Philippine Obstetrical and Gynecological

Society (Foundation), Inc.

CLINICAL PRACTICE GUIDELINES

on
BREAST DISEASES

First Edition

November 2015

vii
Philippine Obstetrical and Gynecological
Society (Foundation), Inc.

CLINICAL PRACTICE GUIDELINES

on
BREAST DISEASES

First Edition

November 2015
____________________________________________________________________

Copyright© 2015

Published by:

Philippine Obstetrical and Gynecological Society (Foundation), Inc.

POGS Building, No. 56 Malakas Street, Diliman, 1100 Quezon City
Telephone Nos.: (632) 921-7647, 921-7557
Fax: (632) 921-9089
Email address: pogsinc@gmail.com
Website: www.pogsinc.o

ISBN 978-621-9537-0-8
All rights reserved. No part of this book may be reproduced in any for
or by any means without prior permission from the publisher.

Printed by:

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(Printing & Publishing House)
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Tel. Nos.: 882-4119 / 882-4120 • Telefax: 882-4120
____________________________________________________________________
 MESSAGE FROM THE PRESIDENT

This publication is an entirely new practice guideline for our Society

and comes at an important time when breast diseases are increasing in its
incidence. We should recognize and acknowledge that as physicians involved
in reproductive health, the breast is another aspect of the care of the woman.
Therefore, screening for various breast pathologies should be a part of our
physical examination of our patients and not merely concentrating on our
pelvic evaluation.

This handbook has been a collaborative effort of several of our members,

headed by Dr. Jericho Thaddeus P. Luna and Dr. Debby P. Songco. Of
course, the completion of this guideline was made possible too by the various
members who were the stakeholders in critiquing this material. Let me extend
my sincere appreciation for the work of coming up with an entirely new and
relevant material for the practical use and reference of our colleagues.

I am hopeful that the contents of this work will augment our knowledge and
understanding of another very common category of diseases in women. The
Committee’s work and the Society’s thrust to provide information for our
further education is exemplified again in this guideline.

We continually endeavor to create relevant materials for the use of our

members. The access to our Society’s guidelines is one of the benefits of
being a POGS member. Again, congratulations to the Committee and all the
participants in the development of this material. I do hope that we will be able
to enhance your clinical practice.

Greetings to all!

DITAS CRISTINA D. DECENA, MD

President
Philippine Obstetrical and Gynecological Society (Foundation), Inc. (POGS), 2015

i
BOARD OF TRUSTEES 2015

OFFICERS

Ditas Cristina D. Decena, MD

President

Blanca C. De Guia-Fuerte, MD, MSc

Vice President

Christia S. Padolina, MD
Secretary

Benjamin D. Cuenca, MD
Treasurer

Ma. Socorro M. Solis, MD

Public Relations Officer

BOARD OF TRUSTEES
Mayumi S. Bismark, MD
Virgilio B. Castro, MD
Marlyn T. Dee, MD
Jericho Thaddeus P. Luna, MD
Enrico Gil C. Oblepias, MD
Ronaldo R. Santos, MD

ii
 COMMITTEE ON CLINICAL PRACTICE GUIDELINES, 2015

Jericho Thaddeus P. Luna, MD

Chair

MEMBERS
Ma. Luisa S. Acu, MD Joseph U. Olivar, MD Rommel Z. Dueñas, MD
Ireene G. Cacas, MD Marjorie I. Santos, MD Ramon M. Gonzalez, MD
Jennifer T. Co, MD Ma. Victoria V. Torres, MD Shiela T. Magpale, MD
Christine D. Dizon, MD Mario A. Bernardino, MD Catherine Joie Carelle R. Ong, MD
Agnes S. Estrella, MD Lourdes B. Capito, MD Debby P. Songco, MD
Mila Z. Ibay, MD Ma. Cristina P. Crisologo, MD
MANAGING EDITOR
Ana Victoria V. Dy Echo, MD

TECHNICAL STAFF ASSISTANT

Ms. Rosario Q. Anecito

TASK FORCE ON CPG ON BREAST DISEASES, 2015

Jericho Thaddeus P. Luna, MD
Chair

Debby P. Songco, MD
Co-Chair

MEMBERS
Ana Victoria V. Dy Echo, MD
Sherri Ann L. Suplido MD
Marianne D. Capco, MD

TASK FORCE REVIEWERS AND PLENARY REVIEWERS

Rainerio S. Abad, MD Raquel T. Llanera, MD Leedah R. Nisperos, MD
Rodante P. Galiza, MD Maria Lourdes T. Solidium, MD Caesar V. Tongo, MD
Michele V. Ramchandani, MD Sylvia R. Calingo, MD Grace D. delos Angeles, MD
Violeta Ellen D. Abelita, MD Jocelyn Z. Mariano, MD Catherine Joie Carelle R. Ong, MD
Dyan L. Gaudiel, MD Debby P. Songco, MD Jean Anne B. Toral, MD
Ves C. Ramones, MD Shirley Castro, MD Pressie P. Eclarin, MD
Maria Rizalina B. Adalid, MD Carolina Paula C. Martin, MD Maria Clara D.L. Ozaeta, MD
Elizabeth S. Go, MD Alice M. Sun-Cua, MD Ma. Victoria V. Torres, MD
Rico E. Reyes, MD Grace P. Cayabyab, MD Lenny Beth L. Engay, MD
Charmaine Claire T. Agcaoili, MD Amparo M. Medina, MD Ma. Lorcelli P. Parado, MD
Catherine T. Jison, MD Sherri Ann L. Suplido, MD JanetteP. Tuquero, MD
Ricalyn B. Rivera, MD Lilli May T. Cole, MD Amy P. Estrella, MD
Emille Teresa B. Apepe, MD Rogelio P. Mendiola, MD Johan B. Pilotin, MD
Rosalie E. Junio, MD Mina Sirikit C. Tagra, MD Aurora L. Valdez, MD
Alejandro R. San Pedro, MD Leilani C. Coloma, MD Elizabeth F. Felipe, MD
Ruth Junk L. Aposaga, MD Realino G. Molina, MD Ma. Wilhelmina A. Pineda, MD
Enrique V. Labios, MD Aurora B. Tajan, MD Florentina A. Villanueva, MD
Helen Grace Te-Santos, MD Ma. Lourdes B. Coloma, MD Odelind C. Flores, MD
Marie Scent Vera F. Benedicto, MD Yvonne D. Nacis, MD Sarah B. Pingol, MD
Mary Jocelyn Y. Laygo, MD Charisse Sharon E. Tan, MD Amaryllis O. Yazon, MD
Marjorie I. Santos, MD Barbara Ann B. Coma, MD Maria Cristina C. Franada, MD
Andrew Rouldan B. Buizon, MD Encarnita D.G. Nicolas, MD Irene B. Quinio, MD
Susan P. Lazaga, MD Corazon V. Tanchuling, MD Ana Ma. Carmen L. Zaballero, MD
Carmencita S. Solidium, MD Ma. Rhesa D. Delfin, MD Marian C. Dichoso, MD
Diane Rose S. Cajipe, MD Belen P. Rajagukguk, MD
iii
 DISCLAIMER, RELEASE AND WAIVER OF RESPONSIBILITY

● This is the Clinical Practice Guidelines (CPG) on Breast Diseases,

November 2015.

● This is the publication of the Philippine Obstetrical and Gynecological

Society, (Foundation), Inc. (POGS).

● This is the ownership of the POGS, its officers, and its entire membership.

● The obstetrician-gynecologist, the general practitioner, the patient, the

student, the allied medical practitioner, or for that matter, any capacity
of the person or individual who may read, quote, cite, refer to, or
acknowledge, any, or part, or the entirety of any topic, subject matter,
diagnostic condition or idea/s willfully release and waive all the liabilities
and responsibilities of the POGS, its officers and general membership, as
well as the Committee on the Clinical Practice Guidelines and its Editorial
Staff in any or all clinical or other disputes, disagreements, conference
audits/controversies, case discussions/ critiquing.

● The reader is encouraged to deal with each clinical case as a distinct and
unique clinical condition which will never fit into an exact location if
reference is made into any or all part/s of this CPG.

● The intention and objective of this CPG is to serve as a guide, to clarify,

to make clear the distinction. It is not the intention or objective of this
CPG to serve as the exact and precise answer, solution and treatment
for clinical conditions and situations. It is always encouraged to refer to
the individual clinical case as the one and only answer to the case in
question, not this CPG.

● It is hoped that with the CPG at hand, the clinician will find a handy guide
that leads to a clue, to a valuable pathway that leads to the discovery of
clinical tests leading to clinical treatments and eventually recovery.

● In behalf of the POGS, its Board of Trustees, the Committee on The

Clinical Practice Guidelines 2015, this CPG is meant to make each one of
us a perfect image of Christ, the Healer.

iv
TABLE OF CONTENTS

I. Benign Breast Diseases........................................................1

Sherri Ann L. Suplido, MD

II. Breast Pain: Mastalgia....................................................... 10

Marian D. Capco, MD

III. Breast Discharge: Galactorrhea............................................ 23

Debby Pacquing-Songco, MD

IV. Breast Cancer Prevention................................................... 36

Ana Victoria V. Dy Echo, MD

v
 BENIGN BREAST DISEASES
Sherri Ann L. Suplido, MD

BACKGROUND

A palpable breast mass, breast pain and nipple discharge are three of the
more common breast symptoms for which patients seek medical attention.
Common benign breast conditions encountered in the clinical practice of
obstetrics and gynecology are mastitis, breast abscess and fibroadenoma.

I. MASTITIS

Mastitis is an inflammatory breast condition which may or may not be

accompanied by infection. It is usually called lactational or puerperal
mastitis, as it is commonly associated with lactation.1

STATEMENT 1: Mastitis is diagnosed as having a tender,

erythematous, hot, swollen, wedge-shaped area of breast associated
with fever of 38.5°C (101.3°F) or greater with chills, flu-like aching,
and systemic illness which may be infective or non-infective. (Level
II-2, Grade B)

STATEMENT 2: Mastitis can occur early, during the second and

third week postpartum, but commonly occurs up to the 12th week post
delivery, or at any stage during lactation in the first 2 years. (Level II-3,
Grade B)

Supporting Statements:

The largest prospective study of 1730 breastfeeding women was

performed by Hesseltine, et al. in 1948, which showed 121 cases of
mastitis diagnosed in the first 6 months of breastfeeding.4 Fulton in 1945,
in a prospective study of 41,500 births, reported 156 cases of mastitis up
to 2 years and 4 months of breastfeeding.5

STATEMENT 3: Risk factors which may predispose a lactating

woman to the development of mastitis are age; those related to
milk stasis, which may include damaged nipple, colonized with
Staphylococcus aureus; infrequent or missed feedings; poor suck;

1
rapid weaning; maternal and infant illness; increased pressure on the
breast (tight brassiere, etc.); blocked nipple pore; and maternal stress
or fatigue. Other than the fact that these are factors that result in milk
stasis, the evidence for these associations is generally inconclusive.
(Level II-2, Grade B)

STATEMENT 4: The two principal causes of mastitis are milk stasis

and infection, with milk stasis as the primary cause which may or may
not be accompanied by or progress to infection. (Level II-2, Grade B)

STATEMENT 5: Causes of mastitis may be classified according to

the presence of leukocytes and bacteria in the milk: milk stasis (< 106
leukocytes and < 103 bacteria), non-infectious mastitis (> 106 leukocytes
and < 103 bacteria), and infectious mastitis (> 106 leukocytes and > 103
bacteria). (Level I, Grade A)

STATEMENT 6: Breast engorgement or “milk fever”, characterized

by distended breasts and a high fever, occurring on the 2nd or 3rd day of
delivery, and its relation to mastitis have been made for many years,
though the two conditions were not always clearly distinguished,
although prompt removal of milk by suckling in the early stages of
mastitis, or congestion, are used prevent progression of the disease
and abscess formation. (Level II-3, Grade B)

Supporting Statements:

One retrospective study showed that women aged 21-35 were more
likely to develop mastitis compared to those under 21 and over 35.6
Another retrospective study identified women aged 30-34 as having the
highest incidence of mastitis.7

Gunther in 1958 observed that mastitis resulted from stagnation of milk

within the breast, and that the efficient removal of milk as it is formed
could largely prevent it and that infection when it occurred, was not
primary, but resulted from the stagnant milk providing a medium for
bacterial growth.8

A randomized study by Thomsen showed that milk stasis (< 106

leukocytes and < 103 bacteria) improved with continued breast-feeding
alone; non-infectious mastitis (> 106 leukocytes and < 103 bacteria)
required treatment by additional expression of milk after breastfeeding,
and infectious mastitis (> 106 leukocytes and > 103 bacteria) was treated
effectively only with both removal of milk and systemic antibiotics.
Without effective removal of milk, non-infectious mastitis was more

2
likely to progress to infectious mastitis, and infectious mastitis to the
formation of an abscess. He also related cell and bacterial counts to
clinical findings, and found that it was impossible to be certain from
clinical signs whether or not infection had set in.9

STATEMENT 7: Laboratory tests and other diagnostic procedures

are not routinely performed for the diagnosis of mastitis. (Level II-2,
Grade B)

STATEMENT 8: Breast milk culture and sensitivity testing should

be undertaken if there is: (1) no response after 2 days of antibiotic
treatment, (2) if mastitis recurs, (3) if it is hospital-acquired, (4) if the
patient is allergic to usual therapeutic antibiotics, or (5) in severe or
unusual cases.1 (Level II-2, Grade B)

STATEMENT 9: Because milk stasis is often the initiating factor in

mastitis, the most important step in the management is frequent and
effective milk removal. (Level III, Grade C)

STATEMENT 10: The following are steps to the prevention of milk

stasis: (Level III, Grade C)
a. Mothers should be encouraged to breastfeed more frequently,
starting on the affected breast.
b. To help drain the affected area, the infant is positioned at the
breast with the chin or nose pointing to the blockage.
c. Massaging the breast toward the nipple during the feed with an
edible oil or nontoxic lubricant on the fingers may also be helpful
to facilitate milk removal.
d. After feeding, expressing milk by hand or pump may augment
milk drainage and hasten resolution of the condition.

