case report from the field epidermodysplasia verruciformis ...dec 20, 2012 · epidermodysplasia...

173

Epidermodysplasia Verruciformis Case Report Volume 20 Issue 5 December 2012/January 2013

Epidermodysplasia verruciformis (EV) is a rare genodermatosis, first de-scribed by Lewandosky and Lutz in 1922.1 This premalignant lesion has occurred de novo, as well as in patients with impaired cell-mediated immuni-ty, including those infected with HIV, systemic lupus erythematosus2 (SLE), or lymphoma,3 or those who have received a solid organ transplant.4 In immunocompromised and immuno-competent populations, typical clinical findings are similar, and include pity-riasis versicolor-like macules, as well as flat papules and lesions resembling verruca plana. Characteristic histologic features of the disease are the coexis-tence of epidermal thickening, a loose horny layer with a basketweave–like appearance, and the presence of large cells in the spinous and granular lay-ers of the skin, presenting with a large blue-gray cytoplasm often associated with a perinuclear halo.5,6

Heredity

EV can occur sporadically or as an in-herited disorder. This genetic pattern is supported by the results of several observational studies. In the immuno-competent population, approximately 25% to 50% of reported EV cases have occurred in an autosomal recessive pattern.7 In a review of 147 case re-ports of EV, 10% occurred in individu-als with consanguineous parents.8 A

Dr Kaushal is a resident physician in the Department of Internal Medicine at the University of Manitoba in Winnipeg, Canada. Dr Silver is As-sistant Professor in the Department of Internal Medicine at the University of Manitoba. Dr Kasper is Assistant Professor in the Department of Internal Medicine, in the Department of Medical Microbiology, and the Manitoba HIV Program at the University of Manitoba. Dr Severini is Adjunct Professor in the Department of Medical Microbiology and the Public Health Agency of Canada, National Microbiology Laboratory, at the University of Manitoba. Dr Hamza is Assistant Professor in the Department of Pathology and Diagnostic Services of Manitoba at the University of Manitoba. Dr Keynan is Assistant Professor in the Department of Internal Medicine, Department of Medical Microbiology, Depart-ment of Community Health Sciences, and the Manitoba HIV Program at the University of Manitoba. Send correspondence to Amit Kaushal, MD, Department of Internal Medicine, University of Manitoba, Health Sciences Centre, GC440 – 820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9.

Case Report From the Field

Epidermodysplasia Verruciformis in an HIV-Infected Man: A Case Report and Review of the Literature Amit Kaushal, MD, Shane Silver, MD, Ken Kasper, MD, Alberto Severini, MD, Sate Hamza, MD, and Yoav Keynan, MD

2002 report by Sehgal and colleagues was consistent with this finding, dem-onstrating a 30% prevalence of EV in siblings of patients with EV.6 A case series involving a single, large family showed an x-linked pattern of inheri-tance,9 and another large family had several cases of EV, all of which oc-curred in female relatives.10

Genetics

In 2002, Ramoz and colleagues identi-fied the EVER1 and EVER2 loci, which suggested a loss-of-function muta-tion as the cause of susceptibility to the human papillomavirus (HPV) sub-types that are associated with EV.11 The EVER1 and EVER2 genes, which are lo-cated on chromosome 17q25, encode proteins within the endoplasmic reticu-lum.11 Given their proximity (4732 base pairs apart), the full-length proteins en-coded by EVER1 and EVER2 are sus-pected to share 28.6% of their constit-uent amino acids.12 In addition, Krogh and colleagues' work suggests that the EVER proteins would have functions similar to those of integral membrane proteins,13 supporting the hypothesis that mutations at these loci on chro-mosome 17q25 may down-regulate cell-mediated immunity by decreasing cells’ ability to present EV-HPV antigen to T lymphocytes.14 More recently, ad-ditional loci on chromosome 2 have

been identified as potentially confer-ring susceptibility to EV.15,16

EV and HPV

In addition to genetic predisposition, the presence of HPV DNA is virtually requisite to the diagnosis of EV. Specific EV-associated HPV types, referred to as β-HPVs, include HPV-3, -5, -8, -9, -10, -12, -14, -15, -17, -19-25, -36-38, -47 and -50 (see Sidebar). Accordingly, EV is considered a virus-associated prema-lignant condition, eventually leading to nonmelanoma skin cancer (NMSC) in 30% to 70% of patients.17 In these individuals, Bowenoid dysplasia may occur, and a substantial proportion de-velop squamous cell carcinoma (SCC) in the fourth and fifth decades of life.

