Clinical aspects of epidermodysplasia verruciformis

Abstracts

FUNDAMENTOS: A epidermodisplasia verruciforme (EV) é genodermatose rara, caracterizada por infecção disseminada por tipos específicos de vírus papiloma humano (HPV), desenvolvimento de tumores cutâneos malignos e distúrbios imunológicos. OBJETIVOS: Correlacionar aspectos clínicos em 13 doentes com EV, na tentativa de contribuir para melhor conhecimento da enfermidade. MÉTODOS:Avaliação clínica de 13 doentes com EV durante o período de três anos. O diagnóstico clínico foi confirmado pelo exame histopatológico e imuno-histoquímico. RESULTADOS: A EV teve início na infância com lesões de verruga plana-símile e/ou máculas eritematosa na face e região cervical. A consangüinidade foi observada na maioria dos doentes (12/13). Clinicamente, o polimorfismo das lesões foi intenso, caracterizado por lesões de verruga plana-símile, pitiríase versicolor-símile, máculas eritematosas e lesões de queratose seborréica-símile. A transformação maligna das lesões foi observada em oito doentes (62%). O crescimento tumoral provocou perda tecidual importante em 50% dos casos, e em 25% foi registrado óbito pelas metástases. CONCLUSÃO: A EV apresenta alta incidência familiar e provável transmissão autossômica recessiva. O intenso polimorfismo clínico das lesões não afeta o couro cabeludo e mucosas. A apresentação clínica "maligna" foi a mais freqüente (62%), seguida pela "benigna" (23%) e "mista" (15%). Os tumores cutâneos malignos são freqüentes, múltiplos, destrutivos, geram metástases e provocam morte.

Epidermodisplasia verruciforme; papillomavirus humano

CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION

Clinical aspects of epidermodysplasia verruciformis^*

Walmar Roncalli Pereira de Oliveira^I; Cyro Festa Neto ^II; Stephen K Tyring^III

^IPost-graduate doctoral candidate, Medical Faculty Dermatology Department of "Universidade de São Paulo" and Department of Microbiology and Immunology, the University of Texas Medical Brunch, Galveston, Texas, EUA

^IIPh.D., Professor at the USP Medical Faculty Dermatology Department

^IIIPhDMD, Department of Dermatology and Department of Microbiology and Immunology, the University of Texas Medical Branch, Galveston, Texas, EUA

^{Correspondence}

SUMMARY

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by disseminated infection caused by specific types of human papillomavirus (HPV), development of cutaneous malignant tumors and immunological disturbances.

OBJECTIVE: To correlate the clinical features of a group of 13 patients with EV aiming to contribute to knowledge of disease.

METHOD: The clinical evaluation of 13 EV patients during 3 years. The clinical diagnosis was confirmed by histopathological and immunohistochemical findings.

RESULTS: The EV began in childhood with flat warts and/or erithematous macules on the face and neck. The parental consanguinity was observed in most patients (12/13). Clinically the lesions were highly polymorphic with flat wart-like lesions, pityriasis versicolor-like lesions, erithematous macules and seborrheic keratoses-like lesions. The malignant conversion of lesions occured in 8 patients (62%). The tumor growth provoked heavy tissue loss in 50% of patients, and metastatic tumors caused death in 25%.

CONCLUSION: The EV presents high familial incidence and an autosomal recessive mode of inheritance. The high polymorphism clinical doesn't affect the scalp and mucous membrane. The most frequent clinical manifestation is the "malignant" (62%), followed by "benignant" (23%) and "mixed"(15%). The cutaneous tumors are frequent, multiple, destructive, metastasize and cause death.

Key words: Epidermodysplasia verruciformis; papillomavirus, human.

INTRODUCTION

Epidermodysplasia verruciformis (EV) is a rare genodermatosis, characterized by susceptibility to infection in distinct types of human papillomavirus (HPV).^1,2,3 The viruses found in EV are mainly specific to the disease, and are called HPV associated with EV (HPVEV).^4,5 The infirmity is usually initiated in infancy between ages five and eleven, and is manifested by multiple flat wart-like lesions and/or pityriasis versicolor-like macules (PV).^6,7,8 After the third decade of life, roughly 30 to 50% of patients may develop skin cancer, which is frequently multiple and most commonly found in the areas of intense sun-exposure.^5,8,9 The disease shows immunological alterations especially of cell-mediated immunity.^4,10 This immunological deficiency appears to be local and specific, and the presence of genetic poymorphism in the major histocompatibility complex (MHC) determines the inadequate presentation of HPV and its defense cells.^11-15 Patients developed disseminate and long-term infections due to HPV, to which unspecific disturbances of its cellular immunity can link subsequently up.^2,16,17 In this paper, the authors carried out a clinical study of 13 EV patients at the Ambulatório de Oncologia Cutânea (Cutaneous Oncology Outpatient's Clinic) of the Departamento de Dermatologia da Faculdade de Medicina at Universidade de São Paulo (HCFMUSP).

