CASE REPORT
Invasive Micropapillary Carcinoma of Breast:An Under-recognized Entity. A series of Eight Cases
Zeeshan Uddin, MBBS, FCPS, Romana Idrees, MBBS, FCPS,Kanwal Aftab, MBBS, FCPS, and Naila Kayani, MD, FCAP
Department of Pathology and Microbiology, Section of Histopathology, The Aga Khan UniversityHospital, Karachi, Pakistan
n Abstract: Invasive micropapillary carcinoma (IMPC) of breast is a morphologically distinct and relatively uncommonvariant of invasive ductal carcinoma. It is characterized by small clusters of tumor cells with surrounding clear stromalspaces; a tendency for vascular permeation and therefore, an aggressive clinical course. This morphologic pattern can beeasily missed especially in a small biopsy specimen because pathologists may disregard the clear spaces as artifactual.With a tendency of presenting at a higher stage, this morphological pattern needs to be mentioned in the histopathologyreport whenever it is encountered, either in its pure form or admixed with conventional ductal carcinoma. We describe eightcases of IMPC of breast along with their variable clinical presentations. n
Key Words: breast, invasive ductal carcinoma, invasive micropapillary carcinoma
Invasive micropapillary carcinoma (IMPC) of breast
is a morphologically distinct and aggressive variant
of invasive ductal carcinoma which is fairly uncom-
mon. It has characteristic morphological pattern i.e.,
small clusters of tumor cells with surrounding clear
stromal spaces; a tendency for vascular permeation
and therefore, a higher stage at presentation (1).
This clinical significance makes this entity crucially
important to be recognized by pathologists.
This is a retrospective review of eight cases. The
cases are typical of the entity as is the high rate of
vascular invasion and lymph node involvement.
PATIENTS AND METHODS
All eight cases of IMPC were retrieved from the
medical records of the section of Histopathology,
Department of Pathology and Microbiology, Aga
Khan University Hospital. The time period during
which these cases were received was of eight years,
starting from 2004 to 2010. All of the specimens were
grossed according to the guidelines given in Rosai and
Ackerman’s Surgical Pathology, 9th edition. The
formalin-fixed, paraffin embedded tissue sections were
stained with Hematoxylin and Eosin (H&E). The
cases were fully characterized on the basis of morpho-
logical features described in the original articles on
IMPC by Tavassoli and Fisher et al. (1,2). The histo-
logical grading was done using Modified Bloom and
Richardson’s grading system. In a couple of cases,
immunohistochemical studies were carried out to see
the characteristic pattern of Epithelial Membrane
Antigen (EMA) expression as a support to the diagno-
sis of IMPC. The Envision system was used for the
immunohistochemistry. Estrogen and progesterone
studies were performed on request. Likewise,
Her-2 ⁄ neu status by immunohistochemistry with or
without fluorescence insitu hybridization (FISH) was
determined when requested by the clinician.
RESULTS
Demographic and Clinical Features
All of the eight patients were female. The age range
was 36–76 years with a mean age of 53.5 years.
All except one of them presented as palpable lumps
in breast. Two of these seven palpable cases were sus-
picious for malignancy on clinical and ⁄ or radiological
examination. A case was sent with a clinical impres-
sion of hematoma which may be due to the extensive
cystic degeneration and hemorrhage seen in that tumor.
Address correspondence and reprints request to: Dr. Zeeshan Uddin,
MBBS, FSPS, Department of Pathology and Microbiology, The Aga Khan
University, Medical Centre, Stadium Road, P.O. Box 3500,Karachi-74800,
Pakistan, or e-mail: [email protected].
DOI: 10.1111/j.1524-4741.2012.01232.x
� 2012 Wiley Periodicals, Inc., 1075-122X/11The Breast Journal, Volume 18 Number 3, 2012 267–271
One case was clinically interpreted as inflammatory
mass. One of eight cases was picked up as a suspi-
cious density in the left breast during a screening
mammogram. Five out of eight patients had involve-
ment of their left breasts. Laterality was not known in
a single case.
Fine needle aspiration cytology (FNAC) of breast
was sought after in two of the cases. The result of one
of them was inconclusive as it was called as ‘‘papillary
lesion’’ from another institute. The other case was
diagnosed as carcinoma.