Sidebar. Human Papillomavirus (HPV) Subtypes Associated with Epidermodys-plasia Verruciformis (EV) (β-HPV Types)

HPV-3 HPV-15 HPV-24

HPV-5* HPV-17 HPV-25

HPV-8* HPV-19 HPV-36

HPV-9 HPV-20 HPV-37

HPV-10 HPV-21 HPV-38



*β-HPV types most commonly associated with EV

IAS–USA Topics in Antiviral Medicine

174

EV and Cancer

EV lesions harbor numerous copies of HPV, and HPV-5 and HPV-8 have been among the most common types isolated. Of the HPV types associated with EV, a select few β-HPVs appear to have substantial association with oncogenic transformation. HPV-5 and HPV-8 are the types most frequent-ly associated with development of NMSC, accounting for more than 90% of EV-associated cancers.17,18 Despite these relationships, the role of HPV in the development of EV lesions and the eventual malignant transformation of these lesions is not fully understood.

Diagnosis and Treatment

EV is diagnosed based on a combina-tion of clinical, histopathologic, and molecular means. At present, there is no known effective treatment for EV, and no effective preventative strategy for malignant transformation other than perhaps limiting sun exposure.

Natural History

The natural history of EV is delineated based on a small number of cases (ap-proximately 200) that have been re-ported in medical literature. In these cases, EV predominantly occurs as a primary disease associated with HPV. In a minority of cases, EV is found in association with a state of impaired cell–mediated immunity, such as lymphoma, SLE, renal transplant, or HIV infection. In reports of this phe-nomenon, the term acquired epider-modysplasia verruciformis (AEV) has been introduced by Rogers and col-leagues.19 In this review, the term EV-HIV will distinguish the subgroup of EV patients with HIV from the larger group of AEV patients.

In the HIV-infected population, EV has been reported approximately 30 times (see Table). In these cases, the lesions have been similar in clinical and histologic appearance, and HPV has been present on polymerase chain reaction (PCR) testing. Compared with the population with primary

EV, patients with EV-HIV appear to have lower rates of malignant trans-formation. This underrepresentation may be secondary to the rarity of EV in this population, and not necessarily due to a difference in disease biology.

This report presents a recent case of EV-HIV, lists the reported cases of EV-HIV to date, describes genetic sus-ceptibility to EV, and discusses the currently postulated risk of transfor-mation to malignant disease.

Case Report

In December 2009, a 19-year-old man of Ethiopian descent who had immigrated to Canada in 2007 pre-sented for HIV care. The presumed mode of acquisition was heterosexual contact; the patient reported a sexual debut when he was 14 years old. He denied an acute seroconversion ill-ness. His past medical history was re-markable for malaria as a child, which was treated without complications. There was no history of opportunistic infections, and he was not taking any medications at the time of presenta-tion. He had no allergies. Family his-tory did not reveal any relatives with chronic skin conditions.

Initial laboratory test results re-vealed a white blood cell (WBC) count of 4400/µL, hemoglobin of 14.3 g/dL, and a platelet count of 159 × 103/µL. The patient’s renal and liver function test results were within normal lim-its. He had no serologic evidence of opportunistic infections: his test re-sults were negative for antibodies to hepatitis B virus (HBV) and hepatitis C virus (HCV), and showed IgG anti-bodies against hepatitis A virus (HAV), cytomegalovirus (CMV), and toxoplas-mosis. CD4+ cell count and CD4+ percentage were 270/µL and 15% re-spectively, and initial HIV RNA level was 51,000 copies/mL. Genotyping revealed no drug-resistant HIV muta-tions, and antiretroviral therapy was initiated in August of 2010.

During the patient’s initial evalu-ation, a rash involving his upper ex-tremities and back was noted. He indicated that the lesions had been

present since childhood. The lesions consisted of numerous white flat-topped verrucous papules 1 mm to 3 mm in diameter on the upper ex-tremities and trunk. There were also subtle hypopigmented macules with fine scale resembling pityriasis versi-color; these macules were limited to the trunk area. There were no signs of SCC, NMSC, or melanoma (Figures 1 and 2). No family members had similar eruptions, nor did any of his other personal contacts. The pattern and history of this patient’s rash was consistent with EV, and a punch bi-opsy was collected for examination. The biopsy results showed variable thickening of the epidermis, which was composed of variably swollen and pale keratinocytes. The granular

Figure 1. Numerous 1-mm to 3-mm flat-topped white verrucous papules on the up-per extremity.

Figure 2. 1-mm to 3-mm flat-topped verru-cous papules, with some koebnerizing into a linear plaque. Faint and subtle hypopig-mented macules with fine scale can be seen between the verrucous papules.

175


Tab

le 1

. Pub

lishe

d C

ases

of

Epid

erm

odys

plas

ia V

erru

cifo

rmis

in C

ombi

natio

n w

ith H

IV (E

V-H

IV)

Sou

rce

Cas

e N

o.

