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: zeeshanuddin90@yahoo.com.

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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