<p>Micropapillary Breast Carcinoma: From Molecular Pathogenesis to Prognosis</p>

Georgios-Ioannis Verras; Levan Tchabashvili; Francesk Mulita; Ioanna Maria Grypari; Sofia Sourouni; Evangelia Panagodimou; Maria-Ioanna Argentou

doi:10.2147/BCTT.S346301

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Review

Micropapillary Breast Carcinoma: From Molecular Pathogenesis to Prognosis

Authors Verras GI, Tchabashvili L, Mulita F , Grypari IM, Sourouni S, Panagodimou E, Argentou MI

Received 28 October 2021

Accepted for publication 29 January 2022

Published 12 March 2022 Volume 2022:14 Pages 41—61

DOI https://doi.org/10.2147/BCTT.S346301

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Pranela Rameshwar

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Georgios-Ioannis Verras,¹ Levan Tchabashvili,¹ Francesk Mulita,¹ Ioanna Maria Grypari,² Sofia Sourouni,³ Evangelia Panagodimou,⁴ Maria-Ioanna Argentou¹

¹Department of Surgery, Breast Unit, University Hospital of Patras, Patras, Greece; ²Department of Pathology, University Hospital of Patras, Patras, Greece; ³Department of Radiology, University Hospital of Patras, Patras, Greece; ⁴Department of Gynecology, University Hospital of Patras, Patras, Greece

Correspondence: Francesk Mulita, Department of Surgery, Breast Unit, University Hospital of Patras, Patras, Greece, Tel +30 6982785142, Email [email protected]

Abstract: Invasive micropapillary carcinoma (IMPC) of the breast is an infrequent type of breast cancer often discussed for its potency for lymphovascular invasion and difficulty in accurate imaging estimation. Micropapillary carcinomas are noted to be present as larger tumors, of higher histological grade and a notably higher percentage of disease-positive lymph nodes. Hormonal and HER-2 positivity in IMPC is also commoner when compared to other NST carcinomas. IMPC occurs either as a pure form or more often as a component of mixed Non-Specific Type (NST) carcinoma. The latest data suggest that despite having comparable survival rates to other histological subtypes of breast carcinoma, effective surgical treatment often requires extended surgical margins and vigilant preoperative axillary staging due to an increased incidence of lymph node invasion, and locoregional recurrence. Moreover, the presence of micropapillary in situ components within tumors also seems to alter tumor aggression and influence the nodal disease stage. In this review, we present an overview of the current literature of micropapillary carcinoma of the breast from biology to prognosis, focusing on biological differences and treatment.

Keywords: micropapillary, breast cancer, sentinel lymph node biopsy, lymphovascular invasion, mastectomy

Introduction

Invasive micropapillary carcinoma (referred to as IMPC) is a rare, distinct histological subtype of breast carcinoma. First described as an entity by Fisher et al in 1980,¹ it was not until 1993 that the term and classification was introduced by Siriaunkgul et al.² While micropapillary histological architecture is found in 2–8% of all breast cancers, pure micropapillary carcinoma is infrequent and comprises 0.9–2% of breast carcinomas.³ Mean age of diagnosis is 50–60 years, and it is predominantly found in females, with only a few cases for male IMPC reported.^4–10 This review aims to provide an overview of the effect of micropapillary histology on lymph node invasion, LVI, and prognosis. Also, the effect of micropapillary component within non-pure IMPC is discussed, and any recorded differences regarding IMPC treatment compared to other histological subtypes are considered.

There is a distinct pathological morphology of IMPC, consisting of hollow cell clusters with granular or eosinophilic cytoplasm,¹¹ arranged in a pseudopapillary manner, devoid of fibrovascular cores and laid out in an “inside-out” manner, with the luminal cellular surface being the outermost.^1,12–18 This arrangement is best presented when MUC1/EMA staining is used, so much so that “reversed” staining of these markers is considered a hallmark of IMPC, shared only by mucinous histology.^19–21 The distinctive histological features of pure micropapillary carcinoma can be seen in Figure 1A–D, as taken from one of our cases.¹⁶¹

Figure 1 (A–D) In low magnification, through an atrophic mammary gland a neoplastic population is recognized, infiltrating the remaining ducts (A). The cells are organized in clusters, forming small-sized glandular structures and nests, arranged in a micropapillary pattern (B). Occasionally, a small proportion of them acquire a central lumina. Fibrovascular cores are absent. (C) The neoplastic cells have a moderate amount of eosinophilic cytoplasm and small round nuclei with condensed chromatin and intermediate pleomorphism. (D). In another slide of this lesion, a lymphovascular emboli is recognized (D). The morphology is highly suggestive of invasive micropapillary carcinoma, so immunohistochemical markers are performed to establish the diagnosis.