Sex

Ag

e,

Year

sPa

tter

n o

f

Dis

trib

uti

on

Des

crip

tio

n o

f Sk

in L

esio

ns

HPV

Ty

pe(

s)C

D4+

C

ells

/µL

HIV

RN

A

Copi

es/m

LM

alig

nan

t

Tran

sfor

mat

ion

Co

mm

ents

Pros

e et

al,

1990

391

M10

Face

, che

st, b

ack

Shin

y, h

ypop

igm

ente

d fla

t w

arts

, PV

5-

--

-

Berg

er e

t al

, 19

9140

2

M34

Che

st, d

orsa

l sur

face

s of

upp

er e

xtre

miti

es,

hand

, fac

e

Flat

, slig

htly

ker

atot

ic p

apul

es 2

-5 m

m in

di

amet

er5,

8-

--

Dia

gnos

ed w

ith E

V 3

mon

ths

afte

r H

IV d

iagn

osis

3M

35H

ands

, fac

eFl

at, s

light

ly k

erat

otic

2-5

mm

pap

ules

5, 8

--

-D

iagn

osed

with

EV

5 y

ears

af

ter

HIV

dia

gnos

is

4M

28D

orsa

l sur

face

of

hand

s, f

orea

rms

Skin

-col

ored

hyp

opig

men

ted

mac

ules

N/A

--

--

Barz

egar

et

al, 1

99835

5M

26Ex

trem

ities

, fac

e,

trun

k, s

calp

Flat

-top

ped,

non

scal

ing

skin

-col

ored

or

hypo

pigm

ente

d sm

all p

apul

es5

< 3

00-

-Ba

schk

e-Lo

ewen

stei

n an

al

tum

or; i

nter

fero

n al

fa-2

a an

d zi

dovu

dine

tre

atm

ent

led

to

part

ial i

mpr

ovem

ent

in E

V

6M

32Fa

ce, t

runk

, dor

sal

surf

ace

of h

ands

, pr

oxim

al e

xtre

miti

es

Hyp

opig

men

ted

papu

les,

1-3

mm

, PV-

like

mac

ules

5<

300

--

-

7M

32N

eck,

che

st, s

houl

-de

rs, e

xtre

miti

esEr

ythe

mat

ous,

hyp

opig

men

ted

1-10

mm

m

acul

es20

(in

1 m

acul

ar

lesi

on o

nly)

< 3

00

--

-

Haa

s et

al,

2001

41

8M

45C

hest

, fac

e, d

orsa

l su

rfac

es o

f ex

trem

i-tie

s

Flat

, war

ty, s

light

ly k

erat

otic

mac

ules

5, 8

, 14,

19

, 21

1025

0,00

0C

ellu

lar

atyp

ia

“not

pro

mi-

nent

”

Dia

gnos

ed w

ith E

V 1

1 ye

ars

afte

r H

IV d

iagn

osis

(198

3),

trea

ted

with

ART

; tre

ated

for

M

AC

, and

EV

cle

ared

Trau

ner

et

al, 2

00242

9

M58

Gro

inSc

aly,

ery

them

atou

s fla

t pa

pule

s co

ales

c-in

g in

to p

laqu

es8

187

76,1

35-

4-ye

ar h

isto

ry o

f EV

Car

ré e

t al

, 20

0314

10M

38Fo

rear

ms,

nec

klin

e,

trun

k, t

high

sEr

ythe

mat

ous,

flat

-top

ped

papu

les

5, 1

416

252

,160

-Im

prov

ed C

D4+

cou

nt a

nd

HIV

RN

A le

vel w

ith A

RT; n

o im

prov

emen

t in

EV

Dav

ison

et

al, 2

00437

11M

44Fa

ce, c

hest

, lim

bsFl

at p

apul

es r

esem

blin

g pl

ane

war

ts, v

io-

lace

ous

papu

les

rese

mbl

ing

liche

n pl

anus

an

d ke

rato

tic r

eddi

sh-b

row

n pl

aque

s

5, 8

,14

, 3, 7

100-

200

Und

e-te

ctab

leBo

wen

oid

dy

spla

sia

HIV

+ s

ince

198

7, 2

-yea

r sk

in

erup

tion

Hu

et a

l, 20

0443

12M

11Fa

ce, t

runk

, ex-

trem

ities

Clu

ster

ed, p

ink,

flat

-top

ped,

pol

yang

ular

pa

pule

s an

d pl

aque

, ran

ging

fro

m 2

-6

mm

848

9-

-Tw

o H

ispa

nic

mat

erna

l hal

f-br

othe

rs w

ith H

IV+

mot

her.

