Clinical Opinion ajog.

org

Inflammatory breast cancer: early recognition

and diagnosis is critical
Robert H. Hester, MD; Gabriel N. Hortobagyi, MD; Bora Lim, MD

regardless of the molecular subtype, with

Inflammatory breast cancer is a rare and aggressive malignancy that is often initially the worst outcomes in patients with
misdiagnosed because of its similar presentation to more benign breast pathologies such triple-negative IBC and a 10-year overall
as mastitis, resulting in treatment delays. Presenting symptoms of inflammatory breast survival rate of 17.8%.5
cancer include erythema, skin changes such as peau d’ orange or nipple inversion, Typical initial symptoms of IBC
edema, and warmth of the affected breast. The average age at diagnosis is younger than include erythema, warmth, swelling,
in noninflammatory breast cancer cases. Known risk factors include African American nipple retraction, or a dimpling
race and obesity. Diagnostic criteria include erythema occupying at least one-third of the appearance known as “peau d’ orange,”
breast, edema, peau d’ orange, and/or warmth, with or without an underlying mass; a progressing rapidly over a period of
rapid onset of <3 months; and pathologic confirmation of invasive carcinoma. Treatment several weeks. Often patients describe
of inflammatory breast cancer includes trimodal therapy with chemotherapy, surgery, IBC as a “bug bite” or “heat rash” that
and radiation. An aggressive surgical approach that includes a modified radical mas- rapidly evolves to cover at least one-
tectomy enhances survival outcomes. Although the outcomes for patients with inflam- third of the breast tissue without a
matory breast cancer are poor compared with those of patients with noninflammatory dominant breast mass. IBC may easily
breast cancer, patients with inflammatory breast cancer who complete trimodal therapy be mistaken for an infection such as
have a favorable locoregional control rate, underscoring the importance of a prompt mastitis or a breast abscess. Thus, most
diagnosis of this serious but treatable disease. Obstetrician-gynecologists and other women are likely to seek initial care
primary care providers must recognize the signs and symptoms of inflammatory breast from primary care providers, including
cancer to make a timely diagnosis and referral for specialized care. obstetrician-gynecologists, internists,
emergency physicians, and family
Key words: breast erythema, IBC diagnosis, inflammatory breast cancer, mastitis, peau practitioners. IBC presents a unique
d’ orange, trimodality therapy, tumor emboli diagnostic challenge to the practitioner
and requires a high degree of suspicion.
Figure 1 shows representative photo-
Introduction graphs of IBC seen in a patient with a
Inflammatory breast cancer (IBC) is a timely cancer diagnosis and a patient
rare form of locally advanced breast with a delayed diagnosis.
From the Division of Cancer Medicine, The cancer that comprises 1% to 5% of all
University of Texas MD Anderson Cancer breast cancer cases and leads to a Epidemiology and Risk Factors
Center, Houston, TX (Dr Hester); Department of
disproportionately high rate of breast IBC has distinct epidemiologic charac-
Breast Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, cancererelated deaths at a rate of 8% to teristics that differentiate it from non-
TX (Dr Hortobagyi); and the Department of 10%.1,2 The clinical presentation of IBC IBC cases. The median age at diagnosis
Breast Medical Oncology, Baylor College of is highly unusual among malignancies. is 59 years, generally younger than that in
Medicine, Houston, TX (Dr Lim). IBC is at a minimum stage III at the time non-IBC cases (diagnosed at a median
Received Dec. 28, 2020; revised March 14, of diagnosis, and it is characterized by a age of 62 years).6 Obesity is an estab-
2021; accepted April 4, 2021. shorter median progression-free survival lished risk factor for IBC in both pre-
R.H.H. has no financial disclosures to report. and overall survival time than seen in and postmenopausal women, unlike in
G.N.H. reports receiving a grant from the Breast
non-IBC cases.3 With an annual inci- non-IBC cases, in which the increased
Cancer Research Foundation. B.L. reports
receiving a SWOG Hope foundation grant to dence of female breast cancer in 2020 of risk for breast cancer development with
study single-cell analysis of inflammatory breast 275,000, an estimated 2750 to 13,750 obesity appears to be limited to post-
cancer (IBC) and reports receiving research women in the United States will be menopausal women.7 Unlike in other
funding for IBC clinical trials from Genentech, diagnosed with IBC this year.4 The breast cancers, in IBC, a lack of breast-
Merck, and Puma Biotechnology. B.L. does not
incidence of IBC is on the rise, with the feeding history is associated with a
have a relevant conflict of interest.
most recent data showing an increase higher locoregional recurrence rate,
Corresponding author: Bora Lim, MD. Bora.
Lim@bcm.edu
from 2.0 to 2.5 per 100,000 woman- distant metastasis, and shorter disease-
years. In contrast, the incidence of free survival rates.8 Although data are
0002-9378/$36.00
ª 2021 Elsevier Inc. All rights reserved. noninflammatory breast cancer declined limited, the incidence of IBC among
https://doi.org/10.1016/j.ajog.2021.04.217 over the same period.2 Inflammatory African American women seems to be
breast cancer has a poor prognosis, higher than among White women.6 In a

