Intratumoral oxygenation of invasive squamous cell carcimoma of the vulva is not correlated with regional lymph node metastasis

Introduction: Tumour hypoxia has been found to be associated with tumour aggressiveness. Our primary aim was to explore the relationship between pretreatment tumour oxygenation in primary vulvar carcinoma and nodal status. Our secondary objective was to assess if there was a relationship between the clinical and biological variables.

Methods: 20 women with ISCC of the vulva were assessed with pretreatment primary tumour oxygenation with an Eppendorf pO2 probe. Patients underwent standard surgical management. Pathological assessment of the primary and nodal tissues was then performed. Primary tumour specimens were also stained for microvessel density and carbonic anhydrase IX. The relationship between smoking, preoperative Hgb, tumour CAIX expression, MVD, and Eppendorf pO2 measurements vs nodal metastasis and between these clinical and biological variables was assessed.

Results: Seven patients had positive lymph nodes, 13 had negative nodes. While neither current smoking status, tumour size, tumour oxygen measurements, MVD and CAIX expression correlated with metastatic nodal disease, a low preoperative Hgb correlated with pathological nodal status (p < 0.027).

Conclusions: Although this analysis failed to demonstrate a strong correlation between various measures of tumour oxygenation with nodal metastasis, it may be due to the small number of patients. Only preoperative anaemia is correlated with nodal metastasis in early ISCC of the vulva.

Vulvar cancer; Tumour hypoxia; Nodal metastasis

[1] Al-Ghamdi A., Freedman D., Miller D., Poh C., Rosin M., Zhang L. et al.: "Vulvar squamous cell carcinoma in young women: a clinicopathologic study of 21 cases". Gynecol. Oncol., 2002, 84, 94.

[2] Podratz K.C., Symmonds R.E., Taylor W.F.: "Carcinoma of the vulva: analysis of treatment failures". Am. J. Ohstet. Gynecol., 1982, 143, 340.

[3] Gould N.,K amelle S.,T illmanns T.,S cribner D.,G old M.,W alker J. et al.: "Predictors of complications after inguinal lymphadenectomy". Gynecol. Oncol., 2001, 82, 329.

[4] Donaldson E.S., Powell D.E., Hanson M.B., van Nagell J.R. Jr "Prognostic parameters in invasive vulvar cancer". Gynecol Oneal.,1981,11, 184.

[5] Iversen T.: "The value of groin palpation in epidermoid carcmoma of the vulva". Gynecol. Oncol., 1981, 12, 291.

[6] Sedlis A., Homesley H., Bundy B.N., Marshall R., Yordan E., Hacker N. et al.: "Positive groin lymph nodes in superficial squamous cell vulvar cancer. A Gynecologic Oncology Group Study" Am. J. Ohstet. Gynecol., 1987, 156, 1159.

[7] Brizel D.M.,S cully S.P.,H arrelson J.M.,L ayfield L.J.,B ean J.M., Prosnitz L.R. et al.: "Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma". Cancer Res., 1996, 56, 941.

[8] Brizel D.M., Sibley G.S., Prosnitz L.R., Scher R.L., Dewhirst M.W.: "Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck". Int. J. Rad. Oneal., Biol., Phys., 1997, 38, 285.

[9] Fyles A.W.,M ilosevic M.,W ong R.,K avanagh M.C.,P intilie M., Sun A. et al.: "Oxygenation predicts radiation response and survival in patients with cervix cancer.[erratum appears in Radiother Oncol., 1999, 50, 371]". Radiother. Oncol., 1998, 48, 149.

[10] Hockel M., Schlenger K., Aral B., Mitze M., Schaffer U., Vaupel P.: "Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix". Cancer Res., 1996, 56, 4509.

[11] Nordsmark M., Overgaard M., Overgaard J.: "Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck". Radiother. Oneal., 1996, 41, 31.

[12] Chia S.K.,W ykoff C.C.,W atson P.H.,H an C.,L eek R.D.,P astorek J. et al.: "Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma". J Clin. Oncol., 2001, 19, 3660.

[13] Li H.X., Chang X.M., Song Z.J., He S.X.: " Correlation between expression of cyclooxygenase-2 and angiogenesis in human gastric adenocarcinoma". World J. Gastroenterol., 2003, 9, 674.

[14] Hockel S., Schlenger K., Vaupel P., Hockel M.: "Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer". Int. J. Oncol., 2001, 19, 827.

[15] Chaudhary R., Bromley M., Clarke N.W., Betts C.D., Barnard R.J., Ryder W.D. et al.: "Prognostic relevance of micro-vessel density in cancer of the urinary bladder". Antica. Res., 1999, 19, 3479.