EV

at a

ge 6

yea

rs -

8 y

ears

in b

oth

13M

12A

s ab

ove

As

abov

e8

402

--

As

abov

e

Bona

mig

o et

al

, 200

74414

M14

Face

, upp

er t

runk

, up

per

extr

emiti

es,

hand

s, a

nd k

nees

Hyp

ochr

omic

mac

ules

and

flat

pap

ules

-22

482

,000

-H

CV

+; E

V a

t ag

e 3

Hul

tgre

n et

al

, 200

74515

M41

Entir

e bo

dy1-

3 m

m s

moo

th h

ypop

igm

ente

d pa

pule

s-

--

-


176

Tab

le 1

. Pub

lishe

d C

ases

of

Epid

erm

odys

plas

ia V

erru

cifo

rmis

in C

ombi

natio

n w

ith H

IV (E

V-H

IV) (

cont

inue

d)

Sou

rce

Cas

e N

o.

Sex

Ag

e,

Year

sPa

tter

n o

f D

istr

ibu

tio

nD

escr

ipti

on

of

Skin

Les

ion

sH

PV

Typ

e(s)

CD

4+

Cel

ls/µ

LH

IV R

NA

Co

pies

/mL

Mal

ign

ant

Tr

ansf

orm

atio

nC

om

men

ts

Che

n et

al,

2008

4616

M56

Che

st, a

bdom

en,

back

, arm

s, le

gsH

ypop

igm

ente

d, t

hin,

pin

k, fl

at-t

oppe

d pa

pule

s co

ales

cent

to

plaq

ues

-24

518

50-

-

Berk

et

al,

2009

4717

M42

Upp

er t

runk

, hea

d,

neck

Hyp

o- a

nd h

yper

pigm

ente

d pa

pule

s an

d pl

aque

s-

7-

--

Roge

rs e

t al

, 20

0919

18M

22Ex

trem

ities

Whi

te m

acul

es, 2

-6 m

m5,

19

8362

,700

--

19M

32C

hest

, gro

in, a

xilla

, up

per

extr

emiti

es,

trun

k

Pink

-bro

wn,

flat

-top

ped

papu

les

525

3<

50

--

Burg

er e

t al

, 20

1038

20F

14N

eck

and

chin

On

the

low

er le

gs, t

he

dors

um o

f fee

t, an

d sc

atte

red

over

the

trunk

Upp

er b

ody:

num

erou

s hy

popi

gmen

ted

verr

ucou

s pa

pule

s an

d sm

all p

laqu

es

Low

er b

ody

and

trun

k: b

lack

-bro

wn

papu

les

5-

--

Hom

ozyg

ous

for

TMC

6 ge

ne

mut

atio

n

Jaco

belli

et

al, 2

01136

21F

39Fa

ce, t

runk

, lim

bsFl

at w

arts

, lic

heno

id8

615

< 5

0-

EV e

rupt

ion

at a

ge 1

5; H

IV

diag

nosi

s at

age

33

22F

40Fl

at w

arts

, PV-

like

lesi

ons

2210

40<

50

--

23M

47Fl

at w

arts

, lic

heno

id le

sion

s3,

8, 1

933

4<

50

Bow

enoi

d dy

spla

sia

Hod

gkin

s, H

CV

+

24F

43Tr

unk,

lim

bs, g

roin

Flat

war

ts, P

V-lik

e5,

876

9<

50

--

25M

51Tr

unk,

lim

bs, a

xilla

eFl

at w

arts

, PV-

like

553

6<

50

Inva

sive

ep

ider

moi

d dy

spla

sia

-

26M

47Tr

unk,

lim

bsFl

at w

arts

, PV-

like

5, 3

8, 6

530

4<

50

--

27M

41Fa

ce, t

runk

Flat

war

ts, P

V-lik

e8,

20,

22,

24

495

< 5

0 -

-

28M

45Fa

ce, t

runk

Flat

war

ts-

210/

200

200

-M

ultic

entr

ic C

astle

man

di

seas

e, H

BV+

29M

44Fa

ce, t

runk

, lim

bsFl

at w

arts

-78

108,

000

-La

rge

B-ce

ll ly

mph

oma

30F

50Tr

unk,

lim

bsFl

at w

arts

, lic

heno

id-

383

200

Bow

enoi

d dy

spla

sia

Larg

e B-

cell

lym

phom

a,

HBV

+

31F

51Tr

unk,

lim

bsFl

at w

arts

1954

0<

50

--

Kau

shal

et

al, 2

012

32M

19C

hest

, bac

k, e

x-tr

emiti

esFl

at-t

oppe

d w

hite

pap

ules

, flat

war

ts

and

lesi

ons

rese

mbl

ing

PV20

270

51,0

00-

-

ART

indi

cate

s an

tiret

rovi

ral t

hera

py; E

V, e

pide

rmod

yspl

asia

ver

ruci

form

is; F

, fem

ale;

HBV

+, h

epat

itis

B vi

rus-

infe

cted

; HC

V+

, hep

atiti

s C

viru

s–in

fect

ed; H

IV+

, HIV

-infe

cted

; HPV

, hu

man

pap

illom

aviru

s; M

, mal

e; M

AC

, Myc

obac

teriu

m a

vium

com

plex

; PV,

pity

riasi

s ve

rsic

olor

; TM

C6,

tra

nsm

embr

ane

chan

nel-l

ike

prot

ein

6.