392 American Journal of Obstetrics & Gynecology OCTOBER 2021

ajog.org Clinical Opinion

recent study, African American women

FIGURE 1
with IBC were more likely than White or
Hispanic women to present with stage IV
Examples of inflammatory breast cancer presentation
disease and more likely than other ethnic
groups to present with triple-negative
(hormone receptor negative [HR-
]/human epidermal growth factor re-
ceptor 2 negative [HER2-]) disease.9 A
recent study showed that oral contra-
ceptive use and regular alcohol con-
sumption of 1 or more drinks per day
were modifiable risk factors for IBC.
However, more extensive studies are
needed to confirm these findings. The
degree of relevant family history seems
to be similar or lower in patients with
IBC than in patients with non-IBC,
although still higher than in the general
population.10 There is no difference in
the rate of breast cancer gene (BRCA)
mutations between patients with IBC
and those with non-IBC. Among pa-
tients who test positive for BRCA mu-
tations, those with IBC were younger at
the time of diagnosis than those with
non-IBC.11

Differential Diagnosis
The differential diagnosis of IBC in-
cludes both mastitis (either lactational or
unrelated to lactation) and idiopathic
granulomatous mastitis, as summarized
in Table 1. Radiation-induced inflam-
mation from treatment for early-stage
breast cancer or an atypical fungal
infection can also present like IBC. These
conditions are readily diagnosed by skin
biopsy and dermatopathologic evalua-
tion. Although mastitis is a more com-
mon diagnosis in young women during
or after pregnancy, a careful history and
consideration of IBC in the differential
diagnosis along with meticulous clinical
monitoring are all critical for the early
recognition of IBC. Any woman diag-
nosed with mastitis should have a prompt
follow-up to ensure resolution of symp-
toms after a course of antibiotics and to
definitively rule out IBC. When clinical
suspicion is high, breast imaging such as a
mammogram or ultrasound is recom-
mended along with a tissue biopsy for
pathologic confirmation. A delayed
diagnosis significantly affects patients’
survival, and thus, a timely and accurate
diagnosis, along with the early institution
Pictures of 2 patients with inflammatory breast cancer are shown. Both patients had slight erythema
and peau d’orange when gentle pressure was applied, which would not be seen in normal breast
tissue or a typical breast cancer presentation. Both patients reported differences in the size of the
affected breast vs the contralateral normal breast before diagnosis.
Hester. Inflammatory breast cancer. Am J Obstet Gynecol 2021.
of treatment, is critical. An expert in edema or fullness (48%), skin dimpling
established IBC centers of excellence can or discoloration (46%), and nipple
further evaluate suspicious cases before a inversion (16%). Erythema was the
precise pathologic diagnosis. dominant presenting symptom in White
and Hispanic patients, whereas edema or
Diagnostic Criteria and Pathology fullness was the main presenting symp-
The diagnostic criteria for IBC are tom in African Americans. Notably, only
summarized in Table 2.12 Typical about 26% of cases may have a palpable
symptoms include erythema occupying breast lump.9
more than one-third of the breast, Routine screening mammography
edema, peau d’ orange, and warmth, does not seem to be effective in early
which may or may not be associated with detection of IBC and is the least sensitive
an underlying palpable mass. The time among breast imaging modalities.13 In
from onset to full presentation is usually patients with symptoms but not a precise
within 3 months and is never more than initial diagnosis, bilateral breast and
6 months (to distinguish it from a locally nodal ultrasounds are helpful. Ultra-
advanced non-IBC). In a retrospective sound imaging typically shows skin
review of 248 patients with IBC, the most thickening (93%), single or multiple
common presenting clinical signs or masses (85%), parenchymal edema
symptoms included erythema (62%), (78%), and axillary lymphadenopathy

