CDK-216/ vol. 41 no. 5, th. 2014342

TINJAUAN PUSTAKA

INTRODUCTIONThe “Tree Man” phenomenon was made into mainstream media when a man was reported with excessive growth of warts forming tree-like barks mainly on hands and feet and less sporadically on neck and face. The disease was made apparent starting from childhood when the patient suff ered a minor knee cut while playing. Small warts emerged from the close vicinity of the wound, and later it progressed rapidly to eventually towards the whole body (fi gure 1). This attracted a professor from University of Maryland to investigate him with greater details. He was diagnosed with Epidermodysplasia verruciformis (EV)

and commenced treatment regimens in collaboration with Indonesian doctors to formulate the best therapeutic strategies for the disease. So far, the treatments have been well and the patient is recovering.

DEFINITIONEpidermodysplasia verruciformis (EV) is a dermal genetic disorder with a very rare occurences, caused by autosomal recessive genetic disorder with ranges from 10% to 20% of the patients. This genetic trait increased vulnerability to Human Papillomavirus infection manifested in macules and papules growth with diff erent severity. The disease

was fi rst documented by Felix Lewandowsky and Wilhelm Lutz, can also be referred as Lewandowsky-Lutz dysplasia. Most cases has an onset from early infancy up to as late as 20 years old, and in some cases, middle ages.1

Epidermodysplasia verruciformis poses a high risk in transforming the benign viral cutaneous lesion at the onset of the disease to become malignant tumor or carcinoma.

ETIOLOGYGeneticEV emerges from genetic disorder which increases patients’ vulnerability to the virus.

ABSTRACTEpidermodysplasia verruciformis is a rare dermal disease made popular by “Tree Man” in November 2007. The disease is caused by rare autosomal recessive hereditary genetic disorder located on chromosome 17 which causes mutation on EVER1 and EVER2 genes. An abnormality in Major Histocompatibility Complex Class II (MHC II) allele DC-DQ has also been documented in patients in America, Europe and Africa continents. These mutations increased vulnerabilities to Human Papillomavirus (HPV) causing uncontrolled wart growth, prominent in arms, neck, and legs. The common initial detection of Epidermodysplasia verruciformis is through biopsy on predicted premalignant and malignant skin lesions. Further confi rmatory analysis can be performed by in-situ hybridization and polymerase chain reaction. The medical treatment is generally not defi nitive; typically with topical drugs such ad imiquimod, 5-fl uorouracil, vitamin A derivative 13-cis retinoic acid, interferon alpha or cholecalciferol analogues (Vitamin D). For severe cases, surgical procedures to remove excessive warts are necessary.

Key words: Epidermodysplasia verruciformis, HPV, biopsy, imiquimod, surgery

ABSTRAKEpidermodysplasia verruciformis merupakan penyakit kulit langka yang dikenal sejak kemunculan manusia pohon pada November 2007. Penyakit ini disebabkan oleh kelainan genetik keturunan autosomal resesif di kromosom 17 yang menyebabkan mutasi gen EVER1 dan EVER2. Selain itu, juga ditemukan kelainan pada Major Histocompatibility Complex kelas II (MHC II) pada alel DC-DQ pada pasien di benua Amerika, Eropa dan Afrika. Semua mutasi abnormal ini menyebabkan kerentanan terhadap infeksi Human Papillomavirus (HPV) yang menyebabkan pertumbuhan kutil tak terkontrol terutama di daerah tangan, leher dan kaki. Tindakan awal deteksi Epidermodysplasia verruciformis adalah biopsi daerah lesi yang diprediksi premaligna dan maligna, dapat dikonfi rmasi dengan proses in-situ hybridization dan polymerase chain reaction. Terapi tidak defi nitif, dermatologis biasanya menggunakan obat topikal seperti imiquimod dan 5-fl uorourasil, senyawa turunan vitamin A asam 13-cis retinoik, interferon alfa atau analog kolekalsiferol (Vitamin D). Untuk kasus parah, diperlukan operasi untuk membuang kutil yang berlebih. Richard Sutejo. Epidermodysplasia verruciformis: gejala, penyebab, diagnosis dan terapi.

