REVIEW

Pathological criteria and practical issues in papillary lesionsof the breast – a review

Yun-Bi Ni & Gary M TseDepartment of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong,

Hong Kong

Ni Y-B & Tse G M

(2016) Histopathology 68, 22–32. DOI: 10.1111/his.12866

Pathological criteria and practical issues in papillary lesions of the breast – a review

Papillary lesions of the breast include a broad spec-trum of lesions, ranging from benign papilloma, papil-loma with atypical ductal hyperplasia (ADH) orductal carcinoma in situ (DCIS) to papillary carci-noma. The accurate diagnosis of mammary papillarylesions is a challenge for pathologists, owing to theoverlapping features among these lesions. In thisreview, some of the diagnostic criteria of papillarylesions are discussed, with special emphasis on some

key morphological features, namely fibrovascularcores, epithelial proliferation in a solid pattern, intra-ductal papilloma complicated by ADH or DCIS, andinvasion and its mimics. The roles of immunohisto-chemistry, and the interpretation of myoepithelial cellmarkers, hormone receptors, and high molecularweight cytokeratin, are addressed. Finally, novelbiomarkers and genetic aberrations in papillarylesions are summarized.

Keywords: biopsy, breast, papillary lesions

Introduction

Papillary lesions of the breast can present with nippledischarge when centrally located, or as palpablemasses when they are located near the surface or arerelatively large. Mammography, ultrasound and mag-netic resonance imaging may reveal the deeperlesions. Sometimes the smaller lesions can also beidentified incidentally in breast biopsies obtained forother reasons. Papillary lesions include a broad spec-trum of lesions, ranging from benign papilloma, papil-loma with atypical ductal hyperplasia (ADH) orductal carcinoma in situ (DCIS) to papillary carci-noma. In a large cohort of benign breast biopsies,papillomas account for 5.3% of the cases.1 In theNetherlands Cancer Registry, papillary carcinomasare seen in 0.7% of the malignant breast tumours.2

Morphologically, papillary lesions of the breast arecharacterized by the presence of arborizing fibrovas-cular cores derived from the wall of the ducts, whichare often distended by the papillary lesions. Thesefibrovascular cores are, in turn, lined by layers ofepithelial cells, with or without a complete layer ofintervening myoepithelial cells.The accurate diagnosis of papillary lesions contin-

ues to be a challenge for pathologists. The underlyingcauses of this diagnostic difficulty are multiple. Differ-ent papillary lesions may possess overlapping mor-phological and immunohistochemical (IHC) features;there are limitations regarding the usual diagnosticsamples [core needle biopsy (CNB) or fine needle aspi-ration cytology]; and there is a lack of consensus onthe subsequent management strategy based on CNBdiagnosis. Studies have been performed to determinewhether specific biomarkers could improve the accu-racy of pathological diagnosis. The pathogenesis ofpapillary lesions is enigmatic, with only a few studieshaving characterized their molecular aberrations.This rather scanty information is still helpful in

Address for correspondence: G M Tse, Department of Anatomical

and Cellular Pathology, Prince of Wales Hospital, Ngan Shing

Street, Shatin, NT, Hong Kong. e-mail: garytse@cuhk.edu.hk

© 2015 John Wiley & Sons Ltd.

Histopathology 2016, 68, 22–32. DOI: 10.1111/his.12866

understanding their pathogenesis and biologicalbehaviour, and may shed light on the differentialdiagnosis.In this review, the diagnostic criteria of papillary

lesions are discussed, with emphasis on some practi-cal diagnostic issues, including differentiating differentpapillary lesions on the basis of histological and IHCfeatures. Management options based on CNB diagno-sis will also be evaluated. Finally, new adjunctbiomarkers and the genetic aberrations of breast pap-illary lesions are also summarized.

