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Topical acyclovir treatment of herpes zoster in
immunocompromised patients
Myron J. Levin, M.D.,* John A. Zaia, M.D.,** Brenda J. Hershey,
R.N.,*
L. Gray Davis, M.Sc.,
***
Gayle
V.
Robinson, R.N.,
**
and
Anthony C. Segreti, Ph.D.***
Boston MA Research Triangle Park NC
and Duarte
CA
Topical acyclovir favorably influences the healing
of
localized herpes zoster in
immunocompromised patients. This therapy, or placebo, was applied
to
forty-three patients in a random access, double-blind trial, four times daily for
10
days, beginning within 72 hours after the onset of skin lesions. The
mean time
to
pustulation is decreased from 12.4
to
6.7 days and the mean
time to crusting is decreased from 16.0 to 11.4 days (p
=
0.038 and 0.086,
respectively) by topical treatment. The mean time to 50% healing is
decreased from 24.5 to 15.2 days and the mean time to 100% healing is
decreased from 34.9 to 25.8 days (p = 0.023 and 0.033, respectively).
Favorable effects in treated patients are not associated with a more rapid
decline in lesion virus titer, but do accrue without any toxicity.
J AM ACAD
DERMATOL 13:590-596, 1985.)
Herpes zoster
is
an unpleasant
and
often severe
illness that occurs frequently in patients with de
fective cell-mediated immunity.
1-4
Although there
is some risk of virus dissemination in these pa
tients, the most common morbid events are painful
skin lesions lasting several weeks, postherpetic
neuralgia, bacterial superinfection, and postpone
ment of scheduled chemotherapy. Three systemic
antiviral
agents-human
leukocyte interferon, ad
enine arabinoside (Vira-A), and acyclovir (Zovi
rax)-favorably influence the course
of
herpes
zoster
in
immunocompromised patients.
5
•
1o
Each
From the Dana-FarberCancer Institute, Boston,
*
Wellcome Research
Laboratories, Research 'I'riangle Park,
***
and
the City of Hope
Medical Center, Duarte.
**
Supported by grants from the Burroughs Wellcome Co., from the
Louis and Sydell Bruckner Memorial Fund, and from the National
Institutes
of
Health,
CA
19589.
Accepted for publication June
12,
1985.
Reprint requests to:
Dr.
Myron J. Levin, C-227, University
of
Col
orado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO
80262/303-394-850I.
59
..tccelerates cutaneous healing and reduces visceral
complications when begun for early localized dis
ease. However, the use of human leukocyte inter
feron is associated with significant side effects,
and the use
of
either intravenous adenine arabi
noside or acyclovir requires hospitalization for
therapy.
An
oral formulation
of
acyclovir is cur
rently being used in clinical trials
to
treat herpes
zoster in immunocompromised patients, but there
is no information yet on its efficacy.
An alternate approach to
the treatment
of
herpes
zoster would be to apply acyclovir directly to the
cutaneous lesions. This is effective therapy for
localized cutaneous herpes simplex infections in
immunocompromised patients.
11
f the topical for
mulation were also efficacious for localized herpes
zoster in these patients, it would obviate the need
for intravenous therapy. An effective topical drug
for herpes zoster might also be used to enhance
the favorable effects obtained with parenteral ther
apy, might allow a reduction in the duration of
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Volume 13
Number
4
October, 1985
Topical acyclovir treatment
of
herpes zoster 591
Table I. Entry characteristics for patients in the topical acyclovir trial
Study center
Dana-Farber
City ofHope
Combined
Characteristic Acyclovir
I
Placebo
Acyclovir
I
Placebo Acyclovir
I
Placebo
Race
White 15
18
4
5
19
23
Other
2 0 1
0
3 0
Sex
Female
6
8
4
4
10 12
Male
11
10
1
1
12
Age*
\2
±
19
41
±
25
35
±
30
46
±
17
33 ± 21
42
±
23
Underlying illness
Bone marrow transplan-
5 0
0
5
tation
Lymphoproliferative ma- li
9
5
3
16
12
Iignancy
Other
malignancy
4
3 0
0
4
3
Other immunosuppressive
1
I
0 2
1
3
illness
Lesion duration before entry* 1.6
±
0.8
1.8
±
0.9
2.0
±
1.2 2.0
±
1.2
1.7
±
0.9 1.8
±
1.0
Lesion area (cm
2
)* 120
± 105
161
±
191
145 ±
65
118 ± 87
126
±
97
151 ±
178
*Mean
±
standard deviation.
such therapy, and might enhance the value of oral
acyclovir for treating herpes zoster. We describe
a clinical trial in which a 5% ointment
of
acyclovir
was applied directly to herpes zoster lesions in
immunocompromised patients.
