Abstract
The clinical significance of lymphangiogenesis in cervical cancer remains controversial. Our aim was to investigate the correlation between lymphangiogenesis, lymphatic vessel invasion (LVI) and tumor metastasis, invasion and prognosis in squamous cell cervical cancer. Paraffin sections of 90 patients with FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) Ib1-IIa squamous cell cervical cancer were stained for immunohistochemistry with a D2-40 monoclonal antibody against the carcinoembryonic antigen M2A. The lymphatic vessel density (LVD) and LVI were measured, and their relationship with the clinicopathological data was analyzed. D2-40-positive lymphatic vessels were found in 75 of the 90 patients (83.3 %). All D2-40-positive vessels were located in peritumoral areas. The mean±SD of the peritumoral LVD was 10.08±4.16. The positive rate of LVI was 32.0 % (24/75). The recurrence rate of patients with LVD >10 (62.1 %, 18/29) was significantly higher than that of patients with LVD ≤10 (34.8 %, 16/46, P = 0.021). The 5-year recurrence-free survival rate of patients with LVD >10 (41.0 %) was significantly lower than that of patients with LVD ≤10 (67.0 %, P = 0.045). Univariate analysis showed that the peritumoral LVD (≤10 vs >10) was correlated with LVI (absent vs present, P = 0.016). The peritumoral LVD and LVI showed no correlation with age, FIGO stage, tumor size, tumor grade, depth of invasion, or pelvic lymph node metastasis (all: P > 0.05). Peritumoral lymphangiogenesis was correlated with the recurrence and recurrence-free survival in patients with squamous cell cervical cancer. Examination of peritumoral LVD in these patients might therefore help to estimate the risk of recurrence.
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References
Balsat C, Blacher S, Signolle N, Beliard A, Munaut C, Goffin F, Noel A, Foidart JM, Kridelka F (2011) Whole slide quantification of stromal lymphatic vessel distribution and peritumoral lymphatic vessel density in early invasive cervical cancer: a method description. ISRN Obstet Gynecol 2011:354861
Birner P, Schindl M, Obermair A, Breitenecker G, Kowalski H, Oberhuber G (2001) Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer. Int J Cancer 95:29–33
Botting SK, Fouad H, Elwell K, Rampy BA, Salama SA, Freeman DH, Diaz-Arrastia CR (2010) Prognostic significance of peritumoral lymphatic vessel density and vascular endothelial growth factor receptor 3 in invasive squamous cell cervical cancer. Transl Oncol 3:170–175
Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G (2005) Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 11:8364–8371
Gupta GP, Massagué J (2006) Cancer metastasis: building a framework. Cell 127:679–695
Hirakawa S, Hong YK, Harvey N, Schacht V, Matsuda K, Libermann T, Detmar M (2003) Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 162:575–586
Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099
Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282:33671–33680
Longatto-Filho A, Pinheiro C, Pereira SM, Etlinger D, Moreira MA, Jubé LF, Queiroz GS, Baltazar F, Schmitt FC (2007) Lymphatic vessel density and epithelial D2-40 immunoreactivity in pre-invasive and invasive lesions of the uterine cervix. Gynecol Oncol 107:45–51
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682
Padera TP, Kadambi A, Tomaso E di, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886
Partanen TA, Alitalo K, Miettinen M (1999) Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer 86:2406–2412
Pepper MS, Tille JC, Nisato R, Skobe M (2003) Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314:167–177
Roy S, Chu A, Trojanowski JQ, Zhang PJ (2005) D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas. Acta Neuropathol 109:497–502
Schoppmann SF, Schindl M, Breiteneder-Geleff S, Soleima A, Breitenecker G, Karner B, Birner P (2001) Inflammatory stromal reaction correlates with lymphatic microvessel density in early-stage cervival cancer. Anticancer Res 21:3419–3423
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198
Sotiropoulou N, Bravou V, Kounelis S, Damaskou V, Papaspirou E, Papadaki H (2010) Tumour expression of lymphangiogenic growth factors but not lymphatic vessel density is implicated in human cervical cancer progression. Pathology 42:629–636
Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191
Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K (2002) Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2:573–583
Urabe A, Matsumoto T, Kimura M, Sonoue H, Kinoshita K (2006) Grading system of lymphatic invasion according to D2-40 immunostaining is useful for the prediction of nodal metastasis in squamous cell carcinoma of the uterine cervix. Histopathology 49:493–497
Van der Auwera I, Cao Y, Tille JC, Pepper MS, Jackson DG, Fox SB, Harris AL, Dirix LY, Vermeulen PB (2006) First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer 95:1611–1625
Van Trappen PO, Pepper MS (2002) Lymphatic dissemination of tumour cells and the formation of micrometastases. Lancet Oncol 3:44–52
Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324:1–8
Yonemura Y, Endou Y, Tabachi K, Kawamura T, Yun HY, Kameya T, Hayashi I, Bandou E, Sasaki T, Miura M (2006) Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2–40. Hum Pathol 37:1193–1199
Zaganelli FL, Carvalho FM, Almeida BG, Bacchi CE, Goes JC, Calil MA, Baracat EC, Carvalho JP (2010) Intratumoral lymphatic vessel density and clinicopathologic features of patients with early-stage cervical cancer after radical hysterectomy. Int J Gynecol Cancer 20:1225–1231
Zhang JP, Lü WG, Chen HZ, Zhou CY, Xie X (2005) Tumor lymphangiogenesis in cervical squamous cell carcinoma and its clinical significance (in Chinese). JZhonghua Yi Xue Za Zhi 85:1551–1554
Zhang SQ, Yu H, Zhang LL (2009) Clinical implications of increased lymph vessel density in the lymphatic metastasis of early-stage invasive cervical carcinoma: a clinical immunohistochemical method study. BMC Cancer 9:64
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X.Y. and L.J.H. designed the experiments. L.L.Z acquired the clinical data. C.L.P. conducted the experiments and searched for the references. X.Y., C.L.P., R.H.L., and C.M.Y. analyzed the data. X.Y. and L.J.H. wrote the manuscript.
This study was supported by the Sci-Tech Project Foundation of Guangdong Province (2007B060401071).
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Xiong, Y., Cao, LP., Rao, HL. et al. Clinical significance of peritumoral lymphatic vessel density and lymphatic vessel invasion detected by D2-40 immunostaining in FIGO Ib1-IIa squamous cell cervical cancer. Cell Tissue Res 348, 515–522 (2012). https://doi.org/10.1007/s00441-012-1384-x
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DOI: https://doi.org/10.1007/s00441-012-1384-x