 |
|
Retinoids Strongly and Selectively Correlate With Keratin 13 and Not Keratin 19 Expression in Cutaneous Warts of Renal Transplant Recipients
Willeke A. M. Blokx, MD;
Jurgen V. Smit, MD;
Elke M .G. J. de Jong, MD, PhD;
Monique M. G. M. Link;
Peter C. M. van de Kerkhof, MD, PhD;
Dirk J. Ruiter, MD, PhD
Arch Dermatol. 2002;138:61-65.
ABSTRACT
| |
Objective To compare the expression of keratin (K) 13 and K19 in cutaneous warts
of renal transplant recipients (RTRs) and immunocompetent individuals (ICIs).
Design Retrospective, nonrandomized immunohistochemical study.
Patients and Methods Specimens from cutaneous warts of RTRs and ICIs were retrieved from
the archives of the Department of Pathology, University Medical Center St
Radboud, Nijmegen, the Netherlands. Twenty-one warts from RTRs and 21 from
ICIs were examined. Nine RTRs (10 specimens) received either systemic acitretin
or topical all-trans retinoic acid, and their effect
on both keratins was assessed.
Main Outcome Measures Frequency and expression patterns of K13 and K19 in warts of RTRs vs
ICIs and the effect of retinoids.
Results A significantly higher percentage of warts of RTRs expressed K13 compared
with warts of ICIs (86% vs 14%, 18 vs 3 cases, respectively; P<.001). In warts of RTRs, retinoid treatment correlated significantly
with a particularly strong, segmental K13 expression pattern, which we termed zebroid. Without use of retinoids, K13 was mostly restricted
to suprabasal single cells. Keratin 19 was absent in all warts of both patient
groups.
Conclusions Retinoids strongly correlate with K13 in a characteristic zebroid pattern
in warts of RTRs, making K13 a sensitive marker for retinoid bioactivity in
skin (lesions) of RTRs. In non–retinoid-treated RTRs, K13 is also frequently
found in warts but without the dramatic zebroid pattern noted in retinoid-treated
warts.
INTRODUCTION
EPITHELIAL KERATINS comprise a heterogenous group of acidic (type I)
and neutral-to-basic (type II) proteins. As a general rule, they are coexpressed
in specific pairings, each pair consisting of a type I and a type II keratin
(K). For instance, in normal adult skin, keratin pairs K5/K14 and K1/K10 predominate
in the basal layer and the suprabasal compartment, respectively.1
The type I keratins K13 and K19 are usually expressed separately in
adult epithelia. Combined expression occurs only in fetal skin. Both keratins
are thought to be absent in normal skin of adults except at certain body sites,
such as the penile foreskin, which still contains K13. Furthermore, K13 is
abundantly present in adults in internal stratified epithelia and is associated
(with terminal differentiation) with suprabasal expression.1-4
Expression of K19 in adults is found in simple epithelia, such as most glandular
epithelia.
In the past few years, several murine and in vitro studies have demonstrated
that vitamin A and its derivates (retinoids) are important regulators of epidermal
differentiation and affect keratin gene expression. In cultured keratinocytes,
the induction of an embryonic type of differentiation by retinoids with reinduction
of K13 and K19 expression has been well documented.5-6
In vivo topical application of retinoids on photo-aged human skin also showed
induction of K13.7
Although retinoids are used as chemopreventive agents for inhibiting
skin cancer in renal transplant recipients (RTRs),8-9
to the best of our knowledge there are no studies regarding the effects of
retinoids on keratin expression in the skin or skin lesions of these patients.
Renal transplant recipients develop multiple warts and skin neoplasms.
Immunosuppressive treatment, sun exposure, and viral infection with human
papillomavirus are all implicated in the etiology of cutaneous tumorigenesis
in RTRs.10-14
The frequent simultaneous occurrence of warts and skin cancers in RTRs led
us to the assumption that the verrucae or warts in RTRs might be more prone
to become malignant than equivalent lesions in healthy immunocompetent individuals
(ICIs). The existence of high- and low-risk papillomas was previously shown
in mice models of cutaneous carcinogenesis.15
Interestingly, these high-risk papillomas expressed K13, which was absent
in low-risk papillomas.
