Epidermodysplasia Verruciformis


Article Author:
David Myers


Article Editor:
Eric Fillman


Editors In Chief:
Shane Havens
Jim Wang
Koushik Tripathy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/13/2019 11:27:37 PM

Introduction

The connection between viral infection and certain forms of carcinogenesis has been well established, especially with regards to human papillomavirus (HPV). Specific types of HPV have been implicated more strongly with carcinogenesis and the spectrum of dysplasia development. Epidermodysplasia verruciformis (EV) is a genetic dermatologic condition in which patients show a decreased immunologic ability to defend against and eradicate certain types of HPV, leading to persistent infection and increased lifetime risk of development of cutaneous dysplasia and malignancy. Persons with this disease develop HPV-derived cutaneous lesions at a much higher rate than the general population. This genodermatosis manifests mainly as verrucous cutaneous lesions such as multiple persistent verrucae, pityriasis versicolor-like lesions, and other verrucous or "warty" cutaneous lesions as well as the development of Bowen disease and squamous cell carcinoma. The lesions of EV tend to exhibit a characteristic histopathologic appearance. EV is a very rare genetic disease, but much research has been done on this entity as it has allowed insights into viral infection and their role in carcinogenesis pathways. There are broadly 2 forms of EV, the classic form being the inherited or primary type, inherited in an autosomal recessive pattern, while a separate acquired or secondary type is a clinically almost indistinguishable condition that is observed mainly in HIV-infected, immunocompromised, or immunosuppressed individuals.[1][2]

Etiology

Epidermodysplasia verruciformis (EV) is caused by a reduced ability by the immune system to fend off and eradicate human papillomavirus (HPV) infection. Since EV was first described in 1922 by Lewandowsky and Lutz[3], many different types of HPV have been implicated in the development of cutaneous lesions in patients with EV. The most commonly identified HPV types found in EV related cancers are HPV5 and HPV8. These 2 types have been found to be present in up to 90% of EV-related skin cancers.[4] Other types of HPV that are alternatively commonly found include 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 38, 47, and 50.[5] One study showed that HPV5 was the most common single type isolated, and contrary to other literature results, HPV3, HPV14, and HPV20 were more commonly isolated than HPV8.[6] This autosomal recessive condition in its primary (in other words, inherited) form is caused by a mutation of TMC6/EVER1 or TMC8/EVER2, which is believed to impart a defect in the ability to mount an immune response to certain HPV types within keratinocytes.[7] Interestingly, these patients with typical EV do not generally display reduced immune capabilities against other infectious pathogens. The beta-HPV types identified in patients with EV who develop skin malignancies are found throughout the general population, and in persons without the EVER mutations or EV, these HPV types have not been shown to produce dysplasia or malignancy otherwise.[8]

Malignant transformation of cutaneous epidermal lesions in EV is usually observed in association with HPV5, HPV8, HPV17, HPV20, and HPV47. These lesions usually develop in patients in their 30s, decades after the initial presentation.[9][10][11][3]

In patients with the acquired form of EV, also known as an atypical form, there is usually a history of some form of immunodeficiency, often treatment related. This occurrence of EV in relation to immunodeficiency (other than as occurs in the inherited type) is thought to be specifically due to T-cell mediated immunodeficiency in patients with pre-disposing genetic mutations such as in RHOH and STK4, among others. Not all patients with these mutations who are immunosuppressed will develop EV-like disease. This is much different than typical EV, wherein characteristic mutations are inherited display full penetrance.[12][13] Interestingly, a case has been reported of a patient who developed EV lesions in an acquired fashion due to trauma from Brazilian hot wax hair removal of the pubic region. The patient had a history of renal transplant 5 years earlier and a pancreatic transplant 3 years earlier. The area was denuded from the hot wax treatment, and as it healed, a brownish red cutaneous plaque developed that when biopsied was diagnosed as an EV lesion. The patient denied family or personal history of EV lesions. The lesion was successfully treated with topical 0.1% tretinoin and showed better resolution of lesion and less post-inflammatory increased pigmentation as compared with cryotherapy of another portion of the lesion treated concurrently.[14]

Epidemiology

Epidermodysplasia verruciformis (EV) is a very rare condition. A review of literature performed by Imahorn et al. in 2017 found about 500 patients with this disease reported in the literature worldwide.[6] Patients with typical EV develop EV lesions early in childhood and continue to develop new lesions throughout life.[8] These cutaneous lesions persistently infected with beta-HPV may progress to non-melanoma skin cancer, and between 30% to 70% of patients with EV will develop squamous cell carcinoma within their lifetime.[15][16][17] No bias for gender or specific geographical distribution has been identified.[18]