Kata kunci: Epidermodysplasia verruciformis, HPV, biopsi, imiquimod, bedah

Epidermodysplasia verruciformis - symptoms, causes, diagnosis and treatment

Richard SutejoFakultas Biomedis (Biomedicine), Indonesia’s International Institute for Life Science (i3L),

Jakarta, Indonesia

Alamat korespondensi email: richard.sutejo@i3l.ac.id

343CDK-216/ vol. 41 no. 5, th. 2014

TINJAUAN PUSTAKA

The genetic anomaly stems out from the mutation of EVER1 and EVER2 genes which is located on chromosome 17q25. The functions of EVER1/EVER2 genes, which are also named as Transmembrane Channel-like Protein 6 (TMC6) and TMC8 genes, respectively, have been indicated to serve as zinc transporter by interacting with zinc-transporter 1 protein.2

Zinc-binding proteins have been found to be very important in great variety of viruses to maintain virus life cycle such as adenoviruses, retroviruses, rotaviruses, herpesviruses, polyomaviruses and papillomaviruses. Zn2+ ion is required for the activation of AP-1 transcriptional activity through PI3K-Akt and JNK pathway to assist viral proteins production. Also, free zinc ions alter the expression levels of certain cellular genes, and many of which are relevant to the viral life cycle, for example cellular immunity and antiviral responses. The activity of EVER1 and EVER2 has been indicated to assist cellular defense against virus infection by limiting available zinc ions.3

Another factor linked to the progression of the disease is major histocompatibility complex class II (MHC II) located at alleles (DR-DQ) in patients from regions of America, Europe and Africa. MHC class II molecules play huge role in immune system by exposing antigens to stimulate T cells in order to be able to remove those by phagocytosis, or receptor-mediated endocytosis. These molecules are highly variable in general populations. The experts found that –DRB1, -DQA10501, -DQB10301 type of MHC II were greatly more common in patients with EV, which could represent susceptible alleles with stronger predisposition to EV.4

Several cases of EV has also been described with close association with immu-nesuppression cases such as HIV positive, immunocompromised, organ transplantation or idiopathic lymphopenia.5

VirologyHuman Papillomavirus (HPV) is a double-stranded DNA (dsDNA), small, non-enveloped virus and contain circular double DNA as viral genome with length of 7,900 base pairs. HPVs infect mainly keratinocytes of the skin or mucous membranes. The infections can be non-symptomatic, benign papillomas in form of warts or squamous cell papillomas, or malignant and life-threatening cancers such as cervical cancer. More than 120 types of HPVs have been identifi ed so far and experts refer those by numbers. In EV case, numerous HPV types, such as HPV-4, -5a, -5b, -8,-9, -12, -14, -15, -17, -19, -25, -36, -38, -47, and -50, have been identifi ed. Among EV patients, HPV-5 and HPV-8 are the most abundant causative agents reported.6

HPVs transform keratinocytes, changing the characteristics to be rapidly growing by suppressing cellular anti-oncogenic proteins p53 and pRb, and at the same time promoting pro-oncogenic HPV viral E6 and E7 proteins to alter cell cycle and apoptosis.7

In EV case, HPV proteins of E6 and E7 are detected in abundance, which explains extensive tumorigenesis in EV. In cancerous lesions, the high-risk HPV types, such as HPV types 5, 8, and 47, are able retain and continuously express the E6 and E7 portions of the viral genome to cause cell immortalization by inhibiting apoptotic

Figure 1 The “Tree Man”. Much advanced stage of

Epidermodysplasia verruciformis (EV) which manifests as

tree bark-like warts grown mostly on feet and hands area

with lesser intensity on face and neck

Figure 2 Epidermodysplasia verruciformis cutaneous lesions

on the forehead of an 8-year-old boy characterised by fl at

macules varying from fl esh-colored to reddish brown or

brown plaques, with slightly scaly surfaces and irregular

borders

Figure 3 Verrucous or seborrheic keratosis–like lesions of Epidermodysplasia verruciformis on (A) head, (B) leg, (C) trunk

CDK-216/ vol. 41 no. 5, th. 2014344

TINJAUAN PUSTAKA

pathway, resulting in transformation of normal human keratinocytes into malignant cells.