Supporting Statements:

Thomsen, et al. demonstrated that emptying of the breast resulted in

a significant decrease in the duration of symptoms and a significantly
improved outcome.10 Infectious mastitis without treatment was followed
by a good result in only 15% of the cases, and 11% developed abscesses.
Emptying of the breast increased the rate of a good outcome to 50% and
significantly decreased the duration of symptoms.

STATEMENT 11: Another approach for a swollen breast is promoting

fluid drainage toward the axillary lymph nodes. This is performed
with the mother reclined, and with gentle hand motions start stroking
the skin surface from the areola to the axilla. (Level III, Grade C)

3
STATEMENT 12: There is no evidence of risk to the healthy, term
infant of continuing breastfeeding from a mother with mastitis. (Level
III, Grade C)

STATEMENT 13: Women who are unable to breastfeed should

express the milk from breast by hand or pump, as sudden cessation
of breastfeeding leads to a greater risk of abscess development than
continuing to feed. (Level III, Grade C)

STATEMENT 14: Rest, adequate fluids, and nutrition are also

important in the management of mastitis. (Level III, Grade C)

STATEMENT 15: Application of heat with a hot pack on the breast

just prior to feeding may help with the let-down and milk flow; and
after feeding or expression of milk from the breasts, cold packs can
be applied to the breast in order to reduce pain and edema. (Level III,
Grade C)

STATEMENT 16: Hospital admission should be considered for

women who are severely ill, require intravenous antibiotics, or do not
have supportive care at home. (Level III, Grade C)

Statement 17: Rooming-in of the infant with the mother is required so

that breastfeeding can continue. (Level III, Grade C)

STATEMENT 18: Analgesics may help with the milk let-down

reflex, and an anti-inflammatory drug such as ibuprofen, which is
compatible with breastfeeding, may be more effective in reducing the
inflammatory symptoms than a simple analgesic. (Level III, Grade B)

STATEMENT 19: For mild symptoms of mastitis present for less

than 24 hours, conservative management such as effective milk
removal and supportive measures may be sufficient; but if symptoms
are not improving within 12-24 hours or if the woman is acutely ill,
antibiotics should be started.1 (Level III, Grade B)

STATEMENT 20: There is little evidence to evaluate the effect of

antibiotic therapy on mastitis in general.14 (Level I, Grade B)

STATEMENT 21: The most common pathogen in infective mastitis

is penicillin-resistant Staphylococcus aureus and the preferred
antibiotics are usually dicloxacillin or flucloxacillin 500 mg by PO 4x/
day for 10-14 days, or as recommended by local antibiotic sensitivities.
(Level III, Grade C)

4
 S TAT E M E N T 22: First-generation cephalosporins are also generally
acceptable as first-line treatment, but may be less preferred because
of their broader spectrum of coverage. (Level III, Grade C)

Supporting Statements:

Cochrane review shows that there is a lack of properly-designed

randomized controlled trials (RCTs) to evaluate the best antibiotic
therapy for treating mastitis, and only one RCT, which was
underpowered, was suitable for review that compared two types of
antibiotics (amoxicillin, cephradine) in a small group of 25 women
with mastitis.

S TAT E M E N T 23: The following are recommended to prevent

mastitis: (Level III, Grade B)
a. Mothers should be counseled to improve infants’ attachment to
the breast.
b. Feeds should not be restricted.
c. Mothers should be taught to hand-express when the breasts are
too full and a breast pump may also be used.
d. Mothers should be taught to check their breasts for masses, pain
and erythema.
e. Breastfeeding mothers should have adequate rest.
f. Good hygiene should be practiced among mothers and health
care providers as S. aureus is a common commensal organism
often present in hospitals and communities.

II. BREAST ABSCESS

Approximately 3% of women with mastitis will develop breast abscess,

which is characterized by a well-defined area of the breast which is
hard, red and tender. This occurs despite appropriate management of
mastitis, wherein the initial systemic symptoms and fever may have
resolved.

S TAT E M E N T 1: A diagnostic breast ultrasound will identify fluid

or pus collection. (Level III, Grade C)

S TAT E M E N T 2: The abscess can often be drained by needle

aspiration, which itself can be diagnostic as well as therapeutic, and
may be done serially and ultrasound- guided. (Level III, Grade C)

5
 Supporting Statements:

A retrospective study on 43 women with breast abscess in 2004 showed

that ultrasound-guided needle aspiration of abscesses < 3 cm and
ultrasound-guided catheter drainage of abscesses 3 cm or larger are
successful means of treating breast abscesses.

A study by Dixon in 1988 on 6 women showed that repeated aspirations

of large abscesses along with oral antibiotics have been effective.16

STATEMENT 3: Surgical drainage may be necessary if the abscess is

very large or if there are multiple abscesses, after which breastfeeding
on the affected breast should be resumed, along with a course of
antibiotics should follow drainage of the abscess. (Level III, Grade B)

III. FIBROADENOMA

Fibroadenomas are common benign lesions of the breast that usually

present as a single breast mass in young women. Oftentimes, the
clinician faces the dilemma whether to excise the mass or to monitor it
through periodic follow-up examinations.

STATEMENT 1: Fibroadenoma usually presents as a discrete solitary

breast mass of 1 to 2 cm, situated in the upper outer quadrant although
they can be located anywhere in the breast. These are usually smooth,
mobile, nontender, and rubbery in consistency. (Level III, Grade C)

STATEMENT 2: Breast sonography is often used for the diagnosis

of fibroadenomas, characterized as round or oval solid masses, with
smooth contours and weak internal echoes in a uniform distribution
and intermediate acoustic attenuation. (Level II-3, Grade B)

STATEMENT 3: The yield of mammography in young women is

low, and its role in the diagnosis of fibroadenomas is limited. (Level
II-3, Grade B)

Supporting Statements:

A study by Grazzi, et al. evaluated the role of sonography and

mammography in the diagnosis of fibroadenoma. Sensitivity, specificity
and positive predictive values (PPV) compared with histology were 45%,
50% and 79% for mammography, 34%, 69% and 82% for ultrasound.

6
STATEMENT 4: Fine needle aspiration has become a popular
method in the evaluation of breast masses. (Level II-3, Grade B)
Supporting Statements:

The overall diagnostic efficacy the different modalities, which are

manual breast examination, imaging and cytology, is approximately
70% to 80%, but they provide a 95% (+2% SD) accurate differentiation
between a benign and a malignant lesion.

STATEMENT 5: Conservative management is recommended for

fibroadenomas, as they are benign breast lesions, and may regress
spontaneously. (Level II-2, Grade B)

Supporting Statements:

In Cant, et al.’s follow-up studies on clinically diagnosed fibroadenomas,

persistent lesions were excised after 3 years and these were found in the
histologic examinations of 97% of these cases. These findings suggest
that the other benign lesions had resolved spontaneously during 1 to
3 years, that the remaining masses were true fibroadenomas, and that
conservative management is warranted.

A report by Wilkinson detailed the outcome after clinical diagnosis of

mammary fibroadenoma in 110 women aged under 35 years.22 After
fine needle aspiration cytology, and subsequent exclusions and failures
of follow-up, 92 lesions were observed for a mean of 47 weeks (range
13-90 weeks), with regular measurements until removal of persisting
lesions at 12 months. Fifteen lesions disappeared and 56 had the classical
histology of fibroadenoma, mean size 2.5 cm; 30 of the latter continued to
grow throughout the study. Cytology is essential to exclude malignancy
if conservative treatment is considered, and is helpful in identifying a
benign lesion. A period longer than 12 months may be required for
resolution of a fibroadenoma and removal under local anesthesia as a
day case offers a simple alternative.

STATEMENT 6: In women in which fibroadenoma is diagnosed

before 35 years old, conservative management with a protocol of
follow-up every 6 months in order to detect any changes of the lesion
is recommended. (Level III, Grade C)

STATEMENT 7: Fibroadenomas that either do not completely

regress, or remain unchanged by the age of 35, should be excised
surgically and those that become larger should be excised without
delay. (Level III, Grade C)

7
 STATEMENT 8: In patients with a family history of breast cancer,
or known changes of complex fibroadenoma, excisional biopsy is
recommended once diagnosis is established. (Level III, Grade C)

REFERENCES:

1. World Health Organization. Mastitis: Causes and management. WHO/

FCH/CAH/00.13. Geneva: WHO, 2000.
2. Lawrence RA. The puerperium, breastfeeding, and breast milk. Curr Opin
Obstet Gynecol 1990;2:23-30.
3. Inch S, Renfrew MJ. Common breastfeeding problems. In: Chalmers I,
Enkin M, Keirse M (Eds). Effective Care in Pregnancy and Childbirth.
Oxford University Press, Oxford, United Kingdom, 1989:1375-1389.
4. Hesseltine HC, Freundlich CG, Hite KE. Acute puerpural mastitis: Clinical
and bacteriological studies studies in relation to penicillin therapy. Amer J
Obstet Gynecology 1948;55:778-788.
5. Fulton AA. Incidence of puerperal and lactational mastitis in an industrial
town of some 43,000 inhabitants. British Med J 1945;1:693-696.
6. Jonsson S, Pulkkinen MO. Mastitis today: incidence, prevention and
treatment. Annales Chirurgiae Et Gynaecologiae.Supplementum,
1994;208:84-87.
7. Kaufmann R, Foxman B. Mastitis among lactating women: Occurrence
and risk factors. Social Science and Medicine 1991;33(6):701-705.
8. Gunther M. Discussion on the breast in pregnancy and lactation.
Proceedings of the Royal Society of Medicine 1958;51(Section of General
Practice):305-309.
9. Thomsen AC. Infectious mastitis and occurrence of antibody-coated
bacteria in milk. Am J Obstet Gynecol 1982;144(3):350-351.
10. Thomsen AC, Espersen T, Maigaard S. Course and treatment of milk
stasis, noninfectious inflammation of the breast, and infectious mastitis in
nursing women. Am J Obstet Gynecol 1984; 149(5):492-495.
11. Thomsen AC, Hansen KB, Moller BR. Leukocyte counts and microbiologic
cultivation in the diagnosis of puerperal mastitis. Am J Obstet Gynecol
1983;146(8):938-941.
12. Naish FC. Breast feeding. A guide to the natural feeding of infants. Oxford,
Oxford Medical Publications, 1948.
13. Bolman M, Saju L, Oganesyan K, et al. Recapturing the art of therapeutic
breast massage during breastfeeding. J Hum Lact 2013;29:328-331.
14. Jahanfar S, Ng CJ, Teng CL. Antibiotics for mastitis in breastfeeding
women. Cochrane Database Syst Revs 2013, Issue 2. Art. No.: CD005458.
DOI: 10.1002/14651858.CD005458.pub3.
15. Hager WD. Mastitis. In: Mead PB, Hager WD editor(s). Infectious Protocols
for Obstetrics and Gynaecology. Montvale, NJ: Medical Economics
Publishing 1992:27-32.
16. Dixon JM. Repeated aspiration of breast abscesses in lactating women.
BMJ 1988;297:1517–1518.
17. Ulitzsch D, Nyman MKG, Carlson RA. Breast abscess in lactating women:
US-guided treatment. Radiology 2004;232:904-909.

8
18. Amin L, et al. ABM Clinical Protocol Number 4: Mastitis. Revised 2014.
Breastfeeding Med 2014;9(6);239-243.
19. Haagensen CD. Disease of the breast. 3rd Ed. Philadelphia, Pa; W.B.
Saunders; 1996:267–83.
20. Dent DM, Cant PJ. Fibroadenoma. World J Surg 1989;13:706-10.
21. Foster ME, Garrahan N, Williams S. Fibroadenoma of the breast: a clinical
and pathological study. J R Coll Surg Edinb 1988;33:13-6.
22. Wilkinson S, Anderson TJ, Rifkind E, Chetty U. Fibroadenoma of the
breast: a follow up of conservative management. Br J Surg 1989;76:390-1.
23. Greenberg R, Skornick Y, Kaplan O. Management of breast fibroadenomas.
J General Internal Med 1998;13:640-645.

