Characteristics of the Lesions and Risk of Malignant Conversion Associated with the Type of Human Papillomavirus Involved in Epidermodysplasia Verruciformis1

[CANCER RESEARCH 39, 1074-1082, March 1979] 0008-5472/79/0039-0000$02.0O Characteristics of the Lesions and Risk of Malignant Conversion Associated with the Type of Human Papillomavirus Involved in Epidermodysplasia Verruciformis1

Gerard Orth, Stefania Jablonska, Maria Jarzabek-Chorzelska, Slavomir Obalek, Genowefa Rzesa, Michel Favre, and OdIle Croissant

Unite de Recherche sur rEtiologie Virale des Cancers Huma!ns, LA 147 CNRS, u 140 INSERM, lnstitut Gustave-Roussy, 94800 villejuIf, France (G. 0., M. F.J;Department of Dermatology, WarsawSchool of Medicine, Warsaw, Poland (S. J., M. J-C., S. 0., G. A.); and unite d'Oncologie virale, Ddpartement de virologie, lnstitut Pasteur, 75015 Paris, France (0. C.J

ABSTRACT or Bowen's carcinomas), but squamous or basal call carci nomas are also found (9, 11, 15, 25). Many cases occur in Fourteen patients with apidarmodysplasia vermucifommis families, and EV has bean considered as a ganodermatosis, were studied to correlate the type of human papilbomavimus probably transmitted by an autosomal recessive gene (11, (HPV) found in benign lesions to their clinical aspects and 15, 23). Most of the patients thus far investigated showed to the course of the disease; nine patients ware familial abnormal cell-mediated immunity (5, 22). cases, and six had carcinomas. The type of the virus was Flat wart-like EV lesions ware shown to be transmittable determined by the RNA-DNA filter hybridization technique, by auto- or heteroinoculation (10, 11, 14). Typical papibbo using complementary ANA's transcribed from the DNA's of mavirus particles ware regularly found by electron micros the four types of HPV's previously identified, and by immu copy in benign lesions (1, 6, 7, 23, 25, 26, 29). They were nofluorascenca studies, using antisera specific for the four also observed by some authors in in situ carcinomas (3, 25, types of viruses. HPV type 3 was found in seven patients 29) but were never detected in advanced malignant lesions presenting lesions of only the varmuca plana type. These (1 , 3, 8, 9, 25, 27, 29). It was bong thought that the virus cases ware mostly stationary or abortive and showed no found in EV lesions was responsible for all viral skin warts malignant conversion. HPV type 4 was detected in four (19, 24). It is only recently that different types of HPV patients with lesions of different types: vary flat, often showing distinct antiganic properties and only little DNA reddish warts; reddish plaques; and pitymiasis vemsicobor sequence homology were characterized in skin lesions (4, bike pigmented or achmomic plaques. All these patients 17â€”21)andthat tha association of EV with particular types showed cancers. Both types of viruses ware found in two of HPV was demonstrated (20, 21). Of the 4 HPV types patients: HPV type 3 in flat wart-like lesions and, for one characterized in our studies, 2 of them, HPV-3 and HPV-4, patient, in large confluent pigmented plaques and HPV type ware found in EV lesions (20). Furthermore, our previous 4 in reddish or pitymiasis varsicobom-like plaques. One of study involving 11 patients (5 of them with cancers) had these patients had early malignant lesions (Bowen's dis suggested that the aspect of EV lesions and the probability ease), and the other had multiple carcinomas. For one of malignant transformation could depend on the virus type patient, the type of virus could not be identified because of (20). The aim of the present studies is to extend these an insufficient amount of material. results to 3 additional patients (one with cancers) and to These results point to the moleof virus in the pathoganasis analyze the correlation between the type of the virus, the of epidammodysplasia vammuciformis,together with genetic clinical aspect of the lesions, and the course of the disease. and immunological factors. They suggest, in addition, dif fement oncogenic potentials for viruses involved in the disease. MATERIALSAND METHODS Sample Collection. Scrapings and biopsies of lesions INTRODUCTION were collected from patients with EV who ware attending the Department of Dermatology, Warsaw School of Medi EV2 (13) is a mare, lifelong disease characterized by cine (Table 1). For virus purification and viral DNA extrac disseminated skin lesions which usually resemble flat warts tion, repeated samples from some patients and, for some of but may appear also as reddish plaques or pitymiasis vemsi them, from various types of lesions were collected in color-bike pigmented or achromic lesions (for review, sea Eagle's minimum essential medium containing antibiotics Aafs. 9, 11, 15, and 25). Malignant transformation of some and ware stored until use at â€”70Â°.Forimmunofluorescenca of the lesions has bean observed in 25 to 30% of the cases; studies, biopsies ware either processed immediately or cancers are usually of the Bowan's type (Bowan's disease frozen in liquid nitrogen 12 to 24 hr after collection in culture medium. I Supported by Grant PR6. 26/76 for Cancer Research from the Polish Virus PurIfication and Viral DNA Preparation. EV HPV's Government and Grants ATP 28.76.60, CRL 76.4.100.1 , ASR 1.005, and 014 from Institut National de Ia Sante et de Ia Recherche MÃ©dicale. ware purified from the pooled scrapings of each of the 2 The abbreviations used are: EV, epidermodysplasia vemruciformis; HPV, patients, T. G., J. K., E. D., J. D., and S. M., and HPV-1and human papillomavirus; HPV-3, human papillomavirus type 3; HPV-4, human HPV-2 were purified from deep plantar warts and hand papillomavirustype4; HPV-1,humanpapillomavirustype1; HPV-2,human papillomavirus type 2; cRNA, complementary RNA. common warts, respectively, as previously described (18, Received July 5, 1978; accepted November 15, 1978. 20). Viral DNA's were obtained either by extraction from the