CLINICAL PRESENTATIONEV may begin as early as infancy in the form of fl at, wart-like lesions and plaques on the face, limbs or neck (fi gure 2). The clinical course of EV is rather erratic. It may stay benign or progress into verrucous plaques and nodules, even become uncontrolled and transformed to be invasive squamous cell carcinoma, or in other cases, the lesions disappear and replaced by new ones in other areas. Commonly found primary skin lesions in EV consist of two types. The fi rst one is fl at, wartlike lesions similar to verruca plana with fl at-topped papules with scaly, hyperpigmented or hypopigmented confl uent patches or plaques. The second one is fl at macules and reddish brown plaques with slightly scaly surfaces and irregular borders resembling tinea versicolor (fi gure 3). Those papules may coalesce into large plaques on more advanced stage.

Clinical RecognitionThe clinical features are accessed based on the symptoms, mainly on cutaneous changes such as plane warts or pityriasis versicolor-like lesions, and red or brownish plaques, with persistent and progressive eff ect without any involvement of mucous membranes or lymph nodes, and in some cases, malignancies. The more comprehensive diagnosis of EV should be initiated upon the appearance and growth of verrucous lesions and when the condition is not relieved by the administration of ordinary treatment regimen. On the next step, medical practitioners can perform biopsies on the aff ected regions. The most apparent biopsy fi ndings can be observed on the epidermis. The typical histologic manifestation of EV is a verruca plana–like lesion with mild hyperkeratosis and acanthosis, in which the keratinocytes contain perinuclear halos and blue-gray pallor (fi gure 4). Perinuclear halos are specifi c cytopathic eff ect, which depicted in the fi gure as clear cells in the granular and spinous layers with occasional enlarged, hyperchromatic, and atypical nuclei. Further confi rmatory step can be achieved by performing in-situ hybridization targeting HPV DNA targetting on the upper layer on the epidermis (fi gure 5).

TREATMENT AND MANAGEMENTThere is no consensus on fi rst-treatment therapy for EV. The preventive measures are not limited to using sun-protection or totally avoid sun as soon as the confi matory diagnosis has been made. The therapeutic measures can be further divided into non-surgical and surgical methods.

Non-surgical MethodsImiquimod Imiquimod is a topically applied medication

that works by modulating immune response. Imiquimod activates Toll-like receptor (TLR7), one of the cellular receptors that detects foreign and pathogen substances. The cellular activation will then upregulate cytokines, such as interferon-α, interleukin-6 and tumor necrosis factor-α (TNF-α) to activate immune cells like Natural Killer (NK) cells, macrophages, B-lymphocytes and cytotoxic T-lymphocytes to halt viral infection by activating cell death/apoptosis mechanism, viral genetic material

Figure 4 Epidermis thickening (acanthosis), with prominent granular layer, and koilocytotic keratinocytes, characterized

by perinuclear halos and blue-gray pallor (blue arrow) shown from verrucous skin in EV patient in initial stage. (Staining:

hematoxylin and eosin; Magnifi cation: x150)

Figure 5 Histologic biopsy of a verrucous skin lesion from a patient with EV, which depicts the characteristic microscopic

features of specifi c cytopathic eff ect, such as, the presence of clear cells (blue arrow) and an occasional enlarged,

hyperchromatic, atypical nucleus (red arrow) in the epidermis with koilocytotic keratinocytes. These changes are seen in

human papillomavirus (HPV)-associated epithelial lesions (Staining: hematoxylin-eosin stain, Magnifi cation:x250) (Left).

