papillary and neuroendocrine breast lesions: the who stance

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/his.12463 This article is protected by copyright. All rights reserved.

Received Date : 27-Feb-2014

Revised Date : 13-May-2014

Accepted Date : 16-May-2014

Article type : Review

Papillary and neuroendocrine breast lesions: the WHO stance

Puay Hoon Tan, FRCPA

1Stuart J Schnitt, MD

2Marc J van de Vijver, MD

3Ian O Ellis, FRCPath

4Sunil R Lakhani, FRCPA

Department of Pathology, Singapore General Hospital, Singapore

1Beth Israel Deaconess Medical Center, Boston, USA

2Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands

3University of Nottingham, Nottingham City Hospital NHS Trust, Nottingham, United

Kingdom

4Department of Anatomical Pathology, Pathology Queensland; Department of Molecular and

Cellular Pathology, School of Medicine, University of Queensland; University of Queensland

Centre for Clinical Research, The Royal Brisbane & Women's Hospital, Brisbane,

Queensland, Australia

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This article is protected by copyright. All rights reserved.

Correspondence to:

Dr Puay Hoon Tan

Department of Pathology, Singapore General Hospital

Level 7, Diagnostics Tower, Academia

20 College Road, Singapore 169856

Tel: 65 63214874

Fax: 65 62226826

Email: [email protected]

Running head: papillary and neuroendocrine lesions

Abstract

In this review, we highlight adaptations in the WHO 2012 classification of papillary and

neuroendocrine breast lesions as compared to the previous 2003 version. Consensus criteria

for distinguishing atypical ductal hyperplasia from ductal carcinoma in situ within an

intraductal papilloma are proposed. Absence of myoepithelial cells around the wall of an

encapsulated papillary carcinoma, while raising consideration of an indolent tumour with

minimal invasion, is currently regarded as in situ disease for staging purposes. The majority

of solid papillary carcinomas are classified as in situ tumours, but lesions with irregular

tumour islands within desmoplastic stroma may be considered invasive. Diagnosis of solid

papillary carcinoma without further qualification as either in situ or invasive disease is

discouraged. When invasive papillary carcinoma is seen in the breast, metastatic papillary

carcinoma from other organ sites needs to be excluded.

WHO 2012 classifies neuroendocrine breast tumours into well differentiated neuroendocrine

tumour, small cell carcinoma, and invasive breast carcinoma with neuroendocrine

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differentiation. There is currently no clinical impact of identifying neuroendocrine

differentiation in conventional invasive breast carcinomas apart from acknowledging its

frequent occurrence in subtypes such as the hypercellular variant of mucinous carcinoma and

solid papillary carcinoma.

Key words: World Health Organisation, classification, papillary tumours, neuroendocrine

differentiation

Introduction

Pathological classification of breast tumours allows their categorisation into morphologically

distinct groups, promoting understanding of different breast diseases and their biological

behaviour. The recently published 4th edition of the World Health Organisation (WHO)

Classification of Breast Tumours, with contributions from an international panel of breast

pathologists, is a volume that is entirely dedicated to the description of breast tumours for the

purpose of standardizing classification worldwide [1]. In addition to microscopic criteria that

define tumour types, there is incorporation of relevant updated molecular information as well.

In this review, we focus on papillary and neuroendocrine breast tumours, commenting on

changes from the previous edition of the WHO classification [2], and expand on the basis and

concepts of categorising these entities from the WHO perspective.

