Malaysian J Pathol 2008; 30(1) : 57 – 61
Fine needle aspiration cytology of neuroendocrine carcinoma of the
breast - a case report and review of literature
KADIR Abdul AR MBBS, IYENGAR Krishnan R MD, Dip.NB, PEH Suat Cheng FRCPath, PhD and YIP
Cheng Har* FRCP
Departments of Pathology and *Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur,
Neuroendocrine carcinomas of the breast are uncommon tumors known to occur in the elderly.
While focal neuroendocrine differentiation may be noted in many ductal and lobular carcinomas,
the term neuroendocrine carcinoma is to be applied when more than 50% of the tumor shows such
differentiation. This case report details the cytological features of a neuroendocrine carcinoma that was
encountered in our hospital. The fine needle aspiration (FNA) smears showed discohesive polygonal
cells with abundant cytoplasm, many of which contained eosinophilic granules located at one pole.
Histology of the mastectomy and axillary lymph nodes specimen from this patient showed features
of neuroendocrine carcinoma - solid type, with metastasis, confirmed with immunohistochemistry.
The patient is disease free seven months after surgery. This case highlights the need to closely
observe cytological details to identify this rare tumor that may otherwise appear to be invasive
duct carcinoma – not otherwise specified on FNA. The implications of diagnosing neuroendocrine
differentiation for prognosis and management are also discussed.
Keywords: Fine needle aspiration, breast, neuroendocrine carcinoma.
Neuroendocrine (NE) carcinomas are uncommon
tumors of the breast which have distinct
morphological features, but poorly defined
treatment strategies. The fine needle aspiration
(FNA) cytological findings of breast carcinoma
with NE differentiation have previously been
described1 in both primary and metastatic
locations. However, because of their rarity, these
lesions may be overlooked by cytopathologists.
We present a case of primary breast carcinoma
with NE differentiation in an 84-year-old female
initially diagnosed as infiltrating ductal carcinoma
on FNA and review the available literature on
its cytomorphologic features.
An 84-year-old female patient presented with
a firm, non-tender, 2cm mass in the lower
outer quadrant of the right breast. General
examination did not show any other abnormality.
The patient underwent FNA procedure followed
by mammography and ultrasound examination.
Mammogram showed predominantly fat
replaced breasts. Vascular calcification was
present bilaterally. A 2.5cm 3 2cm lesion
in left lower outer quadrant was seen. No
suspicious calcifications were present. Ultrasound
examination showed a well-defined but lobulated
lesion in the lower outer quadrant of the left
breast measuring 1.6cm x 2.2cm x 1.9cm. The
right breast appeared unremarkable.
FNA smears stained with May Grunwald Giemsa
(MGG) stain showed moderate cellularity with
clusters of mildly pleomorphic and plasmacytoid
epithelial cells, arranged in acinar and cribriform
pattern with many dissociated cells (Fig.1 a &
b). Occasional cells with prominent nucleoli
were also seen. On review, it was noticed that
there were cells containing coarse azurophilic
granules in the cytoplasm, particularly evident
at cell borders and poles (Fig.1 c, d).
Address for correspondence and reprint requests: Krishnan R Iyengar, Associate Professor, Department of Pathology, Faculty of Medicine, University
of Malaya, 50603 Kuala Lumpur, Malaysia. Telephone: 603 7967 5765; Fax: 603 7955 6845; Email: email@example.com
Malaysian J PatholJune 2008
FIG. 1: a and b. Cribriform and acinar clusters in FNA cytology. MGG, X200; c. Azurophilic granules in the
cytoplasm of tumour cells (MGG, X400); d. the granules showing a polar distribution (MGG, X1000.
FIG. 2. Tumour cells (a) forming solid nests separated by thin fibrous stroma (H&E, x100); (b) vague rosetting
(H&E, x200); (c) Spindle shaped cells displaying a few mitosis (H&E, x400); (d) positive for oestrogen
receptor (ER), chromogranin (CG), synaptophysin (SY) and neuron specific enolase (NSE). (DAB
NEUROENDOCRINE BREAST CARCINOMA
The tumour was 1.5cm in diameter with
a well-defined but lobulated margin and a
whitish-gray homogenous cut surface. Light
microscopy (Fig. 2 a,b,c) revealed a cellular
tumour, composed of solid nests and trabeculae
without tubule formation and forming palisades
and rosette structures focally. The tumour cells
ranged from oval to spindle and plasmacytoid,
separated by delicate fibrous stroma. They had
mildly pleomorphic elliptical nuclei with fine
chromatin. The cytoplasm was eosinophilic
and finely granular. There were 10 mitoses per
10 HPF and no lymphovascular permeation.
The adjacent breast tissue showed cribriform
type of ductal carcinoma-in-situ (DCIS) with
similar cytomorphology. Islands of invasive duct
carcinoma showed deficient myoepithelial layer
(Fig. 3a) in contrast to the DCIS component as
shown by immunohistochemical staining for
smooth muscle actin (SMA) (Dako, Denmark).
Three out of 17 axillary lymph nodes showed
metastasis with perinodal tumour deposits.
Immunohistochemical examination was
performed on formalin-fixed paraffin-embedded
(FFPE) tissue after antigen retrieval in Tris-
EDTA buffer for 12 minutes in a standard
pressure cooker. Immunohistochemistry showed
positive expression of oestrogen receptor (ER)
(NeoMarkers, Fremont, USA), progesterone
receptor (PR) (Dako, Denmark), neuron specific
enolase (NSE) (Dako, Denmark), synaptophysin
(SY) (Dako, Denmark) and chromogranin (CG)
(Dako, Denmark), by the tumour cells (Fig. 2 d).
The DCIS areas showed patchy positivity with
neuroendocrine markers (Fig. 3, b, c and d). There
was no overexpression of c-erbB-2 oncoprotein.