9
 MASTALGIA
Marian D. Capco, MD

INTRODUCTION

Breast pain or mastalgia is one of the most frequent reason for consultation
with an obstetrician-gynecologist. There is often extreme anxiety associated
with breast pain, particularly because of the fear that the pain is a symptom of
breast cancer. This concern is the primary reason most women seek medical
consult for mastalgia. Breast pain during lactation or after weaning is not
included in this definition.

INCIDENCE

Mastalgia is a common distressing complaint often presenting in women

30-50 years old. Approximately 70-80% of women experience severe breast
pain at some point in their lives.1 The prevalence of breast pain in clinical
populations range from 41% to 69%.2 Only about half of patients with breast
pain seek medical advice.3 It is less common in Asian cultures, affecting only
about 5% of women.4

Although mastalgia is common, the impact it has on everyday life should not
be underestimated. Majority of symptomatic patients (59%) describe their
symptoms as distressing.2 However, in 10-15% of patients, the mastalgia is
so severe that it interferes with daily activities and may require repeated
investigations and treatment.2,5

There is a higher prevalence of breast pain among premenopausal than

postmenopausal women. Increasing age, larger breast cup size, and lower
fitness and activity levels were also associated with higher prevalence of
mastalgia.2 Sedentary lifestyle has been reported in up to 80% of women
complaining of breast pain.6

CLASSIFICATION

Breast pain is typically approached according to its classification as:

1. Cyclical
2. Non-cyclical
3. Extramammary (non-breast)

10
The classification is important because the assessment and response to
treatment are different for the different types of breast pain.

Diffuse pain is described as involving greater than 25% of the breast and
axillary tissue and focal as involving less than 25% of the breast and axillary
tissue.

1. Cyclical breast pain

This type of breast pain has a temporal association with the menstrual
cycle and is the most common type of mastalgia. It is more prevalent in
women in their 3rd and 4th decades of life and accounts for 2/3 of all breast
pain symptoms.5 Mild premenstrual mastalgia lasting 1-4 days can be
considered normal. However, up to 30% of patients may experience
severe breast pain for more than 5 days and 15% report limitation to
their daily activities. Criteria for the diagnosis of cyclic mastalgia are:
(a) pain severity > 4.0 cm measured on a 10.0-cm visual analog scale, and
(b) pain duration of at least 7 days each month.3 The pain is often diffuse
and bilateral, described as sharp, shooting, stabbing, throbbing, heavy or
aching affecting the upper outer quadrants of the breast. It may radiate to
the upper arm and axilla. Cyclic mastalgia characteristically starts in the
days (even up to 1-2 weeks) before menstruation and gradually increases
in severity. It is often associated with bilateral breast engorgement and
heaviness. Cyclical breast pain tends to subside once menstruation has
started and often disappears after a few days. The pain can continue for
many years and will usually disappear after menopause. Spontaneous
resolution may occur in up to 22% of patients and persist in 65% of
patients even after treatment.8

The etiology of cyclical mastalgia is not well understood but the

relationship to the menstrual cycle makes a hormonal connection likely.
It is postulated that cyclical breast pain is due to hormonal stimulation of
breast parenchyma at the end of the luteal phase of the menstrual cycle.8
Several causes of mastalgia have been implicated including abnormal
levels of inflammatory cytokines, elevated estrogen, low progesterone,
or an imbalance in the ratio of estrogen and progesterone.5 Women who
suffer from mastalgia may have breast tissue with increased sensitivity
to estrogen and may have associated increased levels of prolactin.4,7

Cyclic breast pain is the most commonly associated symptom in a

benign breast lesion known as fibrocystic change. Fibrocystic change is
the most common lesion of the breast and covers a spectrum of clinical
signs, symptoms, and histologic changes. The term refers to a histologic
picture of fibrosis, cyst formation, and epithelial hyperplasia. It is

11
 common in women 35 to 55 years of age, but rare in postmenopausal
women not taking hormone replacement therapy (HRT). The cysts are
palpable in 7% of patients with fibrocystic change and are described as
smooth, movable, tender, multiple or bilateral.5 These symptoms often
coincide with the premenstrual phase of the cycle when cysts may
appear or enlarge indicating also a hormonal connection. Fluctuations
in size and rapid appearance or disappearance of the breast cysts are
common.

2. Noncyclical breast pain

This type of breast pain has no relationship to the menstrual cycle. It

is less common and accounts for approximately 31% of women seen
in breast pain clinics.3 Noncyclical mastalgia may be intermittent or
constant and is described usually as heavy, aching, pulling, stabbing or
pinching. It tends to be unilateral and well localized within a quadrant
of the breast, often sub-areolar or medial. In contrast to cyclical breast
pain, it presents much later in life usually in the 4th and 5th decades.5
Most women are postmenopausal at the onset of the symptom.

Noncyclical mastalgia is more likely to have an anatomical rather

than hormonal etiology. Some causes of noncyclical breast pain
include pregnancy, mastitis, stretching of Cooper’s ligaments,
diabetic mastopathy, traumatic fat necrosis, thrombophlebitis, breast
cysts, benign tumors or cancer.3,7 A wide range of drugs have been
associated with breast pain including combined oral contraceptives,
antidepressants, cardiovascular drugs, metronidazole and cimetidine.3
This type of mastalgia is more difficult to treat; however it can
spontaneously resolve in up to 50% of cases.8

3. Extrammamary breast pain

Extramammary pain is perceived to be located in the breast but is

actually related to an extramammary site. It has no pattern, can occur at
any age, and is almost always unilateral. The origin of extramammary
pain is variable. A common cause of extramammary breast pain is
due to inflammation of the costochondral junctions of the chest wall
(Tietze’s disease). Other common causes include chest wall muscular
pain, costal cartilage symptoms, herpes zoster, radiculopathies, and rib
fractures. Referred pain from cardiac, pulmonary and gastrointestinal
etiologies, such as angina, pneumonia and esophagitis, respectively,
need to be excluded.

12
EVALUATION

STATEMENT 1: Comprehensive history and thorough physical exami-

nation of the breasts and regional lymph nodes are necessary in patients
presenting with mastalgia. Further examination of the chest wall, spine,
upper extremities, heart, lungs and abdomen may be necessary to rule out
extramammary causes of breast pain. (Level II, Grade A)

Supporting Statements:

A systematic approach to mastalgia incorporates a comprehensive history of

the pain, including the duration, site, severity, relationship to the menstrual
cycle and impact on every day life. In addition, any family history of breast
cancer and history of intake of medications should be taken into account.
A thorough clinical breast examination requires careful inspection and
palpation of each breast (including nipple and areolar) and examination of
the regional lymph nodes. The chest wall should be carefully palpated to
exclude extramammary causes of mastalgia. Examination of the cervical and
thoracic spine, shoulders, upper extremities, heart, lungs and abdomen may
also be necessary.

Retrospective reporting of breast pain characteristics by patients have been

proven to be inaccurate.7 Prospective daily recording of pain characteristics
and the impact on their daily lives for at least 2 months using the Cardiff Breast
Pain chart or other visual analogue scales may provide a more accurate and
comprehensive data.7 This can also help define whether mastalgia is cyclical
or noncyclical.

STATEMENT 2: A pregnancy test should be performed, if suggested by

the history.

Supporting Statement:

Pregnancy test should be performed to rule out estrogen secreting ovarian

tumor.6,7

STATEMENT 3: Appropriate ragiographic imaging is only indicated in

focal noncyclical mastalgia. Radiological investigation is not indicated in
young women with no risk factors, presenting with cyclical mastalgia and
a normal breast examination. (Level I, Grade A)

Supporting Statements:

Breast pain alone is not an indication for imaging. The incidence of breast
cancer in patients presenting with mastalgia as an isolated symptom is

13
extremely low, about 1.2%.9 In the majority of cases of cyclical mastalgia,
radiological imaging is not warranted in the absence of additional breast
examination findings. When there are associated or incidental focal clinical
signs in the breast (localized tenderness, nodularity, swelling or a lump)
imaging is necessary. If infection or abscess is suspected, an initial ultrasound
scan should be performed and any fluid or pus aspirated and cultured.10
Mammography must be considered for women over the age of 35 who
present with noncyclical breast pain, particularly for those with additional
risk factors such as family history of breast cancer. In younger patients,
breast ultrasound may be the initial imaging modality because of the higher
sensitivity of ultrasound in younger patients compared to mammography.

The American College of Radiology set the following guidelines based on

their February 2015 Appropriateness Criteria for Evaluation of Breast Pain:11
1. Women with cyclical and/or bilateral nonfocal breast pain or tenderness
usually do not require nonroutine imaging due to the low yield of
finding a specific cause.
2. In patients with noncyclical, unilateral, or focal breast pain that is
not extramammary in origin, imaging can be pursued to exclude the
unlikely presence of breast cancer as the cause of pain, to determine
a benign but treatable etiology, or to offer reassurance that there is no
anatomic abnormality present.
3. In symptomatic women less than 30 years of age, ultrasonography is
more accurate in making a diagnosis than mammography.
4. In the 30-39 year old age group, adding unilateral or bilateral
mammography may be appropriate, since some of the small cancers
found at the site of pain as reported in several studies were only
visible mammographically. Mammography may also be indicated in
patients under the age of 30 if a suspicious lesion is found on the initial
ultrasound examination, or if the patient’s history or risk status justifies
the radiation exposure.
5. Mammography should be performed with ultrasound in patients aged
40 and older, or in a patient of any age who would normally qualify for a
mammogram based on risk factors and the date of the last mammogram.
6. There are no data to suggest that breast magnetic resonance imaging
(MRI) or nuclear imaging (breast-specific gamma imaging [BSGI] or
positron emission mammography [PEM]) meet the risk/benefit or cost
effectiveness criteria to be considered useful in the workup of breast
pain.

It is worth mentioning that although radiologic evaluation is not indicated

in many cases of mastalgia, imaging is useful to alleviate patient anxiety and
guide physicians in considering possible treatment options. Reassurance is
often cited as the main reason for imaging of these patients. Many women

14
with mastalgia do not seek further medical attention after reassurance that
their pain is not due to breast cancer.

STATEMENT 4: Ultrasonographic evaluation is indicated in patients with

mastalgia associated with fibrocystic change of the breast. Aspiration may
be performed without ultrasonographic guidance if the cyst is palpable.
(Level II, Grade A)

Supporting Statements:

In patients with mastalgia associated with fibrocystic change,

ultrasonographic evaluation is indicated. Aspiration may be performed
without ultrasonographic guidance if the cyst is palpable. Benign cyst fluid
is straw-colored to dark green to brownish and does not need to be submitted
for cytologic evaluation. The patient should be reexamined at a short interval
thereafter for cyst recurrence. Cysts will recur in 30% of patients, cause
anxiety, and require repeated evaluations.5

Fibrocystic change or presence of breast cysts alone is not associated with an

increased risk of breast cancer unless there are other risk factors present such
as family history of breast cancer. Tissue biopsy should be performed in the
presence of the following findings:
• No cyst fluid is obtained
• The fluid is bloody
• The fluid is thick
• The cyst is complex
• There is an intracystic mass
• A mass persists after aspiration
• A persistent mass is noted at any time during follow-up

STATEMENT 5: Psychological assessment and support may be needed

for some women with severe mastalgia. (Level I, Grade B)

Supporting Statements:

Women with severe mastalgia were found to have higher levels of anxiety,
depression and social dysfunction.4 Even after appropriate treatment, these
women continued to experience residual anxiety and pain.

TREATMENT

Several factors limit the clinical management of mastalgia. One of the most
important of these factors is the subjective nature of the breast pain. It is
difficult to quantify mastalgia. The challenge in managing breast pain is to

15
strike a balance between appropriate investigation, simple reassurance and
treatment.

Patients with moderate to severe mastalgia for more than 5 days each month
for the last 6 months or with pain that interferes with daily activities will
require pharmacologic treatment. On the visual analogue scale, a score of 3
or more may be an indication to initiate treatment.5

STATEMENT 6: Education and reassurance should be the first-line

treatment in the management of mastalgia. (Level II-1, Grade A)

Breast pain is an unlikely symptom of malignancy, and when malignancy is

excluded by a clinical breast examination and appropriate breast imaging for
focal breast pain, the most important treatment is reassurance.4,12 Reassurance
was found to be effective for 85.7% of mild mastalgia, 70.8% of moderate
cases, and 52.3% of severe cases.4 Reassurance was more effective for cyclical
rather than noncyclical mastalgia.

In addition to simple reassurance, other lifestyle changes may benefit

mastalgia. Sedentary lifestyle has been reported in women complaining of
mastalgia, particularly the noncyclical type. In these women, exercise may
improve pain via release of endorphins.7 However, there is still limited data
to recommend exercise as a form of management.

