Epidermodysplasia Verruciformis Case Report Volume 20 Issue 5 December 2012/January 2013
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
Epidermodysplasia verruciformis (EV)
is a rare genodermatosis, first described by Lewandosky and Lutz in
1922.1 This premalignant lesion has
occurred de novo, as well as in patients
with impaired cell-mediated immunity, 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 immunocompetent populations, typical clinical
findings are similar, and include pityriasis versicolor-like macules, as well
as flat papules and lesions resembling
verruca plana. Characteristic histologic
features of the disease are the coexistence of epidermal thickening, a loose
horny layer with a basketweave–like
appearance, and the presence of large
cells in the spinous and granular layers 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 inherited disorder. This genetic pattern
is supported by the results of several
observational studies. In the immunocompetent population, approximately
25% to 50% of reported EV cases have
occurred in an autosomal recessive
pattern.7 In a review of 147 case reports of EV, 10% occurred in individuals with consanguineous parents.8 A
2002 report by Sehgal and colleagues
was consistent with this finding, demonstrating 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 inheritance,9 and another large family had
several cases of EV, all of which occurred in female relatives.10
Genetics
In 2002, Ramoz and colleagues identified the EVER1 and EVER2 loci, which
suggested a loss-of-function mutation as the cause of susceptibility to
the human papillomavirus (HPV) subtypes that are associated with EV.11 The
EVER1 and EVER2 genes, which are located on chromosome 17q25, encode
proteins within the endoplasmic reticulum.11 Given their proximity (4732 base
pairs apart), the full-length proteins encoded by EVER1 and EVER2 are suspected to share 28.6% of their constituent 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 chromosome 17q25 may down-regulate
cell-mediated immunity by decreasing
cells’ ability to present EV-HPV antigen
to T lymphocytes.14 More recently, additional loci on chromosome 2 have
been identified as potentially conferring 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 premalignant 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 develop squamous cell carcinoma (SCC)
in the fourth and fifth decades of life.
Sidebar. Human Papillomavirus (HPV)
Subtypes Associated with Epidermodysplasia 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
HPV-12
HPV-22
HPV-47
HPV-14
HPV-23
HPV-50
*β-HPV types most commonly associated
with EV
Dr Kaushal is a resident physician in the Department of Internal Medicine at the University of Manitoba in Winnipeg, Canada. Dr Silver is Assistant 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, Department 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.
173
IAS–USA
Topics in Antiviral Medicine
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 frequently 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 combination 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 (approximately 200) that have been reported 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 phenomenon, the term acquired epidermodysplasia verruciformis (AEV) has
been introduced by Rogers and colleagues.19 In this review, the term EVHIV 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 transformation. 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 susceptibility to EV, and discusses the
currently postulated risk of transformation to malignant disease.
Figure 1. Numerous 1-mm to 3-mm flattopped white verrucous papules on the upper extremity.
Case Report
In December 2009, a 19-year-old
man of Ethiopian descent who had
immigrated to Canada in 2007 presented 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 illness. His past medical history was remarkable 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 presentation. He had no allergies. Family history did not reveal any relatives with
chronic skin conditions.
Initial laboratory test results revealed 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 limits. He had no serologic evidence of
opportunistic infections: his test results were negative for antibodies to
hepatitis B virus (HBV) and hepatitis
C virus (HCV), and showed IgG antibodies against hepatitis A virus (HAV),
cytomegalovirus (CMV), and toxoplasmosis. CD4+ cell count and CD4+
percentage were 270/µL and 15% respectively, and initial HIV RNA level
was 51,000 copies/mL. Genotyping
revealed no drug-resistant HIV mutations, and antiretroviral therapy was
initiated in August of 2010.
During the patient’s initial evaluation, a rash involving his upper extremities and back was noted. He
indicated that the lesions had been
174
Figure 2. 1-mm to 3-mm flat-topped verrucous papules, with some koebnerizing into
a linear plaque. Faint and subtle hypopigmented macules with fine scale can be seen
between the verrucous papules.
present since childhood. The lesions
consisted of numerous white flattopped verrucous papules 1 mm to
3 mm in diameter on the upper extremities and trunk. There were also
subtle hypopigmented macules with
fine scale resembling pityriasis versicolor; 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 biopsy was collected for examination.
