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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


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


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

8/11/2019 Pi is 0190962285702022


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

8/11/2019 Pi is 0190962285702022


Voiume 13

Number 4

October, 1985


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;

8/11/2019 Pi is 0190962285702022


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


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.

8/11/2019 Pi is 0190962285702022


Levin

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

of

Dermatology

apy for mucocutaneous herpes simplex infections in im

munocompromised patients. Lancet 1:1389-1394, 1981.

14. Wade JC, Newton B, McLaren C, et

al;

Intravenous

acyclovir to treat mucocutaneous herpes simplex virus

infection after marrow transplantation: A double-blind

trial. Ann Intern Med 96:265-269, 1982.

15. Straus SE, Smith HA, Brickman C, et

al:

Acyclovir for

chronic mucocutaneous herpes simplex virus infection in

immunosuppressed patients. Ann Intern Med 96:270

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)

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