Secretory carcinoma of the breast containing the ETV6-NTRK3 fusion gene in a male: case report and review of the literature
© Arce et al; licensee BioMed Central Ltd. 2005
Received: 22 March 2005
Accepted: 17 June 2005
Published: 17 June 2005
Secretory carcinoma (SC) of the breast is a rare and indolent tumor. Although originally described in children, it is now known to occur in adults of both sexes. Recently, the tumor was associated with the ETV6-NTRK3 gene translocation.
A 52-year-old male was diagnosed with secretory breast carcinoma and underwent a modified radical mastectomy. At 18 months the tumor recurred at the chest wall and the patient developed lung metastases. He was treated concurrently with radiation and chemotherapy without response. His tumor showed the ETV6-NTRK3 translocation as demonstrated by fluorescent in situ hybridization (FISH).
SC is a rare slow-growing tumor best treated surgically. There are insufficient data to support the use of adjuvant radiation or chemotherapy. Its association with the ETV6-NTRK3 fusion gene gives some clues for the better understanding of this neoplasm and eventually, the development of specific therapies.
SC of the breast is one of the rarest types of breast cancer accounting for less than 1% of all breast cancers. This entity was initially termed "Juvenile breast cancer" by McDivitt and Stewart, based on the fact that the average age of the seven patients described in their series was nine year-old with range of three to fifteen years . Subsequently, more cases in children [2–6] and adults [7–12] were described. Therefore, it was recommended that the descriptive term SC replace the designation "juvenile carcinoma". Secretory breast carcinomas have a characteristic balanced translocation, t(12;15), that creates a ETV6-NTRK3 gene fusion. The finding of a fusion transcript in SC and the demonstration that ETV6-NTRK3 could transform murine mammary epithelial cell lines has challenged widely accepted beliefs on breast carcinogenesis . This specific translocation is associated with congenital fibrosarcoma and mesoblastic nephroma, two morphologically similar pediatric mesenchymal tumors with no epithelial features . The biological consequence of this translocation is the fusion of the dimerization domain of a transcriptional regulator (ETV6) with a membrane receptor tyrosine kinase (NTRK3) that activates the Ras-Mek1 and PI3K-Akt pathways which are important for breast cell proliferation and survival [15, 17]. In only a few cases of secretory carcinoma the presence of the translocation has been confirmed. In the seminal report by Tognon 12 out of 13 cases tested positive  whereas Makretsov et al., found 3 out of 4 confirmed secretory carcinomas cases positive and at the same time screened 481 invasive breast carcinomas of which only one gave positive signal. This tumor was later confirmed to be a secretory carcinoma .
A 52 year-old male presented to our institution having undergone local excision of a left breast tumor one month previously. The tumor had measured 7 × 5 cm. The mass had been present for 10 years. At physical examination there was evidence of recent surgery and the patient had a 1 cm ipsilateral axillary lymph node. Serum tumor markers and other routine blood test were normal. The liver ultrasonography, chest X-ray and bone scan were negative for metastases.
Secretory carcinoma is a very rare type of breast carcinoma. Lamovec and Bracko  reported 4 cases of SC in a retrospective series of 7038 breast carcinoma cases, and Botta et al  found one case of SC among 3000 breast carcinoma cases.
Data on 17 males with Secretory Breast Cancer
Duration of symptoms
SM + RT (axilla)
WLE + ALND
NED 6 m
NED 8 m
LE + ALND
NED 45 m
MRT + CT+ RT
NED 12 m
NED 20 m
NED 9 m
46 Male-female transexual
MRM + CT
AWD 25 m
SC's can demonstrate several histological patterns including, solid, microcystic, and ductal, with many tumors containing all three patterns . The tumor cells are polygonal with granular eosinophilic cytoplasm. Atypia is minimal or absent and mitotic activity is low . A typical finding is the presence of intracellular and extracellular secretions . This secretory material is periodic acid-Schiff and alcian blue positive [24, 25]. In this tumor there was no expression of steroid receptors or HER2. A recent study has reported than only 4 and 2 out of 13 cases expressed the estrogen and progesterone receptor respectively and only two were HER2 positive . In the current case, the tumor had the t(12;15) ETV6-NTRK3 fusion gene (Fig. 4).
