A case of cytokeratin 20-positive large-cell neuroendocrine
carcinoma of the breast
Kae Okoshi Æ Æ Tatsuyoshi Saiga Æ Æ Shigeo Hisamori Æ Æ
Keiko Iwaisako Æ Æ Hisato Kobayashi Æ Æ Hiroki Ogawa
Received: 16 June 2008/Accepted: 13 July 2009/Published online: 11 August 2009
? The Japanese Breast Cancer Society 2009
crine carcinoma of the breast. A 63-year-old woman was
admitted to our hospital with a firm mass in the right breast.
Mammography revealed a high-density mass with specula,
and ultrasonography showed a heterogeneous hypoechoic
mass with irregular margin and posterior acoustical shad-
owing. She underwent breast-conserving surgery with axil-
lary lymph node dissection. Histopathologically, the tumor
consisted of large cells with polygonal and prominent nuclei
and a small amount of eosinophilic cytoplasm, and these
cells showed palisading arrangement with fibrous stroma.
The tumor cells were positive for neuroendocrine markers
such as NSE, synaptophysin, CD56 (NCAM), but not for
chromogranin A. Interestingly, the tumor cells showed
reactivity for cytokeratin 20 but not for cytokeratin 7. The
immunostaining pattern is different from the usual adeno-
carcinoma of the breast. The patient received postoperative
remained disease-free for 44 months.
We report a rare case of large-cell neuroendo-
Breast ? Cytokeratin 7 ? Cytokeratin 20
Large-cell neuroendocrine carcinoma ?
Primary neuroendocrine carcinoma of the breast is rare and
the immunohistochemical patterns vary. In 2003 the World
Health Organization (WHO) divided breast cancer with
neuroendocrine features into solid, atypical, small cell/oat
cell, and large-cell neuroendocrine carcinoma . To date,
there has only been one case report of the large-cell type
The combination of cytokeratin 7 (CK7) and cytokeratin
20 (CK20) immunoprofiling has been helpful in identifi-
cation of the primary site of origin of various adenocarci-
nomas. Most breast carcinomas express CK7 but not CK20
. There are no published reports of large-cell carcinoma
of the breast revealed by immunostaining of CK7 and
CK20. We here present a case of breast neuroendocrine
carcinoma of the large-cell type which is CK7-/CK20?
and compare it with other neuroendocrine carcinomas.
A 63-year-old woman was referred to our hospital with a
firm mass in the right breast. She had first undergone
radical mastectomy for invasive ductal carcinoma of the
left breast 14 years previously. We reviewed the HE slides
and found that a uniform single population of carcinoma
cells with low-grade atypia formed punched out laminal
spaces and micropapillary structures within ducts, and the
cells showed little tendency to invade. Although there was
some difficulty in differentiating the tumor from the ductal
K. Okoshi (&) ? S. Hisamori ? K. Iwaisako
Department of Surgery, Graduate School of Medicine,
Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku,
Kyoto 606-8507, Japan
Department of Pathology, Otsu Red Cross Hospital,
1-1-35 Nagara, Otsu, Shiga 520-8511, Japan
Department of Radiology, Otsu Red Cross Hospital,
1-1-35 Nagara, Otsu, Shiga 520-8511, Japan
Department of Surgery, Otsu Red Cross Hospital,
1-1-35 Nagara, Otsu, Shiga 520-8511, Japan
Breast Cancer (2012) 19:360–364
carcinoma in situ, on the basis of the histological features
in some parts of the intraductal components, for example
loss of basement membrane of the ducts, it was reasonable
to assume that the tumor was an invasive ductal carcinoma
She received systemic therapy with oral doxifluridine
for several years after the surgery. There had been no
evidence of recurrence or metastasis for 14 years until she
noticed a lump in the right breast.
The right tumor was 2 cm in diameter and was located
in the upper outer quadrant of her right breast. Mammog-
raphy (MMG) revealed a high-density mass with specula
(Fig. 2a, b). Ultrasonography revealed a heterogeneous
hypoechoic mass with irregular margin and posterior
acoustical shadowing, measuring 16.9 9 11.1 mm in
diameter (Fig. 2c).
Aspiration biopsy cytology (ABC) resulted in class V,
and breast-conserving surgery with axillary lymph node
dissection was performed. Pathologically the tumor was
classified as pT2 pN0 M0 Stage IIA according to the
Histological examination revealed that the tumor con-
sisted of large cells with irregular hyperchromatic nuclei
and a small amount of eosinophilic cytoplasm. Undiffer-
entiated cancer cells with accumulation of collagen fiber
showed palisading and/or a ribbon-like structure with solid
components (Fig. 1b). Because of destruction of the ductal
structure by the cancer cells, intraductal component could
not be confirmed in the right carcinoma in the HE slide.
Additionally, immunohistochemistry by p63 detected only
scattered cells and no layered myoepithelial cells in the
carcinoma (data not shown).
Immunohistochemical staining demonstrated cytoplas-
mic positivity for NSE, synaptophysin, and CD56 in more
than 50% of the tumor cells, although the cells were neg-
ative for chromogranin A (Fig. 3a–d). Interestingly, they
were positive for CK20, and CK7 was not expressed
(Fig. 4a, b). The tumor was negative for both estrogen and
progesterone receptors. HER-2 was 1?. Grimelius staining
was positive (Fig. 5). The tumor of the right breast was
considered to be a new primary large-cell neuroendocrine
carcinoma of the breast, because the histological findings
were quite different from her left breast cancer which had
been resected 14 years previously. In addition, further
examinations for distinguishing the primary or metastatic
neuroendocrine tumor, for example chest and abdominal
CT, revealed no evidence of distal lesions.