STATEMENT 7: The use of a well-fitting bra that provides good support

should be considered for the relief of cyclical and noncyclical mastalgia.
(Level II-3, Grade B)

Supporting Statements:

A well-fitting brassiere has been shown to give 75-85% of patients relief of

symptoms with no associated side effects.4 Symptomatic women may benefit
from counseling regarding proper selection of a bra.3,7

STATEMENT 8: A change in dose, formulation, or scheduling should be

considered for women on HRT. HRT may be discontinued if appropriate.
(Level III, Grade C)

Supporting Statements:

Breast pain may be due to intake of HRT or oral contraceptives. Hormone

therapy may result to varying degrees of breast pain ranging from mild and
temporary to severe and persistent.4 Mastalgia due to oral contraceptives
often resolves after a few cycles.

16
Currently there is insufficient and conflicting data whether oral contraceptives
cause or relieve cyclic mastalgia. Patients suffering from mastalgia due to
chronic fibrocystic change may even have reduction and remission of pain
after intake of combined oral contraceptives.13

STATEMENT 9: Flaxseed should be considered as a first-line treatment

for cyclical mastalgia. (Level I, Grade A)

Supporting Statements:

In a study done by Vaziri, et al. (2014), flaxseed bread diet was effective in
decreasing the intensity of cyclical mastalgia.14 This was supported by an
earlier Canadian study in 2000 that revealed breast pain was significantly
decreased in patients taking 25 g of flaxseed daily in a muffin.4

STATEMENT 10: Topical nonsteroidal anti-inflammatory gel, such as

diclofenac 2%, should be considered for pain control for localized treatment
of mastalgia. (Level I, Grade A)

Supporting Statements:

Topical nonsteroidal anti-inflammatory gel is an alternative treatment for

both cyclical and noncyclical mastalgia.4,5,15 Oral anti-inflammatory agents
such as naproxen has not been proven to be effective in the treatment of
mastalgia.16

STATEMENT 11: Tamoxifen 10 mg daily or danazol 200 mg daily should

be considered when first-line treatments are ineffective. (Level I, Grade A)

Supporting Statements:

The most comprehensively researched endocrine treatments for mastalgia

are danazol, tamoxifen and bromocriptine.

Danazol is a synthetic testosterone which binds to androgen and progesterone

receptors. Danazol at 200 mg daily can reduce both cyclical and noncyclical
mastalgia in 60-80% of patients.7 However, relapse rate after termination of
treatment is as high as 70% but recurrent pain is often less severe.7 The main
factor limiting the use of danazol is its range of adverse effects: weight gain,
amenorrhea, depression, hot flashes, hirsutism, deepening of the voice, and
acne.4,8 It is also contraindicated in women with history of thromboembolic
disease. It is teratogenic and interferes with the use of oral contraceptive
pills. To minimize the side effects of danazol, it can be given only during the
luteal phase.3,4

17
Tamoxifen is an estrogen receptor blocker. Low dose tamoxifen 10 mg
daily produces a high response rate with 80-90% success after 6 months of
treatment.4,7 Relapse rate after discontinuation of treatment is about 30%.7
Common adverse effects associated with tamoxifen use include hot flashes,
menstrual irregularity/amenorrhea, weight gain, nausea and vaginal
dryness. Major concern over tamoxifen use is its known association with
endometrial cancer and thromboembolic events.4,7

S TAT E M E N T 12: Bromocriptine at 5 mg daily is an effective alternative

treatment in patients whom danazol or tamoxifen is contraindicated or
cannot be tolerated. (Level I, Grade B)

Supporting Statements:

Bromocriptine is a dopaminergic agonist which inhibits the release of

prolactin. The dose of 2.5 mg twice daily has a response rate of 47-88% and
clinical improvement is sustained even after cessation of the medication.3
It may be used in women with history of thromoboembolic disease.
Bromocriptine is contraindicated in patients being treated with diuretics
or hypotensive drugs. Reasons for discontinuation include postural
hypotension, headache, nausea, vomiting and dizziness. Side effects can
be reduced if bromocriptine is taken with meals and an incremental dosing
regimen is used with stepwise increases of 1.25 mg during a period of 2
weeks.

S TAT E M E N T 13: Treatment with gonadotropin-releasing hormone

(GnRH) agonist should be reserved for severe refractory mastalgia.
(Level II, Grade A)

Supporting Statements:

GnRH agonists are synthetic analogues of hypothalamic GNRH. Continuous

administration of GnRH agonists (3.6 mg or 3.75 mg each month) results
in suppression of pituitary and ovarian hormone production. Studies
involving the GnRH agonist goserelin showed clinical improvement of
cyclical and noncyclical mastalgia in up to 67-81% of cases.3,17 The efficacy
of goserelin was 100% in patients with recurrent mastalgia and 56% in
women who did not respond to prior endocrine treatment with tamoxifen,
danazol or bromocriptine.3 Adverse effects associated with GnRH agonist
use include symptoms of menopause such as hot flashes, headache,
nausea, fatigue, depression, anxiety, irritability, loss of libido and vaginal
dryness.3,7,17 GnRH agonist use is limited to short term courses in cases of
severe refractory mastalgia because long term use of this drug (> 6 months)
can lead to irreversible decline in trabecular bone mineral density.

18
S TAT E M E N T 14: Centchroman at 30 mg daily or Toremifene given at
30 mg daily is an effective endocrine treatment in patients suffering from
mastalgia. (Level I, Grade B)

Supporting Statements:

Centchroman or ormeloxifene is a nonsteroidal anti-estrogen agent that

selectively binds with estrogen receptor in the breast and endometrium.
In a study comparing centchroman (30 mg daily) with danazol (100 mg
daily), the response rate of the centchroman group was 89.7% compared to
69.44% in the danazol group after 12 weeks of treatment. The relapse rate
was lower in the centchroman group with 71.05% of patients (vs. 42.42%)
remaining relieved of mastalgia 3 months after stopping the treatment.18 A
study comparing centchroman (30 mg daily) and tamoxifen (10 mg daily)
revealed both drugs were equally effective in the treatment of mastalgia
with higher frequency of side effects such as dizziness and development of
ovarian cysts in the centchroman group.19

Toremifene, a new member of the family of selective estrogen receptor

modulator (SERM), is a nonsteroidal antiestrogen similar to tamoxifen that
blocks the effects of estrogen in the breast tissue. The therapeutic effect
of toremifen is comparable to that of tamoxifen in treating mastalgia and
has fewer adverse events than tamoxifen. Adverse effects associated with
toremifene include headaches and nausea and unlike tamoxifen there are
no associated increased risk for endometrial cancer. In a study comparing
toremifene to placebo, there was a 64% reduction in median pain scores in
the group given toremifene at 20 mg daily starting at cycle day 15 until next
menstruation versus 26% reduction in the placebo group.20 Toremifene
given at 30 mg daily for 3 cycles was effective in treating patients with
cyclical and noncyclical mastalgia with a response rate of 76.7% and 48.1%,
respectively.21

At present, both centchroman and toremifene are not available in the

Philippines.

A preliminary study on the effect of acupuncture on noncyclical breast pain

showed a 56-67% decrease in mastalgia with the treatment.22 However,
more studies are needed to evaluate the effect of acupuncture on breast
pain.

The following measures are no longer recommended for the treatment of

mastalgia:4,8
Diets low in fat and high in carbohydrate, or low in caffeine.
Evening primrose oil
Progestogen-only contraceptives

19
 Antibiotics
Diuretics
Pyridoxine
Tibolone
Vitamin E

STATEMENT 15: Surgery in the form of mastectomy or partial mastectomy

should not be considered an effective treatment for mastalgia. (Level III,
Grade E)

*Obtained from: Kataria K, Dhar A, Srivastava A, Kumar S, Goyal A. A systematic review of

current understanding and management of mastalgia. Indian J Surg 2014;76(3):217-222.

20
REFERENCES:

1. Goyal A. Breast pain. Clin Evid (Online) 2011. pii: 0812.

2. Scurr J, Hedger W, Morris P, Brown N. The prevalence, severity, and
impact of breast pain in the general population. Breast J 2014;20(5):508-513.
3. Smith RL, Pruthi S, Fitzpatrick LA. Evaluation and management of breast
pain. Mayo Clin Proc 2004;79(3):353-72.
4. The Society of Obstetricians and Gynaecologists of Canada (SOGC)
Guidelines on Mastalgia. J Obstet Gynaecol Can 2006;28(1):49-71.
5. Berek JS, et al (Eds). Berek and Novak’s Gynecology, 15th Ed 2012;
Lippincott Williams and Wilkins.
6. Tavaf-Motamen H, Ader DN, Browne MW, Shriver CD. Clinical evaluation
of mastalgia. Arch Surg 1998;133(2):211-214.
7. Millet AV, Dirbas FM. Clinical management of breast pain: A review. CME
Review Article. Lippincott Wiliams and Wilkins. 2002;57(7).
8. Kataria K, Dhar A, Srivastava A, Kumar S, Goyal A. A systematic review
of current understanding and management of mastalgia. Indian J Surg
2014;76(3):217-222.
9. Joyce DP, Alamiri J, Lowery AJ, Downey E, Ahmed A, et al. Breast clinic
referrals: Can mastalgia be managed in primary care? Irish J Med Science
2014;183(4):639-42.
10. Willett AM, Michell MJ, Lee M Jr. Best practice diagnostic guidelines for
patients presenting with breast symptoms. 2010. Department of Health,
UK
11. American College of Radiology February 2015 Appropriateness Criteria
for Evaluation of Breast Pain.www.acr.org.
12. Barros ACSD, Mottola J, Ruiz CA, Borges MN, Pinotti JA. Reassurance in
the treatment of mastalgia. Breast J 1999;5(3):162-165.
13. Leonardi M. [Hormonal contraception and benign breast disease.
Evaluation of a treatment protocol for chronic mastopathy with mastalgia].
Minerva Ginecol. 1997;49(6):271-6.
14. Vaziri F, Zamani Lari M, Samsami Dehaghani A, Salehi M, Sadeghpour H,
et al. Comparing the effects of dietary flaxseed and omega-3 Fatty acids
supplement on cyclical mastalgia in Iranian women: a randomized clinical
trial. Int J Fam Med Print 2014;174532.
15. Colak T, Ipek T, Kanik A, Ogetman Z, Aydin S. Efficacy of topical
nonsteroidalantiinflammatory drugs in mastalgiatreatment. J Amer Coll
Surgeons 2003;196(4):525-30.
16. Kaviani A, Mehrdad N, Najafi M, Hashemi ES, Yunesian M, et al.
Comparison of naproxen with placebo for the managementof noncyclical
breast pain: A randomized, double-blind, controlled trial. World J Surg
2008;32:2464-2470.
17. Mansel RE, Goyal A, Preece P, Leinster S, Maddox RP, et al. European
randomized, multicenter study of goserelin (Zoladex) in the management
of mastalgia. Am J Obstet Gynecol 2004;191(6): 1942-9.
18. Tejwani PL, Srivastava A, Nerkar H, Dhar A, Hari S, et al. Centchroman
regresses mastalgia: A randomized comparison with danazol. Indian J
Surg 2011;73(3):199-205.

21
19. Jain BK, Bansal A, Choudhary D, Garg PK, Mohanty D. Centchroman vs
tamoxifen for regression of mastalgia: a randomized controlled trial. Int J
Surg 2015;15:11-6.
20. Oksa S, Luukkaala T, Maenpaa J. Toremifene for premenstrual mastalgia:
A randomised, placebo-controlled crossover study. Br J Obstet Gynecol
2006;713-718.
21. Gong C, Song E, Jia W, Qin L, Guo J, et al. A Double-blind randomized
controlled trial of toremifen therapy for mastalgia. Arch Surg
2006;141:43-47.
22. Thicke LA, Hazelton JK, Bauer BA, Chan CW, Huntoon EA, et al.
Acupuncture for treatment of noncyclic breast pain: A pilot study. Am J
Chinese Med 2011;39(6):1117-1129.

