Histological Classification of Breast Cancer 3

Histological Classification of Breast Cancer 2

Alessandra Fabbri, Maria Luisa Carcangiu, and Antonino Carbone

CONTENTS 2.1
Epidemiology and Risk Factors
2.1 Epidemiology and Risk Factors 3
2.2 Histological Classification 4 Breast cancer is the most common cancer of women
2.2.1 Grading 4 worldwide (Parkin et al. 1984). There have been sus-
2.2.2 TNM 4 tained increases in the incidence of this cancer in
2.2.3 Carcinoma in Situ 6 developing countries in recent years. Breast cancer
2.2.4 Invasive Breast Cancer 8
accounts for 22% of all female cancers, which is more
2.2.5 Invasive Ductal Carcinoma
(Not Otherwise Specified, NOS) 8 than twice the occurrence of cancer in women at any
2.2.6 Invasive Lobular Carcinoma 10 other site (Parkin et al. 2001). Male breast cancer is
2.2.7 Tubular Carcinoma 10 rare compared with female breast cancer. Female:
2.2.8 Invasive Cribriform Carcinoma 10 male incidence ratios vary from 70 to 130 around
2.2.9 Medullary Carcinoma 11
2.2.10 Mucinous Carcinoma 11
the world.
2.2.11 Invasive Papillary Carcinoma 11 Breast cancer incidence, as with most epithelial
2.2.12 Invasive Micropapillary Carcinoma 11 tumours, increases rapidly with age. The curves
2.2.13 Apocrine Carcinoma 11 show a characteristic shape, rising steeply up to
2.2.14 Metaplastic Carcinoma 12
menopausal age and less rapidly or not at all after-
2.2.15 Glycogen-Rich Clear Cell Carcinoma 12
2.2.16 Lipid-Rich Carcinoma 12 wards. Around the 1990s, breast cancer incidence
2.2.17 Adenoid Cystic Carcinoma and varied 10-fold worldwide, indicating important dif-
Acinic Cell Carcinoma 12 ferences in the distribution of the underlying causes
2.2.18 Paget’s Disease of the Nipple 12 (Parkin et al. 2001). There is substantial variation in
2.2.19 Inflammatory Carcinoma 12
breast cancer rates among different countries. Rates
References 12 are some six times higher in the USA, Canada and
northern Europe than in Asia or among black popu-
lations in Africa. These international differences in
breast cancer rates do not appear to be determined
primarily by variation in genetic susceptibility.
Abstract Studies of populations migrating from low- to high-
risk areas, which show that migrant populations
Cancer of the breast is one of the most common approach the risk of the host country in one or two
human neoplasms, accounting for one quarter of all generations (Balzi et al. 2003; Kliewer and Sith 1995;
cancers in females. It is associated with the western Ziegler et al. 1993; Buell 1973; Prentice et al. 1988),
life style. Risk factors include early menarche and clearly suggest an important role of environmental
late childbirth. Breast cancer is further character- factors in the aetiology of the disease.
ized by a marked genetic susceptibility. The typ- The aetiology of breast cancer is multifactorial
ing of invasive breast cancer, its histological vari- and involves diet, reproductive factors and related
ants and their grading systems are well established. hormonal imbalances. The known risk factors for
More difficult is the classification of the pre-invasive breast cancer (Table 2.1) can be understood as mea-
breast lesions that are now increasingly detected by sures of the cumulative exposure of the breast to
mammography. oestrogen and, perhaps, progesterone. The actions
4 A. Fabbri, M. L. Carcangiu, and A. Carbone
of these ovarian hormones (and the hormones used
in combination oral contraceptives and hormone re-
placement therapy) on the breast do not appear to be
genotoxic, but they do affect the rate of cell division.
Their effects on breast cancer rates are manifest in
their effects on proliferation of the breast epithelial
