Breast Paul

C. Stomper,

MD

J. Van

#{149} Bradley

Voorhis,

MD

#{149} Veronica

A. Ravnikar,

MD

Imaging

#{149} Jack

E. Meyer,

MD

Mammographic Changes Associated with Postmenopausal Hormone Replacement Therapy: A Longitudinal Study’

A retrospective study of radiologic findings from 50 postmenopausal women who underwent hormone replacement therapy was performed to determine the frequency and distribution of changes in the screenfilm mammographic appearance of breast tissue between pretreatment and posttreatment mammography. Twelve (24%) of the women developed increased parenchymal density during a median follow-up of 18 months (range, 6-39 months). Mammographic changes included diffuse increase in density in seven (14%) of the women; increased multifocal, asymmetric densities in two (4%); and cyst formation in three (6%) A greater percentage of women who received estrogen-progesterone replacement (26%, 10 of 38) demonstrated changes than those who received estrogen alone (17%, two of 12), but the difference was not statistically significant. The authors conclude that benign increases in mammographic density associated with postmenopausal hormone replacement therapy are not uncommon, and they suggest that the serial changes observed in some women may diminish the sensitivity of mammography for the earlier detection of breast cancer. Index 00.5

terms:

Breast,

#{149} Hormones,

Radiology

1990;

parenchymal

pattern,

00.5

174:487-490

the Department of Radiology, Memorial Institute, School

cine

Biomedical

666 Elm Departments

St.

(B.J.V.V., Brigham ical

VAR.) and and Women’s

School,

vision

(.

Boston.

requested

September

reprint

Science,

Buffalo, NY of Obstetrics

August

RSNA,

1990

to P.C.S.

Rosof Mcdiat Buffalo,

(P.C.S.); and Gynecology

Radiology Hospital,

18; accepted

requests

SUNY

14263 and

Received

URRENT

hormone in

(J.E.M.), Harvard June

2; revision September

30,

the

Mcd1989;

received 22.

Address

re-

medical opinion replacement

menopausal

women,

and

MATERIALS

favors therapy

This

such

literature

that

compared

pretreat-

and

AND

study

women

therapy is being widely prescribed. Proved benefits of estrogen replacement therapy include the prevention of vasomotor symptoms, genital atrophy, and osteoporosis (1-3). Possible adverse effects include an increased risk of endometrial cancer unless estrogen is combined with progestenone therapy (4). Recent case-control studies show no increased risk of breast cancer in women taking hormone replacement therapy (5,6). The mole of progesterone in possibly decreasing breast cancer risks is controversial (7,8). Peck and Lowman (9) first discussed the observation that postmenopausal estrogen replacement therapy could produce benign changes in the breast panenchyma demonstrable by mammography and that, following cessation of hormone therapy, regression of these changes could be seen radiologically. They suggested that in certain patients, estrogen therapy should be discontinued to enhance the nadiologic as well as clinical detection of early breast cancer. Bland et al (10), in a matchedcohort study of 405 postmenopausal patients, did not show a significant difference in xemomammographic parenchymal patterns between patients treated with hormones and untreated patients. We know of no studies in the

From well Park and

C

seen

breast

of 50 consecutive

at a specialized screening

menopause

clinic

of the

Brigham

and

Women’s

Hospital,

who

the

following

criteria:

met

woman both

was by

that and

shown

symptoms

menopausal

and

mange;

screen-film

by

within

hormone

ists

and (d)

in

pen-

to the

therapy

start

and

of

at ap-

1-year intervals thereafter; replacement therapy was maintained

throughout

and

was

prior

replacement

tiated

hormone were

values

(b) high-resolution

1 year

proximately (c) hormone

Each

determination

mammography

formed

Boston, (a)

to be postmenopausa!

serum follicle-stimulating luteinizing hormone

by

the

the

clinical

course

patients

had

of

no

mi-

special-

the

study;

prior

breast

cancer, significant alteration in body weight during the period of the study, concurrent systemic illness, breast-related symptoms,

on history

on had on

not

undergone

was

52 years

surgery.

tients

The

of thyroid

disorder,

breast

median

irradiation

age

of

(range,

the

pa-

40-69

years).

Seventeen (34%) of the women were aged 40-49 years; 33 (66%) were aged 50 years or greater.

