1. review Annals of Oncology 20: 1763–1770, 2009
doi:10.1093/annonc/mdp245
Published online 14 July 2009
Breast carcinoma—rare types: review of the literature
R. Yerushalmi1*, M. M. Hayes2 & K. A. Gelmon1
1
Division of Medical Oncology and 2Department of Pathology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Received 23 February 2009; accepted 26 March 2009
Invasive breast cancer is a heterogeneous disease in its presentation, pathological classification and clinical course.
However, there are more than a dozen variants which are less common but still very well defined by the World Health
Organization (WHO) classification. The rarity of many of these neoplasms does not allow large or randomized studies
to define the optimal treatment. Many of the descriptions of these cancers are from case reports and small series. Our
review brings updated information on 16 epithelial subtypes as classified by the WHO system with a very concise
histopathology description and parameters helpful in the clinic. The aim of our review is to provide a tool for breast
cancer caregivers which will enable a better understanding of the disease and its optimal approach to therapy. This
may also stand as a clinical framework for a future understanding of these rarer breast cancers when gene analysis
review
work is reported.
Key words: breast carcinoma, epithelial breast cancer, prognosis, treatment, triple negative, World Health
Organization classification
introduction definition of breast cancer. The rarity of many of these
neoplasms does not allow large or randomized studies to define
Invasive breast cancer is a heterogeneous disease in its the optimal treatment. Many of the descriptions of these
presentation, pathological classification and clinical course. cancers are from case reports and small series.
Most tumors are derived from mammary ductal epithelium, Our review brings updated information on 16 epithelial
principally the terminal duct-lobular unit, and up to 75% of the subtypes as classified by the WHO system [1] with a very
diagnosed infiltrating ductal carcinoma are defined as invasive concise histopathology description and parameters helpful in
ductal carcinoma, not otherwise specified (IDC-NOS). The the clinic. The aim of our review is to provide a tool for breast
second most common epithelial type is invasive lobular cancer caregivers which will enable a better understanding of
carcinoma which comprises of 5%–15% of the group. the disease and its optimal approach to therapy. This may also
However, there are more than a dozen variants which are less stand as a clinical framework for a future understanding of
common but still very well defined by the World Health these rarer breast cancers when gene analysis work is reported.
Organization (WHO) classification. Our review is based on Pubmed research updated to
Recently, there has been an increased emphasis on the December 2008.
immunohistochemical and genetic profile of tumors and these
classifications are evolving as a standard part of the diagnostic
process. This novel approach pushes aside traditional good prognosis, ER positive
descriptive definitions. An estrogen receptor (ER)-negative
ductal (NOS) as well as adenoid cystic, acinic and metaplastic Findings are summarized in Table 1.
carcinoma may all receive the title of triple-negative disease and
this may affect decision making for those less familiar with the tubular carcinoma
nuances of the rare tumor types. Furthermore, the classification definition and epidemiology. The definition of a tubular
using gene expression profile was established using a cohort of carcinoma (TC) requires tumor purity with 90% tubular
ductal carcinoma NOS, without including cancers of special architecture. The characteristic finding histologically is open
types. We therefore indicate that it is extremely important to tubules composed of single layer of epithelial cells and cellular
highlight what is known about the different behavior of each desmoplastic stroma. Nuclear grade is low. TC comprises of
tumor and gather together the published data with the goal of 0.7%–10.3% of the invasive epithelial breast cancer (IEC) and is
marrying the rare tumor types with a current molecular more likely to occur in postmenopausal women. A population-
based study of nodal metastases with 171 TC patients has found
the proportion of cases with axillary nodal involvement at
*Correspondence to: Dr R. Yerushalmi, Division of Medical Oncology, British Columbia
Cancer Agency, 600 W 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6. Tel: presentation to be lower in TC than in the grade 1 IDC group
+1-604-877-6000-2594; Fax: +1-604-877-0585; E-mail: ryerushalmi@bccancer.bc.ca (12.9% and 23.9%, respectively) [2]. A smaller study (n = 33)
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

2. review Annals of Oncology
Table 1. Good prognosis typically ER-positive tumors component >50% of the lesion. The pure type contains mucin
in all of the IDC. The WHO classification divides this tumor
Dominant HER-2 Axillary lymph into three different subtypes: (i) mucinous carcinoma (ii)
profile node involvement % cystadenocarcinoma and columnar cell mucinous carcinoma
Tubular Negative 13–25 [2, 3] and (iii) signet ring cell carcinoma [1]. Pure mucinous
Invasive cribriform Negative 14.3 [4, 5] carcinomas represent 1%–4% of all breast cancers, with
Pure mucinous Negative £5 [6, 7] a reputation of presenting at one of the oldest median ages
Invasive solid papillary Negative 0 [8] (71 years). Despite often having a large tumor size, the axillary
Apocrine 50% £4 [9] lymph nodes are rarely involved; in a recent large series, 111
Solid neuroendocrinea Negative £40 (n = 8) [10] patients with mucinous breast cancer were identified. Ninety-
six (86%) patients underwent nodal evaluation either by
a
Does not differ from other carcinomas and depends very much on its sentinel lymph node biopsy or by axillary dissection. Fourteen
histological grade (see text). patients (13%) were found to have lymph node metastasis.
ER, estrogen receptor.
