Skin Carcinoma Arising From Donor Cells in a Kidney ... · regimen was an association of...

Skin Carcinoma Arising From Donor Cells in a Kidney

Transplant Recipient

Selim Aractingi,1,2Jean Kanitakis,

4Sylvie Euvrard,

4Caroline Le Danff,

2Isabelle Peguillet,

3

Kiarash Khosrotehrani,1Olivier Lantz,

3and Edgardo D. Carosella

2

1Unite de Dermatologie, Hopital Tenon; 2SRHI (DRM/DSV), CEA, Hopital St. Louis; 3Laboratoire d’Immunologie, Institut Curie, Paris;and 4Service de Dermatologie, Hopital Edouard Herriot, Lyon, France

Abstract

The incidence of skin cancer is increased in transplantrecipients. UV radiation, papillomaviruses, and immunosup-pression participate in the pathogenesis of these tumors. Inaddition, donor cells may leave the grafted organ, reachperipheral tissues and either induce immune phenomena orpossibly take part in tissue remodeling. Herein, we investigat-ed the possible involvement of donor cells in the developmentof skin tumors in kidney allograft recipients. We analyzed aseries of 48 malignant and benign cutaneous tumorsdeveloping in 14 females who had been grafted with a malekidney. The number of male cells was measured on micro-dissected material by quantitative PCR for Y chromosome. Inthe samples with high levels of male cells, fluorescent in situhybridization (FISH) with X and Y probes and/or immuno-FISH with anticytokeratin antibodies were carried out. Malecells were detected in 5/15 squamous cell carcinomas andBowen disease (range 4-180 copies), 3/5 basal cell carcinomas(91-645), 6/11 actinic keratosis (7-102), 2/4 keratoacanthoma(22-41), and 2/5 benign cutaneous lesions (14-55). In a basalcell carcinoma specimen with a high number of male cells,FISH showed that most cells within the tumoral buds were XY.In this lesion, immuno-FISH showed the presence of XYcytokeratin-positive cells indicating that the tumor nestscontained male keratinocytes. In contrast, in other femaletransplants, male cells present in the tumors were notepithelial. In conclusion, stem cells originating from a graftedkidney may migrate to the skin, differentiate, or fuse askeratinocytes that could, rarely, undergo cancer transforma-tion. (Cancer Res 2005; 65(5): 1755-60)

Introduction

Solid graft transplantation is associated with an increased risk ofneoplasms, essentially cutaneous carcinomas, and to a lowerdegree, lymphomas (1–3). In kidney graft recipients, the relativerisk of development of skin carcinomas is 10 to 250 times higherthan in matched controls (4). UV-induced mutations (5, 6), humanpapillomavirus infections (7, 8), and immunodepression have beenimplicated in the pathogeny of these tumors. Occurrence ofcarcinomas is also correlated with human leukocyte antigen Bmismatching between donor and recipient (9) suggesting the

involvement of immunologic phenomena. In solid organ transplantrecipients, hematopoietic donor cells are frequently found inrecipient blood and microchimeric cells are found in differenttissues (10, 11). This phenomenon may be involved in low-gradegraft versus host disease (12), or in contrast, in specific tolerancetowards the donor (13). Besides, plasticity of hematopoietic stemcells has been shown with possible differentiation of CD34-positivetransferred cells into epithelial cells such as keratinocytes (14).Similarly, fetal microchimerism may participate in tissue repair orremodeling because a fully differentiated thyroid follicle wascomposed of male XY cells in a female patient—previouslypregnant with a male baby—who had a progressively enlarginggoiter (15). Thus, donor cells which circulate in the recipient bodymay have immunomodulatory activity and/or differentiate intovarious tissues.To investigate the possible involvement of these two phenomena

in transplant recipient tumor development, we measured theamount of donor-derived cells in benign and malignant skinspecimens from kidney transplant recipients. Fluorescent in situhybridization (FISH) on specimens displaying high amounts ofdonor cells allowed us to find one basal cell carcinoma (BCC)deriving from the donor.

