Clinicopathological Evaluation of the Potential Anatomic Pathways of Systemic Metastasis from Primary Breast Cancer Suggests an Orderly Spread Through the Regional Lymph Nodes

Abstract

Background Two conflicting hypotheses as to how breast cancer (BC) accesses the systemic circulation dominated the 20th century and affected surgical treatment. We hypothesized that tumor lymphovascular invasion (LVI) at the primary tumor site favors lymphatic and not blood vessel, capillaries, and systemic metastases (Smets) are dependent upon regional lymph node (RLN) mets. Methods Data from BC patients undergoing RLN biopsy was professionally abstracted and maintained in a prospective, precisely managed, single-institution database. Associations of RLN, LVI, and Smets were estimated by univariate and multivariate backward logistic regression models and patient-affiliated demographic, clinicopathologic, treatment type, and molecular marker data. Results Of 3329 patients, followed 1–22 years (mean 7.8), 463 of 3329 (13.9%) showed LVI, 742 of 3329 (22.3%) had RLN mets, and 262 of 3329 (7.9%) had Smets. Smets occurred in 52 of 252 (21% with LVI+/RLN+); 116 of 2301 (5% with LVI−/RLN−); 65 of 465 (14% with LVI−/RLN+); and 17 of 207 (8% with LVI+/RLN−), p = 0.021 for association between LVI and Smets for RLN+ patients but not for RLN− patients ( p = 0.051). Positive RLN, larger tumor size, and higher grade (all p < 0.001) were predictive of Smets by the multivariable model, whereas positive LVI was not. Conclusions LVI predicts RLN mets in BC. RLN is critical to Smets from BC, whereas LVI on its own is not. Smets occur significantly more commonly when both LVI and RLN mets occur together. LVI is, thus, likely to be primarily lymphatic invasion, and rarely, blood vessel invasion, supporting the Halsted paradigm. LVI and RLN together predict clinical outcome better than either alone. Graphic Abstract

The Prognostic Significance of Anisomycin-Activated Phospho-c-Jun NH2-Terminal Kinase (p-JNK) in Predicting Breast Cancer Patients’ Survival Time

“…Meanwhile, as results of univariate and multivariate Cox regression analyses suggested, occupation, US-LNM, US-BIRADS, clinical T stage, clinical N stage, clinical TNM stage, tumor size, pathological T stage, postoperative endocrine therapy, postoperative targeted therapy, and lymph vessel invasion were significant prognostic factors in predicting patients’ improved DFS and OS. Lymph vessel invasion is thought to play an important role in tumor metastasis, and acts as the modulation of antitumor immune responses ( David Nathanson et al, 2020 ; Testa et al, 2020 ; Wang et al, 2020 ). The tumor angiogenesis and its indicative vascular density are closely related to the prognosis of breast cancer ( Huang et al, 2020 ; Koch et al, 2020 ).…”

The Multifaceted Effects of Breast Cancer on Tumor-Draining Lymph Nodes

“…However, patients with BC with positive regional LNs have higher rates of systemic metastasis compared with those with node-negative disease. 98 Furthermore, patients with BC with LN micrometastasis (<2 mm) have a reduced incidence of distant metastasis compared with patients with macrometastasis. 99 Several studies found that patients with extracapsular extension, the growth of cancer cells outside the LN capsule, have poor prognosis 100 and thus patients with macroscopic extranodal disease may benefit from axillary LN dissection to prevent locoregional recurrence.…”

Histologic Discordance Between Primary Tumor and Nodal Metastasis in Breast Cancer: Solving a Clinical Conundrum in the Era of Genomics

“…NGS can reveal novel insights regarding tumor heterogeneity, clonal evolution, and the metastatic process [4]. Primary and locally relapsed breast tumors usually have similar genomic profiles and morphology, suggesting that the metastasis originated from the primary tumor [5]; however, differences in biomarker expression [6], degree of lymphovascular invasion [7], and progression of histologic grade [8] can occur between the primary tumor and recurrent or distant metastatic breast tumors.…”