Papillary breast lesions

In the most recent 4th edition of the WHO classification of breast tumours, papillary lesions

include the intraductal papilloma (including both central and peripheral varieties within this

section), intraductal papillary carcinoma, encapsulated papillary carcinoma and solid

papillary carcinoma. In comparison, the previous edition (3rd edition) published in 2003

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contained separate sections for central, peripheral and atypical papillomas [2]. The atypical

papilloma was defined in that edition as harbouring the presence of focal atypical epithelial

proliferation with low grade nuclei, resembling atypical ductal hyperplasia (ADH) or small

foci of low grade ductal carcinoma in situ (DCIS), with an uncertain risk of progression to

invasive breast cancer which was thought to be similar to the non-atypical papilloma if atypia

was confined within papilloma, and a higher risk if atypia was observed outside the

papilloma [2, 3]. The term ‘atypical papilloma’ is avoided in the 4th edition. Instead, specific

histological criteria for ADH and DCIS occurring within an intraductal papilloma are

elaborated (described below), and the risk of subsequent invasive breast cancer development

in such lesions is believed to be increased to 7.5x that of the general population, with an

ipsilateral predominance [4]. In a separate study, relative risk for intraductal papillomas with

ADH or atypical lobular hyperplasia was similar to that when atypical hyperplasia occurred

in breast parenchyma in the absence of papilloma, with the risk being bilateral [5].

The handling of papillary lesions on small biopsies was not encompassed in the scope of the

WHO classification. While the presence of atypical features or carcinoma in a papillary

neoplasm on core biopsy necessitates surgical excision, whether a papillary lesion with

benign appearances observed on core biopsy similarly requires excision is less clear [6]. An

approach adopted at many institutions and screening programs is for partially sampled benign

papillary lesions to be completely excised due to the risk of undersampling a worse lesion [6-

8], and this may be accomplished through a mammotome procedure. Some studies however,

suggest that papillary lesions with benign findings on core biopsy may be followed up [9-11].

Micropapillomas that are incidentally discovered on core biopsies do not require further

management.

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Intraductal papilloma with ADH and DCIS

The previously used term ‘atypical papilloma’ encompassed both ADH and DCIS within an

intraductal papilloma. Apart from being ambiguous and lacking precision, this term lumps

two different entities under the same umbrella, merging a benign alteration (ADH) with a

malignant one (DCIS) in an ‘atypical’ category. In the current 4th edition, criteria used to

define ADH and DCIS within an intraductal papilloma are clearly provided [1]. While

proportion of involvement of the intraductal papilloma by the abnormal epithelial

proliferation has been used by some authors to distinguish ADH from DCIS [12, 13], the

2012 WHO Working Group recommends relying on size as a criterion, with 3 mm being the

cutoff (figure 1). A low nuclear grade atypical epithelial proliferation measuring less than 3

mm within an intraductal papilloma is diagnosed as ADH, whereas a similar

cytoarchitecturally abnormal epithelial population measuring 3 mm or more is regarded as

DCIS within an intraductal papilloma [4]. It is acknowledged that scientific evidence for this

size criterion is lacking [14, 15] but the WHO Working Group has adopted this as a

pragmatic guideline that allows broad application to routine diagnostic practice. An

advantage is in the consistency of defining a measurable threshold size whereas the approach

using proportion of involvement results in variability depending on the size of the papilloma.

When the abnormal epithelial proliferation shows intermediate or high nuclear grade, DCIS

should be diagnosed regardless of extent.

The WHO 4th edition also makes a distinction of papilloma with DCIS from papillary

DCIS/intraductal carcinoma. Papillary DCIS is considered a de novo in situ malignant

papillary process without a morphologically recognisable benign papilloma in its

background. In contrast, papilloma with DCIS shows an underlying, identifiable benign

papilloma upon which the abnormal epithelial proliferation is engrafted.