Pathological classification of papillarylesions of the breast

In the World Health Organization (WHO) classifica-tion of breast tumours, papillary lesions are classifiedas intraductal papilloma, intraductal papillary carci-noma, encapsulated papillary carcinoma, and solidpapillary carcinoma. Invasive papillary carcinoma isnow grouped under rare tumours, but not under pap-illary lesions.3–7

I N T R A D U C T A L P A P I L L O M A

Intraductal papillomas can be divided into central(solitary) and peripheral (multiple), which share simi-lar structures of arborescent fibrovascular cores cov-ered by myoepithelial cells and epithelial cells; theformer may be attenuated and become inconspicuous.The periphery of the lesion also shows a layer ofmyoepithelial cells (Figure 1). In benign papillomas,

the epithelial cells may show usual ductal hyperplasia(UDH) or squamous or apocrine metaplasia. Never-theless, epithelial cell mitoses are absent or extremelyrare. Other histological features that may be superim-posed on intraductal papillomas include haemor-rhage, infarction, stromal fibrosis (in extremeexamples, the papillary architecture may be obscured;this is termed sclerosed papillomas or ductal adeno-mas), and mucinous, clear cell and sebaceousmetaplasia.8,9

Intraductal papillomas may also be complicated byADH or DCIS. These are characterized by focal abnor-mal epithelial proliferation with cytological and archi-tectural features of low-grade ductal neoplasia. Inthese areas, myoepithelial cells may be scanty orabsent. The accurate separation between these twodiagnoses remains a contentious issue. Some authorshave proposed using a percentage criterion (30% or90%),10,11 whereas others have proposed an extentcriterion (≥3 mm),12 for a diagnosis of papilloma withDCIS to be made. Although the extent criterion(ADH, atypical focus of <3 mm; DCIS, atypical focusof ≥3 mm) has been recommended by the WHOworking group, it is also acknowledged to be a prag-matic guideline lacking scientific evidence.3,13,14

When the abnormal epithelial proliferation showsintermediate or high nuclear grade features, DCISshould be diagnosed regardless of the extent contain-ing atypical cells, and the 3-mm rule does notapply.15

Intraductal papillomas without atypia but with sur-rounding proliferative changes incur a two-fold rela-tive risk for subsequent carcinoma as compared withthe general population, and this is similar to otherforms of proliferative breast disease without atypia.The risk is higher in multiple papillomas than in soli-tary papilloma.1,16 The relative risk of developingbreast cancer in patients with papillomas with atypiais 5- to 7.5-fold greater than in patients with papillo-mas without atypia.1,12,16

I N T R A D U C T A L P A P I L L A R Y C A R C I N O M A

In intraductal papillary carcinomas, the ducts andthe terminal ductal lobular units are filled with slen-der, branching fibrovascular stalks, covered by a sin-gle population of neoplastic cells. The neoplastic cellsare usually columnar, with low-grade to intermedi-ate-grade nuclei (Figure 2). They are arranged intoone to several layers, and may form different geomet-ric patterns, including micropapillary, cribriform orsolid. There are absent or scanty myoepithelial cellsseparating the papillae and the epithelial proliferation.

Figure 1. Intraductal papilloma. The inset highlights fibrovascular

cores covered by a layer of myoepithelial cells with overlying

epithelial cells within a duct, and the peripheral myoepithelial cell

layer.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

Papillary lesion of the breast 23

A myoepithelial cell layer is usually identified at theperiphery of the lesions. Sometimes, these lesions mayshow a dimorphic cell population, with a second pop-ulation of clear epithelial cells that may sometimes bemistaken for myoepithelial cells.17 Intraductal papil-lary carcinomas are usually multifocal and peripheralin distribution.

E N C A P S U L A T E D P A P I L L A R Y C A R C I N O M A

Encapsulated papillary carcinomas possess a thickfibrous capsule, and, within the capsule, there is pro-liferation of delicate fibrovascular stalks covered bymonotonous neoplastic cells, in mostly solid to cribri-form patterns. Typically, these lesions lack myoepithe-lial cells both around the fibrovascular cores and atthe periphery (Figure 3).18,19 The exact nature ofencapsulated papillary carcinomas is not known. Thelack of myoepithelial cells has led some authors topropose an invasive nature,18,19 but others have sug-

gested encapsulated papillary carcinomas to be in-situlesions, by demonstrating the presence of intact base-ment membrane with collagen type IV staining.20