177


cell layer was thickened and con-tained prominent variably sized gran-ules. These features were in keeping with EV (Figure 3).

The presence of HPV was confirmed by DNA amplification of an approxi-mately 460-base pair (bp) target on the L1 gene, using a general PCR method for EV-associated HPV types.20 Direct sequencing of the PCR products fol-lowed by use of Basic Local Assign-ment Search Tool (BLAST) identified HPV-20, with 95% sequence identity. The “clean” peaks of the sequence suggested that only HPV-20 DNA was amplified from this sample, but the presence of other types in this or other lesions cannot be completely excluded.

The lesions were present prior to the diagnosis of HIV, and subsequent-ly increased in number; however, a temporal association between HIV acquisition and the progression of EV could not be established. In addition, there was no evidence of a pheno-typic change associated with HIV, and the initiation of antiretroviral therapy did not result in modification of the lesions.

Discussion

HPV Disease and HIV

There is an increased prevalence of HPV infection in HIV-infected patients and decreased clearance of HPV in HIV-infected patients compared with immunocompetent controls, and possibly an increased rate of disease reactivation in HIV infection.21-24 Ad-ditionally, the incidence of SCC in HIV-infected patients is 5-fold higher than that in the HIV-uninfected popula-tion.25 This suggests that in the case of oral and anogenital HPV, there is an in-creased likelihood of malignant trans-formation. Of note, a large propor-tion of patients with HPV-associated NMSC never manifest EV. Oftentimes, the first recognized cutaneous lesion is that which pathologically shows Bowenoid dysplasia, SCC, or basal cell carcinoma (BCC). Several studies have demonstrated that β-HPV types are more common than other HPV types in NMSC, and that HPV is more prevalent in SCC than in BCC lesions,

ranging from 84.1% and 75%, respec-tively in immunocompromised popu-lations, compared with 59.7% and 27.8%, respectively, in immunocom-petent populations.26-28

In patients with HIV, the natural his-tory of β-HPV infections—those that lead to EV—has been incompletely ex-amined. Accordingly, there is a paucity of epidemiologic data. In contrast to this, there are many population-based studies of oral and anogenital HPV in-fections in HIV-infected patients. HPV types have been identified in and asso-ciated with a large proportion of anal, penile, and cervical intraepithelial neo-plasia (AIN, PIN, and CIN, respective-ly), and there is some representation from the β-HPV family.29,30 In an epi-demiologic study of HIV-seropositive men with AIN or PIN, AIN was noted in 156 of 263 (59.3%) patients, and PIN in 11 of 263 patients (4.2%).31 Of these, β-HPV DNA was isolated from a total of 7 patients who represented 5 cases of AIN and 4 cases of PIN. There was only 1 case in which β-HPV levels were greater than levels of higher-risk α-HPV, and this occurred in a patient with PIN. There is also limited docu-mentation of β-HPV sequences in the female genital tract. In a study by Favre and colleagues, EV-associated HPV types were found in cutaneous le-sions of a pregnant woman who had developed EV at an early age.32 HPV was subsequently isolated from her amniotic fluid and placenta, and was also noted in cervical scrapings. No viral sequences were noted in periph-eral blood, and vertical transmission to amniotic and placental tissue was suspected. A later report described a female patient with known HIV infec-tion, HBV infection, and prior injection drug use, who developed CIN.33 HPV-5 and -16 sequences were isolated from biopsy specimens.33 Upon initiation of antiretroviral therapy, the patient man-ifested EV lesions across several areas of sun-exposed skin; the lesions tested positive for HPV-5. These previously described findings may signify that β-HPV plays a role in some cases of PIN and CIN, or may represent coinfec-tion with β-HPV and higher-risk α-HPV types. At present, there is no evidence

Figure 3. Histology, skin (right arm): There is variable thickening of the epidermis, which is composed of swollen and pale keratinocytes (black arrow). The granular cell layer is thick-ened and contains prominent, variably sized granules (white arrow).

Tab

le 1

. Pub

lishe

d C

ases

of

Epid

erm

odys

plas

ia V

erru

cifo

rmis

in C

ombi

natio

n w

ith H

IV (E

V-H

IV) (

cont

inue

d)

Sou

rce

Cas

e N

o.

