CASE REPORT

Synchronous unilateral triple breast cancers composed of invasiveductal carcinoma, invasive lobular carcinoma, and Paget’s disease

Shunsuke Onoe • Hitoshi Tsuda • Sadako Akashi-Tanaka •

Takahiro Hasebe • Eriko Iwamoto •

Takashi Hojo • Takayuki Kinoshita

Received: 22 June 2010 / Accepted: 7 October 2010

� The Japanese Breast Cancer Society 2010

Abstract We report a case of synchronous unilateral

triple breast cancers comprising invasive ductal carcinoma

(IDC), invasive lobular carcinoma (ILC), and Paget’s dis-

ease. A 57-year-old woman with a left breast mass was

referred to our hospital. Mammography revealed only an

isodense area with foci of microcalcification in the lateral

area of the left breast. Ultrasonography revealed 2 hypo-

echoic masses in the outer lower and inner upper areas, and

these 2 lesions were diagnosed by core needle biopsy as

ILC and IDC, respectively. Left total mastectomy with

sentinel lymph node biopsies was performed. In addition to

the ILC and IDC, histological examination also identified

Paget’s disease. Breast cancer often manifests as multiple

unilateral lesions; however, it is sometimes difficult to

determine whether these tumors have developed multi-

centrically or have multifocally invaded from an intra-

ductal carcinoma. This case was clearly diagnosed to have

occurred multicentrically because of the absence of conti-

nuity among the 3 tumors, the presence of a non-invasive

component in all 3 tumors, and different histopathological

findings. The synchronous unilateral development of ILCs

is well known. Cases of synchronous unilateral triple or

more breast cancers were reviewed, and their histopathol-

ogical characteristics, including the incidence of Paget’s

disease, is discussed.

Keywords Synchronous unilateral breast cancer � Triple

cancer � Invasive lobular carcinoma � Invasive ductal

carcinoma � Paget’s disease

Abbreviations

IDC Invasive ductal carcinoma

ILC Invasive lobular carcinoma

ER Estrogen receptor

PgR Progesterone receptor

DCIS Ductal carcinoma in situ

Introduction

Invasive ductal carcinoma (IDC) is the most common type

of malignant tumor of the breast [1]. Invasive lobular

carcinoma (ILC) is less common than IDC, which is known

for its relatively high frequency of bilateral occurrence [2]

and for its multicentric development, both synchronically

and unilaterally. Paget’s disease accounts for only 1–2% of

female breast carcinomas [3–6]. In some patients, Paget’s

disease caused no clinical abnormalities, and the disease

was detected only by histological examination [7].

Among patients with primary breast cancer, the inci-

dence of synchronous unilateral double breast cancers is

estimated to be 9–75%, and the incidence of triple breast

cancers is much lower. Herein, we report a patient with

synchronous unilateral triple breast cancers, comprising

IDC, ILC, and Paget’s disease. We also discuss the

S. Onoe (&) � H. Tsuda � T. Hasebe

Pathology Section, Clinical Laboratory Division,

National Cancer Center Hospital,

5-1-1 Tsukiji, Chuoku, Tokyo 104-0045, Japan

e-mail: sonoe@ncc.go.jp

S. Akashi-Tanaka � E. Iwamoto � T. Hojo � T. Kinoshita

Breast Cancer Group, Surgical Oncology Division,

National Cancer Center Hospital, Tokyo, Japan

T. Hasebe

Pathology Consultation Service, Clinical Trials and Practice

Support Division, Center for Cancer Control and Information

Section, National Cancer Center, Tokyo, Japan

123

Breast Cancer

DOI 10.1007/s12282-010-0245-2

multicentric development of breast cancers including

Paget’s disease.

Case report

A 57-year-old woman was referred to our hospital for the

examination of a left breast mass. The tumor was detected

during a periodic health examination in a general hospital.

Physical examination revealed a well-defined, 1.5-cm-wide

elastic-hard mass in the lateral part of the left breast, along

with mild erosion of the ipsilateral nipple and areola.