OCTOBER 2021 American Journal of Obstetrics & Gynecology 393

Clinical Opinion ajog.org

TABLE 1
Differential diagnosis of breast erythema
Clinical Inflammatory breast Idiopathic granulomatous
presentation cancer Lactational mastitis Nonlactational mastitis mastitis
Time course Duration <6 mo Acute onset (d) Subacute to chronic (d to wk) Chronic (mo)
Area of breast >One-third of breast Any area of breast Periareolar inflammation, Multiple simultaneous areas
involvement involved involvement; can with or without abscess of peripheral infection with
progress to abscess abscesses
Systemic symptoms Axillary lymphadenopathy, Fever, malaise, myalgia, Fever, malaise, myalgia, flu- Axillary adenopathy, fever,
or absence of systemic flu-like symptoms like symptoms malaise
symptoms
Epidemiologic Median age, 59 y Women of childbearing Young women (who Young women (often in the
characteristics age, 2%e10% of frequently smoke), those months to years after
breastfeeding women with diabetes, and who are childbirth)
immunocompromised
Risk factors Obesity, family history of First 3 months of Smoking Elevated prolactin levels
cancer breastfeeding
Hester. Inflammatory breast cancer. Am J Obstet Gynecol 2021.

(76%).14 When a palpable breast mass is
present, it is targeted for a core biopsy (in
addition to a fine-needle biopsy of any
suspicious axillary lymph nodes). Breast
magnetic resonance imaging can further
aid in detecting the biopsy target via
identification of occult tumors not
identified with other imaging modal-
ities. Magnetic resonance imaging may
also allow visualization of additional
features, including skin involvement,
tenting vessel pattern, edema, and mul-
ticentric disease.13 We encourage prac-
titioners to obtain medical photography
to document the baseline presentation
and monitor the disease during treat-
ment and surgical planning.
Pathologic analysis should confirm an
invasive breast carcinoma. IBC is often
associated with pathologic infiltration of
dermal lymphatics by tumor emboli,
which accounts for the characteristic
edema and skin changes that are the
hallmarks of IBC. Although the presence
of tumor emboli in dermal lymphatics is
pathognomonic for IBC (Figure 2), it is
not required to make the diagnosis nor is
it always visualized in the biopsy spec-
imen. Lobular histologic characteristics
are seen less commonly in IBC than in
non-IBC cases (4.5% compared with
8%). Unlike in non-IBC, lobular histol-
ogy in IBC does not significantly affect
the overall survival.15
Treatment
Essential to the treatment of IBC is tri-
modal therapy with chemotherapy, sur-
gery, and radiation. Unfortunately, a
2014 study showed that 1 in 3 women
with IBC does not receive this baseline
standard of care.16 Neoadjuvant
chemotherapy is used with the goal of
complete pathologic response before
surgery and because surgery is often not
possible at presentation because of the
extent of the disease. A course of
chemotherapy is followed by a modified
radical mastectomy (which includes full
axillary node dissection) and chest wall
radiation with regional nodal radiation.
An aggressive surgical approach has been
shown to improve both local and distant
disease control, thus enhancing survival
outcomes. Of note, a modified radical
mastectomy is strongly recommended
instead of a skin-sparing mastectomy or
breast-conserving surgery because most
clinical trials that showed the equivalent
outcomes in breast conservation plus

TABLE 2
Inflammatory breast cancer diagnostic criteria
Must meet criteria:
 Erythema occupying at least one-third of the breast
 Edema, peau d’ orange, and warmth, with or without an underlying palpable mass
 Rapid onset, with duration no longer than 6 mo
 Pathologic confirmation of invasive carcinoma (core biopsy preferred)
Supports diagnosis:
 Two skin punch biopsies with a dermal lymphatic invasion of tumor emboli
Hester. Inflammatory breast cancer. Am J Obstet Gynecol 2021.

