GYNECOMASTIA DUE TO HORMONE THERAPY FOR ADVANCED PROSTATE

Tumori, 90: 410-415, 2004
GYNECOMASTIA DUE TO HORMONE THERAPY FOR ADVANCED PROSTATE
CANCER: A REPORT OF TEN SURGICALLY TREATED CASES AND A REVIEW
OF TREATMENT OPTIONS
Domenico Prezioso, Giuseppe Piccirillo, Raffaele Galasso, Vincenzo Altieri, Vincenzo Mirone, and Tullio Lotti
Department of Urology, University of Naples “Federico II”, Italy
Aims and background: Gynecomastia is an abnormal increase in
the volume of the male breast that is generally considered to
be due to an increased estrogen/androgen ratio. Pathological
causes of gynecomastia include organic diseases and therapy,
such as the administration of estrogens and antiandrogens,
which alter the ratio of circulating hormones. Hormone therapy
for prostate cancer is generally well tolerated but often accompanied by the occurrence of gynecomastia and breast pain or
tenderness. The increased use of antiandrogens as monotherapy is leading to an increase in the number of patients affected
by gynecomastia. Treatments are available to alleviate or prevent the development of gynecomastia, including medical
treatment with antiestrogens and aromatase inhibitors. Alternatively, mastectomy with excision of the gland, liposuction or
an association of the two techniques have proved to be effective. Radiation therapy may provide effective relief from the
breast pain associated with gynecomastia. In this paper we
show the good results of mastectomy performed with a lower
semicircular periareolar incision in men suffering from gynecomastia due to antiandrogen therapy for inoperable
prostate cancer. In addition, we present a review of the various
techniques used for the treatment of gynecomastia.
Methods and study design: During the period from September
1998 to May 2001, 10 patients receiving hormone treatment for
metastatic or inoperable prostatic cancer were selected for
the study if they had breast pain and bilateral gynecomastia.
Five of these patients had been offered prophylactic radiotherapy before treatment but refused, while the remaining five
patients had refused radiotherapy after hormone treatment.
These patients were therefore given the option of surgical
treatment. Before surgery all patients underwent clinical and
ultrasound examination of the breast. All surgical samples
were examinated histopathologically. During follow-up clinical
examinations were carried out one week, one month, six
months, one year and two years after surgery.
Results: The results were satisfactory in all patients especially
from an aesthetic point of view. Moreover, breast pain disappeared about one week after surgery. After a follow-up of 6-36
months (average, 22.8 months) no recurrences were observed. Only a few immediate postoperative complications
were recorded (hematoma in one case and seroma in another). Histological examination of the excised glands showed fibrosclerotic tissue and a small amount of fat.
Conclusion: Surgical liposuction can be considered an effective treatment for gynecomastia, in particular in the very early
stages because the breast becomes irreversibly fibrous as the
disease progresses. This surgical technique is simple and effective and is therefore to be considered favorable, especially
because of the very short hospitalization and the absence of
complications.
Key words: gynecomastia, gynecomastia and prostate cancer, gynecomastia and hormone therapy, gynecomastia and antiandrogens, gynecomastia and mastectomy, gynecomastia and radiation therapy, gynecomastia and antiestrogens, gynecomastia and
aromatase inhibitors, mastodynia and prostate cancer.
Introduction
Gynecomastia is an abnormal increase in the volume of
the male breast, characterized by a tender discoid enlargement 2-4 cm in diameter beneath the areola, with hypertrophy of the gland and the surrounding fatty tissue. This
pathological change may occur unilaterally or bilaterally
and, according to most authors, it is generally considered
to be due to an increased estrogen/androgen ratio. Physiological gynecomastia associated with a change in hormone levels has been reported in newborns, boys at the
time of puberty and older men1,2. Pathological causes of
gynecomastia include organic diseases and therapy, such
as the administration of estrogens and antiandrogens3,
which alter the ratio of circulating hormones.
Orchiectomy, administration of luteinizing hormonereleasing factor (LH-RH) agonists, or the use of antiandrogens alone or in combination represent the standard
care for patients with metastatic or inoperable prostate
cancer. Nonsteroidal antiandrogen monotherapy gives
no difference in survival compared to combined androgen blockade or castration in patients with nonmetastatic locally advanced cancer, while there are significant
quality-of-life benefits in terms of sexual interest and
physical capacity4,5. Hormone therapy for prostate cancer seems to be generally well tolerated but is often accompanied by the occurrence of gynecomastia and pain
or tenderness in the breast (mastodynia). The results of
recent studies report an incidence of gynecomastia and
breast pain from 3% to 12.7% with the use of the LHRH agonist leuprolide6,7.