Node positivity was associated with larger tumor size (mean
2.7 cm). None of the 31 patients with tumor size <1 cm had
reported on 25% of the cases to involve axillary nodes, most known lymph node metastasis (24 were node negative, and
often micrometastases [3]. seven were not evaluated with sentinel lymph node biopsy or
diagnostic imaging. TC has a variety of presentations, but it is axillary dissection) [17]. In contrast to this study, there are
mostly seen on mammography as a small spiculated mass and reports on small tumors <1 cm presenting with at least a 5%
on sonography as an irregular mass with posterior acoustic incidence of nodal involvement [6, 7].
shadowing [11]. imaging. Pure mucinous carcinomas present an imaging
immunohistology. Most of the cases are ER (>90%) and challenge due to their isoechogenic appearance on ultrasound
progesterone receptor (PgR) positive with a low proliferation [18]. Typical magnetic resonance imaging (MRI) demonstrates
index. HER-2 status (as determined by immunohistochemical a gradually enhancing contrast pattern and a very high signal
staining or fluorescence in situ hybridization) and epidermal intensity on T2 images [19, 20].
growth factor receptor are negative [12]. immunohistology. These are mostly well-differentiated lesions
prognosis. Survival is not significantly different from that of the frequently associated with positive ERs (>90%) and PgRs (81.5%)
general population [13], even with positive axillary lymph nodes and HER-2-negative disease. However, rare cases with HER-2-
[14]. Five-year disease-free survival (DFS) for node-positive positive staining have been reported but these may need review.
patients was 94% (n = 64). Interestingly, in this series, the 5-year prognosis. Mucinous tumors have a favorable prognosis with
DFS of those who did not receive systemic treatment was 100%. 5-, 10-, 15- and 20-year survival rates of 94%, 89%, 85% and
81%, respectively [7]. Node involvement was associated with
invasive cribriform carcinoma a significant worse 5-year DFS or overall survival (OS) [13].
definition and epidemiology. These grade 1 tumors are Other traditional parameters such as age, T size, nuclear grade
characterized by a cribriform pattern in the majority of the and PgR status also significantly influence outcome [7].
invasive component. Tumors are divided into pure, classical
and mixed forms of invasive cribriform carcinoma (ICC). In invasive solid papillary carcinoma
the classical and the mixed forms, <50% of the tumor consists
definition and epidemiology. The literature is unclear whether
of other histological types [4]. This tumor accounts up to 3.5%
solid papillary carcinoma (SPC) is a form of in situ carcinoma
of the IEC, hence the data are based on case reports and small
or a true invasive malignancy and the WHO classification
series. The mean age is 53–58 years. Page et al. reported 14.3%
defines invasive SPC as a separate entity. SPC characteristically
of the cases to involve axillary lymph nodes [4, 5].
has papillae with focal solid areas. Ductal carcinoma in situ
diagnostic imaging. Stutz et al. reported on eight radiological (DCIS) is present in >75% of cases and lymphatic vessel
cases. Only four were seen on mammography and the invasion in one-third of the cases. The tumor comprises <1% to
ultrasound was not entirely typical of breast carcinoma [15]. 2% of IEC and typically presents in postmenopausal women
with only 15% of reported cases occurring under the age of 50.
immunohistology. ER is positive in 100% and PgR in 69% of the
Otsuki et al. reported on 20 patients with pure SPC and no
cases [5]; HER-2 is negative [16].
axillary lymph node involvement [8].
prognosis. In an older series, the 5-year survival was 100% for
pure and ‡50% ICC, 88% for <50% ICC and 78.3% for the IDC immunohistology. In total, 100% of the tumors are ER positive
controls [5]. Ten-year breast-specific survival for the pure cases and HER-2 negative and 80%–100% are PgR positive. Almost
was 100% [4]. all cases show positive staining for chromogranin and 40%
are also positive for synaptophysin [8, 21].
pure mucinous carcinoma imaging. The sonographic features are indistinguishable
definition and epidemiology. The mucinous neoplasms are from papillomas. The only differential finding between
characterized by the production of abundant extracellular and/ noninvasive and invasive papillary cancers was circumscribed
or intracellular mucin. The definition requires a mucinous margins [22].
1764 | Yerushalmi et al. Volume 20 | No. 11 | November 2009

3. Annals of Oncology review
prognosis. Of the 1603 breast cancers reviewed in the National although we are cautious of this claim with the small number of
Surgical Adjuvant Breast and Bowel Project (NSABP)-04 study, cases reported.
35 had papillary features and only three experienced treatment
failure at 5 years [23]. Node-negative patients who had been
enrolled in the NSABP B-06 study revealed an improved survival
good prognosis, ER negative
after 10 years of follow-up compared with IDC-NOS [24]. Findings are summarized in Table 2.
apocrine carcinoma medullary carcinoma
definition and epidemiology. Microscopically, apocrine definition and epidemiology. This carcinoma is composed of
carcinomas (ACs) demonstrate the same architectural growth poorly differentiated cells with no glandular structures, scant
pattern as invasive ductal carcinomas of no special type, differing stroma, circumscribed margins and a prominent
only in their cytological appearance. The cells are characterized lymphoplasmacytic infiltrate. If most but not all the features are
by typical apocrine features with abundant eosinophilic granular present, the tumor is identified as ‘atypical medullary
cytoplasm and prominent/multiple nucleoli. There is no agreed carcinoma’ (AMC) [1]. Medullary carcinoma (MC) comprises
definition and some pathologists now confirm their diagnosis 1%–7% of IEC. In a large series of almost 1500 patients with
by staining for gross cystic disease fluid protein-15 [9, 25]. MC, only 27% had involved nodes. Although MC is not an
Axillary lymph node incidence varies from 1% to 4% but there indication for BRCA gene screening, there are growing data
is extremely sparse information in the literature. that indicate that MC may correlate with BRCA1 gene
mutation [30].
immunohistology. These tumors are reported as ER positive in
3.8%–60% of cases, PgR positive in 4.8%–40%, HER-2 positive diagnostic imaging. MC commonly manifests as well-
in 50%, with a proliferation index of 6.9%–23.7% and p53 circumscribed masses. Magnetic resonance mammography
alteration in 46%–50%. Androgen receptors are positive in appearance is nonspecific and often indicative of a benign
56%–100% of AC [9]. lesion [35, 36].
prognosis. AC has a similar prognosis to IDC-NOS when immunohistology. MC shares common characteristics with the
matched for stage and grade [26]. basal type breast cancer. Most of the tumors are hormone receptor
and HER-2 negative and CKT 5/6 positive (94%) [30, 37].
neuroendocrine tumors MC but not AMC lacks Bcl-2 and there are data that show
they differ in expression of human leukocyte antigen-DR, b2-
definition and epidemiology. Neuroendocrine (NE) was not
microglobulin, E cadherin and beta-catenin compared with
recognized as a single entity until the last WHO’s classification.
other tumors [38].
