Case 3 -
Neuroendocrine Carcinomas of the Breast
Stanford University School of Medicine
Click on each slide thumbnail image for an enlarged view
An 84-year-old woman is noted to have a 1 cm mass in the
right breast on a screening mammogram. The nodule is palpable and appears as an oval, well-circumscribed
solid mass on ultrasound. An FNA biopsy is performed (Figures A,B).
Case 3 - Figure A - Monotonous population of discohesive cells with cytologically bland, round nuclei. At first glance, these cells appear lymphoid but most of the cells in this field are stripped of cytoplasm and represent bare nuclei. Rare intact cells are present in the right-hand half of the photomicrograph. Note the absence of lymphoglandular bodies in the background (Diff-Quik, 200X).
Case 3 - Figure B - Higher power view shows intact cells with eccentric nuclei and moderate amounts of granular cytoplasm (Diff-Quik, 400X).
Aspirate smears are cellular and show a monotonous
population of tumor cells with round nuclei and finely granular chromatin. The majority of the cells are
stripped of cytoplasm but scattered intact cells have scant to moderate amounts of cytoplasm which ranges
from clear to finely granular. Many cells appear plasmacytoid with eccentric nuclei. No lymphoglandular
bodies are identified.
Immunohistochemical stains, performed on a destained
smear, show that the tumor cells are positive for chromogranin and negative for CD45.
Histology and Clinical Follow-up
The patient underwent excision of the
nodule. On gross examination, a well-circumscribed 0.9 cm tan nodule resembling a lymph node was
identified. Histologic sections show tightly packed nests of uniform, small round tumor cells, which
focally infiltrates into surrounding adipose tissue. A sentinel lymph node was replaced by tumor.
Immunohistochemical stains, performed on sections of the breast nodule, show that the tumor cells
diffusely express the neuroendocrine markers chromogranin and synaptophysin. Stains for calponin and p63
highlight the absence of myoepithelial cells around the tumor cell nests, consistent with an invasive
process. In addition, stain for E-cadherin was negative, supporting lobular differentiation.
The histologic diagnosis was invasive neuroendocrine lobular carcinoma. The patient was staged as IIA
(T1bN1M0). The tumor recurred as multiple skin metastases five months after initial diagnosis.
Discussion: Neuroendocrine Carcinomas of the Breast
Neuroendocrine breast carcinomas are uncommon, representing 2-5% of all carcinomas of the
breast.  They typically occur in elderly women (mean age 72 years) and present as a breast
mass or, less commonly, as nipple discharge.
Neuroendocrine carcinomas are variants of primary breast adenocarcinomas that exhibit neuroendocrine
differentiation in greater than 50% of the tumor cells.
These tumors have been called
"primary carcinoid tumors of the breast" in the past but this term has been controversial and is no
longer generally accepted. Occasional studies have reported the presence of scattered neuroendocrine
cells in normal mammary epithelium but most studies have failed to identify these cells. In addition,
unlike in the gastrointestinal tract or lung, hyperplastic or benign neoplastic neuroendocrine lesions of
the breast have not been identified. Based on these findings, neuroendocrine carcinomas of the breast
are considered to acquire neuroendocrine differentiation rather than to arise from pre-existing
neuroendocrine cells in the breast.
Both ductal and lobular carcinomas can exhibit neuroendocrine differentiation. If greater than 50% of
the tumor cells exhibit neuroendocrine differentiation by immunohistochemical stains for chromogranin and
synaptophysin, it is classified as a neuroendocrine carcinoma. If only scattered cells exhibit
neuroendocrine differentiation, it is classified as breast carcinoma, NOS, with neuroendocrine features.
Breast carcinomas of the usual type have been found to exhibit focal neuroendocrine differentiation in
10-18% of cases.
Neuroendocrine differentiation, both greater than and less than 50%, has not been shown to be
prognostically significant. Rather, prognosis is driven by the grade of the tumor.
Neuroendocrine carcinomas of the breast exhibit the usual range of differentiation from well to
poor and also encompass the undifferentiated small cell carcinomas.
moderately-differentiated neuroendocrine carcinomas are often associated with mucinous or apocrine
differentiation within the tumor.
Although uncommon, neuroendocrine carcinomas in the breast may represent a metastasis from another
site. Immunohistochemical stains can be helpful in cases where this is a consideration. Primary
neuroendocrine carcinomas of the breast are typically CK7(+)/CK20(-). Well- and
moderately-differentiated carcinomas will also express BRST-2 (GCDFP-15) and estrogen and progesterone
Neuroendocrine breast carcinomas are characterized cytologically by cellular smears, which show a
discohesive population of tumor cells with uniform, round nuclei that often have a plasmacytoid
appearance. The chromatin varies from finely granular to stippled. Nucleoli range from inconspicuous to
small and distinct. Cytoplasm varies in amount but is generally moderate. Eosinophilic granules can be
identified on Giemsa or Diff-Quik stained air-dried smears in the periphery of the cytoplasm. In
plasmacytoid cells, these granules are located at one pole, giving the appearance of a cap. They
represent neurosecretory granules and are positive for neuroendocrine markers. While these eosinophilic
granules are characteristic of neuroendocrine carcinomas, they are not present in every case.
In this case, based on the aspirate smears, the cytologic features raised the differential diagnosis
of a well-differentiated carcinoma vs. a low-grade lymphoma. Most of the cells are stripped of
cytoplasm, giving the impression of a uniform population of discohesive round cells with scant
cytoplasm. The scattered intact cells have a plasmacytoid appearance but lack the characteristic clumped
chromatin pattern and perinuclear clearing of plasma cells. In addition, the absence of lymphoglandular
bodies ("blue blobs") argues against a lymphoid process. Distinction between a lobular carcinoma and
neuroendocrine carcinoma can be difficult. In this case, the surgical excision showed a neuroendocrine
lobular carcinoma. Plasmacytoid appearance and discohesion can be seen with both but features that
pointed toward neuroendocrine differentiation were the monotony of the tumor cell population, round
nuclei without nuclear membrane irregularities, and granular cytoplasm.
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