Surgery with an intention of cure was carried out
in all of these cases except the one which was con-
fused with hematoma. In the later case, curettage was
attempted initially with subsequent modified radical
mastectomy (MRM). In the remaining cases, different
diagnostic ⁄ therapeutic approaches were undertaken
which have been described in Table 1. One of the
cases was subjected to frozen section. However, the
lesion was probably not adequately resected because
the frozen sections as well as the permanent sections
from the entirely submitted specimen revealed only
benign breast tissue. Later on, the diagnosis of IMPC
was made on the additional material which was
obtained by an open incisional biopsy and sent for
routine histological evaluation. Status of lymph nodes
was known in seven of eight cases. A patient was
given neoadjuvent chemotherapy after the initial diag-
nosis of carcinoma given on trucut biopsy.
Gross Features
There were no distinctive gross features. Most of
the tumors were solid grey white to light brown with
infiltrating edges. Prominent necrosis with hemorrhage
was noted in two of the cases including the one show-
ing cystic degeneration. The mean tumor size was
2.9 cm (1.7–4.5 cm).
Histological Features
Histologically, all of them showed characteristic
morphology of IMPC i.e., invasive epithelial nests
having cohesive clusters of cells within surrounding
cleft-like clear spaces (Fig. 1). The cells were cuboidal
to polygonal forming papillae without any definitive
fibrovascular cores. The cell showed abundant eosino-
philic cytoplasm and pleomorphic nuclei with clumped
chromatin and occasional prominent nucleoli. There
Table 1 Pathological features and demographics of eight patients of invasive micropapillarycarcinoma (IMPC) of breast
Case #
Age
yrs Laterality
Type of
surgery
Previous
diagnosis of
Ductal carcinoma,
NOS (if any)
Tumor size,
largest
dimension
(cm)
Tumor
grade* I-III DCIS
Vascular
invasion
Nodal
status ER PR Her-2 ⁄ neu
1 36 NA Lumpectomy ) 2.8 II ) + 1 ⁄ 1 NA NA
2 64 Left WLE ) 2.5 I + solid ) 0 ⁄ 7 + 2+, FISH)3 54 Left Trucut, MRM + 4 III ) ++ 14 ⁄ 15 ) 3+
4 58 Left WLE ) 1.7 II ) ) NA NA NA
5 50 Left MRM ) 4 II + cribriform,
micropapillary
+ 3 ⁄ 17 + 1+
6 55 Left MGNLE, WLE,
MRM
+ 2.3 II ) ) 1 ⁄ 15 + 1+
7 76 Right MRM + 1.7 II + solid ++ 18 ⁄ 18 + 2 + FISH+
8 35 Right Trucut, MRM + 4.5 III + solid, cribriform, comedo ++ 8 ⁄ 8 + NA
*Grading done by modified Bloom & Richardson’s grading system.MGNLE = mammoguided needle localization excision ; MRM = modified radical mastectomy; WLE = wide local excision.
Figure 1. Invasive micropapillary carcinoma of breast showing
cohesive clusters of epithelial cells with surrounding characteristic
clear spaces. Note the presence of papillae without fibrovascular
cores (H&E, 20X).
268 • uddin et al.
was no desmoplasia in the surrounding stroma. In two
patients, features of conventional ductal carcinoma
were also seen in addition to IMPC. In one of them,
two components were admixed in the same tumor,
while in the other one; there were two lesions, 4 cm
apart in different quadrants of breast. One measuring
1.5 · 1.2 cm showed an ordinary ductal carcinoma
morphologically and the other one which measured
1.7 · 1.5 cm was IMPC. Regarding the tumor grade,
most fell into grade II i.e., five out of eight cases. Two
were graded III tumors while a single case of grade
I IMPC was seen. Vascular permeation by the tumor
cells was identified in five cases with three showing
extensive angioinvasion. Insitu component was noted
in four cases (<5% of tumor in all four cases. All of
them were ductal carcinoma insitu (DCIS), with solid
and cribriform patterns being the most common. One
case showed micropapillary type DCIS, while another
case had areas of comedo type DCIS (see Table 1).
Four out of eight patients underwent an initial
small biopsy. For some reasons, all four of them were
diagnosed as conventional ductal carcinoma based on
the initial biopsy material. In the remaining four cases,
either the small biopsy was not attempted or there
was no record available regarding this.
Lymph Node Involvement
At least some information of lymph node status was
known in seven cases. A case of wide local excision
was sent without lymph node sampling. Six of the
cases had axillary dissection done, in addition to wide
local excision or mastectomy. There was one case in
which a single lymph node was sampled. The details of
lymph node involvement are mentioned in Table 1.