Serum tumor marker levels (carcinoembryonic antigen,

carbohydrate antigen 15–3) were within normal limits.

Mammography revealed only an isodense area measur-

ing 15 9 15 mm with calcifications in the medial area of

the left breast (Fig. 1). Ultrasonography of the left breast

revealed 2 hypoechoic masses, 1 in the outer lower area

measuring 11 9 11 9 10 mm and another in the inner

upper area measuring 26 9 14 9 9 mm (Fig. 2). The cal-

cifications corresponded to the tumor in the inner upper

area. No abnormal findings were found in the nipple on

ultrasonography.

We obtained specimens from 2 lesions of the left breast

by performing core needle biopsies, the diagnoses of which

were ILC in the outer lower area and IDC in the inner

upper area. We performed a total mastectomy of the left

breast, with a sentinel lymph node biopsy.

Macroscopic examination revealed 2 whitish solid

lesions with irregular borders: one in the outer lower area,

measuring 20 9 17 9 10 mm (lesion 1) and the other in

the inner upper area, measuring 22 9 20 9 15 mm (lesion

2). No tumor was detected in the nipple on gross exami-

nation (Fig. 3).

Upon histological examination, the tumor cells in lesion

1 were found to lack cohesion and exhibit a tendency to

form slender strands arranged in a linear fashion. The

tumor cells were arranged in concentric rings around the

ducts and lobes (Fig. 4a). We diagnosed the tumor as an

ILC, histological grade 1. The tumor had an intraductal

component and the tumor size, including the intraductal

component, was 4.0 9 1.5 9 2.0 cm. There was no lym-

phovascular invasion. The invasive component of the

tumor was negative for HER2 (score 0), positive for

estrogen receptor (ER) (Allred score 8), and positive for

progesterone receptor (PgR) (Allred score 6) upon immu-

nohistochemical analysis.

In lesion 2, the tumor cells showed a small nest pattern

without tubular formation, accompanied with abundant

fibrous stroma (Fig. 4b). The tumor cells showed large,

pleomorphic, and hyperchromatic nuclei with prominent

nucleoli. We diagnosed this tumor as an IDC, scirrhous

carcinoma, histological grade 3. Tumor 2 also had an

intraductal component and the tumor size, including the

intraductal component, was 3.2 9 2.0 9 1.5 cm. There

was no lymphovascular invasion. The tumor was found to

Fig. 1 Mammography showed only an isodense area with areas of

microcalcification, 15 9 15 mm, in the medial part of the left breast

(arrows)

Fig. 2 Ultrasonography

revealed 2 hypoechoic masses,

one an invasive lobular

carcinoma (ILC) measuring

11 9 11 9 10 mm in the outer

lower area (arrows) and the

other an invasive ductal

carcinoma (IDC) measuring

26 9 14 9 9 mm in the inner

upper area (arrowheads)

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be HER2 positive (score 3?), but ER and PgR negative

(Allred score 0, each) upon immunohistochemical analysis.

Furthermore, Paget cells with clear cytoplasm and

irregular nuclei with prominent nucleoli were seen in the

epidermis of the nipple (Fig. 4c). The Paget cells extended

over an area measuring 3.5 9 2.1 cm in the left nipple and

areolar region. No invasion was seen, and the noninvasive

components were positive for HER2 (score 3?) and neg-

ative for ER and PgR (Allred score 0, each).

The tumors in this case were clearly multicentric in

origin because of the absence of continuity among the 3

tumors, the presence of a non-invasive component in all 3

tumors, and the different histopathological appearance. All

4 sentinel lymph nodes from the left axilla were negative

for metastasis.

Postoperative adjuvant chemotherapy was administered,

with 60 mg/m2 doxorubicin and 600 mg/m2 cyclophos-

phamide 4 times every 3 weeks, followed by 6 mg/m2

trastuzumab every 3 weeks for 1 year. She has no signs of

recurrence 2 years after the operation.