cell. The activation of oncogenes and inactivation of
tumour-suppressor genes (e.g. BRCA1, TP53) pro-
duce a sequence of genetic changes that lead to a
malignant phenotype.
As endogenous hormones directly affect the risk
of breast cancer, there is reason for concern about
the effects on breast cancer risk if the same or
closely related hormones are administered for ther-
apeutic purposes. Specific environmental exposure
operative in the development of breast cancer (e.g.,
radiation, alcohol, exogenous hormones) have been
identified, but carry a lower risk.
More than most other human neoplasms, breast
cancer often shows familiar clustering. Two high-
penetrance genes have been identified (BRCA 1/2)
that greatly increase the breast cancer risk. Table 2.1
shows the events of reproductive life that have
been considered to be risk factors for breast cancer
in women. Breast cancer occurs more frequently
among women who have an early menarche, remain
nulliparous or, if parous, have few children with a
late age at first delivery. Finally, late age at meno-
pause also increases the risk (Kelsey et al. 1993).
Table 2.1. Breast cancer risk factors
Early menarche
Late menopause
Obesity (postmenopausal women)
Oestrogen replacement therapy
Older age at first full-tem birth
Nulliparity
Oral contraceptives
2.2
Histological Classification
The most significant effort in the classification of tu-
mours of the breast was that produced by the World
Health Organization (Tavassoli and Devilee 2003).
Other identified subentities have been listed in the
classification reported in the last edition (third se-
ries) of the fascicle “Tumors of the mammary gland”
issued by the US Armed Forces Institute of Pathol-
ogy (Rosen and Oberman 1992).
All carcinomas of the breast, both invasive and
non-invasive, are classified on the basis of the histo-
logical and/or cytological appearance. Irrespective
of the type of carcinoma, a number of gross find-
ings should always be recorded including site, size,
shape, consistency, colour, gross appearance of mar-
gins, relationship to adjacent mammary (skin, nip-
ple) and extramammary structures (fascia, muscle),
and the number of foci that appear malignant.
2.2.1
Grading
In situ ductal carcinoma and all invasive tumours
are routinely graded. Among the various grading
systems that have been proposed, the combined
grading method of Elston and colleagues from
Nottingham, England, which is a modification of
the grading system originally elaborated by Scarff,
Bloom and Richardson, is currently the most widely
used in Europe (Bloom et al. 1957; Robins et al. 1995;
Elston and Ellis 1991). In this system three param-
eters are evaluated: tubule formation, nuclear poly-
morphism and mitotic rate. A numerical scoring
system of 1–3 is used to ensure that each factor is
assessed individually.
The three values are added together to produces
scores of 3 to 9, to which the grade is assigned:
• Point total 5: grade 1, well differentiated;
• Point total 6–7: grade 2, moderately differentiated;
• Point total 8–9: grade 3, poorly differentiated.
2.2.2
TNM
Breast cancer staging is useful because of its ability
to estimate prognosis. It also provides valuable in-
formation about appropriate treatment options for
each cancer stage (Sobin and Wittekind 2002).
The principal changes incorporated into the
recently revised staging system for breast cancer
(Tables 2.2 and 2.3) are related to the size (micro-
metastases and isolate tumour cells), number, loca-
tion and methods of detection of metastases to the
regional lymph nodes (IHC staining and molecular
techniques such as reverse-transcriptase polymerase
chain reaction, RT-PCR).
 Histological Classification of Breast Cancer 5