Photomicrograph of the same skin lesion with in-situ hybridization procedures to detect HPV DNA, which is apparent with

spherical-to-ovoid shaped positive nuclear staining. (Right)

345CDK-216/ vol. 41 no. 5, th. 2014

TINJAUAN PUSTAKA

degradation, phagocytosis or virus release inhibition.8

The outcome of imiquimod treatment has been positive with successful recovery,9-10 but shown to be ineff ective in patients with defective cell mediated immunity.11

5-Fluorouracil (5-FU)5-Fluorouracil (5-FU) is a anti-metabolic agent mainly used in various cancer treatment, such as colorectal, anal, oesophageal, stomach, breast, pancreatic and skin cancers.12

The drug can be administered via intravenous injection and/or topical application. It works by inhibiting thymidylate synthase (TS) activity, which will deprive the cancerous cells of thymidine monophosphate required for DNA replication, triggering thymineless cell death.13

The success of treatment of EV with 5-FU has been reported in patients.14-15

Interferons (IFNs)Interferon treatments works by modulating and mimicking natural body interferons to remove pathogens. IFNs have been known to have antiviral, antiseptic and anticarcinomic properties which are benefi cial to the treatment of EV. IFNs are delivered most likely by intramuscular injection. The initial clinical effi cacy study to treat EV with interferon-α alone has shown to be eff ective.16

However, combination treatment has been demonstrated to be more successful, such as combination with acitretin,17 ribavirin on HIV patient.18

Derivatives of Vitamin A (acitretin) and Vitamin D analoguesVitamin A derivatives has been employed to

treat many types of diseases, mainly psoriasis, infl ammatory skin disorders and skin aging. Acitretin is one of the retinoids generally used to treat EV with high success rate. It comes with trade name Soriatane or Neotigason. It acts by binding to nuclear receptors that regulate gene transcription, hence blocking overproliferating keratinocytes and suppressing epidermal hyperdysplasia. It has been reported to be effi cacious in combination with interferon α-2a,17 peginterferon α-2b,19 and imiquimod.20

Other commonly used Vitamin A derivatives is 13-cis retinoic acid, which is also used in conjunction with interferons.21-22

Vitamin D analogues work with similar mechanism by modulation of epidermal proliferation and diff erentiation, and inhibition immune induction. Its usage and effi cacy with combination of isotretinoin have been demonstrated.23

Photodynamic therapy (PDT)Photodynamic therapy utilizes photo-sensitizing mediated agents to increase target cells vulnerability to light sources. The photosensitizing agents are generally preferentially absorbed by hyperproliferative cells and have low intake and minimal eff ects on healthy cells, which is a suitable treatment for EV. The commonly used photosensitizing agent for cancerous skin is 5-aminolevulinic acid (ALA) and methylaminolevulinate (MAL). The body will activate the photosensitizing eff ect by transforming ALA and MAL into porphyrin, which then will excite upon exposure to light and accumulate reactive oxygen species (ROS) which will trigger cell death (apoptosis) and necrosis to malignant cells.24

Another advantage is that the accumulated

ROS is only confi ned intracellularly and will not aff ect adjacent cells. In EV, the usage of 5-ALA and followed by irradiation using lambda light source (580-740 nm wavelength) has been shown to be effi cacious.25

Surgical MethodSurgical method includes removal and elimination of benign and premalignant skin lesions by surgery or cryosurgery. Many successful removal of the lesions with surgery has been described, for example fusiform excision with a curette and application of trichloroacetic acid (TCA) resulted in no appearance of lesion for 3.5 years,26 surgical excision and postoperative radiotherapy,27 liquid nitrogen and excision surgery.28

Besides, skin grafting from non-infected and sun protected skin methods are also reported.29

