Secretory Carcinoma of the Breast With Multiple Distant Metastases in Brain and Unfavorable Prognosis: a Case Report and Literature Review

Background: Secretory carcinoma of the breast is one of the rarest entities accounting for less than 0.15% of all inltrating breast carcinomas. It has characteristic histopathological and molecular features and more favorable prognosis. In this case report, we describe a local advanced secretory carcinoma of the breast with chemo-resisted for neoadjuvant chemotherapy and unfavorable prognosis. Case Presentation: A hard, painless and palpably bossed mass about 12 cm in diameter occupied most of the left breast of a 39-year-old woman and xation to the overlying skin. Breast ultrasonography and magnetic resonance imaging (MRI) scan gave the same grading as BI-RADS IV. A needle biopsy was performed and pathological diagnosis was secretory carcinoma. Neoadjuvant chemotherapy (NAC) was then performed, after which ultrasonography and MRI scan revealed the tumor was partial response for EC therapy while progressive disease after the DC therapy. The tumor showed chemo-resisted for neoadjuvant chemotherapy. Left breast mastectomy and axillary lymphadenectomy were subsequently performed. Tumor cells were triple-negative and positive for S-100 and periodic acid-Schiff (PAS) staining. Fluorescence in-situ hybridization (FISH) analysis indicated the fusion arrangement of ETV6-NTRK3 gene. The patient underwent multiple distant metastases in brain, and died of these metastases 19 months after initial diagnosis. Conclusion: Secretory carcinomas of breast have been described as a low-grade histologic subtype with a favorable prognosis. This case showed chemo-resisted for neoadjuvant chemotherapy, multiple distant metastases, and nal an unfavorable prognosis. Further research is needed to better understanding of its behavior and treatment of this rare tumor.


Introduction
Secretory carcinoma is a very rare type of breast carcinoma. It was rst reported in children and known as juvenile breast carcinoma [1], but now it is clear to occur in adults of both sexes. Secretory carcinoma of breast has characteristic histopathological and immunohistochemical features [2]. Recently, it has been shown that the ETS variant 6-neurotrophic tyrosine kinase receptor type 3 (ETV6-NTRK3) gene fusion is associated with secretory carcinoma [3,4]. Secretory carcinoma of breast was generally described with a favorable prognosis and suggested that treatment should be as conservative and non-aggressive as possible [5].
Here, we report a case of a 39-year-old woman who suffered from a local advanced secretory carcinoma of the breast with chemo-resisted for neoadjuvant chemotherapy and subsequent multiple brain metastases and unfavorable prognosis. The aim of this report is to help to better understand the behavior of this rare tumor in order to develop a standard approach to treatment.

Case Presentation
Clinical history A 39-year-old woman who noted a lump in her left breast for 13 months and which increased rapidly for 2 months. In May 2017, the patient rstly admitted to our hospital. She had no past history of malignancy and no family history of breast carcinoma.
In physical examination, a hard, painless and palpably bossed mass about 13.0 cm in diameter occupied most of the left breast and xation to the overlying skin (Fig. 1a). There were no abnormalities in the right breast. MRI scan revealed a focal high-density mass of 11.0×12.0 cm and gave the grading as BI-RADS IV (Fig. 1b). Breast ultrasonography revealed a huge mass of size 11×11 cm, shaped regularly in the left breast and a hypoechoic mass about 2.8×1.0 cm in the left axilla. Ultrasonography examination also graded the breast mass for BI-RADS IV (Fig. 1c). The resulting pathological diagnosis for needle biopsy was secretory carcinoma and the disease in this patient was staged as T4N1M0 (Stage IIIB).
Neoadjuvant chemotherapy was then performed with 4 cycles of Epirubicin/Cyclophosphamide (EC) regimens and 2 cycles of Docetaxel/Carboplatin (DC) regimens. Physical examination was routinely performed after each cycle of chemotherapy. As shown in Table 1, the tumor size gradually decreased in the rst 4 cycles of EC regimens while conversely, increased in 2 cycles of DC regimens. Figures of physical examination, MRI scan and Ultrasonography during the whole course of neoadjuvant chemotherapy also revealed the tumor was partial response for EC regimens therapy while progressive for DC regimens (Fig. 1a-1i).
This patient completed modi ed radical mastectomy (left breast mastectomy and left axillary lymphadenectomy) and consecutive latissimus dorsi breast reconstruction in October 2017. 4 cycles of Fluorouracil/Epirubicin/cyclophosphamide (FEC) regimens were continuously given. Radiotherapy was carried out to the chest wall and drainage areas (50Gy/25f). The patient was switched to intensive chemotherapy with oral Capecitabine for 8 cycles.
In October 2018, the patient was hospitalized again with the complaints of a headache and an ataxia.
Brain MRI scan showed multiple metastases in left occipital lobe, bilateral frontal lobe and left side of the cerebellum, and the largest mass had a maximum diameter of 3.5 cm (Fig. 2a-c). Whether there were metastases in other organs was unclear. She nally gave up treatment and died in March 2019. The disease-free survival and overall survival of this patient were 10 months and 19 months, respectively. Table 1 Tumor size by physical examination during NAC. On gross examination, the needle biopsy specimen pre-chemotherapy was strip-like, gray-red, slightly hard in texture, and nothing special. The mastectomy specimen after chemotherapy covering with skin and nipple was submitted for examination. Cut surface showed about a mass of 8×7×5 cm, with white-gray multiple nodules and obvious accompanied by bleeding and necrosis. No nipple and periareolar lesion were seen (Fig. 3). 15 lymph nodes were detected in the separate axillary tissues.