The biopsy results showed variable
thickening of the epidermis, which
was composed of variably swollen
and pale keratinocytes. The granular
M
M
6
7
175
13
15
12
Hu et al,
200443
Hultgren et
al, 200745
M
11
Davison et
al, 200437
14
M
10
Carré et al,
200314
Bonamigo et
al, 200744
M
9
Trauner et
al, 200242
M
M
M
M
8
Haas et al,
200141
M
M
M
4
5
M
3
Barzegar et
al, 199835
M
2
Berger et al,
199140
M
1
41
14
12
11
44
38
58
45
32
32
26
28
35
34
10
Shiny, hypopigmented flat warts, PV
Description of
Skin Lesions
Erythematous, hypopigmented 1-10 mm
macules
Entire body
Face, upper trunk,
upper extremities,
hands, and knees
As above
Face, trunk, extremities
Face, chest, limbs
Forearms, neckline,
trunk, thighs
Groin
1-3 mm smooth hypopigmented papules
Hypochromic macules and flat papules
As above
Clustered, pink, flat-topped, polyangular
papules and plaque, ranging from 2-6
mm
Flat papules resembling plane warts, violaceous papules resembling lichen planus
and keratotic reddish-brown plaques
Erythematous, flat-topped papules
Scaly, erythematous flat papules coalescing into plaques
Chest, face, dorsal Flat, warty, slightly keratotic macules
surfaces of extremities
Neck, chest, shoulders, extremities
-
-
8
-
224
402
489
100200
5, 8,
14, 3, 7
8
162
187
10
5, 14
8
5, 8, 14,
19, 21
-
-
-
-
-
-
-
-
-
Baschke-Loewenstein anal
tumor; interferon alfa-2a and
zidovudine treatment led to
partial improvement in EV
-
Diagnosed with EV 5 years
after HIV diagnosis
Diagnosed with EV 3 months
after HIV diagnosis
-
Comments
82,000
-
-
Undetectable
52,160
76,135
-
-
-
-
Bowenoid
dysplasia
-
-
-
HCV+; EV at age 3
As above
Two Hispanic maternal halfbrothers with HIV+ mother. EV
at age 6 years - 8 years in both
HIV+ since 1987, 2-year skin
eruption
Improved CD4+ count and
HIV RNA level with ART; no
improvement in EV
4-year history of EV
250,000 Cellular atypia Diagnosed with EV 11 years
“not promi- after HIV diagnosis (1983),
treated with ART; treated for
nent”
MAC, and EV cleared
-
< 300
20 (in 1
macular
lesion only)
-
-
-
-
-
-
< 300
-
-
-
-
CD4+ HIV RNA Malignant
Cells/µL Copies/mL Transformation
< 300
5
Face, trunk, dorsal Hypopigmented papules, 1-3 mm, PVlike macules
surface of hands,
proximal extremities
N/A
5, 8
5
Skin-colored hypopigmented macules
Flat, slightly keratotic 2-5 mm papules
5, 8
5
HPV
Type(s)
Flat-topped, nonscaling skin-colored or
hypopigmented small papules
Extremities, face,
trunk, scalp
Dorsal surface of
hands, forearms
Hands, face
Chest, dorsal surfaces Flat, slightly keratotic papules 2-5 mm in
of upper extremities, diameter
hand, face
Face, chest, back
Case Sex Age, Pattern of
No.
Years Distribution
Prose et al,
199039
Source
Table 1. Published Cases of Epidermodysplasia Verruciformis in Combination with HIV (EV-HIV)
Epidermodysplasia Verruciformis Case Report Volume 20 Issue 5 December 2012/January 2013
176
M
F
F
F
M
F
M
M
M
M
M
F
F
19
20
21
22
23
24
25
26
27
28
29
30
31
Burger et al,
201038
Jacobelli et
al, 201136
19
51
50
44
45
41
47
51
43
47
40
39
14
32
22
42
56
Pink-brown, flat-topped papules
White macules, 2-6 mm
Hypo- and hyperpigmented papules and
plaques
Hypopigmented, thin, pink, flat-topped
papules coalescent to plaques
Chest, back, extremities
Trunk, limbs
Trunk, limbs
Face, trunk, limbs
Face, trunk
Face, trunk
Trunk, limbs
Trunk, limbs, axillae
Trunk, limbs, groin
Face, trunk, limbs
Flat-topped white papules, flat warts
and lesions resembling PV
Flat warts
Flat warts, lichenoid
Flat warts
Flat warts
Flat warts, PV-like
Flat warts, PV-like
Flat warts, PV-like
Flat warts, PV-like
Flat warts,
lichenoid lesions
Flat warts, PV-like lesions
Flat warts,
lichenoid
Upper body: numerous hypopigmented
On the lower legs, the verrucous papules and small plaques
dorsum of feet, and
Lower body and trunk: black-brown
scattered over the trunk papules
Neck and chin
Chest, groin, axilla,
upper extremities,
trunk
Extremities
Upper trunk, head,
neck
Chest, abdomen,
back, arms, legs
Description of
Skin Lesions
20
19
-
-
-
8, 20, 22,
24
5, 38, 65
5
5, 8
3, 8, 19
22
8
5
5
5, 19
-
-
HPV
Type(s)
270
540
383
78
210/200
495
304
536
769
334
1040
615
-
253
83
7
245
51,000
< 50
200
108,000
200
< 50
< 50
< 50
< 50
< 50
< 50
< 50
-
< 50
62,700
-
1850
-
-
Bowenoid
dysplasia
-
-
-
-
Invasive
epidermoid
dysplasia
-
Bowenoid
dysplasia
-
-
-
-
-
-
-
HIV RNA
CD4+
Malignant
Cells/µL Copies/mL Transformation
-
-
Large B-cell lymphoma,
HBV+
Large B-cell lymphoma
Multicentric Castleman
disease, HBV+
-
-
-
-
Hodgkins, HCV+
-
EV eruption at age 15; HIV
diagnosis at age 33
Homozygous for TMC6 gene
mutation
-
-
-
-
Comments
ART indicates antiretroviral therapy; EV, epidermodysplasia verruciformis; F, female; HBV+, hepatitis B virus-infected; HCV+, hepatitis C virus–infected; HIV+, HIV-infected; HPV,
human papillomavirus; M, male; MAC, Mycobacterium avium complex; PV, pityriasis versicolor; TMC6, transmembrane channel-like protein 6.