SUMMARYEpidermodysplasia verruciformis is a rare dermal disease caused by rare autosomal recessive hereditary genetic disorder located on chromosome 17q25 which causes mutation on EVER1 and EVER2 genes. These mutations increased vulnerabilities on Human Papillomavirus (HPV) causing prominent and uncontrolled wart growth on arms, neck, and legs. The common initial detection of Epidermodysplasia verruciformis is through biopsy on predicted premalignant and malignant skin lesions. Further confi rmatory analysis can be performed by in-situ hybridization and polymerase chain reaction. The medical treatment is generally not defi nitive; typically with topical drugs such as imiquimod, 5-fl uorouracil, vitamin A derivative 13-cis retinoic acid, interferon alpha or cholecalciferol analogues (Vitamin D). For severe cases, surgical procedures to remove excessive warts are necessary.

DAFTAR PUSTAKA

1. Gul U, Kilic A, Gonul M, Cakmak SK, Bayis SS. Clinical aspects of epidermodysplasia verruciformis and review of the literature. Int J Dermatol. 2007 Oct;46(10):1069-72.

2. Lazarczyk M, Pons C, Mendoza JA, Cassonnet P, Jacob Y, Favre M. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by

cutaneous oncogenic human papillomaviruses. J Exp Med. 2008 Jan 21;205(1):35-42.

3. Lazarczyk M, Favre M. Role of Zn2+ ions in host-virus interactions. J Virol. 2008 Dec;82(23):11486-94.

4. Majewski S, Jablonska S, Orth G. Epidermodysplasia verruciformis. Immunological and nonimmunological surveillance mechanisms: role in tumor progression. Clin Dermatol. 1997 May-

Jun;15(3):321-34.

5. Jacobelli S, Laude H, Carlotti A, Rozenberg F, Deleuze J, Morini JP, et al. Epidermodysplasia verruciformis in human immunodefi ciency virus-infected patients: a marker of human

papillomavirus-related disorders not aff ected by antiretroviral therapy. Arch Dermatol. 2011 May;147(5):590-6.

6. Patel T, Morrison LK, Rady P, Tyring S. Epidermodysplasia verruciformis and susceptibility to HPV. Dis Markers. 2010;29(3-4):199-206.

CDK-216/ vol. 41 no. 5, th. 2014346

TINJAUAN PUSTAKA

7. Ganguly N, Parihar SP. Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis. J Biosci. 2009 Mar;34(1):113-23.

8. Bilu D, Sauder DN. Imiquimod: modes of action. Br J Dermatol. 2003 Nov;149 Suppl 66:5-8.

9. Berthelot C, Dickerson MC, Rady P, He Q, Niroomand F, Tyring SK, et al. Treatment of a patient with epidermodysplasia verruciformis carrying a novel EVER2 mutation with imiquimod. J

Am Acad Dermatol. 2007 May;56(5):882-6.

10. Heratizadeh A, Volker B, Kupsch E, Wichmann K, Kapp A, Werfel T. [Successful symptomatic treatment of epidermodysplasia verruciformis with imiquimod 5% cream]. Hautarzt. 2010

Dec;61(12):1052-5.

11. Janssen K, Lucker GP, Houwing RH, van Rijssel R. Epidermodysplasia verruciformis: unsuccessful therapeutic approach with imiquimod. Int J Dermatol. 2007 Nov;46 Suppl 3:45-7.

12. Alvarez P, Marchal JA, Boulaiz H, Carrillo E, Velez C, Rodriguez-Serrano F, et al. 5-Fluorouracil derivatives: a patent review. Expert Opin Ther Pat. 2012 Feb;22(2):107-23.

13. Fernandez-Contreras ME, Sanchez-Prudencio S, Sanchez-Hernandez JJ, Garcia de Paredes ML, Gisbert JP, Roda-Navarro P, et al. Thymidylate synthase expression pattern, expression level

and single nucleotide polymorphism are predictors for disease-free survival in patients of colorectal cancer treated with 5-fl uorouracil. Int J Oncol. 2006 May;28(5):1303-10.

