Breast Cancer

Vol. 6 No. 2 April 1999

Case Report
Breast Carcinoma with Osteoclast-like Giant Cells: A Case
Report and Review of the Japanese Literature
Michiyo Saimura .1, Takashi Fukutomi .1, Hitoshi Tsuda .2, Sadako Akashi-Tanaka *~, and Takeshi Nanasawa *~

A 41-year-old premenopausal woman with a 3.5 cm freely mobile mass in the upper outer quadrant
of the right breast was admitted to our hospital. Fine needle aspiration showed malignant epithelial cells
and many multinucleated osteoclast-like giant cells (OGCs). Excisional biopsy revealed an invasive
ductal carcinoma. A right modified radical mastectomy was subsequently performed. Macroscopically
the tumor was well circumscribed with a dark brown cut surface. Microscopically, the tumor was a grade
2 invasive ductal carcinoma with many multinucleated OGCs adjacent the tumor cells and hemorrhage
and infiltration of inflammatory cells in the stroma. The intra-mammary metastasis also contained OGCs
and stromal reactions. By enzyme immunoassay, the tumor cells were negative for estrogen receptor but
positive for progesterone receptor. The tumor cells were negative for both c-erbB-2 and p53. The OGCs
showed positive immunostaining with the monoclonal antibody CD68, demonstrating a histiocytic origin.
Lymph nodes were free of metastasis. We also review the Japanese literature concerning breast
carcinoma with OGCs.
Breast Cancer 6:121-126, 1999.

Key words: Osteoclast-like giant cell, Breast carcinoma

Breast carcinoma with osteoclast-like giant

cells (OGCs) is a very rare type of mammary neo- Case Report
plasm. Since the first report in 1931~), fewer than
100 breast carcinomas with OGCs have been A 41-year-old woman was admitted to the
reported2).Though most of these lesions are invasive National Cancer Center Hospital in June 18, 1998
ductal carcinomas, invasive lobulal~, squamous% with a 3.5 cm painless, well-demarcated, firm mass
papillary% tubular% mucinous% and metaplastic in the upper outer quadrant of her fight breast.
carcinomas7)with OGCs have been reported. This Ultrasonography revealed a circumscribed and
tumor type has occasionally been diagnosed by partially lobulated hypoechoic mass, suggesting
fine needle aspiration cytology that showed the phyllodes tumor (Fig 1). Mammogram showed an
presence of the characteristic OGCs. The histo- irregular-shaped mass in the right breast, but
genesis of the OGCs has been the subject of neither spicule formation nor microcalcification
debate, and both epithelial and hisfiocytic origins
have been proposed.
We report a case of breast carcinoma with OGCs
and intra-mammary metastasis and review the
Japanese literature. The cytological and histologi-
cal appearance of this unusual tumor are de-
scribed.

* ~Departmentof Surgical Oncology, National Cancer Center Hospital,

and *2Pathology Division, Nationa/Cancer Center ResearchInstitute.
Reprint requests to Takashi Fukutomi, Department of Surgical
Oncology, National Cancer Center Hospital, 5 1-1, Tsukiji, Chuo-ku,
Tokyo 104-0045, Japan.
Abbreviations:
OGC, Osteoclast-hkegiant cell; PTH, Parathyroid hormone
Fig 1. Ultrasonography shows a circumscribed and partially
Received October 2, 1998; accepted February 1, 1999 Iobulated hypoechoic mass.