Results of Immunohistochemistry
In two cases, immunohistochemical studies were
carried out to see the characteristic pattern of EMA
expression seen in IMPC. It typically stained periph-
eral cells of the tumor cell clusters as well as the bor-
ders of stromal spaces (Fig. 2). Immunohistochemical
expression of ER & PR was ordered by the clinician
in six cases with five of them showed strong nuclear
staining for either of them. Her-2 ⁄ neu protein expres-
sion by immunohistochemistry was determined on
request in five cases. One was scored as 3+, two oth-
ers as 2+ and still two others as 1+. FISH studies were
carried out in both of the cases scored as 2+. One
showed Her-2 ⁄ neu gene amplification while the other
one was negative.
DISCUSSION
Invasive micropapillary carcinoma (IMPC) is a
morphologically distinct variant of invasive ductal car-
cinoma, characterized by small clusters of epithelial
cells within artifactual stromal spaces and relatively
more common angioinvasion and lymph node metas-
tases. It accounts for less than 2% of all the invasive
breast carcinomas (1).
Micropapillary pattern in breast carcinomas was
first described by Fisher et al. in 1980 who referred it
as ‘‘exfoliative appearance’’ (2). The term invasive
micropapillary carcinoma was first coined in 1993 by
Siriaunkgu and Tavassoli in their series of nine cases
from the Armed Forces Institute of Pathology (3). This
characteristic pattern can be seen admixed with con-
ventional ductal carcinoma or may present in its pure
form. In a series presented by Luna More et al.,
micropapillary differentiation was found in 2.7% of
all the consecutive 986 cases of breast carcinomas (4).
Dominant micropapillary pattern was seen in less than
2% of all invasive breast cancers (4,5). Although four
of the eight examples that we present here, were ini-
tially diagnosed as invasive ductal carcinoma, not
otherwise specified (NOS), but all except one of these
cases were purely of micropapillary morphology in
their excision specimens. One of these four had two
separate tumors, one was ductal, NOS, the other one
was IMPC. When the previous slides of those three
cases were reviewed, it was realized that probably this
initial interpretation was limited due to crushing arti-
facts commonly seen in small biopsies or the clear
Figure 2. Invasive micropapillary carcinoma of breast exhibiting
characteristic pattern of immunohistochemical EMA expression i.e.,
staining peripheral cells of the tumor clusters as well as the
borders of stromal spaces.
Invasive Micropapillary Carcinoma of Breast • 269
stromal spaces were ignored as being only artifactual
rather than indicative of micropapillary pattern.
The reported age range at diagnosis and the distri-
bution in terms of laterality does not differ from
ordinary ductal carcinomas (1,3,6). The age range in
our series is 36–76 years. Interestingly, for some rea-
sons most of our cases (05 ⁄ 08, 62.5%) in which later-
ality was known, were from the left side. This finding
is similar to results presented by Kim et al. who found
the left breast affected in 60% (23 of 38) of their
cases (7). Most cases present as palpable breast lumps,
but occasional examples of mammographically picked
lesions, like one of our cases, are also seen (3). A high
proportion of patients (72–77%) have axillary lymph
node metastasis at the time of presentation (1,2,4,6).
Six out of seven cases (with lymph node sampling) in
the current series showed positive axillary lymph
nodes; included among them is the mammographically
detected nonpalpable case 6 of IMPC.
Grossly, the pure IMPCs are lobulated due to
expansile pattern of growth with the tumor size rang-
ing from 0.3 to 3.0 cm in one series (1,3). It has been
said that tumors having >50% micropapillary pattern
tend to have a larger mean size i.e., 6 cm as compared
to the cases with lesser amount of this pattern (mean
size of 3.5 cm) (8). However, these gross descriptions
do not suggest any specific features (8). The mean
tumor size in our series is 2.9 cm (1.7–4.5 cm).