M
M
18
Rogers et al,
200919
32
M
17
Berk et al,
200947
Kaushal et
al, 2012
M
16
Case Sex Age, Pattern of
No.
Years Distribution
Chen et al,
200846
Source
Table 1. Published Cases of Epidermodysplasia Verruciformis in Combination with HIV (EV-HIV) (continued)
IAS–USA
Topics in Antiviral Medicine
Epidermodysplasia Verruciformis Case Report Volume 20 Issue 5 December 2012/January 2013
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 thickened and contains prominent, variably sized granules (white arrow).
cell layer was thickened and contained prominent variably sized granules. These features were in keeping
with EV (Figure 3).
The presence of HPV was confirmed
by DNA amplification of an approximately 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 followed by use of Basic Local Assignment 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 subsequently 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 phenotypic 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 Additionally, the incidence of SCC in HIVinfected patients is 5-fold higher than
that in the HIV-uninfected population.25 This suggests that in the case of
oral and anogenital HPV, there is an increased likelihood of malignant transformation. Of note, a large proportion 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,
177
ranging from 84.1% and 75%, respectively in immunocompromised populations, compared with 59.7% and
27.8%, respectively, in immunocompetent populations.26-28
In patients with HIV, the natural history of β-HPV infections—those that
lead to EV—has been incompletely examined. Accordingly, there is a paucity
of epidemiologic data. In contrast to
this, there are many population-based
studies of oral and anogenital HPV infections in HIV-infected patients. HPV
types have been identified in and associated with a large proportion of anal,
penile, and cervical intraepithelial neoplasia (AIN, PIN, and CIN, respectively), and there is some representation
from the β-HPV family.29,30 In an epidemiologic 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 documentation of β-HPV sequences in the
female genital tract. In a study by
Favre and colleagues, EV-associated
HPV types were found in cutaneous lesions 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 peripheral blood, and vertical transmission
to amniotic and placental tissue was
suspected. A later report described a
female patient with known HIV infection, 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 manifested 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 coinfection with β-HPV and higher-risk α-HPV
types. At present, there is no evidence
IAS–USA
Topics in Antiviral Medicine
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 represented in the EV-HIV population are
HPV-5 and -8, with several cases having 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 erythematous 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) displayed 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 associated 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 descriptors for HPV-8 associated lesions.
EV manifestation is similar clinically, histologically, and virologically in
patients with and without HIV. Jacobelli reported the largest case series of EVHIV thus far, and noted that HPV was
found in all skin biopsy specimens.36 In
particular, HPV-5 or HPV-8 were isolated in 75% of specimens, a proportion
similar to that reported for immunocompetent 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 researchers 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 detection. The diagnosis of HIV consistently 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 infection and first eruption of EV lesions. In
that series, the median age at HIV diagnosis was 27 years, and the median
age at EV eruption was 40 years. Only
1 case of EV predated the HIV diagnosis. Of the cases of EV that occurred
after HIV infection, the mean time
from HIV diagnosis to EV manifestation was 10 years. The interval from
HIV acquisition to EV manifestation is
likely longer than 10 years due to delays in HIV diagnosis. In the reported
cases of EV-HIV, development of dysplasia 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 substantial 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 longstanding 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. Additionally, the definition of NMSC may have
varied between investigators, and the
subsequent cutaneous surveillance
methods were beyond the scope of
most reports. Furthermore, publishing reports soon after the diagnosis of
178
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 inferences about the importance of HIV in
the genesis of EV.
Further investigation in these areas
may help identify populations predisposed to develop EV, and develop therapies that are effective in treating EV
as well as preventing malignant transformation. Additional inquiry into the
effectiveness of antiretroviral therapy
for treating or preventing EV is warranted, specifically in patients with EV
that developed in the context of immunocompromise.
Financial Affiliations: Drs Kaushal, Silver,
Kasper, Severini, Hamza, and Keynan have
no relevant financial affiliations to disclose.
(Updated 01/15/13)
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