This classification differentiates between four different
subtypes: (i) small-cell carcinoma (SCC); (ii) large-cell prognosis. Paradoxical to its histology features, MC usually has
carcinoma; (iii) solid NE carcinoma; and (iv) atypical carcinoid a good prognosis. In one series, 10-year distant relapse-free
tumor. Our experience shows that the NE differentiation has survival reached 95% [30]. In another study, 10-year OS was 85%
no prognostic influence and on the whole they behave as per for MC as compared with 68% in the IDC-NOS patients [39].
their Nottingham grade [27]. Studies are hampered by lack of reproducibility of the
For simplification, this section describes the solid pathological diagnosis, small numbers of patients and poor
neuroendocrine subtype (SN) which represents a better statistical power.
prognosis group. (The SCC subtype is described in the ‘poor
prognosis, ER positive’ section.) The tumors consist of densely secretory breast carcinoma
cellular, solid nests and trabeculae of cells separated by delicate definition and epidemiology. Secretory breast carcinoma (SBC)
fibrovascular stroma [1]. Prevalence is up to 0.5% of breast is also known as juvenile carcinoma. This is an extremely rare
cancers. In a small series of eight patients, three presented with tumor with limited data available.
involved axillary lymph nodes. Two distinctive pathological characteristics of SBC are
immunohistology. As per the definition, there is synaptophysin intracellular/extracellular secretion and granular eosinophilic
or chromogranin immunohistochemical expression in 50% of cytoplasm of the neoplastic cells. Although secretory carcinoma
the cells. Typically, these tumors present with ER- and PgR- may occur in adults, the median and mean age are 33 and
positive and HER-2-negative status [10].
Table 2. Good prognosis typically ER-negative tumors
gene expression. Profile of endocrine carcinoma overlaps with
those of mucinous carcinomas [28]. Dominant HER-2 Axillary lymph
imaging. There is no specific imaging presentation in the profile node involvement %
limited number of SN tumors reported. Medullary Negative 27 [30]
Secretory Negative 15 [31]
prognosis. The outcome of these cancers does not differ from Adenoid cystic Negative 0–4.6 [32, 33]
other carcinomas and depends very much on its histological Acinic cell Negative 17 [34]
grade [27, 29]. The immunoprofile is reminiscent of the
luminal A subtypes, and hence a good prognosis is expected, ER, estrogen receptor.
Volume 20 | No. 11 | November 2009 doi:10.1093/annonc/mdp245 | 1765

4. review Annals of Oncology
40 years, respectively. The literature mentions nodal and local recurrences were recorded. Larger series are required
involvement in 15% of the patients at presentation [31]. for definite conclusions [49].
imaging. SBC frequently appears as a small benign/intraductal
lesion on sonography [40]. poor prognosis, ER positive
immunohistochemistry. This subtype has the triple-negative Findings are summarized in Table 3.
phenotype (ER, PgR, and HER-2 negative). It has been
high-grade small-cell NE carcinoma
demonstrated that SCs of the breast consistently harbor the
t(12;15)ETV6-NTRK3 translocation [41]. The literature describes 40 cases of breast small cell NE
carcinoma (SCC) but this may be underreporting. This
prognosis. SBC has a favorable prognosis in children and neoplasm is similar to NE tumors presenting in the lung or
adolescents but seems slightly more aggressive in older patients. with extrapulmonary areas and share the same tumor markers.
Metastatic cases have been reported [1]. Diagnosis requires ruling out a nonmammary origin [53].
The presence of in situ component may be helpful but is not
adenoid cystic carcinoma essential [50, 54]. Most patients are in the sixth or seventh
definition and epidemiology. Adenoid cystic carcinomas (ACCs) decades of life and 59% present with involved lymph nodes.
are characterized by a mixture of proliferating glands, immunohistology. As per the definition, it expresses NE
myoepithelial cells and stromal/basement elements. Data in the markers, neurone-specific enolase, protein gene product 9.5,
literature are based on 200 cases. The tumor represents 0.1% chromogranin and synaptophysin, in 50% of the cell
of breast carcinoma and is diagnosed predominantly in population [1]. Most of the cases are positive for cytokeratin
postmenopausal women. Pain is a prominent symptom due to CAM5.2, AE1/3 and cytokeratin 7 as well. Surprisingly, the
neural involvement [42]. Most of the reports document a low tumor often expresses ERs and PgRs and this correlates with the
rate of axillary involvement of 0%–4.6%; however, there are degree of differentiation; well-differentiated tumors are the
some small series that report on up to 27% lymph node more likely to express hormone receptors with a varied
metastases [32, 33]. frequency of 0%–50%. Her-2 status is typically negative [55, 56].
immunohistochemistry. The tumor displays triple-negative imaging. Radiological findings are not specific but meet the
phenotype [43, 44]. However, a study with 28 patients found criteria for a suspicious mass [57].
46% of the cases to be ER positive and 36% to be PgR positive
[45]. In another study, all (n = 18) cases were c-kit (CD-117) prognosis. SCC tumor is considered an aggressive tumor with
positive. MIB-1 antibody (monoclonal antibody that is a poor prognosis. However, there are some reports about long-
immunoreactive with Ki-67) stains demonstrate low term survival when the diagnosis is made early [58]. NE
proliferative fraction [46]. differentiation using synaptophysin, chromogranin A, and
neuron-specific enolase had no prognostic influence [27].
prognosis. The 5-, 10- and 15-year OS rates were 85%–88%, 75%
and 60%, respectively, for ACC. Millar et al. reported an invasive micropapillary carcinoma
incidence of 26% (n = 5) for second malignancies at 15 years. definition and epidemiology. Hollow aggregates of malignant
The majority of the second cancers were not within the treated or cells and lymphatic invasion is a common feature of this tumor,
contralateral breast [33]. Metastases are rare and have been ranging from 72.3% to 91% of cases [51]. The pure variant is
reported to spread many years from diagnosis and without prior extremely rare. Mean age is 52.5 years (range 33–78). As
nodal disease [45, 47]. The most frequent site of metastases is opposed to the pure SPC, 70% of the patients present with
lung. Patients may live many years with metastases. involved axillary lymph nodes [51, 52].
