1 Modern Pathology 2010 Vol: 24(1):90-97. DOI: 10.1038/modpathol.2010.180

Stem cell markers (cytokeratin 15, cytokeratin 19 and p63) in in situ and invasive cutaneous epithelial lesions

The inherent longetivity of stem cells causes them to be susceptible to multiple genetic hits. Thus, it is not surprising that stem cells are implicated in the etiopathogenesis of select cutaneous neoplasms. However, most studies to date are restricted to the use of a single marker (p63, cytokeratin-15 or cytokeratin-19) and do not appear to compare distribution of stem cell markers in a spectrum of cutaneous in situ versus invasive epithelial malignancies. In this study, we evaluate expression of cytokeratin-15, cytokeratin-19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis (n=29), squamous cell carcinoma in situ (n=30), bowenoid papulosis (n=15) and squamous cell carcinoma, well differentiated (n=29) in order to evaluate the role of stem cell marker expression in the grading and development of in situ and invasive malignancies. For cytokeratin-15, expression was retained in actinic keratosis (38%), squamous cell carcinoma in situ (53%) and bowenoid papulosis (60%) but appeared to be lost in squamous cell carcinoma (3%) with statistically significant differences observed between groups that retained versus those that did not (P<0.05 for all three); for cytokeratin-19, patchy yet basal expression was noted in actinic keratosis (21%), patchy and suprabasal expression was noted in squamous cell carcinoma in situ (37%), bowenoid papulosis (13%) and squamous cell carcinoma (24%) with no statistically significant differences between groups; for p63, expression was retained in actinic keratosis (90%), squamous cell carcinoma in situ (87%), bowenoid papulosis (60%) and squamous cell carcinoma (100%) with no statistically significant differences between groups. In summary, our findings expand the neoplasms which involve stem cells to include cutaneous epithelial malignancies. Differential localization of each of these markers argues in favor of stem cell heterogeneity.

Mentions
Figures
Figure 1: Representative examples of immunohistochemical staining profiles with stem cell markers CK15, CK19 and p63. (a–d) Actinic keratosis with loss of CK15 and retention of p63 (a) H&E 10 × , (b) CK15, (c) CK19 and (d) p63. Arrow in c highlights positive staining of internal control i.e. eccrine coil. (e–h) Squamous cell carcinoma in situ with retention of CK15 and p63 (e) H&E 10 × , (f) CK15, (g) CK19 and (h) p63. (i–l) Bowenoid papulosis with retention of CK15 and p63 (i) H&E 10 × , (j) CK15, (k) CK19 and (l) p63. (m–p) Squamous cell carcinoma, well differentiated with loss of CK15 and retention of p63 (m) H&E 10 × respectively, (n) CK15, (o) CK19 and (p) p63. Figure 2: Representative examples of differing immunohistochemical staining with stem cell marker CK19. (a–c) Actinic keratosis with patchy and basal CK19 staining (a) 4 × , (b) 20 × , (c) H&E 10 × . (d–f) Squamous cell carcinoma in situ with patchy and suprabasal CK19 staining (d) 4 × , (e) 20 × , (f) H&E 10 × . (g–i) Bowenoid papulosis with patchy and suprabasal CK19 staining (g) 4 × , (h) 20 × , (i) H&E 10 × . (j–l) Well-differentiated squamous cell carcinoma with patchy, suprabasal and diffuse CK19 staining (j) 4 × , (k) 20 × , (l) H&E 10 × . Figure 3: Schematic representation of stem cell marker expression most commonly observed in in situ and invasive malignancies based on findings from current study.
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References
  1. Abbas O, Mahalingam M. Epidermal stem cells: practical perspectives and potential uses. Br J Dermatol 2009;161:228-236 , .
  2. Kloepper JE, Tiede S, Brinckmann J, et al. Immunophenotyping of the human bulge region: the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche. Exp Dermatol 2008;17:592-609 , .
    • . . . Stem cells in human skin are adult or tissue-specific stem cells that maintain normal tissue turnover and repair by replenishing specialized differentiated cells.1 Their main characteristics include the ability to renew indefinitely (self-renewal) and multipotency or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.1, 2 Given that the existence of varied populations of stem cells in human skin with diverse differentiation capacities is now indisputable, more recent evidence implicating stem cells in the etiopathogenesis of cutaneous neoplasms is not entirely surprising.3, 4, 5 Properties of self-renewal, increased profilerative capacity and multipotency, inherent to a normal stem cell, are believed to be of relevance in tumor maintenance.1, 3, 4, 5 There are some who believe that, in select cancers, the lesional neoplastic cells may actually originate from mutated normal stem cells.1, 3, 4, 5 . . .