The present study shows that RTR-associated warts in contrast to warts
in normal ICIs indeed show pronounced K13 expression.This suggests that altered
keratin expression may reflect an important molecular event inherent in the
malignant degeneration of warts in RTRs. Furthermore, this K13 expression
in warts of RTRs strongly correlates with retinoid therapy, but, in contrast
to findings in animal studies and in cultured human keratinocytes,5 we could not demonstrate an effect of retinoids on
K19 expression in these patients. Retinoid-related K13 expression in epithelial
skin lesions of RTRs displays a highly characteristic pattern, which we termed zebroid, making K13 a useful marker for evaluating the
effect of retinoid treatment in these patients.
MATERIALS AND METHODS
TISSUE SAMPLES
For this retrospective immunohistochemical study, we retrieved formalin-fixed
and paraffin-embedded skin specimens from warts of RTRs (21 specimens from
18 patients; average age, 50.8 years; mean duration of immunosuppression,
16.4 years) and healthy ICIs (21 specimens from 19 patients; average age,
33.3 years) from archival material at the Department of Pathology, University
Medical Center St Radboud, Nijmegen, the Netherlands.
RETINOID TREATMENT
Nine RTRs (10 specimens) received retinoids. In 3 patients (4 specimens),
topical all-trans retinoic acid (concentration, 0.025%-0.05%) was used, and
6 patients received systemic acitretin (dose at time of biopsy, 10-35 mg).
Patients taking systemic acitretin participated in a clinical trial, unrelated
to the present study, studying the effects of systemic retinoids on cutaneous
carcinogenesis in RTRs. Inclusion criteria for this trial were either the
presence of at least 1 squamous cell carcinoma (SCC) in the patient's history
or the presence of 10 or more actinic keratoses, with at least 1 confirmed
histologically. Initially, most patients taking acitretin started with 30
to 35 mg/d, a dosage that prevented SCCs in RTRs in an earlier study.8 However, in a relatively large number of patients,
doses of acitretin had to be lowered because of mucocutaneous adverse effects
(peeling of palms and soles and/or cheilitis). Retinoid- and non–retinoid-treated
patients showed no obvious differences with respect to duration, dosage, and
type of immunosuppression, all factors implied in the etiology of skin cancers
in immunosuppressed patients (data not shown).
HISTOPATHOLOGIC EXAMINATION
Histologic examination of all studied lesions was revised according
to World Health Organization definitions of verrucae.16
The verrucae consisted predominantly of common warts or verrucae vulgares,
with a smaller group of verrucae plana, especially in ICIs, usually on the
hands and feet. Condyloma acuminata and anogenital warts were not included.
IMMUNOHISTOCHEMICAL ANALYSIS
Immunohistochemical analysis was performed on all specimens by using
standard avidin-biotin-peroxidase complex system with either diaminobenzidine
and/or 3-amino-9-ethylcarbazole as the chromogens. In brief, 4-µm-thick
paraffin sections were deparaffinized, hydrated, and washed in buffered phosphate.
For K13 staining, sections were cooked in buffered citrate (10mM, pH
6.0) in a microwave oven 2 times for 5 minutes each (600 W). After a cooling
down period of (at least) 20 minutes and preincubation with 20% normal horse
serum for 15 minutes, the sections were incubated with undiluted primary antibody
overnight at 4°C. We used 2 mouse monoclonal primary antibodies, 1C7 (immunoglobulin
G2a) and 2D7 (immunoglobulin G2b), both recognizing K13.17
As a positive control, normal esophageal tissue was used. After incubation
with primary antibodies, sections were incubated for 30 minutes with biotinylated
horse antimouse (1:200 dilution) (Vector Laboratories, Burlingham, Calif),
followed by incubation for 45 minutes with avidin-biotin complex (1:50 dilution)
(Vector Laboratories). For development with 3-amino-9-ethylcarbazole, avidin-biotin
complex concentrations were doubled.
