ARTICLE
The skin is a site of immune responses and the epidermis contains the
basic elements involved in these responses (T cells, Langerhans cells,
which are antigen presenting cells, and cytokines). Because of its anatomic
structure, it serves as a defense against infections. It is also an important
target of immunosuppressive treatments leading to a down-regulation of
the skin immunity.
In immunocompetent populations, human papillomaviruses (HPVs) are known
to induce benign skin warts, which spontaneously regress and occasionally
persist. Organ transplant recipients who are under immunosuppressive treatment
for a long period of time are at a highly increased risk of developing
skin complications, mainly warts and squamous cell carcinomas (SCC), several
years after their transplantation [1, 2]. The incidence of skin cancers
and particularly SCC is high. In this population, HPV DNA belonging to
several types can be detected in the lesions (Table
I). Some observations suggest a strong association between SCC
and warts and the SCC are more aggressive than in the general population.
Although it is well known that HPV can induce different kinds of warts,
the role of HPV infection in the progression of benign skin lesions towards
malignancy remains unclear. This question is important since more and
more patients suffering from renal or heart deficiencies receive transplants.
For these patients, it is necessary to find an appropriate therapy, to
avoid recurrence and/or to prevent the appearance of skin lesions without
graft rejection.
Several factors are associated with the development of SCC including
the duration of immunosuppressive therapy, HPV infection, genetic host
and immunologic factors, exposure to UV light, viral and cellular oncogenes,
deregulation of transcription factors, the principal factors being immunosuppres-sive
treatment and UV irradiation.
The increased risk of warts and SCC due to immunosuppressive
treatment
Among viral infections in the epidermis, HPVs are of major importance.
The earliest link between warts and skin cancers was noted for the rare
genetic disorder involved in epidermodysplasia verruciformis (EV); wart
lesions progress to SCC in 30 to 50% of these patients and HPV types 5
and 8 are common in the lesions [3]. In organ transplant patients, the
frequency of warts and SCC is significantly related to immunosuppressive
treatment [1, 2]. Common or plane warts usually occur in renal transplant
recipients 2 or 3 years post-transplantation; their frequency reaches
70-80% of patients after 5 years [4]; in some patients they tend to spread
and to recur after usual treatments. In many cases, warts preceded SCC.
In a group of renal transplant recipients from the Netherlands, the overall
incidence of SCC was 250 times higher than in the general population [5]
and the cumulative incidence increased with time: 10% after 10 years,
40-45% after 20 years, 70% after 25 years. In Australia, the percentage
is even higher, 40% developed skin cancers after 10 years and 70% after
20 years [2, 6]. The frequency of SCC was higher in heart than in kidney
transplant patients, appearing 3-4 years after heart grafting [7]. The
frequency of benign warts and SCC was found to depend significantly on
the skin type, light-skinned people being the most susceptible [8]. Furthermore,
these lesions are frequently associated with multiple benign, premalignant
or malignant lesions and occur in patients about 20 years earlier than
in the normal population [7, 9].
Thus, the appearance of warts and SCC may be a reflection of the degree
of immunosuppression in organ transplant patients and represents an efficient
marker. Indeed, until now, there has been no reliable biochemical or functional
test to help clinicians in the follow-up of the level of immunosuppression
in grafted patients.
Kinetics of HPV infection
and evolution of cancer in the epidermis
In the general population, HPV infection is a very common disease and
more than 75 distinct HPV types have been identified in malpighian squamous
epithelia [10]. Most of them are responsible for benign skin warts or
mucosal lesions such as external genital condylomas which regress spontaneously.
Only in some cases, HPV types 16, 18, 31, 33, 35, 51 are associated with
cancers especially with cervical cancers and may be responsible for malignancy.
All HPV genomes encode 9-10 open reading frames and have the potential
to synthesize 12-15 gene products. Three different regions have been identified
(Table II): (1) a non-coding
region of about 1,000 bp which controls viral replication and transcription;
(2) a region that encodes early genes E1 to E7; (3) a region
that encodes the late genes, L1 and L2.
Though HPV 16 and 18 are the most common types found in malignant genital
lesions, HPV infections do not always lead to malignancy; other factors
are required for full malignant transformation and if HPV is essential,
alone it is not sufficient [11]. In skin tumors harboring HPV DNA, the
steps of progression from benign lesions to malignancy remain unknown.
The kinetics of HPV infection in the epidermis is not yet well understood,
even in the general population and in vitro studies have not yet
permitted the establishment of the virus cycle in keratinocytes [12].
It is suspected that HPV infection starts in the basal cell layer which
contains a few keratinocyte stem cells still able to divide and that the
infecting virus particles can reach these cells through skin injuries,
however no HPV cell-receptors have yet been identified [13]. In situ
studies on tissue sections indicate that the mRNA transcription pattern
changes considerably in the different layers of the epidermis. For example,
HPV E6 and E7 gene signals were found in the basal cell
layers of the epithelium; E1/E4 gene transcripts were abundant
in the middle and upper parts of the epithelium of benign tumors; transcripts
coding for late proteins L1 and L2 were detected in the terminally differentiated
keratinocytes [14]. DNA replication is found in the upper cell layers
[15]. In most cases and especially in skin warts and skin cancers, HPV
DNA is episomal. In warts, viral genomes are mostly incorporated into
a particle or capsid which consists of the L1 and L2 proteins.