14. Litwin MS, Ryan RF, Ichinose H, Reed RR, Kremetz ET. Proceedings: Use of 5 fl uorouracil in the topical therapy of skin cancer: a review of 157 patients. Proc Natl Cancer Conf. 1972;7:549-

61.

15. van Ruth S, Jansman FG, Sanders CJ. Total body topical 5-fl uorouracil for extensive non-melanoma skin cancer. Pharm World Sci. 2006 Jun;28(3):159-62.

16. Androphy EJ, Dvoretzky I, Maluish AE, Wallace HJ, Lowy DR. Response of warts in epidermodysplasia verruciformis to treatment with systemic and intralesional alpha interferon. J Am Acad

Dermatol. 1984 Aug;11(2 Pt 1):197-202.

17. Anadolu R, Oskay T, Erdem C, Boyvat A, Terzi E, Gurgey E. Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. J Am Acad Dermatol. 2001

Aug;45(2):296-9.

18. Javelle E, Lightburne E, Dukan P, De Biasi C, Morand JJ. Human immunodefi ciency virus (HIV)-associated epidermodysplasia verruciformis eradicated after interferon-alpha and ribavirin

treatment. Int J Dermatol. 2014 Feb 14.

19. Gubinelli E, Posteraro P, Cocuroccia B, Girolomoni G. Epidermodysplasia verruciformis with multiple mucosal carcinomas treated with pegylated interferon alfa and acitretin. J Dermatolog

Treat. 2003 Sep;14(3):184-8.

20. Nijhawan RI, Osei-Tutu A, Hugh JM. Sustained clinical resolution of acquired epidermodysplasia verruciformis in an immunocompromised patient after discontinuation of oral acitretin

with topical imiquimod. J Drugs Dermatol. 2013 Mar;12(3):348-9.

21. Lippman SM, Parkinson DR, Itri LM, Weber RS, Schantz SP, Ota DM, et al. 13-cis-retinoic acid and interferon alpha-2a: eff ective combination therapy for advanced squamous cell carcinoma

of the skin. J Natl Cancer Inst. 1992 Feb 19;84(4):235-41.

22. Toma S, Vincenti M, Palumbo R, Muzio G, Rainero M, Santi P, et al. Results of the association of intralesional recombinant alpha-interferon-2a (alpha-IFN) plus 13-cis-retinoic Acid (13cra) in

the treatment of Basal-cell carcinomas (bcc) of the skin. Int J Oncol. 1993 Dec;3(6):1149-54.

23. Majewski S, Skopinska M, Bollag W, Jablonska S. Combination of isotretinoin and calcitriol for precancerous and cancerous skin lesions. Lancet. 1994 Nov 26;344(8935):1510-1.

24. Issa MC, Manela-Azulay M. Photodynamic therapy: a review of the literature and image documentation. An Bras Dermatol. 2010 Jul-Aug;85(4):501-11.

25. Karrer S, Szeimies RM, Abels C, Wlotzke U, Stolz W, Landthaler M. Epidermodysplasia verruciformis treated using topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol. 1999

May;140(5):935-8.

26. Hoff ner MV, Camacho FM. Surgical treatment of epidermodysplasia verruciformis. Dermatol Surg. 2010 Mar;36(3):363-7.

27. Kim T, Park JC, Roh MR, Park JM, Kim SH, Cho NH, et al. Development of aggressive squamous cell carcinoma in epidermodysplasia verruciformis associated with human papillomavirus

type 22b. Dermatology. 2010;220(4):326-8.

28. Sehgal VN, Luthra A, Bajaj P. Epidermodysplasia verruciformis: 14 members of a pedigree with an intriguing squamous cell carcinoma transformation. Int J Dermatol. 2002

Aug;41(8):500-3.

29. Kunishige JH, Hymes SR, Madkan V, Wyatt AJ, Uptmore D, Lazar AJ, et al. Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J Am Acad Dermatol. 2007 Nov;57(5

Suppl):S78-80.