papillary and neuroendocrine breast lesions: the who stance
TRANSCRIPT
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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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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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This article is protected by copyright. All rights reserved.
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