Table 2.2. Recently revised staging system for breast cancer

Classification Definition

Primary tumour (T)

TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Tis (DCIS) Ductal carcinoma in situ
Tis (LCIS) Lobular carcinoma in situ
Tis(Paget) Paget‘s disease of the nipple with no tumour
(Paget‘s disease associated with a tumour is classified according to the size of the tumour)
T1 Tumour ≤2 cm in greatest dimension
T1mic Microinvasion ≤0.1 cm in greatest dimension
T1a Tumour >0.1 cm but ≤0.5 cm in greatest dimension
T1b Tumour >0.5 cm but ≤1 cm in greatest dimension
T1c Tumour >1 cm but ≤2 cm in greatest dimension
T2 Tumour >2 cm but ≤5 cm in greatest dimension
T3 Tumour >5 cm in greatest dimension
T4 Tumour of any size with direct extension to chest wall or skin, only as described below
T4a Extension to chest wall, not including pectoralis muscle
T4b Oedema (including peau d’orange) or ulceration of the skin of the breast,
or satellite skin nodules confined to the same breast
T4c Both T4a and T4b
T4d Inflammatory carcinoma
Regional lymph node
NX Regional lymph nodes cannot be assessed (e.g., previously removed)
N0 No regional lymph node metastasis
N1 Metastasis in movable ipsilateral axillary lymph node(s)
N2 Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent*
ipsilater internal mammary nodes in the absence of clinically evident axillary lymph-node
metastases
N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or
to other structures
N2b Metastasis only in clinically apparent* ipsilateral internal mammary nodes and in the ab-
sence of clinically evident axillary lymph-node metastasis
N3 Metastasis in ipsilateral infraclavicular lymph node(s), or in clinically apparent* ipsilateral
internal mammary lymph node(s), and in the presence of clinically evident axillary lymph-
node metastasis, or metastasis in ipsilateral supraclavicular lymph node(s) with or without
axillary or internal mammary lymph-node involvement
N3a Metastasis in ipsilateral infraclavicular lymph node(s) and axillary lymph node(s)
N3b Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c Metastasis in ipsilateral supraclavicular lymph node(s)
6 A. Fabbri, M. L. Carcangiu, and A. Carbone

Classification Definition

Regional lymph nodes (pN)†

pNX Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for
pathologic study)
pN0 No regional lymph node metastasis histologically, no additional examination for
isolated tumour cells‡
pN0 (i-) No regional lymph node metastasis histologically, negative immunohistochemical staining
pN0 (i+) Isolated tumour cells identified histologically or by positive immunohistochemical staining,
no cluster >0.2 mm§
pN0 (mol-) No regional lymph-node metastasis histologically, negative molecular findings (RT-PCR)†††
pN0 (mol+) No regional lymph-node metastasis histologically, positive molecular findings (RT-PCR)†††
pN1 Metastasis in one to three axillary lymph nodes, and/or in internal mammary nodes with
microscopic disease detected by sentinel lymph node dissection but not clinically apparent*
pN1mi Micrometastasis (>2 mm, none >2.0 mm)
pN1a Metastasis in one to three axillary lymph nodes
pN1b Metastasis in internal mammary nodes with microscopic disease detected by
sentinel lymph-node dissection but not clinically apparent*
pN1c Metastasis in one to three axillary lymph nodes** and in internal mammary lymph nodes
with microscopic disease detected by sentinel lymph-node dissection but not clinically ap-
parent*
pN2 Metastasis in four to nine axillary lymph nodes, or in clinically apparent* internal mam-
mary lymph nodes in the absence of axillary lymph-node metastasis

Adapted from Greene et al, with permission from Springer Publishing

*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination.
†Classification is based on axillary lymph node dissection with or without sentinel lymph-node dissection. Classification based
solely on sentinel lymph-node dissection without subsequent axillary lymph node dissection is designated (sn) for “sentinel
node”, such as pN0(i+)(sn).
‡Isolated tumour cells are defined as single tumour cells or small cell clusters ≤0.2 mm, usually detected only by immunohis-
tochemical or molecular methods, but which may be verified on haematoxylin and eosin stains. Isolated tumour cells do not
usually show evidence of metastatic activity (e.g., proliferation or stromal reaction).
§Definition of (i+) was adapted in 2003 in order to be consistent with the updated International Union against Cancer (UICC)
classification.
†††RT-PCR: reverse transcriptase/polymerase chain reaction.
**If associated with more than three positive axillary lymph nodes, the internal mammary nodes are classified as pN3b to
reflect increased tumour burden.

2.2.3 phous cells that have effaced the lumen (Bratthauer

Carcinoma in Situ
Carcinoma in situ is a proliferation of malignant
epithelial cells within the ductulo-lobular system
of the breast that on light microscopy shows no
evidence of breaching the basement membrane to
invade the adjacent stroma. There are two forms:
ductal and lobular. Lobular intraepithelial neoplasia
(LIN) is located within the terminal duct-lobular
unit, often accompanied by pagetoid involvement
of the adjacent terminal ducts (Fig. 2.1). These are
markedly distended by a proliferation of monomor-
and Tavassoli 2002). The nuclei are round, regular
and evenly spaced. Intracellular lumens are often
present. The stroma is thinned. No necrosis or mi-
crocalcifications are usually present.
LIN is usually found during the perimenopausal
period, is unapparent clinically and is usually de-
tected incidentally in biopsies that were done because
of other lesions. It is associated with an increase in
the risk of developing invasive breast cancer of any
type, in either breast, and usually many years later.
Ductal carcinoma in situ (DCIS), on the other hand,
is a heterogeneous group of pre-malignant lesions that
 Histological Classification of Breast Cancer 7