    • . . . Studies first suggested cytokeratin-15 (CK15) as a specific marker of stem cells when a restricted CK15-expression was demonstrated in cells of the bulge region of murine and human hair follicles.1, 6, 7 However, our own and other studies have shown that CK15 expression is not only restricted to the bulge, but also involves part or all of the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis, and even eccrine glands.1, 2, 8, 9 Designation of CK15 as a stem cell marker is based on evidence indicating that CK15 positive cells in the bulge region and interfollicular epidermis possess characteristics of stem cell such as self-renewal and multipotency.1, 6, 7 Expression of CK15 in the mitotically active basal cell layers of the hair follicle suggests that CK15 may have a role in regulating an early stage of keratinocytes differentiation and one that predates the fate of a cell becoming epidermal or hair-like.1 . . .
    • . . . Similar to expression of CK15, expression of cytokeratin-19 (CK19) was first thought to be restricted to the bulge region of the hair follicle, but more recent studies have shown up-regulated expression of CK19 in the outermost layer of the outer root sheath in the bulge region of the human hair follicle as well as the outer root sheath proximal and distal to the bulge.1, 2, 10, 11 In vivo and in vitro studies have shown that CK19 may be important in the commitment of stem cells to an epidermal cell fate and differentiation.1 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  3. Kamstrup MR, Gniadecki R, Skovgaard GL. Putative cancer stem cells in cutaneous malignancies. Exp Dermatol 2007;16:297-301 , .
    • . . . Stem cells in human skin are adult or tissue-specific stem cells that maintain normal tissue turnover and repair by replenishing specialized differentiated cells.1 Their main characteristics include the ability to renew indefinitely (self-renewal) and multipotency or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.1, 2 Given that the existence of varied populations of stem cells in human skin with diverse differentiation capacities is now indisputable, more recent evidence implicating stem cells in the etiopathogenesis of cutaneous neoplasms is not entirely surprising.3, 4, 5 Properties of self-renewal, increased profilerative capacity and multipotency, inherent to a normal stem cell, are believed to be of relevance in tumor maintenance.1, 3, 4, 5 There are some who believe that, in select cancers, the lesional neoplastic cells may actually originate from mutated normal stem cells.1, 3, 4, 5 . . .
    • . . . Stem cells in human skin are adult or tissue-specific stem cells that maintain normal tissue turnover and repair by replenishing specialized differentiated cells.1 Their main characteristics include the ability to renew indefinitely (self-renewal) and multipotency or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.1, 2 Given that the existence of varied populations of stem cells in human skin with diverse differentiation capacities is now indisputable, more recent evidence implicating stem cells in the etiopathogenesis of cutaneous neoplasms is not entirely surprising.3, 4, 5 Properties of self-renewal, increased profilerative capacity and multipotency, inherent to a normal stem cell, are believed to be of relevance in tumor maintenance.1, 3, 4, 5 There are some who believe that, in select cancers, the lesional neoplastic cells may actually originate from mutated normal stem cells.1 . . .
  4. Klein WM, Wu BP, Zhao S, et al. Increased expression of stem cell markers in malignant melanoma. Mod Pathol 2007;20:102-107 , .
    • . . . Stem cells in human skin are adult or tissue-specific stem cells that maintain normal tissue turnover and repair by replenishing specialized differentiated cells.1 Their main characteristics include the ability to renew indefinitely (self-renewal) and multipotency or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.1, 2 Given that the existence of varied populations of stem cells in human skin with diverse differentiation capacities is now indisputable, more recent evidence implicating stem cells in the etiopathogenesis of cutaneous neoplasms is not entirely surprising.3, 4, 5 Properties of self-renewal, increased profilerative capacity and multipotency, inherent to a normal stem cell, are believed to be of relevance in tumor maintenance.1, 3 . . .
  5. Kanoh M, Amoh Y, Sato Y, et al. Expression of the hair stem cell-specific marker nestin in epidermal and follicular tumors. Eur J Dermatol 2008;18:518-523 , .
