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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 12/2020

01-11-2020 | Metastasis | Breast Oncology

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

Authors: S. David Nathanson, MD, Shravan Leonard-Murali, MD, Charlotte Burmeister, MS, Laura Susick, PhD, Patricia Baker, BHCS

Published in: Annals of Surgical Oncology | Issue 12/2020

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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

Literature
1.
2.
Fisher B. Laboratory and clinical research in breast cancer-a personal adventure: the David A. Karnovsky memorial lecture. Cancer Res. 1980;40(11):3863–74.
3.
Folkman J. Proceedings: tumor angiogenesis factor. Cancer Res. 1974;34(8):2109–13.PubMed
4.
Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–8.PubMed
5.
Nathanson SD, Miller CG, Paxton JH. The role of lymphangiogenesis in regional lymph node metastasis: animal models. In: Leong SPL, editor. From local invasion to metastatic cancer: involvement of different sites through the lymphovascular system. New York: Humana Press; 2009. p. 211–226.
6.
Mohammed RAA, Martin SG, Gill MS, Green AR, Paish EC, Ellis IO. Improved methods of detection of lymphovascular invasion demonstrate that it is the predominant method of vascular invasion in breast cancer and has important clinical consequences. Am J Surg Pathol. 2007;31(12):1825–33.PubMed
7.
Schoppmann SF, Bayer G, Aumayr K, et al. Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Ann Surg. 2004;240(2):306–12.PubMedPubMedCentral
8.
Pereira ER, Kedrin D, Seano G, et al. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science. 2018;359(6382):1403–7.PubMedPubMedCentral
9.
Brown M, Assen FP, Leithner A, et al. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science. 2018;359(6382):1408–11.PubMed
10.
Nathanson SD. Preclinical models of regional lymph node tumor metastasis. In: Leong SPL, editor. Cancer metastasis and the lymphovascular system: basis for rational therapy. New York: Springer; 2007. p. 129–156.
11.
Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569–75.PubMedPubMedCentral
12.
Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567–75.PubMed
13.
Nathanson SD, Kwon D, Kapke A, Alford SH, Chitale D. The role of lymph node metastasis in the systemic dissemination of breast cancer. Ann Surg Oncol. 2009;16(12):3396–405.PubMed
14.
Chagpar A, Middleton LP, Sahin AA, et al. Clinical outcome of patients with lymph node-negative breast carcinoma who have sentinel lymph node micrometastases detected by immunohistochemistry. Cancer. 2005;103(8):1581–6.PubMed
15.
Yates LR, Gerstung M, Knappskog S, et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med. 2015;21(7):751–9.PubMedPubMedCentral
16.
Fisher E, Gregorio RM, Fisher B, Redmond C, Vellios F, Sommers SC. The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4). Cancer. 1975;36(1):1–85.PubMed
17.
Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle. 2006;5(8):812–7.PubMedPubMedCentral
18.
Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol. 2002;12(2):89–96.PubMed
19.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.PubMed
20.
Virchow R, Chance F, Goodsir J, Osborn S. Cellular pathology as based upon physiological and pathological histology; twenty lectures delivered in the Pathological Institute of Berlin during the months of February, March and April, 1858. London: John Churchill; 1860.
21.
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol. 1995;13(5):1144–51.PubMed
22.
Liotta LA, Kleinerman J, Saidel GM. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974;34(5):997–1004.PubMed
23.
Nathanson SD. Insights into the mechanisms of lymph node metastasis. Cancer. 2003;98(2):413–23.PubMed
24.
Yoshizawa M, Shingaki S, Nakajima T, Saku T. Histopathological study of lymphatic invasion in squamous carcinoma (O-1 N) with high potential of lymph node metastasis. Clin Exp Metastasis. 1994;12(6):347–56.PubMed
25.
Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F, et al. The orderly progression of melanoma nodal metastases. Ann Surg. 1994;220:759–67.PubMedPubMedCentral
26.
Hoshida T, Isaka N, Hagendoorn J, et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res. 2006;66(16):8065–75.PubMed
27.
Nathanson SD, Zarbo RJ, Wachna DL, Spence CA, Andrzejewski TA, Abrams J. Microvessels that predict axillary lymph node metastases in patients with breast cancer. Arch Surg. 2000;135(5):586–93.PubMed
28.
Hirakawa S, Kodama S, Kunstfield R, Kajiya K, Brown LF, Detmar M. VEGF—a induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med. 2005;201(7):1089–99.PubMedPubMedCentral
29.
He Y, Rajantie I, Pajusola K, et al. Vascular endothelial growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 2005;65(11):4739–46.PubMed
30.
Greenlee JD, King MR. Engineered fluidic systems to understand lymphatic cancer metastasis. Biomicrofluidics. 2020;14(1):011502.PubMedPubMedCentral
31.
Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell. 2002;1(3):219–27.PubMed
32.
Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev. 1990;70(4):987–1028.PubMed
33.
Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987;47(12):3038–51.
34.
Avery M, Nathanson SD, Hetzel FW. Lymph flow from murine footpad tumors before and after sublethal hyperthermia. Radiat Res. 1992;132(1):50–3.PubMed
35.
Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK. Pathology: cancer cells compress intratumor vessels. Nature. 2004;427(6976):695.PubMed
36.
Bockhorn M, Jain RK, Munn LL. Active versus passive mechanisms in metastasis: Do cancer cells crawl into vessels, or are they pushed? Lancet Oncol. 2007;8(5):444–8.PubMedPubMedCentral
37.
Willis RA. Pathology of tumours, 3rd edn. London: Butterworth; 1960. p. 167–172.
38.
Pressman JJ, Simon MB. Experimental evidence of direct communications between lymph nodes and veins. Surg Gynecol Obstet. 1961;113:537–41.PubMed
39.
Borodin YI, Tomchek GV. Functional relationships between blood vessels and lymphatic sinuses normally and during experimental disturbances of blood and lymph circulation. Fed Proc Transl Suppl. 1966;25(5):778–80.PubMed
40.
Bron KM, Baum S, Abrams HL. Oil embolism in lymphangiography. Incidence, manifestations, and mechanisms. Radiology. 1963;80(2):194–202.PubMed
41.
Hellman S. Karnovsky memorial lecture. Natural history of small breast cancers. J Clin Oncol. 1994;12(10):2229–34.
Metadata
Title
Clinicopathological Evaluation of the Potential Anatomic Pathways of Systemic Metastasis from Primary Breast Cancer Suggests an Orderly Spread Through the Regional Lymph Nodes
Authors
S. David Nathanson, MD
Shravan Leonard-Murali, MD
Charlotte Burmeister, MS
Laura Susick, PhD
Patricia Baker, BHCS
Publication date
01-11-2020
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 12/2020
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-08904-w

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