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Intraductal papillary carcinoma

Synonymous with papillary DCIS, intraductal papillary carcinoma is accorded a more

expanded account in the 4th edition [1]. The previous volume had required that 90% or more

of papillary processes be completely lacking myoepithelial cells, or that conventional forms

of low grade DCIS be found in 90% or more of the papillary lesion, in order for a diagnosis

of intraductal papillary carcinoma to be made [2]. While the paucity or absence of

myoepithelial cells is a recognised criterion for intraductal papillary carcinoma, the presence

of myoepithelial cells does not negate its diagnosis if other features are characteristic, such as

a monotonous epithelial cell population, intermediate or high nuclear grade features, and

slender fibrovascular cores within which the malignant intraductal papillary process is

present (figure 2). Myoepithelial cells, whether observed on light microscopy or detected

using immunohistochemistry, are interpreted by some authorities as evidence of an

underlying benign papilloma [6], although it may be possible that these myoepithelial cells

are drawn from those surrounding the duct wall as the neoplastic papillae form. The presence

of a dimorphic population with a clear cell component arranged along the basement

membrane that mimics myoepithelial cells is mentioned as a morphological variant of

intraductal papillary carcinoma in the 4th edition [1].

We advocate a panel approach in the use of antibodies to demonstrate myoepithelial cells on

immunohistochemistry. The WHO working group recommends using a 2 to 3 antibody panel

that is selected depending on the type of breast lesion being assessed. For papillary

neoplasms, there is a spectrum of anti-myoepithelial antibodies that can be applied. Apart

from p63 which is widely used as a myoepithelial marker, both CK14 and CK5, amongst

others, are also useful. CK14, like CK5, decorates not only myoepithelial cells but can assist

in distinguishing benign intraductal papilloma with usual ductal hyperplasia from intraductal

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papillary carcinoma. CK14 and CK5 both highlight preserved myoepithelial cells as well as

display heterogeneous positivity in the hyperplastic epithelium of the benign intraductal

papilloma, while they reveal diminished staining in intraductal papillary carcinoma.

Conventional forms of DCIS existing within or partially effacing an intraductal papilloma are

not diagnosed as intraductal papillary carcinoma, but as DCIS within an intraductal

papilloma. A diagnosis of an intraductal papillary carcinoma requires the malignant process

to recapitulate a papillary architecture.

Intraductal papillary carcinoma is often seen with other morphological patterns of DCIS, such

as cribriform, comedo, micropapillary and solid morphologies. Because there is often an

admixture of different architectural patterns in DCIS, there is no specific clinical significance

of any one pattern, and DCIS classification relies primarily on nuclear grade. There are also

no universally defined proportion criteria to designate a pure papillary DCIS in the presence

of other DCIS patterns. However, if there is an overwhelming predominance of a papillary

architecture with only a small amount of other patterns, classification as papillary DCIS is

appropriate.

Encapsulated papillary carcinoma

The 4th edition preferentially uses the term ‘encapsulated papillary carcinoma’ to describe

this entity due to the presence of a thick fibrous capsule that surrounds the tumour, while

acknowledging synonyms of intracystic papillary carcinoma and encysted papillary

carcinoma.

In the previous 3rd edition, ‘intracystic papillary carcinoma’ was the nomenclature used for

this lesion which was regarded as a variant of intraductal papillary carcinoma. It was stated

that ‘a myoepithelial cell layer is usually present in the lining of the duct wall into which the

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papillary carcinoma proliferates’ [2]. Solid and transitional cell variants were described, with

the former being accompanied by mucin and neuroendocrine differentiation, while the latter

contained a proliferation of cells of ‘transitional’ type, though what constituted ‘transitional’

type cells was not clearly stated.

The WHO Working Group for the 4th edition regards encapsulated papillary carcinoma as a

variant of papillary carcinoma, with myoepithelial cells that are absent within the papillae as

well as around the periphery of the tumour (figure 3). The lack of myoepithelial cells at the

periphery is noted on routine light microscopy and corroborated on immunohistochemistry

with a wide panel of myoepithelial markers [16-18]. As an intact myoepithelial cell layer has

been a long-held criterion for absence of invasion, this observation of its loss has led to

postulates that the encapsulated papillary carcinoma may be an indolent tumour with pushing

rounded invasion, or a minimally invasive form of low-grade carcinoma [16, 18]. Other

hypotheses include considering the encapsulated papillary carcinoma as a tumour in

transition from an in situ to invasive phase [17, 18]. Studies that immunohistochemically

evaluated the basement membrane component of these tumours found discontinuity of type

