Tumor-distribution and tumor-stromal-interaction in carcinoma of the cervix uteri

Infiltration and destruction of extracellular matrix (ECM) by degradative enzymes are required to facilitate the spread and invasion of tumour cells. Several types of tumour-associated proteases are responsible for ECM-degradation: matrix metalloproteases, cystine, aspartate and serine proteases (e.g. uPA and PAI-1). They are also associated with pleiotropic functions, including cell adhesion, motogenesis and angiogenesis in cervical carcinomas (CX) and are of prognostic impact.

Inflammatory cellular response begins at CIN 3 and is a hallmark of microinvasion and might be a host-defense reaction against the CX. CX without any peritumoral inflammatory response were accompanied with deep cervical stromal infiltration (> 66%) and poor prognostic outcome. But, tumor-associated macrophages expressing VEGF-C-expressing are involved in peritumoral lymphangiogenesis. Angiogenesis is an essential step of the tumoral growth and of the metastatic dissemination. It provides the nutriments necessary to the tumor. The immunostaining using e.g. CD31, CD34, allows the quantification of vessels or „microvascular density (MVD)“. High MVD is generally located at the front of invasion and associated with advanced stage disease, lymphatic spread and poor prognosis.

Cancer cells not only destroy the pre-existing ECM, but induces new matrix formation, i.e. desmoplastic stromal reaction (DSR). Strong DSR in CX is significantly associated with a spray-like pattern of invasion. Spray-like PI has been determined as the most dissociative kind of growth pattern and is associated with significantly associated with poor tumor cell differentiation (G3) and is correlated with advanced stage disease, lymphovascular space involvement, pelvic lymph node metastases and reduced 5-year overall survival. On molecular level, increased expression of HGF and c-met is associated with high tumor cell dissociation. LVSI is associated with poor prognosis in node negative patients. Infiltration of the corpus uteri, parametrial tissue and the perinueral tissue is accompanied by recurrent disease and poor prognosis.