acinic cell carcinoma immunohistochemistry. About two-thirds of the cases are ER
positive and up to 68% are PgR positive, one-third to one-half
definition and epidemiology. Acinic cell carcinoma is considered of the patients present with HER-2-positive status and 66%
as one of the types of salivary gland-like tumors of the breast with Bcl-2 positive. p53 overexpression was identified in 48% of
that show serous differentiation. Eighteen cases have been the cases [51, 59]. No basal-like immunostaining pattern was
reported in the literature. Ages range from 35 to 80 years. Three detected [60].
cases with positive lymph nodes are recorded [34].
imaging. Mammography is able to diagnose 80% of the cases.
imaging. A well-defined mass creates a differential diagnosis Masses appear with high density. The margins are commonly
with MC, intracystic carcinoma and metaplastic carcinoma [48].
Table 3. Poor prognosis typically ER-positive tumors
immunohistochemistry. This neoplasm is characterized by the
lack of ER, PgR and HER-2. Expression of markers such as
amylase, lysozyme and chymotrypsin is usually seen as in acinic Dominant HER-2 Axillary lymph
cells of the salivary glands. Stains positive for epithelial profile node involvement %
membrane antigen and S100 protein are frequently found. Small cell Negative 59 [50]
Invasive micropapillary £50% 70 [51, 52]
prognosis. The literature categorizes this tumor as a favorable
one; however, even within a short follow-up period, systemic ER, estrogen receptor.
1766 | Yerushalmi et al. Volume 20 | No. 11 | November 2009

5. Annals of Oncology review
speculated; however, in approximately one-third of the lipid-rich carcinoma
patients, indistinct or microlobulated margins were seen. definition and epidemiology. This is defined as a tumor in which
Microcalcifications were present in 43.8% of patients. On 90% of its neoplastic cells contain abundant cytoplasmic
sonography, masses are typically hypoechoic, with only 60% of neutral lipids. Usually, it has very high-grade nuclear features
the masses showing posterior acoustic shadowing [61]. and poorly differentiated growth pattern. The tumor accounts
prognosis. Carcinoma with micropapillary features harbors for 1%–2% of all breast cancer with 84% of reported patients
a poor survival. The amount of IMC component correlates presenting at age £50. In one series, 80% were diagnosed with
strongly with the number of involved axillary lymph nodes. involved axillary lymph nodes and most had more than three
In the 5-year follow-up (range 4–199 months) of 98 positive lymph nodes. In total, 71% (35 of 49) were diagnosed
patients, 10-year OS was 48% and breast-specific survival with stage III disease. Many pathologists do not consider this
was 63.3%. The outcome of the patients did not differ type as a separate entity.
significantly from infiltrating ductal carcinomas of similar imaging. Although the tumors consist of a large proportion of
node status [62, 63]. lipid, they present with a higher density than adjacent tissue at
mammography.
poor prognosis, ERs negative immunohistochemistry. In the largest series (n = 49), 100% of
Findings are summarized in Table 4. the patients presented with ER-negative status. The vast
majority (90%) were PgR negative as well. Her-2
metaplastic carcinoma overexpression was found in 71.4% of this kind of neoplasm,
which was much higher than the 20% expected in the general
definition and epidemiology. This term is used for describing an
invasive breast carcinoma population. High Ki-67 proliferation
adenocarcinoma tumor with a dominant involvement of
activity was found in 55% of the cases.
a metaplastic component which may be of epithelial origin
such as squamous or adenocarcinoma with spindle cell prognosis. The 2- and 5-year OS rates were 64.6% and 33.2%,
differentiation or mesenchymal origin. Most of them are high respectively, with a median OS of 35 months. The only
grade [1]. Metaplastic carcinoma is usually diagnosed with T2 independent factor to predict survival was positive lymph
disease, with a mean size 3.4–4.4 cm and is commonly nodes [66]. In an earlier report, 38.5% of patients died in the
diagnosed in women 50 years of age. The incidence is 1% of first year following mastectomy [73].
all invasive breast carcinoma with a relative high proportion
of African American or Hispanic women (20%) [67, 68]. Most
studies report of a lower rate of axillary nodal involvement ‘unclassified’ due to lack of sufficient
than that is seen with IDC [64, 65]. information
imaging. No unique imaging features are found. glycogen-rich clear-cell carcinoma of the breast
Mammographically, either a circumscribed or an indistinct
definition and epidemiology. This is defined as carcinoma in
lesion is typical. On ultrasound, metaplastic carcinoma reveals
which 90% of the neoplastic cells have abundant clear
more benign features, characterized by oval, round or lobular
cytoplasm containing glycogen [1]. The incidence is 1.4%–3%
solid hypoechoic mass with circumscribed margins. On MRI,
of all breast cancers, presenting at a median age of 57. There is
almost all the cases show T2 hypersignal which is related to the
debate regarding this tumor’s behavior as some small series
necrotic component [69, 70].
report high axillary lymph nodal rate involvement of more than
immunohistology. Most of these high grade neoplasms show a 50% [53], whereas others report a much lower rate—35%
basal-like phenotype, few being positive for hormone receptors (n = 20) [74].
or HER-2 over-expression (0–8%) [69, 71].
imaging. There is not enough available data.
prognosis. These tumors have a high metastatic potential. More
immunohistology. In a series of 20 patients, 35% and 30% were
than 50% of these tumors are associated with local or distal
positive to ER and PgR, respectively. In total, 20% presented
recurrence. The spread is hematogenous rather than lymphatic.
with HER-2-positive status.
Hennessy et al. found a median OS of 37 months [72]. The
median survival from detection of metastatic disease was 8–12 prognosis. Fewer than 100 cases have been reported; thus, it
months [67, 69]. is difficult to draw definitive conclusions. Most authors
have found that this tumor has a poor prognosis but
there is no direct comparison to IDC-NOS based on stage
Table 4. Poor prognosis typically ER-negative tumors
[74, 75].