The increased use of antiandrogens as monotherapy
is leading to an increase in the number of patients affected by gynecomastia6. Studies with bicalutamide8,9
and nilutamide 10,11 have reported gynecomastia and
breast pain in approximately 50% and 24-76% of patients, respectively. This condition was observed in 3079% of patients treated with flutamide12,13.
Correspondence to: Domenico Prezioso, MD, Department of Urology, University of Naples “Federico II”, Via Manzoni 71, 80123, Naples,
Italy. Tel +39-081-5465803 or +39-081-7462504; fax +39-081-5452959 or +39-081-7466154; e-mail dprezioso@libero.it
Received September 4, 2003; accepted December 3, 2003.
SURGICAL TREATMENT OF GYNECOMASTIA BY HORMONE THERAPY
Although gynecomastia is not directly harmful, in an
adult male the enlargement of the breast and the associated pain and tenderness may cause psychological and
social problems, often severe enough to lead to discontinuation of the therapy. It is therefore often necessary
and sometimes essential to find a solution to this – not
only cosmetic – problem.
There are treatments available to alleviate or prevent
the development of gynecomastia, including medical
treatment with antiestrogens and aromatase inhibitors14,15. Several studies of the antiestrogen tamoxifen in prostate cancer patients with gynecomastia have
demonstrated a reduction in breast pain and size16-21.
Aromatase inhibitors should alleviate gynecomastia by
preventing the peripheral aromatization of circulating
androgens to estrogens. However, publications to date
refer only to two prototype compounds, testolactone
and anastrozole22,23. An alternative option is surgery,
which has proved to be effective. The three most frequently used procedures are mastectomy with excision
of the gland, liposuction, and combination of the two
techniques24.
Radiation therapy may provide effective relief from
the breast pain associated with gynecomastia. There are
also several reports indicating that the development of
breast pain and gynecomastia may be prevented by prophylactic irradiation of the breast tissue25-27.
In this paper we show the good results of mastectomy
performed with a lower semicircular periareolar incision in men suffering from gynecomastia due to antiandrogen therapy for inoperable prostate cancer. In addition, we present a review of the various techniques used
for the treatment of this disease which, although less
important than the prostate cancer itself, often leads to
psychological problems that considerably worsen the
patient’s quality of life.
Materials and methods
During the period from September 1998 to May
2001, patients aged 58-70 years receiving hormone
treatment for disease or inoperable prostatic cancer
were selected for the study if they had breast pain and
bilateral gynecomastia. In 10 patients there was marked
enlargement of the breast accounting for a visible
pathological change. Gynecomastia was of grade 2-3
according to Simon and Hoffman’s classification28 and
was not well tolerated because of the associated psychological problems.
Five of the patients had been offered prophylactic radiotherapy before treatment but refused. The remaining
five patients had refused therapeutic radiotherapy after
hormone treatment. They were therefore given the option of a surgical procedure. This was accepted and
surgery was performed in all ten patients. An example
of the preoperative appearance of the affected breasts of
a patient treated with bicalutamide 150 mg/day is
shown in Figure 1. Before surgery all patients underwent clinical and ultrasound examination of the breast.
411
Figure 1 - Presurgical appearance of the breasts of a patient with prostate
cancer treated with bicalutamide 150 mg/day.
All surgical samples were examinated histopathologically. During follow-up clinical examinations were carried out one week, one month, six months, one year and
two years after surgery.
Surgical technique
The surgical procedure was performed under general
anesthesia and involved a lower semicircular periareolar skin incision from a three o’clock to nine o’clock
position along the edge of the pigmented area (Figure
2). The incision was extended to the subcutaneous tissue until the whitish, firm disk of the mammary gland
was exposed. The glandular tissue was dissected laterally from the subcutaneous fat until its edge was reached
and its deeper surface was dissected medially for some
centimeters from the pectoralis fascia. Then the same
dissection procedure was repeated medially and subcutaneously until the subareolar ductal tissue was identified and freed from the areola around the attachment to
the nipple. It is very important to cut the ductal tissue
leaving a 3 to 4-mm-thick piece attached to the nipple.