In transplant recipient lesions, the most frequent HPV types (Table
I) are benign cutaneous types 1, 2 or 4, a series of EV-associated
HPV types or potentially oncogenic cutaneous types 5/8 (usually found
in EV patient carcinomas) and in some cases, mucosal HPV types which are
either benign (types 6/11) or potentially oncogenic (types 16, 18, 35).
Several HPV types can be dectected in a single lesion [16-18]. However,
these results are controversial since some groups found no HPVs at all.
The inconsistencies in these findings may be attributable to technical
problems: different methods (Southern, PCR or in situ hybridization)
of DNA hybridization were used; DNA was extracted either from frozen or
formalin fixed tissues; among the 75 distinct HPV types, only a few HPV
types have been tested; small series of lesions were commonly examined.
Thus, a variety of HPV types may be detected in benign proliferations
and in skin carcinomas of organ transplant recipients; it is possible
that various HPVs, other than EV types may be associated with malignancies.
The same HPV types are found in lesions of immunocompetent and immunocompromised
patients but they are widespread in transplant patients. The prevalence
of HPV DNA was very similar throughout the spectrum of cutaneous neoplasia,
at least in renal transplant recipients; however, it differs from that
found in cervical neoplasia. All the results suggest that, although HPVs
play a role in skin neoplasia of organ transplant patients, they may be
involved in early malignancy stages. In contrast to the HPV 16 or 18 that
are usually integrated in cervical cancers [19], most EV-associated SCC
and samples from renal transplant recipients contain HPV 5 or 8 DNA in
an episomal form [3, 20], integration being a rare event [17]. In vitro
cultures of SCC from some of these patients confirmed detection at early
passages of HPV DNA in an episomal state which persisted [20].
Immunological host risk factors
There is growing evidence that HLA class I or II genes are associated
with a higher risk of organ transplant recipients developing skin cancers.
The HLA A11 gene could exert a protective effect since renal
transplant patients are not concerned with this gene, whereas it is involved
in 12% of the general population [21]. In contrast, the HLA B27
gene represents an increased risk of skin cancers in renal transplant
patients [21] because its expression may be related to the reduced efficiency
in presenting antigen to CD8+ T cells and to the absence of
switch IgM-IgG during HPV infection [22]. MHC class II antigen, HLA DR7
which is frequently expressed in renal transplant patients could be involved
in the impaired response of CD4+ T cells [22, 23]. Similarly,
the frequency of DQW2, increased in renal transplant patients, leads to
a relative sensitivity [24].
In heart transplant recipients, there is no significant association
between skin cancers and HLA A3, HLA A11, HLA DR expression and the number
of mismatches for HLA AB [25].
Local cellular immunity
and HPV
In the general population, non-regressing, HPV-induced skin warts show
a moderate to intense inflammatory reaction of CD3+ T cells
without predominance of CD4+ or CD8+ T cells and
a decrease in the number of antigen presenting cells, the intraepithelial
Langerhans cells [26, 27]. Among adhesion molecules involved in the recruitment
of leukocytes, the expression of endothelial leukocyte adhesion molecule
(E-selectin) and vascular cell adhesion molecule-1 (VCAM-1) is upregulated
on tumor microvessels of HPV-induced lesions [28]. Furthermore, in highly
inflammatory samples of SCC, foci of keratinocytes can express the intracellular
adhesion molecule 1 (ICAM-1), which correlates with the presence of LFA1+
cells observed in close apposition [28]. MHC class II, HLA DR is also
detected on foci of tumor cells and has been attributed to IFN-gamma production
by infiltrating activated T cells [27, 28]. In warts and SCC, no relation
has ever been found between the phenotype modifications of keratinocytes
and the HPV type [26].
Regressing plane warts are characterized by the presence of numerous
Langerhans cells both in the epidermis and dermis, admixed with T cells
next to damaged keratinocytes in the epidermis [29]. These findings suggest
a specific, cell-mediated immunity against virally infected keratinocytes.
By contrast, in carcinomas (basal cell carcinomas and SCC) from the normal
population, CD4+ T cells are predominant within the infiltrate
expressing antigen associated with cellular activation [30] whereas the
number of Langerhans cells is reduced as compared to that of normal epidermis
[26, 27].
In organ transplant patients, the increased susceptibility to skin tumors
has been attributed to a defect in local skin immunity, mainly due to
the immunosuppressive treatment and occurrence of viral warts. Very few
studies have been carried out on local skin immune reactions in transplant
recipient lesions. In normal skin from immunosuppressed patients, the
number of Langerhans'cells is significantly reduced, the lowest density
being in patients on triple drug therapy [31]. The decreased density of
Langerhans cells could contribute to the non-responsiveness of the patients
to HPV as Langerhans cells are the major antigen presenting cells of the
skin. However, the number of Langerhans cells cannot be used to predict
the risk of wart development towards malignancy [31]. In these patients,
the inflammatory reaction surrounding both benign and malignant lesions
is less intense than in immunocompetent patients, with no predominance
of CD4+ or CD8+ T cells; the expression of immune
associated antigens (ICAM-1 and HLA-DR) by keratinocytes is low. These
features do not correlate with the HPV type [32].