    • . . . Stem cells in human skin are adult or tissue-specific stem cells that maintain normal tissue turnover and repair by replenishing specialized differentiated cells.1 Their main characteristics include the ability to renew indefinitely (self-renewal) and multipotency or the capacity to differentiate into multiple specialized cell lineages of the specific tissue.1, 2 Given that the existence of varied populations of stem cells in human skin with diverse differentiation capacities is now indisputable, more recent evidence implicating stem cells in the etiopathogenesis of cutaneous neoplasms is not entirely surprising.3, 4, 5 Properties of self-renewal, increased profilerative capacity and multipotency, inherent to a normal stem cell, are believed to be of relevance in tumor maintenance.1, 3, 4 . . .
  6. Braun KM, Niemann C, Jensen UB, et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in whole mounts of mouse epidermis. Development 2003;130:5241-5255 , .
    • . . . Studies first suggested cytokeratin-15 (CK15) as a specific marker of stem cells when a restricted CK15-expression was demonstrated in cells of the bulge region of murine and human hair follicles.1, 6, 7 However, our own and other studies have shown that CK15 expression is not only restricted to the bulge, but also involves part or all of the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis, and even eccrine glands.1, 2, 8, 9 Designation of CK15 as a stem cell marker is based on evidence indicating that CK15 positive cells in the bulge region and interfollicular epidermis possess characteristics of stem cell such as self-renewal and multipotency.1 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  7. Lyle S, Christofidou-Solomidou M, Liu Y, et al. The C8 144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111:3179-3188 , .
    • . . . Studies first suggested cytokeratin-15 (CK15) as a specific marker of stem cells when a restricted CK15-expression was demonstrated in cells of the bulge region of murine and human hair follicles.1, 6, 7 However, our own and other studies have shown that CK15 expression is not only restricted to the bulge, but also involves part or all of the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis, and even eccrine glands.1, 2, 8, 9 Designation of CK15 as a stem cell marker is based on evidence indicating that CK15 positive cells in the bulge region and interfollicular epidermis possess characteristics of stem cell such as self-renewal and multipotency.1, 6 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
    • . . . Cytokeratin 15, targeting keratinocytes in the bulge region, highlights a population of cells in follicular bulge with characteristics of stem cells.7 These cells appear to be not merely confined to the bulge region but have been identified in fetal and adult sebaceous glands as well as a spectrum of benign and malignant cutaneous neoplasms.7, 16, 17 Based on expression of CK15 in tumors with follicular differentiation, it is believed to be a relatively specific marker for neoplasms of putative hair follicle origin . . .
  8. Hoang MP, Keady M, Mahalingam M. Stem cell markers (cytokeratin 15, CD34 and nestin) in primary scarring and nonscarring alopecia. Br J Dermatol 2009;160:609-615 , .
    • . . . Studies first suggested cytokeratin-15 (CK15) as a specific marker of stem cells when a restricted CK15-expression was demonstrated in cells of the bulge region of murine and human hair follicles.1, 6, 7 However, our own and other studies have shown that CK15 expression is not only restricted to the bulge, but also involves part or all of the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis, and even eccrine glands.1, 2, 8, 9 Designation of CK15 as a stem cell marker is based on evidence indicating that CK15 positive cells in the bulge region and interfollicular epidermis possess characteristics of stem cell such as self-renewal and multipotency.1, 6, 7 Expression of CK15 in the mitotically active basal cell layers of the hair follicle suggests that CK15 may have a role in regulating an early stage of keratinocytes differentiation and one that predates the fate of a cell becoming epidermal or hair-like.1, 2 . . .
    • . . . In sum, we confirm that there appears to be a significant presence of stem or progenitor cells in cutaneous in situ and invasive epithelial malignancies, reaffirming the theory that the epidermis contains hundreds of clonogenic keratinocytes.8, 40 Differential localization of these three populations of stem cells argues in favor of stem cell heterogeneity, a feature already confirmed in follicular stem cells both by us and others.1, 8 The profound cellular heterogeneity also raises the possibility that cells within these different compartments most likely mirror individual developmental pathways in acquisition of the malignant phenotype, which is perhaps why only select stem cells play a role in the grading and development of in situ versus invasive malignancies (Figure 3). . . .