[16] Obermair A., Kohlberger P., Bancher-Todesca D., Tempfer C., Sliutz G., Leodolter S. et al.: "Influence of microvessel density and vascular permeability factor/vascular endothelial growth factor expression on prognosis in vulvar cancer". Gynecol. Oncol., 1996, 63, 204.

[17] Fox S.B., Leek R.D., Bliss J., Mansi J.L., Gusterson B., Galler K.C. et al.: "Association of tumor angiogenesis with bone marrow micrometastases in breast cancer patients". J. Nat. Cancer Instil., 1997, 89, 1044.

[18] Loncaster J.A., Harris A.L., Davidson S.E., Logue J.P., Hunter R.D., Wycoff C.C. et al.: "Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix". Cancer Res., 2001, 61, 6394.

[19] Giatromanolaki A., Koukourakis M.I., Sivridis E., Pastorek J., Wykoff C.C., Gatter K.C. et al.: "Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer". Cancer Res., 2001, 61, 7992.

[20] Beasley N.J., Wykoff C.C., Watson P.H., Leek R., Turley H., Gatter K. et al.: "Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density" Cancer Res., 2001, 61, 5262.

[21] Koukourakis M.I., Giatromanolaki A., Sivridis E., Simopoulos K., Pastorek J., Wykoff C.C. et al.: "Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy". Clin. Cancer Res., 2001, 7, 3399.

[22] Aquino-Parsons C., Luo C., Vikse C.M., Olive P.L.: "Companson between the comet assay and the oxygen rnicroelectrode for measurement of tumor hypoxia". Radiother. Oneal., 1999, 51, 179.

[23] Morley G.W.: "Infiltrative carcinoma of the vulva: results of surgical treatment". Am. J. Obstet. Gynecol., 1976, 124, 874.

[24] Creasman W.T., Phillips J.L., Menck H.R.: "The National Cancer Data Base report on early stage invasive vulvar carcinoma. The American College of Surgeons Commission on Cancer and the American Cancer Society". Cancer, 1997, 80, 505.

[25] Boyce J.,F ruchter R.G.,K asambilides E.,N icastri A.D.,S edlis A., Remy J.C.: "Prognostic factors in carcinoma of the vnlva". Gynecol. Oneal., 1985, 20, 364.

[26] Andreasson B., Nyboe J.: "Value of prognostic parameters in squamous cell carcinoma of the vulva". Gynecol. Oneal., 1985, 22, 341.

[27] Shimm D.S., Fuller A.F.,O rlow E.L.,D osoretz D.E.,A ristizabal S.A.: "Prognostic variables in the treatment of squamous cell carcinoma of the vulva". Gynecol. Oncol., 1986, 24, 343.

[28] DiSaia P.J., Creasman W.T.: "Invasive cancer of the vnlva". In: Clinical Gynecologic Oncology (sixth ed.). Mosby, 2002, 211

[29] Secomb T.W., Hsu R., Dewhirst M.W., Klitzman B., Gross J.F "Analysis of oxygen transport to tumor tissue by microvascular networks". Int. J. Rad. Oncol., Biol., Phys., 1993, 25, 481.

[30] Kimura H., Braun R.D., Ong E.T., Hsu R., Secomb T.W., Papahadjopoulos D. et al.: " Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma". Cancer Res., 1996, 56, 5522.

[31] Graeber T.G., Osmanian C., Jacks T., Housman D.E., Koch C.J., Lowe S.W. et al.: "Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.[comment]" Nature, 1996, 379, 88

[32] Subarsky P., Hill R.P.: "The h ypox1c tumour m1croenvironment and metastatic progression". Clin. Exp. Metast., 2003, 20, 237.

[33] Cairns R.A., Kalliomaki T., Hill R.P.: "Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors". Cancer Res., 2001,61, 8903.

[34] Saarnio J., Parkkila S., Parkkila A.K., Haukipuro K., Pastorekova S., Pastorek J. et al.: "Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. [comment]". Am. J. Pathol., 1998, 153, 279.

[35] Opavsky R., Pastorekova S., Zelnik V., Gibadulinova A., Stanbridge E.J., Zavada J. et al.: "Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships". Genomics., 1996, 33, 480.

[36] Folkman J.: "What is the evidence that tumors are angiogenesis dependent?". J. Nat. Cancer Instil., 1990, 82, 4.

[37] Warde P., O'Sullivan B., Bristow R.G., Panzarella T., Keane T.J., Gullane P.J. et al.: "Tl /T2 glottic cancer managed by external beam radiotherapy: the influence of pretreatment hemoglobin on local control". Int. J. Rad. Oncol.,B iol.,Phys.,1998, 41, 3 47.

[38] Hefler L., Mayerhofer K., Leibman B., Obermair A., Reinthaller A., Kainz C. et al.: "Tumor anemia and thrombocytosis in patients with vulvar cancer". Tumour Biol., 2000, 21, 309.