22
 GALACTORRHEA
Debby Pacquing-Songco, MD

INTRODUCTION

Galactorrhea refers to inappropriate mammary secretion of milky discharge

not immediately related to pregnancy or the needs of a child.1 Bilateral
milky nipple discharge is appropriate only during pregnancy and lactation
and can last up to one year after delivery or after breastfeeding has stopped.2

Isolated or idiopathic galactorrhea is seen in women with normal menses

and normal serum prolactin levels. It has been estimated to occur in up
to 20% of women at some point in their lives and is rarely associated with
malignancy.3,4

CAUSES

S TAT E M E N T 1: When galactorrhea is accompanied by amenorrhea, it

is usually caused by hyperprolactinemia. However, in the presence of
regular ovulatory menses, prolactin is usually normal.5 (Level III, Grade C)

Supporting Statements:

In mammals, the main function of prolactin is lactogenesis. Pituitary

secretion of prolactin is chiefly, if not totally, under the inhibitory control of
hypothalamic dopamine released into the portal circulation, a tonic inhibition
that requires a high output of dopamine.1 Factors that impair dopamine
secretion (excessive nipple stimulation, chest irritation, medications, stalk
effect, estrogen, hypothyroidism) or decreased renal clearance of prolactin
cause hyperprolactinemia.2,6-9

The diagnosis of hyperprolactinemia is made when prolactin level goes

above the upper standard normal limit of 20-25 ng/mL (400-500 mIU/L)
provided that the sample was obtained without excessive venipuncture
sites.10

In women who are hyperprolactinemic, the prevalence of galactorrhea is

25%. Hyperprolactinemia is found in 1/3 of women with amenorrhea, and
in 75% of women who have both amenorrhea and galactorrhea.11

23
STATEMENT 2: The causes of galactorrhea may be physiologic or
pathologic. (Level III, Grade C)

Supporting Statement:

Physiologic galactorrhea may be due pregnancy, excessive manipulation

of the breast or any chest wall disturbance. Nonphysiologic or pathologic
causes of galactorrhea are due to hypothalamic or pituitary lesions, while
some may be brought about by systemic disorders (Table 1).11

Table 1, Causes of Galactorrhea12

Table 1. Causes of Galactorrhea12
HYPERPROLACTINEMIC Lesions involving chest wall
GALACTORRHEA Breast surgery
Burns
Physiologic Herpes zoster
Nipple or breast manipulation
Pregnancy Spinal cord injury
Trauma
Pathologic
Hypothalamic or infundibular lesions Systemic disease
Tumors Hypothyroidism
Craniopharyngioma Renal insufficiency
Germinoma Medication-induced
Meningioma hyperprolactinemia
Infiltrative disorders
Histiocytosis Idiopathic hyperprolactinemia
Sarcoidosis
Others
Rathke’s cleft cysts NORMOPROLACTINEMIC
GALACTORRHEA
Pituitary lesions
Prolactinoma
Acromegaly
Others

Statement 3:
STATEMENT Pituitaryadenoma
3: Pituitary adenoma is oneisof the
onemost
of frequent
the most frequent
causes of c
hyperprolactinemia.
hyperprolactinemia. (Level
(Level III, Grade
III, Grade C) C)

Supporting
Supporting Statements:
Statements:

Prolactinomas
Prolactinomas areare themost
the mostcommon
common functioning
functioning pituitary
pituitarytumor
tumorand accounts f
and
proportion
accounts for aof high
hyperprolactinemia due to prolactin overproduction
proportion of hyperprolactinemia and overs
due to prolactin
Nonfunctioning pituitary adenoma is another etiology of hyperprolactinemia,
induced by compression of the 24 pituitary stalk. Ninety percent (90%) are i
adenomas that rarely increase in size. The rest are macroadenomas (> 10
usually come to clinical attention because of local mass effects. In wom
overproduction and oversecretion. Nonfunctioning pituitary adenoma is
another etiology of hyperprolactinemia, which is induced by compression of
the pituitary stalk. Ninety percent (90%) are intrasellar adenomas that rarely
increase in size. The rest are macroadenomas (> 10 mm) that usually come to
clinical attention because of local mass effects. In women, most prolactinomas
are microadenomas (< 10 mm), and hypersecretion of prolactin leads to
amenorrhea, infertility and galactorrhea.13,14

EVALUATION

STATEMENT 4: A good history and physical examination should be

done to elicit possible causes of galactorrhea.15 (Level III, Grade C)

Supporting Statements:

Questions regarding associated symptoms such as oligomenorrhea or

amenorrhea, decreased libido, infertility, headache, visual disturbance, or
signs pointing to a hypo- or hyperthyroid state should be asked.15,16

There
Thereshould
shouldbebea review
a reviewof drug intakeintake
of drug (Table (Table
2), precipitating factors factor
2), precipitating
(breast stimulation, suckling, sexual intercourse), significant chest surgery,
stimulation, suckling, sexual intercourse), significant chest surgery, past illnesse
past illnesses
thyroid such as
disorders, asthyroid
well asdisorders, as well as
a family history of amultiple
family history of multiple
endocrine neoplasia type
endocrine neoplasia type I. 15,17

Opiate abuse and the use of some illicit drugs (e.g. cocaine and marijuana)
Opiate abuse
possible and the
causes use of some illicit drugs
of hyperprolactinemia. (e.g.
This cocaine and
information is marijuana)
usually omitted b
are also possible causes of hyperprolactinemia.
during history taking and should be asked. 18 This information is usually
omitted by patients during history taking and should be asked.18
Physical examination should include a general survey of the patient’
Physical examination
development, should
as poor include
growth maya general survey
indicate of the patient’s
hypopituitarism, growth
hypothyroidism o
development, as poor
renal failure and thatgrowth mayor
gigantism indicate hypopituitarism,
acromegaly may point hypothyroidism
to a pituitary lesion/tum

Table 2. Medications That Cause Hyperprolactinemia36

Antipsychotics (neuroleptics) Opiates and cocaine
Phenothiazines Antihypertensive medications
Thioxanthenes Verapamil
Butyrophenones Methyldopa
Atypical antipsychotics Reserpine
Antidepressants Gastrointestinal medications
Tricyclic and tetracyclic antidepressants Metoclopramide
Monoamine oxidase inhibitors Domperidone
Selective serotonin reuptake inhibitors Histamine 2 receptor blockers?
Other Protease inhibitors?
Estrogens

Statement 5: Breast examination

25is vital in the evaluation of galactorrhea.
Grade C)
or chronic renal failure and that gigantism or acromegaly may point to a
pituitary lesion/tumor.15

STATEMENT 5: Breast examination is vital in the evaluation of

galactorrhea. (Level III, Grade C)

Supporting Statements:

Pathologic nipple discharge arising from breast tumors should be

differentiated from galactorrhea. Galactorrhea usually appears white or
clear, but may be yellow or even green. It is usually spontaneous rather than
provoked, bilateral and multiductal.19,20

The patient should be examined sitting up and leaning forward. The areolae
should be gently mas­saged toward the nipple in all four quad­rants. Attention
to the presence of palpable masses should be taken in order to rule out a
pathologic breast mass.

It is important to take note that breast and nipple manipulation can transiently
increase prolactin secretion, so prolactin levels should not be checked shortly
after a breast examination.12

If the diagnosis of milk production is in doubt, a Sudan IV staining for fat

droplets in the nipple dis­charge can confirm the diagnosis.12

STATEMENT 6: A pregnancy test should always be done in patients

presenting with galactorrhea. (Level III, Grade C)

Supporting Statements:

Pregnancy and breastfeeding are the most common causes of physiologic

hyperprolactinemia. Rising estrogen concentrations during pregnancy causes
a progressive increase of prolactin levels to around 200-500 ng/mL.10

Pregnant women may lactate as early as the second trimester and may
continue to produce milk for up to two years after cessation of breastfeeding.11

STATEMENT 7: A single serum prolactin determination is recommended

to establish hyperprolactinemia.21 (Level I, Grade A)

Supporting Statements:

A single determination is usually sufficient to establish the diagnosis, but

when in doubt, sampling can be repeated on a different day at 15- to 20-min
intervals to account for possible prolactin pulsatility.22,23

26
In order to avoid false elevations of prolactin, samples must be taken on a
fasting state, preferably drawn in the morning, two hours upon waking.
There should not have been breast stimulation; excessive exercise and
multiple venipuncture sites should be avoided.24

A normal random prolactin measurement <15-20 ng/mL excludes hyper-

prolactinemia.1

A prolactin level > 500 ng/mL is diagnostic of a macroprolactinoma.25

Although a prolactin level > 250 ng/mL usually indicates the presence of a
prolactinoma, selected drugs, including risperidone and metoclopramide,
may cause prolactin elevations above 200 ng/mL in patients without
evidence of adenoma.

S TAT E M E N T 8: If prolactin level is elevated, thyroid stimulating

hormone (TSH) as well as creatinine levels should be obtained. (Level I,
Grade A)

Supporting Statements:

Secondary causes of hyperprolactinemia should be ruled out such as

hypothyroidism and chronic renal disease.15,26

The prevalence of hyperprolactinemia in patients with primary

hypothyroidism has been reported to be as high as 40%, however the
clinical significance and prevalence in subclinical hypothyroidism is still
unknown based on few studies and case reports.27 Primary hypothyroidism
may result in pituitary hyperplasia and diffuse pituitary enlargement that
could lead to misdiagnosis of prolactinoma or pseudoprolactinoma.10

In chronic kidney disease, hyperprolactinemia occurs with a prevalence

ranging from 30-65% primarily due to reduced prolactin clearance and
increased production.28 In an observational study done by Carrero, et al.29
among 457 nondialyzed chronic kidney disease patients (mean age 52 ± 12
years; 229 men) with measurements of flow-mediated dilation (FMD) and
carotid intima-media thickness and one with 173 hemodialysis patients (65
± 12 years; 111 men) with measurements of pulse wave velocity (PWV);
with patients followed for cardiovascular events (n=146, nondialyzed
cohort) or death (n=79, hemodialysis cohort), results showed that
prolactin levels increased along with reduced kidney function. Prolactin
significantly and independently contributed to explain the variance of both
FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but
not intima-media thickness. In Cox analyses, the risk of cardiovascular
events in nondialyzed patients increased by 27% (hazard ratio [HR] 1.27,

27
95% confidence interval [95% CI] 1.17-1.38) for each 10 ng/mL increments
of prolactin.

STATEMENT 9: In patients presenting with galactorrhea and signs of

hypogonadism, reproductive hormonal assays should be checked. (Level III,
Grade C)

Supporting Statements:

Increased prolactin levels inhibit the pulsatile secretion of gonadotropin

releasing hormone (GnRH), alters the pattern of release of luteinizing hormone
(LH) and follicle-stimulating hormone (FSH), and suppresses gonadal
steroidogenesis, thereby resulting in hypogonadotropic hypogonadism
in both males and females. This results in anovulation, amenorrhea, and
vaginal dryness in women, erectile dysfunction in men, and decreased libido,
infertility and osteopenia in both sexes. Reproductive hormones such as
estrogen or testosterone, LH and FSH should be checked.30

STATEMENT 10: If prolactin level is not elevated, then no further

evaluation (i.e. additional hormone testing and magnetic resonance
imaging [MRI]) is needed.4 (Level III, Grade C)

Supporting Statements:

Isolated galactorrhea, with normal menstrual cycle and normal serum

prolactin levels, has been estimated to occur in up to 20% of women, further
evaluation therefore is unnecessary unless galactorrhea is associated with
infertility, hypogonadism and bone loss.31

STATEMENT 11: If no other cause of hyperprolactinemia is found after

history, physical examination and routine testing with MRI to rule out a
pituitary mass is warranted. (Level I, Grade A)

Supporting Statements:

A meticulous history and physical examination can be able to detect the causes
of hyperprolactinemia, further routine testing will help support the diagnosis.
However, despite best efforts and still no cause of hyperprolactinemia
is identified, an MRI with specific pituitary cuts and contract should be
performed.4,21

Computed tomography (CT) scanning and especially MRI can visualize

all macroprolactinomas and pseudoprolactinomas, as well as most
microprolactinomas.10

28
A retrospective study done by Bayrak in 2004 regarding indication for doing
a pituitary imaging in patients with hyperprolactinemia revealed that of
the 86 patients who had pituitary imaging, 23 (26%) had normal findings
and 63 (74%) had pituitary tumor; of these, 47 (55% of total imaged) had
microadenomas and 16 (19% of total imaged) had macroadenomas. There
was a statistically significant association between tumor size and prolactin
level. However, 11% of the patients with microadenomas had prolactin levels
> 200 ng/mL and 44% of the patients with macroadenomas had prolactin
levels between 25-200 ng/mL.32

TREATMENT

STATEMENT 12: In patients presenting with galactorrhea and normal

serum prolactin levels, no further treatment is required unless galactorrhea
is bothersome or is associated with infertility, hypogonadism or bone loss.
(Level III, Grade C)

Supporting Statement:

Most cases of galactorrhea are associated with hyperprolactinemia. However,

in 20% of cases galactorrhea may be idiopathic. In such cases, reassurance and
monitoring can be given to the patient and that treatment using dopamine
agonists be offered in those with bothersome galactorrhea only.4,15 In patients
who present with infertility, hypogonadism or bone loss, such concerns
should be addressed accordingly.31

STATEMENT 13: Medication-induced hyperprolactinemia is treated by

withdrawal of inciting drug if clinically feasible or shifting it to a similar
class that will not cause elevations in prolactin levels. (Level I, Grade B)

Supporting Statements:

The most frequent cause of nontumoral hyperprolactinemia is medications.

The most common inciting drugs are neuroleptics and antipsychotics (i.e.
risperidone, phenothiazines). Its occurrence ranges from 42-89%.33 The
withdrawal of the drug for at least 3 days will decrease prolactin levels
to normal.34 However, if withdrawal of the drug is not feasible, cautious
administration with a dopamine agonist in consultation with the patient’s
physician should be made as exacerbations of psychosis may occur in some
patients.21 An ongoing study, the DAAMSEL (Dopamine Partial Agonist,
Aripiprazole, for the Management of Symptomatic Elevated Prolactin) Study,
is a 4-year study with a target enrollment of 50 women with schizophrenia
treated with risperidone, paliperidone or First-Generation Antipsychotics
(FGAs) and with elevated prolactin and sexual side effects (menstrual

29
abnormalities or galactorrhea) at baseline. Aripiprazole can significantly
improve hyperprolactinemia and related side effects as an adjunct to
haloperidol in people with schizophrenia. Furthermore, aripiprazole added
to dopamine-raising antipsychotics can decrease prolactin levels and lead to
women regaining their menstrual periods.35 However, this drug is still under
investigation and is not available locally.