METHODS
Patient
selection. All patients were immunocom
promised and all had a typical clinical picture
of
acute
dermatomal herpes zoster. This was confirmed by virus
isolation in 78%
of
patients; in the remainder, either
a posit ive cytology for herpesvirus group infection
(Tzanck preparation) was obtained or a fourfold rise in
antibody titer to varicella-zoster virus was documented.
All patients were entered into the trial within 72 hours
of the onset of cutaneous lesions. Patients were ex
cluded if they had evidence of visceral involvement,
if
they were pregnant,
if
the area
of
involved skin ex
ceeded 200 cm
2
, or
if
their serum creatinine or total
bilirubin exceeded 3 mg/dl.
Study design. After obtaining informed consent a
medical history was recorded, the patient was exam
ined, and the location
of
skin lesions was recorded. The
total area involved was measured (product of two great
est dimensions), and a record was made of the per-
centage
of
the total exanthem represented by each
of
the following types of lesions: macule, papule, vesicle,
pustule, qlcer/crust, deep necrotic lesion, residual
swelling, and healed skin.
Five percent acyclovir in polyethylene glycol or
polyethylene glycol alone in 15-gm tubes was randomly
assigned to patients. These were randomly coded by a
computer program by the manufacturer. The contents
of the tubes were unknown to either the physician or
the patient. The ointment was applied by the patient or
a nurse four times a day at 4-hour intervals for 10 days
by rubbing it into the lesion. The average total quantity
used was 74 gm per patient. Extraderrnatomal lesions
were not treated.
Efficacy and tolerance evaluations were made daily
by
one
of
us for 10 days, when possible, and thereafter
at
least weekly for three additional weeks. These eval
uations included recording of vital signs, systemic
symptoms, and pain. Pain was scored as no pain =
1;
mild =
2;
moderate := 3; or severe = 4. Skin lesions
were counted, measured, and classified according to
type. New lesions were recorded separately. All lesions
were evaluated for erythema, pain, edema, and burning
and itching, and the possible relationship of these to
the application of the study drug was recorded.
Virologic studies . Skin lesions were cultured for
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592 Levin et al
J
oumal of the
American
Academy of
Dermatology
14 16 188 10 12
DAY POST ENTRY
4
, - -e_ -e - -e - -e - -e - - ' .
I
,.-
,
,
.
,
,
J
I
,
f ~ _ .
,
1.0
1.0
0.8
0.8
z:
z
0
0
;::
0.6
0.6
a:
,
0
0
a.
,
a.
0
0.4
,
0.4
:
'.,
.
, a.
,
,
0.2
,
0.2
CD
0.0
....
_
CD
0.0
0 2
3
4 5
6
7
9
10
11
a
DAY POST ENTRY
.......
0-0'
.
.
,'* ,e
.
. ..
0.8
0.2
·1.0
z:
g
0.6
a:
o 0.4
a:
a.
0
0.0
10 12
14
16
18
20
22
24 D 1 1 1 1 1 2 2 2 2 2 3 3 3
2468 2468 2468 24
DAY
POST ENTRY
AY
POST ENTRY
e-e-e -e - - ....
,
- . - . - . ~
I
I
e e
I
I
I
.;>-0-0--<0-0
I
.
,
8
..
'
.
.
1.0
0.8
z
a
;::
0.6
a:
a
a.
0
0.4
a:
a.
0.2
®
0.0
ci
2
0----0 PLACEBO
ZOVIRAX
Fig. lA-D. A Proportion of patients with new ksion formation. B Proportion
of
patients
pustulated. C, Proportion
of
patients crusted. D, Proportion of patients healed.
Fig. lE . Proportion of patients 50 healed.
C' -O PLACEBO
ZOVIRAX
1
12 2
2 4 6 8 2 4 6 8 2 4
DAY POST ENTRY
cultured. Varicella-zoster virus plaques were counted,
and the number of plaque-forming units per milliliter
of vesicle f 1 u i ~ was calculated. 12 When vesicles were
no longer present, ulcers or unroofed scabbed lesions
were s w b b e ~ with a premoistened cotton swab and a
determination made only for the presence or absence
of virus.
