Primary small cell neuroendocrine carcinoma of the breast : a report of two cases and review of the literature

Primary neuroendocrine carcinomas of the breast are extremely rare. Neuroendocrine tumors mainly occur in the broncopolmonary system and gastrointestinal tract. The diagnosis of small cell neuroendocrine carcinoma (SCNC) of the breast can only be made if a non mammary site is excluded or if an in situ component can be found. We are going to describe two cases and to discuss their clinical, radiological and pathological manifestations. Introduction: Neuroendocrine tumors are rare and slow-growing neoplasias derived from neuroendocrine cells. We describe two cases of small cell neuroendocrine carcinoma of the breast and discuss their clinical, radiological and pathological manifestations. Case report: Our patients are two Italian females (38 and 36 year-old) with no family history of breast disease. In both cases the diagnosis was confirmed after surgery, when immunohistochemistry revealed a neuroendocrine differentiation of the tumor. The patients are alive and disease free after more than ten years of follow-up. Conclusion: Primary neuroendocrine carcinomas of the breast are extremely rare. The diagnosis of SCNC of the breast can only be made if a non mammary site is excluded or if an in situ component can be found. After surgery, a strict follow-up including octreotide scan should be performed and this doesn’t differ from the one of the usual breast carcinoma.


Introduction
Neuroendocrine tumors are rare and slow-growing neoplasias derived from neuroendocrine cells, which are present throughout the body; they arise especially in the bronchopulmonary system but they have been described also in many extrapulmonary sites including gastrointestinal tract, prostate, bladder, ovary and cervices.Small cell neuroendocrine carcinoma (SCNC) of the breast is rare, accounting for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors [1,2].To our knowledge, only about 30 cases have been reported in the English literature since the first case reported in 1983 [3].We present two cases of primary SCNC of the breast and discuss the clinical, radiological and pathological manifestation.

Case one
A 38 year-old woman had presented for two months a painless mass in the right breast.Clinical investigation revealed no palpable axillary lymph nodes; she had no The patient had a quadrantectomy with right axillary nodes clearance.The resected mass was 843 cm with a tumor mass of 2.11.8cm.The resection margins were clear.The histological examination showed that the tumor was an infiltrating ductal carcinoma with neuroendocrine differentiation (Figure 3a, 3b, 4, 5).The immunohistochemistry was positive for neuroendocrine differentiation markers including neuron specific enolase (NSE), chromogranin and synaptophysin in more than 90% of tumor cells.The estrogen receptor was positive in 90% and progesterone receptors in 20% of the tumor's cells.Histological examination also showed that only 1 out of 16 lymph nodes were positive for metastases.The tumor stage was IIB.Additional chemotherapy, on the base of the current literature, was administrated with FEC and tamoxifen.After 12 years of follow-up with periodic mammography and octreotide scan (Figure 2B), the patient is disease free.Mammography of the right breast show a circumscribed, high density mass (Figure 1).

Case two
A 36 year-old female patient with no family story for breast disease presented with a painless mass in the lower external quadrant of the left breast.There was no nipple retraction, dimpling or palpable axillary lymph nodes.The mammography revealed a roundish high density neoformation and the ecography showed a lump of 15 mm with an inhomogeneous central area (Figure 6).A quadrantectomy with left axillary nodes clearance was performed and the resected mass was 664 cm with a tumor mass of 17 mm.The anatomopathological examination revealed an infiltrating ductal carcinoma.Immunohistochemically, more than 90% of the tumor cells were positive for neuroendocrine differentiation markers, including synaptophysin, chromogranin and neuron specific enolase (NSE).The estrogen receptor was positive in 85% and progesterone receptors in 20% of the tumor's cells.The resection margins were clear.There was no evidence of axillary lymph nodes metastases.The tumor stage was I. Any biopsy was performed prior to quadrantectomy, because of the high suspicion of malignancy showed by mammography.The patient was operated again after five years from the first surgery and a radical quadrantectomy and lymphadenectomy were performed.Definitive histology confirmed a small cells neuroendocrine tumor.The surgery was followed by adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and fluorouracil).After 10 years the patient is disease free.