IMPC is composed of hollow aggregates of epithe-
lial cells with serrated outer borders. On cross sections
these epithelial clusters show tubules with obliterated
lumina and surrounding artifactual stromal spaces
(1,3,8). These characteristic clear spaces which are
also seen in metastatic foci may mimic vascular per-
meation by the tumor but they are not lined by endo-
thelial cells (3). They are caused by the shrinkage of
stromal elements by formalin and therefore not seen
in frozen sections (3). The individual cells are cuboidal
to columnar and have eosinophilic cytoplasm. There is
moderate degree of nuclear pleomorphism and mitotic
activity is generally low. Necrosis and lymphocytic
infiltrate is not a feature of micropapillary carcinoma
(1,3). Peritumoral vascular invasion is seen in 50–
70% of IMPCs (1,4,6). Rare variations in the usual
morphological pattern include microcystic dilatation
of central lumina and apocrine differentiation (8).
Invasive papillary and mucinous carcinomas of
breast are included among the differential diagnoses of
IMPC. The former lacks clear spaces and shows true
papillary cores while the later shows smooth outer
contours of tumor cell clusters and have abundant
mucin in the surrounding stroma which can be high-
lighted with the help of special stains (6,8). Also, met-
astatic micropapillary carcinomas from urinary
bladder and colon along with papillary serous carci-
noma of ovary should also be kept in mind while diag-
nosing a case of IMPC in breast (3). Presence of insitu
component may help in this situation which is com-
monly of micropapillary type, however, cribriform pat-
tern can also be noted (6,8). Presence of comedo type
insitu lesion is seen in cases bearing ordinary ductal
carcinomas with areas of micropapillary pattern (8).
Such mixed cases which comprise of 3–6% of conven-
tional breast carcinomas, usually show a sharp demar-
cation between the two components (1,4). Two (2) of
our cases had ductal carcinoma, NOS components
(one admixed with IMPC, other as separate tumor).
When expression of estrogen receptors (ER) and
progesterone receptors (PR) was analyzed in these
tumors, a high proportion of them were positive for
these receptors (90% and 70% respectively) which
does not match with their often aggressive clinical
behavior (6,9). Similarly, significantly higher percent-
age of IMPC show Her-2 ⁄ neu protein overexpression
as compared to conventional ductal carcinomas (5)
with one series reporting up to 60% of cases showing
Her-2 ⁄ neu overexpression (6). In the current series of
eight cases, immunohistochemical expression of ER &
PR was available in six cases with five (83%) of them
showed strong positivity for these receptors. Her-2 ⁄ neu
by immunohistochemistry was carried out on request
in five cases. One was scored as 3+, two others as 2+
still two others as 1+. FISH studies were carried out in
both of the cases scored as 2+. One showed Her-2 ⁄ neu
gene amplification while the other one was negative.
Epithelial membrane antigen (EMA) typically stains
peripheral cells of the tumor clusters as well as the
borders of stromal spaces. This along with the ultra-
structural finding of microvilli along the surface of
cells suggests that the clear spaces are in fact the tubu-
lar lumina and therefore this arrangement of cells has
been referred to as ‘‘inside out growth pattern’’ (8).
On two of our cases, EMA stain was carried out and
characteristic staining was observed.
Micropapillary pattern has been described in carci-
nomas of various anatomic sites other than breast,
including urinary bladder, colon, lung, and major sali-
vary glands. In addition to a unique morphology,
these tumors share a high propensity for angioinvasion
and lymph node metastases. Therefore, patients
270 • uddin et al.
usually present with a high-stage disease and a poor
clinical outcome compared with that of patients with
conventional carcinoma arising in the same organ site
(10). The presence of lymphovascular invasion in
IMPC of breast has been proven as an independent
adverse prognostic factor (6,7). Most of the studies
showed poor clinical outcome with significantly
shorter over all survival (4–7). However, after stratifi-
cation for the number of involved lymph nodes and
other prognostic factors in multivariate analysis, IMPC
had survival rates similar to conventional ductal
carcinomas (1,8).
The treatment of choice in IMPC is mastectomy and
axillary clearance with adjuvant chemotherapy added
to cases having positive lymph nodes or tumor size
>1 cm (8). A study of 72 cases of IMPC showed that it
is more commonly associated with lymphovascular
invasion, extracapsular extension from lymph node, high
nuclear grade, and a greater degree of loco-regional
recurrence, especially in the axilla and supraclavicular
areas. Therefore, they suggest that axillary and supra-
clavicular radiation therapy should be considered in
IMPC patients with axillary node metastasis (11).
The above described clinical significance i.e., predi-
lection for lymphatic and lymph node metastasis
makes IMPC an important entity to be recognized by
pathologists, especially in small biopsy specimen.
Hence, this pattern should be carefully looked for and
included in the surgical pathology reports.
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