For K19 immunohistochemical analysis, (mouse) monoclonal antibody RCK
108 (Biogenex, San Ramon, Calif) was used. Besides different pretreatment
(0.1% pronase for 10 minutes), the same procedure as used for K13 was followed.
Eccrine ducts and sweat glands served as positive internal controls. Sections
were counterstained with Mayer hematoxylin for 2 minutes.
Immunoreactivity was scored as negative, slightly positive in a suprabasal
single-cell pattern (<10% lesional keratinocytes positive), or strongly
positive in a suprabasal segmental columns pattern (zebroid pattern). Scoring
was performed without knowledge of patient history and use of retinoid therapy.
The Pearson  2 test was used for all statistical analyses,
and significance was set at P<.05.
RESULTS
GENERAL ASPECTS OF IMMUNOSTAINING FOR K13 AND K19
In all cases, immunostaining for K13 was restricted to the cytoplasm.
Slight variations in staining intensity were observed in lesional skin comparing
antibodies 1C7 and 2D7 with overall stronger staining with the 2D7 antibody.
Principally, however, the staining pattern of lesional skin with both antibodies
was identical. Normal esophagus was used as a positive control and showed
strong diffuse suprabasal staining.
Keratin 19 immunostaining was also localized in the cytoplasm. Eccrine
ducts and sweat glands, serving as internal controls, showed marked positivity.
EXPRESSION OF K13 AND K19 IN WARTS OF RTRs VS ICIs AND EFFECTS OF RETINOID
TREATMENT
There was a significant difference in K13 expression between warts of
RTRs and warts of ICIs (P<.001). A high percentage
of warts of RTRs (86%, 18 cases) showed K13 expression, whereas in benign
warts of ICIs almost all lesions were negative except for 3 (14%) of 21 with
suprabasal single-cell positivity (Table
1 and Figure 1). This
statistical difference in K13 positivity remained when we excluded retinoid-treated
patients: 82% K13 positivity in non–retinoid-treated RTRs vs 14% in
controls (P<.001). Besides number of positive
specimens, the proportion of positive lesional cells also differed and was
more pronounced in warts of RTRs: the 3 positive warts of ICIs showed only
suprabasal single-cell positivity (Figure
2); in RTRs, half of the 18 positive warts also showed this suprabasal
single-cell positivity, whereas the other half showed strong positive staining
in a remarkable pattern of segmental positive suprabasal full epithelium thickness
columns (zebroid pattern) (Figure 1B,
D and Figure 2). This particular
pattern was not linked to eccrine ducts or hair follicle structures; the latter
actually seemed to be spared. This zebroid pattern correlated with retinoid
treatment (topical and systemic) when comparing retinoid-treated RTRs (warts
and in situ SCCs) with non–retinoid-treated RTRs (Table 2) (P<.001). Only 1 patient without
(anamnestically traceable) retinoid treatment exhibited the same K13 expression
pattern.
|
|
|
|
Table 1. K13-Positive and K13-Negative Warts in RTRs and ICIs*
|
|
|
|
|
|
|
Figure 1. A, Hematoxylin-eosin staining
of a wart from a retinoid-treated renal transplant recipient (RTR) (original
magnification x40). B, Immunohistochemical analysis of a wart from a
retinoid-treated RTR for keratin (K) 13 (monoclonal antibody 2D7, with diaminobenzidine
as the chromogen) showing the particularly strong 3+ positive zebroid pattern
of alternating suprabasal columns of K13-positive and K13-negative keratinocytes.
This zebroid pattern was significantly correlated to retinoid treatment in
RTRs (original magnification x40). C and D, Wart of a retinoid-treated
RTR showing uncoupled regulation of K13 and K19 expression by retinoids, with
strong zebroid pattern K13 positivity (D), whereas K19 expression is absent
(C). The arrows (C) point to K19-positive sweat glands, which serve as an
internal control (original magnification x40). E, Hematoxylin-eosin
staining of a wart from an immunocompetent individual (ICI) (original magnification
x40). F, Immunohistochemical analysis of a wart from an ICI for K13
(2D7, diaminobenzidine) showing suprabasal single-cell positivity (arrow).