If substitution of existing medication is not feasible, then the patient should

undergo MRI of the hypothalamic/pituitary area or, if MRI is unavailable,
CT. It is much more important to exclude large mass lesions in such a patient
rather than to establish the presence of a microadenoma.36

STATEMENT 14: Hypothyroidism associated with hyperprolactinemia

should be treated with L-thyroxine. (Level III, Grade C)

Supporting Statements:

Long-term or inadequately treated primary hypothyroidism can cause

pituitary hyperplasia that may mimic a pituitary tumor. Hyperprolactinemia
and enlargement of the pituitary gland due to thyroid failure can be reversed
by treatment with L-thyroxine, which may also decrease thyroid releasing
hormone (TRH) drive.37

STATEMENT 15: Dopamine agonist is first line treatment in patients

with hyperprolactinemic disorders. (Level I, Grade A)

Supporting Statements:

Dopamine agonists act by binding to dopamine receptors and act as

functional analogues of the naturally occurring prolactin inhibiting factor,
thereby lowering prolactin secretion as seen in-vivo and in-vitro studies,
as well as suppression of tumor size in animal studies and restoration of
gonadal function for patients harboring symptomatic prolactin-secreting
microadenomas or macroadenomas.38

The greatest experience has been gained with the semi-synthetic ergot
alkaloid bromocriptine, 2-brom-α-ergocryptine. This drug was developed
specifically to inhibit prolactin secretion and does not have the oxytocic and
cardiovascular effects of the parent compound. It usually causes a rapid fall
of prolactin levels to normal.

Bromocriptine (2.5-15 mg daily) normalizes prolactin and decreases

tumor size in 80-90% of patients with microadenomas and in 70% with
large tumors.39 The common side effects of bromocriptine include nausea,

30
vomiting, and orthostatic hypotension. To avoid side effects the starting
dose of bromocriptine should be low and taken at bedtime. Usually 1.25 or
2.5 mg is taken for three days and this is increased by 1.25 or 2.5 mg every
three or four days in divided doses until the usually effective dose of 7.5
mg is attained. Another alternative is to use bromocriptine by intravaginal
administration.

The selective D2 receptor agonist cabergoline (0.25-1 mg twice weekly or 0.5-

2 mg once weekly) is more effective and better tolerated than bromocriptine
and is also effective in treatment of tumors resistant to other dopamine
agonists.

Withdrawal of cabergoline therapy because of adverse events is reported

in less than 3% of patients, compared with about 12% of patients treated
with bromocriptine. Of concern, however, are recent reports describing the
occurrence of valvular insufficiency in patients treated with cabergoline for
Parkinson’s disease. These studies showed that the use of cabergoline in
patients with Parkinson’s disease is associated with an approximately 5-fold
increased risk of newly diagnosed cardiac valve regurgitation.40 However,
such drug is not available locally.

The major shortcoming of therapy with both Dopamine agonists is that

cessation of therapy leads to recurrence of hyperprolactinemia and tumor
re-expansion.41 Pituitary surgery does not reliably lead to a cure, and a
dopamine agonist is the preferred treatment for prolactinomas.

MONITORING PROLACTIN LEVELS

STATEMENT 16: In patients where dopamine agonist therapy has been

started, serial monitoring assesses response. (Level II-3, Grade B)

Supporting Statements:

In order to assess a patient’s response to treatment, follow-up should include

the following:
Serum prolactin Start one month after initial treatment to
guide for treatment intensification.
Once prolactin levels have reached normal
or near normal, every 3-6 months for the first
year and then every 6-12 months thereafter.
MRI Repeat annually

31
 Repeat every three months in patients who:
1. Have macroprolactinoma
2. If prolactin continue to rise while on
dopamine agonist therapy
3. Occurrence of new symptoms
(e.g. visual disturbance, headaches
or other hormonal disorders)
Visual field examination In patients with macroadenomas

The goals of treatment are to normalize prolactin levels or at least bring

them to levels at which gonadal, reproductive or sexual function has been
normalized as well as to decrease tumor size. Over 90% of patients treated
with dopamine agonists will reach these prolactin goals and a lesser number
will achieve significant tumor size reduction.21,30

Therapy may be tapered and even discontinued in patients who have been
treated with dopamine agonist for at least 2 years, or those who have achieved
normal prolactin levels or no remnant of tumor as evidenced by MRI provided
that clinicians be guided by clinical and biochemical monitoring.21 The risk of
recurrence after treatment withdrawal ranges from 26-69%.42

In women on long-term treatment, medication should be discontinued

periodically to determine whether hyperprolactinemia is in remission.
Suggested intervals range from 1 to 5 years; a trial every 2 years or so
seems reasonable. If it is, particularly if the tumor has shrunk, treatment
can be suspended and the patient kept under surveillance. Treatment can be
reinstituted if hyperprolactinemia recurs.43

STATEMENT 17: Symptomatic patients who have not attained normal

serum prolactin levels or did not show significant reduction in tumor size
despite institution of maximum tolerable doses of dopamine agonists
should be referred for surgical management. (Level III, Grade B)

Majority of patients with prolactinomas treated with standard doses of

dopamine agonists respond with normalization of prolactin levels and a
reduction in tumor size. Surgery is indicated in patients who cannot tolerate
medications, have tumors that are resistant to medication or experience rapid
visual loss that does not respond to medical therapy. Unfortunately, long term
surgical cure rates for prolactinomas are poor (50-60% for microadenomas
and 25% for macroadenomas).21

32
Resistance to dopamine agonists can be defined as a failure to achieve
normalization of prolactin levels or no reduction in tumor size after 12-24
months of bromocriptine 15 mg/day or cabergoline 0.5 mg/day; most cases
of resistance to dopamine agonists can be considered partial resistance.
Approximately 24% and 11% of patients demonstrate resistance to
bromocriptine and cabergoline, respectively.40

REFERENCES:

1. Fritz M, Speroff L. Clinical Gynecologic Endocrinology and Infertility 8th

edition. 2011
2. Mazzarelo S. Nipple discharge. CMAJ 2015;187(8).
3. Eastman RC. Acromegaly, hyperprolactinemia, gonadotropin-secreting
tumors, and hypopituitarism. In: Moore WT, Eastman RC (Eds).
Diagnostic Endocrinology. 1990;33-56.
4. Pena KS, Rosenfeld J. Evaluation and treatment of galactorrhea. Am Fam
Physician 2001;63(9):1763-70.
5. Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin
North Am. 2001;30(3):585-610.
6. Santen RJ, Mansel R. Benign breast disorders. N Engl J Med 2005;353(3):275-
285.
7. Vaidyanathan L, Barnard K, Elnicki DM. Benign breast disease: when to
treat, when to reassure, when to refer. Cleve Clin J Med 2002;69(5):425-
432.
8. Melmed S, Kleinberg DL. Anterior pituitary. In: Kronen­berg H, Williams
RH (Eds). Williams Textbook of Endo­crinology. 11th ed. Philadelphia, Pa:
Elsevier Saunders; 2007:155-262.
9. Verhelst J, Abs R. Hyperprolactinemia: pathophysiology and management.
Treat Endocrinol 2003;2(1):23-32.
10. Vilar L, et al. Challenges and pitfalls in the diagnosis of hyperprolactinemia.
Arq Bras Endocrinol Metab 2014;58(1).
11. Schlechte J, Sherman B, Halmi N, et al. Prolactin secreting pituitary
tumours in amenorrheic women: a comprehensive study. Endocr Rev.
1980;1:295-308.
12. Huang W, Molitch, M. Evaluation and management of galactorrhea. Am
Fam Physician 2012;85(11):1073-1080.
13. Schlete J. Approach to the patient: Long term management of
prolactinomas. J Clin Endocrinol Metab 2007;92(8):2861-2865.
14. Tomohiro K. et al. Diagnostic pitfalls of hyperprolactinemia: the
importance of sequential pituitary imaging. BMC Research Notes
2014;7:555.
15. Leung A, Pacaud D. Diagnosis and management of galactorrhea. Am Fam
Physician 2004;70:543-50,553-4.
16. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med
1999;44(12 Suppl):1085-90.
17. Benjamin F. Normal lactation and galactorrhea. Clin Obstet Gynecol
1994;37:887-97.

33
18. Teoh SK, Lex BW, Mendelson JH, Mello NK, Cochin J. Hyperprolactinemia
and macrocytosis in women with alcohol and polysubstance dependence.
J Stud Alcohol 1992;53(2):176-82.
19. Leis H. Management of nipple discharge. World J Surgery 1989;13:736-742.
20. Falkenberry S. Nipple discharge. Obstet Gynecol Clin North Am
2002;29(1).
21. The Endocrine Society’s Clinical Guidelines on the Diagnosis and
Management of Hyperprolactinemia. J Clin Endocrinol Metab 2011;96:273-
288.
22. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, et al. 2006
Guidelines of the Pituitary Society for the diagnosis and management of
prolactinomas. Clin Endocrinol (Oxf) 2006;65:265-273.
23. Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and
prolactinomas. Endocrinol Metab Clin North Am 2008;37:67-99.
24. Majumdar A, Mangal N. Hyperprolactinemia. J Hum Reprod Sci 2013;6(3).
25. Vilar L, Freitas MC, Naves LA, Casulari LA, Azevedo M, et al. Diagnosis
and management of hyperprolactinemia: results of a Brazilian multicenter
study with 1234 patients. J Endocrinol Invest 2008;31:436-444.
26. Meisner A, Fekrazad MH, Royce ME. Breast disease: Benign and
malignant. Med Clin North Am 2008;92:1115-1141.
27. Paroul G, et al. Evaluation of serum prolactin level in patients of subclinical
and overt hypothyroidism. J Clin Diagnostic Res 2015;9(1).
28. Hou SH, Grossman S, Molitch ME. Hyperprolactinemia in patients with
renal insufficiency and chronic renal failure requiring hemodialysis or
chronic ambulatory peritoneal dialysis. Am J Kidney Dis 1985;6:245-249.
29. Carrero J. et al. Prolactin levels, endothelial dysfunction, and the risk of
cardiovascular events and mortality in patients with CKD. Clin J Am Soc
Nephrol 2012;7:207-215.
30. Molitch ME. Prolactinoma management. Endotext Internet NCBI
Bookshelf 2015
31. Agarwat M, et al. Hyperprolactinemia with normal serum prolactin: Its
clinical significance. J Hum Reprod Sci 2010;3(2):111-112.
32. Bayrak A, Peyman S, et al. Pituitary imaging is indicated for the evaluation
of hyperprolactinemia. Fertil Steril 2005;84(1).
33. Meng M, et al. Using aripiprazole to reduce antipsychotic-induced
hyperprolactinemia: metaanalysis of currently available randomized
controlled trials. Shanghai Arch Psychiatry 2015;27(1).
34. Pollock A, McLaren EH. Serum prolactin concentration in patients taking
neuroleptic drugs. Clin Endocrinol (Oxf) 1998;49:513-516.
35. Kelly D. et al. Treating symptomatic hyperprolactinemia in women
with schizophrenia: presentation of the ongoing DAAMSEL clinical
trial (Dopamine Partial Agonist, Aripiprazole, for the Management of
Symptomatic ELevated prolactin). BMC Psychiatry 2013;13:214.
36. Molitch M. Medication-induced hyperprolactinemia. Mayo Clin Proc
2005;80(8):1050-1057.
37. Ahmed M, Banna M, Sakati N. Pituitary gland enlargement in primary
hypothyroidism: a report of 5 cases with follow-up data. Horm Res
1989;32:188-192.
38. Thorner MO. Disorders of prolactin secretion. J Clin Path 30 Suppl 7:36-41.

34
39. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Change RJ, et al.
Bromocriptine as primary therapy for prolactin-secreting macroadenomas:
results of a prospective multicenter study. J Clin Endocrinol Metab
1985;60:698-705.
40. Biller MK, et al. Prolactinomas, Cushing’s disease and acromegaly:
debating the role of medical therapy for secretory pituitary adenomas.
BMC Endocrine Disorders 2010;10:10.
41. Nunes V, et al. Cabergoline versus bromocriptine in the treatment of
hyperprolactinemia: a systematic review of randomized controlled trials
and meta-analysis. Pituitary 2011;14:259-265.
42. Biswas M, Smith J, Jadon D, McEwan P, Rees DA, et al. Long-term
remission following withdrawal of dopamine agonist therapy in subjects
with microprolactinomas. Clin Endocrinol (Oxf) 2005;63:26-31.
43. Yuen B. Hyperprolactinemia in women of reproductive age. Canadian
Fam Physician 1992;38.