IV collagen in 89% of cases [19], or moderate to intense expression of type IV collagen in

encapsulated papillary carcinomas compared to its diminished staining or absence in invasive

disease [17]. The rare finding of axillary lymph node metastases in typical encapsulated

papillary carcinomas is another argument in favour of an invasive process [17, 20], while

documentation of invasion-associated markers with expression patterns intermediate in nature

between DCIS and invasive cancer in this tumour also lends weight to its unique biological

position straddling in situ and invasive disease [21].

Despite ongoing debate regarding the true biological state of this tumour, the WHO Working

Group advocates that the encapsulated papillary carcinoma be staged as Tis (in situ

carcinoma), an approach supported by reports of its indolent behaviour [17, 22, 23]. The

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diagnosis of invasion should be made only when there are permeative epithelial islands

extending beyond the fibrous capsule. This is usually of conventional invasive breast

adenocarcinoma morphology and typically of no special type (invasive ductal carcinoma). In

such cases the invasive tumour size is measured according to the largest extent of the frankly

invasive component, without including the size of the adjacent encapsulated papillary

carcinoma into the overall measurement of T stage [1]. Entrapped epithelial nests subsequent

to needling procedures can mimic invasion and have to be distinguished from true invasion.

Solid papillary carcinoma

Solid papillary carcinoma was not accorded a discrete section in the previous WHO volume.

It was briefly alluded to under the chapter of ‘intracystic papillary carcinoma’ as a solid

variant, while the separate segment on ‘solid neuroendocrine carcinoma’ may be regarded as

a description of this entity [2].

In comparison, the solid papillary carcinoma is described in detail in the latest 2012 edition

[1]. Here, it is defined as a distinctive form of papillary carcinoma composed of expansile

cellular nodules invested by inconspicuous delicate fibrovascular cores, leading to a

morphologically solid growth pattern at low magnification. Neuroendocrine differentiation,

spindle cell morphology and mucin production are frequent (figure 4). A single large

expansile mass or multiple solid closely apposed nodules may be seen. Myoepithelial cells

may be present or absent at the periphery of these nodules, as shown on

immunohistochemistry with myoepithelial markers [24]. Lesions in which myoepithelial

cells are demonstrated around the solid epithelial nodules are regarded as variants of DCIS.

For those composed of rounded nodular masses without any surrounding myoepithelial cells,

the WHO Working Group recommends interpreting them as in situ disease for staging

purposes. A similar concept concerning the status of such lesions as a special rounded form

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of invasive disease with indolent behaviour and extremely favourable prognosis is proposed

[23]. Metastasis can be encountered in the absence of established invasion but is rare [24].

However, irregularly shaped epithelial islands with jagged contours devoid of myoepithelial

cell cuffs, arranged in a geographic jig-saw pattern set within a desmoplastic stroma (figure

5), may be diagnosed as invasive solid papillary carcinoma [1].

While the majority of solid papillary carcinomas are considered equivalent to in situ disease,

this unique morphological pattern of solid papillary carcinoma can also incorporate invasive

forms as described above. In order to avoid ambiguity and to allow appropriate classification

and clinical management, it is therefore useful to explicitly state if a particular case of solid

papillary carcinoma is histologically regarded as in situ cancer, or if it fulfils microscopic

features of the invasive counterpart. A diagnosis of “solid papillary carcinoma” without

further qualification is not recommended.

Conventional forms of invasive carcinoma, such as mucinous carcinoma and carcinomas of

no special type (invasive ductal carcinoma), may be seen arising in association with solid

papillary carcinoma, and should be classified and staged accordingly.