Notes: Reproduced from: Verras GI, Mulita F, Tchabashvili L, et al. A rare case of invasive micropapillary carcinoma of the breast. Menopause Review/Przegląd Menopauzalny. 2022;21(1):1-8. doi:10.5114/pm.2022.113834.¹⁶¹ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/).

IMPC is emerging as an oncological and surgical challenge, due to a plethora of characteristics that constitute this histological pattern, interestingly, both elusive and aggressive. Namely, its tendency to present as a palpable mass, often of increased size and higher grade compared to the invasive ductal carcinoma (IDC), currently the most diagnosed type of breast cancer. Another especially troublesome aspect of IMPC is the comparatively increased incidence of lymphovascular invasion (LVI) characterized by both carcinomatous emboli,^22,23 and clinically positive axillary lymph nodes,²³ which naturally alters the surgical and adjuvant treatment regiments to more aggressive ones, with comparative prognosis still being a point of ongoing debate.^5,24–28

Review Methodology

Current literature search on micropapillary carcinoma was performed using the PubMed, SCOPUS and Cochrane Library databases. Studies in the fields of Medicine, Biology, Molecular Biology and Genetics were included. Each report was screened independently for relevance, and the Mendeley referencing tool was used for duplicate detection. Keywords used included “micropapillary breast carcinoma”, “micropapillary DCIS”, “micropapillary cancer” “invasive micropapillary breast carcinoma”. The selection process (carried out under the latest PRISMA guidelines for reporting²⁹), can be seen in Figure 2. A total of 155 reports were included in the review: 117 original articles, 9 review articles, 24 case reports, 2 meta-analyses, and 3 opinion letters/editorials.

Figure 2 Report selection flowchart.

Lymphovascular Invasion and Lymph Node Involvement

We have collected results from several published studies with variable sample sizes and characteristics. A brief summary of study findings on tumor size, lymph node involvement, and LVI presence can be seen in Table 1. One of the most studied respects of IMPC thus far is the seemingly increased frequency of lymphovascular invasion and lymph node (often clinically evident) involvement.^{13,15,22,30–40} A recent study by Lewis et al,⁴¹ published in 2019, used a sample of 2660 patients diagnosed with pure IMPC, one of the largest case series to date. The study demonstrated confirmed regional lymph node metastasis in 55.2% of the patients at the time of diagnosis, with other researchers such as Gokce et al reporting percentages up to 79.6%.³³ Risk factors associated with nodal involvement in IMPC include tumor size, ER negativity, and advanced age.⁴²

Table 1 Data on Tumor Size, Tumor Grade, Nodal Status and LVI from Included Studies

To put things in perspective, a comparison between IMPC and Invasive Ductal Carcinoma (IDC) is often deemed appropriate, since IDC is undoubtedly the most studied type of breast carcinoma. A comparative study by Hashimi et al¹⁵ showed that only 49.5% of the patients with IDC had any nodal involvement, and in fact N3 stage occurred in only 15.6% of the patients, as opposed to 33% in the IMPC group. Lymphovascular involvement has also been found to be more common among IMPC patients, as shown in a study by Tang et al,¹³ with 14.7% versus only 0.1% in the IDC group, and a staggering 94.7% being reported by Gokce et al.³³ Both points are of great surgical significance, since radiologically, clinically or biopsy-proven positive lymph nodes have been an indication for more extensive surgery and axillary dissection.^13,32 It is indicative that Tang et al reported selection of partial mastectomy in 7.4% of the IDC group, as opposed to 3.0% of the IMPC group.¹³ A previous study by Paterakos et al⁴³ showcased not only lymphovascular involvement in 95% of the patients but also a relation with higher-grade tumors at presentation and higher scores on the mitotic index.