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. Role of Virus in EV vinions (20) or by selective extraction from the lesions (18), were incubated for 30 mm at 37Â°with fluorescein-labebed and DNA concentration was determined by electron micros anti-HPV-1 bgG. For indirect immunofluorescanca tests, copy as previously described (18). sections ware incubated for 30 mm at 37Â°with diluted Molecular Hybridization Experiments. DNA's from HPV antisera or preimmune sara and then, after washing, with 1, HPV-2, J. D. HPV, and J. K. HPV (taken as prototypical fluorascein-labebad anti-guinea pig IgG rabbit lgG at a HPV-3 and HPV-4, respectively), as well as from T. G. HPV, concentration of 0.5 mg/mI (fluorescein to protein molar were transcribed in vitro into cANA's, using Escharichia ratio ranging from 1 to 2.5)(16, 20). Sectionsware mounted coli ANA polymerasa containing a-factor (a gift from S. in buffered glycerol (pH 8.0), examined, and photographed Saragosti, Institut Pasteur, Paris, France) (18). cRNA-DNA with an American Optical Company microscope or a Zeiss filter hybridization under paraffin (12) was performed as Photomicroscope II. previously reported (18, 20). Immunofluorescence Studies. Direct and indirect immu RESULTS nofluomascenca tests were performed mainly as described by Bautnar at al. (2). Specific guinea pig antisera ware MorphologyofEV Lesionsas Relatedto the VirusType raised against full particles of HPV-1 (G 121, G 122), HPV-2 (G 206), HPV-3 [using J. D. HPV (G 280) or E. D. HPV (G Characteristics of EV Lesions. The 14 patients studied 281)], and HPV-4 [using S. M. HPV (G 271)] or against empty are presented in Tables 1 and 2. Nine were familial cases, particles of HPV-4 [using J. K. HPV (G 251) or S. M. HPV (G and 6 had cancers. All patients had lesions on the domsaof 264)]. These sara had been used in previous studies (18, the hands and on the face, and most of them had lesions on 20), except G 271 , which was obtained under the conditions the extremities and the trunk. Patients showed various described for other EV HPV's (20). Fluomascain-babeled lgG types of lesions: (a) flat wart-bike lesions, somewhat more fractions with a fbuorasceinto protein molar ratio of 2 or 5 elevated on the domsa of the hands (Fig. 1) but in some were prepared from anti-HPV-1 antiserum as previously patients almost at the skin level and often reddish (Fig. 2); described (16) and ware used in direct immunofluorescanca (b) reddish plaques, usually on the trunk (Fig. 3); (c) scaling tests at a concentration of 0.5 mg/mI. Anti-HPV-2, anti-HPV brownish or achmomic lesions resembling pityriasis vemsi 3, and anti-HPV-4 antisera were used in indirect immunoflu color (Fig. 4); (d) large, pigmented, irregularly shaped orescance tests at a dilution of 1/80 to 1/320. Tissues confluent plaques (Fig. 5); and (a) common warts intemmin embedded in Tissue-Tek II O.C.T. compound medium (Lab glad with vemrucaplana-type lesions (Fig. 6). Tek Products) ware cut in a cryostat (SLEE, London, Eng Molecular HybridizationData. In our previousstudies land) at â€”20Â°.Seven-sm-thicksections were set on gelatin (20), characterization of the virus present in lesions of coated slides, fixed for 10 mm at â€”2@Y'inacetone, and patients with EV was performed by molecular hybridization washed for 20 mm in 0.05 M sodium phosphata/0.1 M NaCI without taking into account the clinical types of the lesions. (pH 7.2). For direct immunofluomescence tests, sections However, results indicated the occurrence of HPV-3 in