Clinical laboratory ~ t u d i e s . Tests performed at en
try
included: hemoglobin concentration and hematocrit;
platelet, red blood cell, reticulocyte, and differential
white blood cell counts; serum levels
of
glucose, uric
acid, alkaline phosphatase, blood urea nitrogen, cre
atinine, and serum aspartate aminotransferase; and uri
nalysis. These were repeated on study days 3 and 11,
and weekly for three ~ d d i t i o n a l weeks.
Statistical analysis. Time-to-event variables sucb as
healing time were analyzed using Cox's regression
model.* In this model, the hazard (instantaneous risk
of an event) for a treatment group can vary over time
but is assumed to be a constant multiple of the hazard
rate for the other group. The ratio of hazard rates or
*Cox DR: Regression models and life tables. J R Stat Soc Series B
34:187-220, 1972.
..
'
. . .
.
-o-<ro-<:J
,;
i
~ . .
.
.
.
,..
0 l L . . . Z . L ~ . . . L . . J : ~ J . . . . . J . . . J L . . . . . L J . . . J . J . . . . L . . L . ~
0.2
0.8
1.0
z
o
Ii 0.6
a
a..
ii
0 4
a..
varicella-zoster virus at entry and at each clinic visit
until complete healing occurred. Vesicle fluid was ob
tained with a calibrated capillary tube and placed in
cold viral transport media. This was kept cold and cul
tured within 2 hours on hurpan embryonic lung fibro
blast monolayers in six-well tissue culture plates. Four
serial tenfold dilutions of the original specimen were
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Voiume 13
Number 4
October, 1985
Topical acyclovir treatment
of
herpes zoster 593
0.0
' - . . . - - l . . . - - - - - ' - - . .L - - . 1 _L . - . l . . . - . .L - -L - - l - - l . . . - - - - - ' - - -L - - I . - - I
o 2 4 6 8 10
12 14 16 18
20
22 24
26 28 30
DAY
POST ENTRY
B
3 4 5 6
DAY POST ENTRY
0.0 --_- --_- --_.1.. .-_ --_ --_.1.. .-_ ----
o
z
o
0.6
o
a.
0.4
a
0.8
0.2
1.0
e .
,
,
\
\
1.0
0.8
i
0
i=
0.6
a:
0
c.
0
0.4
a:
c.
0.2
II
. e e .
\
\
e .
e,
. e e e e e e e e e .
0--0 PLACEBO
e- -e ZOVIRAX'
0--0 PLACEBO
e - - e
ZOVIRAX'
Fig. 2. Proportion of patients
with
pain.
Fig.
3.
Proportion of patients with positive viral culture.
relative risk is then constant over time and can be
used to compare time-ta-event curves over
the
entire
follow-up period. In this study, we calculated the rel
ative
risk as
the
ratio of the hazard in the acyclovir
group to the hazard in the placebo group. Relative risks
greater than 1 indicate that the acyclovir group is re
sponding (e.g., healing) more quickly
than
the placebo
group. The p value caiculated
is
based on a null hy
pothesis of
rio
difference between the treatment groups,
Le., a relative risk of 1.
Means
and
associated standard errors
for
time-to
event variables were calculated
by the
Kaplan-Meier
method.
*
Proportions were compared with Fisher's
Ex
act Test. All p values analyzing treatment
group dif
ferences were one-sided.
:RESULTS
Patient characteristics at entry
Forty-five patients were entered into the trial:
thirty-five from the Dana-Farber Center and ten
from the City of Hope Medical Center (Table I).
Nine patients were followed for less than 30 days.
Seven of these were included in the analysis of
one
or
more parameters where sufficient infor
mation
was
available (two acyclovir-treated were
lost to follow-up on days 7 and 11; five placebo
treated were lost
to
follow-up on days 4, 7, 8, 8,
and 22). Two patients were excluded from efficacy
evaluation because they were available for only
one day
of
follow-up. Both were
In
the placebo
group. The patients were predominantly white and
*Kaplan EL, Meier
P:
Nonparametric estimation from incomplete
observations.
J
Am Stat Assoc 53:457-481,
1958.
were evenly distributed according to sex. Patients
in
the two study centers were comparable with
respect to age and the time elapsed before the
herpes zoster was treated. The acyciovir group was
younger than the placebo group, but the age range
was very wide for both groups, and the difference
was
not significant. Mean lesion duration at entry
was
1.7 or
1.8
days for both groups. Mean lesion
size on entry was 125 to 150 cm
2
, again with a
wide range and with no statistically significant dif
ference between the groups. On entry, 75% of both
groups
of
patients had vesicles predominantly
while the remainder had maculopapular lesions
predominantly.