Table 2.3. Recently revised staging system for breast cancer

Fifth Edition Sixth Edition

Size of regional Micrometastases were defined as tumour
lymph-node metastases deposits not larger than 2.0 mm and classi-
fied as pN1a
No quantitative distinction was made
between micrometastases and isolated
tumour cells
Number of regional The number of affected axillary lymph
lymph- node metastases nodes was considered only in subcatego-
ries of pN1
Location of regional Metastases in infraclavicular lymph nodes
lymph-node metastases (axillary level III) were considered equiva-
lent to metastases in other axillary lymph
nodes
Metastases to the internal mammary nodes
were classified as N3/pN3
Metastases to the supraclavicular lymph
nodes were classifies as M1
The use of descriptors to No descriptors were used
indicate size and method
of detection of nodal
metastases
Micrometastases are distinguished from isolated
tumour cells on the basis of size
Micrometastases are defined as tumour deposits
larger than 0.2 mm, but not larger than 2.0 mm
and classified as pN1mi. Isolated tumour cells
are defined as tumour deposits not larger than
0.2 mm identified by either standard histology
or by immunohistochemical staining. They are
classified as pN0(i+)
Major classification of lymph node status are
defined by the number of affected axillary lymph
nodes
Metastases in the infraclavicular lymph nodes
are classified as N3, because of their association
with extremely poor prognosis
Metastases to the internal mammary nodes are
classified as N1, N2 or N3, based on the size of
the lesion and the presence or absence of con-
current axillary nodal involvement
Metastases to the supraclavicular lymph nodes
are classified as N3
The descriptor (i+) is used to indicate the pres-
ence of isolated tumour cells not larger than 0.2
mm by either standard histology or by immuno-
histochemical staining. The descriptor (i-) means
no detectable tumour cells by either histology or
immunohistochemical staining.
The descriptor sn is used to indicate that the
staging classification was based solely on sentinel
lymph node dissection.
The descriptor (mol+)/(mol-) is used to designate
cases that are negative by standard histological
staining for regional lymph node metastasis and in
which reverse transcriptase-polymerase chain reac-
tion was used to assess the node for tumour cells

are usually asymptomatic and impalpable, but may be

identifiable on mammography as foci of microcalcifi-
cation (Holland et al. 1994). The classification of DCIS
is based primarily on cytonuclear differentiation and,
secondarily, on architectural differentiation (cellular
polarisation). Three categories are defined:

Poorly differentiated DCIS is composed of cells with

markedly pleomorphic nuclei, evidence of individ-
ual cell necrosis and autophagocytosis. Mitoses and
central necrosis are often present. The growth pat-
tern may be solid, pseudo-cribriform or micropapil-
lary. This sub-type has the highest risk of stromal
invasion (Fig. 2.2). Fig. 2.1. Lobular intraepithelial neoplasia
8 A. Fabbri, M. L. Carcangiu, and A. Carbone
Intermediately differentiated DCIS is composed
of cells showing some pleomorphism, but not so
marked as in the poorly differentiated group. There
is always evidence of some architectural differen-
tiation, whereas necrosis and calcification are vari-
able.
Well-differentiated DCIS consists of cells with
monomorphic nuclei. Architectural differentiation
is pronounced, and the growth pattern may be crib-
riform, micropapillary and clinging. Necrosis is not
present (Fig. 2.3).
Lesions in the poorly differentiated group are
usually Neu (c-erbB-2) positive and are less fre-
quently oestrogen and progesterone receptor posi-
tive, conversely to those in the well-differentiated
group. The treatment of DCIS depends on the size
and distribution of the lesion. The status of excision
margins around the tumour remains the most im-
portant factor in terms of risk of local recurrence.
Microinvasive carcinoma (size limit of 1 mm) is
rare and occurs mostly in association with in situ
carcinoma, usually of the poorly differentiated type
(Rosen 1997).
2.2.4
Invasive Breast Cancer
Invasive breast cancer is a group of malignant epi-
thelial tumours characterized by invasion of adja-
cent tissue and a marked tendency to metastasize
to distant sites. Breast cancer arises from the mam-
mary epithelium, most frequently from the cells of
the terminal duct lobular unit. The vast majority
of these tumours are adenocarcinomas. They ex-
Fig. 2.2. Poorly differentiated ductal carcinoma in situ
hibit a wide range of morphological phenotypes and
specific histological types. The typing of invasive
breast cancer and its histological variants is well es-
tablished in the WHO Classification (Tavassoli and
Devilee 2003) (Table 2.4).
2.2.5
Invasive Ductal Carcinoma
(Not Otherwise Specified, NOS)
This is a heterogeneous group, which represents the
most common type of invasive carcinoma, compris-
ing between 40% and 75% in the published series
(Elston and Ellis 1991; Elston and Ellis 1998). Ductal
NOS tumours, like all other major forms of breast
cancer, are less common below the age of 40 (Kollias
et al. 1997). These tumours have no specific macro-
scopic features. There is marked variation in size;
they can have an irregular, stellate outline or nodular
configuration. They are firm, and the cut surface is
usually grey-white with yellows streaks (Fig. 2.4).
Architecturally, the tumour cells may be ar-
ranged in cords, clusters and trabeculae, but the
predominantly invasive pattern is solid with occa-
sionally glandular differentiation. The stromal com-
ponent is extremely variable. There may be a highly
cellular fibroblastic proliferation, a scanty connec-
tive tissue or marked hyalinization with elastosis.
Tumour cells have a variable appearance, with cyto-
plasm often abundant and eosinophilic. Nuclei may
be regular or pleomorphic with prominent nucleoli.
Mitotic activity may be increased in the poorly dif-
ferentiated form.
Invasive carcinoma is often associated with high
grade ductal carcinoma in situ, but all other patterns
Fig. 2.3. Well-differentiated ductal carcinoma in situ with a
cribriform pattern of growth
 Histological Classification of Breast Cancer 9

Table 2.4. Histological classification of carcinoma of breast [adapted from WHO (Tassavoli and
Devilee 2003)]