This pattern of K13 expression was also typical of warts from non–retinoid-treated
RTRs (original magnification x40). G, In situ squamous cell carcinoma
(ISSCC) of an RTR showing K13 (2D7) expression partially centered around hair
follicle structures (original magnification x40). This staining pattern
differs considerably from the retinoid therapy–related zebroid K13 pattern.
H, Perilesional skin specimen from an ISSCC of an RTR receiving retinoid treatment.
Immunohistochemical analysis of K13 (2D7) shows the same zebroid pattern as
in lesional skin of most warts of retinoid-treated RTRs (original magnification
x25).
|
|
|
|
|
|
|
Figure 2. Keratin 13 expression patterns
in warts of renal transplant recipients (RTRs) vs immunocompetent individuals
(ICIs).
|
|
|
|
|
|
|
Table 2. Strong Keratin 13 (K13) Positivity (Zebroid Pattern) and Nonzebroid
K13 Positivity vs Retinoid Therapy in Renal Transplant Recipients
|
|
|
Most warts were superficially excised, with no perilesional skin available.
In 1 retinoid-treated RTR, the perilesional skin showed K13 positivity comparable
with the previously described zebroid pattern. All warts in both groups were
negative for K19, with use of retinoids having no demonstrable effect on K19
expression (Figure 1C-D).
COMMENT
Data from numerous animal and in vitro studies5-6,18-20
with cultured human keratinocytes indicate that retinoids affect epidermal
proliferation and differentiation. Retinoids proved to repress differentiation-specific
keratins (K1/K10) and strikingly reinduced expression of K13 and K19, 2 keratins
that are only coexpressed in fetal skin and are not usually present in the
epidermis of adults.2, 4 In contrast
to these findings of coupled K13 and K19 induction by retinoids, Agarwal et
al21 were the first to report uncoupled regulation
of K13 and K19 expression in a human SCC cell line.
Our in vivo data with immunohistochemical evaluation of K13 and K19
expression in warts of RTRs vs ICIs show that retinoids used as chemoprotective
agents in RTRs for preventing skin cancer also strongly relate only to K13,
and not K19, expression. Our finding of retinoid therapy–related uncoupled
K13 and K19 expression in these patients could be 3-fold. First, the retinoid
concentration in our patients could be sufficient to enhance K13 expression
but not K19 expression. Earlier findings6 in
human epidermal cultures showed stronger induction of K13 than K19 by retinoids
with an already marked increase of K13 in response to low levels of retinoids,
whereas for K19 induction a higher retinoid concentration was necessary. Although
the dosage of systemic retinoids taken by many of our patients had to be lowered
during treatment because of severe mucocutaneous adverse effects, no induction
of K19 was found in patients still receiving the higher dosages of acitretin.
Second, the response of keratinocytes to retinoids in vitro might not be representative
of the response in vivo, and retinoids in humans in vivo might not induce
an embryonic type of differentiation and might only selectively induce K13
expression. In the only previous in vivo study7
on the effects of retinoids in photo-aged skin only K13, and not K19, expression
was studied. Finally, this differentiation toward esophageal-type epithelium
in contrast to so-called embryonic-type differentiation found in animals and
in vitro could be specific for skin and skin lesions in RTRs: earlier studies19 already showed that effects of retinoids differed
in normal compared with diseased keratinocytes.