Discussion

Breast cancer often manifests as multiple lesions. The

incidence of synchronous multiple breast cancers occurring

unilaterally is reported to vary from 9 to 75% [8]. These

tumors may include not only true multicentric cancers but

Fig. 4 Histopathological features of 3 carcinomas in the left breast.

a Invasive lobular carcinoma. The tumor cells are arranged in

concentric rings around a non-cancerous duct. b Invasive ductal

carcinoma. The tumor cells form a small nest pattern with

abundant fibrous stroma. The cancer cell nuclei show pleomor-

phism in size and shape, and have prominent nucleoli. The

histological diagnosis is scirrhous carcinoma, nuclear grade 3.

c Paget’s disease. Paget cells with clear cytoplasm and irregular

nuclei with identifiable nucleoli are seen in the basal layer in the

epidermis of the nipple

Fig. 3 Gross features of a surgically resected specimen; IDC invasive

ductal carcinoma; ILC invasive lobular carcinoma; Paget Paget’s

disease

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also multiple invasive cancer nodules originating from a

ductal carcinoma in situ (DCIS) by multifocal invasion and

intramammary metastasis [8, 9].

Between September 1991 and July 1995, data on the

synchronous ipsilateral multiplicity of primary breast can-

cers were available for 903 patients treated at the National

Cancer Center Hospital, Tokyo. The multicentric origin of

multiple cancers was defined and histopathologically dif-

ferentiated from multifocal invasion, as described

previously [8]. In brief, synchronous unilateral multiple

cancers were defined as multicentric in origin when:

1. multiple tumors were not combined via a DCIS com-

ponent; and

2. they did not show evidence of satellite lesions.

Of the patients studied, 38 (4.2%) had double primary

cancers, 9 (1.0%) had triple primary cancers, and 2 (0.24%)

had 4 primary cancers in a single breast. One patient (#3)

Table 1 Synchronous unilateral triple primary breast cancer

Case/age/side No. Tumor histology Size(cm) Lymph node

metastasis

(positive/total)

Follow up (outcome) Note

1/44/R 1 IDC scirrhous G3 1.4 1/7 9 y 6 mo (A)

2 IDC scirrhous G2 1.4

3 IDC scirrhous G1 1.0

2/62/L 1 IDC scirrhous G3 1.6 11/33 11 mo (DOD)

2 IDC scirrhous G3 1.3

3 IDC scirrhous G3 1.2

3a/47/L 1 IDC papillotubular G2 3.4 2/15 6 y 3 mo (AWD) Contralateral breast cancer

(metachronous)2 IDC scirrhous G2 0.9

3 DCIS G1 1.0

3b/45/L 1 IDC papillotubular G2 1.9 0/24 8 y 3 mo (AWD)

2 IDC scirrhous G2 0.8

3 IDC scirrhous G2 0.9

4 IDC scirrhous G1 0.7

4/47/L 1 IDC papillotubular G2 2.0 7/22 8 y 9 mo (A) Contralateral breast cancer

(metachronous)2 IDC scirrhous G2 1.5

3 DCIS G2 1.1

5/66/L 1 IDC scirrhous G3 2.0 0/8 9 y 5 mo (AWD) Contralateral DCIS

(metachronous)2 IDC scirrhous G2 1.6

3 IDC scirrhous G1 1.5

6/41/R 1 Tubular G1 1.6 0/10 11 y 10 mo (A)

2 Tubular G1 1.3

3 Tubular G1 1.0

7/45/R 1 IDC scirrhous G2 1.4 1/25 10 y 1 mo (A) Contralateral breast cancer

(synchronous)2 Tubular G1 0.4

3 Tubular G1 0.2

8/41/R 1 IDC scirrhous G3 2.4 1/13 10 y 0 mo (A)

2 IDC scirrhous G2 1.5

3 IDC scirrhous G2 1.0

9/55/R 1 ILC G2 1.9 6/16 17 y 6 mo (AWD)

2 ILC G2 1.8

3 ILC G2 1.7

4 ILC G2 0.6

10/42/L 1 ILC G2 2.8 0/3 9 y 11 mo (A) Contralateral breast cancer

(synchronous)2 ILC G2 1.7

3 ILC G2 0.9

G grade, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, L left, R right, A alive without disease, AWD alive with disease, DODdead of disease, y year, mo months

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had bilateral triple or more metachronous cancers. In

Table 1, 11 cases of triple or more breast cancers are

presented. None of these 11 cases included Paget’s disease.