PATIENTS AND METHODS

At the HCFMUSP Cutaneous Oncology Outpatient's Clinic, 13 patients were given follow-up treatment over a three-year period.

The diagnosis was performed by means of medical history taking, clinical, and anatomopathologic and immunohistochemical examination.

MEDICAL HISTORY TAKING AND PHYSICAL EXAMINATION

The clinical history of each patient was raised by attempting to identify the main factors that may have influenced the course of the infirmity. The following heredograms were compiled based on the information obtained.

^Heredograms

General physical examination was carried out initially, followed by a complete dermatological examination. Patients were examined monthly.

HISTOPATHOLOGICAL EXAM

Benign cutaneous lesions of varied morphology and the cutaneous tumors were entirely or partially removed by excision surgery or 4-mm punch biopsy, and submitted to anatomopathological examination, preparations were made using the hematoxiiline-eosine staining technique.

IMMUNOHISTOCHEMISTRY (IHC)

The method employed was Streptavidin-Biotin. The Rabbit Antibovine Papillomavirus (BPV-1) antibody was used to avoid causing a false positive reaction in human DNA tissue.

The IHC findings showed the HPV antigens are located in the cell nucleus of the third superior of the epithelium, observing the brownish-gold colored precipitins caused by cromogen in the nucleus of these cells.¹⁸

It is a method sensitive to productive benign lesions, but shows less sensitivity to the dysplastic tissues.¹⁸This is due to the fact of the large amount of free viral DNA present in the benign lesions that are to be progressively incorporated into the DNA of the host cell during the process of carcinomatous transformation.^1,33

This method was performed on 23 skin samples of EV patients.

RESULTS

Clinical Evaluation - The age range of patients was between 14 and 40 years. Consanguinity was observed in 12 patients, of which 10 had at least one sibling affected by the disease. Twelve patients had chronic sun-exposure, estimated to be more than 10 years in duration. The onset of the disease occured during infancy, with flat wart-like lesions or erythematous macules mainly on the face and cervical region. The lesions showed intense clinical polymorphism with diffuse distribution, but it was preserved by the scalp and mucoses. The seborrheic keratoses-like lesions, present in 46% of cases, were found mainly on the forehead, in the cervical region and thorax. Pruritus and ardor (urinae) were referred to occasionally and associated with sun-exposure. Mental retardation was observed in three patients (23%). These data are summarized in table 1.

The malignant cutaneous tumors were detected in eight patients (62%), 25 years being the average age for appearance of the first lesions. In all, the initial malignant lesions developed on the forehead with a clinical and histopathologic form of squamous cell carcinoma. The patients developed multiple tumors and numerous actinic keratose-like lesions in cutaneous regions most exposed to the sun. In 50% of cases, invasive tumor growth was observed with important tissue loss. In 25%, the presence of metastasis was observed for lymphonodes and the breasts. These data have been summarized in table 2.

Histopathological Findings - In the benign lesions, the presence of large clear and dysplasic cells was observed with vacuolated nuclei and cytoplasm with prominent granules of kerato-hyaline (viral cytopathic effect), in the upper layers of the epithelium. In the flat wart-like lesions of malignant form, the cytopathic viral effect was similar, but it was initiated in the suprabasal layer and extended to the upper layers of the epithelium.

The seborrheic keratose-like lesions showed the cytopathic viral effect of the EV, associated with the histopathologic findings characteristic of this type of lesion. The malignant lesions present mainly histological forms of Bowen's diskeratosis and spinocellular carcinoma.

Immunohistochemistry (IHC)-The flat wart-like lesions of all the patients showed positive results. The seborrheic keratosis-like and squamous cell carcinoma lesions of patient number 9 and the Bowen's disease lesion of patient number 12 also showed positive results.

DISCUSSION

EV is a genodermatosis characterized by infection disseminated by HPV, frequent malignant transformation of its lesions and immunological alterations.^4,15 It is considered the first model in human beings of cutaneous carcinogens induced by HPV.^1,4

The patient showed no preferential distribution as to sex or race.^7,9,19 In this study, there was equal distribution between the sexes and a higher incidence in Caucasians, but the group is too small to be able to infer anything about these aspects.

EV may be familial or sporadic.^1,2 Participation of genetic factors in EV is pertinent, as they determine the infection by distinct types of HPV (HPVEV and HPV 3 and/or 10). High familial incidence, frequent consanguine ties, occurrence between siblings, and infrequent affliction in successive generations has led most authors to consider the disease transmission as autosomal recessive, though there are reports of possible recessive inheritance linked to chromosome X.^6,20,21

Of the 13 patients studied, numbers 1 and 2, 8 and 9, and 10, 11 and 12 were siblings, completing the total of eight familial cases. Patients 4 and 6 reported having siblings with EV. In spite of the fact that Androphy et al.²¹ consider the sporadic form as having the highest occurrence, it was only found in three patients.