Table 1 Patientswith EVâ€• Ageat1 Stmalig

nantcon

var Cell-me at onset of im munity@'Remarks1.PatientsSexAge (ym)Age disease (yr)sion (ym)Camcinomass'diated D.2.T.G.M52543++â€”BmothemofJ. K.andH. J.K.F38517+++â€”3. H.D.F4611â€”MothemofE.D.,D.D.,andW.D.4.E.D.F227â€”5.D.D.F21715+â€”6.

W. D. disappeared after biopsies P.8.A.P.F2510+9.7. R. P.M M9 475.5 Early childhood+ NDdWarts Father of A.

E. I.F184â€”Fathem with long-standing, flat hands10. warts on case11J. D.M43Early childhood37++ +â€”Nonfamilial case12.. J. G.M247â€”Nonfamiliab

case13.M. G.M217â€” to Â±Nonfamilial case14.5. M.M22820+ +â€”Nonfamilial R.M.M36235+Â±Nonfamilialcase

Cl Characteristics of benign lesions ama described in Table 2. b @,premalignant lesions of Bowen's type (carcinoma in situ) and single carcinoma; ++, multiple Bowen's carcinomas; + + + , invasive carcinomas, at various sites. C Depressed (â€” ), lowered (Â± ), om preserved (+ ) nonspecific cell-mediated immunity, as checked by in vitro methods and cutaneoustests (5).3 d ND, not done.

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Table 2 EVPatientsExtensionaMorphology Characteristics of the benign lesions of patients with and distribution of skin lesions@'Activityâ€•HPV

wart type Reddish Pitymiasis vemsi- Pigmented warts1. ElevatedtypedFlat Very flat plaques color type plaquesCommon T.G.++Hands,face Trunk Tmunk,amms, thighs+++42. J. K.++++Hands, feer Face, ex- Whole skin Trunk, arms tmemities++++43. H.D.++Hands,feat, Faca,ex forearms, tmemities legsâ€”34. AsH.D.+35,ED.++AsH.D. D.D.+++AsH.D. AsH.D. Neck,tmunk, Tmunk,thighs arms, thighs++++3,46. handsâ€”37.W. D.+Face, R.P.+Handsâ€”Inconclusive8. Faceâ€”39.A. P.+Hands Faceâ€”310.E. I.+Hands J.D.++++Face,ex- Trunk Trunk,amms, Legs thighs++++3,411. tmemities J.G.+Hands FaceHands, leg, foot+3,212. MG.++Hands Face, thighs, legs++313. S.M.+++Face,ex- Tmunk,ex- Trunk tremities+++414. tmemities R.M.+++Face,ex- Tmunk,ex- Trunk tmemities tremities++4 @ a hands and face; ++, hands, face, and some at other locations; +++, widespread; ++++, generalized. b Flat wart-type lesions are either somewhat elevated or vary flat, almost at the skin level. Reddish plaques are flat maculam lesions (up to 2 cm). Pitymiasis vemsicobom-typelesions are brownish scaling or achmomic plaques. Pigmented plaques are dark brown, large, confluent, and immegulamlyshapedlesions. Common warts are elevated hypemkematoticpapules. C. _ , no new lesions for many years; + to + + + + , from a few new lesions to extensive spreading at the time of studies. d As determined in a previous study (20) and in this study. e The typical elevated flat wart-like lesions observed at first gmadually flattened throughout the years. Although still slightly raised, the lesions are clearly distinct from those of the patient's relatives (Cases 3 to 6).