Materials and Methods

Specimens. A series of 48 routine cutaneous biopsies from 14 femalerecipients grafted with a male kidney were collected for this study.

Paraffin-embedded sections of different thicknesses were used for

microdissection or FISH, or FISH together with immunohistochemistry(immuno-FISH). In addition, control specimens corresponding to BCCs

from nongrafted females (n = 8), from nevi obtained from prepubertal

girls (n = 8), and from male inflammatory skin, nevi, and BCC (n = 5)

were also analyzed.

Evaluation of the Density of Inflammatory Infiltrate. Because the

peripheral blood of transplant recipients may also contain donor cells, we

evaluated the inflammatory infiltrate found in these tumors. Skin cancersarising in grafted recipients are known to disclose less dense inflammatory

infiltrates when compared with similar tumors in immunocompetent

individuals (16). Thus, finding differences in microchimerism in skin

samples could simply reflect differences in inflammation with passiverecruitment of donor circulating cells within the skin tumors. Blinded

evaluation of the inflammatory infiltrate was done by one of us (J. Kanitakis).

The density was graded as discrete (1), median (2), or intense (3).

Microdissection. Microdissection was done on thick paraffin-embedded

8-Am sections. Special precautions were taken to prevent PCR contamina-

tion. Sections were carried out by a single female technician, each timeusing a new slide box and a sterile knife. Sections were deparaffinized in

toluene for 10 minutes, rinsed in four successive ethanol solutions (pure,

75%, 50%, and 30%) and finally in water. After drying, the sections were

incubated in 2.5% glycerol for 3 minutes. In order to obtain identicalvolumes of microdissected tissue in all specimens, a 4 mm diameter surface

was delineated with a 4 mm punch biopsy. Then, using the tip of a sterile

Note: O. Lantz and E.D. Carosella share senior authorship.Present address of S. Aractingi and K. Khosrotehrani is: Upres EA 2936, UFR St.

Antoine (Universite Paris VI) 27, rue de Chaligny, 75012 Paris, France.Requests for reprints: Edgardo Carosella, SRHI (DRM/DSV), CEA, Hopital St.

Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. Phone: 33-1-53 72 21 98; Fax: 33-1-48 03 19 60; E-mail: [email protected].

I2005 American Association for Cancer Research.

www.aacrjournals.org 1755 Cancer Res 2005; 65: (5). March 1, 2005

Research Article

Research. on July 28, 2020. © 2005 American Association for Cancercancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

needle (25-gauge), the 4 mm surface was gently scraped until detachment.The material attached to the needle was transferred into an Eppendorf tube

and pooled material from two consecutive sections was subjected to the

digestion process described below.

Real-time Quantitative PCR. Scraped material from the tissue

sections was digested with 50 mmol Tris-HCl, 1 mmol EDTA, Tween 20

0.5%, 200 Ag/mL proteinase K in a final volume of 50 AL at 37jC overnight

followed by denaturation at 95jC for 20 minutes. Ten microliters of thedigested material was amplified in a 25 AL volume with the following SRY

primers: 245R, 5V-CCC CCT AgT ACC CTg ACA ATg TAT T-3V; and 109F,

5V-Tgg CgA TTA AgT CAA ATT CGC-3V, the probe being 142T-Fam/Tamra:

5V-AgC AgT AgA gCA gTC Agg gAg gCA gA-3.To enable quantitation, a scale was constructed by digestion of serial

dilutions of male cells into 2,000 female cells (the average number of

amplifiable genomes recovered from 1/5 of the digested tissue sections).The scales were amplified in the same experiments as the experimental

samples to compute absolute values for SRY copies. Real-time

quantitative PCR was carried out in an ABI prism 7700 apparatus. The

reaction mixture was 10 mmol Tris-HCl, 50 mmol KCl, 4 mmol MgCl2,200 Amol/L deoxynucleotide triphosphate, 0.4 Amol/L 5V- and 3V-primers,