Roughly 10% of EV patients result from consanguine marriages.^6,20In this study, however, the authors observed that only patient 6 was not an offspring from a consanguine marriage. There was no report of affliction in ancestors, suggesting that the form of transmission of the case here reported is probably autosomal recessive.

The disease was often initiated during infancy, though cases have been described of earlier onset (after birth) and later (third and fourth decades).^6,7,17 17 In the patients analyzed, onset varied from 3 to 12 years of age.

The most frequent initial lesion is of the flat wart-like type, located mainly on the dorsa of the hand. PV-type macules, characteristic of the disease, develop a few years after the first lesion. They are initially erythematous, but hypochromic in later stages of the disease. In the follow-up presented here, 46% of patients had both flat wart-like initial lesions and erythematous macules, located mainly in the face and cervical region.

The clinical condition of EV may show flat warts, associated with non-oncogenic HPV 3 and/or 10, denominated as "benign form", or it is expressed polymorphically with a tendency to malignization, associated to multiple HPVEVs (some oncogenic), denominated as "malignant form".^3,4,5,7 The initial presence of flat warts, followed by the appearance of characteristic polymorphism of malignant form, define the "mixed form".^17,24 The clinical evaluation of the patients here in focus was carried out according to this classification.

The benign form was observed in patients 2, 4 and 6 (23%), who only showed disseminated flat wart lesions. Some of these lesions converged, forming large pigmented plaques on the forehead, torso and limbs. Isomorphism was a frequent finding (Figure 1). No cutaneous tumors appeared, not even in patient 4, a 37-year-old Caucasian with a history of chronic sun-exposure, i.e. potentially oncogenic factors.

This clinical form demonstrated a difficult differential diagnosis with non-EV flat warts. In these patients, the latter possibility was dismissed, because the three patients showed consanguinity and familial history of the disease. Lesions were clinically greater, forming large strongly pigmented plaques.⁸

The malignant form was observed in most patients (62%), who demonstrated intense polymorphic clinical manifestation, with flat wart-like lesions, PV-type, erythematous-squamous plaques, seborrheic keratosis-like, keratosis actinic-like and cutaneous cancers. (Figure 2).

The mixed form was observed in patients 3 and 8 (15%) (Figure 3). The possible explanation for the development of this form in some patients would be an important deficiency in cellular immunity caused by disseminated and long-term infection due to HPV-3, which becomes susceptible to HPVEVs.^17,24

For the time being, there is no explanation for the fact that the population studied has obtained this frequency of distribution of its clinical forms. Nor do any reports exist of this frequency in revised works.

The presence of these seborrheic keratosis-like lesions only of malignant and mixed clinical forms (Figure 4) suggests their association with HPVEVs. It calls attention to the high incidence (46% of cases) of these lesions in the patients analyzed in this paper, because such a description is not frequent in the literature.^25,26

The mucoses and scalp were preserved. Palmoplantar wart lesions were found in 38% of patients, a fact diverging from the cases reviewed in which this localization is exceptional.^8,27,28

The disease evolves without symptoms or with discrete pruritus. Roughly 38% of patients referred to discreet pruritus occasionally after sun-exposure, leading the authors to believe little importance is attached to the clinical condition of the disease.

Cases have been reported of spontaneous regressions in benign lesions of EV.^5,7,29 In what follows, progressive evolution of the disease was observed in all of the disease forms, without a tendency to remission. The patients did not demonstrate diseases either, (or were receiving immunosuppressor therapy) which can justify a generalized infection by HPV and cutaneous cancer (syndrome similar to EV).^12,13,14,27

In three siblings (23%), variable degrees of mental retardation were observed, showing a rate higher than the 10% referred to in the literature.⁹

The histopathological test is an important diagnostic method of the disease. It is possible to individualize the cytopathic effect of the viral infection in the lesions,^1,7,16,30 which were demonstrated in all wart lesions, independent of clinical manifestation.

