A case of invasive micropapillary carcinoma of the breast involving extensive lymph node metastasis

Invasive micropapillary carcinoma (IMPC) was described by Fisher as an invasive papillary cancer with an exfoliative appearance [1]. Pettinato et al. reported an invasive ductal carcinoma resembling ovarian serous carcinoma as a ‘pseudopapillary carcinoma of the breast’ [2]. IMPC was first reported by Siriaunkgul and Tavassoli in 1993 as a rare subtype of epithelial tumor of the breast [3]. The percentage of IMPC in all breast cancers is estimated to be 1.7% to 2.7% [4, 5]. IMPC is characterized by an inside-out growth pattern forming a micropapillary or tubular-alveolar arrangement [3], invasion to the lymphatic or vascular space and a high frequency of lymph node metastasis [4, 6‐8].

IMPC is associated with a poor prognosis. Luna-More et al. reported that of 27 patients with micropapillary carcinoma, all of them had metastasis to axillary lymph nodes. Twelve of these patients were followed-up, six of whom died after an average of 22 months from the initial treatment [4].

We herein report a patient with IMPC who had 59 lymph node metastases, and who has remained free of recurrence for over 7 years.

We herein report a case of IMPC with no recurrence for over 7 years despite the presence of extensive lymph node metastasis. IMPC is a relatively new disease concept, and is a rare subtype of epithelial tumor of the breast. Most cases of IMPC are associated with nodal metastases and a poor prognosis [6].

Metastases to axillary lymph nodes were seen in 71.2% to 100% of IMPC cases [4, 10, 11]. The metastases were typically multiple, with 51% of cases having three or more positive lymph nodes [6], and the average number of metastatic lymph nodes was 10.7 [11]. In addition, lymphatic and vascular invasion has been reported in 33% to 67% of cases [3, 4, 8]. The number of nodal metastases is associated with the prognosis in breast cancer, regardless of the pathological type [12]. Nassar et al. reported that the nodal status and skin involvement were the only parameters that predicted a poor prognosis in IMPC [6]. The prognosis of IMPC is significantly worse than that of invasive ductal carcinoma of the scirrhous type, and the 5-year overall survival rate of IMPC is 50.5%, compared to 85.6% in scirrhous type cases [11]. The 5-year recurrence rate was 62.6% for IMPC and 24.0% for scirrhous type tumors [11]. However, a recent study showed that the disease-specific survival rate in IMPC was similar to that of invasive ductal carcinoma (91.9% versus 88%) [13]. In the report, IMPC with ER negative and lymph node metastasis (≥4) was significantly associated with worse 5-year disease-specific survival and 5-year overall survival [13].

The mechanism underlying the high incidence of lymph node metastasis in IMPC has not been fully elucidated. Ide et al. reported invasive carcinoma of the breast comprising an IMPC component with significantly higher incidence of lymph node metastasis and invasion [14]. The tumors involving an IMPC component, which is positive for hormone receptors and negative for HER2, tend to have a higher incidence of nodal metastasis compared with their counterparts in all invasive carcinomas. In contrast, lesions containing an IMPC component and classified as hormone receptor negative and HER2 positive have a lower incidence of nodal metastasis [14]. CD24 has been reported as another marker for IMPC related to lymph node metastasis. CD24 is an adhesion mucin-like molecule, and its expression could increase the ability of cancer cells to metastasize [15] and invade lymph nodes [16]. In our case, the expression of CD24 was positive in the epithelial lesion of the mammary duct (Figure 3e). Our case was positive for both ER and CD24, but negative for HER2, and the number of lymph nodes with metastasis was 59, agreeing well with the previous descriptions.

We had considered that the prognosis of this patient would be very poor. However, more than 7 years have passed since the patient’s surgery without relapse. We were therefore interested in determining whether there was any particular reason for the comparatively good prognosis of this patient.