Tumor size at diagnosis has also been a much-discussed issue regarding IMPC. Hao et al compared the percentage of tumors larger than 5cm at the time of diagnosis, reporting 4.3% in IMPC and 3% in IDC.⁴⁴ Ye et al demonstrated that IMPC presented at a higher stage tumor at diagnosis also attributed to a larger size, in a meta-analysis.⁴⁵ It is worth noting that the reported difference in mean tumor size can be attributed to the rapid growth patterns of IMPC, as well as its insidious presentation, leading to larger tumors being diagnosed more often.^38,46 However, more basic research on the underlying molecular biology of IMPC is needed. Another point of concern is the lack of specific guidelines regarding the percentage of micropapillary element required to report a tumor as partially or purely micropapillary. This leads to a lack of systematic sample classification and comparison.^13,32,47,48

Pathology – HR and HER2

Molecular testing has provided an insight on the correlations of the hormonal status and clinical presentation, treatment, and prognosis of IMPC patients. Authors report higher percentages of estrogen receptor (ER) and progesterone receptor (PgR) positive tumors when comparing IMPC with IDC.^{1,3,14,49–52} Collected data on the hormonal status of IMPC tumors, and relevant comparisons from included studies can be found in Table 2. Positive ER staining has been commented upon as positively associated with survival duration in a large series of IMPC patients.^49,52,53 A large study by Cui et al¹⁴ reported 88% ER positivity and 64% PgR positivity when studying IMPC specimens. A study conducted by Lewis et al, including 865 cases, has reported that the IMPC tumors are characterized as Luminal A in 75.3% of the instances, Luminal B in 14.8%, HER2-enriched in 4.7%, and Triple Negative in 5.2%.⁴¹ However, most studies have found that micropapillary carcinomas tend to be in the Luminal B category when genomic sequencing is used instead of staining alone.^54–56 While the incidence of the triple-negative classification seems to be lower in IMPC, it is associated with higher-grade tumors, higher disease stage at diagnosis, and an increase in total mastectomies performed.^{7,15,44,57–59}

Table 2 Data on Hormone Receptor and HER-2 Status of IMPC Patients from Included Studies

Overall, in terms of surveillance, hormonal positivity and HER2-positive staining are reported to be higher in IMPC than IBC.^55,60 However, no difference in survival rates is reported between HER2-positive and HER2-negative groups. According to the authors,^{14,28,41,49,61,62} this is largely attributed to the latest HER2 targeting biological therapeutic regimens added to systemic therapy. A noteworthy study, run by Perron et al, provided insight into the expression of HER2 in IMPC. In particular, it is suggested that due to the tumor’s peculiar histological arrays, the interpretation of HER2 staining in IMPC should be updated from the previously known ASCO/CAP recommendations.⁶² The authors mention that HER2 expression in IMPC by immunohistochemistry (IHC) ranges from 12.5% to 95%, possibly a result of scoring variability before the 2007/2013 guidelines.⁵⁴ Furthermore, they analysed 1684 IMPC cases by IHC alone and found 11.6% to be positive (3+) and 29.4% to be equivocal (2+). Analysis of further 1272 IMPC cases by in situ hybridization (ISH) alone showed 20.4% of the cases were HER2-amplified and 7.4% were equivocal. Upon dual analysis of 411 cases by both IHC and ISH, 4.4% of the cases were found to be positive (3+) by IHC and of these, 83.3% were HER2-amplified. Interestingly, they showed that 43% of IMPCs with a HER2 staining score of 1+ were found to be HER2-amplified by ISH.⁵⁴ They also claim that the morphology of the tumor seems to exclude the luminal side of the cells from staining. Therefore, they suggest lowering the “1+” categorization to tumor staining described as “weak to moderate but incomplete”. In fact, further testing of equivocal staining seemed to yield HER2 positivity in 35% of the specimens, indicating that a more inclusive definition would benefit many IMPC patients by encompassing them in HER2 targeted treatment, a finding also reported by more research groups.⁵⁴

Lymphovascular Tropism

With the emergence of readily available methods of genomic and molecular analysis, a pathogenetic mechanism to explain the increased incidence of vascular, lymphovascular, and lymph node involvement has been proposed. As discussed earlier, IMPC cases appear with higher percentages of nodal involvement¹⁵ and lymphovascular involvement was detected in 14.7% to as high as 94.7% of the IMPC cases, compared to IDC cases.^13,33