Retinoid treatment significantly correlated with a specific pattern
of K13 expression in skin lesions of RTRs. This pattern, which we termed zebroid
because of alternating suprabasal columns of K13-positive and K13-negative
keratinocytes, is suggestive of a genetic mosaicism, reflecting clonal expansion
of genetically altered stem cells. In warts and slightly dysplastic skin of
RTRs, segments of epidermis may contain keratinocytes with a genetic abnormality,
making them more susceptible to inductive actions of retinoids. Future studies
might unravel the underlying genes that are involved in this process and whether,
for instance, (transforming types of) human papillomavirus might play a role.22
Interpretation of the biological impact of K13 expression in retinoid-
and non–retinoid-treated warts of RTRs could be 2-fold. The first interpretation
relates the presence of K13 in skin to differentiation, in parallel to internal
squamous epithelia, in which K13 is restricted to the suprabasal epithelial
compartment and is associated with differentiation. Retinoids, by inducing
K13 expression or directing keratinocytes toward (esophageal) differentiation,
might be chemopreventive by "freezing" cells in this differentiated state
and preventing them from (further) dedifferentiating. Results of previous
studies6, 23-24 of
retinoid effects on epidermal keratinocytes have shown that in response to
retinoid treatment, higher molecular weight keratins, typically encountered
in squamous epithelia, disappear, and synthesis of 2 new low molecular-weight
keratins, a 40- and a 52-kd keratin, corresponding to K19 and K13, respectively,
is enhanced. In the absence of vitamin A, the opposite occurs, with an enhanced
terminal epidermal type of differentiation.25
Retinoid-induced esophageal-type differentiation could provide an explanation
for the cosmetic improvement of lesional skin in these RTRs, who often had
multiple hyperkeratoses before treatment: esophageal epithelium is, in contrast
to the keratinizing epidermis, a nonkeratinizing squamous epithelium. By inducing
nonkeratinizing differentiation, retinoids could lower the number of hyperkeratotic
skin lesions. As an adverse effect, in normal skin the diminished cutaneous
keratinization caused by retinoids leads to desquamation of palms and soles,
which usually show the most prominent keratinization. On the lips, the outer
cutaneous side becomes more vulnerable because of differentiation toward wet
epithelium, leading to cheilitis, another known adverse effect of acitretin
treatment also present in our patients.8-9,26
The second interpretation relates the presence of K13 to a more dedifferentiated
and potentially malignant phenotype. Regarding cutaneous carcinogenesis, malignant
transformation is heralded by a switch from production of high-molecular-weight
keratins usually present in adult skin (K1/K10) to low-molecular-weight keratins
also characteristic of fetal skin and simple epithelia (eg, K8/K18 and K19).1 Presence of K13, a low-molecular-weight embryonic
keratin, would fit within this concept. It is tempting to attribute relevance
to the high frequency of K13 in warts of RTRs and to speculate that it may
be related to the higher susceptibility of warts in these patients to become
malignant. This would be analogous to mouse models on skin carcinogenesis
in which aberrant K13 expression is a consistent finding in chemically and
v-Ha-ras–induced papillomas and SCCs.15, 27-28
In in situ SCCs of RTRs and ICIs we found frequent K13 expression in 75% and
45% of lesions, respectively (20 in situ SCCs tested within each group, data
not shown), which is in concert with this second hypothesis. The pattern of
K13 expression in in situ SCCs of both groups was different from the retinoid
therapy–related K13 expression (zebroid pattern, compare Figure 1B, G). Only 4 RTRs with in situ SCCs used retinoids, and
in these patients the retinoid therapy–related zebroid K13 pattern was
most pronounced or only present in perilesional, slightly dysplastic skin
(Figure 1H).
When this latter interpretation would be applicable to retinoid-related
K13 expression, use of retinoids might actually be dangerous for these patients.
This is contradicted by studies of the long-term safety of retinoid therapy,
since no increased incidence of skin cancer is reported.29
Studies of skin cancer chemoprophylaxis with retinoids in RTRs actually showed
reduction in the skin cancer incidence.8
In conclusion, this retrospective in vivo study of embryonic keratin
expression in warts of RTRs shows that retinoids strongly relate to K13 but
not K19 expression. By keeping keratinocytes in this esophageal-type differentiation,
retinoids might act chemopreventively. Retinoids correlate with a highly distinctive
and strong K13 expression, which we termed zebroid, making K13 a useful marker
for evaluating retinoid treatment in these patients. The alternating zebroid
K13 pattern is suggestive of an underlying genetic mosaicism. Even in the
absence of retinoids, a significantly higher percentage of K13 positivity
is found in warts of RTRs compared with warts of ICIs. Future prospective,
randomized, and well-controlled studies need to establish the relevance of
this finding and whether K13, in analogue to mouse models of skin carcinogenesis,
might become a predictive marker for malignant progression.