35
 BREAST CANCER PREVENTION
Ana Victoria V. Dy Echo, MD

INTRODUCTION

In the Philippines, breast cancer is the most common cancer for both sexes
combined (15%), as well as for women (28%). In 2010, an estimated 12,262
new cases are diagnosed, with an associated 4,371 deaths.1

Age is the most important risk factor. The incidence of breast cancer increases
with age, with a significant rise noted by age 30.1

Aside from age, prolonged and sustained exposure to estrogen increases

a woman’s risk for breast cancer. Breast cancer is common among women
with early menarche and/or late menopause, those who never had children,
those with first pregnancy beyond 30 years of age, and those given hormone
replacement therapy (HRT).1

Women considered at HIGH RISK for breast cancer include those with
BRCA1/2 gene mutation (or with a first-degree relative with BRCA1/2
gene mutation), with a strong family history of breast cancer (mother/sister
diagnosed with breast cancer at < 45 years old), personal history of breast
cancer or atypical hyperplasia, radiation treatment to the chest before age
30, and Li-Fraumeni syndrome, Cowden syndrome or Bannayan-Riley-
Ruvalcaba syndrome.

Women without these identified factors are considered at AVERAGE RISK

for breast cancer.

RECOMMENDATIONS

I. PRIMARY PREVENTION

STATEMENT 1: Physical activity and weight management may reduce

the risk of postmenopausal breast cancer. (Level II-3, Grade B)

Supporting Statements:

Moderate to vigorous-intensity physical activity for 4-7 hours per week is

associated with a 15-20% reduction of risk for breast cancer among women.2,3

36
A dose-response relationship is observed, showing a 6% decrease in
breast cancer risk for each additional hour of physical activity per week.1
Epidemiological studies have shown that the risk reduction is even greater
(30% risk reduction) among postmenopausal women.2

Weight management also has an impact on breast cancer prevention among

postmenopausal women. The study by Elaissan, et al. showed that for
women who lost 10 kg or more since menopause, and those who kept
the weight off were at lower risk for breast cancer (relative risk [RR] 0.43,
95% confidence interval [CI] 0.21-0.86, p= 0.01) compared to those who
maintained their weights.4 Similarly, Trentham-Dietz, et al. noted that
among women who reached their highest adult weight before 45 years,
losing weight was associated with a reduced risk of postmenopausal breast
cancer (odds ratio [OR] 0.9, CI 0.84-0.98, per 5 kg). This reduced risk,
however, was not observed for women who achieved their highest weight
after the age of 45 (OR 1.08, 95% CI 1.06-1.11).5

S TAT E M E N T 2: There is some evidence to suggest that dietary

intervention
may reduce a woman’s risk for breast cancer. (Level II-1, Grade C)

Supporting Statements:

The Women’s Health Initiative (WHI) study evaluated the impact of

decreased fat intake and increased intake of fruits and vegetables on breast
cancer risk. The study noted a small but insignificant (9%) decrease in
breast cancer risk among postmenopausal women advised low dietary fat
and high fruits and vegetables intake. This improvement was observed
only among those who had high fat intake at baseline.6

The randomized controlled trial (RCT) by Lappe, et al. noted that giving
vitamin D supplementation at a dose of 1,100 IU/day coupled with calcium
significantly reduces breast cancer risk (RR 0.23) among postmenopausal.7
High intake of soya (> 20 mg isoflavones/day) was also noted to be associated
with lowest risk for breast cancer (OR 0.71, 95% CI 0.6-0.85), compared to
those with very low soy food intake (< 5 mg isoflavanes/day).8

Different societies provide dietary guidelines, which appears to be beneficial

in reducing breast cancer risk. Among these, adherence to the American
Cancer Society (ACS) and World Cancer Research Fund/American Institute
for Cancer Research (WCRF/AICR) dietary/lifestyle guidelines was shown
to decrease breast cancer risk by 22% (after 12.6 years follow-up)9 to 31%10,
as reported in 2 different studies.

37
STAT E M E N T 3: Avoiding identified risk factors, such as smoking and
alcohol intake, may reduce one’s risk for breast cancer. (Level II-1, Grade A)
Supporting Statements:

Smoking is associated with increased risk for breast cancer. Among

premenopausal women, an incidence rate ratio (IRR) of 1.21 (95% CI 0.09-
1.62) was noted. The risk was even higher for women who started smoking
before age 18 with an accumulated > 20 pack years (IRR 1.7, 95% CI 1.05-2.75).
Passive smokers likewise demonstrate increased risk for premenopausal
breast cancer (IRR 1.42, 95% CI 1.09-1.85).11 For postmenopausal women, a
modest increase in breast cancer risk was seen among current (HR 1.19, 95%
CI 1.10-1.28) and former hazards ratio (HR 1.07, 95% CI 1.01-1.13) smokers.
The association of smoking to breast cancer development was stronger among
women without a family history of breast cancer (HR 1.24, 95% CI 1.15-1.35
vs. HR 0.94, 95% CI 0.78-1.13).12

Alcohol intake is the only dietary factor established to be associated with

increased risk for breast cancer. A meta-analysis of observational studies has
shown that postmenopausal women who drink alcohol had a 22% (95% CI
9%-37%) higher risk of breast cancer compared to those who do not drink
alcohol; with each additional 10 g alcohol per day increasing breast cancer
risk by 10% (95% CI 5%-15%).13

STATEMENT 4: For women at high risk for breast cancer, the use of
selective estrogen receptor modulators (SERMs) decreases the risk of breast
cancer development. (Level I, Grade A)

Supporting Statements:

The SERM tamoxifen is the first U.S. Food and Drug Administration (FDA)-
approved agent for reducing breast cancer risk but did not gain wide
acceptance for prevention, largely because it increased endometrial cancer and
thromboembolic events. The FDA approved the SERM raloxifene for breast
cancer risk reduction following its demonstrated effectiveness in preventing
invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR).
Raloxifene caused less toxicity, including reduced thromboembolic events
and endometrial cancer. A meta-analysis of 9 trials (83,399 participants) has
shown that the use of SERMs resulted in a 38% (p < 0.0001) overall reduction
in incidence of all breast cancers, with an estimated 10 year cumulative
incidence of 6.3% in the control group and 4.2% in the SERMs group. The
risk reduction capacity was larger during the first 5 years of follow-up (42%,
HR 0.58, 95% CI 0.51-0.66, p < 0.0001) than in 5-10 years (25%, HR 0.75, 95%
CI 0.61-0.93, p = 0.007).14

An updated analysis in an effort to better understand how tamoxifen and

raloxifene differ, particularly in regard to their relative effects on noninvasive

38
disease, was reported. STAR eligibility criteria included postmenopausal
status and 5-year breast cancer risk of at least 1.66% (actual mean risk was
4.03%). STAR women were randomly assigned to receive either tamoxifen
(20 mg/d) or raloxifene (60 mg/d) for 5 years. Of the originally randomized
19,747 women, 19,490 participated in the STAR follow-up was described
in the updated report. The risk ratio (RR; raloxifene:tamoxifen) for
invasive breast cancer was 1.24 (95% CI, 1.05– 1.47) and for noninvasive
disease was 1.22 (95% CI, 0.95–1.59). Compared with the initial results, the
RRs widened for invasive and narrowed for noninvasive breast cancer.
Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36–0.83; P = 0.003)
for endometrial cancer (this difference was not significant in the initial
results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI,
0.60–0.93) for thromboembolic events. There were no significant mortality
differences. Long-term, raloxifene retained 76% of the effectiveness of
tamoxifen in preventing invasive disease and grew closer over time to
tamoxifen in preventing noninvasive disease, with far less toxicity (e.g.,
highly significantly less endometrial cancer). These results have important
public health implications and clarify that both raloxifene and tamoxifen
are good preventive choices for postmenopausal women with elevated
risk for breast cancer. These updated data should encourage widespread
acceptance of raloxifene and a greater acceptance of tamoxifen for breast
cancer risk reduction. 15

STATEMENT 5: For women diagnosed with breast cancer, aromatase

inhibitors (AIs) may be given to prevent breast cancer relapse. (Level II-2,
Grade B)

Supporting Statements:

Anastrazole was evaluated among postmenopausal women at increased risk

for breast cancer. The International Breast Cancer Intervention Study (IBIS)
II study showed that anastrozole 1 mg/day reduced breast cancer incidence
by 53% (HR 0.47, 95% CI 0.32-0.68).16

AIs have the advantage over SERMs in that they are not associated with
increased risk of thromboembolic disease and uterine problems. AIs, however,
are associated with increase to moderate bone/muscle pain and reduced bone
density.17

STATEMENT 6: Prophylactic oophorectomy for BRCA gene mutation

carriers decreases the risk of breast cancer. (Level II-2, Grade B)

Supporting Statements:

Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2

mutation carriers who had undergone risk reducing salpingo-oophorectomy

39
(RRSO). Breast cancer outcomes were investigated in 3 nonoverlapping
studies of BRCA1/2 mutation carriers, 4 of BRCA1 mutation carriers, and 3 of
BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated
in 3 nonoverlapping studies of BRCA1/2 mutation carriers and 1 of BRCA1
mutation carriers. RRSO was associated with a statistically significant
reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR 0.49,
95% CI 0.37-0.65). Similar risk reductions were observed in BRCA1 mutation
carriers (HR 0.47, 95% CI 0.35-0.64) and in BRCA2 mutation carriers (HR 0.47,
95% CI 0.26-0.84). RRSO was also associated with a statistically significant
reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer
(HR 0.21, 95% CI 0.12-0.39). Data were insufficient to obtain separate estimates
for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or
BRCA2 mutation carriers.18

STATEMENT 7: Bilateral prophylactic mastectomy for BRCA gene

mutation carriers, and contralateral prophylactic mastectomy for those with
breast cancer in one breast, may reduce breast cancer risk. (Level I, Grade B)

Supporting Statements:

A systematic review, which included 39 observational studies, 7,384 women,

noted that bilateral prophylactic mastectomy resulted in reduced incidence
of breast cancer and/or disease-specific mortality among BRCA 1/2 gene
mutation carriers. For women diagnosed with breast cancer on one breast,
contralateral prophylactic mastectomy resulted in decreased incidence of
breast cancer but no definite improvement in disease-specific survival.19

B. SECONDARY PREVENTION

STATEMENT 1: There is insufficient evidence to recommend for or

against routine Clinical Breast Examination (CBE) as the primary screening
modality for breast cancer. (Level II-3, Grade A)

Supporting Statements:

Humphrey, et al. has shown that CBE has a sensitivity of 40-69% and a
specificity of 88-99%.20 The lower specificity as compared to a mammography
may result in further work-ups subjecting women to additional imaging
studies and biopsy. In a local study by Pisani, et al., of the 138,392 women
examined, 3,479 had abnormal CBE and 1,220 completed additional diagnostic
work-ups. However, among these women, only 34 (3%) had cancer, 563
(46%) had no detectable abnormalities, and 623 (51%) had biopsy results that
were benign.21

40
Although the benefit of CBE as a screening modality may not be as
evident in countries which widely practiced screening mammography,
CBE as a primary screening approach may have its benefit in countries
without mammography screening programs and with limited healthcare
resources. In the Cairo Breast Screening Trial (CBST), out of 4,116 women
invited to attend the Primary Health Center for CBE, high rates of breast
cancer were observed (8 per 1,000 at the first examination, and 2 per 1,000
among those who attended rescreening).22

The American Medical Association (AMA), the American College of

Radiology (ACR) and the ACS recommend CBE beginning at age 40. The
American College of Obstetrics and Gynecology (ACOG) on the other
hand recommends an earlier initiation of CBE beginning at age 19.

S TAT E M E N T 2: Breast Self-Examination (BSE) is not recommended

as the primary screening modality for breast cancer. (Level I, Grade A)

Supporting Statements:

Two meta-analysis failed to show benefit of BSE in reducing breast cancer

mortality. In the study by Hackshaw, et al., none of the trials evaluated
(20 observational studies, 3 clinical trials) demonstrated a lower mortality
rate among women who regularly practiced BSE (pooled RR 1.01, 95% CI
0.92-1.12) and detected breast cancer during an examination (pooled RR
0.90, 95% CI 0.72-1.12).23 The Cochrane Review evaluated 2 population
based studies (388,535 women) from Russia and Shanghai, and noted no
statistically significant difference in breast cancer among those who had
BSE and the controls (RR 1.05, 95% CI 0.90-1.24). On the other hand, twice
as much biopsies (3406) with benign results were performed in the BSE
group (RR 1.89, 95% CI 1.79-2.0).24

A probable advantage of advising BSE is that, based on the first study,

BSE is associated with considerably more women seeking medical advise
and having biopsies.

The US Prevention Services Task Force (USPSTF)25 and the Canadian Task
Force on Preventive Health Care (CTFPHC) recommends against teaching
BSE to women aged 40 to 69 years. However, the AMA, ACS, ACOG and
American Academy of Family Physicians (AAFP) still support teaching
BSE.

