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Large cell neuroendocrine carcinoma
(Tumours of the Breast…WHO Classification 2003)
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These poorly differentiated tumours are composed of crowded large clusters of cells, with moderate to abundant cytoplasm, nuclei with vesicular to finely granular chromatin and a high number of mitotic figures ranging from 18 to 65 per 10 hpf. Focal areas of necrosis are present. These tumours exhibit neuroendocrine differentiation similar to those encountered in the lung (see also below). |
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Differential diagnosis
A nodule of NE carcinoma in the breast may reflect metastatic carcinoid or small cell carcinoma from another site. lmmunohistochemistry may help to distinguish between metastatic and primary small cell carcinomas. Mammary small cell carcinomas are cytokeratin 7-positive and cytokeratin 20-negative, whereas, for example, pulmonary small cell carcinomas are negative for both. The presence of DCIS with similar cytological features is supportive of breast origin. In addition, the expression of estrogen (ER) and progesterone receptors (PR) and of the apocrine marker GCDFP-15, which is frequently expressed by well and moderately differentiated endocrine breast carcinomas, are supportive of a primary breast carcinoma.
Mammary small cell carcinoma can be confused histologically with lobular carcinoma. The negative immunoreaction for E-cadherin in lobular carcinomas, in contrast to a positive reaction in 100% of small cell carcinomas, is useful in the differential diagnosis.
It is also important to differentiate neuroendocrine breast carcinomas from carcinomas with neuroendocrine differentiation. The latter have immunoexpression for neuroendocrine markers in scattered cells; this feature is noted in 10-18% of breast carcinomas of the usual type. Such focal neuroendocrine differentiation does not seem to carry a special prognostic or therapeutic significance. |
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Immunoprofile
Argyrophilia demonstrated by Grimelius silver precipitation is a feature of neuroendocrine breast carcinomas. Only darkly granulated cells should be considered as argyrophilic .Expression of chromogranin proteins and/or synaptophysin also confirmed evidence of neuroendocrine differentiation. These proteins are identifiable by immunohistochemical and immunoblot analysis. Poorly and moderately differentiated endocrine breast carcinomas of the alveolar subtype, in general, express chromogranin A. The mRNA specific for chromogranin A is detectable by in situ hybridization technique. About 50% of well or moderately differentiated tumours express chromogranin B and A and only 16% express synaptophysin. A monoclonal antibody against neurone-specific enolase (NSE) has also been used and is expressed in 100% of small cell carcinomas of the breast, whereas chromogranin A and synaptophysin are expressed in about 50% of such cases. In addition, 20% of small cell mammary carcinomas express thyroid transcription factor-1 (TTF-1). Immunodetection of pan-endocrine markers may fail to recognize endocrine tumours, which produce but do not retain the specific antigen in the cells. Estrogen (ER) and progesterone receptors (PR) are expressed in the majority of tumour cells in well differentiated tumours, and in more than 50% of small cell carcinomas. Expression of somatostatin receptors (SSR), a known feature of tumours showing neuroendocrine differentiation, has been demonstrated in endocrine breast carcinomas as well.
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Ultrastructure
Different types of dense core granules, whose neurosecretory nature is confirmed by ultrastructural immunolocalization of chromogranin A have been identified by electron microscopy in endocrine breast carcinomas. The presence of clear vesicles of pre-synaptic type is correlated with the expression of synaptophysin. Both dense core granules and mucin vacuoles are present in neuroendocrine mucinous carcinomas. |
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Genetics
Neuroendocrine breast carcinomas have not been correlated to specific gene mutations. |
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Postulated normal counterpart Argyrophilic and chromogranin A-reactive cells, located between the basal myoepithelial and the luminal epithelial cells, have been demonstrated in histologically normal breast tissue surrounding infiltrating and in situ neuroendocrine breast carcinomas. |
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Prognosis and predictive factors: Histological grading is one of the most important prognostic parameters. NE breast carcinomas may be graded using classical criteria described elsewhere.
Excluding the rare small cell variety, 45% of NE breast carcinomas are well differentiated, 40% are moderately differentiated, and only 15% are poorly differentiated. Small cell NE carcinomas should be considered as undifferentiated carcinomas.
Mucinous differentiation is a favourable prognostic factor.
The prognosis of primary small cell carcinomas of the breast depends on the stage of disease at the time of diagnosis. It has been demonstrated that low stage small cell carcinomas respond to conventional treatment without progression of the disease at a follow up of 33 to 48 months. |
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Carcinomas with neuroendocrine features in Ackerman's Surgical Pathology (8 Ed) |
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The term carcinoid tumor was originally proposed for a type of invasive ductal carcinoma exhibiting features consistent with endocrine differentiation. In general, the clinical presentation is no different from that of the ordinary breast carcinoma. Specifically, none of the patients has had carcinoid syndrome, even in the presence of widespread disease. Multicentricity and bilaterality can occur.There are no distinctive gross features.
Microscopically, the tumor cells are small, arranged in solid nests separated by fibrous tissue. Ribbons and rosette-like formations may be formed. Mitoses are generally rare. The presence of an intraductal component and of mucin secretion has been detected in a minority of the cases. The microscopic diagnosis includes lobular carcinoma and a metastasis to the breast of a carcinoid tumor located elsewhere. |
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The tumor cells of carcinoid tumor of the breast are argyrophilic but not argentaffin and are found to contain dense-core secretory granules of various types ultrastructurally.
The nature of this neoplasm has been controversial from the very first description. It has even been suggested that the argyrophilia and the dense-core secretory granules are not an indication of neuroendocrine differentiation at all but rather of lactalbumin secretion by the tumor cells. To be sure, not all membrane-bound dense core cytoplasmic granules are of neurosecretory type. However, the immunohistochemical positivity that has been obtained for chromogranin, synaptophysin, and neuron-specific enolase, and in some instances for specific hormone peptides, would seem to verify that these tumors do indeed exhibit signs of endocrine differentiation. Whether this justifies calling them carcinoid tumors is another matter. It seems to us that they are the example of a phenomenon similar to that described in practically all other organs (i.e., that of a carcinoma arising from primitive epithelial cells with the capacity to differentiate focally or extensively towards an endocrine line). Such carcinomas otherwise resemble ordinary ductal-type carcinoma in most other ways: occasional presence of an in situ component, frequent positivity for estrogen receptors, pattern of metastases, and outcome. Therefore we like to view and designate this tumor as invasive ductal carcinoma with (neuro) endocrine differentiation or features, a term we prefer to the alternative designation argyrophilic carcinoma. According to Azzopardi et al., this tumor constitutes about 5% of all breast carcinomas.
It should be mentioned here that there are breast carcinomas of other morphologic patterns in which endocrine features have been found: the already mentioned mucinous carcinoma, small cell (oat cell) carcinoma, invasive ductal-type carcinomas of ordinary type, and some types of in situ ductal carcinoma. Interestingly, carcinoid tumors of the conventional type are virtually nonexistent in the breast. We have seen only one case that had morphologic and histochemical features (argentaffinity) identical to those of classic (insular) carcinoid tumors of midgut derivation; remarkably, it was associated with the presence of argentaffin cells in the adjacent breast epithelium. |
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