Invasive papillary carcinoma

In the current 4th edition of the WHO breast tumour classification, invasive papillary

carcinoma is relegated to the section of ‘rare types’ of invasive breast carcinoma [1]. This

tumour subtype has likely endured misclassification in the past, with the literature having

included both in situ and invasive forms under the same umbrella [2]. The illustration

provided in the 3rd edition demonstrated an encapsulated papillary carcinoma with adjoining

infiltrative carcinoma (no special type), and did not exemplify invasive papillary carcinoma.

Invasive papillary carcinoma in its pure form, defined as revealing a papillary architecture in

more than 90% of its invasive component, is rare (figure 6). Papillary metastases from other

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organ sites such as the lung and ovary ought to be considered when an invasive carcinoma

with a predominantly papillary pattern is encountered in the breast [1]. While its rarity has

prevented firm prognostic conclusions of invasive papillary breast carcinoma, with most

reports linking its behaviour to grade and stage, recent data have suggested a favourable

clinical outcome [25].

Carcinomas with neuroendocrine differentiation

Evidence of neuroendocrine differentiation in breast tumours has been investigated and

deliberated for decades with little consensus on the significance of its presence [26-39]. Part

of this uncertainty is likely related to differing definitions of what constitutes neuroendocrine

differentiation, leading to inconsistencies in classification of this group of tumours. In

earlier days, argyrophilia was often regarded as a histochemical surrogate for neuroendocrine

differentiation [40, 41], with corroboration on electron microscopy [39, 42, 43]. Although

argyrophilia was reportedly detected in approximately 25% of breast carcinomas, only about

6% of breast carcinomas with argyrophilia were believed to be truly neuroendocrine in

nature; in the rest of the cases, the argyrophilia was attributed to secretory features [40].

Similarly, ultrastructural dense core granules could reflect secretory products rather than

neuroendocrine granules [44].

With the advent of immunohistochemistry, positive reactivity of tumour cells for

neuroendocrine markers such as synaptophysin and chromogranin has served as light

microscopic evidence of neuroendocrine differentiation [26, 29, 32-35, 45]. A recent study

demonstrated that a subset of breast cancers that lacked immunohistochemical expression of

neuroendocrine markers exhibited upregulation of neuroendocrine related genes, but the

significance of this observation is not clear [46].

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Among all invasive breast cancers, neuroendocrine differentiation has been reported in 4% to

30% of cases [1, 15, 26, 35, 46] based on immunohistochemistry. The wide range in the

reported frequency of neuroendocrine differentiation is likely related to a variety of factors

including the particular markers studied and the threshold used for marker positivity. Special

type breast cancers with frequent neuroendocrine marker expression are the hypercellular

(Capella type B) variant of mucinous carcinoma and solid papillary carcinoma [1].

In the 2003 edition of the WHO breast tumour classification, primary neuroendocrine breast

carcinomas were defined as a group of neoplasms displaying morphological features similar

to neuroendocrine tumours of the gastrointestinal tract and lung, with expression of

neuroendocrine markers in more than 50% of the tumour cell population. Invasive

carcinomas, not otherwise specified, with focal neuroendocrine differentiation, were excluded

from this classification [2]. With this approach, the categories of neuroendocrine breast

tumours described were solid neuroendocrine carcinoma originating from solid papillary

carcinoma; small cell/oat cell carcinoma morphologically resembling the lung counterpart;

large cell neuroendocrine carcinoma, also similar to that encountered in the lung; and

metastatic carcinoid.

The 2012 WHO Working Group acknowledged that the 50% threshold of

immunohistochemical expression for delineating a breast tumour as neuroendocrine was

arbitrary. As with the 2003 edition, the WHO 2012 definition of breast carcinomas with

neuroendocrine features is maintained as those with morphological features similar to

neuroendocrine tumours of the gastrointestinal tract and lung. Additionally, invasive

carcinomas, both special and non special types, with neuroendocrine differentiation, are

included in this group without requiring a specific threshold for neuroendocrine marker

positivity [1]. Thus, breast tumours with neuroendocrine features are classified into 3 groups:

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neuroendocrine tumour, well differentiated (carcinoid-like); neuroendocrine carcinoma,

poorly differentiated or small cell carcinoma; and invasive carcinoma with neuroendocrine

differentiation. This allows taxonomic simplification of this spectrum of morphologically

heterogeneous tumours, with emphasis on clinically and diagnostically relevant subsets.