Genetic studies have also shown variable results, withsome showing similar genetic changes in encapsu-lated papillary carcinomas and invasive carcino-mas,21 and others showing that encapsulatedpapillary carcinomas were closer to carcinomasin situ.22 Thus, although the true genetic nature ofencapsulated papillary carcinomas remains unsettled,they may be considered either as indolent invasivecarcinomas (because of the lack of an outer myoep-ithelial cell layer) or carcinomas ‘in transition’ fromin situ to invasive.A minority of encapsulated papillary carcinomas

may be associated with an invasive component. Theinvasive component is characterized by tumour cellsshowing an infiltrative pattern extending beyond thefibrous capsule of the lesion and inducing a stromalreaction. This invasive component may be papillary,or may adopt the pattern of infiltrating duct carci-noma, no special type.Staging of encapsulated papillary carcinomas has

been controversial. If there is component of conven-tional invasive carcinoma, the stage should followonly the invasive component. In the absence ofthese invasive foci, the staging is suggested to beTis.5 The goal is to prevent overtreatment of suchlesions.23,24

Although most encapsulated papillary carcinomasare of low and intermediate nuclear grade, a distinctproportion may show high-grade cytonuclearfeatures. This group of encapsulated papillary carci-nomas are more likely to be oestrogen receptor(ER)-negative and of larger size, and are more fre-quently associated with stromal invasion.25 It is sug-gested that this group should be managed in asimilar fashion to conventional forms of invasivebreast carcinoma, based on established clinicopatho-logical parameters.25

Figure 2. Intraductal papillary carcinoma. The inset highlights

fibrovascular cores covered by neoplastic cells with low-grade

nuclei without intervening myoepithelial cells.

A B

Figure 3. A, Encapsulated

papillary carcinoma. B, p63

highlights the lack of

myoepithelial cells both around

the fibrovascular cores and at

the periphery. The inset shows

the positive myoepithelial

staining in the adjacent

normal breast tissue as a

control.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

24 Y-B Ni & G M Tse

S O L I D P A P I L L A R Y C A R C I N O M A

Solid papillary carcinomas are composed of multiplenodular masses arising from duct-like structures, andform a ‘geographical’ pattern. Although the neoplasticcell proliferation is usually cellular, and the papillarystructure is not prominent, an underlying fibrovascu-lar stromal network can still be observed. The neoplas-tic cells are oval or spindle-shaped, with low-grade tointermediate-grade nuclei. Occasionally, these epithe-lial cells may show streaming (and hence be confusedwith florid epithelial hyperplasia) or accumulation ofextracellular mucin. Very often, they also show IHCexpression of neuroendocrine markers. Frequently,these tumour cell nests lack surrounding myoepithelialcells (Figure 4),26 and they may be diagnosed as intra-ductal papillary carcinoma (with florid epithelialhyperplasia), particularly if a peripheral myoepithelialcell layer can be demonstrated. The categorization ofsolid papillary carcinomas is still controversial. In somecases, an obvious invasive component may be seen,and these tend to show mucinous or neuroendocrinedifferentiation, although other histological subtypeshave also been described.27–29 For staging purposes, itis recommended that solid papillary carcinoma withoutdefinite invasion be staged as Tis6; and when invasivefoci are present, they should be staged on the basis ofthe invasive foci only.

I N V A S I V E P A P I L L A R Y C A R C I N O M A

Primary invasive papillary carcinomas are extremelyrare,30 and their diagnosis should follow stringent cri-teria of invasive carcinomas harbouring a papillaryarchitecture with papillae formed by malignant cellsclosely related to fibrovascular cores, and possessing apermeative front.7 An in-situ component is rare, and,when present extensively, should prompt a diagnosisof papillary carcinoma (in situ) with focal invasion. Insome of the previous studies reporting on clinical out-

comes of invasive papillary carcinomas, the diagnosticcriterion was not clear, so little is known of the clinicalbehaviour of invasive papillary carcinoma when astringent diagnostic criterion is used. Survival datafrom the Netherlands Cancer Registry have demon-strated the absence of a survival difference betweenin-situ and invasive papillary lesions.2