In the flat wart-like lesions of malignant form, the viral cytopathic effect was observed from the suprabasal layer until the upper layers of the epidermis, which is characteristic in lesions caused by HPVEV (mainly HPV 5 and 8).¹² In benign lesions, the viral cytopathic effect was only observed in the upper layers of the epithelium, granted the aspect of "bird eyes", characteristic of this kind of disease.^8,13

The positive immunohistochemical results in the wart samples of all EV patients indicate the presence of the HPV antigen. The negative results in seborrheic and actinic keratosis-type lesions, and cutaneous tumors could be justified by the reduced sensitivity of the method applied in dysplasic tissues.^1,13

EV is accepted as a pre-malignant condition. The malignant transformation occurs in about 30 to 50% of cases and is associated with oncogenic HPVEVs, genetic factors of the host cell, and actions of the extrinsic co-carcinogens, mainly UVB and radiotherapy.^{1,5,8,12,28,31,32}

Patients can prematurely show solar elastosis and numerous actinic keratosis-like lesions in the areas of greatest photoexhibition.^8,28,33 These lesions demonstrate clinical characteristics equal to those observed population in general, but with more malignization power.^8,12,13,28 There was no solar elastosis observed in these patients, but all of those who went on to develop cutaneous tumors had previously shown actinic keratosis-like lesions.

All patients with malignant condition developed cutaneous tumors, and showed a 62% malignization rate. This rate may be underestimated due to the study's short observation period (three years) and due to the fact that patients 7 and 9, without tumors, were younger than the age suggested as the beginning of cutaneous tumor development in EV (from 24 to 30 years of age).^6,23

Patients with mixed form, one pardo and one black patient, did not develop tumors, in spite of being compromised by oncogenic HPVEVs and intense sun-exposure. The absence of tumors is probably due to the protector role of melanin and to the short exposure time to HPVEVs in this clinical form of the disease.

Tumor development in EV is a multiple-step process, with onset mainly in sun-exposed skin.^13,30 In this sampling, the shortest duration observed, from ages 11 to 25, could be justified by the greater degree of sun-exposure to which these patients were subjected.

Most malignant tumors (roughly 50%) developed on the forehead of patients, which may be justified by the joint or isolated action of the following factors: 1) greater area exposed to ultra-violet rays; 2) presence of long-life cells, stem cells, hair follicles, probable reserves of HPVEV; 3) synergic action of chemical carcinogens (squalus and fatty acids in sebum).^8,28

Patients developed multiple tumor lesions, the majority with spinocellular-type carcinoma and Bowen's disease, which confers with the research literature.^1,5,6,7

The invasive behavior of malignant tumors in EV has been described, but it has slow growth and good prognosis, except when treated with radiotherapy. The latter situation is one with which metastatic disease, 30 usually invading the regional lymphatic ganglions,^8,9,28 is associated.

In this study, the authors observed noticeably aggressive behavior by the cutaneous tumors, which compromised the muscular, cartilaginous and bone tissues, and orbits and meninges. Tumor aggressivity due to the planned application of radiotherapy might be justified in patient numbers 2, 6 and 13. Radiotherapy provokes the release of a large amount of immunosuppressor cytokines TNF-alpha (tumor necrosis factor alpha), which determines more aggressive tumor behavior with formation of metastases.^12,13,14,30In the other patients, the aggressive behavior could be explained by prolonged sun-exposure associated with Fitzpatrick's skin type-II.

Although there have been reports of death by EV due to advanced malignant tumors, there is no reported case of death in young persons. In this sampling, however, patients 2 and 10, 34 and 32 years of age, respectively, death was due to development of aggressive spinocellular carcinoma of the face with subsequent affliction of the cerebral tissue.

CONCLUSIONS

Data analysis justified the conclusion that EV is a genodermatosis of high familial incidence, especially present in children from consanguine marriages. Transmission of EV is probably recessive autosomal. They begin as flat wart-like and/or erythematous macules on the face and cervical region in general. Intense polymorphism of cutaneous lesions develop with diffuse distribution, except for the scalp and mucosa. The subjective symptoms are infrequent and irrelevant. The most common clinical manifestation of the disease is the "malignant" form (62%), followed by "benign" (23%) and "mixed" (15%) forms.

The seborrheic keratosis-like lesions are probably caused by HPVEVs, because only carriers with "malignant" and "mixed" forms of the disease were identified, and viral cytopathic effect of the disease was detected by histopathological exam.

Malignant cutaneous tumors are not very frequent. Predominantly multiple (75% of diseases), they develop in the areas most exposed to the sun, especially on the forehead. They are especially invasive spinocellular and in situ carcinoma types, followed by basocellular carcinoma. They demonstrated very aggressive behavior, invaded subjacent tissues (65%), generated metastases (38%) and induced death (25%).

REFERENCES

Received in January, 19th of 2001.

Approved by the Consultive Council and accepted for publication in April, 2nd of 2002.

*Work done at "Ambulatório de Oncologia Cutânea do Departamento de Dermatologia da Faculdade de Medicina da Universidade de São Paulo"

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Publication Dates

• Publication in this collection
  12 May 2006
• Date of issue
  Oct 2002

History

• Received
  19 Jan 2001
• Accepted
  02 Apr 2002