 2006 K23, K24, K78, K79, K80: keratins with still unknown expression pattern 2001 2004 2005 2005 Keratins as diagnostic markers in tumor pathology 2002b 2006 Adenocarcinomas 3 colorectal adenocarcinomas 3 − + 3 1992 1995 1998 2002b 2005 2004 2006 Adenocarcinomas of the stomach 1998 2002b adenocarcinomas of the pancreas the biliary tract 3 3 1998 2002b 1992 1993 1998 + − adenocarcinomas of the ovary the endometrium the lung breast carcinomas 1986 1998 1995 1996 2004 2001 1983 1991 1987 1998 2005 2007 2002 2005 renal cell carcinomas 1988 1993 2002b 2005 2007 1988 2007 malignant mesotheliomas 1989 1998 2002a 2006 Neuroendocrine tumors 1992 2001 2007 2007 Transitional cell carcinomas 1998 1999 1992 1999 Squamous cell carcinomas 1998 4 4 1998 2006 1998 Perspectives 2006 2007 2006 One may also expect for the future that the diagnostic application of keratins, although already established in tumor pathology, will be further refined and extended. Examples of very recent new developments in tumor classification are the recognition of the basal-like subtype of breast cancer on the basis of the expression of K5 and the prognostic relevance of K19 in endocrine pancreatic tumors. At the moment, the panel of keratins introduced into routine diagnosis as histopathological tumor markers is distinctly small, essentially consisting of K5, K7, K8/K18, K19, and K20. Furthermore, the expression patterns of a battery of special keratins were detected only in the last few years and these keratins are just started to be involved into tumor diagnostic studies. Not to forget that at the time 5 out of the 54 human keratins are still uncharacterized in their expression sites and patterns and possibly, their expression in neoplasia might have a potential as diagnostic markers. Since all keratins have an exquisite cell type- and differentiation stage-specific regulation and expression pattern, it might well be that upon future research further keratins will be introduced as markers for certain diagnostic questions in pathology to widen and to refine the diagnostic potential of keratins.