Dominant HER-2 Axillary lymph
profile % node involvement %
oncocytic carcinoma (malignant oncocytoma)
Metaplastic 0–8 20 [64, 65]
definition. The WHO classification requires 70% of the cells to
Lipid rich 71 80 [66] be oncocytic ones; however, only very few case reports are
published. Thus, we have found that no significant conclusion
ER, estrogen receptor. can be drawn.
Volume 20 | No. 11 | November 2009 doi:10.1093/annonc/mdp245 | 1767

6. review Annals of Oncology
sebaceous carcinoma bud without jeopardizing local control and to avoid rib, lung
definition and epidemiology. This carcinoma is characterized by and other tissue damage. Thus, radiation may be omitted
a lobular or nested growth pattern of tumor cells variably according to some experts but again, there is only scanty data.
admixed with those displaying sebaceous differentiation. To As we cannot create systemic treatment algorithms using
our knowledge, only seven cases have been reported in the randomized trials with level one evidence due to the rarity of all
literature with ages ranging from 43 to 83 years. Sebaceous these tumors, can we use small case reports? Diab et al. found
tumor may precede internal malignancies and a genetic that axillary node involvement was a poor prognostic feature in
consultation to rule out Muir–Torre Syndrome should be mucinous carcinomas but not in TCs. Their conclusion was
considered. A case with involved lymph node at presentation that systemic adjuvant therapy and node dissection may be
was reported [76]. avoided in many patients with TC [13]. This conclusion is in
accordance with the recent knowledge regarding the lack of
immunohistochemistry. The hormone receptor status is sensitivity of luminal A breast cancers to chemotherapy and the
typically positive; however, two cases were reported to be role of endocrine treatments [83, 84]. However, further data
negative. No HER-2 overexpression was detected. In three are required before completely changing our guidelines for
analyzed cases, the percentage of Ki-67-positive tumor cells was these tumors.
relatively high and ranged from 16% to 38% [77]. ACC as a histological definition appears to have both
prognosis. Sebaceous carcinoma (SC) is generally felt to have prognostic and predictive significance by some authors as there
a worse prognosis than other cutaneous carcinomas. Due to are concerns regarding the sensitivity of this subtype to
the only scant published data, it is difficult to compare it with chemotherapy based mainly on the documented low response
the breast IDC-NOS. SC that had metastasized to the bone and rate in the head and neck adenoid cystic literature. There are
skin was reported .The case may imply on its aggressive data that this tumor has some response to chemotherapy drugs
potential [77, 78]. such as anthracyclines and 5-fluorouracil as well as more
modern agents such as paclitaxel [85, 86]. Large series,
however, are not available.
treatment data from the literature Recently, there has been interest in the platinum agents and
These epithelial tumors are far too rare to have been studied they have been incorporated into the arsenal of treatment of the
with specific randomized clinical trials to determine the triple-negative or basal subtypes. Several studies had shown
optimal surgical, radiation, chemotherapeutic or endocrine activity of these agents in the metastatic and neoadjuvant
treatment. Although occasionally these rare tumor types have treatment but larger studies are still pending. Knowing that
been included in large trials, the numbers are too small to draw phase III trial results for these rare types will not be
any conclusions regarding their response to treatment. In most forthcoming, can we make a leap and recommend platinum
situations, they have been treated with standard therapy as agent in the adjuvant setting for certain rare triple-negative
there are no data to indicate special protocols. subtypes such as metaplastic or the aggressive small-cell
Surgery is the first step of treatment of most of the early tumors? There is certainly rationale in administering adjuvant
breast cancers. The standard of care is lumpectomy/ cisplatin regimen in SCC breast cancer. This tumor has an
mastectomy with sentinel node biopsy (SNB). Many of the aggressive course and there are data showing a high rate of
special types such as tubular, cribriform, medullary and response in small-cell lung and extrapulmonary metastatic
mucinous have a low risk for regional involved lymph nodes disease. If NE breast cancers are just another extrapulmonary
but without more data, it is not clear whether SNB can be safely site of small-cell tumors, they may be treated in a similar
omitted. fashion but we do need to remember that for the adjuvant
Adjuvant radiation therapy has shown its benefit in breast breast cancer setting, this is not an evidence-based
cancer not only as a local control procedure but also as recommendation. For other types of these tumors, further
a treatment to prolong survival. ‘Favorable tumors’ tend to studies are necessary before treatment algorithms can
have lower rate of local and distant recurrences. When be created.
comparing IDC-NOS to medullary, tubular and mucinous
types, no statistically significant differences were found in the
local–regional failure rate among the four groups. In total, 31%
summary
of TCs and up to 37.5% of ACCs that had been treated with Rare epithelial breast cancers are a heterogeneous group of
excision only developed local recurrence [33, 47, 79]. malignancies with different behaviors and prognoses. Although
The significant parameters were still the traditional ones: histopathology has been our standard, there is now the
age, margins, lymphovascular invasion and extensive DCIS question of whether it is time to apply new technologies such as
[13, 39, 80]. microarrays and deep gene analysis to further understand these
Baker has stated that pure TC 1 cm in size could be treated rare tumors. Are they all really unique subtypes or not? Can
by excision only [81]. However, the NSABP B-20 trial that had they be classified according to their molecular or genetic
randomly assigned patients with small IDC tumors to yes/no features? Are the older histological subtypes of value in
adjuvant radiation could not find any subgroup which did not understanding the behavior of these rare tumors and are they
benefit from radiation therapy [82]. The secretory type which is really classifying specific tumors or not?
typically diagnosed in young girls represents a possible We have tried to classify these tumors with the data we have
exception since there is a strong effort to preserve the breast currently on ER status and outcome. These broad groups of
1768 | Yerushalmi et al. Volume 20 | No. 11 | November 2009

7. Annals of Oncology review
estrogen-positive good outcome or poor outcome or similar 13. Diab SG, Clark GM, Osborne CK et al. Tumor characteristics and clinical outcome
estrogen-negative groups may be helpful in terms of of tubular and mucinous breast carcinomas. J Clin Oncol 1999; 17(5):
1442–1448.