Figure 2 - Surgical incision performed during mastectomy.
412
Figure 3 - Postsurgical appearance of the breasts of a patient with prostate
cancer treated with bicalutamide 150 mg/day.
After removal of the disk and careful control of bleeding, the wound was closed by approximating the margins using 3/0 Vicryl Rapide sutures and a compressive
dressing was applied. The dressing was removed after
48 hours and the sutures were removed after seven
days.
Results
The median operating time was 60 minutes (±15) for
bilateral mastectomy. All patients were discharged the
day after surgery. The results were satisfactory in all patients, especially from an aesthetic point of view (Figure 3). Moreover, breast pain disappeared about one
week after surgery. After a follow-up of 6-36 months
(average, 22.8 months) no recurrences were observed.
Immediate postoperative complications were
hematoma in one case and seroma in another. No delayed complications such as nipple necrosis or abnormal scar retraction with areolar deformity were observed except for the loss of areolar tactile sensation in
one case.
Histological examination of the excised glands
showed a large proportion of fibrosclerotic tissue and a
small amount of fat.
Discussion and conclusion
Gynecomastia is a troublesome complication of hormone therapy for advanced prostate cancer because of
the associated breast pain and the psychological problems arising from the cosmetic appearance. With the increasing use of hormone therapy for early prostate cancer, the incidence of gynecomastia also needs to be investigated in this population. Studies on antiandrogen
therapy, either as immediate hormonal treatment or as
adjuvant to therapy with curative intent, in patients with
localized or locally advanced prostate cancer should
provide this information.
D PREZIOSO, G PICCIRILLO, R GALASSO ET AL
Gynecomastia is most common in the first nine
months of antiandrogen therapy, with new cases rarely
occurring subsequently. Treatment should be performed
very early because gynecomastia of more than one
year’s duration is more likely to show a poor response
to therapy due to the irreversible accumulation of fibrous glandular tissue.
In this report a simple technique is described that is
very easy to perform. In our patients there were few
postoperative complications and the aesthetic results
were good, with negligible scarring or other complications in the areolar area. No drain was placed to avoid
further cosmetic defects, even though postoperative
bleeding and hematomas have been reported in many
studies. In the present study there were two cases with
local accumulation of fluid, which spontaneously resolved with no further consequences
Histopathological examination of the excised glands
from the patients who underwent hormone treatment for
prostate cancer showed decreased ductal proliferation
and progressive increase in fibrosclerotic tissue. In spite
of the reports in the literature that emphasize the good
efficacy and limited side effects of prophylactic irradiation of the male breast, we could not use this treatment
in our patients because of poor compliance. All our patients were very afraid to undergo radiation treatment
and, in spite of our reassurance, categorically refused
this therapeutic option, considering it at very high risk
of sequelae and therefore too “dangerous” to treat a benign condition. Surgical removal of the mammary gland
can be considered a very effective way to treat this type
of gynecomastia, especially after the first year of antiandrogen treatment.
Numerous methods to treat gynecomastia have been
reported, indicating that there is no generally accepted
satisfactory approach. A large number of surgical procedures have been described in the literature, including
various types of techniques and incisions. Surgeons aim
to reduce the breast size to normal contours, to eliminate painful tissue and to restore the patient’s chest to
an acceptable cosmetic shape.
In 1946 Webster described a subcutaneous mastectomy through an areolar or periareolar incision that could
be inferior or lateral29, in 1969 Letterman placed the incision in the upper half of the areola, which did not lead
to hypertrophic scarring in his experience30, and in 1984
Saad and Kay described a circumareolar incision31.
Colombo-Benkmann32 performed surgical treatment
in 100 patients and obtained satisfactory results in 86%,
while minor complications such as skin retraction, hypertrophic scars, hypesthesia and skin redundancy occurred in 53% of cases, significantly more often in
grade III and II gynecomastia. In 81% of the breasts
(grade I and II gynecomastia) a lower periareolar incision was performed and hematomas occurred in 11.4%
of these cases. In order to reduce the incidence of complications such as hypesthesia, Pitanguy suggested a
transareolar incision33. In a study involving 24 cases he
performed the new technique in 53.3% with satisfactory
SURGICAL TREATMENT OF GYNECOMASTIA BY HORMONE THERAPY
results in all patients, except for one case where a hypertrophic scar occurred.