Hormone replacement therapy ed of estrogen alone in 12 patients combination estrogen-progesterone placement

in

38 patients.

consistand re-

Estrogen

thera-

consisted of 0.05 mg of transdenmal tradiol every 3 days in 27 women, 0.625 mg of conjugated equine estrogen each

es-

py

day

in eight

cnonized

women,

and

estradiol

Progesterone

each

therapy

13-25

of the

the

cycle

in

eight

ment

(Senographe

CGR

USA,

Paris;

2.5

acetate

on each

women, acetate on

and each

mg

of

day

1 .0 mg day of

obtained

screen-film

by

us-

equip-

500T,

General

Ontho-M

film

screens, Eastman-Kodak, With the exception

10 mg

on days

27 women,

women. were

high-resolution

of miof

acetate

cycle in three All mammograms

ing

mg

in 15 women.

consisted

medmoxypmogestenone in

1.0

day

of medroxypnogestenone

of the cycle of nonethindrone

ment and posttreatment mammograms to determine the changes seen over time in a series of women undergoing hormone therapy. This study was undertaken to determine the frequency and distnibution of changes in the screen-film mammographic appearance of breast

METHODS

consisted

Electric

and

Rochester, of five pretreatment

Min-R NY).

undergoing

mammognaphic studies performed at outside centers, all mammography was performed within the clinic. The mammograms were interpreted by

therapy.

two mammogmaphems mammographic

tissue

group

before

and

after

treatment

in

of carefully monitored women estrogen or combination estrogen-progesterone replacement

a

(P.C.S., panenchymal

J.E.M.). pattern

The on

487

a.

b.

Figure 18

1.

(a)

months

Pretreatment

mammograms

of estrogen-progesterone

of a 52-year-old replacement

woman

therapy

show

show diffuse

a. (a) Pretreatment mammograms of a 69-year-old woman breast panenchyma. (b) Mammograms obtained after 13 estrogen-progesterone replacement therapy show diffuse density. (c) Mammograms obtained after 27 months of

treatment

show

pretreatment oblique

progressive

bilateral projections

was retrospectively lows: dense (greater sue), fatty (greaten on heterogeneous tions). The anatomic relations of dense

have

been

field

(1 1). The

described

mammogmaphica!!y tively

categorized

serial

diffuse

increase

change);

488

pamenchyma.

(b)

Mammograms

obtained

after

density.

means

.

categorized as fo!than 90% dense tisthan 90% fatty tissue), (all

other combinaand pathologic mammographic

contissue

by Page

and

changes

observed

were

then

as follows:

on cyst development of ultrasound [US]).

Radiology

in density.

craniocaudal of each woman

Winc.

retrospecno

change;

diffuse increase in density (at least 10% change); increased multifoca!, asymmetric densities that did not exhibit mass effect or architectural distortion (at least 10% by

breast

in

b.

Figure 2. show fatty months of increase in

the and

heterogeneous increase

(confirmed The follow-

up

period

tween

was

the

start

defined

acquisition of the most ment mammognam. Ninety-five percent vals and statistical

as the

of hormone

interval

recent

were

and

posttneat-

confidence

Fisher exact tests analysis (12).

be-

therapy

interused

for

RESULTS The mammographic panenchymal pattern on the pretreatment mammogram was categorized as dense in nine (18%) of the women, fatty in six (12%), and heterogeneous in the re-

February

1990

Figure

3.

months

(a)

Pretreatment

mammograms

of estrogen-progesterone

replacement

a. Figure

of

a 47-year-old

therapy

woman

show

show

increased

b. 4

(a) Pretreatment

mammogram

fatty

breast

multifocal,

panenchyma.

asymmetric

woman

ed no change. tnibution

Volume

174

#{149} Number

2

(arrows).

of

heterogeneous

breast

on the mammograms interval, 13%-38%). 38 (76%) demonstratThe these

obtained

after

29

d.

shows

chymal density (95% confidence The remaining

35 (70%). During a median period of 18 months 6-39 months), 12 (24%) of 50 developed increased pamen-

Mammograms

c. of a 42-year-old

12 months of estrogen replacement alone shows formation of circumscribed masses. (c) US scan (arrow). The more superficial lesion demonstrated increased sound transmission on other images. of treatment shows resolution of the posterior cyst and enlargement of the anterior cyst (arrow),

maining follow-up (range, women

(b)

densities

frequency changes

and are

dis-

out-

lined in the Table and illustrated in Figures 1-4. Thirty-two (64%) of the women underwent one follow-up mammographic study only. Ten of the 12 women who exhibited serial changes underwent mammography at approximately 1 year and 2 years after the start of therapy. Six (60%) demonstrated change at 1 year; four (40%) first demonstrated change 2 years after therapy. Two of 12 (17%) women receiving estrogen therapy alone demonstrated serial change over a median followup period of 15 months (mange, 6-25 months). Ten (26%) of 38 women me-

parenchyma.

