Small cell neuroendocrine carcinoma of the breast: a report
of three cases and review of the literature
T Adegbola, C E Connolly, G Mortimer
J Clin Pathol 2005;58:775–778. doi: 10.1136/jcp.2004.020792
Small cell neuroendocrine carcinoma of the breast is a rare
tumour with less than 30 cases reported in the literature. The
clinicopathological findings of three cases of primary
neuroendocrine carcinoma of the breast and a review of
the pertinent literature are presented. The morphological and
immunohistochemical patterns of this tumour are similar to its
pulmonary counterpart. Expression of neuroendocrine mar-
kers is inconsistent, so morphology is the mainstay of
diagnosis. Size is a very important prognostic factor in this
tumour, as in breast carcinomas of the usual type.
ovary, and cervix.1–5The histological appearances of these
tumours in all sites are similar. Reports also suggest that the
clinical course of extrapulmonary SCNC is as aggressive as its
pulmonary counterpart.1 5 6Primary SCNC of the breast is as
rare as it is in other extrapulmonary sites. Fewer than 30
cases have been reported in the literature, with the largest
series of nine cases reported by Shin et al.4This tumour is
thought to be distinct from tumours of the usual type with
neuroendocrine differentiation.6The distinction is particu-
larly important in view of the perceived more aggressive
behaviour of SCNC.1 5 6We report three cases of primary
SCNC of the breast on our file, one of which has been
mall cell neuroendocrine carcinoma (SCNC) has been
described in many extrapulmonary sites including
breast, larynx, gastrointestinal tract, prostate, bladder,
A 46 year old, para 0+1, woman presented with a right breast
lump. Clinical examination revealed a painless, firm mobile
mass with no palpable axillary lymph nodes. She had no
relevant past medical history. Her father had carcinoma of
the thyroid gland but there was no family history of breast
cancer. Clinical and radiological investigations (computerised
tomography and positron electron tomography) did not
reveal tumour elsewhere in the body. The patient had simple
excision of the tumour, the histology of which showed SCNC,
1.0 cm in size. No axillary clearance was performed. She was
further treated with radiation to the chest wall and local
lymph nodes, followed by six courses of cisplatin and VP16.
She is alive and free of disease 48 months after lumpectomy.
A 60 year old woman presented with a subareolar mass in her
right breast of short duration. She was a smoker and known
asthmatic. She had ovarian cystectomy 30 years before the
breast lump, the histological diagnosis of which is not
known. There was no relevant family history. Clinical
examination revealed a firm subareolar mass with no axillary
lymphadenopathy. Radiological and clinical examination
failed to reveal tumour elsewhere in the body. She had a
simple lumpectomy, which was diagnosed as SCNC with foci
of an in situ ductal component. The size of the tumour was
1.7 cm. Axillary clearance was not performed. She then had
radiotherapy and six courses of cisplatin and VP16. The
patient died of disease 20 months after surgery.
A 61 year old woman presented with left breast and left
axillary masses measuring 1.7 cm and 4 cm, respectively.
There was no relevant medical history or family history of
breast cancer. The two lumps were excised and both
diagnosed as SCNC. The axillary mass was a lymph node
completely replaced by tumour. No axillary dissection was
carried out, but there was no clinical evidence of another
node being involved. She was further treated by radiation to
the chest wall and regional lymph nodes and six courses of
VP16 and cisplatin. A recent positron electron tomography
scan showed a small lesion in the left lung. She is alive with
metastatic disease six months after excision.
MATERIALS AND METHODS
The archival haematoxylin and eosin stained slides from the
three cases of primary breast SCNC were reviewed and fresh
sections cut where indicated. Immunohistochemical analysis
was performed as a batch on 4 mm sections of each tumour
using the avidin–biotin peroxidase technique (table 1). Using
the antigen retrieval methods, antibodies, and dilutions
shown in table 1, expression of the following was assessed:
CAM5.2, cytokeratin 7 (CK7), CK20, oestrogen receptor,
progesterone receptor, HER2, and neuroendocrine markers
Abbreviations: CK, cytokeratin; SCNC, small cell neuroendocrine
carcinoma; WHO, World Health Organisation
Immunohistochemical procedure and
BioGenex, San Ramon,
Boil to 97˚C
CK, cytokeratin; ER, oestrogen receptor; NSE, neurone specific enolase;
PR, progesterone receptor.