One
patient in the acyclovir group
had pustules along with vesicles. The underlying
diseases were similarly distributed between
the
two study centers except that all the bone marrow
transplant reCipients were entered at the Dana-Far
ber Center. Five
of
these six patients were assigned
to
the placebo group. Thirty percent
of the
acy
clovir recipients and
40
of
the
placebo recipients
received immunosuppressive therapy within 7
days prior to the onset of herpes zoster.
Analysis of efficacy
There was a trend for new lesions
to
Cease ap
pearing sooner in the acyclovir-treated patients
(mean, 3 .0 days) than in the placebo recipients
(mean, 4.2 days) (Fig. 1, A; P
=
0.094, Cox s
model). Time to pustulation was significantly
shortened by acyclovir (Fig. 1, B P
=
0.038,
Cox's model). The mean time to crusting was also
shortened from 16.0 to 11.4 days (Fig. 1, C;
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9 Levin et al
Table II Summary of efficacy analyses
Mean duration (days)'
Journal
of
the
American Academy of
Dermatology
Significance
Variable Acyclovir I Placebo
Relative riskt
1
P value:j:
Duration of new lesion formation
Time to pustulation
Time to crusting
Time to total healing
Time to 50 healing
Duration
of
pain
Duration of viral shedding
3.0
6.7
11.4
25.8
15.2
12.6
3.7
4.2
12.4
16.0
34.9
24.5
22.7
4.1
1.54
1.81
1.59
2.14
2.12
1.42
1.11
0.094
0.038
0.086
0.033
0.023
0.195
0.383
'Means
are
calculated using the Kaplan-Meier method.
tRelative risks are calculated using Cox's regression model.
*p values are one-sided and based on Cox's regression model.
p
=
0.086, Cox's model). Time to total healing
was shortened from a mean of 34.9 days to 25.8
days by acyclovir (Fig. 1, D; P = 0.033, Cox's
model). The time to 50% healing of lesions was
also significantly decreased by acyclovir (Fig. 1,
E; P = 0.023, Cox's model). The only patient
who failed to heal completely during the obser
vation period (some necrotic culture-negative le
sions were present at 56 days) was in the placebo
group. When this patient was excluded from the
analysis, the mean time to 50% healing was still
significantly shorter
in
the acyclovir-treated group
(15.2 days vs 21.2 days; p = 0.042, Cox's
model). Although most bone marrow transplant
recipients received placebo, a separate analysis
showed that they were not different in any of
the parameters of healing from other immuno
suppressed patients receiving placebo (data not
shown). Therefore, they were subsequently ana
lyzed with the rest of the study group.
The duration of pain was calculated for patients
with pain at entry; recurrences of pain were not
considered. Thirty-seven patients
had pain on entry
(19 acyclovir; 18 placebo). The baseline pain score
was 2.9 and 3.0, respectively, for the two treat
ment groups. The subsequent loss of pain was not
significantly different between the
two groups
(Fig. 2; P = 0.195, Cox's model). The proportion
with pain persisting after 19 days was 12.5% in
the treated group compared with 40 in the pla
cebo recipients (p
=
0.18; Fisher's Exact Test).
Extradermatomal lesions occurred with equal fre
quency (15 placebo recipients; 13 acyclovir recip-
ients) and
in
equal numbers (mean lesion number
of
nine in each group). Seven
of
the placebo re
cipients and four of
the
acyclovir recipients had
25
or more dermatomallesions (p = 0.22; Fish
er's Exact Test). No visceral involvement was
observed.
Sixty percent of patients were culture-positive
for varicella-zoster virus on the day of entry, with
an initial mean titer of 10
3
.
0
plaque-forming units
per milliliter; an additional 18 of patients with
negative first cultures had varicella-zoster virus
recovered
in
subsequent cultures. The proportion
of culture-positive patients who continued shed
ding virus was not affected by therapy (Fig. 3),
nor was the virus titer significantly decreased by
acyclovir
on
days 2 through 4 in those whose cul
tures were positive (data not shown). However,
only one of twenty-one placebo recipients failed
to shed virus at some time, while six of twenty
two treated patients remained culture-negative
throughout (p
=
0.05; Fisher's Exact Test).
