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The Epidemiology ofInflammatory Breast Cancer

Paul H. Levine and Carmela Veneroso

The epidemiology of inflammatory breast cancer (IBC) has been of great interest to a number ofinvestigators, but epidemiological research has been hampered by the lack of an agreed upon casedefinition and the relatively small number of patients available to any single investigator orinstitution. Several features of IBC have become apparent through population-based studies, which,although varying somewhat in case definition, generally agree on some key features of the disease.These include the incidence of the disease, apparently less than 3% of breast cancer cases in theUnited States, the younger age of onset compared to non-inflammatory breast cancer, the muchhigher incidence in Black women compared to White, the generally poor outcome of this diseasecompared to non-inflammatory breast cancer, and the continued increase in reported incidence,particularly as compared with non-inflammatory breast cancer in general and locally advancedbreast cancer (LABC) in particular. There is an apparent striking geographic pattern, with a higherpercentage of cases reported from North Africa, best documented in Tunisia. The risk factors fordeveloping IBC are suggested by smaller studies with concordant conclusions, and some appear tobe different than the risk factors for developing breast cancer in general. For example, obesityappears to be a risk factor for premenopausal IBC but is not for premenopausal non-inflammatorybreast cancer. In addition, there is evidence that a young age at first birth predisposes to IBC butis protective against developing non-inflammatory breast cancer. In some malignancies, the use ofmolecular markers is helpful in defining subgroups that could assist in improving case definition aswell as predicting prognosis. The increasing combination of improved epidemiologic and labora-tory methods will hopefully accelerate our understanding of this challenging disease.Semin Oncol 35:11-16 © 2008 Elsevier Inc. All rights reserved.

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nflammatory breast cancer (IBC) is a challengingdisease characterized by rapid progression, poorsurvival and distinct skin changes often suggestive

f infection. The epidemiology of IBC is emerging verylowly for two reasons: (1) it only affects approxi-ately 2.5% of breast cancer patients in the United

tates1 and therefore there are few if any single centershat see enough patients to put together a representa-ive series for a population appropriate for epidemio-ogic study; and (2) there has been no consistent caseefinition for epidemiologic studies, thus making mosttudies not comparable. Because IBC appears to beore common in North Africa than in the United

tates, a considerable investigative effort on this dis-ase has been focused in that region, particularly Tuni-

epartment of Epidemiology and Biostatistics, The George Washington UniversitySchool of Public Health and Health Services, Washington, DC.

ddress correspondence to Paul H. Levine, MD, Department of Epidemiology andBiostatistics, The George Washington University School of Public Health andHealth Services, Ross Hall 118, 2300 I St NW, Washington, DC 20037. E-mail:paulhlevine@earthlink.net

270-9295/08/$ - see front matter

d2008 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2007.11.018

eminars in Oncology, Vol 35, No 1, February 2008, pp 11-16

ia where approximately 50% of breast cancer casesave been identified as having an aggressive form of theisease2 meeting the American Joint Committee onancer (AJCC) case definition of IBC.3 In this chaptere will review the available data on the epidemiologyf IBC, discuss the problems in developing a caseefinition, and propose approaches to collecting rele-ant information to improve our understanding of thetiology of this disease.

A number of important epidemiologic aspects of IBCre known, such as the higher incidence in African-mericans, the younger age at onset, and the relativelyoor prognosis compared to breast cancer overall.ther aspects, such as the incidence of disease, the

dentification of risk factors, the consistency of biomar-er assays, and even the effectiveness of different ther-peutic modalities,4 are difficult to interpret in largeart because of the absence of an agreed upon caseefinition for IBC. Any study, particularly an epidemi-logical study, depends on the case definition, andherefore in this chapter we will first focus on the

iverse case definitions in use and possible approaches

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12 P.H. Levine and C. Veneroso

o better define IBC. Subsequently, we will reviewhose epidemiologic features that are well defined re-ardless of the case definition, what is known about theisk factors for IBC, and current approaches towardsmproving the case definition using laboratory assays.