(neurone specific enolase, PGP 9.5, chromogranin, and
synaptophysin). The clinical charts were also reviewed.
All the patients were female, and their ages, clinical findings,
treatments, and outcomes are outlined in table 2. None of the
patients had a history of previous carcinoma or family history
of breast cancer. One patient was a smoker. They all
presented within one to two months of noticing the tumour.
All the patients had lumpectomy followed by irradiation to
the chest wall and regional lymph nodes, in addition to six
courses of chemotherapy (cisplatin and VP16).
The tumours were 1.0 cm, 1.7 cm, and 1.7 cm, respectively,
with poorly circumscribed fleshy white to tan cut surfaces
and focal areas of necrosis. The 4.0 cm axillary lymph node in
the third patient was completely replaced by tumour.
All three tumours had similar morphology. They were
composed of fairly uniform small dark cells disposed in nests
and trabecular patterns separated by bands of fibrous tissue.
The cells had a high nucleocytoplasmic ratio, small hyper-
chromatic nuclei with inconspicuous nucleoli, scanty cyto-
plasm, and poorly defined cytoplasmic borders. There were
areas of dirty necrosis and the mitotic count ranged from 10
to 20/10 high power fields. Foci of an in situ component
similar to the infiltrating tumour were identified in case 2
(fig 1). No in situ or invasive ductal or lobular carcinoma of
the usual type was seen.
Table 3 shows the results of immunoperoxidase staining. The
tumours were negative for CD45 and HMB45. The in situ
components in case 2 showed a similar immunohistochem-
ical profile to the invasive component.
Primary SCNC of the breast is a rare tumour with less than 30
cases reported in the literature. Most cases are found in
women, as is the case with breast carcinoma of the usual
type. Only one case occurring in a 52 year old man has been
reported in the literature.8The reported age of incidence
varies from 40 to 70 years, with a higher incidence in women
greater than 60 years. There is considerable similarity
between the morphological and histochemical features of
these tumours and pulmonary small cell carcinomas.4–6 8
The histogenesis is still unclear, because the presence of
neuroendocrine cells in normal breast has not been proved
conclusively.9 10It has been suggested that SCNC is a variant
of metaplastic carcinoma arising from usual lobular or ductal
carcinoma.4This position is strengthened by the dimorphic
appearance of the tumour in a large number of reported
Clinical summary of the cases
Case 1Case 2Case 3
Lumpectomy, irradiation, and chemotherapy Lumpectomy, irradiation, and chemotherapy Lumpectomy, irradiation, and chemotherapy
Free of disease (48 months)Dead within 20 months
Positive ipsilateral node
Alive with disease (6 months)
situ component in one of the
carcinomas. (B) Another in situ
(A) Section showing the in
Immunohistochemical pattern of the tumours
Case 1 Case 2Case 3
Staining: +, weak or focal; ++, moderately strong; +++, strong diffuse
CK, cytokeratin; ER, oestrogen receptor; NSE, neurone specific enolase;
PR, progesterone receptor.
cases.4 11However, some believe that SCNC is a distinct type
of breast carcinoma different from the usual types of
carcinoma, with variable degrees of neuroendocrine differ-
entiation and carrying a worse prognosis.1 6The presence of
an intraductal component with a morphological and immu-
nohistochemical profile similar to the invasive component, as
in one of our cases (case 2), lends support to the hypothesis
of a primary small cell carcinoma in its own right. Primary
SCNC also occurs, as already stated, in many other sites
where neuroendocrine cells are normally absent or not
readily identifiable, including the ovary and prostate.