Recent studies have shown an overexpression of metalloproteinases and adherence molecules,^{6,15,46,50,63–65} as well as several cytotropic molecules, namely TNF-α, TNFreceptor II, E-cadherin, kindlin-2, integrinβ1, plakoglobin and β-catenin overexpression, occurring within pure IMPC cancer cells.^{50,51,66–70} Interleukin 1-β is associated with high microvascular density in IMPC tumors, as well as nodal metastases.⁷¹ N-cadherin, an adhesive protein, was also upregulated in IMPC cells when compared to non-IMPC cells.⁷² Well-known tumor chemotaxis factors SDF-1/CXCR4 also facilitate nodal invasion in IMPC.⁷³ The findings mentioned above are indicative of the tumor cell’s ability to separate from neighboring cells, and invade the vascular and lymphatic systems, exhibiting a certain tropism towards lymphatic metastasis.^15,50,74,75

The upregulation of glucose transporters has also been observed in a small number of patients, with significant differences in genomic expression when compared to non-IMPC tumors.⁷⁶ The authors hypothesized that the apparent increase in GLUT-1 transporters with the simultaneous expression of hypoxia-inducible transcription factors is another process that enables IMPC cells to adapt, survive, and metastasize more than their non-IMPC counterparts.⁷⁷

Another molecular-based study target that can give additional insights in the lymphovascular tropism of the tumors has been the observed predominance of CD44-positive and CD24-negative phenotype on IMPC cells. Alterations in the expression of these two molecules are partially responsible for certain stem cell properties that tumor cells exhibit (self-renewal, survivability, proliferation, lack of apoptosis). Among them, CD24 loss was associated with tumor spread and invasion.^78,79 Indeed, a study by Li et al demonstrated a higher percentile presence of such cells, in comparison to IDC tumors, namely 48.5% versus 31.9%.⁷⁸ CD44 loss was also found to be significantly higher in IMPC tumors when compared to NST tumors and was also associated with lymph node metastasis in IMPC patients as well.^69,80 CD146 expression is also positively correlated with high microvascular density and was found to be more significant in IMPC rather than NST tumors.⁸¹ These findings serve as a plausible explanation of the IMPC invasive lymphotropic properties. A recent study by Kramer et al showed that IMPC tumor cells were in a highly epithelial state and did not use the EMT pathway, but rather form cell clusters during invasion and metastasis.⁸²

The utilization of deep mRNA sequencing has also demonstrated at least 45 different miRNAs thought to be involved in IMPC development,⁸³ and karyotype studies have also shown certain reproducible aberrations, such as gain of chromosomes 1q,8q,17q,20q and loss of chromosomes 1p,8p,13q,16q,20q, involved in the depolarization of IMPC cells.^3,84–86 Among them, alterations in chromosome 8 seem to affect known malignancy-associated genes and could be one of the causes for the tumor’s invasive behavior.⁸⁷ Other common genetic variations encountered specifically in IMPC include ESR1, KDR, ARID1B, ATR genes.^88,89 Loss of LTZS1 expression is associated with IMPC development and nodal infiltration.⁹⁰

The Role of Micropapillary Element or Micropapillary DCIS

A much-discussed topic in the study of IMPC is the significance and impact of micropapillary DCIS, or micropapillary foci, encountered within breast cancer tumors. Presence of micropapillary DCIS was associated with significantly larger tumor size and higher grade,^91,92 as well as lymphatic invasion with nodal metastases.^93,94 Recurrence rates, when micropapillary DCIS alone is present, also seem to be elevated,⁹¹ with a study reporting 29% versus 8% when compared to patients with non-micropapillary DCIS histology.⁹¹ All this is thought to be the result of higher histological grade tumors having a distinctly aggressive comedo necrosis⁹⁶ and micro-invasion profile, thus explaining the local and locoregional recurrence of disease despite treatment.^43,91,97 Another characteristic of micropapillary DCIS is the presentation as a large, multifocal, and often under-diagnosed breast tumor, as reported by a study from MD Anderson Cancer Centre.⁹⁸ Literature indicates unfavorable recurrence profiles whenever such DCIS histology was present. In fact, even incomplete “inside-out” histological patterns, even without being characterized as micropapillary, are associated with LVI, nodal invasion, poorer survival, and larger tumor size when found in NST carcinomas.^99,100

