Nomogram for predicting preoperative lymph node involvement in patients with invasive micropapillary carcinoma of breast: a SEER population-based study

Invasive micropapillary carcinoma (IMPC) of the breast was first described by Fisher et al. in 1980 [1], and then defined by Siriaunkgul and Tavassoli in1993 [2]. In 2003 World Health Organization (WHO) guidelines for histologic classification of tumors of the breast, IMPC was considered as a rare subtype of invasive breast carcinoma, accounting for approximately 2% to 8% of all breast cancers [3]. Over the past decades, a series of studies have conducted to explore clinical-pathologic characteristics, clinical outcomes, prognostic factors and underlying mechanisms of IMPC.

Fundamental research concerning IMPC, in conjunction with clinical practice, had confirmed that IMPC was linked to high frequency of lymph nodal metastasis (LNM) and lymphovascular invasion (LVI) [4‐8]. Axillary lymph node metastasis is one of the most important prognostic determinants for patients with breast cancer. Accurately preoperative assessment of lymph node involvement has become an essential issue with respect to determining the need for neoadjuvant therapy and aiding in axillary lymph nodes dissection decision making or other alternative treatment options.

However, the relatively low incidence of IMPC makes it robustly difficult to characterize the nature course of this aggressive subset of breast carcinoma. Till now, the factors contributing to the lymphotropic nature of IMPC had not yet been fully understood and need to be further elucidated. Although studies indicated that tumor-infiltrating lymphocytes (TILs) [9], cytokines, membrane proteins (such as stromal cell-derived factor-1 and its receptor CXCR4, caveolin-1) [10‐12], epigenetic regulators (such as miRNAs (let-7b, miR-30c, miR-148a, miR-181a, miR-181b), promoter hypermethylation of the LZTS1 gene) [13, 14] were associated with lymph node metastasis, there was no convenient nomogram facilitating preoperative prediction of the lymph node involvement.

The objective of this retrospective study was to determine the clinicopathologic characteristics correlating with lymphotropic nature of IMPC. Furthermore, a nomogram was constructed by applying the identified factors to predict the lesions likely to be regional lymph node involvement prior to surgery.

IMPC is a rare subtype of breast carcinoma listed by the World Health Organization histologic classification of tumors of the breast in 2003, and presumed to be more aggressive than invasive ductal carcinoma (IDC) [3]. In agreement with the previous IMPC series, the positive rate of ER ranges from 25 to 91%, 13% to 82% of PR, as well as 36% to 100% of HER2 [18‐25]. In our study, the positive rate of ER, PR and HER2 is 89.48%, 77.83% and 19.43% respectively. Besides, the positivity of involving lymph nodes, histological grade, tumor size and stage is similar to that of previous researches.

Although substantial controversy existed, most previous studies had demonstrated that IMPC was associated with advanced and aggressive clinicopathologic features, and the survival outcomes of IMPC was generally accepted to be worse than those of IDC [26‐28]. To make matters worse, the standard treatment strategy of IMPC is unavailable and the rather low frequency of IMPC renders it difficult to directly compare its clinical outcomes and pathologic features to IDC. According to previous investigation, there were some commons and differences between IMPC and IDC in the aspect of contributors to lymph node involvement. Although some controversy existed, hormonal receptor status and tumor size were generally accepted to account for lymph node involvement both in IMPC and IDC, which was consistent with our results. While histological type, lymphovascular invasion (LVI), number of involved sentinel lymph nodes and extranodal extension were assumed to attribute to lymph node involvement of IDC, and their effects on IMPC need to be further research [29‐32]. Thus, currently almost all IMPC patients were treated according to standard IDC treatments [33].