Pathophysiology

The majority of HPV infection within cutaneous keratinocytes is cleared in the general population without progression to malignancy. In the general population, infection with HPV types 3 and 10 are mainly associated with development of verruca vulgaris.[1] In persons with Epidermodysplasia verruciformis (EV), a decreased innate ability to clear HPV infection leads to persistent infection and progression to dysplasia and malignancy in the form of widespread pityriasis versicolor-like lesions and verruca plana like lesion formation as well as increased risk of persistent infection with beta-HPV leading to development of non-melanoma skin cancer. Mutations of TMC6/EVER1 or TMC8/EVER2 account for over 50% of the mutations which are responsible for the inherited form of EV.[7] The exact mechanisms on cellular and/or molecular levels which lead to increased susceptibility to HPV infection and persistence within keratinocytes are not known, but some hypotheses suggest that the TMC6/EVER1 or TMC8/EVER2 are transmembrane channel proteins that serve to limit and restrict viral replication and gene expression of beta-HPV within keratinocytes.[19] These proteins may also influence zinc transporters which affect the intracellular zinc concentration. Zinc plays a pivotal role in transcription factors which activate steps in the HPV life cycle. AP-1 is one such factor affected by the zinc concentration and involved in HPV cellular proliferation.[20] Merkel cell polyomavirus has also been identified in EV lesions.[21]

Histopathology

Histopathologic examination of EV lesions shares many characteristics of verruca-type lesions. Hyperkeratosis and parakeratosis, acanthosis with koilocytic cellular atypia and pale eosinophilic cytoplasm are characteristic of EV type lesions. The histologic finding of "blue cells" are pathognomonic for HPV infected keratinocytes in EV, and the "blue" appearance of these cells can be used as an indication of EV related disease. This "blue" appearance refers to cells exhibiting pale blue cytoplasm with the presence of abundant basophilic keratohyalin granules.[22] Actinic keratoses and Bowen's type lesions may also be encountered. Actinic keratoses appear as disordered and atypical keratinocytes in the superficial epithelium but should not have full thickness epidermal atypia. Bowen's type lesions have pagetoid scatter of highly atypical keratinocytes within the epidermis.

History and Physical

Patients with both inherited and acquired EV present with identical lesions, characterized by verruca plana-like sometimes scaly, often flat, lesions and papules usually on the trunk, neck or face, or appearing similar to pityriasis versicolor lesions. These lesions appear in multiple places, and in the case of inherited EV, may begin to appear as early as infancy and continue throughout the patient's life. They will usually appear on skin areas exposed to ultraviolet (UV) light. A family history of EV would be quite helpful in the diagnosis. For acquired EV, history of HIV or immunosuppression medical therapy would be vital to diagnosis.[8][3]

Evaluation

Definitive evaluation and diagnosis depend on dermatologist clinical examination and a pathologist's histopathologic examination of the skin lesions, which are suspected to be due to EV disease. Indeed, due to the characteristic findings histopathologically, and when found in conjunction with a familial history of EV or patient history of the early development of multiple EV-like lesions, the diagnosis of this disease is more problematic due to its rarity and the clinician's lack of awareness than to the diagnostic difficulty of the disease itself. Dermatologic clinical evaluation and histopathologic examination of suspected EV-like lesions are necessary to arrive at the correct diagnosis. Molecular analysis identifying known mutations associated with EV is now also possible.[23][24]

Treatment / Management

No definitively effective treatment for EV exists. However, several possible treatments are recommended from excision to other therapies such as acitretin and imiquimod, interferons with retinoids, cimetidine (although there is debate as to the efficacy of this treatment), to topical calcipotriol. As EV lesions tend to occur in sun-exposed areas of skin, sun exposure protection counseling and adherence are also important to the management of this condition. Any suspiciously malignant lesions should be excised to evaluate histopathologically. Patients with EV will require annual or more frequent check-ups with dermatologists to evaluate for development of new worrisome lesions.[25][26][27][28] Although radiation therapy is used often in non-EV patients with conjunctival squamous cell carcinoma, it is contraindicated in patients with EV as this has been observed to cause the development of more invasive and serious lesions.[29] In non-conjunctival cases of squamous cell carcinoma which have metastasized, radiation therapy may be a consideration as an adjunct to other treatments.[30]

Differential Diagnosis

Important entities to consider when evaluating EV lesions are verruca-associated lesions, any lesion with hyperkeratosis and parakeratosis, seborrheic keratosis, actinic keratosis, squamous cell carcinoma, among others. Importantly, in the case of EV, the lesions will present in multiples and at a young age (as early as infancy for inherited EV) or with a history of immunosuppression; whereas, other lesions on the differential would usually present as solitary lesions or at a later age.[1]

Staging

If a patient with EV develops squamous cell carcinoma, there is currently no TNM staging system for cutaneous squamous cell carcinoma.