  9. Pozdnyakova O, Mahalingam M. Involvement of the bulge region in primary scarring alopecia. J Cutan Pathol 2008;35:922-925 , .
    • . . . Studies first suggested cytokeratin-15 (CK15) as a specific marker of stem cells when a restricted CK15-expression was demonstrated in cells of the bulge region of murine and human hair follicles.1, 6, 7 However, our own and other studies have shown that CK15 expression is not only restricted to the bulge, but also involves part or all of the outermost layer of the outer root sheath of the human hair follicle, the basal layer of the epidermis, and even eccrine glands.1, 2, 8, 9 Designation of CK15 as a stem cell marker is based on evidence indicating that CK15 positive cells in the bulge region and interfollicular epidermis possess characteristics of stem cell such as self-renewal and multipotency.1, 6, 7 Expression of CK15 in the mitotically active basal cell layers of the hair follicle suggests that CK15 may have a role in regulating an early stage of keratinocytes differentiation and one that predates the fate of a cell becoming epidermal or hair-like.1, 2 . . .
  10. Lyle S, Christofidou-Solomidou M, Liu Y, et al. Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype. J Investig Dermatol Symp Proc 1999;4:296-301 , .
    • . . . Similar to expression of CK15, expression of cytokeratin-19 (CK19) was first thought to be restricted to the bulge region of the hair follicle, but more recent studies have shown up-regulated expression of CK19 in the outermost layer of the outer root sheath in the bulge region of the human hair follicle as well as the outer root sheath proximal and distal to the bulge.1, 2, 10, 11 In vivo and in vitro studies have shown that CK19 may be important in the commitment of stem cells to an epidermal cell fate and differentiation.1, 2, 12 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  11. Michel M, Török N, Godbout MJ, et al. Keratin 19 as a biochemical marker of skin stem cells in vivo and in vitro: keratin 19 expressing cells are differentially localized in function of anatomic sites, and their number varies with donor age and culture stage. J Cell Sci 1996;109:1017-1028 , .
    • . . . Similar to expression of CK15, expression of cytokeratin-19 (CK19) was first thought to be restricted to the bulge region of the hair follicle, but more recent studies have shown up-regulated expression of CK19 in the outermost layer of the outer root sheath in the bulge region of the human hair follicle as well as the outer root sheath proximal and distal to the bulge.1, 2, 10, 11 In vivo and in vitro studies have shown that CK19 may be important in the commitment of stem cells to an epidermal cell fate and differentiation.1, 2, 12 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  12. Morris RJ. A perspective on keratinocyte stem cells as targets for skin carcinogenesis. Differentiation 2004;72:381-386 , .
  13. Pellegrini G, Dellambra E, Golisano O, et al. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 2001;98:3156-3161 , .
    • . . . Transcription factor p63 is considered to be a homologue of the p53 tumor suppressor gene.13, 14, 15 Although in vitro studies have initially identified p63 as a keratinocyte stem cell marker, more recent in vivo studies have shown that p63 expression is not restricted to epidermal stem cells but also involves basal and suprabasal epidermal cells as well as the outer root sheath and hair matrix of hair follicles.13, 14, 15 Thus, it may be a marker of transient amplifying cells rather than of stem cells . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  14. Reis-Filho JS, Torio B, Albergaria A, et al. p63 expression in normal skin and usual cutaneous carcinomas. J Cutan Pathol 2002;29:517-523 , .
    • . . . Transcription factor p63 is considered to be a homologue of the p53 tumor suppressor gene.13, 14, 15 Although in vitro studies have initially identified p63 as a keratinocyte stem cell marker, more recent in vivo studies have shown that p63 expression is not restricted to epidermal stem cells but also involves basal and suprabasal epidermal cells as well as the outer root sheath and hair matrix of hair follicles.13 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  15. Koster MI, Kim S, Roop DR. p63 deficiency: a failure of lineage commitment or stem cell maintenance? J Investig Dermatol Symp Proc 2005;10:118-123 , .
    • . . . Transcription factor p63 is considered to be a homologue of the p53 tumor suppressor gene.13, 14, 15 Although in vitro studies have initially identified p63 as a keratinocyte stem cell marker, more recent in vivo studies have shown that p63 expression is not restricted to epidermal stem cells but also involves basal and suprabasal epidermal cells as well as the outer root sheath and hair matrix of hair follicles.13, 14 . . .