AUTHOR INFORMATION
Accepted for publication May 15, 2001.
We thank Peter C. M. de Wilde, MD, PhD, for statistical assistance and
Goos N. van Muijen, MD, PhD, for providing monoclonal antibodies 1C7 and 2D7
and for critically reading the manuscript.
Corresponding author and reprints: Willeke A. M. Blokx, MD, Department
of Pathology, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen,
the Netherlands (e-mail: w.blokx{at}pathol.azn.nl).
From the Departments of Pathology (Drs Blokx and Ruiter and Ms Link)
and Dermatology (Drs Smit, de Jong, and van de Kerkhof), University Medical
Center St Radboud, Nijmegen, the Netherlands.
REFERENCES
| |
1. Smack DP, Korge BP, James WD. Keratin and keratinization. J Am Acad Dermatol. 1994;30:85-102.
ISI
| PUBMED
2. Moll R, Moll I, Wiest W. Changes in the pattern of cytokeratin polypeptides in epidermis and
hair follicles during skin development in human fetuses. Differentiation. 1982;23:170-178.
FULL TEXT
|
ISI
| PUBMED
3. Kuruc N, Leube RE, Moll I, Bader BL, Franke WW. Synthesis of cytokeratin 13, a component characteristic of internal
stratified epithelia, is not induced in human epidermal tumors. Differentiation. 1989;42:111-123.
FULL TEXT
|
ISI
| PUBMED
4. Van Muijen GN, Warnaar SO, Ponec M. Differentiation-related changes of cytokeratin expression in cultured
keratinocytes and in fetal, newborn, and adult epidermis. Exp Cell Res. 1987;171:331-345.
FULL TEXT
|
ISI
| PUBMED
5. Korge B, Stadler R, Mischke D. Effect of retinoids on hyperproliferation-associated keratins K6 and
K16 in cultured human keratinocytes: a quantitative analysis. J Invest Dermatol. 1990;95:450-455.
FULL TEXT
|
ISI
| PUBMED
6. Kopan R, Traska G, Fuchs E. Retinoids as important regulators of terminal differentiation: examining
keratin expression in individual epidermal cells at various stages of keratinization. J Cell Biol. 1987;105:427-440.
FREE FULL TEXT
7. Rosenthal DS, Roop DR, Huff CA, et al. Changes in photo-aged human skin following topical application of all-trans
retinoic acid. J Invest Dermatol. 1990;95:510-515.
FULL TEXT
|
ISI
| PUBMED
8. Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during
acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled
study. J Clin Oncol. 1995;13:1933-1938.
FREE FULL TEXT
9. Yuan ZF, Davis A, Macdonald K, Bailey RR. Use of acitretin for the skin complications in renal transplant recipients. N Z Med J. 1995;108:255-256.
ISI
| PUBMED
10. Penn I. Neoplastic complications of transplantation. Semin Respir Infect. 1993;8:233-239.
PUBMED
11. Barr BB, Benton EC, McLaren K, et al. Human papilloma virus infection and skin cancer in renal allograft
recipients. Lancet. 1989;1:124-129.
ISI
| PUBMED
12. Boyle J, MacKie RM, Briggs JD, Junor BJ, Aitchison TC. Cancer, warts, and sunshine in renal transplant patients: a case-control
study. Lancet. 1984;1:702-705.
ISI
| PUBMED
13. Seckin D, Gulec TO, Demirag A, Bilgin N. Renal transplantation and skin diseases. Transplant Proc. 1998;30:802-804.
FULL TEXT
|
ISI
| PUBMED
14. Webb MC, Compton F, Andrews PA, Koffman CG. Skin tumour posttransplantation: a retrospective analysis of 28 years'
experience at a single centre. Transplant Proc. 1997;29:828-830.