Cytokines also play a major role in the host immune response by regulating
the development and function of immunocompetent cells. In HPV infections,
epidermal cytokines participate in the control of the local immunosurveillance
mechanisms. Among them, TNFalpha secreted by activated macrophages and
tumor cells [28, 33] can act as a negative autocrine growth factor and
may contribute to influence the migration out of the epidermis of Langerhans
cells either directly or indirectly through the release of other immune
mediators. The tumor itself may produce immunosuppressive factors responsible
for immune dysregulation. Recent data indicate that both in vivo
and in vitro, tumor cells derived from SSC express IL10 mRNA and
protein [34] suggesting that IL10 may be a constituent of the tumor milieu
which contributes to suppressing the local immune response.
Thus, in organ transplant patients, HPV infection is a consequence of
a drastic decrease of the local skin immunosurveillance. The presentation
of virus-specific antigen being MHC restricted may explain the higher
risk in organ transplant recipients of developing cancer. HPV infection
of keratinocytes modifies the cellular microenvironment by producing and
secreting various mediators of the inflammatory reaction which may indirectly
influence the progression of a benign lesion towards cancer. Noxious stimuli
such as UV irradiation [35], may be very significant factors in transplant
patients.
Immunological risk related to sun exposure
Excessive sunlight exposure is a major cause of several forms of carcinomas
[36]. In the normal population, the incidence of SCC and basal cell carcinomas
is proportional to the cumulative, life-time sunlight exposure and these
carcinomas typically occur on areas of the body exposed to sunlight. UV
irradiation effects are believed to be mediated by systemic T lymphocytes
induced by immunosuppression, possibly due to the release of epidermal
cytokines such as IL10 triggered by UV-induced epidermal cell damage and
the induction of suppressor T cells. Low doses of UV irradiation affect
Langerhans cells in their integrity, their capacity for migration and
antigen presentation [36, 37]. Locally, UV irradiation abolishes immunological
responsiveness and contact hypersensitivity to a universally sensitizing
dose of a contact applied to exposed skin sites in 40% of normal, adult
Caucasian volunteers [38].
Apart from immunological effects, UVB can cause DNA damage encountered
in the development of malignancy. In transplant recipients, it is likely
that sun exposure strengthens the immunosuppression caused by the immunosuppressive
treatment. As the incidence of SCC depends greatly on the amount of sun
exposure and since lesions occur within a shorter delay with increasing
latitude [2, 6, 39], it is not surprising that the risk of developing
SCC is increased with sun exposure in immunosuppressed patients.
Incidence of oncogenes
In humans, some viral oncogenes [11] and cellular oncogenes (ras,
c-myc, p53 and erb-B2) are believed to be useful in the evaluation
of the predisposition, diagnosis and prognosis of cancer [40]. These oncogenes
are associated either with a gain or a loss of function leading to alterations
in cell growth and death control mechanisms.
Most findings on HPV oncogenes have been obtained from HPV types 16
or 18 (Table II). E6 and
E7 have been extensively studied as they are very often integrated after
disrupting the E1 and E2 genes in cervical lesions or in
cell lines derived from such lesions [11, 19]. The E2 gene has
a dual role in viral transcription by activation and repression processes;
E1 and E2 proteins regulate the expression of viral proteins, replication
of virions and integration of E6-E7 genes into the host genome
[13]. Similarly, the HPV 16 E5 gene has a role during transcription
and in early stages of carcinogenesis through EGF receptors. Indeed, little
is known about the regulation of E1, E2, E5, E6 and E7 in
the group of skin HPV types.
Few investigations have been carried out on modulations of cellular
oncogene expression in skin lesions from immunocompetent or transplant
patients.
In both populations, c-Ha-ras gene mutations in SCC were described
with a variable frequency [41-43] at codon 12. Amplification of c-myc,
c-Ha-Ras was found in some benign and malignant skin biopsies and
was more frequent in biopsies containing potentially oncogenic HPV types
[44]. These findings differ from those in uterine carcinomas with mutations,
deletion and amplification of c-myc and c-Ha-ras. In skin
malignancy, cooperation of other oncogenes may be required, as indicated
by in vitro experiments with adenovirus E1a, to transform cultured
cells. In transplant patients the low incidence of c-myc modifications
could be explained by the inhibition effect of cyclosporin A.
p53 and pRB are tumor suppressor genes which may be involved
in the cell deregulation on the cell proliferation.
p53 has a role in differentiation, apoptosis, senescence and
cancer development. p53 mutations are responsible for the development
for many malignancies since the DNA damaged cells are involved in a pathway
which depends on extracellular or viral proteins.