Enhancing Healthcare Team Outcomes

Epidermodysplasia verruciformis is a very rare condition with no definitive treatment. Large randomized controlled trials do not exist to recommend specific treatment strategies. This genodermatosis is best handled an an interprofessional team effort including dermatology, general surgery, radiation oncology, and medical geneticists. In conjunctival squamous cell carcinoma, there are reported cases where radiation therapy may have induced more invasive transformation of lesions, and in these cases, current recommendations should be discussed between treating physicians and consultants. Identifying patients with this disease early on in the course of development and treating suspicious lesions is important to avoid more serious malignancies. Reducing sun exposure may help decrease the development of more malignant skin lesions and should. Encouraging patient follow-up and compliance with treatment and prevention strategies should be stressed as lesions may develop and progress to malignancy or even metastatic disease if left untreated.[29][30] (Level V)


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Epidermodysplasia Verruciformis - Questions

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A 30-year-old male presents with multiple flat cutaneous lesions that appear similar to seborrheic keratoses. He says was diagnosed in the past year with HIV/AIDS. Which of the following genetic mutations would most likely be implicated in the development of these cutaneous lesions?



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A mother brings in her 2-year-old male infant due to concerns regarding multiple flat, scaly red to red-brown cutaneous lesions. The mother and father of the child are not together. The mother denies any history of similar appearing lesions but says that the vaguely remembers that the child's father who she has been separated from since before the child was born has some sort of hereditary skin condition, something about developing lots of warts or wart-like things. She remembers that the father always wore large hats, long sleeves, and lots of sunscreens. The dermatologist suspects a certain hereditary skin condition and biopsies one of the lesions from the child. Which of the following would likely be found on histopathologic examination?



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A 42-year-old man presents to his primary care provider with a rapidly changing darkly pigmented skin lesion on his shoulder. The patient has a history of epidermodysplasia verruciformis and admits he frequents the beach and does not like to wear protective clothing or sunscreen often. His family has a history of multiple squamous cell carcinomas of the skin, and he has also had cutaneous squamous cell carcinomas excised in the past. Histologic examination identifies pagetoid atypical melanocytes present within the epidermis and confluent growth of melanocytes along the dermal-epidermal junction. No definitive atypical melanocytes are identified within the epidermis. Which of the following risk factors is most likely associated with the development of this lesion?



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A patient with epidermodysplasia verruciformis develops a squamous cell carcinoma of the conjunctiva. Which of the following treatments modalities may be contraindicated in the management of this lesion?



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Which of the following Human papillomavirus (HPV) types are most highly associated with the development of cutaneous lesions seen in epidermodysplasia verruciformis?



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Epidermodysplasia Verruciformis - References

