Invasive micropapillary carcinoma (IMPC) is a special variant of breast carcinoma initially described by Fisher et al. in 1980, as an invasive papillary cancer with an exfoliative appearance [1]. Siriaunkgul and Tavassoli in 1993 first suggested the term ‘invasive micropapillary carcinoma’ of the breast and Luna-Moré et al. also later described it in 1994 [2][3].

Invasive micropapillary carcinoma is composed of small, hollow or morula-like clusters of cancer cells, devoid of fibrovascular cores and surrounded by clear stromal spaces, characterized by a complete reversal of cell polarity (Figure 1). This is supported by an inside-out immunostaining pattern with MUC1 and EMA, which stain the cytoplasmic membrane oriented towards the stroma.

Moreover, E-cadherin immunoexpression was reported to be altered in IMPC [4]. These changes might be related to the higher frequency of lymphovascular invasion and lymph node metastasis.

Luna-More et al. reported two series of IMPC emphasizing the lymphotropism of this tumor and its frequent spread to axillary lymph nodes [3][5]. Hence, IMPC is considered an aggressive variant of breast carcinoma. However, pure invasive micropapillary growth pattern is rarely observed and most series reported to date are small, describe mixed cases of IMPC with invasive ductal carcinoma, not otherwise specified, and have short follow-up intervals [6].

The aim of this study was to retrospectively analyze the clinicopathologic features and follow-up data of 61 patients diagnosed with pure IMPC, to verify the behavior and outcome of this subtype of breast carcinoma.

Sixty-one cases of pure invasive micropapillary carcinoma of the breast, diagnosed and treated between January 2006 and December 2015 at the Instituto Português de Oncologia do Porto Francisco Gentil EPE, Portugal, were identified from the Department of Pathology files. Pure IMPC was morphologically defined as a tumor with exclusive micropapillary growth pattern. All cases with micropapillary carcinoma mixed with other patterns were excluded. In patients receiving neoadjuvant chemotherapy, the biopsy result prior to chemotherapy was in accordance with surgical specimens.

Patients’ clinical features, follow-up and survival data were obtained from medical charts and registry records. For each patient, gender; age at diagnosis; size, grade and tumor multifocality; the presence of lymphovascular invasion and axillary lymph node metastasis; hormone receptors and HER2 overexpression status, therapeutic interventions (neoadjuvant and adjuvant treatments, type of surgery); disease recurrence; and disease-specific mortality were retrieved.

The tumors were graded using the Nottingham grading system [7]. Multifocality was defined as the existence of at least two foci of invasive tumor, with normal breast parenchyma in between [8]. Immunohistochemical (IHC) analysis was performed for estrogen receptors (ER), progesterone receptors (PR) and HER2 status. Results were considered positive for ER and PR if nuclear immunoreactivity was present in at least 10% of the neoplastic cells. For a case to be considered positive for HER2, strong membranous staining in at least 10% of the tumor cells was required [9] (Figure 2). Equivocal cases (2+) were evaluated by FISH, and cases with HER2 amplification were considered positive. Follow-up ranging from 6–122 months was available in all cases.

Statistical analyses were verified in their categorical variables by chi-square test and in their numerical variables with student’s t-test. Results were considered to be significant at p < 0.05.

Of the 61 patients, 60 were female and 1 was male. The patient’s age at presentation ranged from 32 to 78 years (mean 54.0 years). The initial clinical manifestation was a palpable mass in 33 patients (54%) and a mammographic abnormality in 28 patients (46%). All patients underwent mammography, breast ultrasound and biopsy before surgery or neoadjuvant chemotherapy.

Regarding therapeutic interventions, 14 (23%) received neoadjuvant chemotherapy: one patient received an anthracycline-based therapy alone and 13 were treated with a combination of anthracyclines and taxanes; 25 (41%) were submitted to breast conserving surgery (BCS) and sentinel lymph node biopsy (SLNB); 16 (26%) to total mastectomy and SLNB; 4 (7%) underwent BCS and axillary lymph node dissection (ALND); and 16 (26%) had modified radical mastectomy. Of the 41 patients initially submitted to SLNB, 16 (39%) required a subsequent ALND due to positive lymph node metastasis.

Of all cases, 51 (84%) received radiotherapy; 55 (90%) received adjuvant hormonal therapy; 17 (28%) had trastuzumab; and adjuvant chemotherapy was given to 38 (62%) patients: four patients received an anthracycline-containing therapy alone, 32 were treated with a combination of anthracyclines and taxanes and two patients received a CMF regimen (cyclophosphamide, Methotrexate and 5-fluorouracil combination). Of the total mastectomies performed, in two patients (13%) immediate breast reconstruction was done. In all cases of SLNB, a triple technique with lymphoscintigraphy, radiotracer and blue dye was performed.