121
SaimuraM, et al
was seen (Fig 2). However, these examinations
together raised the suspicion of breast carcinoma.
The levels of three tumor markers (CEA, ST-439,
CA15-3) and serum calcium were within the
normal ranges.
Fine needle aspiration cytology revealed malig-
nant epithelial cells and numerous multinucleated
giant cells (Fig 3). The tumor cells had oval, uni-
form and relatively large nuclei with fine dispers-
ed chromatin and one or two small nucleoli scattered
diffusely or forming various-sized loose clusters.
The multinucleated giant cells contained up to 10
or more nuclei, had large and deeply staining cyto-
plasm, and resembled osteoclasts seen in bone. A
small number of mononuclear histiocytic cells
were also observed.
An excisional biopsy proved this tumor to be an
invasive ductal carcinoma. The patient underwent
Fig 2. Mammography demonstrates an irregular-shaped mass
without spicula formation or calcification on the right breast in
a cranio-caudal view.
Fig 3. Aspiration cytology reveals a combination of malignant
epithelial cells and numerous osteoclast-like giant cells (Papa-
nicolaou, X200).
122
Breast Carcinomawith Osteoclast-likeGiantCells
a right modified radical mastectomy with lymph
node dissection. The tumor's cut surface was well
circumscribed and dark brown in color, measur-
ing 3.0• 2.7 cm. Microscopically, the tumor was
composed of a 95% invasive component and a 5%
non-invasive component. It was histological grade
2, and showed a papillotubular pattern with bleed-
ing and infiltration of inflammatory cells in the
stroma (Fig 4, top)SL Numerous OGCs were ob-
served in the glandular lumina and in the stroma
adjacent to the tumor cells (Fig 4, bottom). The
OGCs demonstrated neither phagocytotic nor
mitotic activity. Additionally, in the lower outer
quadrant apart from the main lesion, a smaller
tumor was found. Histologically, this tumor was
also an invasive ductal carcinoma containing
OGCs and stromal reactions similar to those seen
in the main lesion. No intraductal component was
Fig 4. Top, The tumor is composed of an invasive ductal-
carcinoma, showing a papillotubular pattern, with extra-
vasation, bleeding, and infiltration of inflammatory cells into
the stroma (hematoxylin and eosin, X50). Bottom, Multi-
nucleated OGCs are seen in the stroma or the glandular
lumina, adjacent to the tumor cells (hematoxylin and eosin,
X200).
Breast Cancer Vol. 6 No. 2April 1999
seen (Fig 5). Therefore, we judged this tumor to
be an intra-mammary metastasis of the main tumor.
i formalin-fLxed paraffin-embedded tissue sections
Fig 5. An intra-mammary metastasis contains 9
bleeding and infiltration of inflammatory cells in the stroma.
Top, Lower magnification (hematoxylin and eosin, X IO0).
Bottom, Higher magnification (hematoxylin and eosin,
X200).
Table 1. Antibodies Used and Immunohistochemical Resuits in the Present Case
Antibody (Source)
CD68 (Dakopatts, mouse monoclonal)
Epitheiiai membrane antigen
(Dakopatts, mouse monoclonal)
Cytokeratin (AE 1/AE3)
(Boehringer Mannheim, mouse monoclonal)
Vimentin (Dakopatts, mouse monoclonai)
S-100
(Nihon-Kotai kenkyujo, mouse monoclonal)
Glial fibrillary acidic protein
(Dokopatts, mouse monoclonal)
a-Smooth muscie actin
(Dakopatts, mouse monoclonal)
c-erbB-2 (Nichirei, rabbit polyclonal)
p53 (Novocastra, mouse monoclonal)
OGCs, Osteoclast-like giant ceiis; 4-, Positive; --, negative.
Estrogen receptor was negative, but progesterone
receptor was positive (606.1 fmol/mg protein) by
enzyme immunoassay. Axillary lymph nodes were
free of metastasis. No postoperative chemotherapy
was given. The postoperative course was uneventful.
The patient remains disease free 3 months after
operation.
Immunohistochemistry
The immunohistochemical profile of this case
are summarized in Table 1. Routinely processed,
were immunohistochemically stained using the
standard avidin-biotinylperoxidase complex method,
with 3,3Ldiaminobenzidine tetrahydrochloride-
hydrogen peroxide as the chromogen. The tumor
cells stained strongly with a mouse anti-cyto-
keratin AE1/AE3 antibody (Boehringer Mann-
heim, Mannheim, Germany) (Fig 6, top) and a
mouse anti-epithelial membrane antigen antibody
(Dakopatts, Glostrup, Denmark), while the OGCs
and stromal mononuclear cells did not stain. Stain-
ing with CD68 (Dakopatts), which reacts with
macrophages (Fig 6, bottom), and the internal
control marker, vimenfin (Dakopatts), showed in-
tense cytoplasmic staining in both the OGCs and
the stromal mononuclear cells, but negative stain-
ing in the tumor cells. The tumor cells did not
with
stain for c-erbB-2 (Nichirei, Tokyo, Japan) or p53
(Novocastra, Newcastle, UK)9~.
Reactivity Reactivity of stromal Reactivity of
of OGCs mononuciear cells tumor ceils
-k-
- §
m
+
4- + m
m
m
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Saimura M, et al Breast Carcinoma with Osteoclast-like Giant Cells