In normal populations, p53 mutations occur commonly in skin SCC
and are located on the highly conserved domains of the gene but the absolute
rate of mutations varies between 10 and 90% [41, 45, 46]. The predominating
patterns of mutations are C –>T and CC –>TT changes, that
are only induced by UV. In renal transplant patients, the prevalence of
SCC mutations does not significantly differ from that of the normal population
and similar exon mutations are reported [47, 48]. Accumulation of p53
protein observed by immunohistochemistry may be significant since morphologically,
p53 immunoreactivity is associated with areas of epidermal dysplasia and
the abundance of staining increases with progression to neoplasia [47].
As p53 immunopositivity does not always accompany p53 mutations
[45] this implies that factors other than the p53 gene mutation
play a role in the accumulation of p53 protein in skin cancer. Cell cycle
arrest and programmed cell death are commonly accompanied by the accumulation
of wild-type p53 protein, cyclin-dependent kinase (cdk) inhibitor p21
(WAF1/C1P1), an underphosphorylated form of Rb protein, and an increased
expression of cyclin D1. In malignant skin tumors, p53 and cyclin D1 expression
are positive at the same incidence [49]. In vitro, UV irradiation
affects normal and immortalized keratinocytes differently: the level of
wild-type p53 protein significantly increases in normal cells but is not
altered in immortalized keratinocytes.
The retinoblastoma gene (RB) has a central role in cell growth
because of its cell cycle-dependent phosphorylation and its property of
binding with a variety of proteins including the transcription factor
E2F in its underphosphorylated form, cyclins A, D and E and cdk [50].
p53 and Rb genes are also important in HPV-induced lesions
since they can be bound to the viral oncogenes E6 and E7
respectively, of HPV 16 or 18 particularly in cervical lesions, leading
to inactivation of their normal function. However, this association is
less efficient with low risk HPV 6/11 [11] and does not occur with potentially
oncogenic cutaneous HPV 8 [14].
In skin lesions from organ transplant recipients, there is no relation
between the presence or the absence of HPV DNA and p53 accumulation in
malignant lesions but this accumulation increases with the malignant state.
As low risk HPV either do not bind p53 or bind with a lower efficiency,
if HPV is involved in cutaneous carcinogenesis, it probably acts by a
different mechanism from that found in anogenital cancer. It cannot be
excluded that p53 mutations could be due to the deleterious effect
of UV before or after graft.
Growth factors
Among several growth and antigrowth factors identified as acting on
keratinocyte proliferation, colony stimulating factor (CSF1), EGF and
TGFalpha stimulate the growth of keratinocytes, acting at the G1
phase and interacting with cyclin A, cyclin D and protein kinase C [51]
whereas TGFß represents a family of keratinocyte growth inhibitors
[52]. TGFß blocks the shift from G1 to S phase to suppress
the expression of cyclin A, cyclin E and cdk.
In epithelial lesions, HPV genes may interact with these factors since
HPV 16 E6 and E7 expression in transformed cells is suppressed
by TGFß1, TGFß2 and EGF [14], whereas E5 has an independent,
transforming activity which is amplified in the presence of EGF and PDGF
receptors [53].
Transcription factors
Numerous families of nuclear factors (NFs) known to play a key role
in the normal cell cycle may be involved by virtue of their interaction
in abnormal tumoral cell proliferation. Three of them (NFkappaB, AP1 and
E2F) are all expressed in skin cells and are consistently responsible
for protein deregulation in various processes [14, 54]. Their activation
depends mainly on the phosphorylation and oxidation-reduction reactions
and on stimuli, such as viral genes, cellular genes, immune response genes,
physical or chemical agents [55] permitting immediate cell adaptation.
In organ transplant patients, many transcription factors may interact
in cascade to induce keratinocyte activation leading to epidermal tumors.
Cyclosporin A, which is responsible for general immunosuppression, activates
NFkappaB although to a lesser extent than AP1 and NF1. It deregulates
cellular calcineurin by the formation of a complex with its cytosolic
receptor cyclophylin; thus, it can indirectly inhibit AP1 transcription
factor, which in turn blocks transcription of several genes such as cytokines
[56]. AP1, E2F and NFkappaB can activate with other factors, HPV oncogene
transcription by stimulation of the initiation of cell cycle events and
enhancement of phosphorylation [14]. UVB-irradiation contributes to activate
NFkappaB activity of DNA binding [57]. In vivo, low doses of UVB-irradiation
upregulate both transcription factors AP-1 and NFkappaB, within a few
minutes [58] and cytokine genes are stimulated [59].
Incidence of various infections
Organ transplant patients are prone to a number of infections by bacteria,
fungi, chlamydia and viruses (CMV, HSV, hepatitis). These infections lead
to the production of factors which could affect either the keratinocytes
or their environment and can thus interfere with other mediators, especially
at the level of cytokine production and secretion, to modify the keratinocyte
phenotype. Such interference, which has been demonstrated in vitro
in cells infected with HSV1, results in a reduced mRNA expression of HPV
type 18 [60].