Review of literature
We reviewed all the English literature on PubMed about the neuroendocrine carcinoma of the breast from 1983 to 2012, considering, for each article, the authors, the number of cases described (and for each case we considered the size of the tumor, the expression of estrogen receptors and the patient's status at the end of the follow-up) and the year of publication.The cases described were 114, the median age was 57 years (range 28-87 years), the estrogen receptors were positive in the 50% of the cases (Table 1).

Discussions
Neuroendocrine tumors of the breast are rare, accounting for less than 0.1 % of all breast cancer and less than 1% of all neuroendocrine tumors [1].The age of incidence reported in literature varies from 40 to 70 years, with higher incidence in women over 60 years (our cases are in an early age).SCNC may represent either metastatic or primary lesions and carcinoma of the breast can be diagnosed if the presence of a non mammary primary site can be ruled out clinically, or an in situ is detected histologically or both [3].It is important to differentiate primary breast neuroendocrine tumor from metastatic disease of the breast because of the differences in treatment.
To exclude a primary lung tumor a thorax X-ray and ct should be performed.Primary locations such as pancreas, stomach and bowel are excluded by performing an abdomen ct.Furthermore an octreotide scan is helpful to identify other sites of endocrine tumors [4].
On mammography, unlike common breast carcinomas, which tend to have poorly defined margins and associated microcalcifications, neuroendocrine tumors may appear     as sharply circumscribed masses and often mimic fibroadenomas, cystitis or intramammary lymph nodes [1].However the radiological features are nonspecific, and a fine-needle aspiration or core-needle biopsy examination is necessary for the diagnosis.Obviously, care should be taken to not provoke a carcinoid crisis, which can result from compressing the breast during mammography and fine-needle biopsy examination [1].
The histogenesis is still unclear because the presence of neuroendocrine cells in normal breast has not been proved conclusively.It has been suggested that SNSC is a variant of metaplastic carcinoma arising from a lobular or ductal carcinoma [2].However some believe that SCNC is a distinct type of breast carcinoma different from the usual type.
Histologically, SCNC is similar to those arising from other sites [3].The tumor cells are small and round or oval, and have a large nuclear cytoplasmatic ratio.The nuclei are hypercromatic with inconspicuous or no nucleoli.
There is usually a high mitotic count.The expression of neuroendocrine markers by SNSC is very important [2].
Although some of these tumors are poorly differentiated, the positivity for neuroendocrine markers including synaptophysin, chromogranin and neuron specific enolase (NSE) will give strong support to the diagnosis, and this should be carefully searched for; both our cases were positive.
The prognostic relevance of neuroendocrine differentiation in breast carcinoma is a subject of debate.Although most studies reported an appreciably worse prognosis a few did not [2].However the prognosis could be better in tumors detected at a smaller size, without lymph node involvement and with hormone sensitivity [17].Finally a strict follow-up including mammography and octreotide scan should be performed to detect possible relapse or the arising of a carcinoma of the usual type, as showed by our case two.

Conclusions
Primary neuroendocrine carcinomas of the breast are extremely rare.The diagnosis of SCNC of the breast can only be made if a non mammary site is excluded or if an in situ component can be found.After surgery, a strict follow-up including octreotide scan should be performed and this doesn't differ from the one of the usual breast carcinoma.On the base of current literature, the small cells neuroendocrine tumor of the breast does not differ, about the surgical approach, from the others histologies.Also for this rare tumor the estimated size by preoperative examinations play a critical role in the choice of surgical strategy, among more conservative or more radical operations.A special attention should by reserved for the regional lymphnodes, because these tumors frequently metastasize to that level, as we can infer from our literature review.

Figure 1
Figure 1 Mammography revealed a circumscribed high-density lump in the lower external quadrant of the right breast

Figure 5 Figure 6
Figure 5 Histopathological findings reveal a neuroendocrine tumor

Figure 4
Figure 4 Section showing positive staining for synaptophysine

Table 1
The clinical pathological findings of all published cases of SCNC of the breast Spinelli C et al., J Cancer Res Ther 2013, 1(7):186-193