It should be noted that metastatic papillary carcino-mas, including those from the ovary, thyroid, and lung,need to be fully ruled out when a diagnosis of primaryinvasive papillary carcinoma of the breast is made. Sec-ond, in terms of terminology, invasive papillary carci-noma should also be distinguished from invasivecarcinoma arising in conjunction with encapsulatedand solid papillary carcinomas. In the latter setting, theterm papillary carcinoma (in situ) with invasion shouldbe used. Third, invasive papillary carcinoma shouldnot be confused with invasive micropapillary carci-noma, which is an aggressive form of invasive breastcarcinoma that is more likely to be associated withlymphovascular invasion, axillary lymph node metas-tases,31,32 higher cyclin D1 expression, a higher prolif-eration rate and MYC (8q24) amplification thaninvasive carcinoma of no special type.33 Morphologi-cally, invasive micropapillary carcinomas are devoid oftrue fibrovascular cores, and are characterized by thepresence of hollow or morula-like clusters of neoplasticcells surrounded by clear spaces. The apical portion ofthe cells faces the stroma around the tumour clustersinstead of facing the central lumen of the acinar struc-ture (inside-out pattern). Electron microscopy studies34

and mucin studies35 support the concept of reverse ori-entation of tumour cells in this lesion.

Practical issues with papillary lesions of thebreast

In the characterization and differentiation of papillarylesions, there are many practical issues that are

A B

Figure 4. A, Solid papillary

carcinoma. B, Synaptophysin

highlights the neuroendocrine

differentiation.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

Papillary lesion of the breast 25

problematic for the practising pathologists in routinehandling and diagnosis. These problems mainly arisein several areas, as follows: (i) overlapping morpho-logical features among benign, atypical and malig-nant papillary lesions; (ii) overlapping IHC stainingpatterns among benign, atypical and malignant papil-lary lesions; and (iii) further management of breastpapillary lesions based on diagnosis in CNBs.

O V E R L A P P I N G M O R P H O L O G I C A L F E A T U R E S

Fibrovascular coresThe cytological and architectural patterns of benignand malignant papillary lesions show significant over-lap. Although papillomas have been described as pos-sessing broad, pinkish and fibrotic fibrovascular coresas compared with papillary carcinomas,24,36 it wasrecently reported that these broad fibrovascular coresmay also be seen in malignant (and atypical) papil-lary lesions (Figure 5).37 This highlighted the factthat the size of fibrovascular cores may not be aninfallible criterion for differentiation of papillarylesions, especially between intraductal papillomas andintraductal papillary carcinomas.

Epithelial proliferation with spindled nuclei and nuclear‘streaming’ in a solid configurationPapillary lesions are commonly complicated byepithelial proliferation. Problems in diagnosis arisewhen the proliferative epithelial cells show spindlednuclei and nuclear ‘streaming’ in a solid configura-tion. At the benign end of the spectrum, florid epithe-lial hyperplasia tends to show spindled nuclei withstreaming, whereas the less common lesion showing

an alarmingly similar morphology is solid papillarycarcinoma with neuroendocrine differentiation (Fig-ure 6). The latter lesion characteristically occurs inolder women, and tends to be slowly growing.28 Thehaematoxylin and eosin morphologies of these entitiescan sometimes be totally indistinguishable, and itmay be necessary to resort to immunohistochemistry(discussed below) to achieve reliable differentiation.

Intraductal papillomas complicated by ADH or DCISIntraductal papillomas may be complicated by super-imposed ADH or DCIS, with the latter diagnosis hav-ing more sinister implications. Nevertheless, concreteevidence of the difference in outcome has not beenwell reported. The WHO panel recommended use ofthe quantitative criterion of 3 mm.3 This differentia-tion based on a quantitative difference creates apotential problem in assigning diagnostic labels andin communication with surgeons and patients, as abiopsy from a ‘papilloma with DCIS’ may only showa <3-mm focus of atypical epithelial hyperplasia,resulting in a biopsy diagnosis of ‘papilloma withADH’. To the unwary, this may be seen erroneouslyas an undercall/false negative on the part of thepathologist.