Sex

Ag

e,

Year

sPa

tter

n o

f D

istr

ibu

tio

nD

escr

ipti

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178

that patients who have developed EV demonstrate increased susceptibility to other, non-β-HPV subtypes.34

EV in HIV

The β-HPV types most commonly rep-resented in the EV-HIV population are HPV-5 and -8, with several cases hav-ing tested positive for HPV-14 as well. Please refer to the Table for a list of the reported cases of EV-HIV to date. Of the cases reviewed, the current case report is the third case of HPV-20 being found with EV-HIV, and it appears to be only the second case in which HPV-20 was the sole type, although the presence of other HPV types in other lesions cannot be excluded. Of the 3 known HPV-20 cases, the phenotypic manifestations varied. Barzegar and colleagues (case 7) reported on a patient who had ery-thematous macules on the neck, chest, and upper extremities, and the patient reported by Jacobelli and colleagues (case 27) had pityriasis-like lesions on the face and trunk.35,36 The subject of the current case report (case 32) dis-played flat-topped white papules and flat warts and lesions that resembled pityriasis versicolor on the chest, back, and extremities. In other cases of EV, HPV-5 seemed predominantly associ-ated with flat lesions, many of which involved the face and neck. Of these, there were several in which HPV-5 was not the only HPV type found. There were no obvious consistencies in de-scriptors for HPV-8 associated lesions.

EV manifestation is similar clini-cally, histologically, and virologically in patients with and without HIV. Jacobel-li reported the largest case series of EV-HIV thus far, and noted that HPV was found in all skin biopsy specimens.36 In particular, HPV-5 or HPV-8 were isolat-ed in 75% of specimens, a proportion similar to that reported for immuno-competent patients with EV. Women and men were equally affected, and EV was concomitant with substantial immunodeficiency (median CD4+ cell count of 170 cells/µL), which was consistent with the presumed role of impaired cell-mediated immunity in this disease. In other patients, the re-searchers found that the EV eruption

occurred in conjunction with initiation of antiretroviral therapy.

In the majority of cases, PCR was the primary method of HPV type de-tection. The diagnosis of HIV consis-tently predated the EV lesions, though there were several reports in which the lesions may have been present prior to HIV infection.36 The series of 11 cases reported by Jacobelli and colleagues reports the chronology of HIV infec-tion and first eruption of EV lesions. In that series, the median age at HIV di-agnosis was 27 years, and the median age at EV eruption was 40 years. Only 1 case of EV predated the HIV diagno-sis. Of the cases of EV that occurred after HIV infection, the mean time from HIV diagnosis to EV manifesta-tion was 10 years. The interval from HIV acquisition to EV manifestation is likely longer than 10 years due to de-lays in HIV diagnosis. In the reported cases of EV-HIV, development of dys-plasia was infrequently reported, and progression to NMSC was noted a total of 4 times in the 30 cases reviewed.36,37 Two of these 4 cases were associated with HPV-5, which, along with HPV-8, is noted to predispose to malignancy. A third case of NMSC was associated with other HPV types, and the fourth case reported did not disclose HPV typing.

Several points are essential to the interpretation of these data. First of all, it is important to note that in a sub-stantial number of cases, the sequence of EV appearance in relation to HIV infection was not clearly delineated, leaving the possibility that the patient had a diagnosis of primary EV. In the current report, the patient’s longstand-ing presence of skin lesions suggests a diagnosis of primary EV predating the acquisition of HIV. The limited number of cases of EV-HIV makes it difficult to draw conclusions with respect to the course of disease and the response (or lack thereof) to antiretroviral therapy and immune reconstitution. Addition-ally, the definition of NMSC may have varied between investigators, and the subsequent cutaneous surveillance methods were beyond the scope of most reports. Furthermore, publish-ing reports soon after the diagnosis of

EV-HIV could lead to underreporting of subsequent malignant transformation. Finally, there are limited genetic data on EV-HIV, with few identified patients being tested for EVER1 and EVER2 gene mutations.38 This limits infer-ences about the importance of HIV in the genesis of EV.

Further investigation in these areas may help identify populations predis-posed to develop EV, and develop ther-apies that are effective in treating EV as well as preventing malignant trans-formation. Additional inquiry into the effectiveness of antiretroviral therapy for treating or preventing EV is war-ranted, specifically in patients with EV that developed in the context of immu-nocompromise.

Financial Affiliations: Drs Kaushal, Silver, Kasper, Severini, Hamza, and Keynan have no relevant financial affiliations to disclose. (Updated 01/15/13)

References1. Lewandowsky F, Lutz W. Archives of

dermatology and syphilology. Berlin: 1922:141(193).