Invasive ductal carcinoma, not otherwise specified (NOS) 8500/3

Mixed type carcinoma

Pleomorphic carcinoma 8022/3

Carcinoma with osteoclastic giant cells 8035/3

Invasive lobular carcinoma 8520/3

Tubular carcinoma 8211/3

Invasive cribriform carcinoma 8201/3

Medullary carcinoma 8510/3

Mucinous carcinoma and other tumours with abundant mucin

Mucinous carcinoma 8480/3

Cystadenocarcinoma and columnar cell mucinous carcinoma 8480/3

Signet ring cell carcinoma 8490/3

Invasive papillary carcinoma 8503/3

Invasive micropapillary carcinoma 8507/3

Apocrine carcinoma 8401/3

Metaplastic carcinomas 8575/3

Pure epithelial metaplastic carcinomas 8575/3

Mixed epithelial/mesenchymal metaplastic carcinomas 8575/3

Lipid-rich carcinoma 8314/3

Adenoid cystic carcinoma 8200/3

Acinic cell carcinoma 8550/3

Glycogen-rich clear cell carcinoma 8315/3

Inflammatory carcinoma 8530/3

Lobular carcinoma in situ 8520/2

Ductal carcinoma in situ 8500/2

Microinvasive carcinoma

may be seen (Fig. 2.5). If a ductal carcinoma NOS is
accompanied by a second distinct morphologic pat-
tern (lobular), the cancer is defined as mixed. There
are several variants of ductal carcinoma NOS: pleo-
morphic (a high grade cancer characterized by pro-
liferation of pleomorpic and bizarre tumour giant
cells) (Silver and Tavassoli 2000); with osteoclastic
giant cells (Gupta 1996); with choriocarcinomatous
features (Horne et al. 1976). Approximately 70–80%
of ductal NOS breast cancers are oestrogen receptor
positive, and between 15–30% of cases are ERBB2
positive.
2.2.6
Invasive Lobular Carcinoma
Invasive lobular carcinoma represents 5–15% of in-
vasive breast tumours and is frequently multifocal
and bilateral (Winchester et al. 1998). It is character-
10 A. Fabbri, M. L. Carcangiu, and A. Carbone
Fig. 2.4. Invasive ductal carcinoma (NOS)
Fig. 2.5. Invasive ductal carcinoma associated with high
grade ductal carcinoma in situ
Fig. 2.6. Invasive lobular carcinoma
ized by indistinct tumour margins. This neoplasm
is composed of non-cohesive cells individually dis-
persed or arranged in single fi le linear pattern (In-
dian fi le) in a fibrous stroma. The neoplastic cells
have round or notched ovoid nuclei and a thin rim
of cytoplasm with an occasional intracytoplasmic
lumen (signet ring cells) (Fig. 2.6).
There are different patterns: classical (Martinez
and Azzopardi 1979), solid (Fechner 1975), alveolar
(Shousha et al. 1986), pleomorphic, (Weidner and
Semple 1992) and mixed (Martinez and Azzopardi
1979). The admixture of a tubular growth pattern
and small uniform cells arranged in a linear pattern
defines the variant known as tubulo-lobular carci-
noma (Fisher et al. 1977). All of these patterns are
associated with lobular carcinoma in situ.
About 70–95% of lobular carcinomas are ER posi-
tive and 60–70% are PR positive (Sastre-Garau et al.
1996). Overexpression of ERBB2 is lower than in in-
vasive ductal carcinoma, with the exception of the
pleomorphic pattern (Soomro et al 1991).
2.2.7
Tubular Carcinoma
This is a special type of carcinoma with favour-
able prognosis that accounts for under 2% of in-
vasive breast cancer in most series. It consists of a
haphazard distribution of rounded and angulated
tubules with open lumens, lined by only a single
layer of epithelial cells separated by abundant reac-
tive fibroblastic stroma. The cancer cells are small
and regular, with little nuclear pleomorphism and
scanty mitotic figures (Patchefsky et al. 1977). Duc-
tal carcinoma in situ (usually of low grade) is found
in association; occasionally the in situ component
is of lobular type. Oestrogen and progesterone re-
ceptors are always positive and ERBB2 is negative
(Papadatos et al. 2001).
2.2.8
Invasive Cribriform Carcinoma
This is a carcinoma with an excellent prognosis that
accounts for 0.8–3.5% of breast cancers (Venable et
al. 1990). The tumour cells are small and show a
low to moderate degree of nuclear pleomorphism.
The tumour is arranged as invasive islands (often
angulated), within which well-defi ned spaces are
formed by arches of cells. Mitoses are rare. As-