patients showing only flat wart-type lesions and, for Patient from the reddish and pityniasis versicobor-like brownish J. D., in confluent pigmented plaques, while HPV-4 was plaquespresentontheback ofPatientJ.D. forsome years found in patients showing reddish plaques and/or pityniasis (which have been spreading lately) annealed only with HPV varsicobor-lika lesions together with somewhat flatter and 4 cANA. These lesions had not been tasted previously. Two reddish vamrucaplana-typa lesions (Table 2). viral DNA preparations obtained from lesions collected from Molecular hybridization data reported in Table 3 ware the lags of this patient (Fig. 5) at a 1-year interval ware both obtained on 3 new patients and on different types of lesions of HPV-3 type, but the most macant showed also some of several patients, using cANA's specific for the 4 types of annealing with HPV-4 cANA, coinciding with the eruption HPV's, with J. D. and J. K. HPV's as prototypical HPV-3 and of a few reddish and brownish plaques at this location. HPV-4, respectively. With the conditions used, 50 to 60% of Clear evidence for infection by HPV-3 and HPV-4 was also the radioactivity binds to filters when homologous DNA's found for Patient D. D., whose wart-like lesions [analogous and cANA's are hybridized, while almost no annealing is tothoseof hermother,H. D.,and sister,E.D. (Fig.1)]ama observed between hatemobogous prototypical cRNA's and clearly due to HPV-3 and whose reddish plaques [similar to DNA's. Of the 3 new patients, Patient T. G., showing reddish those of her aunt, J. K. (Fig. 3), and uncle, T. G.] are due to plaques and pityniasis varsicolor-lika lesions, was found to HPV-4. HPV-2 was detected in the typical common warts of be infected by HPV-4, while Patient M. G., showing only Patient J. G. (Fig. 6), while the viral DNA found in his flat wart-bike lesions, was infected by HPV-3. The limited wart-like lesions hybridized only with HPV-3 cRNA. The amount of material from Patient A. P. did not allow conclu lesser extant of hybridization observed, as compared to sions. A lesser extant of annealing was observed when HPV-3 prototypical DNA, confirms previous results obtained T. G. and J. K. HPV cANA's ware hybridized with J. K. and for this patient, which showed the genetic heterogeneity of T. G. DNA's, respectively, as compared to homologous viruses belonging to type 3 (20). However, HPV-4 was found hybridizations, confirming the genetic heterogeneity al both in flat vamruca plana-typa lesions and in reddish and ready reported for viruses belonging to type 4 (20). Data pityniasis vemsicobor-bike plaques (Fig. 4) of Patient A. M., as further reported in Table 3 show that viral DNA obtained previously found for the different lesions of Patients J. K.