There were no significant adverse experiences
and it was never necessary too discontinue topical
therapy because of a local cutaneous reaction.
Table II summarizes the analysis of seven study
parameters.
DISCUSSION
Topical application of acyclovir in a 5 oint
ment favorably influenced the course of herpes
zoster in immunocompromised patients. Time to
complete healing, or
to 50
healing, was signif
icantly shortened (Figs.
lD
and IE). This latter
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Volume 13
Number 4
October, 1985
parameter may be a more sensitive measure of
antiviral activity, since it should be less affected
by the poor tissue healing that characterizes some
patients who are chronically
i l l
and who are re
ceiving immunosuppressive therapy. In a previous
study of herpes zoster in immunocompromised pa
tients, this measure
of
efficacy was less susceptible
to individual patient variation and to observer in
terpretation.
9
The three measures
of
progression
to
healing that were also analyzed demonstrated a
very favorable trend toward improvement in the
patients receiving topical acyclovir (Figs. 1,
A
B
and
C .
Acyclovir has been used previously intrave
nously
to
treat herpes zoster in both immuno
compromised
8
and in otherwise normal patients.
9.10
In the latter situation intravenous therapy was dra
matically effective in that all parameters of healing
were shortened, pain was reduced in most patients,
and the duration of virus excretion was shortened.
However, there was no effect
on
the proportion
of patients with pain persisting past
14
to 21
days. On the other hand, an intravenous trial
clearly demonstrated that parenteral acyclovir
could prevent or abort cutaneous dissemination
and/or visceral involvement in immunocompro
mised patients.
8
In our topical trial, pain resolution was not sig
nificantly faster in the acyclovir recipients. How
ever, only three of nineteen treated patients had
pain 2 weeks after the onset
of
the illness, while
seven of eighteen of the placebo recipients had
persistent pain (p
=
0.18; Fisher's Exact Test). A
larger study will be required to fully define the
value
of
topical acyclovir in decreasing late per
sistence
of
pain.
The effects of topical acyclovir were achieved
without a concomitant decrease in the frequency
of
varicella-zoster virus isolation. Careful quan
titative culture methods failed to demonstrate any
acyclovir-related decrease in the titer of varicella
zostervirus in the positive specimens obtained dur
ing the first
3
days
of
treatment.
It
should be noted
that all previous studies treating herpes simplex
virus or varicella-zoster infections with acyclovir,
adenine arabinoside, and interferon correlated
clinical success with significant inhibitory effects
on virus shedding.5-'L'3-'5 This difference in our
Topical acyclovir treatment
of
herpes zoster
trial cannot
be
explained
by
obvious methodologic
errors since our yield of positive cultures from
patients before treatment and from placebo-treated
patients (>75
%)
is almost identical to that reported
by Bean et al,
9
and we had previously optimized
our culture technics. 12 Furthermore, the chronicity
of the skin lesions in our patients (mean healing
time
of
35 days and mean pustulation time of 12.4
days in untreated patients) offered ample oppor
tunity for recovery
of
varicella-zoster virus.
A role for topical acyclovir
in
the therapy of
herpes zoster in immunocompromised patients is
suggested by the results reported here, but that
role requires further definition.
Any
salutatory ef
fects are likely to be exerted only on dermatomal
cutaneous lesions, whereas parenteral or oral ther
apy will still be required for some patients
in
the
early stage of this disease to prevent dissemination
of varicella-zoster virus. However, topical therapy
may offer an additive effect to that obtained with
intravenous or oral therapy, and
it
might shorten
the time
of
therapy by these other routes. This, in
tum, would limit the period
of
hospitalization re
quired for intravenous therapy and might decrease
the incidence
of
side effects occasionally reported
with intravenous acyclovir.
9
REFERENCES
1.
Atkinson K, Meyers JE, Storb R, et
a1:
Varicella-zoster
virus infection after marrow transplantation for aplastic
anemia or leukemia. Transplantation 29:47-50,
1980.
2. Dolin R, Reichman RC, Mazur MH, Whitley RJ:
Herpes
zoster-varicella infections in immunosuppressed patients.
Ann Intern Med 89:375-388, 1978.
3. Schimpff S, Serpick
A,
Stoler B, et
a1:
Varicella-zoster
infection inpatients with cancer. Ann InternMed76:241
254, 1972.
4.
Feldman S, Hughes WT, Kim HY: Herpes zoster
in
chil
dren with cancer.