FULL TEXT
|
ISI
| PUBMED
15. Yuspa SH. The pathogenesis of squamous cell cancer: lessons learned from studies
of skin carcinogenesis. J Dermatol Sci. 1998;17:1-7.
FULL TEXT
|
ISI
| PUBMED
16. Heenan PJ, Elder DE, Sobin LH. International Histological Classification of Tumours. Vol 12. 2nd ed. Berlin, Germany: Springer-Verlag; 1996.
17. van Muijen GN, Ruiter DJ, Franke WW, et al. Cell type heterogeneity of cytokeratin expression in complex epithelia
and carcinomas as demonstrated by monoclonal antibodies specific for cytokeratins
nos. 4 and 13. Exp Cell Res. 1986;162:97-113.
FULL TEXT
|
ISI
| PUBMED
18. Eichner R, Kahn M, Capetola RJ, Gendimenico GJ, Mezick JA. Effects of topical retinoids on cytoskeletal proteins: implications
for retinoid effects on epidermal differentiation. J Invest Dermatol. 1992;98:154-161.
FULL TEXT
|
ISI
| PUBMED
19. van Rossum MM, Mommers JM, van de Kerkhof PC, van Erp PE. Coexpression of keratins 13 and 16 in human keratinocytes indicates
association between hyperproliferation-associated and retinoid-induced differentiation. Arch Dermatol Res. 2000;292:16-20.
FULL TEXT
|
ISI
| PUBMED
20. Griffiths CE, Elder JT, Bernard BA, et al. Comparison of CD271 (adapalene) and all-trans retinoic acid in human
skin: dissociation of epidermal effects and CRABP-II mRNA expression [see
Comments]. J Invest Dermatol. 1993;101:325-328.
FULL TEXT
|
ISI
| PUBMED
21. Agarwal C, Rorke EA, Boyce M, et al. Retinoid-dependent transcriptional suppression of cytokeratin gene
expression in human epidermal squamous cell carcinoma cells. Differentiation. 1993;52:185-191.
FULL TEXT
|
ISI
| PUBMED
22. Pirisi L, Batova A, Jenkins GR, Hodam JR, Creek KE. Increased sensitivity of human keratinocytes immortalized by human
papillomavirus type 16 DNA to growth control by retinoids. Cancer Res. 1992;52:187-193.
FREE FULL TEXT
23. Elias PM. Retinoid effects on the epidermis. Dermatologica. 1987;175(suppl 1):28-36.
24. Stadler R, Muller R, Detmar M, Orfanos CE. Retinoids and keratinocyte differentiation in vitro. Dermatologica. 1987;175:45-55.
25. Vahlquist A, Torma H. Retinoids and keratinization: current concepts. Int J Dermatol. 1988;27:81-95.
ISI
| PUBMED
26. Gupta AK, Goldfarb MT, Ellis CN, Voorhees JJ. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol. 1989;20:1088-1093.
ISI
| PUBMED
27. Sutter C, Strickland JE, Welty DJ, Yuspa SH, Winter H, Schweizer J. v-Ha-ras–induced mouse skin papillomas exhibit aberrant expression
of keratin K13 as do their 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate–induced
analogues. Mol Carcinog. 1991;4:467-476.
ISI
| PUBMED
28. Nischt R, Roop DR, Mehrel T, et al. Aberrant expression during two-stage mouse skin carcinogenesis of a
type I 47-kDa keratin, K13, normally associated with terminal differentiation
of internal stratified epithelia. Mol Carcinog. 1988;1:96-108.
ISI
| PUBMED
29. Vahlquist A. Long-term safety of retinoid therapy. J Am Acad Dermatol. 1992;27:S29-S33.
RELATED ARTICLE
Archives of Dermatology Reader's Choice: Continuing Medical Education
Arch Dermatol. 2002;138(1):139.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Immunohistochemical Effects of Temporary Cessation of Long-term Acitretin Treatment in Keratinocytic Intraepidermal Neoplasia of Renal Transplant Recipients
Blokx et al.
Arch Dermatol 2003;139:671-673.
FULL TEXT
|