HAT DEFINES IBC

elevant Historical Background

The historical background of IBC, which was re-ently reviewed,5 apparently begins with Sir Charlesell in 1814, who observed that “a purple color on thekin over the tumor accompanied by shooting pains isvery unpropitious beginning.”6 Regarding case defi-

ition, we will focus on the term “inflammatory carci-oma of the breast,” which was first used by Lee andannenbaum in 1924,7 noting that “as the diseaserogresses, the skin becomes deep red or reddish-urple, and to the touch is brawny and infiltrated. The

nflamed area presents a distinct raised periphery afterhe fashion of erysipelas. The examiner with his eyeslosed . . . can distinguish the sharp contrast betweenormal and affected tissue.” The most widely referencedase definition at the present time is that of the AJCC,3

hich states, in part, that “inflammatory carcinoma is alinicopathologic entity characterized by diffuse ery-hema and edema (peau d’orange) of the breast, oftenithout an underlying mass. These clinical findings

hould involve the majority of the breast . . . It is im-ortant to remember that inflammatory carcinomas primarily a clinical diagnosis. Involvement of theermal lymphatics alone does not indicate inflamma-ory carcinoma in the absence of clinical findings.”

In parallel with these reports focusing on the clinicaleatures of IBC were a number of studies on the his-opathologic features beginning with an observation byryant,8 who suggested that lymphatic obstructionould be producing the marked swelling of the breastnd inflammatory signs. The recognition of the impor-ance of dermal lymphatic invasion (DLI) was noted byaylor and Meltzer,9 who considered this findingpathologic proof” of IBC. Saltzstein10 brought theathologic findings to a new level, describing the ag-ressive course of four patients with dermal lymphaticnvasion and no clinical signs of IBC and used the termclinically occult inflammatory carcinoma of thereast.”

In subsequent studies comparing “occult IBC” andlinically apparent IBC,11,12 the prognosis of occult IBCas consistently better than clinically apparent IBC. A

eport from a single-institution study by Lucas anderez-Mesa11 included three groups of patients: group 139 patients) had clinical and pathologic features ofBC; group II (19 patients) had clinical but no patho-ogic evidence of IBC; and group III (15 patients) had

arcinomatous emboli in the dermal lymphatics with- m

ut clinical signs, comparable to Saltzstein’s occult IBC.he first two groups with clinical signs had equallyoor survival (�20% 3-year survival and �10% 5-yearurvival) and those with occult IBC (group III) had auch better 3-year survival (70%) but the 5-year sur-

ival (20%) was far less than that expected for non-nflammatory breast cancer. Amparo et al,12 addingormone receptors to their analysis, compared 163atients with clinical signs of IBC (CIC) defined as “aiopsy-proven breast neoplasm and diffuse or morehan two-thirds involvement of the breast with clini-ally inflammatory signs” as compared with occult IBCOIC) where there was pathologically proven involve-ent of dermal lymphatics without any clinical signs.he CIC group was significantly younger (median age,2.3 years) versus the median age of 63.8 in the OICroup. Furthermore, the CIC group was significantlyore likely to be estrogen receptor–negative (72.6%)

ersus the OIC group (48.4%). Finally, the 5-year andverall survivals were significantly worse in the CICroup (25.6% and 27%, respectively) versus the OICroup (51.6% and 60.2%, respectively). Since occultBC thus far appears biologically closer to other popu-ation-based series of IBC and has a more favorableutcome than cases with any clinical signs, and sinceoutine examination of the skin is not performed byathologists in breast cancer patients, for epidemio-

ogic purposes we will include occult IBC as part of thepectrum of aggressive breast cancer. The risk factorsor aggressive non-inflammatory breast cancer are sim-lar to those for IBC (see below) and both have markedifferences from the risk factors for less aggressiveon-inflammatory breast cancer (as defined by tumorrade) and therefore information on aggressive non-nflammatory breast cancer will be included in thishapter.

he Variability of Case Definitions

Restricting the diagnosis of IBC to those cases withlinical involvement of more than half the breast isroblematic for several reasons: (1) population-basedegistries accept those with pathologic confirmationinvasion of the dermal lymphatics) as IBC regardless ofhe extent of clinical involvement1,13–15; (2) evaluationsf population-based data in the Surveillance, Epidemi-logy and End Results (SEER) Program of the Nationalancer Institute (NCI)1,13 support the evidence that

imited clinical signs of IBC and/or pathologic evidencef DLI have the same poor prognosis as those meetinghe AJCC case definition (with some exceptions asoted below); (3) numerous clinicians and researchersummarizing their experience also include patientsith clinical features confined to less than half of thereast4; and (4) the experiences with Tunisian pa-ients16 and the North American patients in the Inflam-

atory Breast Cancer Registry17,18 indicate that those pa-

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Epidemiology of IBC 13

ients with limited clinical signs have the same biologicaleatures as those meeting the AJCC case definition.