394 American Journal of Obstetrics & Gynecology OCTOBER 2021

ajog.org
radiation therapy vs mastectomy alone
excluded patients with IBC.13 Skin
involvement as well as the general failure
of sentinel lymph node mapping in pa-
tients with IBC also support the recom-
mendation for a modified radical
mastectomy. Specifically, sentinel lymph
node biopsy failed to map sentinel nodes
in 75% of patients with IBC in a pro-
spective clinical trial; therefore, full
axillary lymph node dissection remains
the standard of care.17 Among patients
with metastatic disease, a retrospective
review showed improved 5-year overall
survival and distant progression-free
survival rates among those patients
who underwent surgery vs no surgery
(47% vs 10% and 30% vs 3%, respec-
tively).18 Neoadjuvant and adjuvant
systemic chemotherapy regimens for
IBC are similar to those used in non-IBC
cases, including doxorubicin, cyclo-
phosphamide, and a taxane. Anties-
trogen and HER2-directed therapies are
employed for patients whose tumors
express these markers. Postmastectomy
radiation therapy is indicated in all cases
and should be targeted to the chest wall
and axillary, supraclavicular, infracla-
vicular, and mammary chain lymph
nodes. When possible, we recommend
enrollment into targeted therapyebased
clinical trials to achieve an optimal
response. Delayed reconstruction is
preferred over immediate reconstruction
owing to the requirement for an
adequate radiation dose to the at-risk
internal mammary nodes and deep
chest wall and the likelihood of radiation
therapy adversely affecting the immedi-
ate reconstruction cosmetics. Experts do
not recommend a contralateral prophy-
lactic mastectomy at the time of first
surgery because further nononcologic
surgery may delay radiation therapy
administration and may lead to local
recurrence.13
Outcomes
Before 2006, even with multimodality
therapy, the 15-year overall survival rate
for patients with IBC remained poor
at only 20% (compared with 50% for
patients with stage IIIA non-IBC).19
The advent of HER2-directed therapy
and other therapies, such as
immunotherapy, contributed to
improving the 2-year IBC overall sur-
vival rate from 74% to 85%. The 3-year
overall survival rate improved from
63% to 82% in a study population of all
HR types.20 The data from the Neo-
adjuvant Herceptin trial, which
included HER2-positive IBC cases,
showed an improved 5-year event-free
survival (64% compared with 24%)
and 5-year overall survival rate (74%
compared with 44%) with the addition
of anti-HER2 therapy.21 In 1 study
population of patients with IBC, 84%
had operable tumors following neo-
adjuvant systemic therapy. There was an
84% 5-year locoregional control rate
among the patients who completed
trimodal treatment, 47% 5-year distant
metastasis-free survival rate, and 51%
5-year overall survival rate. For the
subset of patients in that study with a
complete clinical response to neo-
adjuvant chemotherapy, the 5-year local
control rate was 95%. Patients who were
unable to complete trimodal therapy
owing to disease progression or early
disease recurrence more commonly had
supraclavicular lymph node involve-
ment at the time of presentation.22
These data underscore both the
importance of multimodality therapy
and the early engagement of multidis-
ciplinary experts.
Imperative for Prompt Diagnosis
Because of the aggressive nature of IBC,
early diagnosis is crucial. As such, IBC
must be ruled out in any patient pre-
senting with breast erythema. Critical
clinical clues that point to IBC instead
of an infectious cause include age over
50 years, erythema occupying more
than one-third of the breast, and lack of
systemic symptoms such as fever and
malaise. On diagnosis, prompt referral
to an academic tertiary care center with
an established multidisciplinary clinic
for the treatment of IBC can facilitate
patient enrollment into clinical trials,
providing newer and potentially life-
saving treatment options. Given its
similar clinical appearance to mastitis
or breast abscess and frequent lack of a
palpable breast mass, IBC can present a
diagnostic challenge to primary care
OCTOBER 2021 American Journal of Obstetrics & Gynecology
Clinical Opinion
FIGURE 2
Hematoxylin and eosin staining
for tumor emboli
Hematoxylin and eosin staining of tumor emboli
in the dermal lymphatic structure in a skin punch
biopsy from a patient with inflammatory breast
cancer is shown.
Hester. Inflammatory breast cancer. Am J Obstet
Gynecol 2021.
physicians. Likewise, routine screening
mammography may not detect IBC.
Given the severe but treatable nature of
IBC, obstetrician-gynecologists and
other primary care physicians should
maintain a high index of malignancy
suspicion when a patient presents with