At present, 5 (50%) of these 10 patients have synchronous

or metachronous cancer in the contralateral breast.

Nonetheless, it is sometimes difficult to distinguish

multicentric cancers from monocentric cancers. Diagnosis

of the clonal origin of multiple tumors on the basis of the

criteria above was shown to be compatible with diagnosis

of their multicentric origin by clonal analysis using genetic

alterations, i.e., loss of heterozygosity on chromosome 16q

[8]. Therefore, it seems reasonable to diagnose morpho-

logically synchronous unilateral multiple cancers on the

basis of the absence of continuity and the absence of

satellite nodules. In this case, there were 3 cancers that

were separated from each other and that showed distinct

histological findings. Therefore, these tumors can be

definitively diagnosed to be of multicentric origin.

In a previous study, synchronous multiple cancers, both

unilateral and bilateral, showed characteristic histopathol-

ogical features, i.e., a lower nuclear grade [10]. These

multiple cancers were frequently IDCs of nuclear grades 1

or 2 (63%, 24 of 38), whereas IDCs of nuclear grade 3,

which is usually common, was infrequent, accounting for

only 5% of tumors (2 of 38) [10].

Of the 35 tumors from 10 patients with triple or more

breast cancers listed in Table 1, 15 (43%) were of histo-

logical grade 1 or 2. In addition, lower-grade cancers, e.g.,

ILC and tubular carcinoma, were also frequent—7 (20%)

and 5 (14%) tumors, respectively. Interestingly, there was

not a single case of IDC, solid-tubular subtype. In this case,

one tumor was an ILC, which is a frequent component of

synchronous multicentric breast cancers; the other 2 tumors

were an IDC of nuclear grade 3 and Paget’s disease.

Paget’s disease is reported to occur in 1–4% of all breast

cancer patients [3–6]. In this case, Paget’s disease was

considered to be an independent in-situ carcinoma and to

constitute one of the multicentric breast cancers. Most

cases of Paget’s disease are associated with a DCIS com-

ponent of comedo or solid pattern, and are very rarely

associated with a special subtype of ductal carcinoma (e.g.,

papillary and medullary carcinoma) or lobular carcinoma

[11, 12]. Ashikari et al. [3] reported that only 4 and 2 of

204 cases of Paget’s disease were associated with lobular

carcinoma in situ and ILC, respectively. Previous reports

have usually described synchronous bilateral breast can-

cers. However, one study [10] has reported that the histo-

pathological characteristics of node-negative multiple

breast cancers are similar in synchronous bilateral tumors

and synchronous unilateral tumors. Therefore, although

there were no detailed descriptions, we consider the

coexistence of IDC, ILC, and Paget’s disease in a single

breast to be a very rare event.

Paget’s disease causes no clinical abnormalities in

10–28% of patients and is detected only on histological

examination of nipple specimens obtained during a mas-

tectomy [7], as in this case. Half of patients with Paget’s

disease have a palpable tumor in the breast [3, 13]. An

invasive carcinoma was detected in more than 90% of

women who had Paget’s disease accompanied by a mass

[3, 13].

In conclusion, we have reported a case of synchronous

unilateral triple breast cancers that showed distinct histo-

logical features and included Paget’s disease. We have

reviewed previous cases of synchronous unilateral triple or

more breast cancers at our institute, and clarified that the

occurrence of multiple cancers including Paget’s disease is

rare.

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