conceptualizing where we are going but need further
assessment. As well, the poor prognosis of some of these 14. Cabral AH, Recine M, Paramo JC et al. Tubular carcinoma of the breast: an
institutional experience and review of the literature. Breast J 2003; 9(4):
subtypes reflects the need for a better adjuvant treatment and 298–301.
an understanding of these specific groups based on both their
15. Stutz JA, Evans AJ, Pinder S et al. The radiological appearances of invasive
histological appearance and their molecular staining. cribriform carcinoma of the breast. Nottingham Breast Team. Clin Radiol 1994;
We are proposing and organizing a consortium of 49(10): 693–695.
investigators from around the world to gather a sizable number 16. Soomro S, Shousha S, Taylor P et al. c-erbB-2 expression in different histological
of these rare tumor types, assess the tumors centrally by types of invasive breast carcinoma. J Clin Pathol 1991; 44(3): 211–214.
modern array technology and try to group these with outcome 17. Barkley CR, Ligibel JA, Wong JS et al. Mucinous breast carcinoma: a large
and treatment data. This has been established for the common contemporary series. Am J Surg 2008; 196(4): 549–551.
tumors and we have many leads as to their subclassification 18. Memis A, Ozdemir N, Parildar M et al. Mucinous (colloid) breast cancer:
but a further analysis of these rare tumors is also needed. This mammographic and US features with histologic correlation. Eur J Radiol 2000;
exercise may provide the necessary information to begin to 35(1): 39–43.
further understand the behavior of these tumors and to begin 19. Kawashima M, Tamaki Y, Nonaka T et al. MR imaging of mucinous carcinoma of
the breast. AJR Am J Roentgenol 2002; 179(1): 179–183.
to classify them according to their relevant features.
20. Okafuji T, Yabuuchi H, Sakai S et al. MR imaging features of pure mucinous
Subsequently, there may be a role for trials using
carcinoma of the breast. Eur J Radiol 2006; 60(3): 405–413.
a contemporary classification to look at uniform treatment
21. Reiner A, Reiner G, Spona J et al. Histopathologic characterization of human
modalities and begin to establish treatment algorithms and breast cancer in correlation with estrogen receptor status. A comparison of
guidelines. Until such time, we believe broad classifications into immunocytochemical and biochemical analysis. Cancer 1988; 61(6):
the good and bad prognostic groups may be helpful for the 1149–1154.
clinician faced with a patient with one of these tumors and only 22. Kim TH, Kang DK, Kim SY et al. Sonographic differentiation of benign and
anecdotal case histories for reference. malignant papillary lesions of the breast. J Ultrasound Med 2008; 27(1): 75–82.
23. Fisher ER, Palekar AS, Redmond C et al. Pathologic findings from the national
surgical adjuvant breast project (protocol no. 4). VI. Invasive papillary cancer. Am
acknowledgement J Clin Pathol 1980; 73(3): 313–322.
The authors declare no conflict of interests. 24. Fisher ER, Anderson S, Redmond C et al. Pathologic findings from the national
surgical adjuvant breast project protocol B-06. 10-year pathologic and clinical
prognostic discriminants. Cancer 1993; 71(8): 2507–2514.
references 25. Miller WR, Shivas AA, Franchimont P et al. Breast gross cystic disease protein 15
in human breast cancer in culture. Eur J Cancer Clin Oncol 1988; 24(2):
1. Tavassoli FA, Devilee P. World Health Organization Classification of Tumors,
223–228.
Tumors of the Breast and Female Genital Organs, 2nd edition. Lyon, France:
IARC Press 2003. 26. Japaze H, Emina J, Diaz C et al. ‘Pure’ invasive apocrine carcinoma of the
breast: a new clinicopathological entity? Breast 2005; 14(1): 3–10.
2. Kader HA, Jackson J, Mates D et al. Tubular carcinoma of the breast:
a population-based study of nodal metastases at presentation and of patterns of 27. Makretsov N, Gilks CB, Coldman AJ et al. Tissue microarray analysis of
relapse. Breast J 2001; 7(1): 8–13. neuroendocrine differentiation and its prognostic significance in breast cancer.
Hum Pathol 2003; 34(10): 1001–1008.
3. Leikola J, Heikkila P, von Smitten K et al. The prevalence of axillary lymph-node
metastases in patients with pure tubular carcinoma of the breast and sentinel 28. Weigelt B, Horlings HM, Kreike B et al. Refinement of breast cancer classification
node biopsy. Eur J Surg Oncol 2006; 32(5): 488–491. by molecular characterization of histological special types. J Pathol 2008;
216(2): 141–150.
4. Page DL, Dixon JM, Anderson TJ et al. Invasive cribriform carcinoma of the
29. Sapino A, Papotti M, Righi L et al. Clinical significance of neuroendocrine
breast. Histopathology 1983; 7(4): 525–536.
carcinoma of the breast. Ann Oncol 2001; 12 (Suppl 2): S115–S117.
5. Venable JG, Schwartz AM, Silverberg SG. Infiltrating cribriform carcinoma of the
30. Vu-Nishino H, Tavassoli FA, Ahrens WA, Haffty BG. Clinicopathologic features
breast: a distinctive clinicopathologic entity. Hum Pathol 1990; 21(3): 333–338.
and long-term outcome of patients with medullary breast carcinoma managed
6. Li CI, Uribe DJ, Daling JR. Clinical characteristics of different histologic types of with breast-conserving therapy (BCT). Int J Radiat Oncol Biol Phys 2005; 62(4):
breast cancer. Br J Cancer 2005; 93(9): 1046–1052. 1040–1047.
7. Di Saverio S, Gutierrez J, Avisar E. A retrospective review with long term follow 31. Vieni S, Cabibi D, Cipolla C et al. Secretory breast carcinoma with metastatic
up of 11,400 cases of pure mucinous breast carcinoma. Breast Cancer Res sentinel lymph node. World J Surg Oncol 2006; 4: 88.
Treat 2008; 111(3): 541–547.