An apparently useful model for the consideration ofhe spectrum of disease manifestations leading to IBCas proposed by Denoix,19 who used the term pousee

volutive or rapidly progressing breast cancer in whichhe most advanced form, PEV 3, as used in the Tunisiantudies,20 is defined as “a designation given to patientsith inflammation covering more than half the breast

urface,” which is clearly compatible with the AJCCase definition. Cases with PEV 2 in Tunisia, whichave inflammatory signs affecting less than half thereast, did slightly better than PEV 3 cases in the first 3ears but had virtually identical poor survival at 4 yearsnd beyond.16 A useful modification of the IBC caseefinition that had been in use tacitly for PEV has beenroposed; it includes the development of the clinicalanifestations of the tumor in 4 months or less,21 an

mportant distinction that allows the separation of IBCrom LABC.

An important consideration regarding the AJCC caseefinition is that increasing awareness of IBC may bellowing recognition earlier before it involves half ofhe breast. This possibility is raised by the earlier de-cription of Taylor and Meltzer,9 who noted that “in theajority of cases the disease seems to begin with a

ocalized tumor”. . . with a “history of a lump in thereast present for some weeks before the overlyingkin suddenly became red.” A similar finding was re-orted by Bonnier et al,22 who noted a better outcome

n patients with a more circumscribed tumor. Theseuthors referred to this category of patients as “pseudo-BC” but “early IBC” would appear to be a more suit-ble term.

A recent paper from Tunisia23 reports several phe-omena of interest, such as a continuing trend towardarly diagnosis, smaller tumor size in women seen inrivate medical facilities than those seen in publicospitals, and an apparent decrease in cases with clin-

cal features of IBC. The increased awareness of IBCeading to earlier diagnosis and less extensive disease isupported by the patients in our IBC Registry, manyatients describing their lesions as being quite small

nitially, perhaps the size of an insect bite or a bruise,ut then progressing rapidly with the diagnosis of IBCeing made before the involvement of half the breast.ecause of the importance of tumor stage in indicatingrognosis and the rapid progression of IBC, which ishought to be accompanied by disseminated microme-astases at the outset, perhaps the disease stage usuallyonsidered as T4d should be modified to separate IBCnto two categories, one for the extensive involvementsed by AJCC to define the disease and another forore limited disease comparable to PEV 2.As noted above, on presentation IBC may be difficult

o distinguish from LABC in the absence of a careful b

istory defining the acuteness of onset. The distinctions important because of the difference in survival, withBC having a median survival time of 2.9 years versus.4 years for LABC according to the SEER data.1 Bothay be treated initially with chemotherapy but the

iology is quite different since micrometastases areeen at the outset in IBC but are less likely in LABC,hich is usually due to delay in diagnosis. Biologicifferences between IBC and LABC in addition to sur-ival were noted in two NCI reports,1,24 with IBC hav-ng an age-dependent increase until menopause, whileABC keeps increasing as do most carcinomas, includ-ng non-inflammatory breast cancers.