Liposuction34 is a surgical technique that corrects abnormal and excessive collections of adipose tissue and
is considered by many authors as one of the most effective treatments for gynecomastia, especially because of
the low incidence of sequelae. As liposuction removes
fatty tissue only, gynecomastia mainly due to glandular
hypertrophy requires more strenuous work and diligence, and additional sharp dissection to remove the
parenchyma is often needed. In a report by Samdal35,
among 62 patients who were treated with a combined
approach 37 (60%) were very satisfied with the results
and 19 (31%) were satisfied.
However, despite these good results, liposuction is
not likely to be effective in gynecomastia of patients
with hormone-treated prostate cancer, due to the increase in glandular tissue and the lack of fatty tissue.
Webster classified gynecomastia into three types:
glandular, fatty-glandular and simple fatty, according to
the most frequent tissue type. The glandular type can be
characterized by different levels of fibrotic tissue30. Patients with a glandular component require surgical removal of the gland, while in case of simple fatty gynecomastia liposuction alone seems to be appropriate;
wherever there is a fatty glandular form, surgery combined with liposuction gives good results.
In 1973 Simon described another classification where
patients were grouped into categories according to the
size of the gynecomastia:
I) minor but visible breast enlargement without skin
redundancy;
II) moderate breast enlargement without skin redundancy;
III) moderate breast enlargement with minor skin redundancy;
IV) gross breast enlargement with skin redundancy simulating a pendulous female breast.
Patients of group I and II require minimal solutions
and rarely a skin incision, but in group III and IV the
marked excess skin should be removed and a
mastopexy-type procedure is required.
The overall aim of surgery is to provide a normal
breast and chest contour with minimal signs of surgery.
Incisions outside the areola should be avoided, as
should removal of the nipple, because these procedures
often result in hypertrophic scarring. Most authors suggest a hemi-circumareolar or periareolar incision and
preservation of the nipple. There is general agreement
that the operation is cosmetic and should be performed
by surgeons with appropriate experience because the
development of unaesthetic scarring may result in a
worse problem than the original condition.
With regard to other treatment options, there are
many reports in the literature on therapeutic and especially prophylactic irradiation of the male breast. In a
study by Gangai36 10 patients were treated by radiation
therapy with a dose of 300 rads to each nipple and areo-
413
la on alternative days for a total dose of 900 rads in air.
Hormonal treatment was started two days following the
completion of radiation. After a one-year follow-up no
patient had symptoms related to the breasts, and only in
three cases was minimal hypertrophy noted. In all patients there was a complete lack of nipple sensitivity, localized tenderness or pain, but none of them showed
any skin changes secondary to radiation.
In a similar study, Malis37 divided the patients into
two groups: the 18 patients in group A received bilateral
breast irradiation prior to starting estrogen therapy
while the 10 patients in group B were placed on therapeutic maintenance doses of estrogens for 2 to 12 weeks
before radiation was started. Each patient received a total orthovoltage dose of 900 rads given in increments of
300 rads, alternating the breasts daily. After a follow-up
of 12 to 21 months, 11 patients of group A had no gynecomastia and the remaining seven had only mild
breast hypertrophy, while in group B breast enlargement
was mild in two patients, moderate in five patients and
severe in three patients.
In order to determine the side effects of irradiation,
Wolf38 conducted a double-blind study of 12 patients
followed for more than 18 months (the longest followup being 27 months). All patients received a total dose
of 1000 rads to the nipple area in one sitting. At the end
of the treatment, all patients showed varying degrees of
redness of the irradiated area with subsequent scaling,
which disappeared two to three months after irradiation,
while half of the patients had transient slight tenderness
of the irradiated nipple. No other side effects were observed.
In a study of 1986 Fass26 performed a retrospective
analysis of 87 patients referred for radiation treatment
before receiving DES for prostate cancer from 1972 to
1982. All patients were treated with 4 MV 60 Co superficial X-rays at doses ranging from 1200 to 1500 cGy in
three fractions. After an average follow-up of four
years, gynecomastia was absent in 67 patients, mild in
nine, moderate in eleven and severe in one patient. Radiation was also very effective in preventing mammalgia. Complications occurred in only two patients and
consisted of allergic reactions to the dye used in marking the treatment fields.
In a Scandinavian trial of 1999 the incidence of gynecomastia was 28% of 283 patients with locally advanced prostate cancer taking flutamide following single-dose radiotherapy to the breast (12-15 Gy), compared with 67% in non-irradiated patients27.