rapid-onset changes such as erythema,
skin dimpling, swelling, or nipple
retraction in a unilateral breast. -
REFERENCES
1. Susan G; Komen Breast Cancer Founda-
tion. Inflammatory breast cancer. 2019.
Available at: https://ww5.komen.org/Breast
Cancer/Inflammatory-Breast-Cancer.html.
Accessed November 29, 2019.
2. Hance KW, Anderson WF, Devesa SS,
Young HA, Levine PH. Trends in inflammatory
breast carcinoma incidence and survival: the
surveillance, epidemiology, and end results
program at the National Cancer Institute. J Natl
Cancer Inst 2005;97:966–75.
3. Fouad TM, Kogawa T, Liu DD, et al.
Overall survival differences between patients
with inflammatory and noninflammatory breast
cancer presenting with distant metastasis at
diagnosis. Breast Cancer Res Treat
2015;152:407–16.
4. National Cancer Institute Surveillance.
Epidemiology, and End Results Program. Can-
cer stat facts: female breast cancer. 2019.
Available at: https://seer.cancer.gov/statfacts/
html/breast.html. Accessed December 1, 2019.
395
Clinical Opinion
5. Masuda H, Brewer TM, Liu DD, et al.
Long-term treatment efficacy in primary in-
flammatory breast cancer by hormonal re-
ceptor- and HER2-defined subtypes. Ann
Oncol 2014;25:384–91.
6. Anderson WF, Schairer C, Chen BE,
Hance KW, Levine PH. Epidemiology of inflam-
matory breast cancer (IBC). Breast Dis 2005-
2006;22:9–23.
7. Chang S, Buzdar AU, Hursting SD. Inflam-
matory breast cancer and body mass index.
J Clin Oncol 1998;16:3731–5.
8. Stecklein SR, Reddy JP, Wolfe AR, et al. Lack
of breastfeeding history in parous women with
inflammatory breast cancer predicts poor
disease-free survival. J Cancer 2017;8:
1726–32.
9. Fouad TM, Ueno NT, Yu RK, et al. Distinct
epidemiological profiles associated with inflam-
matory breast cancer (IBC): a comprehensive
analysis of the IBC registry at the University of
Texas MD Anderson Cancer Center. PLoS One
2018;13:e0204372.
10. Moslehi R, Freedman E, Zeinomar N,
Veneroso C, Levine PH. Importance of heredi-
tary and selected environmental risk factors in
the etiology of inflammatory breast cancer: a
case-comparison study. BMC Cancer 2016;16:
334.
11. Gutierrez Barrera AM, Fouad TM, Song J,
et al. BRCA mutations in women with
396 American Journal of Obstetrics & Gynecology OCTOBER 2021
inflammatory breast cancer. Cancer 2018;124:
466–74.
12. Dawood S, Merajver SD, Viens P, et al. In-
ternational expert panel on inflammatory breast
cancer: consensus statement for standardized
diagnosis and treatment. Ann Oncol 2011;22:
515–23.
13. Ueno NT, Espinosa Fernandez JR,
Cristofanilli M, et al. International consensus on
the clinical management of inflammatory breast
cancer from the Morgan Welch Inflammatory
Breast Cancer Research Program 10th Anni-
versary Conference. J Cancer 2018;9:1437–47.
14. Abeywardhana DY, Nascimento VC,
Dissanayake D, et al. Review of ultrasound
appearance in inflammatory breast cancer: a
pictorial essay. J Med Imaging Radiat Oncol
2016;60:83–7.
15. Raghav K, French JT, Ueno NT, et al. In-
flammatory breast cancer: a distinct clinico-
pathological entity transcending histological
distinction. PLoS One 2016;11:e0145534.
16. Rueth NM, Lin HY, Bedrosian I, et al.
Underuse of trimodality treatment affects sur-
vival for patients with inflammatory breast can-
cer: an analysis of treatment and survival trends
from the National Cancer Database. J Clin Oncol
2014;32:2018–24.
17. DeSnyder SM, Mittendorf EA, Le-
Petross CL, et al. Prospective feasibility trial of
sentinel lymph node biopsy in the setting of
ajog.org
inflammatory breast cancer. Clin Breast Cancer
2018;18:e73–7.
18. Akay CL, Ueno NT, Chisholm GB, et al.
Primary tumor resection as a component of
multimodality treatment may improve local
control and survival in patients with stage IV in-
flammatory breast cancer. Cancer 2014;120:
1319–28.
19. Low JA, Berman AW, Steinberg SM,
Danforth DN, Lippman ME, Swain SM. Long-
term follow-up for locally advanced and inflam-
matory breast cancer patients treated with
multimodality therapy. J Clin Oncol 2004;22:
4067–74.
20. Tsai CJ, Li J, Gonzalez-Angulo AM, et al.
Outcomes after multidisciplinary treatment of
inflammatory breast cancer in the era of neo-
adjuvant HER2-directed therapy. Am J Clin
Oncol 2015;38:242–7.
21. Gianni L, Eiermann W, Semiglazov V, et al.
Neoadjuvant and adjuvant trastuzumab in pa-
tients with HER2-positive locally advanced
breast cancer (NOAH): follow-up of a rando-
mised controlled superiority trial with a parallel
HER2-negative cohort. Lancet Oncol 2014;15:
640–7.
22. Bristol IJ, Woodward WA, Strom EA, et al.
Locoregional treatment outcomes after multi-
modality management of inflammatory breast
cancer. Int J Radiat Oncol Biol Phys 2008;72:
474–84.