The patient received postoperative radiotherapy and was
given uracil and tegafur. She has remained disease-free for
In 2003 the World Health Organization (WHO) divided
neuroendocrine breast cancer into three histologic types:
solid, small cell, and large-cell neuroendocrine carcinoma
. Scattered neuroendocrine differentiation has been
detected in 10–50% of breast carcinomas, depending on the
definition and the detection methods used [4–7]. The WHO
classification defines mammary neuroendocrine tumors as
having morphological features similar to those of neuro-
endocrine tumors from the gastrointestinal tract and lung,
with expression of neuroendocrine markers by more than
50% of the cells . Although there are several reports of
small-cell neuroendocrine carcinoma of the breast [8–17],
primary large-cell carcinoma is rare, and, to the best of our
knowledge, only one case of a pure tumor has been
reported to date . In our case, microscopically the tumor
consisted of large cells with polygonal and prominent
nuclei and a small amount of eosinophilic cytoplasm.
Undifferentiated cancer cells with fibrous stroma showed
palisading arrangement. Furthermore, the tumor cells were
positive for neuroendocrine markers. More than 50% of the
Fig. 1 Histopathological findings of the left (a) and right (b) breast
carcinoma. a Uniform single population of carcinoma cells with low-
grade atypia formed punched out laminal spaces and micropapillary
structures within ducts, and the cells showed little tendency to invade.
b The tumor consisted of large cells with polygonal nuclei and a small
amount of eosinophilic cytoplasm. Undifferentiated cancer cells with
accumulation of collagen fiber showed unclear palisading structure
with solid components
Breast Cancer (2012) 19:360–364361
tumor cells were positive for NSE, synaptophisin, and
CD56, and all the tumor cells were negative for chro-
reported to arise in many organs including the lungs ,
colon [19–21], ovary , and urinary bladder [23–25].
Therefore, it is important to exclude the possibility that the
tumor is the result of metastasis from another organ. In our
case, because there was no lesion in the lungs or the
abdominal organs, we diagnosed the tumor as primary
large-cell carcinoma of the breast.
Expression of CK7 and CK20 is commonly used to help
distinguish adenocarcinomas derived from different sites.
CK7 is expressed in a wide variety of epithelial neoplasms,
including the lung, salivary gland, endometrium, and
breast. CK20 is distributed predominantly in carcinomas of
the colon and pancreas and in Merkel cell tumor of skin.
Recently, the coordinated expression of CK7 and CK20 has
been used to determine the site of origin of carcinomas.
Each immunophenotype is associated with a group of
epithelial neoplasms. Breast carcinoma is known to be CK7
positive and CK20 negative . Adegbola et al. 
reviewed several reports of small-cell carcinoma of the
breast and reported that all the tumors showed at least focal
positivity for CK7 and were negative for CK20. However,
there is one case report that describes a small-cell carci-
noma of the breast showing negative staining for CK7 and
20 . In the World Health Organization Classification of
Tumors, the authors mentioned that immunohistochemistry
may help to distinguish between metastatic and primary
small-cell carcinomas (mammary small-cell carcinomas
are CK7-positive and CK20-negative). We diagnosed that
the right tumor originated from the mammary gland on the
basis of clinical course and radiological examination
despite the unusual immunostaining pattern of CK7(-) and
No neuroendocrine cells have been detected in human
breasts studied by immunohistochemistry and electron
microscopy , and the histogenesis of neuroendocrine
carcinoma of the breast is unclear. It has been suggested
Fig. 2 a Mammography of the
right breast reveals a high-
density mass with speculation,
with a diameter of 2 cm.
b Magnified view of the nodule.
c Ultrasonography of the right
breast shows an irregular mass
with heterogeneous low
echogenicity and accentuated
362 Breast Cancer (2012) 19:360–364
that small-cell neuroendocrine carcinoma is a variant of
metaplastic carcinoma arising from usual lobular or ductal
carcinoma . On the other hand, some authors have
reported that small-cell neuroendocrine carcinoma is a
distinct type of breast carcinoma different from the usual
types of carcinoma [16, 17].
Large-cell carcinoma of the colon has a poor prognosis
similar to that of the lung [20, 21]. Similarly, large-cell
neuroendocrine carcinoma of the ovary seems to be an
aggressive tumor that generally has a poor prognosis .
Because there is no report describing the prognosis of
large-cell neuroendocrine carcinoma in breast carcinomas,
more cases and long-term follow up data are needed for
for his helpful advice and technical support. A summary of this case
The authors are grateful to Dr. Rei Takahashi
Fig. 4 Immunohistochemical
staining showed that the tumor
cells expressed cytokeratin 20
(a) but not cytokeratin 7 (b)
Fig. 3 The tumor cells showed
immunoreaction for NSE (a),
synaptophysin (b) CD56
(NCAM) (c), but not for
chromogranin A (d)
Fig. 5 The Grimelius stain reveals fine black granules in the
cytoplasm of carcinoma cells
Breast Cancer (2012) 19:360–364363
report was presented at the 15th Congress of the Japanese Breast Download full-text
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