References

Gül U,Kiliç A,Gönül M,Cakmak SK,Bayis SS, Clinical aspects of epidermodysplasia verruciformis and review of the literature. International journal of dermatology. 2007 Oct     [PubMed]
de Oliveira WR,Festa Neto C,Rady PL,Tyring SK, Clinical aspects of epidermodysplasia verruciformis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2003 Jul     [PubMed]
Tanigaki T,Endo H, A case of epidermodysplasia verruciformis (Lewandowsky-Lutz, 1922) with skin cancer: histopathology of malignant cutaneous changes. Dermatologica. 1984     [PubMed]
Patel T,Morrison LK,Rady P,Tyring S, Epidermodysplasia verruciformis and susceptibility to HPV. Disease markers. 2010     [PubMed]
Gewirtzman A,Bartlett B,Tyring S, Epidermodysplasia verruciformis and human papilloma virus. Current opinion in infectious diseases. 2008 Apr     [PubMed]
Ramoz N,Rueda LA,Bouadjar B,Montoya LS,Orth G,Favre M, Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nature genetics. 2002 Dec     [PubMed]
de Jong SJ,Imahorn E,Itin P,Uitto J,Orth G,Jouanguy E,Casanova JL,Burger B, Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses. Frontiers in microbiology. 2018     [PubMed]
Crequer A,Picard C,Patin E,D'Amico A,Abhyankar A,Munzer M,Debré M,Zhang SY,de Saint-Basile G,Fischer A,Abel L,Orth G,Casanova JL,Jouanguy E, Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PloS one. 2012     [PubMed]
Crequer A,Troeger A,Patin E,Ma CS,Picard C,Pedergnana V,Fieschi C,Lim A,Abhyankar A,Gineau L,Mueller-Fleckenstein I,Schmidt M,Taieb A,Krueger J,Abel L,Tangye SG,Orth G,Williams DA,Casanova JL,Jouanguy E, Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. The Journal of clinical investigation. 2012 Sep     [PubMed]
Imahorn E,Yüksel Z,Spoerri I,Gürel G,Imhof C,Saraçoğlu ZN,Koku Aksu AE,Rady PL,Tyring SK,Kempf W,Itin PH,Burger B, Novel TMC8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease. Journal of the European Academy of Dermatology and Venereology : JEADV. 2017 Oct     [PubMed]
Lazarczyk M,Cassonnet P,Pons C,Jacob Y,Favre M, The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections. Microbiology and molecular biology reviews : MMBR. 2009 Jun     [PubMed]
Orth G, Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Seminars in immunology. 2006 Dec     [PubMed]
Mertz KD,Schmid M,Burger B,Itin P,Palmedo G,Schärer L,Kutzner H,Fernández Figueras MT,Cribier B,Pfaltz M,Kempf W, Detection of Merkel cell polyomavirus in epidermodysplasia-verruciformis-associated skin neoplasms. Dermatology (Basel, Switzerland). 2011 Feb     [PubMed]
Gubinelli E,Posteraro P,Cocuroccia B,Girolomoni G, Epidermodysplasia verruciformis with multiple mucosal carcinomas treated with pegylated interferon alfa and acitretin. The Journal of dermatological treatment. 2003 Sep     [PubMed]
Lutzner MA,Blanchet-Bardon C,Orth G, Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. The Journal of investigative dermatology. 1984 Jul     [PubMed]
Partridge ME,Pariser RJ, Ocular and cutaneous squamous cell carcinoma in an African American man with epidermodysplasia verruciformis resulting in blindness and death. Journal of the American Academy of Dermatology. 2003 Nov     [PubMed]
Huang S,Wu JH,Lewis DJ,Rady PL,Tyring SK, A novel approach to the classification of epidermodysplasia verruciformis. International journal of dermatology. 2018 Aug 29     [PubMed]
Przybyszewska J,Zlotogorski A,Ramot Y, Re-evaluation of epidermodysplasia verruciformis: Reconciling more than 90 years of debate. Journal of the American Academy of Dermatology. 2017 Jun     [PubMed]
Pereira de Oliveira WR,Carrasco S,Neto CF,Rady P,Tyring SK, Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis. The Journal of dermatology. 2003 Mar     [PubMed]
Lutzner MA,Blanchet-Bardon C, Epidermodysplasia verruciformis. Current problems in dermatology. 1985     [PubMed]
Anadolu R,Oskay T,Erdem C,Boyvat A,Terzi E,Gürgey E, Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. Journal of the American Academy of Dermatology. 2001 Aug     [PubMed]
Micali G,Nasca MR,Dall'Oglio F,Musumeci ML, Cimetidine therapy for epidermodysplasia verruciformis. Journal of the American Academy of Dermatology. 2003 Feb     [PubMed]
de Oliveira WR,Neto CF,Rivitti EA, The lack of a clinical effect of cimetidine in the treatment of epidermodysplasia verruciformis. Journal of the American Academy of Dermatology. 2004 Jun     [PubMed]
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. The Journal of experimental medicine. 2008 Jan 21     [PubMed]
Rajabi MT,Ghasemi H,Safizadeh M,Jamshidi S,Asadi-Amoli F,Abrishami Y,Oestreicher JH, Conjunctival squamous cell carcinoma with intraocular invasion after radiotherapy in epidermodysplasia verruciformis. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2014 Apr     [PubMed]
Vohra S,Sharma NL,Shanker V,Mahajan VK,Jindal N, Autosomal dominant epidermodysplasia verruciformis: a clinicotherapeutic experience in two cases. Indian journal of dermatology, venereology and leprology. 2010 Sep-Oct     [PubMed]
Nindl I,Gottschling M,Stockfleth E, Human papillomaviruses and non-melanoma skin cancer: basic virology and clinical manifestations. Disease markers. 2007     [PubMed]
Adachi A,Kiyono T,Hayashi Y,Ohashi M,Ishibashi M, Detection of human papillomavirus (HPV) type 47 DNA in malignant lesions from epidermodysplasia verruciformis by protocols for precise typing of related HPV DNAs. Journal of clinical microbiology. 1996 Feb     [PubMed]
Yutsudo M,Hakura A, Human papillomavirus type 17 transcripts expressed in skin carcinoma tissue of a patient with epidermodysplasia verruciformis. International journal of cancer. 1987 May 15     [PubMed]
Kirchhof MG,Au S, Brazilian waxing and human papillomavirus: a case of acquired epidermodysplasia verruciformis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2015 Feb 3     [PubMed]

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