PIDEMIOLOGIC FEATURES OF IBC

While there are some differences among the fourarge population-based studies,1,13–15 many of the fea-ures are similar. For example, all papers document thatBC has a higher incidence in Black women compared to

hite women and in both groups IBC occurs at aounger age than non-inflammatory breast cancers. Thepecific details differ considerably because they coverifferent time periods ranging from 1975-198113 to 1988-000,1 they use different data bases—SEER for three1,13,14

nd the North American Association of Central Canceregistries (NAACCR) for one15—and most important

hey select different patients, with two1,13 using bothlinical and pathologic criteria to select patients andwo14,15 restricting their cases to those defined patho-ogically as IBC. For pathologic definition, all four usednternational Classification of Diseases for Oncologyorphology code 8530/3. Regarding racial/ethnic dif-

erences, Blacks had at least a 50% higher incidencehan Whites, were diagnosed at an earlier age, and hadshorter survival, as also seen in non-IBC breast cancer.ingo et al15 also looked at other racial-ethnic groups

nd noted that Hispanic women had the youngestean age of onset (50.5 years) compared to 55.2 forlack women and 58.1 for White women. Other find-

ngs of interest, approached and analyzed differently inhe four studies, were increasing incidence in IBC overime,1,14 the similarly poor survival in clinically andathologically defined cases,1,13 and the improving sur-ival in recent years with important advances in che-otherapy.1,14 The increasing incidence in IBC con-

rasts markedly with non-inflammatory breast cancer,hich has leveled off since 2001-2003.25

Other observations include a generally higher tumorrade and more estrogen receptor (ER)-negative tu-ors than among non-inflammatory breast cancer caseshere the incidence of ER� and ER� tumors is equal.1

n regard to the incidence of IBC, the use of thelinical codes (EOD-E 70 for tumor extension andOD-S 998 for tumor size) now available in SEERndicates that IBC comprises 2.5% of all incident

reast cancer cases,1 which is a higher rate than

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eported in the two studies using only pathologicallyiagnosed IBC.

ISK FACTORS

The studies on risk factors for aggressive breastancer, including IBC, have not been based on largeumbers of patients, but several interesting observa-ions have been made. If the data on IBC and aggressivereast cancer are considered together, they generallyupport each other and therefore will be considered inarallel. The most striking observation is that the risk

actors for aggressive breast cancer, including IBC, dif-er significantly from the risk factors for breast cancern general. One important difference is in age at firstirth, with early age at first birth protecting againstreast cancer, but women with aggressive breast can-er are more likely to have their first child at a youngerge than women with less aggressive breast cancer.his was noted in the Tunisian PEV patients, where 14f 15 premenopausal women with first births at the agef 18 or earlier were diagnosed as PEV-positive. Thisnding was weakly supported by the study of Changt al,26 who compared 68 IBC patients with 143 non-nflammatory breast cancer patients and 134 patients

ith cancer at other sites and found the lowest mediange at first live birth in the IBC patients, but the differ-nce was not statistically significant. In a comparison of16 patients with aggressive breast cancer as definedy tumor grade, 99 patients with non-aggressive breastancer, and 135 patients from our IBC registry, bothBC patients and the non-IBC patients with aggressivereast cancer were more likely to have a first childefore age 20 than the breast cancer patients withon-aggressive breast cancer, and the patients withggressive breast cancer were three times more likelyo have their first child before age 20 than the patientsith non-aggressive breast cancer.27

Another consistent finding is high body mass indexBMI) as a risk factor seen in premenopausal as well asostmenopausal women.26 Since relative weight is as-ociated with a reduced or similar risk of breast cancern premenopausal women in general,28 this appears toe another example of a difference between IBC andon-inflammatory aggressive breast cancer versus non-ggressive breast cancer. Other intriguing but less wellocumented observations relate to the possible associ-tion of IBC with pregnancy and lactation. In oneunisian study,20 pregnancy-associated breast canceras defined as breast cancer occurring in a womanho was either pregnant or lactating at the time the

umor was discovered. In this series, 79% of the 52omen who had pregnancy associated with breast

ancer were PEV-positive compared to 67% of thoseith no pregnancy association (�2 � 6.32, P � .01).wo other possibly related findings were the strong

ssociation with rural residence, an apparent surrogate i

or socioeconomic status, and an apparent associationith breast feeding. In the 1980 Tunisian series (20),

5% of the rural patients were PEV-positive comparedith 54% of the 136 urban patients (�2 � 10.2,�.001). Since urban residence in Tunisia is associated

n general with a higher socioeconomic status, thisbservation is supported by the more recent Tunisianeries,23 which noted larger tumors and a higher fre-uency of those compatible with IBC in women treated

n public hospitals compared to those seen in therivate sector. The effect of socioeconomic status waslso reported by Le et al,29 who compared IBC patientsith non-inflammatory breast cancer patients andoted that increased breast feeding was a risk factor forBC as well as lower socioeconomic status in theirrench–North African population.