    • . . . Despite the promiscuous distribution of CK15, CK19 and p63, these markers are still being used as stem cell markers, based on irrefutable evidence that a proportion of the cells in the skin that stain positively with these markers have stem cell characteristics of self-renewal and multipotency.1, 2, 6, 7, 10, 11, 13, 14, 15 In this study, we perform immunohistochemical stains to CK15, CK19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis, squamous cell carcinoma in situ, bowenoid papulosis, and squamous cell carcinoma in order to determine the following: . . .
  16. Jih DM, Lyle S, Elenitsas R, et al. Cytokeratin 15 expression in trichoepitheliomas and a subset of basal cell carcinomas suggests they originate from hair follicle stem cells. J Cutan Pathol 1999;26:113-118 , .
    • . . . Cytokeratin 15, targeting keratinocytes in the bulge region, highlights a population of cells in follicular bulge with characteristics of stem cells.7 These cells appear to be not merely confined to the bulge region but have been identified in fetal and adult sebaceous glands as well as a spectrum of benign and malignant cutaneous neoplasms.7, 16, 17 Based on expression of CK15 in tumors with follicular differentiation, it is believed to be a relatively specific marker for neoplasms of putative hair follicle origin . . .
    • . . . In keeping with this hypothesis, we have previously reported expression of CK15 in microcystic adnexal carcinoma and desmoplastic trichepithelioma, with negative expression in squamous cell carcinoma including squamous cell carcinoma with ductal differentiation.16, 18 Findings from the current study confirm this in that we found loss of CK15 in 97% of cases of squamous cell carcinoma . . .
  17. Bieniek R, Lazar AJ, Photopoulos C, et al. Sebaceous tumours contain a subpopulation of cells expressing the keratin 15 stem cell marker. Br J Dermatol 2007;156:378-380 , .
    • . . . Cytokeratin 15, targeting keratinocytes in the bulge region, highlights a population of cells in follicular bulge with characteristics of stem cells.7 These cells appear to be not merely confined to the bulge region but have been identified in fetal and adult sebaceous glands as well as a spectrum of benign and malignant cutaneous neoplasms.7, 16, 17 Based on expression of CK15 in tumors with follicular differentiation, it is believed to be a relatively specific marker for neoplasms of putative hair follicle origin . . .
  18. Hoang MP, Dresser KA, Kapur P, et al. Microcystic adnexal carcinoma: an immunohistochemical reappraisal. Mod Pathol 2008;21:178-185 , .
    • . . . In keeping with this hypothesis, we have previously reported expression of CK15 in microcystic adnexal carcinoma and desmoplastic trichepithelioma, with negative expression in squamous cell carcinoma including squamous cell carcinoma with ductal differentiation.16, 18 Findings from the current study confirm this in that we found loss of CK15 in 97% of cases of squamous cell carcinoma . . .
  19. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 1996;122:135-140 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  20. Tiede S, Kloepper JE, Bodo E, et al. Hair follicle stem cells: walking the maze. Eur J Cell Biol 2007;86:355-376 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  21. Li L, Xie T. Stem cell niche: structure and function. Annu Rev Cell Dev Biol 2005;21:605-631 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  22. Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 2005;437:275-280 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  23. Sirard C, Lapidot T, Vormoor J, et al. Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. Blood 1996;87:1539-1548 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  24. Cobaleda C, Gutiérrez-Cianca N, Pérez-Losada J, et al. A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 2000;95:1007-1013 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  25. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-5828 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  26. Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994;1:661-673 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  27. Oliveira LR, Jeffrey SS, Ribeiro-Silva A. Stem cells in human breast cancer. Histol Histopathol 2010;25:371-385 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  28. Park DM, Rich JN. Biology of glioma cancer stem cells. Mol Cells 2009;28:7-12 , .