0.6 Amol/L probe, 1 unit Taq Platinum (Invitrogen, Carlsbad, CA), in a

final volume of 25 AL.An example of a Y scale is shown in Fig. 1. The assay allowed the

detection of one to two male cells (Fig. 1). The presence of amplifiable

material and the absence of inhibitors in all samples was checked by

amplifying a T cell receptor-a constant locus with the following primers and

probe 5V-Cah, AgAACCCTgACCCTgCCgTgT, 3V-Cah, gggCTggggAA-gAAggTgTCTT, pCah-Fam/Tamra hCA, gCATgTgCAAACgCCTTCAACAACA.

Only samples harboring more than 500 copies of T cell receptor-a were

taken into account.

Fluorescent In situ Hybridization. Samples harboring more than 20

copies of Y sequence by PCR as well as a few negative controls were

analyzed by FISH when material was available. FISH was carried out asdescribed (17). Briefly, 5-Am skin sections were deparaffinized and then

rehydrated in ethanol series. DNA was denatured by incubation in

0.2 mol/L HCl for 15 minutes. After incubation with proteinase K, the

slides were treated with 4% formaldehyde and dehydrated. The XY cocktailprobes (Vysis, Downers Grove, IL) was applied and after closure with

rubber cement, the probes and the DNA were denatured and incubatedovernight at 42C. The next day, counterstaining was done with 0.03 Ag/mL

4V,6-diamidino-2-phenylindole. The percentage of male cells was quanti-

fied by counting the intranuclear X,Y spots in several fields using the

following formula:

100YðX�YÞ

2þ Y

Combined Immunohistochemical Analysis and FISH. The procedure

was done as described above until the counterstaining step. Slides were

incubated with mouse anti-human cytokeratin AE1/AE3 for 2 hours andrevealed with 7-amino-4-methylcoumarin-3-acetic acid–conjugated anti-

mouse immunoglobulin (Coger). Readings of FISH and immuno-FISH were

done using confocal microscopy. CD45 staining was done as previously

described (18).

Case Report of gr9-Bearing Patient. This patient was a 33-year-old

female grafted with a male kidney for membranoproliferative glomerulo-

nephritis in 1983. She was of fair complexion (phototype II). The donor washuman leukocyte antigen A1/A2, B8/B27, whereas the patient was human

leukocyte antigen Aw30/w32, B5/B40, DR2/DR6. The immunosuppressive

regimen was an association of azathioprine and steroids. She had numerous

sessions of cryotherapy for actinic keratosis and surgical excisions of fiveBCC (including the gr9), four squamous cell carcinomas, two keratoacan-

thomas, and seven actinic keratoses. The gr9 tumor was excised in 2000,

that is, 17 years after the transplantation. She was not married and reportedno prior pregnancies. She had been transfused only before transplantation

in 1982, but the RBC donor sex was not known.

Results

In Allograft Recipients, Microchimerism is Found in AllCategories of Skin Specimens. To detect the presence of malecells in allograft recipient skin tumors, DNA was recovered fromthe tumor tissue sections and subjected to Y sequence-specificPCR amplification. Amplification curves of the samples were

Figure 1. SRY real-time PCR analysis ofmale cells diluted in female cells. Theexperiment shows that one to twomale cells are detected. The curvescorresponding to the prepubertalfemale nevus are not presented becausethere was no signal.