2. Tanigaki T, Kanda R, Sato K. Epidermo-dysplasia verruciformis (L-L, 1922) in a patient with systemic lupus erythemato-sus. Arch Dermatol Res. 1986;278(3):247-248.

3. Barr BB, Benton EC, McLaren K, et al. Papillomavirus infection and skin can-cer in renal allograft recipients. Lancet. 1989;2(8656):224-225.

4. Gross G, Ellinger K, Roussaki A, et al. Epidermodysplasia verruciformis in a pa-tient with Hodgkin's disease: character-ization of a new papillomavirus type and interferon treatment. J Invest Dermatol. 1988;91(1):43-48.

5. Majewski S, Jablonska S. Epidermo-dysplasia verruciformis as a model of human papillomavirus-induced ge-netic cancer of the skin. Arch Dermatol. 1995;131(11):1312-1318.

6. Sehgal VN, Luthra A, Bajaj P. Epidermo-dysplasia verruciformis: 14 members of a pedigree with an intriguing squamous cell carcinoma transformation. Int J Der-matol. 2002;41(8):500-503.

7. Orth G. Epidermodysplasia verrucifor-mis: a model for understanding the onco-genicity of human papillomaviruses. Ciba Found Symp. 1986;120):157-174.

8. Lutzner MA. Epidermodysplasia verruci-formis. An autosomal recessive disease characterized by viral warts and skin can-cer. A model for viral oncogenesis. Bull Cancer. 1978;65(2):169-182.

9. Androphy EJ, Dvoretzky I, Lowy DR. X-linked inheritance of epidermodyspla-sia verruciformis. Genetic and virologic

179


studies of a kindred. Arch Dermatol. 1985;121(7):864-868.

10. Rajagopalan K, Bahru J, Loo DS, et al. Fa-milial epidermodysplasia verruciformis of Lewandowsky and Lutz. Arch Dermatol. 1972;105(1):73-78.

11. Ramoz N, Rueda LA, Bouadjar B, et al. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002;32(4):579-581.

12. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitiv-ity of progressive multiple sequence alignment through sequence weight-ing, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994;22(22):4673-4680.

13. Krogh A, Larsson B, von HG, et al. Pre-dicting transmembrane protein topology with a hidden Markov model: applica-tion to complete genomes. J Mol Biol. 2001;305(3):567-580.

14. Carre D, Dompmartin A, Verdon R, et al. Epidermodysplasia verruciformis in a pa-tient with HIV infection: no response to highly active antiretroviral therapy. Int J Dermatol. 2003;42(4):296-300.

15. Akgul B, Kose O, Safali M, et al. A distinct variant of Epidermodysplasia verrucifor-mis in a Turkish family lacking EVER1 and EVER2 mutations. J Dermatol Sci. 2007;46(3):214-216.

16. Azzimonti B, Mondini M, De AM, et al. CD8+ T-cell lymphocytopenia and lack of EVER mutations in a patient with clini-cally and virologically typical epidermo-dysplasia verruciformis. Arch Dermatol. 2005;141(10):1323-1325.

17. Majewski S, Jablonska S. Do epidermo-dysplasia verruciformis human papillo-maviruses contribute to malignant and benign epidermal proliferations? Arch Dermatol. 2002;138(5):649-654.

18. Lane JE, Bowman PH, Cohen DJ. Epider-modysplasia verruciformis. South Med J. 2003;96(6):613-615.

19. Rogers HD, Macgregor JL, Nord KM, et al. Acquired epidermodysplasia verruciformis. J Am Acad Dermatol. 2009;60(2):315-320.

20. Berkhout RJ, Tieben LM, Smits HL, et al. Nested PCR approach for detection and typing of epidermodysplasia verrucifor-mis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J Clin Microbiol. 1995;33(3):690-695.

21. Sun XW, Ellerbrock TV, Lungu O, et al. Hu-man papillomavirus infection in human immunodeficiency virus-seropositive women. Obstet Gynecol. 1995;85(5 Pt 1): 680-686.

22. Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactiva-tion of human papillomavirus in human immunodeficiency virus-positive women.

J Natl Cancer Inst. 2005;97(8):577-586.23. de Pokomandy A, Rouleau D, Ghattas G,

et al. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis. 2009;199(7):965-973.

24. Cameron JE, Hagensee ME. Oral HPV complications in HIV-infected patients. Curr HIV/AIDS Rep. 2008;5(3):126-131.

25. Adler DH. The impact of HAART on HPV-related cervical disease. Curr HIV Res. 2010;8(7):493-497.

26. Harwood CA, Surentheran T, McGregor JM, et al. Human papillomavirus infection and non-melanoma skin cancer in immu-nosuppressed and immunocompetent individuals. J Med Virol. 2000;61(3):289-297.