    • . . . What does this mean? A universally accepted paradigm is that to attain the complete transformed phenotype, a cell must accumulate multiple ‘hits’ in the form of progressive alterations within its chromosomes and irreversible changes in a number of genes.19 A stem cell with its lifespan comparable to the organism and inherent characteristic of ‘slow cycling’ is the perfect candidate for accumulations of such hits.20, 21, 22 Evidence for the role of stem cells in cancers is continually mounting with cells with stem cell-like features being identified in several malignancies.23, 24, 25 Examples include identification of leukemia cell lines with stem cell-like features, breast cancer stem cells and glial tumor stem cells with the capacity of differentiating into both glial and neuronal cell forms.26, 27, 28 Based on CK15 expression, findings from the current study expand the spectrum of lesions incriminating stem cells to include atypical in situ epithelial subgroups such as actinic keratosis, squamous cell carcinoma in situ and bowenoid papulosis . . .
  29. Zhong LP, Chen WT, Zhang CP, et al. Increased CK19 expression correlated with pathologic differentiation grade and prognosis in oral squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:377-384 , .
    • . . . Aberrant expression of CK19 has been reported in oral and, more recently, in cutaneous squamous cell carcinoma and pagetoid squamous cell carcinoma in situ.29, 30, 31In oral squamous cell carcinoma, CK19 expression correlated significantly with pathologic grade of differentiation in a study using immunohistochemistry and RT-PCR for CK19 mRNA detection.29 Similar to this, in cutaneous squamous cell carcinoma, Chen et al noted a significant increased expression of CK19 in cutaneous squamous cell carcinoma compared to actinic keratoses and Bowen's disease and, significant differences were also noted between CK19 positive populations harbored in Bowen's disease and actinic keratosis with higher numbers of CK19 positive cells noted in the former.32 In contrast, we observed no significant differences in CK19 expression between actinic keratosis (21%), squamous cell carcinoma in situ (37%), bowenoid papulosis (13%), and squamous cell carcinoma (24%) . . .
  30. Takeda T, Sugihara K, Hirayama Y, et al. Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias. J Oral Pathol Med 2006;35:369-375 , .
    • . . . Aberrant expression of CK19 has been reported in oral and, more recently, in cutaneous squamous cell carcinoma and pagetoid squamous cell carcinoma in situ.29, 30, 31In oral squamous cell carcinoma, CK19 expression correlated significantly with pathologic grade of differentiation in a study using immunohistochemistry and RT-PCR for CK19 mRNA detection.29 Similar to this, in cutaneous squamous cell carcinoma, Chen et al noted a significant increased expression of CK19 in cutaneous squamous cell carcinoma compared to actinic keratoses and Bowen's disease and, significant differences were also noted between CK19 positive populations harbored in Bowen's disease and actinic keratosis with higher numbers of CK19 positive cells noted in the former.32 In contrast, we observed no significant differences in CK19 expression between actinic keratosis (21%), squamous cell carcinoma in situ (37%), bowenoid papulosis (13%), and squamous cell carcinoma (24%) . . .
  31. Raju RR, Goldblum JR, Hart WR. Pagetoid squamous cell carcinoma in situ (pagetoid Bowen's disease) of the external genitalia. Int J Gynecol Pathol 2003;22:127-135 , .
    • . . . Aberrant expression of CK19 has been reported in oral and, more recently, in cutaneous squamous cell carcinoma and pagetoid squamous cell carcinoma in situ.29, 30, 31In oral squamous cell carcinoma, CK19 expression correlated significantly with pathologic grade of differentiation in a study using immunohistochemistry and RT-PCR for CK19 mRNA detection.29 Similar to this, in cutaneous squamous cell carcinoma, Chen et al noted a significant increased expression of CK19 in cutaneous squamous cell carcinoma compared to actinic keratoses and Bowen's disease and, significant differences were also noted between CK19 positive populations harbored in Bowen's disease and actinic keratosis with higher numbers of CK19 positive cells noted in the former.32 In contrast, we observed no significant differences in CK19 expression between actinic keratosis (21%), squamous cell carcinoma in situ (37%), bowenoid papulosis (13%), and squamous cell carcinoma (24%) . . .
  32. Chen S, Takahara M, Kido M, et al. Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma. Br J Dermatol 2008;159:952-955 , .