Harmonisation of terminology with that used to classify neuroendocrine tumours of the

gastrointestinal tract and lung is also achieved for the first 2 groups of breast tumours with

neuroendocrine features.

Neuroendocrine tumour, well differentiated

These are usually low nuclear grade and sometimes intermediate nuclear grade invasive

carcinomas that resemble the carcinoid tumour occurring in the gastrointestinal tract and lung.

They are composed of tumour cells that may assume spindle and plasmacytoid appearances

with occasional clear cell features [1]. When seen in the breast, the possibility of metastatic

carcinoid originating from another primary organ site should be excluded [15, 47]. Presence

of accompanying in situ carcinoma [15] and positive immunohistochemical reactivity for

CK7, gross cystic disease fluid protein and mammaglobin support a primary breast origin

[47].

Neuroendocrine carcinoma, poorly differentiated/small cell carcinoma

Morphologically identical to similar tumours of the lung, occurrence of these tumours in the

breast also warrant the need to exclude the possibility of a metastatic lesion. An in situ

component [48, 49] and concurrent invasive carcinoma of ductal or lobular subtypes favour a

primary breast origin [49]. Histologically, these tumours show high nuclear-cytoplasmic

ratios, smoky dense chromatin, nuclear moulding, a brisk mitotic rate, areas of necrosis and

frequent lymphovascular emboli (figure 7). Immunohistochemical presence of thyroid

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transcription factor 1 (TTF1) cannot be used to verify a lung origin since this marker is also

expressed by a large proportion of extrapulmonary small cell carcinomas [50]. While there

are reports of aggressive behaviour of small cell carcinoma of the breast, it has been

suggested that the prognosis may not be as dire as originally thought [49].

Large cell neuroendocrine carcinoma, poorly differentiated, can also be encountered though

these tumours would most likely be relegated to the poorly differentiated invasive breast

carcinomas with neuroendocrine differentiation.

Invasive breast carcinoma with neuroendocrine differentiation

These are invasive carcinomas with special type or no special type histomorphology that are

accompanied by neuroendocrine differentiation [1] (figure 8). The hypercellular variant of

mucinous carcinoma and the invasive form of solid papillary carcinoma contribute to a

significant proportion of such tumours. As immunohistochemistry for neuroendocrine

markers is not routinely performed on all invasive breast carcinomas, an exact estimate of

neuroendocrine differentiation is not available although, as noted above, there are reports of

up to 30% disclosing neuroendocrine marker expression [1].

As neuroendocrine differentiation can be seen in several morphological subtypes of invasive

breast carcinoma, the recommendation is to primarily classify these tumours according to the

recognisable histological subtype, appending the accompaniment of neuroendocrine

expression if present. For instance, if a solid papillary carcinoma histologically shows

invasive characteristics and also demonstrates neuroendocrine expression, it should be

diagnosed as solid papillary carcinoma (invasive) with neuroendocrine differentiation.

Synaptophysin and chromogranin are considered the most specific markers for

neuroendocrine differentiation and form a commonly used neuroendocrine marker panel [51].

While antibodies to neuron specific enolase and CD56 can be more sensitive and have been

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utilised by some authors, they are less specific and if applied to a case, it is recommended

that they be regarded for screening only and not for confirmation of neuroendocrine

differentiation [51]. Hormone receptors (ER and PR) are frequently expressed while HER2 is

usually negative in these tumours. It has been suggested that assessment of proliferative

index with Ki67 may offer more useful information than mitotic count in prognostication of

breast carcinomas with neuroendocrine differentiation [28].