Micropapillary DCIS within NST tumors also differs when compared to non-otherwise specified DCIS within NST tumors. Higher incidence of vascular invasion, increased stage at diagnosis, high recurrence rates and increased lymph node infiltration are all well documented.¹⁰¹

A relatively common histological combination is that of mucinous breast carcinoma with micropapillary DCIS.^102–107 Approximately 20% of all mucinous carcinomas are classified as “Mucinous Carcinoma with Micropapillary Features (MPMC)”.^20,108,109 MPMC demonstrates higher percentages of lymphovascular invasion and lymph node invasion than mucinous breast carcinoma, likely explained by the higher instances of metastasis-associated mutations in genes associated with the PI3K-Akt, mTOR, AMPK signaling pathways,^20,110 such as in GATA3 (20%), TP53 (20%) and SF3B1 (20%).²⁰ Comparison with pure mucinous carcinomas has demonstrated lower frequency of HER2-positivity (20% for IMPC versus none of the mucinous carcinoma of breast¹¹¹) and PR-negativity, lower nuclear grade and overall more aggressive biological behavior,^111–115 as well as worse prognosis.^105–107 Micropapillary mucinous carcinoma also shows evidence of being from the same lineage as pure IMPC, a finding that would explain their much-observed combination.¹¹⁶

IMPC Imaging

The mammographic appearance of IMPC is thought to be often nonspecific, and most lesions are an irregular, spiculated high-density mass, with scattered microcalcification in about 66.7% of the cases, often resembling IDC or DCIS.^117–121 Micropapillary DCIS imaging in simple mammography often has a segmental or scattered microcalcification pattern.^98,122,123 In fact, microcalcification patterns in mammography have been associated with worse prognosis in IMPC.¹²⁴ Mammographic evaluation has a clear trend to underestimate the true disease size when IMPC is concerned.^97,98,122 False-negative rates in mammography evaluation have been reported as high as 12% for IMPC patients,¹²⁵ whereas patients with Invasive Lobular Carcinoma have false-negative rates higher than 14%,¹²⁶ and up to 19%.¹²⁷

Figure 3 (A) Preoperative and pre-treatment MRI image of IMPC. White arrow indicates the central mass of the lesion along with mass and non-mass enhancement. (B) MRI findings post-PST consistent with complete pathologic response. White arrow indicates local scarring in the mass area after PST. Although imaging indicated complete pathological response, residual disease was still found in the scarring area when examined under a microscope, and complete mastectomy was deemed appropriate.

When utilizing the ultrasound (U/S), the lesions are mainly hypoechoic, and it has been reported that the use of U/S often misses the true depth of the IMPC tumor invasion.^26,119 A single hypoechoic lesion with irregular margins is the most encountered finding in U/S evaluation.^{117,122–129} In one study, micropapillary DCIS evaluation with U/S yielded a false-negative rate of 47%, and in those that were identified, the true extent was underestimated in 81% of the cases.¹²² Addition of shear wave elastography has been reported as helpful in better estimating IMPC tumors.^130,131 Axillary evaluation of IMPC patients often yields suspicious lymph nodes with cortical thickening, and authors report positivity rates of suspicious nodes in 69% of the patients.¹²⁸

MRI study is the most helpful at IMPC distinction, with the lesions presenting as spiculated, irregular masses with characteristic rapid enhancement and delayed washout patterns.^118,132 Patterns of single or multiple irregular mass with rapid washout waveforms are the most well-recognized patterns of IMPC presentation in MRI.^125,128 Mass and non-mass enhancement have also been previously described, while not as frequently as a solitary enhancing mass presentation.^91,119,122 The probability of a non-mass enhancement of the lesion being found in MRI ranges from 16.7% to 38.9%.¹³³ The non-mass enhancement is attributed to local lymphovascular infiltration, a finding attributed to the lesion pathology. In literature, non-mass enhancement of IMPC has also been attributed to the presence of DCIS within the lesion, an observation that needs larger case series for validation.^128,133 Multifocal IMPC lesions are also better diagnosed and more accurately staged with MRI, compared to any other modality.^{43,91,98,122,125,128,133} While MRI may be the best imaging modality for IMPC, there is still a percentage of lesions that will be missed, especially diffuse multifocal lesions with extensive DCIS or residual disease after PST.^117,134 An example of pre- and post-PST MRI imaging of micropapillary carcinoma can be seen in Figure 3.