Invasion and its mimicsTrue/frank invasion in a papillary lesion needs to bedifferentiated from mimics, including benign glandu-lar entrapment and mechanical dislodgement duringa previous biopsy.38,39 Stromal fibrosis is commonlyseen in papillomas, and epithelial components maybecome entrapped in the fibrotic area and may mimicinvasive carcinoma. However, a genuine diagnosis ofmalignancy should not be based only on an appar-ently infiltrative pattern. Instead, the diagnosis of car-cinoma must rest on the cytological and architecturalcharacteristics of the papillary tumour itself. Onlyafter having determined that a papillary tumourshows features of malignancy should one considerthe question of whether the irregular epithelial clus-ters in the adjacent fibrotic tissue reflect entrapmentor invasion. Several features are helpful, as follows(Table 1) (Figure 7): (i) in benign glandular entrap-ment, the benign epithelial cells are arranged inirregular but smoothly contoured clusters, and tendto flow in the direction of the fibroblasts and bundlesof collagen, whereas the invasive foci are seentraversing the normal stroma in different directions;(ii) the benign entrapped glandular component typi-cally shows a polygonal shape that is compressed intolong and slender cords, whereas the invasive fociretain an open and sometimes angulated glandularFigure 5. Broad fibrovascular cores in solid papillary carcinoma.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

26 Y-B Ni & G M Tse

lumen; and (iii) myoepithelial cells are alwaysretained, albeit sometimes attenuated in theentrapped benign glands, and these can be high-

lighted by IHC staining, whereas the invasive foci aredevoid of myoepithelial cells.Mechanical displacement of the epithelium is par-

ticularly prone to occur in encapsulated papillary car-cinoma when the capsule is punctured by the corebiopsy needle, as friable tumour fragments escapetogether with cyst fluid.40 Its differentiation fromtrue/frank invasion is best determined by histologicalexamination, as IHC staining for myoepithelial cellswill not be helpful in this setting,38,41 because bothdifferentials are negative for mypepithelial cells. Thepossible clues are the associated haemorrhage, hae-mosiderin-laden macrophages, fat necrosis, inflamma-tion, granulation tissue, and possible needle tractreaction. However, one should also keep in mind thepossibility of stromal invasion in an area that wasadjacent, by chance, to the needle tract.

O V E R L A P P I N G I H C F E A T U R E S

The use of IHC staining in the evaluation of papillarylesions has become routine. The most frequently usedgroups of markers include p63, high molecularweight cytokeratins (HMWCKs), and hormone recep-tors, mostly ER. The IHC phenotypes of papillarylesions are summarized by the WHO panel (Table 2).4

It is generally accepted that, in benign papillarylesions, p63 and HMWCKs are positive, and ER showsheterogeneous staining. For malignant lesions, p63and HMWCKs are negative, and ER shows homoge-neous staining. There are, however, many exceptionsto these rules, and sometimes these rules can be diffi-cult to apply.For hormone receptors such as ER, homogeneous

or heterogeneous staining has not been well defined,and thus can be difficult to differentiate; as a result,this criterion alone may not be very reliable. In astudy focusing on the IHC panel of cases with incon-sistent diagnosis on CNB and excisional specimens,ER homogeneous staining was arbitrarily defined asuniform strong nuclear reactivity of >60% of the

A B

Figure 6. Epithelial

proliferation with spindled

nuclei and nuclear ‘streaming’.

A, Florid hyperplasia in

intraductal papilloma. B, Solid

papillary carcinoma.

Table 1. Features that are helpful in differentiating benignglandular entrapment and invasive foci

FeaturesBenign glandularentrapment Invasive foci

Arrangement ofepithelial cells

Irregular but smoothlycontoured clusters,flow in the directionof the fibroblasts andbundles of collagen

Traversing thenormal stroma indifferent directions

Architectures ofepithelial cellclusters

Polygonal shapecompressed into longand slender cords

Open andsometimesangulated lumen

Myoepithelialcells

Present Absent

Figure 7. Benign glandular entrapment in intraductal papilloma.