The clinical implication of identifying neuroendocrine differentiation in invasive breast

carcinomas is uncertain, with some reports suggesting that this has no prognostic value [29,

32, 34, 35] and others suggesting that it is associated with either a better [30, 31, 33] or a

worse [26, 27] prognosis. Some of the difficulty in determining if there is prognostic impact

lies in the heterogeneity of tumours encompassed under this rubric of neuroendocrine

tumours, with inclusion of both indolent special subtypes as well as the aggressive high grade

carcinomas. Until more conclusive data become available, it appears that there is currently

no specific prognostic value in determining neuroendocrine differentiation in conventional

invasive breast carcinomas, other than recognising its frequent occurrence in certain special

subtypes whereby its presence may be of diagnostic utility, such as in solid papillary

carcinoma.

Conclusion

The WHO perspectives on the classification of papillary and neuroendocrine breast lesions

are elaborated, based on underpinning principles of a consensus pragmatic approach with

provision of reproducible criteria that can be applied to routine surgical pathology practice

from a global standpoint. Nomenclature and taxonomy continue to evolve as more scientific

data become available through research and technological advances. In particular, an

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increasing understanding of the molecular and genomic alterations underlying various breast

cancer subtypes will further change the manner in which we classify breast tumours.

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Figure legends

Figure 1. A. Intraductal papilloma with an atypical epithelial proliferation measuring more than 3 mm in maximal dimension, fulfilling criteria for low nuclear grade ductal carcinoma in situ within an intraductal papilloma. B. Immunohistochemistry for CK14 shows diminished staining among the atypical epithelial cell population, while decorating myoepithelial cells lining some of the papillary fronds.

Figure 2. Intraductal papillary carcinoma (papillary ductal carcinoma in situ) shows papillary fronds covered by stratified columnar cells with uniform hyperchromatic nuclei.

Figure 3. A. Encapsulated papillary carcinoma with a rounded fibrous wall enclosing anastomosing papillary fronds projecting into a cystic space. B. Immunohistochemistry for the myoepithelial marker p63 shows absence of myoepithelial cells in the wall of the lesion.

Figure 4. A. Solid papillary carcinoma (in situ) at low magnification, composed of expansile rounded nodular epithelial masses. B. Medium magnification shows a relatively bland

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population of epithelial cells with ovoid to elongated nuclei, indistinct nucleoli and scant mitoses. Fine congested fibrovascular septa course into the solid epithelial islands. C. Immunohistochemistry for p63 shows patchy retention of myoepithelial cells at the periphery of the epithelial islands, indicating a non-invasive process. D. Synaptophysin is diffusely expressed in the cytoplasm of the epithelial cells on immunohistochemistry, confirming their neuroendocrine nature.

Figure 5. Solid papillary carcinoma (invasive). In rare situations, solid papillary carcinoma may assume irregular jagged contours within a desmoplastic stroma, with absent myoepithelial cells on immunohistochemistry. Such lesions are considered invasive.

Figure 6. Invasive papillary carcinoma, with the invading tumour forming papillary structures.

Figure 7. A. Small cell carcinoma of the breast, composed of cords of tumour cells with hyperchromatic nuclei, scant cytoplasm, pyknosis and nuclear moulding. B. Immunohistochemistry for synaptophysin shows diffuse cytoplasmic reactivity of the tumour cells, confirming their neuroendocrine nature.

Figure 8. A. Infiltrative carcinoma, no special type, composed of irregular solid islands of tumour cells that invade adipose tissue. Focal luminal differentiation is observed in some of the tumour nests. B. These tumour islands show neuroendocrine expression on immunohistochemistry with synaptophysin.

Acknowledgements

All authors contributed to the content and editing of the manuscript. PH Tan and SJ Schnitt provided the figures.

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papillary and neuroendocrine breast lesions: the who stance

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