The most frequent clinical presentation is of an asymptomatic mobile mass, which is usually subareolar. The tumor size varies from 1 cm to 16 cm with an average diameter of 3 cm. [7, 16]. Our patient had a mass of 7 cm × 5 cm. As the patient reported that the lesion had been present for at least 10 years, it had behaved in a slow growing, indolent fashion. This is supported by other reported cases . In this regard, Biallo et al., have reported a MIB1 labeling index of 11.4% (range: <1 to 34%) .
Surgery is considered the primary treatment of secretory carcinoma, however, due to scarcity of reported cases no published guidelines for surgical management exist. There are however, many cases reported of patients who had suffered a local recurrence, therefore mastectomy appears to be a sound surgical choice [1, 5, 7, 9–11, 22, 24, 25]. There are no data however on conservative treatment but this option could be explored particularly in cases where breast development has not yet occurred. In regard to the management of the axilla, the overall incidence of axillary lymph node infiltration is around 30% in children and adults regardless of gender [21, 24], hence axillary lymph node dissection is advocated by some authors for tumors ≥2 cm [7, 24]. Nevertheless, sentinel node biopsy, may be useful for secretory carcinomas. A recent report on a 9-year-old girl treated with simple mastectomy and axillary sentinel lymph node biopsy shows that this is feasible .
Postoperative radiotherapy [19, 21] and adjuvant chemotherapy [7, 28] have been used on at least two occasions. There is at present insufficient evidence to recommend either approach in the management of secretory carcinoma.
Local recurrence after a long disease-free interval has been described in numerous cases; [1–3, 5, 9, 11, 28] however these occurred in patients that underwent conservative surgery. This is the second case reported with chest wall recurrence after mastectomy. In the other case the patient was treated with wide local excision and she is alive at 11-month follow-up. In contrast, our case also presented distant recurrence .
Distant metastases from secretory carcinoma are extremely rare with only four cases reported . Our case is the fifth case who developed distant metastases, this, despite having only two positive lymph nodes at resection. Another recently reported patient remained disease free at a follow-up of 13 months despite having 12 out of 14 positive nodes and not having received adjuvant chemotherapy .
There are several reported cases of patients with secretory breast carcinoma with distant metastases who were treated with either single agent or combination chemotherapy without success. Among the drugs reported are 5-FU, vindesine, mitomycin and prednisone, adriamycin, epirubicin, cyclophosphamide, carboplatin, and even newer active agents such as docetaxel. These data clearly show that this neoplasm is not chemosensitive, as all of the patients treated with chemotherapy showed disease progression while on treatment [7, 10, 20] and . In our case, despite using UFT alone and with concomitant radiotherapy there was no response. These observations are in contrast with reports on the high chemosensitivity to common agents (vincristine, cyclophosphamide, adriamycin, dactinomycin and ifosfamide) for congenital fibrosarcomas and mesoblastic nephromas, two other neoplasms associated with the translocation ETV6-NTRK3 . This suggests that secretory breast carcinoma, due perhaps to its slow growing behavior, acquires additional genetic alterations than ultimately confer chemoresistance. It will be very useful to establish cancer cell lines from this tumor type to study whether the chemoresistance is a general phenomenon or drug specific.
Secretory carcinoma is a rare slow-growing tumor that is best approached by surgical treatment. There are insufficient data to support the use of adjuvant radiation and/or chemotherapy. Its association to the ETV6-NTRK3 fusion gene gives some clues for the better understanding of this neoplasm and may eventually lead to the development of specific therapies.
The authors want to thank the patient for providing his consent for the publication of this report.
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