sociated intraductal carcinoma, generally of the
cribriform type, is observed in as many as 80% of
cases. Oestrogen and progesterone receptors are
positive in 100% and 69% of the cases, respectively
(Venable et al. 1990).
2.2.9
Medullary Carcinoma
This is a carcinoma with a good prognosis, which
represents between 1 and 7% of all breast cancers.
A high frequency of this tumour type has been
reported in patients with BRCA1 germ line muta-
tions (Wargotz and Silverberg 1988; Marcus et al.
1996). It is composed of poorly differentiated cells
arranged in large sheets, with no glandular struc-
tures, scant stroma and a prominent lymphoplas-
macytic infi ltrate. Classically, five morphological
criteria have been said to characterize medullary
carcinoma: syncytial growth pattern in over 75%
of the tumour; absence of glandular structures,
diffuse lymphoplasmacytic stromal infi ltrate,
lymphoid follicles and/or epithelioid granuloma,
marked nuclear pleomorphism and complete his-
tological circumscription. Tumours showing the
association of a predominantly syncytial architec-
ture with only two or three of the other criteria
are usually designated as atypical medullary car-
cinoma (Ridolfi et al. 1997). Medullary carcinoma
lacks oestrogen receptor expression (Ponsky et al.
1984).
2.2.10
Mucinous Carcinoma
Pure mucinous carcinoma accounts for about 2% of
all breast cancer in patients over 60 years and has
a favourable prognosis (Scopsi et al. 1994). Macro-
scopically, the tumour appears as a glistening ge-
latinous nodule with pushing margins. Microscopi-
cally, it is characterized by proliferation of clusters
of generally uniform round cells with a thin rim of
eosinophilic cytoplasm floating in lakes of mucus
(Fig. 2.7). These lesions are further subdivided into
cellular and hypocellular variants. Grimelius stain
and chromogranin and synaptophysin immunos-
tain demonstrate in a high proportion of cases neu-
roendocrine differentiation (Feyrter and Hartmann
1963). Mucinous carcinoma is oestrogen receptor
positive (Shousha et al. 1989).
Histological Classification of Breast Cancer 11
Fig. 2.7. Mucinous carcinoma, hypocellular variant
2.2.11
Invasive Papillary Carcinoma
This tumour type comprises less than 1–2% of all
breast cancers and is characterized by a relatively
good prognosis (Schneider 1989). It represents a pap-
illary intraductal carcinoma located within a large
cystic duct and characterized by thin fibrovascular
stalks with a myoepithelial cell layer and a neoplas-
tic cell population with areas of infi ltrating duct
carcinoma (Leal et al. 1998).
2.2.12
Invasive Micropapillary Carcinoma
This is a carcinoma composed of small clusters of
tumour cells lying within clear stromal spaces re-
sembling dilatated vascular spaces. This growth
pattern accounts for less than 2% of all invasive
breast cancers and often is associated with the pres-
ence of vascular invasion and axillary lymph node
metastases (Paterakos et al. 1999).
2.2.13
Apocrine Carcinoma
This is a rare cancer (0.3–4%) in which the tumour
cells show cytological and immunohistochemical
features of apocrine cells in 90% or more of the
tumour (Frable and Kays 1968). Apocrine cells have
abundant eosinophilic cytoplasm and vesicular
nuclei with prominent nucleoli, and are typically
GCDFP15 positive. It should be noted, however, that
expression of GCDFP15 is a feature common to many
variants of breast carcinoma (Mazoujian 1983).
12 A. Fabbri, M. L. Carcangiu, and A. Carbone
2.2.14
Metaplastic Carcinoma
This tumour accounts for less than 1% of all in-
vasive cancers (Huvos 1973). These are a hetero-
geneous group of neoplasms generally character-
ized by an admixture of adenocarcinoma with
dominant areas of spindle cell, squamous and /or
mesenchymal differentiation. There are two forms:
purely epithelial and mixed epithelial/mesenchy-
mal (Wargotz and Norris 1990; Kaufman et al.
1984). Oestrogen and progesterone receptors are
always negative.
2.2.15
Glycogen-Rich Clear Cell Carcinoma
This is a rare cancer (1–3%) in which more than 90%
of the neoplastic cells have abundant clear cyto-
plasm containing glycogen (Hull and Warkel 1986).
The hormone receptor status is similar to that of
ductal carcinoma NOS.
2.2.16
Lipid-Rich Carcinoma
This is a breast cancer in which approximately 90%
of the neoplastic cells contain abundant cytoplasmic
neutral lipids (Dina and Eusebi 1997).
2.2.17
Adenoid Cystic Carcinoma and
Acinic Cell Carcinoma
These neoplasms are the breast counterpart of the
homonymous tumours that occur in the salivary
gland (Lamovec et al. 1989).
2.2.18
Paget’s Disease of the Nipple
This term is applied to the presence of malignant
glandular epithelial cells within the squamous epi-
thelium of the nipple, almost always in association
with an underlying intraductal or infi ltrating car-
cinoma. In general, the Paget cells have the same
immunophenotype as the underlying carcinoma
(Cohen et al. 1993)
2.2.19
Inflammatory Carcinoma
This is a form of advanced breast carcinoma with
prominent dermal lymphatic infi ltration by tumour
and a lymphoplasmacytic infi ltrate (Rosen 2001).
Acknowledgements
The authors thank Maria Morelli for her help in the
preparation of this manuscript and for her editorial
assistance.
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