The prognostic relevance of neuroendocrine differentiation
in breast carcinoma is a subject of debate. Although most
studies reported an appreciably worse prognosis,1 5 6a few did
not.4 9This discrepancy may result from non-separation of
pure neuroendocrine carcinoma from carcinoma of the usual
type with areas of neuroendocrine differentiation.6 11There is
no mention of the degree of differentiation in some of the
reported cases.6 11In addition, the neuroendocrine compo-
nent in most of the tumours of the usual type falls into the
moderately to well differentiated World Health Organisation
(WHO) category. Most of the reported pure SCNC cases show
an appreciably worse prognosis. Using the WHO criteria, all
our cases fall into the poorly differentiated SCNC category. A
uniform standard for diagnosis of neuroendocrine carcinoma
as is the case with mucinous carcinoma should be set, and
the degree of differentiation according to the current WHO
classification of neuroendocrine carcinoma should be clearly
stated for reasonable comparison.
‘‘Positive neuroendocrine markers will give strong support
to the diagnosis, and this should be carefully searched
Size is an important prognostic factor in breast carcinoma
in general.4 9Shin et al found that patients with a mean
tumour size of 5.2 cm did appreciably worse than those with
a mean tumour size of 2.6 cm. The second woman (case 2) in
our series with a tumour size of 1.7 cm died within 20
months of diagnosis. The woman with a 1.0 cm tumour (case
1) is alive and free of disease 48 months after diagnosis.
The immunoprofile of epithelial markers in our series is
similar to most reported cases.1 4 5 8 11All the tumours showed
at least focal positivity for CAM 5.2 and CK7 and were
negative for CK20. This is also consistent with the immuno-
profile of breast carcinoma of usual types.12In contrast,
Merkel cell carcinomas are positive for CK20 and negative for
CK7, whereas SCNCs of the lung are negative for both
markers.13This may be useful in differentiating between
The expression of neuroendocrine markers by SCNC is
inconsistent.9 14 15This is not surprising in view of the fact
that these tumours are poorly differentiated. Some have
argued that the diagnosis of these tumours rests on routine
haematoxylin and eosinmorphology,14 15
expression of neuroendocrine markers should not be used
as an exclusion criterion. However, positive neuroendocrine
markers will give strong support to the diagnosis, and this
should be carefully searched for. All our cases showed diffuse
positivity for neurone specific enolase (fig 2) and PGP9.5,
weak to moderate staining for chromogranin (fig 3), and two
were positive focally for synaptophysin, which as pointed out
above supports the diagnosis.
Positive expression of oestrogen and progesterone recep-
tors in SCNC of the lung and a few other sites has been
reported. Thus, their expression in SCNC is not definite proof
of mammary origin. Oestrogen and progesterone receptors
were expressed in 67% and 56% of cases reported by Shin et
al. All three of our cases were negative for oestrogen and
progesterone receptors and HER2.
In summary, SCNC is a distinct type of primary breast
tumour. The prognosis may not be as poor as previously
portrayed, especially for early stage disease.
The authors wish to thank Dr M Keane, Mr J Nee, and Dr N Faheem
for providing clinical information on these cases, and Ms F Devlin for
the high quality laboratory technical support.
in the invasive component.
Section showing positive staining for neurone specific enolase
Section showing positive staining for chromogranin in the
Take home messages
N We report three rare cases of small cell neuroendo-
crine carcinoma of the breast
N The morphological and immunohistochemical patterns
of this tumour are similar to its pulmonary counterpart
N Expression of neuroendocrine markers is inconsistent,
so morphology is the mainstay of diagnosis
N Size is a very important prognostic factor in this
tumour, as in breast carcinomas of the usual type
N The prognosis may not be as poor as previously
thought, particularly for early stage disease
Case report 777
T Adegbola, C E Connolly, G Mortimer, Department of Histopathology,
University College Hospital, Galway, Republic of Ireland
Correspondence to: Dr T Adegbola, Department of Histopathology,
University College Hospital Galway, Republic of Ireland; tadegbola@
Accepted for publication 26 October 2004
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