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Table 3 with anti-HPV-3 antiserum (Fig. 7, a and b), while her Identification of HPV present in EV lesions by cRNA-DNA reddish plaques gave a positive reaction only with anti-HPV hybridization 4 antiserum (Fig. 7, C and d). In addition, results show that, for17Filter hybridization under paraffin (12) was performed at 37Â° for most patients, no antigen could be detected with the 4 withabouthr in 0.3 M NaCI/0.03 M sodium citmata/50% fommamide types of antisera in some of the samples tested. Widely of[3H]cRNA50 ng of viral DNA (except A. P. DNA) and 3000 cpm per filter (specific20).% activity, 3 to 4 x 10@cpm/@g)(18, variable amounts of viral antigens were also observed in a previous study of numerous common warts of a patient of radioactivity bound on filtemsafterhy bmidization with [3H]RNA's complementary to infected with HPV-2 (18). differentDNA'sbHPV-3 MalignantConversionas Relatedto the VIrusType Found HPV-4(J.D. in EV Lesions T.G.DNA (J.K. HPVHPV-1on fiItems@' HPV-1 HPV-2 HPV) HPV) Malignant conversion of lesions was observed only in the 0.8HPV-2 55.9 0.3 0.1 0.3 6 patients infected with HPV-4, 2 of them being infected 1.0HPV-3 0.2 58.0 0.5 0.1 also with HPV-3 (Tables 1, 2, and 5). In Patient 0. 0., â€”0.5HPV-4(J. D. HPV) 0.1 0.3 61 .2 0.2 28.3T.G.(J. K. HPV) 0.5 â€”0.2 â€”0.1 49.0 infected with both viruses, lesions were of early Bowen's 57.5M. 0.6 0.4 0.3 13.4 disease type (carcinoma in situ) (Fig. 8) and ware controlled G.Face;A' by topical 5-fluorouracil. In other patients, malignant be NDâ€•Hands; 0.1 0.9 44.2 0.6 sions were of Bowen's carcinoma type; they were usually â€”A. A 0.1 0.8 45.3 â€”0.1 â€”J.P. (hands;A) ND ND 0.3 â€”0.1 multiple, mostly on light-exposed parts of the body, and D.Back; sometimes invasive (Fig. 9); metastases were never ob â€”Lags;DB, C â€”0.1 0.1 â€”0.1 15.4 served. â€”Legs; 0.2 0.1 42.6 1.0 â€”D. 0 0.1 0.2 56.4 8.3 0.Hands;A DISCUSSION â€”Legs; 0.1 â€”0.1 46.0 0.4 â€”Tmunk;B,CA â€”0.1 0.2 47.5 2.4 Our studies indicate that the clinical aspect of the lesions, â€”J. 0.1 â€”0.2 2.2 28.7 the course of the disease, and the malignant conversion in G.Hands; EV are rebated to the type of HPV responsible for the â€”Leg;EA 0.1 â€”0.1 9.6 â€”0.2 â€”Palm;E â€”0.3 53.4 0.8 â€”0.2 infection. Patients infected with HPV-3 alone show flat wart â€”A. â€”0.2 33.4 1.0 1.0 like lesions, a more protracted course of the disease, and M.Hands; no malignant conversion (Tables 1 and 2). This includes â€”Legs;A'A' â€”0.3 0.3 0.1 13.5 abortive and/or stationary familial cases; in one of them, â€”Back; â€”0.2 0.2 1.8 20.5 the lesions did not reappear after removal. HPV-4 infection -Tmunk;B,CB, C ND ND 3.4 23.1 â€”Human ND ND 0.6 11.9 results in flatter vemmucaplana-lika lesions, often reddish, 0.5Humanthymus 0.2 0.2 0.6 0.5 only slightly elevated on the dorsa of the hands, associated liver 0.1 0.1 0.1 1 .5 ND with reddish plaques and pityriasis versicobor-like lesions a Viral DNA's were obtained from vinions extracted from a single mostly on the trunk. It was always associated with carcino plantam wart (HPV-1), pooled common warts of a single patient mas. (HPV-2), limb lesions of patient J. 0. (HPV-3),and whole-body Two patients were found to be infected by both viruses. lesions of Patients J. K. (HPV-4) and T. G. Other viral DNA's were selectively extracted from lesions of different sites and momphol One of them showed all the different types of lesions and ogy: flat wart-like lesions, elevated (A) or very flat (A'); reddish had multiple premalignant or early malignant lesions of plaques (B); pitymiasis vemsicobom-like plaques (C); pigmented Bowan's disease type. It is worth stressing that her mother, plaques (0); and common warts (E). A. P. DNA corresponded to sister, and brother were infected with HPV-3 and showed DNA selectively extracted from very few lesions and showing no no malignant lesions, whereas hemaunt and uncle were viral DNA molecules when checked by electron microscopy. b [3H]cRNA's were obtained by in vitro tmanscmiption with E. coli infected with HPV-4 and had multiple cancers. The second RNA polymerase of pumified Form 1 HPV-1 or HPV-2 DNA molecules patient showed, in addition, large, pigmented, confluent and of J. 0., J. K., and T. G. HPV DNA molecules extracted from plaques on the begsdue to HPV-3 and had cancers, includ vimions(18, 20). ing an invasive carcinoma of the forehead. Ha was first C ND, not done. considered to be infected only by HPV-3 (20) on the basis of molecular hybridization data obtained with 6 DNA prepama and S.M. (20). tions from limb lesions including large pigmented plaques Immunofluorescence Studies. The association of distinct until the plaques on his back were tasted. Finally, HPV-2 types of HPV with particular cutaneous lesions has been was detected in typical common warts intermingled with studied by the immunofluorescenca technique, using spa elevated vammucaplana-lika lesions due to HPV-3 in one cific antisera against each of the 4 HPV types. Previous patient. This virus has bean shown to be preferentially studies have shown that viral capsid antigens are detected associated with common warts (18, 19), so its possible role in the nuclei of the upper keratinizing cells and in kamatin in the few cases described as EV and showing hypertrophic ized cells of the lesions (18, 20). Aesults reported in Table 4 typical common warts (15, 28) should be considered. confirm the data obtained by molecular hybridization axpem In conclusion, this study shows that the morphological imants. This is best illustrated for Patient D. 0. , whose aspects of lesions and the type of HPV associated with them typical flat wart-like lesions gave a positive reaction only may be of prognostic significance. It further reinforces our