27. Harwood CA, Proby CM. Human papillo-maviruses and non-melanoma skin can-cer. Curr Opin Infect Dis. 2002;15(2):101-114.

28. Iftner A, Klug SJ, Garbe C, et al. The preva-lence of human papillomavirus genotypes in nonmelanoma skin cancers of nonim-munosuppressed individuals identifies high-risk genital types as possible risk factors. Cancer Res. 2003;63(21):7515-7519.

29. Gross G, Pfister H. Role of human papillo-mavirus in penile cancer, penile intraepi-thelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 2004;193(1):35-44.

30. Munoz N, Bosch FX, de SS, et al. Epide-miologic classification of human papil-lomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518-527.

31. Kreuter A, Brockmeyer NH, Weissen-born SJ, et al. Penile intraepithelial neo-plasia is frequent in HIV-positive men with anal dysplasia. J Invest Dermatol. 2008;128(9):2316-2324.

32. Favre M, Majewski S, De JN, et al. A pos-sible vertical transmission of human pap-illomavirus genotypes associated with epidermodysplasia verruciformis. J Invest Dermatol. 1998;111(2):333-336.

33. Mermet I, Guerrini JS, Cairey-Remonnay S, et al. Cervical intraepithelial neoplasia associated with epidermodysplasia verru-ciformis HPV in an HIV-infected patient: a manifestation of immune restoration syn-drome. Eur J Dermatol. 2007;17(2):149-152.

34. Orth G. Epidermodysplasia verruciformis. In: Howley P, Salzman N, eds. The Pap-illomaviruses. New York: Plenum Press; 1987:199-243.

35. Barzegar C, Paul C, Saiag P, et al. Epi-dermodysplasia verruciformis-like erup-tion complicating human immunode-ficiency virus infection. Br J Dermatol. 1998;139(1):122-127.

36. Jacobelli S, Laude H, Carlotti A, et al.

Epidermodysplasia verruciformis in hu-man immunodeficiency virus-infected patients: a marker of human papillo-mavirus-related disorders not affected by antiretroviral therapy. Arch Dermatol. 2011;147(5):590-596.

37. Davison SC, Francis N, McLean K, et al. Epidermodysplasia verruciformis-like eruption associated with HIV infection. Clin Exp Dermatol. 2004;29(3):311-312.

38. Burger B, Kind F, Spoerri I, et al. HIV-positive child with epidermodyspla-sia verruciformis-like lesions and ho-mozygous mutation in TMC6. AIDS. 2010;24(17):2758-2760.

39. Prose NS, von Knebel-Doeberitz C, Miller S, Milburn PB, Heilman E. Widespread flat warts associated with human papil-lomavirus type 5: a cutaneous manifes-tation of human immunodeficiency virus infection. J Am Acad Dermatol. 1990;23(5 Pt 2):978-981.

40. Berger TG, Sawchuk WS, Leonardi C, et al. Epidermodysplasia verruciformis-as-sociated papillomavirus infection com-plicating human immunodeficiency virus disease. Br J Dermatol. 1991;124(1):79-83.

41. Haas N, Fuchs PG, Hermes B, et al. Re-mission of epidermodysplasia verrucifor-mis-like skin eruption after highly active antiretroviral therapy in a human immu-nodeficiency virus-positive patient. Br J Dermatol. 2001;145(4):669-670.

42. Trauner MA, Ruben BS, Hatcher SL, et al. Groin eruption in an HIV-positive man: epidermodysplasia verruciformis (EDV). Arch Dermatol. 2002;138(4):527-532.

43. Hu W, Nuovo G, Willen M, et al. Epider-modysplasia verruciformis in two half brothers with HIV infection. J Cutan Med Surg. 2004;8(5):357-360.

44. Bonamigo R, Maldonado G, Londero RM, et al. Epidermodysplasia verruciformis-like disorder in a teenager with HIV and HCV infections. Pediatr Dermatol. 2007;24(4):456-457.

45. Hultgren TL, Srinivasan SK, DiMaio DJ. Epidermodysplasia verruciformis oc-curring in a patient with human immu-nodeficiency virus: a case report. Cutis. 2007;79(4):307-311.

46. Chen P, Jr., Kamino H, Walters RF, et al. Epidermodysplasia verruciformis in the setting of HIV infection. Dermatol Online J. 2008;14(10):1.

47. Berk DR, Bruckner AL, Lu D. Epider-modysplasia verruciform-like lesions in an HIV patient. Dermatol Online J. 2009;15(1):1.

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case report from the field epidermodysplasia verruciformis ...dec 20, 2012 · epidermodysplasia...

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