S TAT E M E N T 3: Screening mammography is recommended for

average-risk women starting at age 40. (GPP)

41
Supporting Statements:

Mammography is the primary breast cancer screening modality, with

reported sensitivity of 77-95%, and specificity of 94-97%.20

The USPSTF recommends against routine screening mammography for

women aged 40 to 49 years based on the results of 2 studies which showed lack
of additional benefit of screening before 50 years, with associated greater harm
seen in women screened in their 40s.26,27 The meta-analysis by Nelson, et al.
(8 RCTs included) showed that the rate of reduction in breast cancer mortality
was similar between women who underwent screening mammography at
age 39 to 49 years and women screened at age 50 to 59 years (15% vs 14%).25
Mandelblatt, et al. showed that screening mammography between the ages
of 50 and 69 years old produced a 17% reduction in mortality (compared
to no screening), with only minor improvements when extending the age
range (additional 3% reduction from starting at age 40 years and 7% from
extending to age 79 years).28 False positive results are noted to be highest
among women aged 40 to 49 years (97.8/1000 per screening round), resulting
in additional imaging tests performed (1.0/1000 per screening round).29 This
recommendation, however, is applicable “if the goal of the national screening
program is to reduce the mortality in the most efficient manner. If the goal
is to efficiently maximize the number of life-years gained, then the preferred
strategy would be to screen starting at age 40.”28

ACOG recommends screening mammography starting at age 40. This

recommendation is based on data from the Surveillance Epidemiology and
End Result Program (SEER) showing that starting screening at age 40 may
result in 6,800 fewer deaths from breast cancer among screened women age
40 to 49.27

ACS recommends that for average risk women, breast cancer screening
should be done starting age 45 years. This is based on observation that the
5-year risk among women 45 and 49 years and women aged 50 to 54 years is
similar (0.9% vs. 1.1%), but the 5-year risk among women 45 and 49 years is
greater than that for woman aged 40 and 44 years (1.1% vs. 0.6%). In addition,
the proportion of all incident breast cancers in the population is similar for
ages 45 to 49 years and 50 to 54 years (10% and 12%), but higher than that of
women with age 40 to 44 (7%).30 However, ACS also mentions that women
should have the opportunity to begin annual screening between 40 and 44
years.

Locally, the POGS Task Force and Consensus Plenary agreed to recommend
breast cancer screening to start at age 40, mainly because of the noted high
incidence of breast cancer among Filipino women.

42
S TAT E M E N T 4: Recommended interval for screening mammography
is annual. (GPP)

Supporting Statements:

A systematic review of RCTs showed that screening every 18 to 33 months

versus annually resulted in the same 23% reduction in breast cancer
mortality.31 Mandelblatt, et al. reported that biennial screening of women
aged 50 to 69 years averted 70 to 90% of breast cancer deaths, with only 2
additional breast cancer deaths averted per 1000 women when screening
was done annually.28 A population-based screening program reported
similar 10-year breast cancer-specific survival rates for women who had
annual and biennial screening mammography.32 A community-based study
found that the likelihood of late stage disease at diagnosis was the same for
2 and 1 year screening intervals.33

The ACS recommends that women should be screened annually from age
45 to 54 years, and then biennially starting at age 55. Although women
aged 55 years and should still have the opportunity to continue screening
annually.30 A systematic review noted that for women less than 50 years,
a significant reduction in mortality was observed for those screened at
intervals less than 24 months (RR 0.82, 95% CI 0.72-0.94). Premenopausal
women were more likely to have advanced stage (RR 1.28, 95% CI 1.01-
1.63), larger tumor size (RR 1.21, 95% CI 1.07-1.37), and poor prognosis
tumor at diagnosis (RR 1.11, 95% CI 1.00-1.22) when screening is done at
interval of 23 to 26 months compared to screening done at 11 to 14 months.
However, as woman gets older, particularly after menopause, the relative
benefits of annual vs. biennial screening become less, and more frequent
screening carries an increased risk of false-positive results.

Again, based on the noted high incidence of breast cancer among Filipino
women, the POGS Task Force and Consensus Plenary agreed to recommend
annual mammography.

The following groups support the recommendation to the biennial

mammography: USPSTF, CTFPHC, AAFP, American College of Preventive
Medicine (ACPM). On the other hand, annual mammography is still
recommended by AMA and ACR.

S TAT E M E N T 5: Digital mammography is superior to film mammography

for women younger than 50 years, those with heterogenously or extremely
dense breasts, or those who are premenopausal or perimenopausal. (Level
I, Grade B)

43
Supporting Statements:

In the Digital Mammography Imaging Screening Trial (DMIST) trial, on RCT

involving 42,760 asymptomatic women, although the reported diagnostic
accuracy of digital mammography is similar to the film mammography for
the average risk women (difference between the 2 procedures area under
curve [AUC] 0.03, 95% CI -0.02 to 0.08, p=0.18), the diagnostic accuracy of
digital mammography was significantly better than film mammography
when used in women less than 50 years (difference in AUC 0.15, 95% CI
0.05-0.25, p=0.002), those with heterogenously dense or extremely dense
breasts (difference in AUC 0.11, 95% CI 0.04-0.18, p=0.003), and those who
are premenopausal or perimenopausal (difference in AUC 0.15, 95% CI 0.05-
0.24, p= 0.002).34

STATEMENT 6: Sonomammography can be considered as a

complementary tool to mammography in assessing dense breast tissue.
(Level I, Grade C)

Supporting Statements:

A systematic review evaluated the role of supplemental breast ultrasound

among women presenting with dense breast tissue on screening
mammography.35 Based on 6 cohort studies, supplemental breast ultrasound
after negative mammographic screening but with findings of dense breast
tissue ACR types 2-4) resulted in breast cancer diagnosis in 0.32% of women.
Biopsy rates were 2.3-4.7%, with a positive predictive value (PPV) of 8.4-
13.7%. Caution, however, should be made in interpreting the results as this
study included population of wide age range, and applicability to women
aged 50-69 years may be questionable.

Another meta-analysis concluded that at present there is not enough

evidence to justify routine use of ultrasonograph as an adjunct to screening
mammography in women at average risk for breast cancer.36

Other current uses of breast ultrasound in evaluation for breast cancer include
evaluation of breast masses to distinguish benign cysts from solid masses,
image-guided breast biopsies, and for local breast cancer staging.37

S TAT E M E N T 7: Ultrasound elastography may be considered as an

additional diagnostic tool in differentiating benign from malignant
lesions in dense breast seen on conventional sonomammography. (Level
II-1, Grade B)

44
Supporting Statements:

Ultrasound elastography is a new technique used to provide more accurate

characterization of breast masses. It combines the use of ultrasound
technology with the basic principles of elastography. In ultrasound
elastography, degree of tissue deformability is assessed by providing
information on its elasticity (i.e. ability of a tissue to be deformed when
subject to an external force, and its ability to resume its original shape
when the force is removed).38 In the scoring syste by Itoh, et al., a tissue
deformability is scored 1 to 5, 1 suggesting deformability of the entire lesion,
and 5 suggesting stiffness of the entire lesion and its surrounding tissue; 1-3
suggesting a benign lesion, while 4-5 suggesting a malignant lesion.39

Comparing the diagnostic capacity of ultrasound elastography to the

conventional ultrasound in differentiating benign from malignant breast
cysts, Itoh, et al. were able to demonstrate the following: sensitivity 86.5%
vs 71.2%, specificity 89.8% vs. 96.6%, and accuracy 88.3% vs. 84.7%.39 Zhi,
et al. compared ultrasound elastography and conventional ultrasound and
mammography in their capacity to differentiate benign from breast malignant
lesions in dense breasts. The study of Zhi noted the highest diagnostic accuracy
and PPV with the use of the ultrasound elastography (accuracy 88.2% in
ultrasound elastography vs. 72.6% in conventional ultrasound, PPV 87.1% in
ultrasound elastography vs. 52.5% in conventional ultrasound, with similar
sensitivity and negative predictive value (NPV) between the 2 diagnostic
tools. By combining ultrasound elastography and ultrasound, the sensitivity
(89.7%), specificity (95.7%) and PPV (89.7%) were further improved.40

Ultrasound elastography is particularly helpful in further evaluation of

breast cysts seen sonomammography. It may reduce the need for biopsy in
lesions classified as BI-RADS 3. In addition, it may also be useful in further
assessing lesions < 5 mm seen on ultrasound, but not seen on mammogram.38

S TAT E M E N T 8: Screening for breast cancer using breast magnetic

resonance imaging (MRI) is not recommended in the general population
of asymptomatic, average-risk women. (Level III, Grade C)

Supporting Statements:

Although MRI has been found to have higher sensitivities (80-95%) as

compared to film mammography, the achievable specificities (72-75%) are
much lower, with associated high false positive (20-80%) and biopsy rates.
In addition, at present MRI has not been studies in the general population
as a screening tool. As such, it is not recommended as a screening modality
for average risk women.41

45
STATEMENT 9: High risk women should start annual screening
mammography beginning at age 30. (Level II-2, Grade B)

Supporting Statements:

De Bock, et al. has noted that women with at least 2 of the following
characteristics: (1) at least 2 female first degree relatives with breast cancer,
(2) at least 2 female 1st or 2nd degree relatives with breast cancer under the
age of 50, (3) at least 1 female 1st or 2nd degree relative with breast cancer
under the age of 40, and (4) any relative with bilateral breast cancer, are
associated with a HR of 10.62 for developing breast cancer at the age of 30.
This study provided a strict criteria of individuals who would truly benefit
from annual breast cancer surveillance at an early age.42

The AAFP and ACPM also recommend the initiation of annual screening
mammography beginning at age 30 for high risk women.

S TAT E M E N T 10: Women at high risk for breast cancer should undergo
MRI as an adjunct to mammography. (Level II-2, Grade B)

Supporting Statement:

A prospective study in Canada compared MRI and ultrasound with film

mammography and CBE in women at high risk for breast cancer. The
reported sensitivity and specificity, in decreasing order, are 77% and
95.4% for MRI, 36% and 99.8% for film mammography, 33% and 96% for
ultrasound and 9.1% and 99.3% for CBE.43

Another prospective study in Netherlands also compared CBE, film

mammography and MRI among 1,909 high risk women, 258 of which are
BRCA1/BRCA2 gene mutation carries. With a median follow-up of 2.9
years, the reported sensitivity for breast cancer detection was 17.9% for
CBE, 33.3% for film mammography, and 79.5% for MRI; specificity was
98.1% for CBE, 95% for film mammography, and 89.8% for MRI.44

Two studies which determined the effectiveness of the combined modality

failed to clearly demonstrate improvement in sensitivity and specificity
of film mammography plus MRI over MRI alone in screening high risk
women.45,46 However, MRI alone as a screening modality for high risk
women cannot be recommended as its effectiveness in decreasing breast
cancer mortality has not been established.

STAT E M E N T 11: Female childhood, adolescent and young adulthood

(CAYA) cancer survivors treated with chest radiation should undergo

46
annual breast cancer screening starting at age 25 or 8 years (whichever
occurs last). (Level III, Grade C)

Supporting Statements:

CAYA cancer survivors treated with chest radiation are at increased risk for
breast cancer, with a cumulative breast cancer incidence of 13-20% by age 40-
45 years, with standardized incidence ratios of 13.3-55.5 and absolute excess
risk of 18.6-79.0 per 10,000 person years. The risk is especially high for those
received radiation of > 20 Gy.47

Surveilance of this group of individuals should start at age 25 or 8 years

after radiation (whichever occurs last). These women should be screened
using a combination of mammography and breast MRI. Although there are
no studies on screening modalities specific for this group of women, the
recommendations given are based on studies of high risk women. As such,
one should be aware of the uncertainty in these diagnostic tests with regards
benefits and harms, i.e. early detection, mortality reduction and gained life-
expectancy vs. false positives, false negatives, radiation exposure, and cost.47

STATEMENT 12: For women with a personal history of breast cancer,

annual mammography is recommended after the date of diagnosis but
annual MRI can also be considered. (Level III, Grade C)

Supporting Statements:

The risk for breast cancer is higher among women with a personal history of
breast cancer (655 cancers in women with personal history of breast cancer
vs. 342 cancers in women with no personal history of breast cancer, detected
within 1 year of screening). When compared to the general population,
screening mammography in this group of women results in higher cancer
rates (10.5/1000 screens, 95% CI 9.7-11.3 vs. 5.8/1000 screens, 95% CI 5.2-6.4),
higher cancer detection rates (6.8/1000 screens, 95% CI 6.2-7.5 vs. 4.4/1000
screens, 95% CI 3.9-5.0). Mammogram, however, has lower sensitivity and
specificty when used among women with a personal history of breast cancer
as compared to the general population (sensitivity 65.4% vs. 76.5%; specificity
98.3% vs. 99%).48

As women with a previous history of breast cancer are considered at high

risk for breast cancer, the addition of MRI as adjunct to mammograms is
recommended, as mentioned in Statement 10.

47
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 This Clinical Practice Guidelines is made
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