32. Page DL. Adenoid cystic carcinoma of breast, a special histopathologic type with
8. Otsuki Y, Yamada M, Shimizu S et al. Solid-papillary carcinoma of the breast: excellent prognosis. Breast Cancer Res Treat 2005; 93(3): 189–190.
clinicopathological study of 20 cases. Pathol Int 2007; 57(7): 421–429. 33. Millar BA, Kerba M, Youngson B et al. The potential role of breast conservation
9. O’Malley FP, Bane A. An update on apocrine lesions of the breast. surgery and adjuvant breast radiation for adenoid cystic carcinoma of the breast.
Histopathology 2008; 52(1): 3–10. Breast Cancer Res Treat 2004; 87(3): 225–232.
10. Lopez-Bonet E, Alonso-Ruano M, Barraza G et al. Solid neuroendocrine breast 34. Reis-Filho JS, Natrajan R, Vatcheva R et al. Is acinic cell carcinoma a variant of
carcinomas: incidence, clinico-pathological features and immunohistochemical secretory carcinoma? A FISH study using ETV6#split apart’ probes.
profiling. Oncol Rep 2008; 20(6): 1369–1374. Histopathology 2008; 52(7): 840–846.
11. Gunhan-Bilgen I, Oktay A. Mammographic features of local recurrence after 35. Linda A, Londero V, Mazzarella F et al. Rare breast neoplasms: is there any
conservative surgery and radiation therapy: comparison with that of the primary peculiar feature on magnetic resonance mammography? Radiol Med (Torino)
tumor. Acta Radiol 2007; 48(4): 390–397. 2007; 112(6): 850–862.
12. Oakley GJ III, Tubbs RR, Crowe J et al. HER-2 amplification in tubular carcinoma 36. Majid AS, de Paredes ES, Doherty RD et al. Missed breast carcinoma: pitfalls and
of the breast. Am J Clin Pathol 2006; 126(1): 55–58. pearls. Radiographics 2003; 23(4): 881–895.
Volume 20 | No. 11 | November 2009 doi:10.1093/annonc/mdp245 | 1769

8. review Annals of Oncology
37. Vincent-Salomon A, Gruel N, Lucchesi C et al. Identification of typical medullary 61. Gunhan-Bilgen I, Zekioglu O, Ustun EE et al. Invasive micropapillary carcinoma of
breast carcinoma as a genomic sub-group of basal-like carcinomas, the breast: clinical, mammographic, and sonographic findings with
a heterogeneous new molecular entity. Breast Cancer Res 2007; 9(2): R24. histopathologic correlation. AJR Am J Roentgenol 2002; 179(4): 927–931.
38. Xu R, Feiner H, Li P et al. Differential amplification and overexpression of HER-2/ 62. Nassar H, Qureshi H, Volkanadsay N et al. Clinicopathologic analysis of solid
neu, p53, MIB1, and estrogen receptor/progesterone receptor among papillary carcinoma of the breast and associated invasive carcinomas. Am J Surg
medullary carcinoma, atypical medullary carcinoma, and high-grade invasive Pathol 2006; 30(4): 501–507.
ductal carcinoma of breast. Arch Pathol Lab Med 2003; 127(11): 63. Chen L, Fan Y, Lang RG et al. Breast carcinoma with micropapillary features:
1458–1464. clinicopathologic study and long-term follow-up of 100 cases. Int J Surg Pathol
39. Thurman SA, Schnitt SJ, Connolly JL et al. Outcome after breast-conserving 2008; 16(2): 155–163.
therapy for patients with stage I or II mucinous, medullary, or tubular breast 64. Pezzi CM, Patel-Parekh L, Cole K et al. Characteristics and treatment of
carcinoma. Int J Radiat Oncol Biol Phys 2004; 59(1): 152–159. metaplastic breast cancer: analysis of 892 cases from the National Cancer Data
40. Mun SH, Ko EY, Han BK et al. Secretory carcinoma of the breast: sonographic Base. Ann Surg Oncol 2007; 14(1): 166–173.
features. J Ultrasound Med 2008; 27(6): 947–954. 65. Wargotz ES, Deos PH, Norris HJ. Metaplastic carcinomas of the breast. II.
41. Tognon C, Knezevich SR, Huntsman D et al. Expression of the ETV6-NTRK3 gene Spindle cell carcinoma. Hum Pathol 1989; 20(8): 732–740.
fusion as a primary event in human secretory breast carcinoma. Cancer Cell 66. Shi P, Wang M, Zhang Q, Sun J. Lipid-rich carcinoma of the breast. A
2002; 2(5): 367–376. clinicopathological study of 49 cases. Tumori 2008; 94(3): 342–346.
42. McClenathan JH, de la Roza G. Adenoid cystic breast cancer. Am J Surg 2002; 67. Luini A, Aguilar M, Gatti G et al. Metaplastic carcinoma of the breast, an unusual
183(6): 646–649. disease with worse prognosis: the experience of the European Institute Of Oncology
43. Azoulay S, Lae M, Freneaux P et al. KIT is highly expressed in adenoid cystic and review of the literature. Breast Cancer Res Treat 2007; 101(3): 349–353.
carcinoma of the breast, a basal-like carcinoma associated with a favorable 68. Tavassoli FA. Classification of metaplastic carcinomas of the breast. Pathol Annu
outcome. Mod Pathol 2005; 18(12): 1623–1631. 1992; 27(Pt 2): 89–119.
44. Trendell-Smith NJ, Peston D, Shousha S. Adenoid cystic carcinoma of the 69. Tse GM, Tan PH, Putti TC et al. Metaplastic carcinoma of the breast:
breast: a tumour commonly devoid of oestrogen receptors and related proteins. a clinicopathological review. J Clin Pathol 2006; 59(10): 1079–1083.
Histopathology 1999; 35(3): 241–248. 70. Velasco M, Santamaria G, Ganau S et al. MRI of metaplastic carcinoma of the
45. Arpino G, Clark GM, Mohsin S et al. Adenoid cystic carcinoma of the breast: breast. AJR Am J Roentgenol 2005; 184(4): 1274–1278.
molecular markers, treatment, and clinical outcome. Cancer 2002; 94(8): 71. Reis-Filho JS, Milanezi F, Steele D et al. Metaplastic breast carcinomas are
2119–2127. basal-like tumours. Histopathology 2006; 49(1): 10–21.