We had performed a complete axillary node dissection from level I to III, and added standard chemotherapy (anthracycline and taxane), endocrine therapy and radiotherapy to the left chest wall and supraclavicular and internal thoracic regions in the present patient. Although there was no contribution of axillary lymph node dissection to the improvement of the survival of the breast cancer patients as determined by a meta-analysis [17], it does seem to be important for local control [18]. Radiation therapy followed by mastectomy has been previously reported to contribute to a better survival rate in patients with breast cancer who have more than four positive lymph nodes [19]. These factors may have been associated with the survival of the present patient. As for the endocrine therapy, the age of this patient was around 40 years old, and considering the number of axillary lymph node metastases, ovarian suppressive function using luteinizing hormone-releasing hormone (LH-RH) agonist might be suitable for this case. This patient was premenopausal before starting chemotherapy; however, the chemotherapy-induced amenorrhea occurred during chemotherapy. There were no data that show the superiority of the tamoxifen plus LH-RH agonist compared to tamoxifen alone after chemotherapy for females older than 40 years of age [20]. Therefore, we did not introduce the LH-RH agonist for this patient. Tamoxifen was given for 5 years as the standard method at that time, although the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial showed that the clinical outcome of 10 years’ intake was better than 5 years’ intake in recurrence and mortality, particularly after 10 years [21].

On the other hand, the intrinsic subtype is also considered to be an important prognostic factor [22, 23]. The prognosis of the luminal A type breast cancer is excellent compared with HER2 positive and triple negative breast cancers. In IMPC, ER positivity has also been demonstrated to be related to a good prognosis [24]. In our case, the tumor was positive for the ER, and negative for the PgR and HER2. The Ki-67 labeling index was only 4.3%. From these IHC markers, this case seems to be classified into a ‘luminal A’ type breast cancer according to the St Gallen International Expert Consensus, 2011 [25]; although Prat et al. recently suggested that ‘luminal A’ in immunohistochemical-based definition is hormone receptor positive/HER2 negative/Ki-67 less than 14%, and PgR more than 20% [26]. Negativity of PgR may be related to the worse prognosis; however, a very low Ki-67 labeling index might be related to better prognosis. It is considered that adjuvant chemotherapy is unnecessary for luminal A type breast cancer without lymph metastasis [27]. However, even when the tumor is luminal A type, chemotherapy is considered necessary if the case is of high risk of recurrence [26]. This case was positive for extensive axillary lymph node metastasis, and the age of the patient was young. Therefore, we decided to add the standard adjuvant chemotherapy of anthracycline and taxane. Further study is required for the indication of the chemotherapy adding to the hormone therapy for the luminal type of breast cancer.

Zhao et al. reported that vascular endothelial growth factor (VEGF)-C promotes the proliferation of peritumoral lymphatic vessels, and that lymphatic invasion and lymph node metastasis are frequently induced in IMPC [28]. In lymphatic metastasis, the cancer cells in the primary site migrate in lymphatic vessels and then adhere to the endothelial lining, which leads to extravasation and the formation of secondary tumor sites. MUC-1, referred to as epithelial membrane antigen (EMA), is a heavily glycosylated transmembrane glycoprotein and expressed on the apical surface of a wide variety of epithelial cells. MUC-1 was reported to be very important in adhesion to endothelial lining [29]. The partial reverse cell polarity in breast carcinoma was reported to be associated with the decrease of immunostaining for MUC-1 and lymphatic tumor spread [30]. We did not examine the immunostaining of MUC-1; however, there may be a relationship between extensive lymph node metastasis and VEGF-C and MUC-1.

At present, it can be concluded that the thorough surgical resection, completion of standard chemotherapy and hormone therapy, radiation to the chest wall and the regional lymph node areas, and ‘luminal A’ subtype might have contributed to the good prognosis of this patient; although other so-far unidentified prognostic factors may also exist.

Written informed consent was obtained from the patient for publication of this Case report and any accompanying images.