OGCs were described in 5 Japanese reports be-

Review of the Japanese Literature
A total of 7 patients with breast carcinoma with
tween 1982 and 1996 ~,I~13).Table 2 shows the clini-
copathological features of these 7 patients and
also the present case. The age of the patients
ranged from 38 to 59 years, with a mean of 43.9
years. The site of the tumor was on the right side
in each case and in the upper outer quadrant in
five cases. The tumors were less than 4.0 cm in
diameter and grossly were mostly well demarcat-
ed and dark brown in color. Five cases showed an
invasive ductal pattern of growth and the others
were papillary, tubular, and invasive lobular car-
cinomas, respectively. Lymph node metastasis
was found in two cases and one (case 6) had a
focus of OGCs in the metastatic lymph node. There
have been no previous reports of intra-mammary
metastasis. All of the patients except for the un-
known cases (case 1, case 7) were alive for be-
tween 3 and 108 months after operation.

Discussion

Carcinoma with OGCs is a rare variant of primary

Fig 6. Top, The OGCs and the stromal mononuclear cells are
immunoreactive with CD68, whereas the tumor cells are not
stained (immunoperoxidase, X lO0). Bottom, The tumor cells
stained strongly for cytokeratin (AE1/AE3), whereas the
OGCs and the stromal mononuclear cells did not stain
(immunoperoxidase, X 100).
breast carcinoma. To date, fewer than 100 cases
have been reported 2), and, to our knowledge, the
present case is the eighth Japanese case for which
clinicopathological findings are well documented.
Despite the unusual histological properties of the
tumor, the clinical features are similar to those of
breast carcinoma generally.
Since the first report by Sugano et al in 1982%
this unique variety of breast carcinoma has been
occasionally diagnosed by aspiration cytology.
The coexistence of OGCs and the tumor cells is
so characteristic that it is possible to make a correct
diagnosis by this method. The diagnosis in the

Table 2. Clinicopathological Features of the Published Cases in Japan

Year of Age Tumor size Outcome

Case Ref diagnosis (years) Site (cm) Margin Color n Histology (months)

1 8) 1981 45 RUO 2.0 X 1.5 C dark brown - IDC unknown

2 9) 1981 39 RUI 3.5 X2.5 C dark brown Jr IDC 24 A
3 10) 1982 59 RLO 3.0X2.5 C dark brown -- IDC 18 A
4 5) 1975 38 RLI 1.0• ID unknown -- papillary
car~:inoma 108 A
5 5) 1984 41 RUO 0.5X0.5 C unknown - tubular
carcinoma 5A
6 5) 1984 40 RU 4.0X4.0 ID unknown -f- IDC 13 A
7 11) 1996 48 RUO 1.5X 1.5 C gray _ invasiv~ Iobular unknown
carc,noma
8 resent
Pcase 1998 41 RUO 3.0X2.7 C dark brown - IDC 3A

Ref, Reference; n, Lymph node metastasis; RUO, Right upper outer; RUI, Right upper inter; RLO, Right lower outer; RLI, Right
lower inter; RU, Right upper; C, Circumscribed; ID, Ill-defined; IDC, Invasive ductal carcinoma; A, Alive.