PET-CT scans are also utilized, showing FDG (fluorodeoxyglucose) uptake of the primary tumor, with high (FDG) uptake being a prognostic factor for worse outcomes regarding breast cancer.^119,135 As discussed earlier, IMPCs are characterized as Luminal A in 75.3% of the cases.⁴¹ Recently, Akin et al investigated how accurately PET-CT scan and MRI could detect breast cancer subtypes in 55 tumors.¹³⁶ They found that although the SUVmax value from PET-CT scan was high for the Luminal A subtype, it was lower than the SUVmax value of the other breast cancer subtypes. PET-CT scan was better at identifying the molecular subtype of the breast cancer; however, MRI was superior at determining the tumor size, thus better for staging.

Treatment Options

Treatment of IMPC remains controversial, especially among breast surgeons. To begin with, there is a lack of guidelines regarding the impact of micropapillary element being present in several histological subtypes, as well as for the pure IMPC subtype itself. The well-known potency for lymphatic spread did influence surgical approaches in the past, since many authors report high percentages of axillary lymph node dissection (ALND) during surgery^32,47 without any current evidence showing a need for more radical axillary approaches.¹³⁷ While surgeons must strive for breast conserving therapy where possible,^137,138 the majority of IMPC case reports were treated with modified radical mastectomy, as shown in a 2017 study by Yu et al, with 99% of the IMPC patients undergoing modified radical, or total mastectomy. Until recently, authors suggested a more radical approach towards locoregional management, with some adding larger surgical margin recommendations,²⁸ and even locoregional radiation therapy to avoid extranodal recurrence. Indications for adjuvant and neoadjuvant treatment administration do not seem to be altered in IMPC, except for more cases being HER2 positive, and therefore candidates for biologically targeted treatment.⁶² Mercogliano et al demonstrated a possible resistance to HER2-directed therapy in IMPC tumors by investigating the mucin 4 (MUC4) molecule.⁶¹ Their study showed that MUC4 was overexpressed in IMPC tumors and had the ability to conceal the target epitope of trastuzumab, leading to treatment resistance and lower survival for IMPC patients (hazard ratio = 2.6, P = 0.0340). It is recommended that physicians have a high degree of suspicion, to avoid underdiagnosis, and to be vigilant in the axillary evaluation of such patients.^44,139 To the best of our knowledge, the effect of adjuvant chemotherapy on survival or complete pathological response (CPR), or the role of the endocrine reaction in IMPCs has not been studied.

Newer developments in diagnostic markers and cancer therapy are currently being investigated for use in IMPC. One study evaluated the molecular profile of IMPC for potential response in immune-checkpoint inhibition treatments but showcased unfavorable status of the target ligands.¹⁴⁰

Regarding the post-operative radiotherapy treatments (PORT), an informative study was published by Wu et al, studying 881 IMPC patients. The study uses a multivariate analysis of several patient factors and determined that both the surgical approach (mastectomy or breast conserving surgery) and the election to undergo PORT or not, did not alter the 5-year BCSS (breast cancer–specific survival) or OS (overall survival), which remained favorable for patients with IMPC. These results are also in line with older, smaller studies.¹⁴¹