The risk factors now under study in North Africanopulations could serve as a useful model for similartudies in the United States. One such risk factor is aroposed increased detection of viral antigens and se-uences resembling mouse mammary tumor virusMMTV) in Tunisia.30,31 The possible relationship ofMTV-related sequences to IBC in the United States is

urrently under investigation.

PPLICATION OF LABORATORYARKERS TO EPIDEMIOLOGIC STUDIES

Laboratory markers show great promise in help-ng improve case definitions for epidemiologic studies.here are several examples of malignancies where lab-ratory markers have been critical, such as in Burkitt’s

ymphoma (BL) where the features of Epstein-Barr virusEBV)-associated BL are distinctly different from mor-hologically indistinguishable non–EBV-associated BL.riginally considered as “endemic” (prominent in sub-

aharan Africa) and “sporadic” (such as in the Unitedtates), EBV-associated BL was found to have a specifichromosome translocation upstream of c-myc and wasssociated with a different clinical pattern and betterurvival than non–EBV-associated BL, which did notave this specific translocation.32 Clinically, non–EBV-ssociated American BL was associated with more bonearrow and peripheral lymph node involvement than

BV-associated African BL and was less responsive tohemotherapy.33

The importance of evaluating laboratory markers inhe context of detailed clinical and epidemiologicaltudies has led us to the development of a classificationor the IBC Registry,17 which is now being applied toaboratory studies18 and may be useful in a variety ofther studies as well.

UMMARY

Our understanding of the epidemiology of IBC, as

n the epidemiology of any disease, requires a clear

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Epidemiology of IBC 15

ase definition. In an attempt to synthesize the ap-roaches taken by different groups, we suggest usingategories of cases according to the presenting featuresnd consider the strong possibility that those with thelinical features of IBC not meeting the AJCC caseefinition represent the same biological entity as thosehat do, but are presenting earlier and are diagnosedarlier. As with the clinical features of IBC, the patho-ogic confirmation of DLI could represent extent ofisease, with earlier cases having less dermal lymphatic

nvolvement and therefore be less likely to be identifiedy routine measures. The experience in Tunisia andrance, where rural residence, lower socioeconomictatus, and prolonged breast feeding correlate withncreased clinical manifestations of IBC also suggestshat the more extensive disease is related in part toelay in diagnosis. In addition to investigating moreexible approaches to case definitions, such as theifferent categories used by the IBC Registry, moreetailed evaluation of risk categories should be applied,

ncluding those used in earlier studies. For example, inddition to mean age at first live birth used by Changt al,26 it may be important to categorize patients intoge groups with particular attention to those under age8, used by Mourali et al,20 or those under age 20, used

n other US studies.27

It is clearly important to investigate and report pre-nd postmenopausal IBC separately. This was apparentn the Tunisian study20 where urban–rural differences

ere seen only in the premenopausal patients, and inhe BMI report by Chang et al26 where the differenceetween risk for aggressiveness in contrast to overallreast cancer incidence could only be shown in pre-enopausal women. The possibility that pre- and post-enopausal IBC may have different etiologies is raised

y the Tunisian studies, where the risk of PEV wasighest in young premenopausal women and graduallyeclined to no increase in risk in the perimenopausalears, only to rise again with increasing age in theostmenopausal women. Could hormonal stimulatione the driving force in premenopausal women andeclining immunity in postmenopausal IBC?

Many questions obviously need to be addressed butt is hoped that increasing attention can be given to IBCn endemic areas, eg, North Africa, as well as non-ndemic areas. In spite of its affecting only 2% to 3% ofS breast cancer patients, IBC is not a minor problem.ot only is it a clinical challenge, but in terms ofumbers, IBC is more common in the United Stateshan acute lymphocytic leukemia of childhood. Themerican Cancer Society estimates that in 200725 thereill be 2,790 new cases of childhood ALL and 178,480

ases of breast cancer, which will include 4,462 casesf IBC if 2.5% of all breast cancers is an accurate

stimate.1

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