The epithelial cells are arranged in irregular but smoothly con-

toured clusters, and are compressed by the collagenized stroma.

They tend to flow in the direction of bundles of collagen. The inset

shows that p63 highlights myoepithelial cells surrounding the

entrapped epithelial cells.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

Papillary lesion of the breast 27

epithelial cells, and 30% (3/10) of papillary carcino-mas were underdiagnosed as benign lesions, whereas67% (2/3) of benign papillary lesions were overdiag-nosed as malignant in CNB specimens.42 Strong anddiffuse ER staining has also been noted in 5% (1/20)of benign papillary lesions in another cohort.43 Inour routine diagnostic work, homogeneous ER stain-ing has also been encountered in papillomas, notablywhen there is a columnar cell-type change seen inthe lining epithelium (Figure 8).p63 is usually used as a myoepithelial marker.

Unlike other myoepithelial markers, p63 showsnuclear staining and minimal cross-reactivity withstromal cells or myofibroblastas, and is thus consid-ered to be a superior myoepithelial marker for diag-nosis.44 When applying a myoepithelial marker forcharacterization of papillary lesions, one has to bemeticulous about the location of the myoepithelialcells. In general, myoepithelial cells in papillarylesions can be considered to reside in two differentcompartments, either within the lesion around thefibrovascular cores, or around the lesion at the duct

wall. It is by assessing myoepithelial cells around thefibrovascular cores inside the lesion that one can dif-ferentiate between benign and malignant papillary

Table 2. Immunohistochemical features of papillary lesions of the breast (adapted from World Health Organization 20124)

p63

HMWCKs Hormonal receptorsPapillary frondsPeripheryof lesion

Intraductal papilloma Positive Positive Positive:Myoepithelial cellsUDH (heterogeneous positivity)Negative:Apocrine metaplasia

Positive (patchy):Luminal cellsUDH (heterogeneouspositivity)Negative:Apocrine metaplasia

Papilloma with ADH orDICS

Positive in papilloma;may be scant in theADH/DCIScomponent

Positive Positive:Myoepithelial cellsUDH (heterogeneous positivity)Negative:Apocrine metaplasiaADH/DCIS

Positive (patchy):Luminal cellsUDH (heterogeneouspositivity)Negative:Apocrine metaplasiaPositive, strong anddiffuse:ADH/DCIS

Intraductal papillarycarcinoma

Negative Positive Negative:

Neoplastic cell population

Positive, strong and diffuse:Neoplastic cell population

Encapsulated papillarycarcinoma

Negative Usually negative Negative:

Neoplastic cell population

Positive, strong and diffuse:Neoplastic cell population

Solid papillarycarcinoma

Solid-papillary areas arenegative

May be negativeor positive

Negative Positive, strong and diffuse

ADH, Atypical ductal hyperplasia; DCIS, Ductal carcinoma in situ; HMWCK, High molecular weight cytokeratin; UDH, Usual ductal hyper-

plasia.

Figure 8. Homogeneous staining for oestrogen receptor (inset) in

intraductal papilloma.

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

28 Y-B Ni & G M Tse

lesions. In general, papillomas have a complete, read-ily demonstrable myoepithelial layer around fibrovas-cular cores, whereas papillary carcinomas tend tolose this layer. In contrast, whereas benign papillarylesions usually show a surrounding myoepithelial celllayer at the duct wall, malignant papillary lesionsmay or may not show an outer myoepithelial celllayer – and the absence of an outer myoepithelial celllayer does not automatically imply invasion. Lesionsthat are categorized as in-situ carcinoma, includingencapsulated papillary carcinomas and some solidpapillary carcinomas, can be devoid of an outermyoepithelial lining (Figure 3).5,6

