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Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer

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Abstract

Metastasis to the regional lymph nodes through the lymphatic vessels is a common step in the progression of cancer and an important prognostic factor in many types of cancer. Recent evidence suggests that VEGF-C promotes lymphangiogenesis, and that tumor lymphangiogenesis in turn promotes lymphatic metastasis. We have studied the role of LVD in breast cancer, and examined whether LVD is associated with lymph node metastasis, VEGF-C expression, or prognosis. In addition, we examined whether VEGF-C mRNA transcript levels were associated with lymph node metastasis and LVD. We began by investigating the lymphatics in primary human breast carcinoma with long-term follow-up (113 cases of invasive ductal and other breast cancers) by quantitative immunohistochemical staining for podoplanin. We then analyzed the relationship between LVD and lymph node status as well as VEGF-C immunoreactivity and other established clinicopathological parameters. The relationship between LVD and prognosis was also studied. VEGF-C mRNA transcript levels were examined by quantitative real-time RT-PCR, in 55 invasive ductal breast carcinomas. This was followed by an analysis of the relationship between VEGF-C mRNA transcript levels and lymph node metastasis as well as LVD. Mean LVD of ‘hot spots’ was 10.2 ± 7.4/each case. LVD was significantly correlated with lymph node metastasis (p < 0.0001), VEGF-C immunoreactivity (p = 0.0084), and podoplanin positive lymphatic invasion (p < 0.0001). Survival curves determined by the Kaplan–Meier method and univariate analysis demonstrated that high LVD was associated with both worse disease free survival (p = 0.0033) and overall survival (p = 0.0391). VEGF-C mRNA transcript levels were also correlated with lymph node metastasis (p = 0.0074) and LVD (p = 0.0409). Increased LVD was correlated with lymph node metastasis and VEGF-C expression. High LVD may be a significant unfavorable prognostic factor for long-term survival in breast cancer.

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Abbreviations

DFS:

disease-free survival

ER:

estrogen receptor

FVD:

Flt-4 positive vessel density

GAPDH:

glyceraldehydes 3-phosphate dehydrogenase

LVD:

podoplanin positive lymph vessel density

LVI:

podoplanin positive lymph vessel invasion

OS:

overall survival

PCR:

polymerase chain reaction

PgR:

progesterone receptor

RT:

reverse transcription

VEGF:

vascular endothelial growth factor

VEGFR:

VEGF receptor

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Authors and Affiliations

  1. Second Department of Pathology, Wakayama Medical University, 811-1, Kimiidera, 641-8509, Wakayama City, Wakayama, Japan

    Yasushi Nakamura, Hironao Yasuoka, Misa Nakamura, Ichiro Mori & Kennichi Kakudo

  2. Department of Pathology, Osaka Police Hospital, Japan

    Masahiko Tsujimoto

  3. Department of Surgery, Osaka Police Hospital, Osaka City, Osaka, Japan

    Shigeru Imabun, Masaaki Nakahara & Kazuyasu Nakao

Authors
  1. Yasushi Nakamura
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  2. Hironao Yasuoka
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  3. Masahiko Tsujimoto
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  4. Shigeru Imabun
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  5. Masaaki Nakahara
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  6. Kazuyasu Nakao
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  7. Misa Nakamura
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  8. Ichiro Mori
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  9. Kennichi Kakudo
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Correspondence to Yasushi Nakamura.

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Nakamura, Y., Yasuoka, H., Tsujimoto, M. et al. Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat 91, 125–132 (2005). https://doi.org/10.1007/s10549-004-5783-x

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