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Table 4 techniquesViralCharacterization of the virus present in different EV lesions by immunofluorescence capsid antigens were detected in frozen 7-j.@m-thick sections of lesions by a direct immunofluomescence technique with fluomescein-labeled anti-HPV-1 guinea pig lgG or by an indirect immunofluorescence technique with anti-HPV-2, anti-HPV-3, and anti-HPV-4 guinea pig antisera and fluomescein-labebed anti-guinea pig IgG rabbit lgG under conditions described in â€œMaterialsandMethods.â€•HPV in:Flat type

wart-type lesions Pitymiasis ver Reddish sicolom-type tested1Patientsâ€• Elevated Very flat plaques lesions Other types of lesions . T. G. HPV-4 (1/2)'@ HPV-4 (3/5) HPV-4 (1/5) 2. J. K. HPV-4(1/4) HPV-4(2/3) HPV-4(4/5) 3. H.D. HPV-3(2/2) HPV-3(1/2) 4. E. D. HPV-3 (4/5) HPV-3 (1/1) 5. D. D. HPV-3 (7/10) HPV-3 (2/3) HPV-4 (5/6) 6. W.D. (0/2) 8. A.P. HPV-3(1/2) 9. El. HPV-3(1/3) 10. J. D. HPV-3 (6/16) HPV-4 (5/5) HPV-4 (1/1) Pigmented plaques: HPV-3 (2/4) 11. J. G. HPV-3 (7/15) Common warts: HPV-2 (3/4) 12. MG. HPV-3(5/6) 13. S. M. HPV-4 (4/4) HPV-4 (1/1) 14. R. M. HPV-4 (2/2) HPV-4 (1/3) HPV-4 (2/3) a No sample available for Patient R. P. (Case 7). b Numbers in parentheses, numbem of positive lesions versus number of lesions tested.

Table5 ously or through interaction with environmental factors, CarcinomasintypeVirus patients withV as relatedto the virus such as actinic radiations. Nevertheless, although mobecu conversionHPV-30/7HPV-44/4HPV-3,typeMalignant lamhybridization and immunofluomascanca evidence for the persistence and the expression of the viral genoma in EV carcinomas must be obtained, our data strongly suggest HPV-42/2 that HPV-4 is associated somehow with malignant progmas a HPV type was not determined for Patient A. P. His lesions weme sion and, thus, that one HPV, at least, has an oncoganic analogous to those of his daughter, A. P., who was infected by potential. HPV-3. Note Added in Proof previous conclusions on the importance of the virus in the Since this manuscript was submitted, a classification of human papillo pathoganasis of EV, together with other factors (20). Ga mavirusesbased on the chronological order of their identification was netic factors are known to play a major role in this disease, proposed. While the designation of HPV-1, HPv-2, and HPv-3 remains unmodified, HPv-4 should now be designated HPv-5 (Coggin, J. H., Jr., and and compilation of literature data on the genetics of EV zur Hausen,H. Meetingreport: workshopon papillomavirusesandcancer. supports transmission by an autosomal recessive gene (15). Cancer Res. 39: 545-546, 1979). Nine of the 14 patients of this study ware familial cases. Three of them belonged to a family of 6 siblings with no ACKNOWLEDGMENTS evidence of EV in the parents (Patients 1 to 3) (Table 1) (5). Three families among the 4 studied showed EV in 2 succas We thank Peter Sheldrick and FranÃ§,oiseBreitburd for fruitful discussion and critical reading of the manuscript; Nicole Jibard and Dominique Fortin sive generations, without evidence of consanguinity (Pa for careful assistance; and Daniel Cany and AyszamdWierczak for preparation tiants 3 to 9). These rates are unexpected in the hypothesis of the illustrations. of a rare autosomal recessive disease. Immunological fac tons appear to be important as wall (5, 22); cell-mediated REFERENCES immunity was abnormal in all the patients of this study except those showing abortive or regressive evolution of 1. Aaronson, C. M., and Lutzner, M. A. Epidermodysplasia verruciformis and epidermoidcarcinoma.Electronmicroscopicobservations.J. Am. the disease (Table 1) (5).3 Med.Assoc.,201:775-777,1967. Our data, especially those on familial cases, indicate that 2. Beutner, E. H., Chorzelski, T. P., Bean, S. F., and Jordon, A. E. the type of infecting HPV determines the clinical aspects of Immunopathology of the skin: labeled antibody studies. pp. 147-197. Stroudsburg: Dowden, Hutchinson, and Ross Inc., 1973. the lesions and bead to a consideration of the robe of the 3, Delescluse,C.,PruniÃªras,M.,Regnier,M., Moreno,G., andArouete.J. virus in their malignant conversion. It cannot be excluded, Epidermodysplasia verruciformis. I. Electron microscope autoradiogra however, that a particular genetic constitution may have 2 phy and tissue culture studies. Arch. Dermatol. Forsch. , 242: 202-215, 1972. distinct consequences: a higher susceptibility to HPV-4 4. Gissmann, L., Pfister, H., and Zur Hausen, H. Human papilloma viruses infection, resulting in lifelong, widespread, benign skin (HPv). Characterization of four different isolates. Virology, 76: 569â€”580, 1977. lesions, and a higher risk for skin cancer, either spontana 5, Glinski, W., Jablonska,S., Langner,A., Obalek, S., Haftek, M., and Proniewska,M. Cell-mediatedimmunityin epidermodysplasiaverruci

