EPC is a rare malignancy of the breast and considered a viariant of DCIS. It accounts for less than 0.5–1% of breast cancer cases and mostly occurs in postmenopausal women but also in men in some cases [1, 2]. EPC is usually considered a variant of carcinoma in situ and treated in accordance with carcinoma in situ management . Papilloma shows positive MEC layers in the papillary lobe, whereas in papillary carcinoma, MEC layers are either completely disappeared or substantially reduced. Moreover, the presence of a layer of MEC at the periphery of nests of papillary carcinoma is used to define the lesion as being in situ rather than invasive. Studies showed that the tumor papilla and periphery of involved spaces lack MEC layers in contrast to DCIS [7, 8]. The lack of MEC layers is an important criterion for distinguishing EPC from other papillary lesions. In the present case, MEC was examined for all lesions, and most papillary carcinomas were evaluated with calponin, CK5/6, and P63 as MEC markers. We were unable to use any of the MEC markers to identify the layer of MEC in the periphery of these lesions that was consistent with that of a previous study .
Hill and Yeh  suggested that differences in intraductal cases without basal membrane endothelial cell staining are best seen as part of a continuum of progression between DCIS and invasive disease. A study that compared the expression of invasion-related proteins in EPC, DICS, and invasive carcinoma demonstrated that the expression of MMP-1 and MMP-9 in EPC is higher than that in DCIS, and the difference between them and invasive carcinoma is not statistically significant. The expression levels of MMP-2 and MMP-7 are similar in EPC and DCIS, but the expression levels of both are lower than that of invasive tumors . These observations may indicate that EPC has the potential to become an invasive cancer and display a clinically indolent behaviour. Pure EPC reportedly has lymph node metastasis and lung metastasis . These features may also indicate that EPC is not DCIS or does not have the potential to become an invasive cancer. Considering EPC as a particular form between DCIS and invasive cancer may be more appropriate. Owing to the low incidence of EPC and the lack of prospective studies, the biological behavior, treatment, and prognosis of this disease remain unclear.
The majority of patients with EPC enrolled in previous studies were postmenopausal women. Males and young women with this disease are rare. In the present case report, one was male, and the average age of the female patients was 53.6 (34–66), which was lower than the average age reported in previous studies .
In this case report, eight patients received CNB, and three cases received excision biopsy initially. EPC was diagnosed in one patients via CNB. Surgical removal of atypical papillary lesions or papillary carcinomas in a core biopsy specimen is generally accepted. In a previous study, the false-negative rate of CNB in differentiating benign from malignant papillary lesions was 8.8%. Moreover, three out of eight patients who were diagnosed with atypical papilloma via CNB was upgraded to malignant lesions after surgical biopsy . On the basis of our experience with CNB, we usually operate parallel to the long axis of the solid part of the tumor. The amount of tissue in this biopsy is not sufficient, and limited CNBs may omit areas of atypia or invasive cancer in the sample provided. Therefore, diagnosing papillary lesions via CNB is chanlenging. Further excision biopsy should be taken to ensure accurate pathologic diagnosis.
The cases included herein were examined via color doppler ultrasound. EPC always demostrates solid and cystic components in ultrasound test. Color ultrasonography often shows round cystic solid masses with clear boundaries with or without calcification. A cystic wall accompanied by papillary nodules is the characteristic sonographic appearance of EPC.
Regardless of whether EPC is associated with DCIS or invasive carcinoma, EPC has a better prognosis than non-EPC breast cancer . A retrospective study of 917 patients with EPC at San Diego Medical Center found no remarkable difference between pure EPC and EPC associated with invasive cancer in terms of long-term survival . A study conducted in China found that at 5 and 10 years, the overall survival rate is 92.2% and 85.6% and the relapse-free rate is 97.2% and 92.0%, respectively . Given that older patients with EPC have more complications than younger patients, the impact on survival rate is inevitable. The relative cumulative survival time of all patients with IPC is 97.3% and 95.6% after 5 and 10 years, respectively .
The surgical treatment of EPC is not controversial, but the optimal surgical method has not been determined yet because of the low incidence of this disease. The three commonly used methods of surgical treatment are modified radical mastectomy, mastectomy combined with sentinel lymph node biopsy (SLNB), and breast-conservation therapy with or without SLNB [10, 14]. In the present case report, two patients received breast-conservation therapy. Breast-conservation therapy is now more widely accepted than in the past, and this therapy does not lead to a substantial increase in tumor recurrence and cancer-related deaths [12, 14]. Some studies on lumpectomy or excisional biopsy without further surgical intervention found that the local recurrence rate of this type of treatment is higher than that of mastectomy, but it has no obvious effects on cancer-related deaths [10, 15] probably because the extent of mass resection does not guarantee a negative margin; nevertheless, this observation also indicates that local treatment has a good therapeutic effect on EPC.
In this study, SLNB was performed in four patients, and ALND was performed in seven patients. None of the patients who underwent SLNB had lymph node metastasis. The patients with positive lymph nodes were those who had EPC associated with invasive carcinoma. These results were consistent with those of previous studies, which reported that positive lymph nodes are mostly related to invasive components . Although lymph node metastasis is well recognized, it has been rarely reported in patients with pure EPC. Lymph node micrometastases were reported in two patients with pure EPC in a previous study . The tumors in both patients were larger than 4 cm in diameter. Nodal involvement tended to be seen with larger tumors. Although the authors noted that occult breast cancer outside of EPC could not be ruled out, diagnosis of pure EPC without axillary lymph node evaluation is still not prudent. Wong et al.  examined sentinel lymph node metastases in patients with different breast cancer histologic subtypes. They found axillary metastases in 7% of patients with papillary cancer and in 8% of patients with DCIS with microinvasion. In view of the current recommendation for the treatment of EPC in accordance with DCIS and because many authors suggest that EPC is a specific form between DCIS and invasive cancer, SLNB is recommended for patients with this disease.
Surgical treatment is the primary therapy for this disease. However, the role of adjuvant therapy is unclear. Pathologic studies suggested that EPC tends to be strongly ER/PR positive and HER2 negative , which is the molecular basis of endocrine therapy. EPC associated with invasive cancer or DCIS are candidates for endocrine therapy of young patients with pure EPC . Endocrine treatment is also recommended for patients who are unfit for surgery and those with recurrent disease . A previous study reported that the incidence of recurrence and the likelihood of death in a third of the patients with EPC who underwent radiotherapy were not affected by this therapy . However, the significance of this result was limited by the limited number of cases and the inconsistent criteria for inclusion of radiotherapy they implemented. A SEER Database study retrospectively enrolled 2568 patients. Among the patients, 34.9% received radiation therapy. The survival rate of patients who received radiation therapy improved compared with that of those who did not receive this therapy. This study recommended radiotherapy for patients who choose to have lumpectomy . The effects of radiation and endocrine therapy on patients with EPC remain unknown. We believe that adjuvant therapy is not an overtreatment, and that additional adjuvant therapy is appropriate for EPC that cannot be adequately excised or is associated with DCIS or invasive cancer components.