CONCLUSION
Although a causal role of HPV in the development of skin cancer has not
yet been proved, several features of HPV infection are in favor of an
induction of cell proliferation in organ transplant recipients: high frequency
of warts, histological signs of wart infection in SCC, development of
SCC at the site of warts, presence of HPV DNA in warts and in SCC, diversity
of HPV types, frequency of multiple infections suggesting a polyclonal
cell growth. Viral oncoproteins and host cell protein could cooperate
to deregulate the cell cycle. The various HPV types encountered in such
lesions probably possess multiple properties to promote tumorigenesis
preventing defense mechanisms against neoplastic proliferation. The high
risk HPV 16 or 18, usually infecting mucosa, could act as carcinogens;
others, HPV 5/8 and HPV 6/11 are dependent on various cofactors in carcinogenesis
[61]. The inactivation of p53 and pRB may initiate a cascade
of events resulting in deregulation of oncogenes and cellular replication,
leading to the persistence of cells that may have initiated neoplastic
alterations [13].
The interactions of p53 and Rb oncogenes with viral oncogenes
E6 and E7 cannot be excluded at least with some HPV types.
Since HPV do not encode a DNA polymerase or the associated factors necessary
to duplicate DNA, they have to induce in the cell the enzymes and substrates
necessary for DNA replication and these different steps may be altered.
As HPV DNA replicates in differentiated keratinocytes which are normally
unable to divide, HPV infection is probably activates both proliferative
and differentiated keratinocytes.
However, factors other than HPV infection are probably involved in keratinocyte
transformation. They include interactions between different factors (cellular
and viral oncogenes, transcription factors, UV irradiation, multiple microbial
infections), modifications of cell cycle regulation by environmental or
immunological factors. All these factors could be involved in the tumour
escaping the immunosurveillance mechanisms which are present under normal
conditions but which are drastically altered in grafted patients.
Finally, in order to control the spread of HPV infection and to prevent
the occurrence of skin cancers in organ transplant patients, the development
of warts requires careful dermatological surveillance.
Acknowledgements
The authors are indebted to Dr. J. Carew for reviewing the English version
of this manuscript. This study was supported by grants from INSERM, ARC
1995, 1996 and Ligue Nationale de Lutte Contre le Cancer, Comité
du Rhône, France, 1995.
REFERENCES
1. Penn I. Tumors of the immunocompromised patient. Ann Rev Med
1988; 39: 63-73.
2. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O'Sullivan
B, Siskind V, Van der Woude FJ, Hardie IR. The risk of skin cancer in
renal transplant recipients in Queensland, Australia. Transplantation
1996; 61: 715-21.
3. Orth G. Epidermodysplasia verruciformis. Salzman NP, Howley P, éds.
In: The Papovaviridae. Plenum Pub Corp, 1987; 2: 199-243.
4. Barr BBB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K,
Hunter JAA. Human papillomavirus infection and skin cancer in renal allograft
recipients. Lancet 1989; 1: 124-9.
5. Hartvelt MM, Bouwes-Bavinck JN, Koote AMM, Vermeer BJ, Vandebroucke
JP. Incidence of skin cancer after renal transplantation in the Netherlands.
Transplantation 1990; 49: 506-9.
6. Hardie IR, Strong RW, Hartley LCJ, Woodruff PWH, Clunie GJA. Skin
cancer in Caucasian renal allograft recipients living in a subtropical
climate. Surgery 1980; 87: 177-83.
7. Euvrard S, Kanitakis J, Pouteil-Noble C, Dureau G, Touraine JL, Faure
M, Claudy A, Thivolet J. Comparative epidemiologic study of premalignant
and malignant epithelial cutaneous lesions developing after kidney and
heart transplantation. J Am Acad Dermatol 1995; 33: 222-9.
8. McLelland J, Rees A, Williams G, Chu T. The incidence of immunosuppression-related
skin disease in long-term transplant patients. Transplantation
1988; 46: 871-4.
9. Euvrard S, Chardonnet Y, Dureau G, Hermier C, Thivolet J. Human papillomavirus
type1-associated squamous cell carcinoma in a heart transplant recipient.
Arch Dermatol 1991; 127: 559-64.
10. De Villiers EM. Human pathogenic papillomavirus types: an update.
Cur Top Microbiol Immunol 1994; 186: 1-12.
11. Tommasino M, Crawford L. Human papillomavirus E6 and E7: proteins
which deregulate the cell cycle. BioEssays 1995; 17: 509-18.
12. Stanley MA. Replication of human papillomaviruses in cell culture.
Antiviral Res 1994; 24: 1-15.
13. Kao GF, Kao WH. Malignant transformation of keratinocytes by human
papillomaviruses. J Cut Pathol 1994; 21: 193-9.
14. Fuchs PG, Pfister H. Transcription of papillomavirus genomes. Intervirology
1994; 37: 159-67.
15. Grussendorf EI, Zur Hausen H. Localization of viral DNA-replication
in sections of human warts by nucleic acid hybridization with complementary
RNA of human papilloma virus type 1. Arch Dermatol Res 1979; 264:
55-63.
16. Soler C, Chardonnet Y, Allibert P, Euvrard S, Schmitt D, Mandrand
B. Detection of mucosal human papillomavirus types 6/11 in cutaneous lesions
from transplant recipients. J Invest Dermatol 1993; 101: 286-91.