3 S. Obalek, W. Glinski, M. Haftek, and S. Jablonska. Comparative studies formis. Dermatologica, 153: 218-227, 1976. on cell-mediated immunity in patients with various types of warts, manuscript 6. Grupper,C., PruniCras,M.,Delescluse,C.,Arouete,J., and Garelly,E. in preparation. Epidermodysplasie verruciforme: etude ultrastructurale et autoradi

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ographique. Ann. Dermatol. Syphiligr., 98: 33â€”47,1971. human papillomavirus that causes skin warts. J. Virol., 24: 108â€”120, 7. Jablonska, S., Biczysko, W., Jakubowicz, K., and Dabrowski, J. On the 1977. viral etiology of epidermodysplasla verruciformis Lewandowsky-Lutz. 19. Orth, G.. Jablonska, S., Breitburd, F., Favre. N., and Croissant, 0. The Electron microscope studies. Dermatologica, 137: 113â€”125,1968. human papillomaviruses. Bull. Cancer (Paris), 65: 151-164, 1978. 8. Jablonska, S., Biczysko, W., Jakubowicz, K., and Dabrowski, J. The 20. Orth, G., Jablonska, S., Favre, M., Croissant, 0., Jarzabek-Chorzelska. ultrastructure of transitional states to Bowen's disease and invasive M. , and Rzesa, G. Characterization of two types of human papillomavi Bowen's carcinoma in epidermodysplasia verruciformis. Dermatologica, ruses in lesions of epidermodysplasia verrucifommis. Proc. Natl. Aced. 140: 186-194, 1970. Sci.U.S.A.,75:1537-1541.1978. 9. Jablonska, S., Dabrowski, J., and Jakubowicz, K. Epidermodysplasia 21. Pass, F., Reissig, M., Shah, K. V.. Eisinger, M., and Orth, G. Identifica vermuciformis as a model in studies on the role of papovaviruses in tion of an immunologically distinct papillomavirus from lesions of oncogenesis. Cancer Res., 32: 583-589, 1972. epidermodysplasia verruciformis. J. NatI. Cancer Inst., 59: 1107-1112, 10. Jablonska, S., Fabjanska, L., and Fommas,I. On the viral aetiology of 1977. epidermodysplasia verruciformis. Demmatologica, 132: 369-385, 1966. 22. Prawer, 5. E., Pass, F., Vance, J. C., Greenberg, L. J., Yunis. E. J.. and 11. Jablonska, S., Maciejewski, W., Dabrowski, J., and Langner, A. Epider Zelickson, A. S. Depressed immune function in epidemmodysplasia modysplasia vermuciformis. In: M. PruniÃ©mas(ed), Biomedical Aspects verrucifommis. Arch. Demmatol.,113: 495â€”499,1977. of Human Wart Virus Infection. pp. 113-135. Lyon: Fondation MÃ©rieux, 23. Rajagopalan, K., Bahru, J., Loo, D. S. C., Tay, C. H., Chin, K. N., and 1976. Tan. K. K. Familial epidemmodysplasiavemruciformisof Lewandowsky 12. Kourilsky, P.. Mercereau, 0., Gros, D., and Tremblay, G. Hybridization and Lutz. Arch. Dermatol., 105: 73-78. 1972. on filters with competitor DNA in the liquid phase in a standard and a 24. Rowson, K. E. K., and Mahy, B. W. J. Human papova (wart) virus. microassay. Biochimie (Paris), 56: 1215â€”1221,1974. Bacteriol.Rev.,31: 110-131,1967. 13. Lewandowsky,F.,andLutz.W.EmFalleinerbishernichtbeschriebenen 25. Aueda, L. A., and Rodriguez, G. Verrugas humanas per virus papova. Hauterkrankung (Epidermodysplasia vermucifommis).Arch. Dermatol. Sy Correlacion clinica, histologica y ultraestructural. Med. Cutanea Ibero philol., 141:193-203,1922. LatinoAmericana,2: 113-136, 1976. 14. Lutz, W. A propos de l'epidermodysplasie verrucifomme. Dermatologica, 26. Ruiter, M., and Van Mullem, P. J. Demonstrationbyelectron microscopy 92:30-42,1946. of an lntmanuclearvirusIn epidermodysplaslaverrucifommis.J. Invest. 15. Lutzner, M. A. Epidermodysplasia verrucifommis: an autosomal recessive Dermatol., 47: 247-252, 1966. disease characterized by viral warts and skin cancer. A model for viral 27. Ruiter, M., and Van Mullem, P. J. Behavior of virus in malignant oncogenesis. Bull. Cancer (Paris), 65: 169-182, 1978. degeneration of skin lesion in epidemmodysplasia verrucifommis. J. In 16. Orth, G., Breitburd, F., and Favre, M. Evidence for antigenic determi vest.Dermatol.,54:324-331,1970. nants shamed by the structural polypeptides of (Shops) rabbit papillo 28. Van Der Meer, J. B. Epidermodysplasiavemruclformls.Reportof a case mavirus and human papillomavirus type 1. Virology, in press, 1978. from Utmecht.In:M. PrunlÃ©ras(ed),BiomedicalAspectsof HumanWart 17. Orth, G., Breitburd, F., Favre,M., and Croissant,0. Papillomaviruses: Virus Infection, pp. 137-143. Lyon: Fondation MÃ©rleux,1976. possible role in human cancer. In: H. H. Hiatt, J. D. Watson, and J. A. 29. Yabe, Y., and Sadakane, H. The virus of epidermodysplaslaverruclfor Winsten (ads.), Origins of Human Cancer, pp. 1043-1068. Cold Spring mis: electron microscopic and fluorescent antibody studies. J. Invest. Harbor: Cold Spring Harbor Laboratory, 1977. Dermatol., 65: 324-330, 1975. 18. Orth, G., Favre, M., and Croissant, 0. Characterization of a new type of