Cancer Research

Cancer Res 2005; 65: (5). March 1, 2005 1756 www.aacrjournals.org



compared with those of serial dilutions of male into female cellsenabling absolute quantification of the male copy number.Numerous negative controls [without DNA and prepubertalfemale skin samples (nevi)] were included in all experiments toshow the absence of PCR contamination. The Y detectionsensitivity was one to two copies. Because the number ofamplifiable genomes was 500 to 3,000 cells as judged byamplifying a one-copy autosomal gene (data not shown), themicrochimerism sensitivity detection limit was between 0.2% and0.03%. In addition, analysis of female peripheral blood lympho-cytes as well as of eight prepubertal females skin samples (nevi)and eight BCC from nongrafted females showed the absence ofany Y signal, confirming the specificity of quantitative PCRwhich has been previously validated by others (19).The complete results are shown in Fig. 2. Amplifiable DNA was

present in 40/48 specimens. Male cells were detected in 5/15squamous cell carcinoma/Bowen specimens, 3/5 BCC, 6/11actinic keratosis, 2/4 keratoacanthoma, and 2/5 benign lesions.In the positive samples, the ranges of male copy numbers were4 to 180 in squamous cell carcinomas, 91 to 645 in BCC, 7 to102 in actinic keratosis, 22 to 41 in keratoacanthoma, and 14 to55 in benign lesions. In the eight nongrafted females with BCC ornevi, male cells were never detected (Fig. 2), confirming thespecificity of the procedure.There was no statistically significant differences in the number

of male cells as well as the number of Y-positive samples betweenthe groups (Kruskal-Wallis test).The mean inflammatory infiltrate densities were 2.3 in the

patients with squamous cell carcinoma/Bowen (range, 1-3), 2.4 in

Figure 2. Quantitative evaluation of SRY sequences in microdissectedspecimens of cutaneous tumors obtained from females grafted with malekidneys. BCC, basal cell carcinomas; SCC/Bowen, squamous cell carcinomaand Bowen’s disease (which is an in situ carcinoma); AK, actinic keratosis;KA, keratoacanthoma; Benign, benign lesions such as warts, molluscum,and nevi. Controls were obtained from prepubertal specimens of female nevi.

Figure 3. X and Y FISH analysis of gr9 and controls.Red spots, Y chromosomes; green spots,X chromosome. A and B, the gr9 BCC with normal XXoverlying epidermis (A ) and several XY cells(white arrows ) in tumoral nests in two differentfields (A and B ). C, male specimen with several XYcells in epidermis and dermis. D, FISH resultof a cutaneous specimen of a female grafted with amale kidney but which did not show the presence of Ysequence by PCR. There was also no male cellby PCR in this specimen.

Carcinoma from Donor Cells in Transplants




those with BCC (1.5-3), 2.35 in the actinic keratosis group (1–3),2.33 in keratoacanthoma (2-2.5), and 1 within benign lesions. Asexpected, the degree of inflammation was significantly lower inthe benign lesions (Kruskal-Wallis test; P < 0.03) but was notdifferent between all the other groups of malignant orpremalignant lesions.A Specimen of Cutaneous Basal Cell Carcinoma Seems to be

Derived From Donor Cells. One specimen (gr9) revealed a veryhigh level of Y sequences by PCR (645 Y sequence; see Fig. 2),suggesting that this peculiar dorsal BCC could have been derivedfrom male keratinocytes. In order to confirm this hypothesis, FISHfor Y and X chromosome was done. In gr9 (Fig. 3A and B), manyXY cells were seen in tumoral buds, the average percentage of malecells in nine fields (taking into account both the tumor buds andthe overlying epidermis) was 40 F 10% (mean F SE). Of note,

normal overlying epidermis only displayed XX cells (Fig. 3A). Thecount of tumoral buds alone showed that there was sometimes upto 105% of cells displaying XY genotype. In control male skin(Fig. 3C), the percentage of male cells was 103 F 5%. In two otherallografted female samples in which PCR had not foundY sequences, FISH was also negative for Y chromosome(an example is shown in Fig. 3D). To more precisely show thatthe tumor epithelial cells were derived from male cells, immuno-FISH with anticytokeratin antibody was carried out. Severalcytokeratin-positive cells within dermal nests seemed to be XY,showing that malignant keratinocytes of this BCC gr9 were male(Fig. 4A and B , to compare with histology, D). In a classic sampleof male BCC, a very similar picture was found (Fig. 4C); not allthe cells displayed Y chromosome. Substitution of anticyto-keratin antibody by IgG showed the absence of any staining,

