—  SPECIALTY CONFERENCE  —

Cytopathology

Case 3 - Neuroendocrine Carcinomas of the Breast

Christina Kong
Stanford University School of Medicine
Stanford, CA


Click on each slide thumbnail image for an enlarged view
Clinical History
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).

Cytologic Findings
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.

Immunohistochemistry
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. [1] They typically occur in elderly women (mean age 72 years) and present as a breast mass or, less commonly, as nipple discharge. [2, 3]

Neuroendocrine carcinomas are variants of primary breast adenocarcinomas that exhibit neuroendocrine differentiation in greater than 50% of the tumor cells. [4, 5] 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. [5, 6]

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. [1, 6]

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. [6, 7] Neuroendocrine carcinomas of the breast exhibit the usual range of differentiation from well to poor and also encompass the undifferentiated small cell carcinomas. [1, 8, 9] Well- and moderately-differentiated neuroendocrine carcinomas are often associated with mucinous or apocrine differentiation within the tumor. [2, 5, 7, 9]

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 receptors. [1]

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. [5, 10, 11, 12]

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.

References

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  2. Tsang WY, Chan JK. Endocrine ductal carcinoma in situ (E-DCIS) of the breast: a form of low-grade DCIS with distinctive clinicopathologic and biologic characteristics. Am J Surg Pathol. Aug 1996;20(8):921-943.
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  9. Papotti M, Macri L, Finzi G, Capella C, Eusebi V, Bussolati G. Neuroendocrine differentiation in carcinomas of the breast: a study of 51 cases. Semin Diagn Pathol. May 1989;6(2):174-188.
  10. Sapino A, Papotti M, Pietribiasi F, Bussolati G. Diagnostic cytological features of neuroendocrine differentiated carcinoma of the breast. Virchows Arch. Sep 1998;433(3):217-222.
  11. Tang W, Taniguchi E, Wang X, et al. Loss of cell cohesion in breast cytology as a characteristic of neuroendocrine carcinoma. Acta Cytol. Sep-Oct 2002;46(5):835-840.
  12. Ng WK, Poon CS, Kong JH. Fine needle aspiration cytology of ductal breast carcinoma with neuroendocrine differentiation. Review of eight cases with histologic correlation. Acta Cytol. Mar-Apr 2002;46(2):325-331.