46. Kleer CG, Oberman HA. Adenoid cystic carcinoma of the breast: value of 72. Hennessy BT, Krishnamurthy S, Giordano S et al. Squamous cell carcinoma of
histologic grading and proliferative activity. Am J Surg Pathol 1998; 22(5): the breast. J Clin Oncol 2005; 23(31): 7827–7835.
569–575. 73. Ramos CV, Taylor HB. Lipid-rich carcinoma of the breast. A clinicopathologic
47. Leeming R, Jenkins M, Mendelsohn G. Adenoid cystic carcinoma of the breast. analysis of 13 examples. Cancer 1974; 33(3): 812–819.
Arch Surg 1992; 127(2): 233–235. 74. Kuroda H, Sakamoto G, Ohnisi K et al. Clinical and pathological features of
48. Tanahashi C, Yabuki S, Akamine N et al. Pure acinic cell carcinoma of the breast glycogen-rich clear cell carcinoma of the breast. Breast Cancer 2005; 12(3):
in an 80-year-old Japanese woman. Pathol Int 2007; 57(1): 43–46. 189–195.
49. Peintinger F, Leibl S, Reitsamer R et al. Primary acinic cell carcinoma of the 75. Hayes MM, Seidman JD, Ashton MA. Glycogen-rich clear cell carcinoma of the
breast: a case report with long-term follow-up and review of the literature. breast. A clinicopathologic study of 21 cases. Am J Surg Pathol 1995; 19(8):
Histopathology 2004; 45(6): 645–648. 904–911.
50. Sadanaga N, Okada S, Shiotani S et al. Clinical characteristics of small cell 76. Alzaraa A, Ghafoor I, Yates A et al. Sebaceous carcinoma of the skin of the
carcinoma of the breast. Oncol Rep 2008; 19(4): 981–985. breast: a case report. J Med Case Reports 2008; 2: 276.
51. Zekioglu O, Erhan Y, Ciris M et al. Invasive micropapillary carcinoma of the 77. Hisaoka M, Takamatsu Y, Hirano Y et al. Sebaceous carcinoma of the breast:
breast: high incidence of lymph node metastasis with extranodal extension and case report and review of the literature. Virchows Arch 2006; 449(4): 484–488.
its immunohistochemical profile compared with invasive ductal carcinoma. 78. Cibull TL, Thomas AB, Badve S et al. Sebaceous carcinoma of the nipple. J
Histopathology 2004; 44(1): 18–23. Cutan Pathol 2008; 35(6): 608–610.
52. Walsh MM, Bleiweiss IJ. Invasive micropapillary carcinoma of the breast: eighty 79. Holland DW, Boucher LD, Mortimer JE. Tubular breast cancer experience at
cases of an underrecognized entity. Hum Pathol 2001; 32(6): 583–589. Washington University: a review of the literature. Clin Breast Cancer 2001; 2(3):
53. Rosen PP. Rosen’s Breast Pathology, 2nd edition. Philadelphia, PA: Lippincott 210–214.
Williams Wilkins 2001. 80. Vo T, Xing Y, Meric-Bernstam F et al. Long-term outcomes in patients with
54. Bigotti G, Coli A, Butti A et al. Primary small cell neuroendocrine carcinoma of mucinous, medullary, tubular, and invasive ductal carcinomas after lumpectomy.
the breast. J Exp Clin Cancer Res 2004; 23(4): 691–696. Am J Surg 2007; 194(4): 527–531.
55. Sapino A, Righi L, Cassoni P et al. Expression of the neuroendocrine phenotype 81. Baker RR. Unusual lesions and their management. Surg Clin North Am 1990;
in carcinomas of the breast. Semin Diagn Pathol 2000; 17(2): 127–137. 70(4): 963–975.
56. Shin SJ, DeLellis RA, Ying L et al. Small cell carcinoma of the breast: 82. Fisher B, Jeong JH, Dignam J et al. Findings from recent national surgical
a clinicopathologic and immunohistochemical study of nine patients. Am J Surg adjuvant breast and bowel project adjuvant studies in stage I breast cancer. J
Pathol 2000; 24(9): 1231–1238. Natl Cancer Inst Monogr 2001; 30: 62–66.
57. Mariscal A, Balliu E, Diaz R et al. Primary oat cell carcinoma of the breast: 83. Goldstein NS, Decker D, Severson D et al. Molecular classification system
imaging features. AJR Am J Roentgenol 2004; 183(4): 1169–1171. identifies invasive breast carcinoma patients who are most likely and those who
58. Kitakata H, Yasumoto K, Sudo Y et al. A case of primary small cell carcinoma of are least likely to achieve a complete pathologic response after neoadjuvant
the breast. Breast Cancer 2007; 14(4): 414–419. chemotherapy. Cancer 2007; 110(8): 1687–1696.
59. Luna-More S, Casquero S, Perez-Mellado A et al. Importance of estrogen 84. Penault-Llorca F, Cayre A, Bouchet Mishellany F et al. Induction chemotherapy
receptors for the behavior of invasive micropapillary carcinoma of the breast. for breast carcinoma: predictive markers and relation with outcome. Int J Oncol
Review of 68 cases with follow-up of 54. Pathol Res Pract 2000; 196(1): 2003; 22(6): 1319–1325.
35–39. 85. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced
60. Kim MJ, Gong G, Joo HJ et al. Immunohistochemical and clinicopathologic salivary gland cancers. J Clin Oncol 2006; 24(17): 2673–2678.
characteristics of invasive ductal carcinoma of breast with micropapillary 86. Till BG, Martins RG. Response to paclitaxel in adenoid cystic carcinoma of the
carcinoma component. Arch Pathol Lab Med 2005; 129(10): 1277–1282. salivary glands. Head Neck 2008; 30(6): 810–814.
1770 | Yerushalmi et al. Volume 20 | No. 11 | November 2009