Figure 4. Immuno-FISH using X,Y cocktail andanticytokeratin AE1/AE3 antibody. A and B,gr9 showing cytokeratin-positive buds, several XYcells being present in these cytokeratin buds(white arrows ). Yellow arrow, a nonepithelial,cytokeratin-negative, male cell. C, result of a malenongrafted BCC showing results similar to gr9. D, theH&E-stained section of gr9 with typical dermalnests of BCC under the epidermis. E, specimen of afemale patient allografted with a male kidneyand with Y sequence positive by PCR. XY cells do notappear to be surrounded by cytokeratin bluestaining, indicating that these male cells were notepithelial (yellow arrow ). F, actinic keratosisdeveloping in the same female as gr9 but at anotherskin site. Presence of a few XY cells surroundedby cytokeratin within proliferating epidermis showsmale keratinocytes in this dysplastic lesion(white arrows ).

Cancer Research




demonstrating the specificity of the immune reaction (data notshown). Interestingly, some nonepithelial XY cells were seenbetween buds in gr9, probably corresponding to inflammatoryinfiltrating cells (Fig 4B , yellow arrow). Of note, the female bearingthe gr9 BCC had nine different skin samples analyzed initially byPCR. Besides gr9, two other specimens (gr42 and gr55) displayedmale sequences by PCR. One of these, an actinic keratosis (gr55)with 47 sequences of Y DNA, showed the presence of somecytokeratin-positive XY cells (Fig. 4F). In contrast, six otherspecimens (two actinic keratosis, two squamous cell carcinomas,one keratoacanthoma, and one BCC) from this woman werenegative by PCR. Two of these were nevertheless analyzed in situand FISH was also negative, demonstrating the correspondencebetween the two techniques. Therefore, the presence of male cellsis restricted to some sites in this female recipient.The analysis by immuno-FISH of six other lesions (gr27, gr28,

gr65, gr68, and gr110) obtained from other female patients, whichshowed the presence of male cells by PCR revealed the presence ofnoncytokeratin-positive XY cells (an example is shown in Fig. 4E ,yellow arrows). Combination of FISH and CD45-common leukocyteantigen-staining was done and also showed the presence of CD45+microchimeric cells (Fig. 5).

Discussion

These results show that in one patient, a skin carcinoma in akidney recipient derived—at least largely—from the donor. Indeed,dissected material from a BCC section revealed a very high level ofmale sequences. Using FISH, male cells were found in the tumornests, but not in the normal epidermis, suggesting clonal expansionof a single donor cell. Finally, immuno-FISH showed in this tumor apicture similar to the control male BCC with nests containing

several cytokeratin-positive male cells. All these data show thatepithelial tumoral buds were indeed largely composed of malekeratinocytes in a female patient. In another specimen obtainedfrom another site of the skin of the same female and featured by anactinic keratosis, a dysplastic preneoplastic lesion, male keratino-cytes were found within the proliferating epidermis. In contrast,seven other cutaneous specimens issued from the same recipientdid not reveal the presence of male epithelial cells, indicating thatthe presence of male keratinocytes within this female was nota generalized finding. Of note, because the study was done onarchival specimens, we could not test the presence of donor cellswithin the recipient’s peripheral blood lymphocytes. However,such findings are frequently described in kidney transplants,reaching levels up to 70% of cases in the literature (19, 20).In accordance, in some skin specimens, there were some donorcells expressing CD45.BCC is a primitive carcinoma of the skin derived from