    • . . . Aberrant expression of CK19 has been reported in oral and, more recently, in cutaneous squamous cell carcinoma and pagetoid squamous cell carcinoma in situ.29, 30, 31In oral squamous cell carcinoma, CK19 expression correlated significantly with pathologic grade of differentiation in a study using immunohistochemistry and RT-PCR for CK19 mRNA detection.29 Similar to this, in cutaneous squamous cell carcinoma, Chen et al noted a significant increased expression of CK19 in cutaneous squamous cell carcinoma compared to actinic keratoses and Bowen's disease and, significant differences were also noted between CK19 positive populations harbored in Bowen's disease and actinic keratosis with higher numbers of CK19 positive cells noted in the former.32 In contrast, we observed no significant differences in CK19 expression between actinic keratosis (21%), squamous cell carcinoma in situ (37%), bowenoid papulosis (13%), and squamous cell carcinoma (24%) . . .
    • . . . However, the scoring system incorporated by us appears to be different from the one utilized by Chen et al with different cut-offs.32 In the study by Chen et al, staining of even 1% was considered positive in the series, while we considered >6% to be positive . . .
    • . . . On a minor note, Chen et al also found a correlation between CK19 expression and the Ki-67 labeling index—a finding that is difficult to reconcile in light of the fact that stem cells are typically quiescent ‘label retaining cells’ while Ki-67 is a nuclear matrix protein that is expressed only in cycling cells not in cells that are resting.32Of interest, in the 26 cases that demonstrated CK19 expression in our study, concurrent loss of CK15 was observed in 13 (50%; 2/6 cases of actinic keratosis, 5/10 cases of squamous cell carcinoma in situ and 6/7 cases of squamous cell carcinoma) . . .
  33. Martens JE, Arends J, Van der Linden PJ, et al. Cytokeratin 17 and p63 are markers of the HPV target cell, the cervical stem cell. Anticancer Res 2004;24:771-775 , .
    • . . . Endocervical reserve cells, the putative target of HPV infection, have been shown to express p63 and CK17, both putatively identifying cervical stem cells.33 Findings from the current study imply that tentative HPV targets might include CK19 positive stem cells . . .
  34. Levrero M, De Laurenzi V, Costanzo A, et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 2000;113:1661-1670 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  35. Pellegrini G, Dellambra E, Golisano O, et al. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 2001;98:3156-3161 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  36. Reis-Filho JS, Schmitt FC. Taking advantage of basic research: p63 is a reliable myoepithelial and stem cell marker. Adv Anat Pathol 2002;9:280-289 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  37. Tsujita-Kyutoku M, Kiuchi K, Danbara N, et al. p63 expression in normal human epidermis and epidermal appendages and their tumors. J Cutan Pathol 2003;30:11-17 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  38. Wrone DA, Yoo S, Chipps LK, Moy RL. The expression of p63 in actinic keratoses, seborrheic keratosis, and cutaneous squamous cell carcinomas. Dermatol Surg 2004;30:1299-1302 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  39. Dotto JE, Glusac EJ. p63 is a useful marker for cutaneous spindle cell squamous cell carcinoma. J Cutan Pathol 2006;33:413-417 , .
    • . . . P63, a nuclear transcription factor that triggers keratinocyte differentiation, is down-regulated in terminally differentiated cells.14, 34, 35 In previous studies, p63 expression has been noted in epidermal and adnexal basal/myoepithelial cells.36, 37 Several studies have shown an increased expression of p63 in cutaneous squamous cell carcinoma, especially in the undifferentiated component of the tumors, suggesting a role for p63 in maintenance of the undifferentiated state of the tumor cells.14, 38, 39 Similar to previous studies, we observed p63 expression in all cases of squamous cell carcinoma but also noted expression in most cases of actinic keratosis (90%), squamous cell carcinoma in situ (87%), and bowenoid papulosis cases (60%), with no statistically significant differences observed between different subgroups. . . .
  40. Hoffman RM. The pluripotency of hair follicle stem cells. Cell Cycle 2006;5:232-233 , .
    • . . . In sum, we confirm that there appears to be a significant presence of stem or progenitor cells in cutaneous in situ and invasive epithelial malignancies, reaffirming the theory that the epidermis contains hundreds of clonogenic keratinocytes.8, 40 Differential localization of these three populations of stem cells argues in favor of stem cell heterogeneity, a feature already confirmed in follicular stem cells both by us and others.1, 8 The profound cellular heterogeneity also raises the possibility that cells within these different compartments most likely mirror individual developmental pathways in acquisition of the malignant phenotype, which is perhaps why only select stem cells play a role in the grading and development of in situ versus invasive malignancies (Figure 3). . . .
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