High molecular weight cytokeratins play an impor-tant role in the evaluation of the nature of any of thesolid epithelial proliferations that frequently compli-cate papillary lesions.45 In general, benign epithelialproliferations (UDH and florid hyperplasia) expressHMWCKs, whereas atypical epithelial proliferations(ADH and DCIS) do not. This is a well-documentedpractice, and the only potential problem is thatHMWCKs should only be evaluated in the solid areas,and not in the papillary areas. Benign luminal cellslining the papillary fibrovascular cores do not alwaysexpress HMWCKs, so a casual observation may resultin an erroneous diagnosis of atypical/malignant papil-lary lesion in a benign papilloma with only scantyluminal epithelium dotting the fibrovascular coresand not expressing HMWCKs.Some authors have also suggested the use of com-

bination of biomarkers, as this may enhance the sen-sitivity and specificity in making a specific diagnosis:the combination of cytokeratin (CK) 5/6 and ER hasbeen recommended for identifying atypical papillarylesions43; another study has recommended CK5/6,p63, and neuroendocrine markers46; and others havesuggested ER and MUC3 in papillary DCIS, but CK5/6and p63 in intraductal papillomas.47 A study usedCK8/18, a luminal cytokeratin, as a component of aCK5/CK8/18/p63 cocktail, and this resulted in 100%sensitivity48; another study showed that a combina-tion of HMWCKs, namely CK5/6, CK14, and 34bE12,gave the best overall specificity and sensitivity foridentifying malignant papillary lesions based only ontheir staining of different morphological patterns,without identifying cell types.49 Thus, the use of morethan one marker is recommended.

F U R T H E R M A N A G E M E N T O F B R E A S T P A P I L L A R Y

L E S I O N S B A S E D O N D I A G N O S I S I N C N B

Core needle biopsy has gained wide acceptance in thediagnosis of breast papillary lesions. The subsequent

management of CNB-diagnosed atypical or malignantpapillary lesions is well established. Malignant papil-lary lesions need to be surgically excised. Atypicalpapillary lesions also need to be excised to determinewhether a more significant lesion is present. How-ever, the management of CNB-diagnosed benign pap-illary lesions is more controversial. A meta-analysisrescreening studies conducted between January 1985and March 2012 demonstrated a substantial risk ofupgrading after surgical excision for CNB-diagnosednon-malignant breast papillary lesions, with a pooledunderestimation rate of 15.7%.50 Subsequent studiesreported a range of 3–33% of CNB-diagnosed benignpapillary lesions being upgraded to atypical or malig-nant categories in surgical excision or imaging fol-low-up.51–62 A topographical and histopathologicalstudy found that ~25% of DCISs associated withpapilloma had a potential risk of sampling error insmall samples of CNBs, owing to an eccentric distri-bution or a low proportion of DCIS within the papil-loma, whereas radiology showed segmentalabnormalities in 83% of these cases.63

Thus, for this group of CNB-diagnosed non-malig-nant papillary lesions, some authors have recom-mended surgical excision, whereas others havesuggested close imaging follow-up, rather than inva-sive surgical procedures. Others have recommendedsurgical excision when segmental abnormalities areseen radiologically, because this might suggest coex-isting DCIS.63

Larger tissue samples significantly improved thepredictive value of benign histology on CNB.61 Papil-lomas sampled with a 12-gauge or larger needle,seven or more cores, or >96 mm may retain theirbenign features upon excision.56

The new adjunct biomarkers and geneticaberrations in differentiating benign andmalignant papillary lesions

Owing to the diagnostic challenge posed by papillarylesions, recent studies have evaluated new biomarkersto differentiate benign papillary lesions from atypicalor malignant ones. Cell cycle markers, includingcyclin B1 and cyclin D1, are independently associatedwith malignancy in papillary lesions. Cyclin B1 wasfound to be useful for identifying malignant papillarylesions (sensitivity, 80%; specificity, 72.7%), whereascyclin D1 showed lower specificity (sensitivity, 86.4%;specificity, 32.6%).64 Cancer stem cell markers havealso been investigated. In an early small cohort,CD44 expression in papillomas was significantly

© 2015 John Wiley & Sons Ltd, Histopathology, 68, 22–32.