keratinocytes. It is a locally invading process and metastasesare extraordinarily rare events despite prolonged evolution. Onlyfew cases of metastatic BCC are reported, these being mainly inlymph nodes or in surrounding soft tissues (21). The hypothesisthat gr9 could be a metastatic BCC transferred from a donor BCClocated within the kidney is unlikely, not only because suchmetastasis are exceptional, but also because the histopathology ofgr9 was typical of a primitive BCC (22). In addition, the gr9 BCCdeveloped 17 years after transplantation, this delay seems toolong for a metastatic evolution. Importantly, male keratinocyteswere present in an actinic keratosis at another cutaneous site inthe same recipient’s skin. Actinic keratosis is a preneoplasticdysplastic lesion which may evolve in a BCC but in contrast cannever derive from a BCC. Of note, other skin cancers, includingBCC, arising at other sites of this female patient were exclusivelycomposed of female cells, demonstrating that this patient wasprone to multiple primitive tumors. Thus, gr9 appears as a maleBCC that could not have originated from an adoptivelytransferred tumor.Several publications recently reported the fate of chimeric cells

in recipient’s tissues. When female patients were grafted with maleperipheral blood hematopoietic stem cells, male cytokeratin-positive keratinocytes were found within the normal skin (14). Intransplanted hearts without any rejection or inflammation, 9% to10% of myocytes, arterioles, and capillaries were in fact issued fromthe host (23). In the same way, in grafted kidneys, 23% to 38% ofmesenchymal cells originated from the recipient rather than thedonor (24). Such seeding does not result only from allogeneictransplantations, but also from pregnancies. Indeed in a female,liver male cells—precisely analyzed by PCR—showed that theseoriginated from a stillbirth which occurred 20 years earlier (25).The presence of fetal mesenchymal stem cells in the marrow offemales has recently been shown (26), while evidence for thepresence of fetal cells differentiated in several types of peripheralorgans in mothers of male babies born several years or decadesbefore were also obtained (27).The kidney recipient female with the gr9 and gr55 tumors had

never been pregnant but was transfused 18 years before. The donorcells which are implicated in carcinogenesis were therefore mostprobably provided by her male grafted kidney rather than by bloodtransfusion. In this observation, the donor cells adopted the hosttissue phenotype. Whether the donor cells giving rise tokeratinocytes are hematopoietic or tissue-specific stem cells (28)is unknown.

Figure 5. Immuno-FISH using X,Y cocktail and anti-CD45 antibody on a skintumor. Presence of a male (donor-derived, arrow) CD45+ cell in the dermis.Attention is required here, because in this experiment, Y chromosome waslabeled in green and X chromosome in red . CD45 staining appears as abrownish-red ring shape around the cell. Nuclei were counterstained with 4V,6-diamidino-2-phenylindole (blue ).

Carcinoma from Donor Cells in Transplants




Our results show that donor cells, displaying a keratinocytephenotype, may undergo cancer transformation in the host. Cancertransformation of these cells is possible. Indeed, these cells willbehave in the recipient’s epidermis as other keratinocytes. Eventsimplicated into cancer transformation in the skin of solid graftrecipients are mainly mutations induced by UV radiation. Humanpapillomavirus infection may augment this process by impairmentof the process of DNA repair or by prevention of apoptosisafter exposure to UV radiation (5–8). Keratinocytes issued fromthe transdifferentiation of donor stem cells may therefore undergotransformation under the influence of the same factors. Alterna-tively, these donor-derived male keratinocytes may be fused cells.Indeed, a recent study have shown that, in vitro , stem cells couldfuse with differentiated cells leading to overdiploid cells whichadopted the differentiated phenotype (29). Because archival speci-mens were fixed, karyotypic analysis was not done, we cannotexclude that such fusion may have occurred here. Overdiploid cellswould be—because of their genetic abnormalities—prone toundergo cancer transformation.A recent study interestingly showed that Kaposi’s sarcoma cells