Prognosis of IMPC

The comparative prognosis of IMPC has been a long-standing debate among scientists. A summary of studies evaluating the prognosis of IMPC can be seen in Table 3. However, recent studies and meta-analyses seem to suggest that there is no tangible difference in disease-free survival, recurrence-free survival, or overall prognosis.^{23,58,142–145} One such meta-analysis, that utilizes a great number of previous prognostic comparative studies, is the one by Hao et al.⁴⁴ After a meticulous process of balancing key characteristics of the two populations (age, lymph nodes, grade, stage), the analysis demonstrated no statistically significant difference in overall survival and disease-free survival between patients with IMPC and those with IDC. Additionally, they demonstrated that the micropapillary subtype did not carry any gravity as an independent prognostic factor. Favorable prognostic factors for patients with IMPC include receipt of radiation treatment, estrogen receptor positivity, age <65 years and <4 positive lymph nodes.^147,148 Lymphovascular invasion and negative ER status are among the most recognized negative predictors for IMPC.⁵³ Lymphatic vessel density and VEGF-C expression are associated with lymph node infiltration in IMPC.¹⁴⁹ It is worth mentioning that there are several older or with fewer patients comparative analyses,^{32,37,47,95,150–153} such as the one of Wu et al,⁷ or Yu et al²⁸ that demonstrated worse recurrence-free survival, despite being in accordance with similar disease-free survival rates. This was attributed to a higher incidence of lymph node recurrence in the IMPC group of patients.^7,28 Therefore, a question arose as to whether locoregional recurrence truly influenced the long-term overall survival of patients with IMPC. A study by Chen et al, also notes that it might be useful to compare overall survival in patient groups with similar nodal involvement and it demonstrated better breast cancer–specific survival as well as overall survival rates in the IMPC group of patients when compared to IDC patients.^15,23,142 A recently published nomogram predicting the individual risk for locoregional recurrence, specific for micropapillary breast carcinoma, could be of use in risk-stratifying these patients.¹⁵⁴

Table 3 Data on Local Recurrence, Distant Metastasis, and Survival from the Included Studies

Several prognostic indicators are being studied for IMPC. In a recent study, sialyl Lewis^X (sLex) and mucin 1 (MUC1) expression in tissue specimens were found to be significantly different in IMPC cells when compared to NOS carcinoma cells. Furthermore, high levels of sLex expression, when combined with low levels of MUC1 expression, were also found to be a reliable prognostic factor for IMPC, making these two molecules potential specialized markers or therapeutic targets.^155,156 Absence of caveolin-1 expression in stromal fibroblasts of IMPC is a candidate predictor for advanced axillary staging at diagnosis, as well as shortened progression-free survival.¹⁵⁷ GATA3 is another IMPC-specific marker that seems to be expressed in tumors with better prognosis lacking however large confirmatory studies^121,158 P63 expression was also found to be significantly associated with high Ki-67 index in IMPC cases, indicating another possible aggression marker that needs further study.¹⁵⁹ Loss of ARID1A function was also noted to negatively correlate with disease-free survival (DFS) and 10-year overall survival (OS), especially in luminal B IMPC tumors.¹⁶⁰

Conclusion

In the past few years, the previously unknown effect of the presence of micropapillary histological elements or pure IMPC on breast cancer has been explored. Due to its rarity as an entity, and the resulting difficulty in patient accumulation, there are not many studies that have produced tangible and statistically significant conclusions regarding all aspects of IMPC.

Micropapillary carcinomas of the breast have a well-recognized lymphovascular tropism that leads to more patients presenting with clinically disease-positive lymph nodes. In fact, the underlying biology of micropapillary histological patterns is detrimental in the lymphatic tropism of tumors, even when they present as a percentage of the malignancy’s histology or as foci of micropapillary DCIS. Basic research has revealed that there is a multitude of adherence molecules and chemotactic factors involved in the histology’s tendency for lymphatic invasion. Future, translational research, perspectives of such findings could include the utilization of said molecules as treatment targets or prognostic predictors for IMPC patients.

This review highlights the importance of approaching a breast cancer patient in accordance with the personalized medicine principles and making prompt therapeutic decisions in an individualized fashion based on the current literature and taking into consideration all aspects of a patient’s ailment. While no specific guidelines exist yet, it is made clear that micropapillary histology has an effect on treatment choices, and breast surgeons should be aware of the possible wider margin excision needed for this type of breast cancer. Further research is needed to confirm the role of chemotherapy and hormone agents, as well as resistance to trastuzumab. Imaging identification of micropapillary breast cancer is often underestimated regarding tumor invasion and size, and among the available options, breast MRI is the best one to perform. Recent research suggests that the – once thought – worse survival prognosis does not hold true; however, the alarming frequency of lymphovascular involvement and disease recurrence makes a more radical surgical approach more appropriate, for both the axillary and breast tumor burden.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure

The authors report no conflicts of interest for this work.

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