124
Breast Cancer VoL 6 No. 2April 1999
present case could also have been obtained via
preoperative aspiration cytology. The OGCs in
breast aspirates may, however, be misinterpreted
as foreign body giant cells, inflammatory giant
cells or megakaryocytes. Furthermore, it should
be noted that similar OGCs can be seen in other
breast tumors such as fibroadenoma, cystosar-
coma phyllodes, extraskeletal osteoclastoma or
malignant fibrous histiocytoma.
Breast carcinomas with cartilaginous and/or
osseous metaplasia and breast carcinomas with
sarcomatoid stromal reaction should be also ruled
out. It has been suggested that giant cell formation
in these tumors may reflect a response to stromal
hemorrhage; however, the association of OGCs
with the tumor cells appears topologically closer
and more consistent than that seen with vascular
changes. Furthermore, the association between
the OGCs and the tumor cells is maintained in
lymph node and visceral metastasis 3,7,14).The present
case also showed OGCs in the intra-mammary
metastasis, which suggests an intimate associa-
tion between the OGCs and the tumor cells.
It has been reported that these tumor cells
have low numbers of estrogen receptors, but high
levels of progesterone receptors 14).The same find-
ing was obtained by enzyme immunoassay in the
present case. However, the hormone receptor
status of the 8 Japanese cases was unknown, c-
erbB-2 and p53 expression was not observed in
the present case, and has not been previously
reported.
Histogenesis of the OGCs has been a subject
of debate 11,1~. Kobayashi et al ~~ and Rosai 16~pro-
posed that they were derived from malignant
epithelium, whereas most authors have supported
a histiocytic origin. In the present case, the strong
immunoreactivity of the OGCs and the stromal
mononuclear cells for the monoclonal antibody,
CD68 and vimentin, along with negative reactivity
for cytokeratin and epithelial membrane antigen,
provided evidence for macrophage derivation.
Athanasou et al showed in an experimental
study that the OGCs isolated from breast car-
cinoma resorbed cortical bone in a manner similar
to osteoclasts, which are directly stimulated by
parathyroid hormone (PTH), and suggested that
OGCs were a specific type of macrophage poly-
karyon 17).Because one of the known effects of PTH
is to increase the number of osteoclasts 18~,the pro-
duction of a PTH-like protein by breast carcinoma
cells may be responsible for the accumulation of
OGCs in this unusual breast carcinoma. However,
there is no substrate for the OGCs to resorb in
the breast, and the precise function and patho-
logical significance of the OGCs in this tumor is
unknown. Since the majority of breast carcinomas
with OGCs expressed reactivity for PTH-like pro-
tein, its role in tumor pathogenesis has been in-
vestigational '9~.
Agnanfis et al have suggested that the presence
of OGCs does not indicate a favorable prognosis,
compared with common types of breast carci-
noma 3). Although breast carcinoma with OGCs is
regarded as a distinct entity, histological grading
of this tumor type can be performed as if the giant
cells are not present. In the present case, an
intermediate histological grade, positive pro-
gesterone-receptor status and the absence of c-
erbB-2 and p53 overexpression indicated that the
tumor was biologically less aggressive. Indeed,
the clinical course of the 8 Japanese cases has
been favourable to date. There have, however,