The tumor size ranged from 0.3–10 cm (mean 2.7 cm). Twenty-one (34%) patients had multifocal tumors composed of separate neoplastic foci. In 60 cases, according to the Nottingham grading system, 38 (63%) tumors were classified as grade 2; 20 (33%) as grade 3; and 2 (3%) as grade 1. Of 49 patients with lymphatic permeation, 37 (76%) had lymphovascular invasion. Of the 61 surgical specimens, axillary lymph node metastases were identified in 38 (62%) cases. The tumor size, multifocality, histological grade 3 and lymphovascular invasion, correlated positively with lymph node metastasis (p < 0.05 in all cases) (Table 1).

The number of sentinel lymph nodes ranged from one to eight (mean 2.4). Among 41 patients submitted to SLNB, 18 (44%) had lymph node metastasis. In 2 (11%) cases, lymph node involvement corresponded to micrometastasis and in 16 (89%) to macrometastasis. In 7 (39%) cases of positive SLNB, the sentinel lymph node was the only node with carcinoma metastasis. The number of metastatic sentinel lymph nodes varied from one to three (mean 1.2).

The number of axillary lymph nodes dissected ranged from 9–42 (mean 16.3). Among 36 patients submitted to ALND, 29 (81%) had lymph node metastasis. The number of metastatic axillary lymph nodes varied from 1–21 (mean 7.4).

Immunohistochemically, hormone receptor analysis was positive for estrogen in 55 (90%) cases and for progesterone in 48 (79%). Overexpression of HER2 was found in 21 (35%) tumors. HER2 positivity correlated with lymph node metastasis (p < 0.05) but there was no significant difference in axillary node metastasis depending on the status of ER or PR (p = 0.513 and p = 0.949, respectively) (Table 1).

Follow-up was available in all 61 cases, ranging from 6–122 months. The mean follow-up period was 61 months. Recurrence occurred in 6 (10%) patients. The time to recurrence ranged from 5–102 months (mean 59 months). Local recurrence was detected in two (3%) cases and distant organ metastasis was discovered in 4 (7%). Of the 61 patients, 3 (5%) died of disease with widespread metastasis, 58–108 months after the initial diagnosis (mean 81 months). There was a correlation between the frequency of positive nodes and a worse prognosis (58% had positive lymph nodes in the alive with no disease (AND) group versus 100% in the alive with recurrent disease/died of disease (ARD/DOD) group, p < 0.05) (Table 2). A significant difference was similarly found between the nodal tumor burden and the outcome. Patients in the ARD/DOD group had higher mean number of metastatic nodes than patients in the AND group (12.3 versus 3.0, respectively, p < 0.05) (Table 2). Age at diagnosis, tumor size, histological high grade, lymphovascular invasion, multifocality and ER, PR and HER2 status were not predictive of adverse outcome.

Breast carcinomas are a heterogeneous group of tumors with numerous histologic morphologies. Invasive micropapillary carcinoma of the breast is a distinct subtype but also a poorly recognized histologic variant of invasive ductal carcinoma. The incidence of IMPC in all primary breast cancers is estimated to be 2.6–6% [4][6][10][11][12][13]. Pure IMPC is a rare entity, representing approximately 0.9–2% of all breast carcinomas [2][13][14]. However, the incidence of IMPC has been increasing since 2008 mostly due to better recognition of this histologic variant from pathologists [15]. In our series, we identified 61 cases. This is one of the largest published series of carcinomas of the breast with exclusively pure micropapillary component.

Moderate relationship between each histologic subtype and its biologic behavior has been revealed in some studies. Some phenotypes represent more aggressive variants associated with poor short-term treatment results [16][17]. Zekioglu et al. reported that 50% of IMPC between 1 and 2 cm had positive lymph nodes and 83% of >2 cm had lymph node metastases [12]. Moreover, Paterakos et al. have suggested that sentinel lymph node biopsy may not benefit patients with IMPC due to the likelihood of positive lymph nodes [13]. In our study, mean tumor size was 2.7 cm, ranging from 0.3–10 cm, which meant the risk of axillary lymph node metastasis was high.