Papillary lesion of the breast 29

higher than that in papillary carcinomas.65 Subse-quently, in a larger cohort of 160 cases, the absenceof CD44 expression was useful for identifying malig-nant papillary lesions (sensitivity, 49.1%; specificity,90%).66 Recently, the absence of CD133 expressionwas also found to be useful for identifying malignantpapillary lesions (sensitivity, 96.8%; specificity,91.4%).67

The pathogenesis of breast papillary lesions is stillenigmatic. Relatively few studies have characterizedmolecular or cell-biological aberrations in papillarylesions. However, the genetic alterations that havebeen identified may be helpful in understanding thepathogenesis and in differential diagnosis. Alterationsin chromosomes 3, 7, 17 and X have been detectedin papillary carcinoma but not in papilloma.68 Chro-mosome 16 mutations have been reported in theearly steps of breast papillary tumorigenesis. A highfrequency of loss of heterozygosity (LOH) at chromo-some 16p13 and 16q21 was detected both in intra-ductal papillomas and papillary carcinomas, whereasLOH at locus 16q23 was limited to malignant lesions.LOH at the TP53 locus is also significantly associatedwith the malignant phenotype.69–71 Additionally, ahigher PIK3CA or AKT mutation frequency was iden-tified in papillomas than in papillary carcinomas,indicating that papillomas could be driven by muta-tions in the PIK3CA–AKT pathway, whereas papillarycarcinomas might develop along a molecular path-way that is somewhat divergent from that of mostbenign papillary proliferations.72

Gene profiling on papillary carcinomas demon-strated that most of them (93.8%, 15/16) could beclassified as the luminal subtype, with the fewremaining cases being of the basal-like subtype. Oncomparison with grade-matched and ER-matchedinvasive carcinomas of no special type, papillary car-cinomas show similar patterns of DNA copy numberalterations, but different transcriptomic profiles, withdown-regulation of proliferation-related, cell assemblyand organization, cellular movement and migrationgenes, and overexpression of genes related to home-ostasis and angiogenesis, suggesting a less invasivephenotype.73 Regarding the distinct papillary histo-logical subtypes, encapsulated papillary carcinoma,solid papillary carcinoma and invasive papillary carci-noma showed similar array-based comparative geno-mic hybridization profiles,21 suggesting that they maybe histological variants of the same entity. However,differences in the transcriptomic profiles related to cellmigration have been found among them, and mayaccount for their different histological features.73

Thus, at present, our knowledge about the genetic

changes of papillary lesions is still limited, and theexact molecular pathogenesis and whether the cur-rent histology-based classification has any molecularbasis remain to be determined.

Conclusions

Papillary lesions include a broad spectrum of lesions,ranging from benign to malignant. Their differentialdiagnoses remain difficult. Although the histology ofthese lesions is now better characterized, there arestill many overlapping features, such as broadfibrovascular cores, epithelial proliferation with spin-dled nuclei and nuclear ‘streaming’ in a solid configu-ration, intraductal papillomas complicated by ADH orDCIS, and invasion and its mimics. The use ofimmunohistochemistry is extremely useful, but oneshould be meticulous in the interpretation, especiallyover the issues of heterogeneous or homogeneousstaining of ER, the location of the myoepithelial cells,and the interpretation of HMWCK expression withinthe lesions. Some novel biomarkers have been pro-posed to be useful for differentiating between benignand malignant papillary lesions. Different geneticaberrations have been identified in different papillarylesions, but their clinical application requires furthervalidation. Pre-excision samples obtained with CNBcan be difficult to interpret, and may result inunavoidable undercall, as the full extent of the lesionmay not be assessable in CNBs. When a difficult CNBis reported, the potential for underdiagnosis should becommunicated to the surgeons. The optimal manage-ment of patients with papillary lesions of the breastrequires full cooperation and understanding amongthe surgeons, radiologists, and pathologists.

Conflicts of interest

The authors state that they have no conflicts ofinterest.

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