17. Stark LA, Arends MJ, McLaren KM, Benton EC, Shahidullah H, Hunter
JAA, Bird CC. Prevalence of human papillomavirus DNA in cutaneous neoplasms
from renal allograft recipients supports a possible viral role in tumour
promotion. Br J Cancer 1994; 69: 222-9.
18. Rübben A, Krones R, Schwetschenau B, Grüssendorf-Conen
EI. Common warts from immunocompetent patients show the same distribution
of human papillomavirus types as common warts from immunocompromised patients.
Br J Dermatol 1993; 28: 264-70.
19. Dürst M, Croce CM, Gissmann L, Schwartz E, Huebner K. Papillomavirus
sequences integrate near cellular oncogenes in some cervical carcinomas.
Proc Natl Acad Sci USA 1987; 84: 1070-4.
20. Purdie KJ, Sexton CJ, Proby CM, Glover MT, Williams AT, Stables
JN, Leigh IM. Malignant transformation of cutaneous lesions in renal allograft
patients. A role for human papillomavirus. Cancer Res 1993; 53:
5328-33.
21. Bouwes Bavinck JN, Vermeer BJ, Claas FHJ, Ter Schegget J, Van der
Woude FJ. Skin cancer and renal transplantation. J Nephrol 1994;
7: 261-7.
22. Bouwes Bavinck JN, Claas FJH. The role of HLA molecules in the development
of skin cancer. Human Immunol 1994; 41: 173-9.
23. Czarnecki D, Watkins F, Leahy S, Dyall-Smith D, Levis A, Nicholson
I, Taif B. Skin cancers and HLA frequencies in renal transplant recipients.
Dermatology 1992; 185: 9-11.
24. Glover MT, Bodmer J, Bodmer W, Kennedy LJ, Brown J, Navarrete C,
Kwan JTC, Leigh IM. HLA antigen frequencies in renal transplant recipients
and non-immunosuppressed patients with non-melanoma skin cancer. Eur
J Cancer 1993; 29A: 520-4.
25. España A, Redondo P, Fernandez AL, Zabala M, Herreros J,
Llorens R, Quintanilla E. Skin cancer in heart transplant recipients.
J Am Acad Dermatol 1995; 32: 458-65.
26. Viac J, Chardonnet Y, Chignol MC, Schmitt D. Papilloma viruses,
warts, carcinoma and Langerhans cells. In Vivo 1993; 7: 207-12.
27. Jackson M, Benton EC, Hunter JJ, Norval M. Local immune responses
in cutaneous warts: an immunocytochemical study of Langerhans' cells,
T cells and adhesion molecules. Eur J Dermatol 1994; 4: 399-404.
28. Viac J, Schmitt D, Claudy A. Expression of adhesion receptors in
epidermal tumors: correlation with TNFalpha expressing cells. Anticancer
Res 1995; 15: 551-6.
29. Iwatsuki K, Tagami H, Takigawa M, Yamada M. Plane warts under spontaneous
regression. Arch Dermatol 1986; 122: 655-9.
30. Markey AC, Churchill LJ, Allen MH, MacDonald DM. Activation and
inducer subset phenotype of the lymphocytic infiltrate around epidermally
derived tumors. J Am Acad Dermatol 1990; 23: 214-20.
31. Bergfelt L, Larko O, Blohmé I. Skin disease in immunosuppressed
patients in relation to epidermal Langerhans' cells. Acta Dermatol
Venereol 1993; 73: 330-4.
32. Viac J, Chardonnet Y, Euvrard S, Schmitt D. Epidermotropism of T
cells correlates with intercellular adhesion molecule (ICAM1) expression
in human papillomavirus (HPV) induced lesions. J Pathol 1992; 168:
301-6.
33. Malejczyk J, Malejczyk M, Köck A, Urbanski A, Majewski S, Hunzelmann
N, Jablonska S, Orth G, Luger TA. Autocrine growth limitation of human
papillomavirus type 16-harboring keratinocytes by constitutively released
tumor necrosis factor alpha. J Immunol 1992; 149: 2702-8.
34. Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura
K. IL-10 production in cutaneous basal and squamous cell carcinomas. A
mechanism for evading the local T cell immune response. J Immunol
1995; 155: 2240-7.
35. Stingl G. The skin: initiation and target site of immune responses.
Recent Results in Cancer Res 1993; 128: 45-57.
36. Streilin JW, Taylor JR, Vincek V, Kurimoto I, Shimizu T, Tie C,
Golomb C. Immune surveillance and sunlight-induced skin cancer. Immunology
Today 1994; 15: 174-9.
37. Cruz PD, Bergerstresser PR. Ultraviolet radiation, Langerhans' cells,
and skin cancer. Arch Dermatol 1989; 125: 975-9.
38. Yoshikawa T, Rae V, Bruins-Slot W, Van den Berg JW, Taylor JR, Streilein
JW. Susceptibility to effects of UVB radiation on induction of contact
hypersensitivity as a risk factor for skin cancer in humans. J Invest
Dermatol 1990; 95: 530-6.
39. Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms
in patients with renal transplants. Arch Dermatol 1986; 122 :1288-93.
40. Simon MM, Sliutz G, Luger TA. Protoncogenes and oncogenes in epidermal
neoplasia. Exp Dermatol 1995; 4: 65-73.
41. Campbell CC, Quinn AG, Rees JL. Codon 12 Harvey-ras mutations are
rare events in non-melanoma human skin cancer. Br J Dermatol 1993;
128: 111-4.
42. Pierceall WE, Murkhopadhyay T, Goldberg LH, Ananthaswamy HN. Mutations
in the p53 tumour suppressor gene in human cutaneous squamous cell carcinomas.
Mol Carcinogenesis 1991; 4: 445-9.
43. Pélisson I, Chardonnet Y, Euvrard S, Schmitt D. Low incidence
of c-Ha Ras mutations in benign and malignant cutaneous lesions from transplant
recipients. Int J Cancer 1993; 55: 915-20.
44. Pélisson I, Soler C, Chignol MC, Euvrard S, Chardonnet Y.
Papillomavirus humains et oncogènes cellulaires (c-myc, c-Ha-ras)
dans les lésions cutanées et muqueuses des sujets transplantés.
Bull Cancer 1992; 79: 471-82.
45. Ziegler A, Lefell DJ, Kunala S, Sharma HW, Gailani M, Simon JA,
Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash DE. Mutation hotspots
due to sunlight in the p53 gene of non-melanoma skin cancers. Proc
Natl Acad Sci USA 1993; 90: 4216-20.
46. Basset-Seguin N, Molès JP, Mils V, Dereure O, Guilhou JJ.
TP53 tumor suppressor gene and skin carcinogenesis. J Invest Dermatol
1994; 103: 102s-6s.
47. Stark LA, Arends MJ, McLaren KM, Benton EC, Shahidullah H, Hunter
JAA, Bird CC. Accumulation of p53 is associated with tumour progression
in cutaneous lesions of renal allograft recipients. Br J Cancer
1994; 70: 662-7.
48. McGregor JM, Farthing A, Crook T, Yu CCW, Dublin EA, Levison DA,
Mac Donald DM. Post-transplant skin cancer: a possible role for p53 gene
mutation but not for oncogenic human papillomaviruses. J Am Acad Dermatol
1994; 30: 701-6.
49. Inohara S, Kitagawa K, Kitano Y. Expression of cyclin D1 and p53
protein in various malignant skin tumors. Dermatology 1996; 192:
94-8.
50. Zerfass K, Schulze A, Spitkovsky D, Friedman V, Henglein B, Jansen-Dürr
P. Sequential activation of cyclin E and cyclin A gene expression by human
papillomavirus type 16 E7 through sequences necessary for transformation.
J Virol 1995; 69: 6389-99.
51. Inohara S, Kitano Y, Kitagawa K. Cell cycle regulators in the keratinocyte
(cyclin-cdk). Exp Dermatol 1995; 4: 1-8.
52. Kato M, Ishizaki A, Hellman U, Wernsted C, Kyogokut M, Miyazono
K, Heldin CH, Funa K. A human keratinocyte cell line produces two autocrine
growth inhibitors, transforming growth factor-ß and insulin-like
growth factor binding protein-6, in a calcium- and cell density-dependent
manner. J Biol Chem 1995; 270: 12373-9.
53. Banks L, Matlashewski G. Cell transformation and the HPV E5
gene. Papillomavirus Rep 1993; 4: 1-4.
54. Mckay IA, Winyard P, Leigh IM, Bustin SA. Nuclear transcription
factors: potential targets for new modes of intervention in skin disease.
Brit J Dermatol 1994; 131: 591-7.
55. Finco TS, Baldwin AS. Mechanistic aspects of NFkappaB regulation.
The emerging role of phophorylation and proteolysis. Immunity 1995;
3: 263-72.
56. Jain J, McCaffrey PG, Valge-Archer VE, Rao A. Nuclear factor of
activated T cells contains Fos and Jun. Nature 1992; 356: 801-4.
57. Simon MM, Aragane Y, Schwartz A, Luger TA, Schwartz T. UVB light
induces nuclear factor kappaB (NFkappaB) activity independently from chromosomal
DNA damage in cell-free cytosolic extracts. J Invest Dermatol 1994;
102: 422-7.
58. Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Vorhees
JJ. Molecular basis of sun-induced premature skin ageing and retinoid
antagonism. Nature 1996; 379: 335-9.
59. Corsini E, Bruccoleri A, Marinovich M, Galli CL. In vitro
mechanism(s) of ultraviolet-induced tumor necrosis factor-alpha release
in a human keratinocyte cell line. Photodermatol Photoimmunol Photomed
1995; 11: 112-8.
60. Karlen S, Offord EA, Beard P. Herpes simplex virions interfere with
the expression of human papillomavirus type 18 genes. J Gen Virol
1993; 74: 965-73.
61. Zur Hausen H. Roots and perspectives of contemporary papillomavirus
research. J Cancer Res Clin Oncol 1996; 122: 3-13.