Some studies have reported that IMPC of the breast is associated with a higher histologic grade and a particular lymphotropic character [3][4][6][12][18][19]. Guo et al. described that high-grade IMPC presented with more positive lymph nodes per case, demonstrating that high histologic grade was correlated with the range of lymph node metastasis [11]. In our study, up to 96% of 60 cases had IMPC with histologic grade 2/3, which is in accordance with the findings of previous series.

Lymphatic vessels invasion is usually a marker of lymph node metastasis. Of 49 patients with lymphatic permeation, we identified 37 cases (76%) with lymphatic vessel invasion. Invasive micropapillary carcinoma is known to have high frequency of lymphatic and axillary lymph node spread. Its incidence has been described as ranging from 72 to 91% [5][6][9][13]. In our study, this incidence was 62% and the burden of metastatic nodal disease was high. Of these cases with positive lymph nodes, 55% had three or more metastatic nodes. However, all cases with sentinel lymph node macrometastasis were radically treated with axillary lymph node dissection, which may have contributed to the overall better outcome of the patients.

Some series have reported estrogen receptors positivity in IMPC of the breast ranging between 25% and 91%, [4][9][11][12][17][20][21] and progesterone receptors positivity between 13% and 82% [4][9][17][20][21]. In our series, estrogen receptors and progesterone receptors expression was detected in 90% and 79%, respectively, which is in agreement with previously reported data. The HER2 overexpression status is not consensual in literature. It has been reported to be in the range of 36–100% [4][11][12][20][21]. In the present study, HER2 was overexpressed in only 35% of the tumors.

Many studies suggested that IMPC appears to be an exception to the general rule that ER positivity is commonly associated to better-differentiated tumors with a favorable outcome. However, one study revealed a poor prognosis in patients with IMPC lacking estrogen receptor expression [15]. Similarly, Luna-Moré et al. have reported that ER positivity was the most powerful predictor of patient survival [22]. More recently, Gokce et al described that ER and PR negativity, as well as HER2 overexpression in all IMPC cases, either pure or mixed forms, significantly correlates with higher local recurrence rates. This study also suggested that ER positivity is associated with longer overall survival in breast cancer patients, regardless of the histologic type of cancer [23]. Thus, the high positivity of estrogen and progesterone receptors and the low rate of HER2 overexpression may explain the favorable outcome observed in our patients.

Table 3 summarizes the comparison between our data and clinicopathological data from previously published series of IMPC of the breast.

Most studies usually report IMPC associated to a poor prognosis. The lymphotropism, aggressive clinical behavior, short disease-free interval and overall survival of IMPC of the breast have been described in the literature [5][6][9][13][18]. However, some authors defend that, despite its propensity for multiple node involvement, the outcome for IMPC patients is similar to that of infiltrating ductal carcinoma, not otherwise specified, with similar axillary lymph node status [6]. In our series, adequate follow-up data were available in all 61 patients with mean follow-up period of 61 months (range 6–122 months). There were only 6 (10%) recurrences in 61 patients with time to recurrence ranging from 5–102 months (mean 59 months). Local recurrence was detected in two (3%) cases and 4 (7%) patients developed distant organ metastasis.

Luna-More et al. described that 20 (37%) patients were dead, within 42 months after the initial diagnosis [22]. In the study of Middleton et al the follow-up in 10 cases showed that 50% of the patients died of disease [18]. Zekioglu et al. reported that 10 (28%) in 36 patients died of disease within nine years [12]. In our study, only three patients (5%) died of disease with widespread metastasis in an average of 81 months of follow-up. Our follow-up data is compared to other series published to date in Table 4.

Yerushalmi et al. [24] and Acevedo et al. [25] have reported a review of literature concerning rare breast tumors indicating its clinical, epidemiological and treatment characteristics and patients’ outcome. Table 5 shows a comparison between our series of pure IMPC and other rare breast tumors regarding clinical features, main histopathological characteristics, axillary lymph node involvement and prognosis.

Our data suggest that multifocal tumors, lymphovascular invasion, lymph node metastasis and the lymphotropic nature of invasive micropapillary carcinoma could explain its aggressive behavior. We found that axillary lymph node metastasis and the degree of axillary node involvement were predicting factors related with poor prognosis. Nevertheless, high levels of estrogen receptors and progesterone receptors and lacking of HER2 overexpression indicate that some cases have been associated with a better prognosis and longer overall survival. The low recurrence and mortality rates observed in our study, comparing with previously published data in literature, may be explained by these biological characteristics and by radical treatment decisions regarding axillary lymph node dissection. Further studies with molecular profiling tests and genomic analysis are needed to verify this correlation and elucidate the prognostic and predictive features of this unique variant of breast carcinoma.

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