Am
J Dis Child 126:178-184,
1973.
5. Merigan Te, Rand KH, Pollard RB,
et
a1: Human leu
kocyte interferon for the treatment
of
herpes zoster in
patients with cancer. N Eng J Med 298:981-987, 1978.
6. Whitley RJ, Ch'ien
LT,
Dolin R, et al: Adenine arabi
noside therapy
of
herpes zosterin the immunosuppressed.
N Engl J Med 294:1193-1199, 1976.
7. Whitley RJ, Soong S-J, Dolin R, et al: Early vidarabine
therapy to control the complications
of
herpes zoster in
immunosuppressed patients. N Eng1 J Mcd 307:971-975,
1982.
8. Balfour HH Jr, Bean B, Laskin OL, et al: Acyclovir halts
progression
of
herpes zoster in immunocompromised pa
tients. N
Eng1
J Med 308:1448-1453, 1983.
9.
Bean B, Braun C, Balfour
HH
Jr: Acyclovir therapy for
acute herpes zoster. Lancet 2:118-121, 1982.
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t
al
10. Peters1und NA, Ipsen J, Schonheyder H,
et
al:
Acyclovir
in
herpes zoster. Lancet 2:827-830, 1981.
11. Whitley RJ, Levin MJ, Barton N,
et a1: Herpes simplex
virus in the immunocompromised host: Natural history
and topical acyclovir therapy. J Infect Dis 150:323-329,
1984.
12. Levin MI, Leventhal S, Masters HA: Factors influencing
quantitative isolation of varicella-zoster virus. J Clin Mi
crobiol 19:880-883, 1984.
13. Mitchell CD, Gentry SR, Boen JR, et al; Acyclovir ther-
Journal of the
American Academy
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277, 1982.
Hyperkeratosis
of
the nipple
and
areola
Deborah S. KUhlman, M.D., Steven J. Hodge, M.D., and
Lafayette
G.
Owen, M.D.
Louisville KY
Hyperkeratosis
of
the nipple and areola is a rare condition.
We
report two
cases
of
hyperkeratosis of the nipple and areola occurring in men with
no
underlying endocrinopathy or synthetic estrogenic drug therapy. Both patients
demonstrated prompt resolution of the hyperkeratosis of the nipples with a
keratolytic gel. Because our cases were not associated with ichthyosis or
epidermal nevus, they best fit into the category of nevoid hyperkeratosis of the
nipples. (J AM ACAD DERMATOL 13:596-598, 1985.)
Hyperkeratosis
of
the nipple
and
areola is a rare
condition. In 1977, Mehregan
and
Rahbari
1
re
ported on two patients and reviewed the literature
of thirteen previously reported cases. The majority
of the reported cases have involved female patients
who had a poor clinical response to topical ap
plication of keratolytic agents or corticosteroid
creams, We report two cases of hyperkeratosis of
the nipple and areola occurring in men who had a
prompt clinical response to a keratolytic topical
preparation.
CASE REPORTS
Case
A 67-year-old white man was seen in October, 1983,
with a 2-month history
of
progressive thickening and
From the University
of
Louisville School of Medicine.
Accepted for publication June 12, 1985.
Reprint requests to: Dr. Steven
J.
Hodge, Division of Dermatology,
School
of
Medicine, University
of
Louisville, Louisville, KY
40292.
596
hyperpigmentation of his nipples and areolae. His
health was otherwise good except for a myocardial in
farction in 1979 and benign prostatic hypertrophy. His
medications included propranolol hydrochloride and ni
fedipine. There is no history of systemic malignancy
or exogenous hormonal therapy. He has been followed
regularly for several skin tumors, consisting of sebor
rheic keratoses, actinic keratoses, and squamous cell
carcinoma.
Physical examination revealed a hyperpigmented,
verrucous right areolawith sparing of the central portion
of the nipple. Three fourths of the left nipple was also
darkly pigmented and verrucous, with central clearing
of the nipple (Fig. 1). Differential diagnosis at the time
of presentation was acanthosis nigricans versus sebor
rheic keratoses. Examination
of
intertriginous areas did
not reveal acanthosis nigricans, and the patient had no
evidence of ichthyosis.
Biopsy of the right areola revealed hyperkeratosis,
acanthosis, and papillomatosis.
Follow-up months later showed no physical change.
A one-week trial of 6 salicylic acid gel (Keralyt Gel)