been only limited data available regarding the
prognosis of this variant, and further studies are
required to clarify the characteristics of this type
of tumor.
References
1) Rosen PP, Oberman HA: Tumors of the mammary
gland. In: Washington DC ed, Atlas of Tumor Patho-
logy, 3rd series, fascicle 7, Armed Forces Institute of
Pathology, pp207-209, 1996.
2) Leroux R: Reaction giganto cellulaire du stroma dans
un epithelioma mammaire. Bull Cancer 20:692-697,
1931.
3) Agnantis NT, Rosen PP: Mammary carcinoma with
osteoclast-like giant cells; A study of eight cases with
follow-updata. Am J Clin Patho172:383-389, 1979.
4) Fisher ER, Gregorio RM, Palekar AS, et al: Muco-
epidermoid and squamous metaplasia and giant cell
tumors. A m J Surg Pathol 7:15-27, 1983.
5) Ichijima K, Kobashi Y, Ueda Y, et al: Breast cancer
with reactive multinucleated giant cells; Report of
three cases. Acta PatholJpn 36:449-457, 1986.
6) Nielsen BB, Kiaer HW: Carcinoma of the breast with
stromal multinucleated giant cells. Histopathology 9:
183-193, 1985.
7) Tavassoli FA, Norris HJ: Breast carcinoma with osteo-
clast-like giant cells. Arch Pathol Lab Med 110:636-
639, 1986.
8) Tsuda H, Hirohashi S, Shimosato Y, et al: Correlation
between histologic grade of malignancy and copy
number of c-erbB-2 gene in breast carcinoma; A
retrospective analysis of 176 cases. Cancer 65:1794-
1800, 1990.
9) Zhang GJ, Tsuda H, Adachi I, et al: Prognostic in-
dicators for breast cancer patients with one to three
regional lymph node metastases, with specialreference
125
Saimura M, et al
to alterations in expression levels of bcl-2, p53 and c-
erbB-2 proteins.Jpn J Clin Onco127:371-377, 1997.
10) Sugano I, Nagao K, Kondo Y, et al: Cytologic and
ultrastructural studies of a rare breast carcinoma with
osteoclast-like giant cells. Cancer 52:74-78, 1983.
11) Suzuki T, Minase T, Narita H, et al: A case of breast
cancer containing osteoclast-like multinucleated giant
cells; Light and electron microscopic study. Jpn J
Cancer Clin 28:1597-1602, 1982 (in Japanese).
12) Kobayashi S, Tobioka N, Samoto T, et al: Breast
cancer with osteoclast-like multinucleated giant cells.
Acta Pathol Jpn 34:1475-1484, 1984.
13) Takahashi T, Moriki T, Hiroi M, et al: Invasive lobular
carcinoma of the breast with osteoclastlike giant
cells; A case report. Acta Cyto142:734-741, 1998.
14) Holland R, Van Haelst UJGM: Mammary carcinoma
with osteoclast-like giant cells; Additional obser-
vations on six cases. Cancer 53:1963-1973, 1984.
15) Reale D, Guarino M, Bianchini E, et al: Infiltrating
126
Breast Carcinoma with Osteoclast-like Giant Cells
lobular carcinoma of the breast, alveolar variant, with
stromal reactive osteoclast-like giant cells; Descrip-
tion of a case. Pathologica 85:525-532, 1993.
16) Rosai J: Carcinoma of pancreas simulating giant cell
tumor of bone; Electron microscopic evidence of its
acinar cell origin. Cancer 22:333-343, 1968.
17) Athanasou CA, Wells CA, Quinn DP, et al: The origin
and nature of stromal osteoclast-like multinucleated
giant cells in breast carcinoma; Implications for
tumour osteolysis and macrophage biology. Br J
Cancer 59:491-498, 1989.
18) Wong GL: Skeletal effects of parathyroid hormone.
In: Peck WA ed, Bone and Mineral Research, 4th ed,
Elsevier, Amsterdam, ppl03, 1986.
19) Iezzoni JC, Bruns ME, Frierson HF, et al: Coex-
pression of parathyroid hormone-related protein and
its receptor in breast carcinoma; A potential auto-
crine effector system. Mod Pathol 11:265-270, 1998.