62. Pfister H, Gross G, Hagedorn M. Characterization of human papillomavirus
3 in warts of a renal allograft patient. J Invest Dermatol 1979;
73: 349-53.
63. Lutzner M, Croissant O, Ducasse MF, Kreis H, Crosnier J, Orth G.
Potentially oncogenic human papillomavirus (HPV5) found in two renal allograft
recipients. J Invest Dermatol 1980; 75: 353-6.
64. Rüdlinger R, Smith IW, Bunney MH, Hunter JAA. Human papillomavirus
infections in a group of renal transplant recipients. Br J Dermatol
1986; 115: 681-92.
65. Gassenmaier A, Fuchs P, Schell H, Pfister H. Papillomavirus DNA
in warts of immunosuppressed renal allograft recipients. Arch Dermatol
Res 1986; 278: 219-23.
66. Bunney MH, Barr BB, McLaren K, Smith IW, Benton EC, Anderton JL,
Hunter JAA. Human papillomavirus type 5 and skin cancer in renal allograft
recipients. Lancet 1987; 2: 151-2.
67. Van der Leest RJ, Zachow KR, Ostrow RS, Bender M, Pass F, Faras
AJ. Human papillomavirus heterogeneity in 36 renal transplant recipients.
Arch Dermatol 1987; 123: 354-7.
68. Rüdlinger R, Bunney MH, Smith IW, Hunter JAA. Detection of
a human papillomavirus type 5 DNA in a renal allograft patient from Scotland.
Dermatologica 1988; 177: 280-6.
69. Blessing K, McLaren KM, Benton EC, Barr BBB, Bunney MH, Smith IW,
Beveridge GW. Histopathology of skin lesions in renal allograft recipients
an assessment of viral features and dysplasia. Histopathology
1989; 14: 129-39.
70. Blessing K, McLaren KM, Morris R, Barr BBB, Benton EC, Alloub M,
Bunney MH, Smith IW, Smart GE, Bird CC. Detection of human papillomavirus
in skin and genital lesions of renal allograft recipients by in situ
hybridization. Histopathology 1990; 16: 181-5.
71. Dyall-Smith D, Trowell H, Mark A, Dyall-Smith M. Benign human papillomavirus
infection in renal transplant recipients. Int J Dermatol 1991;
30: 785-9.
72. Dyall-Smith D, Trowell H, Mark A, Dyall-Smith M. Cutaneous squamous
cell carcinomas and papillomaviruses in renal transplant recipients: a
clinical and molecular biological study. J Dermatol Sci 1991; 2:
139-46.
73. Smith S, Davis IC, Leshin B, Fleischer AB, White WL, Feldman SR.
Absence of human papillomavirus in squamous cell carcinomas of nongenital
skin from immunocompromised renal transplant patients. Arch Dermatol
1993; 129: 1585-8.
74. Tieben LM, Berkhout RJM, Smits HL, Bouwes-Bawinck JN, Vermeer BJ,
Bruijn JA, Van der Woude FJ, Ter Schegget J. Detection of epidermodysplasia
verruciformis-like human papillomavirus types in malignant and premalignant
skin lesions of renal transplant recipients. Br J Dermatol 1994;
131: 226-30.
75. Shamanin V, Glover M, Rausch C, Proby C, Leigh IM, zur Hausen H,
de Villiers EM. Specific types of human papillomavirus found in benign
proliferations and carcinomas of the skin in immunosuppressed patients.
Cancer Res 1994; 54: 4610-3.
76. Berkhout RJM, Tieben LM, Smits HL, Bouwes Bavinck JN, Vermeer BJ,
Ter Schegget J. Nested PCR approach for detection and typing of epidermodysplasia
verruciformis-associated human papillomavirus types in cutaneous cancers
from renal transplant recipients. J Clin Microbiol 1995; 33: 690-5.
77. De Jong-Tieben LM, Berkout RJM, Smits HL, Bouwes Bavinck JN, Vermeer
BJ, Van der Woude FJ, Ter Schegget J. High frequency of detection of epidermodysplasia
verruciformis-associated human papillomavirus DNA in biopsies from malignant
and premalignant skin lesions from renal transplant recipients. J Invest
Dermatol 1995; 105: 367-71.
78. Goldberg LH, Griego RD. Absence of human papillomavirus in squamous
cell carcinomas of nongenital skin from immunocompromised renal transplant
patients: a comment. Arch Dermatol 1995; 131: 107.
79. Euvrard S, Chardonnet Y, Pouteil-Noble C, Kanitakis J, Chignol MC,
Thivolet J, Touraine JL. Association of skin malignancies with various
and multiple carcinogenic and non-carcinogenic human papillomaviruses
in renal transplant recipients. Cancer 1993; 72: 2198-206.
80. Soler C, Allibert P, Chardonnet Y, Cros P, Mandrand B, Thivolet
J. Detection of human papillomavirus types 6, 11, 16 and 18 in mucosal
and cutaneous lesions by the multiplex polymerase reaction. J Virol
Methods 1991; 35: 143-57.
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