The case was signed out as “solid neuroendocrine
carcinoma, with lymph node metastasis and
axillary fat deposits”. Post operative recovery
and subsequent follow up were uneventful.
Although NE tumours may arise anywhere in
the body producing well-defined clinical entities,
primary NE tumour of the breast is uncommon.2
They occur in older women and are often
FIG 3. a. Absence of myoepithelial investment around the tumour islands in contrast to DCIS areas (inset). (Smooth
Muscle Actin (SMA), DAB; X200); b, c, d. Synaptophysin, Chromogranin and Neuron Specific Enolase
(NSE) respectively, were patchily positive in the DCIS areas. (DAB; X40).
Malaysian J PatholJune 2008
positive for oestrogen receptor. A relatively high
proportion (20%) of carcinomas of the male
breast show evidence of endocrine differentiation
in contrast to 5% of breast tumours in women.
Most of the tumours in men have the pattern
of low-grade insular ductal carcinomas.2 Strict
histological criteria have been defined for the
diagnosis of primary NE carcinoma of the breast
that include demonstration of in-situ component
histologically (as in the present case) and/or
absence of a non-mammary site clinically.3
Three histological characteristics that suggest
endocrine differentiation2 in a breast carcinoma
include low nuclear grade (with the exception
of small cell undifferentiated type), palisading
of nuclei at the periphery of the tumour islands
and dense, sparsely cellular collagenous stroma
surrounding it. Spindle cells, cytoplasmic
granules and intra or extracellular mucin
production are other features that may be present.
Sapino et al, in one of the largest series of these
tumours, have described five subtypes: solid
cohesive; alveolar; small cell; solid papillary
and cellular mucinous.4 Neuroendocrine papillary
DCIS may present with bloodstained nipple
discharge in an elderly woman.
In FNA smears, the most important feature
to recognize in this tumour is the presence
of cytoplasmic granules. These granules are
particularly evident in Romanowsky-stained
smears and are located at the apex of the
plasmacytoid cells or diffusely in the cytoplasm
of mucinous or spindle cells.1 It is likely that
the cytological features may vary depending on
histological type, but are not well-characterized
because of the rarity of the condition. A high
index of suspicion may help one to consider this
possibility and apply immunocytochemistry for
identification. The tumour cells have been shown
to be invariably positive for chromogranin.
Although NSE, CG and SY are all common NE
markers, CG is considered more appropriate
because of its localization in the neurosecretory
Dense core granules have been shown to be
present in the apical cytoplasm of normal breast
epithelial cells. These, however are believed
to indicate protein secretion and not endocrine
nature.2 It is believed that NE differentiation does
not indicate an origin from preexisting endocrine
cells, but one expression of differentiation
potential that is inherent in several conventional
type of breast carcinoma. Unlike NE carcinomas
of the lung which have a definite association with
tobacco smoking, primary sporadic NE tumours
in other organs have not been linked with any
definite pathogenetical factors and they often
demonstrate dissimilar cytogenetical changes
At present, a diagnosis of NE carcinoma
does not lead to treatment different from that
for other types of breast carcinoma of the same
stage. The present case showed nodal metastasis;
however, prognosis cannot be commented upon
because of the short follow-up period. Recent
evidence suggests that chromogranin production
in NE breast carcinomas might have clinical and
genetic implications, owing to the biochemical
analogy between granins and BRCA protein.6
Hence, therapy directed against these genetic
markers may be a future treatment strategy.
Likewise, it has been shown that these tumours
express somatostatin receptors which may be
responsible for their slow progression through
autocrine inhibition.7 It would be interesting to
see if a relationship exists between the presence
of chromogranin and tumour progression as well.
It has also been shown that serial evaluation
of circulating plasma chromogranin A(CgA),
a specific marker of neurosecretory activity, is
useful in the follow-up of patients, especially to
detect occult metastasis.7
Conclusion: A diagnosis of NE carcinoma of the
breast is possible in FNA cytology material and
its identification could allow an accurate clinical
study of patients and make it possible to plan
staging and therapy.
1. Sapino A, Papotti M, Pietribiasi F, Bussolati G.
Diagnostic cytological features of neuroendocrine
differentiated carcinoma of breast. Virchows Arch
2. Maluf HM, Koerner FC. Carcinoma of the breast
with endocrine differentiation: a review. Virchows
3. Rosen PP. Mammary carcinoma with endocrine
features. In: Rosen PP, editor. Rosen’s Breast
pathology, 2nd ed. Philadephia: Lippincott William
& Wilkins; 2001.503-8.
4. Sapino A, Righi L, Cassoni P, Parotti M, Pietribiasi
F, Bussolati G. Expression of the neuroendocrine
phenotype in carcinoma of the breast. Semin Diagn
Pathol 2000; 17:127-37.
5. Yao GY, Zhao JL, Lai MD, Chen XQ, Chen PH.
Neuroendocrine markers in adenocarcinoma: an
investigation of 356 cases. World J Gastroenterol
6. Jensen RA, Thompson ME, Jetton TL, Szabo CI,
van der Meer R, Helou B, Tronick SR, Page DL,
King MC, Holt JT. BRCA1 is secreted and exhibits
properties of granin. Nat Genet 1996; 12:303-8.
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NEUROENDOCRINE BREAST CARCINOMA
7. Yoshida R, Ohucfi N, Kimura N. Clinicopatho-
logical study of chromogranin A, B and BRCA1
expression in node-negative breast carcinoma. Oncol
Rep 2002; 9:1363-7.
8. Berutti A, Saini A, Leonardo E, Cappia S, Borasio
P, Dogliotti L. Management of neuroendocrine
differentiated breast carcinoma: a case report. The
Breast 2004; 13: 527-9.