(b) Mammogmam

demonstrates the (d) Mammogram which was again

presence obtained confirmed

obtained

after

of simple cysts after 26 months with US.

ceiving combination estrogen-progestemone therapy demonstrated semial change over a median follow-up period of 18 months (range, 6-39 months). A Fisher exact test showed no significant difference between these percentages (P .70). No breast cancers or mammographic abnormalities warranting biopsy were found in this group of senial screening mammograms.

DISCUSSION It is generally accepted that the mammognaphic density of breast tissue decreases or remains stable after menopause, and that cyst formation is a prernenopausal

(13). breast

Although parenchymal

phenomenon

cohort

studies patterns

Radiology

of show #{149} 489

denser breast tissue patterns in youngem and premenopausal women cornpared with older and postmenopausal women (14,15), little published data show the changes toward less dense breast panenchymal patterns that occur with aging. A series meported by Wolfe (16) showed that such changes generally occur between the ages of 35 and 50 years. In light of this historical experience and the exclusion of known factors that could alter breast density (ie, breast surgery, significant weight loss, mastitis), we believe that the observed serial changes in our postmenopausal study population can be attributed to the effects of hormone replacement therapy. Our observation that 24% of treated women exhibited conversion to mammographically denser breast tissue within a relatively short median follow-up period of 18 months shows that this is not an uncommon occurnence. The observations that four patients first demonstrated changes on the second annual posttreatment mammogram and that two patients (Figs 2, 4) demonstrated increasing density on two consecutive posttreatment mammograms suggest that the frequency and degree of mammographic panenchymal changes is time-rebated and will increase with the duration of hormone replacement therapy. Although the frequency of mammographic changes in women treated with estrogen meplacement alone (17%) was less than in women treated with combined estrogen-progesterone replacement (26%), there was no statistically significant difference. The numbers in this study are too small for the findings to be conclusive. We believe that knowledge of these panenchymal patterns of change (development of diffuse density, asymmetric densities, or cysts) and awareness of the use of hormone replacement therapy by women undergoing screening mammography should prevent mammographers from diagnosing benign changes related to hormone therapy as develop-

490

#{149} Radiology

ment of asymmetric densities on inflammatony change suggestive of malignancy. Careful, shorter-interval, clinical and mammognaphic followup may be appropriate in some cases. However, demonstration of other signs of malignancy (ie, solid masses, architectural distortion, microcalcifications, on skin changes) warrants the usual suspicion and further evaluation. The effect of these honmone-related changes on the sensitivity of mammography for the earlier detection of breast cancer has not been determined. Data from the Breast Cancer Detection Demonstration Project showed a sensitivity of approximately 93% for mammography at the time of screening in women aged 50 years or more, compared with 85% in wornen aged 40-49 years (17). This is usuably attributed to the denser breast parenchyma in younger women and associated potential for obscuration of a soft-tissue, noncalcified, mabignant mass that does not cause appreciable distortion of the surrounding normal breast tissue. For the small percentage of women who exhibit significant increase in breast density during postmenopausal hormone meplacement therapy (Figs 2, 4), the sensitivity of mammognaphic detection of early breast cancer may be diminished. This would occur in older women, who have a greater risk of breast cancer than younger, premenopausal women, who usually have dense parenchymal patterns (18). We believe that for this apparently small subset of women undergoing honmone replacement therapy, it may be prudent for the mammographer to suggest that the referring physician and patient reevaluate the risks and benefits of the patient’s hormone meplacement regimen and consider withdrawing therapy to enhance the nadiologic detection of early breast cancer. U

References 1.

ica!

assistance.

James Frigoletto,

We

Talcott, MD,

We thank Catherine Elliott for their invaluable

are

grateful

MD,

Judy

and

for

Garber,

Kenneth

the

input

MD, Ryan.

No-

of

Frederick MD.

analysis

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considerations climactenic:

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4.

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ne-

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