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 firstly 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 fixation 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 first 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 modified 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 finally 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.
|
Chemotherapy course
|
①
|
②
|
③
|
④
|
⑤
|
⑥
|
⑦
|
⑧
|
|
Length (cm)
|
14.0
|
13.0
|
12.0
|
10.0
|
10.0
|
9.0
|
10.0
|
11.0
|
|
Width (cm)
|
13.0
|
11.0
|
10.5
|
9.5
|
9.5
|
9.0
|
10.0
|
11.0
|
|
Height (cm)
|
8.0
|
6.0
|
4.5
|
4.0
|
3.5
|
4.0
|
4.5
|
5.0
|
① Pre-chemotherapy, ② after 1st cycle of EC, ③ after 2nd cycle of EC, ④ after 3rd cycle of EC, ⑤ after 4th cycle of EC, ⑥ after 1rst cycle of DC, ⑦ after 2nd cycle of DC, ⑧ 25 days after 2nd cycle of DC
Gross features
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).
Immunohistochemistry of the biopsy specimen on review of paraffin embedded blocks showed tumor cells were positive cytoplasm staining for epithelial membrane antigen (EMA, Fig. 4g), S-100 (Fig. 4h), Vimentin, and positive cytomembrane staining for E-Cadherin (Fig. 4i) while triple-negative results for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2). It was also negative staining for androgen receptor (AR), gross cystic disease fluid protein 15 (GCDFP-15), and smooth muscle actin (SMA, Fig. 4j). Ki-67 proliferation index was 50%. The secretory material is positive for periodic acid-Schiff (PAS) staining (Fig. 4k).
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.