However, previous reports of IMPC had confirmed its distinctly morphological and genetic profiles, thus established IMPC of the breast as a special entity. Most patients with IMPC presented with axillary lymph node metastasis at initial diagnosis, the reported lymphatic and lymph nodal spread ranged from 33 to 95% higher than that of IDC [2, 20, 24, 25]. However, the underlying mechanisms were poorly understood, with rare laboratory studies indicated that some regulatory molecules involving with the lymphotropism. Notably, lymph node metastasis was the most important prognosis predictor of IMPC and IDC. Some uncertain and controversial remained concerning the value of sentinel lymph node biopsy (SLNB) in IMPC setting [7].

Management strategies that avoid axillary invasive procedures are needed for lymph node negative patients. If we can predict the state of the axillary lymph nodes before sentinel lymph node biopsy, individuals who are axillary negative could avoid the unnecessary axillary operation. However, the preoperative clinical and imaging examinations of the axilla is a multifactorial event. Moreover, Paterakos et al. had suggested patients with IMPC may not benefit from SLNB [7]. Therefore, the accurate predict and appropriate dispose of axillary lymph nodes shows important clinical significance.

To some extent, to help guide axillary lymph nodes treatment decisions in this subpopulation, we adopted the large-scale population-based SEER database to develop and validate a convenient nomogram for the preoperative individualized prediction of lymph node metastasis in patients with IMPC. By univariate and multivariate analysis, age at diagnosis, ER status and tumor size were independent factors involving the positivity of axillary lymph nodes, and PR had marginal correlation with that. In consideration of previously identified factors, gender, laterality and ethics, contributed to the involvement of lymph nodes. We took these factors to construct nomogram. The nomogram incorporated preoperatively available clinical and certain pathological parameters and had some utility in clinical practice with good discrimination and calibration. With this nomogram, the patients’ axillary lymph nodes status could be accurately predicted, and the clinical practice, especially the surgery planning could be made precisely and individually.

Although the nomogram showed good accuracy for predicting axillary lymph node metastasis, there were some limitations to the data that must be considered when interpreting the results. First of all, the use of retrospective data introduced the possibility of selection bias. Moreover, the vast majority of patients in the study cohort were white, so the estimation may be less precise for patients of nonwhite race. Additionally, the duration of follow-up time in this study should be longer to meet the accurate prediction as survival of breast cancer patients had dramatically improved with the advanced recognition of the nature of this malignancy. Despite these limitations, the established nomogram showed the bootstrap-corrected C-index of 0.734 indicated a sufficient level of accuracy in which C-indices generally range from 0.6 to 0.8.

In summary, we used population-based cohort to develop a nomogram to preoperatively estimate axillary lymph node metastasis in IMPC patients. This clinically useful tool applying readily available clinicopathologic factors to estimate the propensity of positive lymph node and can further facilitate individualized clinical decision making. Of note, the extrapolation of this conclusion to other database should be cautious and the following points should be taken into account. On the one hand, the definitions or evaluation criteria of ER/PR/HER2 status are not clear in this database, and some differences can exist between time periods as indicated by ASCO/CAP and its updates, thus some discrepancies may exist between training and validation sets. On the other hand, the study cohort includes data related to post neoadjuvant chemotherapy surgical samples, and these cases may have been down staged, thus may result in undervaluation of lymph node involvement. Given that, future larger sample sizes and longer follow-up prospective studies are needed to determine the accuracy of the nomogram model and to precisely extract the subpopulations awarding more intensively treatment and surveillance.

In conclusion, we found that younger age at diagnosis, larger tumor lesions, ER negative status and advanced stage were risk factors associated with lymph nodes involvement in IMPC of the breast. Incorporating the previously reported factors with the currently identified risk factors, we constructed the nomogram for preoperatively predict the axillary lymph nodes status with good discrimination and calibration both in the training and validation cohorts. This accessible nomogram will facilitate to making treatment decision individually. With this nomogram, the individual axillary lymph nodes status could be accurately predicted, thus contributing to treatment decision making. Definitely, larger cohorts and/or prospective studies are warranted to further confirm our results.