In a recent study Tyrrell investigated the efficacy and
tolerability of a single 10 Gy dose of radiation before
bicalutamide monotherapy in more than 100 patients
with localized or locally advanced prostate cancer and
found that over a period of 12 months the incidence of
gynecomastia in the radiotherapy group was reduced by
33% (P <0.001) compared with the non-irradiated
group14.
Radiation for the prophylaxis of gynecomastia is usually administered as a single dual low dose to the breast
414
area, which is surrounded by a protective disk. Electron
irradiation is most suitable because the dose can be limited to a few centimeters so that deeper organs such as
the lungs or heart have minimal exposure. Low-dose irradiation is generally well tolerated, causing only reversible adverse effects such as skin erythema, tenderness and discomfort, without any evidence of long-term
complications.
Nevertheless, many studies have shown that irradiation is less effective if started one or more months after
the beginning of hormone treatment, while the best results are obtained on tissues in active proliferation; we
therefore consider radiotherapy after hormone treatment
poorly effective in hormone-induced gynecomastia with
a large proportion of fibrosclerotic tissue.
As regards the radiotherapeutic prophylaxis of gynecomastia, poor patient compliance may represent a
major problem. Patients often refuse irradiation for a
benign disease that affects only an average of 50% of
patients treated with antiandrogens, as reported in
many statistical analyses9-12. However, as radiotherapy
seems to be highly effective on the immature breast,
such prophylaxis is more indicated in younger patients.
The risk of severe adverse events such as a second malignancy needs careful consideration, although patients
very rarely survive long enough to manifest such sequelae.
Medical treatment aims to restore the estrogen-to-androgen balance but is still experimental. Many drugs
have been used, including antiestrogens and aromatase
inhibitors, but the literature published to date is scarce.
Improvement of signs and symptoms of gynecomastia
has been reported in several case studies, but only few
reports, for example the small study by Serels and Melman involving three cases20, included patients with gynecomastia from treatment for prostate cancer. Most
studies reported good results of antiestrogens and aromatase inhibitors, especially in pubertal gynecomastia39.
This treatment option therefore seems to be particularly
effective in actively proliferating tissue and could have
less effect on the fibrotic tissue of hormone-induced gynecomastia. Finally, there is some concern regarding the
safety of this type of drugs in men with prostate cancer,
and few data in this regard are currently available.
D PREZIOSO, G PICCIRILLO, R GALASSO ET AL
A recent paper described an interesting randomized,
double-blind, placebo-controlled, three-arm multicenter trial on the prophylactic use of the antiestrogen tamoxifen and the aromatase inhibitor anastrozole in gynecomastia. This study evaluated the role of the two
agents in the prevention of gynecomastia and breast
pain in patients receiving bicalutamide monotherapy
(150 mg). The authors demonstrated that the prophylactic role of tamoxifen is significant (P <0.0001) at
three months. Prophylactic anastrozole does not reduce
the incidence of gynecomastia and breast pain at three
months or thereafter. The study demonstrated that prophylactic tamoxifen 20 mg daily initiated at the same
time as bicalutamide 150 mg significantly reduces the
incidence of gynecomastia and breast pain, but further
studies are needed to assess the impact of the combination on prostate cancer control. In fact, tamoxifen
seems to increase serum testosterone levels at three
months16. Another study on the preventive role of tamoxifen and anastrozole in patients with prostate cancer induced by bicalutamide was conducted more recently and seems to confirm the positive data about tamoxifen, which appears to be safe and not to influence
the PSA response17.
In conclusion, due to the increased use of antiandrogen monotherapy for prostate cancer the incidence of
gynecomastia and mastodynia is destined to rise. Physicians and patients have a number of options for its management, but the supporting data are relevant only for
prophylactic low-dose irradiation, whose tolerability
and efficacy are good, especially if electrons are used to
irradiate tissue to a limited depth. However, long-term
follow-up data for this treatment are not available and
the exact risk of the development of a malignancy is unknown. Consequently, a considerable number of patients find the potential risk unacceptable and therefore
refuse this treatment option.
With regard to the surgical options, liposuction can
be considered effective only in the very early stages because, with the progression of gynecomastia, the breast
becomes irreversibly fibrous. On the basis of the previous reports the authors favor this surgical technique because it is simple and effective, requires only short hospitalization and has very few complications.
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