Microscopic features
Microscopic examination for biopsy specimen prechemotherapy revealed the tumor cells are arranged combinations of microcystic (Fig. 4a) and solid patterns (Fig. 4b), and characteristically contained abundant extracellular secretory material. The cells had abundant granular eosinophilic cytoplasm and round moderate grade nuclei. There was no perineural or vascular invasion. The biopsy hence suggested a secretory carcinoma of the breast. For the mastectomy specimen, the tumor also displayed the combinative structures of microcystic and solid patterns (Fig. 4c) and a pushing border near to skin (Fig. 4d), accompanied by massive necrosis and hemorrhage. Responding to neoadjuvant chemotherapy, the tumor cells showed obvious morphological changes in some areas, such as nuclear concentration and fragmentation of tumor cells and pleomorphic giant tumor cells with eosinophilic and foamy cytoplasm (Fig. 4e). Isolated tumor cell was detected in one enlarged axillary lymph node (Fig. 4f).
Fluorescence in-situ hybridization (FISH) analysis indicated the fusion translocation t (12;15) of ETV6-NTRK3 gene. As shown in Fig. 4l, the red signal represented ETV6 gene, and the green signal represented NTRK3 gene, and there were number of ETV6-NTRK3 fusion signals detected by FISH.

Discussion
Secretory carcinoma of breast is one of the rarest entities accounting for less than 0.15% of all in ltrating breast carcinomas [2]. It was rst described in 1966 by McDivitt and Stewart as a rare breast neoplasia identi ed in female children and adolescents, at the average age of nine [1]. But now it was clear to occur in adults of both sexes [6][7][8]. The typical clinical presentation of secretory carcinoma of breast is a slowgrowing, painless, well-circumscribed, palpable mass occurring anywhere but more common in the outer upper quadrant of breast [9]. Microscopically, secretory carcinoma of breast is arranged with a solid, microcystic and tubular structure, composed of cells that produce abundant intracellular and extracellular milk-like secretory material, intensively positive for alcian blue or PAS. The tumor cells have low-grade features with small to medium sized, oval to round nucleus, scant mitotic activity and abundant granular eosinophilic cytoplasm. Occasionally, the papillary growth area can also be the dominant structure.
In addition to breast, secretory cancer can also occur in other organs which containing secretory glands, such as parotid gland, salivary gland, sweat gland, lacrimal gland and thyroid [12][13][14][15][16][17]. Secretory carcinoma occurs in other organs shows the same combinative structures of cribriform patterns, solid patterns, and microcystic patterns, and extracellular secretion positive for Alcian blue or PAS. The ETV6-NTRK3 gene fusion are also showed in secretory carcinomas occurring in the breast and other organs. Recently, some novel gene mutations of secretory carcinomas occurring in the salivary glands were reported. Sasaki et al found a case with CTNNA1-ALK fusion [18] and Black et al reported another case harboring two gene fusions, ETV6-RET and EGFR-SEPT14 [19], expanding the molecular characterization of secretory carcinoma beyond the ETV6-NTRK3 gene mutation.
Due to scarcity of reported cases, there are no consensus guidelines for treatment. Surgery is considered the mainstay of treatment of secretory carcinoma. The demonstration of late local recurrence has led many to propose mastectomy for the patients with this disease [30]. In adults, a simple mastectomy, at minimum, is recommended. Modi ed radical mastectomy has been favored by some authors in cases with tumor sizes greater than 2 cm and poor gross circumscription [31]. Adjuvant chemotherapy and radiation have been tried for the disease without much success [23].
Tavassoli and Norris [6] suggested three features that indicated a favorable prognosis in secretory carcinoma of the breast: (1) tumor size less than 2 cm; (2) age of less than 20 years at diagnosis; and (3) circumscribed margins. Unfortunately, none of these three features was present in our case. After completing the medical inspection, 4 cycles of EC regimens and 2 cycles of DC regimens neoadjuvant chemotherapy was rstly used because of its large tumor size (12 cm) and late clinical stage (T4N1M0/ IIIB). The tumor was partial response for EC regimens therapy while progressive for DC regimens. Avoided losing the opportunity of surgical treatment, modi ed radical mastectomy was performed immediately. 4 cycles of FEC regimens and 8 cycles intensive chemotherapy were continuously given. Radiotherapy was carried out to the chest wall and drainage areas. The patient was then switched to intensive chemotherapy with oral Capecitabine for 8 cycles. But regrettably, multiple brain metastases were found 10 months later and the overall survival of this patient was 19 months.

Conclusion
In this paper, we report a case of secretory breast carcinoma of a 39-year-old female on the basis of imaging, histopathological pattern, immunophenotype and molecular alteration. Different from this rare subtype of breast cancer as described with a low-grade histologic and favorable prognosis, our case showed chemo-resisted for neoadjuvant chemotherapy and multiple distant metastases in brain, and nal an unfavorable prognosis. To the beast of our knowledge, this is the rst report of secretory carcinoma of breast with multiple metastases in brain and died of these metastases.

Consent for publication
Written informed consent was obtained from the patient for publication of the case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.