in renal transplant recipients harbored in five out of eight

samples, markers of the donor demonstrating that suchneoplastic cells may frequently derive from donors (30). However,Kaposi’s sarcoma progenitor cells are possibly hematopoietic cells.Therefore, although the trafficking of donor hematopoietic cells inskin lesions of grafted patients is a frequent phenomenon—asillustrated in the Kaposi’s sarcoma study (30) and in this study (inmost of our samples, male cells were not epithelial)—the presenceof donor-derived epithelial tumoral cells remains a rare event.In conclusion, after transplantation, there are donor cells that

can seed (or fuse with) the skin epithelium where they may rarelyundergo neoplastic transformation. Future studies targeting theorigin of cancers in other situations with putative microchimerism,such as pregnancy or RBC transfusion, may help to determine ifsuch new possibilities exist.

Acknowledgments

Received 8/3/2004; revised 11/23/2004; accepted 12/16/2004.The costs of publication of this article were defrayed in part by the payment of page

charges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Drs. Jeanne Luce Garnier and Nicole Lefrancois, who were in chargeof the kidney transplantation follow-up of the studied patients.

References1. Bouwes Bavinck JN, Hardie DR, Green A, et al. Therisk of skin cancer in renal transplant recipients inQueensland, Australia. A follow-up study. Transplan-tation 1996;61:715–21.

2. Euvrard S, Kanitakis J, Pouteil-Noble C, et al.Comparative epidemiologic study of premalignant andmalignant epithelial cutaneous lesions developing afterkidney and heart transplantation. J Am Acad Dermatol1995;33:222–9.

3. Melosky B, Karim M, Chui A, et al. Lymphoprolifer-ative disorders after renal transplantation in patientsreceiving triple or quadruple immunosuppression. J AmSoc Nephrol 1992;2:S290–4.

4. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ,Vandenbroucke JP. Incidence of skin cancer after renaltransplantation in The Netherlands. Transplantation1990;49:506–9.

5. Boyle J, MacKie RM, Briggs JD, Junor BJ, Aitchison TC.Cancer, warts, and sunshine in renal transplantpatients. A case-control study. Lancet 1984;31:702–5.

6. McGregor JM, Berkhout RJ, Rozycka M, et al. p53mutations implicate sunlight in post-transplant skincancer irrespective of human papillomavirus status.Oncogene 1997;2;15:1737–40.

7. Euvrard S, Chardonnet Y, Pouteil-Noble C, et al.Association of skin malignancies with various andmultiple carcinogenic and noncarcinogenic humanpapillomaviruses in renal transplant recipients. Cancer1993,72:2198–206.

8. de Jong-Tieben LM, Berkhout RJ, Smits HL, et al. Highfrequency of detection of epidermodysplasia verruci-formis-associated human papillomavirus DNA in biop-sies from malignant and premalignant skin lesions fromrenal transplant recipients. J Invest Dermatol 1995;105:367–71.

9. Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ,et al. Relation between skin cancer and HLA antigensin renal-transplant recipients. N Engl J Med 1991;325:843–8.

10. Suberbielle C, Caillat-Zucman S, Legendre C, et al.Peripheral microchimerism in long-term cadaveric-kidney allograft recipients. Lancet 1994;343:1468–922.

11. Sivasai KS, Alevy YG, Duffy BF, et al. Peripheral bloodmicrochimerism in human liver and renal transplantrecipients: rejection despite donor-specific chimerism.Transplantation 1997;64:427–32.

12. Kimball P, Ham J, Eisenberg M, et al. Lethal graft-versus-host disease after simultaneous kidney-pancreastransplantation. Transplantation 1997;63:1685–8.

13. Starzl TE, Demetris AJ, Murase N, Trucco M,Thomson AW, Rao AS. The lost chord: microchimerismand allograft survival. Immunol Today 1996;17:577–84.

