Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics

Padera, Timothy P.; Kadambi, Ananth; Tomaso, Emmanuelle di; Carreira, Carla Mouta; Brown, Edward B.; Boucher, Yves; Choi, Noah C.; Mathisen, Douglas J.; Wain, John C.; Mark, Eugene J.; Munn, Lance L.; Jain, Rakesh K.

doi:10.1126/science.1071420

Cited by 876 publications

(771 citation statements)

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“…Studies that examined the physical dynamics of malignant proliferating tumors have shown that the intratumoral pressure is higher than that in the peritumoral area, which could cause collapse of the intratumoral lymph vessels. 28 This could then hamper invasion of lymph vessels by the invasive tumor cells. We and others had shown that intratumoral lymphatics with tumor emboli do exist; however, most of the LI lesions are located in peritumoral vessels.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker

et al. 2014

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The poor prognostic significance of lymphatic invasion (LI) in breast carcinoma (BC) as a whole and in lymph node (LN)-negative patients in particular has been recognized in several studies; however, its prognostic role in LN-positive patients is still questionable. Aim of the current study was to assess prognostic role of LI in LN-positive BC specimens. Sections from non-selected 557 LN-positive BC specimens were stained with antibody to podoplanin/D2-40. LI was identified and correlated with clinicopathological features and patients' outcome. Twenty-year overall survival (OS), disease-free interval (DFI), and development of distant metastasis (DM) or recurrence were known for all patients. LI was detected in 262/557 (47%) of specimens ranging from 1 to 350 lesion per tumor section. Its presence was associated with higher grade tumors (Po0.0001), negative hormonal receptors (Po0.0001), high HER-2 expression (P ¼ 0.006), and with increased number of positive LNs (P ¼ 0.019). In the whole LN-positive BC, presence of LI was a poor prognostic factor for OS, DFI, and development of DM both in univariate and in multivariate analysis. In further stratification of patients, LI was associated with poorer prognosis in patients with single positive LN and not in patients with 41 positive LN. In T1N1 stage, LI was highly associated with poor OS (P ¼ 0.002), DFI (Po0.0001), and DM (Po0.0001). In T2N1 patients, LI was associated only with poorer DFI (P ¼ 0.037) but not with death or DM. In the two former patient groups, LI lost significance in multivariate analysis. In conclusion, LI is a poor prognostic factor in LN-positive BC particularly for patients having single positive LN. LI therefore would add further prognostic significance when considered in treatment in those patients. We recommend incorporation of LI in breast carcinoma staging and in prognostic indices.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker

et al. 2014

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“…Initial studies investigated lymphatics in xenografted sarcomas and reported that vessels were only found in peritumoural areas and absent from the intratumoural compartment [9,10]. With advances in imaging techniques, intratumoural lymphatics were detected and found to be functional, with tumour cells detected flowing within the vessels [11].…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies on xenografted tumours reported that lymphatics were only present in peritumoural areas and absent from the intratumoural compartment [9,10]. Such studies also suggested that these vessels were the main route for metastasis and that lymphangiogenesis did not seem to play a role in this process.…”

Section: Introduction and Aimsmentioning

confidence: 99%

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

Mohammed

Ellis

Elsheikh

et al. 2008

Breast Cancer Res Treat

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Controversy exists regarding the topography of lymph vessels in breast cancer, their usefulness as prognostic factors, relationship with angiogenesis and whether active lymphangiogenesis occurs within the tumour. A series of 177 well-characterized breast cancers, with long term follow up, were stained with D2-40, CD31 and CD34. Distribution of lymphatics and lymph vessel density (LVD) were assessed in three areas, intratumoural, peripheral and peritumoural and correlated with clinicopathological criteria and patient prognosis. Microvessel density (MVD) was assessed and correlated with LVD. Double immunohistochemical staining with D2-40 and MIB-1 was carried out to assess the proliferative status of lymphatics and of the tumour emboli within. Peritumoural lymphatics were detected in all tumours whereas peripheral and intratumoural lymphatics were detected in 86 and 41% of specimens, respectively. Tumours with higher total LVD were significantly associated with the presence of lymph node (LN) metastasis and shorter overall survival (OS). In multivariate analysis, tumour grade, LN status and the presence of lymphovascular invasion, but not LVD, were independent poor prognostic factors. No association was found between LVD and MVD. Proliferating lymphatics were detected in 29% of specimens and were significantly associated with dense inflammatory infiltrate. In conclusion, lymphatics are located primarily in the peritumoural and peripheral areas in breast cancer and seem to play an important role in disease progression by being routes for tumour dissemination. The lack of correlation between lymphangiogenic and angiogenic characteristics suggests two distinct processes and the presence of active lymphangiogenesis, albeit in a small portion of specimens, may have important therapeutic implications.Keywords Angiogenesis Á Breast cancer Á D2-40 Á Lymphangiogenesis and prognosis Introduction and aims

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“…The silencing mechanism is triggered by double-stranded RNA that causes specific degradation of the homologous target mRNA. [24][25][26][27] This new approach has been successfully applied to inhibit virus replication 28 and tumorigenicity. 29 Recent reports have described DNA vector-based strategies for delivery of small interfering RNA (siRNA) into mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Calcium carbonate nanoparticle delivering vascular endothelial growth factor-C siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo

et al. 2008

Cancer Gene Ther

104

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Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics

Cited by 876 publications

References 20 publications

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker

Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

Calcium carbonate nanoparticle delivering vascular endothelial growth factor-C siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo

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