Fig. 1. Typical flat wart-like lesions. Dorsum of the hand of Patient E. D. Fig. 2. Very flat, reddish, wart-type lesions. Dorsum of the hand of Patient S. M. Fig. 3. ReddIsh plaqueswith some brown and achromic lesions resembling pityriasisversicolor. Chest of PatientJ. K. Fig. 4. Achromic plaques resembling pltyriasls versicolor lesions together with a few reddish and brown-reddish small plaques. Back of Patient R. M. Fig. 5. Large, pigmented (dark brown). Irregularly shaped, confluent plaques. Leg of Patient J. D. Fig. 6. Common warts (arrows) together with elevated flat wart-like lesions. Hand of Patient J. G. Fig. 7. DetectIon of viral antigens In the superficial layers of different lesions of Patient D. D. by the indirect immunofluorescence test. Adjacent frozen sections of a flat wart-like lesion (a and b) and of a reddish plw@ue(c and d) were incubated with antl-HPV-3 antiserum (G 290) at a 1/160 dIlution (a and c) or with antl-HPV-4 antiserum (G 251) at a 1/160 dilutIon (b and d) and, after washing, with fluorescein-labeled anti-guinea pig lgG rabbit globulins. x 260. Fig. 8. Multiple lesions of Bowen's disease type (carcinomain situ) intermingled with flat wart-like lesions. Forehead of Patient D. D. Fig. 9. InvasIve carcinoma. Forehead of Patient J. K.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. Characteristics of the Lesions and Risk of Malignant Conversion Associated with the Type of Human Papillomavirus Involved in Epidermodysplasia Verruciformis

Gérard Orth, Stefania Jablonska, Maria Jarzabek-Chorzelska, et al.

Cancer Res 1979;39:1074-1082.

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