14. Korbling M, Katz RL, Khanna A, et al. Hepatocytesand epithelial cells of donor origin in recipients ofperipheral-blood stem cells. N Engl J Med 2002;346:738–46.

15. Srivatsa B, Srivatsa S, Johnson KL, Samura O, Lee SL,Bianchi DW. Microchimerism of presumed fetal originin thyroid specimens from women: a case-control study.Lancet 2001;358:2034–8.

16. Viac J, Chardonnet Y, Euvrard S, Chignol MC,Thivolet J. Langerhans cells, inflammation markersand human papillomavirus infections in benign andmalignant epithelial tumors from transplant recipients.Dermatology 1992;19:67–77.

17. Johnson KL, Zhen DK, Bianchi DW. The use of FISHon paraffin-embedded tissue sections for the study ofmicrochimerism. BioTechniques 2000;29:1220–4.

18. Khosrotehrani K, Stroh H, Bianchi DW, Johnson KL.Combined FISH and immunolabeling on paraffin-embedded tissue sections for the study of micro-chimerism. BioTechniques 2003;34:242–4.

19. Elwood ET, Larsen CP, Maurer DH, et al. Micro-chimerism and rejection in clinical transplantation.Lancet 1997;349:1358–60.

20. Krovvidi SR, Alevy GL, Duffy BF, et al. Transplantation1997;64:427–32.

21. Snow SN, Sahl W, Lo JS, et al. Metastatic basal cellcarcinoma. Report of five cases. Cancer 1994;73:328–35.

22. Giri DD, Gupta PK, Hoda RS. Cytologic diagnosisof metastatic basal cell carcinoma. Report of a casewith immunocytochemical and molecular pathologicconsiderations. Acta Cytol 2000;44:232–5.

23. Quaini F, Urbanek K, Beltrami AP, et al. Chimerism ofthe transplanted heart. N Engl J Med 2002;346:5–15.

24. Grimm PC, Nickerson P, Jeffery J, et al. Neointimaland tubulointerstitial infiltration by recipient mesen-chymal cells in chronic renal-allograft rejection. N EnglJ Med 2001;345:93–7.

25. Johnson KL, Samura O, Nelson JL, McDonnell M,Bianchi DW. Significant fetal cell microchimerism in anontransfused woman with hepatitis C: Evidence oflong-term survival and expansion. Hepatology 2002;36:1295–7.

26. Khosrotehrani K, Johnson KL, Cha DH, Salomon R,Bianchi DW. Transfer of fetal cells with multilineagepotential to maternal tissue. JAMA 2004;292:75–80.

27. O’Donoghue K, Chan J, de la Fuente J, et al.Microchimerism in female bone marrow and bonedecades after fetal mesenchymal stem-cell trafficking inpregnancy. Lancet 2004;364:179–82.

28. Al-Awqati Q, Oliver JA. Stem cells in the kidney.Kidney Int 2002;61:387–95.

29. Terada N, Hamazaki T, Oka M, et al. Bone marrowcells adopt the phenotype of other cells by spontaneouscell fusion. Nature 2002;416:542–5.

30. Barozzi P, Luppi M, Facchetti F, et al. Post-transplantKaposi sarcoma originates from the seeding of donor-derived progenitors. Nat Med 2003;9:554–61.

Cancer Research




2005;65:1755-1760. Cancer Res Sélim Aractingi, Jean Kanitakis, Sylvie Euvrard, et al. Transplant RecipientSkin Carcinoma Arising From Donor Cells in a Kidney

Updated version

http://cancerres.aacrjournals.org/content/65/5/1755

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. (CCC)Click on "Request Permissions" which will take you to the Copyright Clearance Center's

.http://cancerres.aacrjournals.org/content/65/5/1755To request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



Skin Carcinoma Arising From Donor Cells in a Kidney ... · regimen was an association of...

Documents

Transcript of Skin Carcinoma Arising From Donor Cells in a Kidney ... · regimen was an association of...