PoC - Physics of Cancer - Annual Symposium
Invited Talk, Thursday, 15:00 – 15:30  
Tumor cells dissociation and peritumoral stromal rearrangement in squamous cell carcinoma of the uterine cervix

Lars-Christian Horn

University of Leipzig, Institute of Pathology, Division of Breast, Gynecologic & Perinatal Pathology, Liebigstraße 26, 04103 Leipzig, Germany

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Objectives: During tumor infiltration, cancer cells not only destroy the pre-existing extracellular matrix, but usually induce new matrix formation by activating the peritumoral stromal cells; that is, desmoplastic stromal reaction (DSR) at the front of invasion (juxtatumoral stroma). CD 34 staining has been reported in normal endocervical stroma and its loss as an indicator for peritumoral stromal remodelling in case of invasive cancer. In squamous cell carcinoma of the head and neck there is a myofibroblastic switch within the juxtatumoral stroma within the process of tumor invasion, characterised by the upregulation SMA. Additionally, different patterns of invasion (representing different grades of tumor cell dissociation) have been described in various tumors and are associated with prognostic outcome. In that context in different studies we evaluated the association between different patterns of invasion and the grade of peritumoral stromal remodelling.

Methods: Squamous cell carcinoma of the uterine cervix (CX) were re-evaluated histologically regarding the PI, using a three-level scoring system. Closed PI was defined as cohesive growth with well-delineated (pushing) borders. In finger-like PI the tumor grows in solid cords/trabecles. Highly dissociative growth in small groups or single cells was defined as spray-like PI. Types of PI were correlated clinocopathologic variables and features of juxtatumoral stromal remodelling. DSR, defined as a proliferation of myofibroblastic cells with intercellular edematous change and entrapped island of normal endocervical stroma was scored from none to weak, moderate or strong.
CD 34 and SMA immunohistochemistry was performed and staining results were scored as negative/low (<5% stromal cells positive), moderate (5-50% stroma positive) or high (>50% stroma positive). 

Results: In 661 CX (FIGO IB to IIB) 60% of the tumors showed a spray-like PI, 30% a finger-like PI, and only 7.4% were of the closed type. Spray-like PI showed a significant correlation with advanced stage disease, lymphovascular space involvement, poorly differentiated tumors and pelvic lymph node metastases. Spray-like PI was accompanied by a reduced 5-year overall survival when compared to the finger-like and closed PI (68.7% vs. 80.9% vs. 88.5%; p=0.0004). In multivariate analysis, using COX-regression model, the PI represented as independent prognostic factor. 
In a study of 88 CX (FIGO-stage IB to IV) tumors with spray-like PI showed a significantly stronger desmoplastic reaction compared to the finger-like PI (p<0.0001) and were significantly associated with poor tumor cell differentiation (p=0.018). Moderate or strong DSR was associated with G2 and G3 carcinomas (p=0.027). 
In a cohort of 102 CX the majority of cases (78.2%) showed a marked reduction/loss of CD 34-staining (negative/low/moderate staining), whereas 71.6% of the cases represented an upregulation of SMA (high staining pattern).

Conclusions: Spray-like PI, (i.e. highest degree of tumor cell dissociation) is associated with advanced tumor stages, increased rate of recurrency and a reduced overall survival. The intensity of desmoplastic stromal response (DSR), as understood in the context of a remodelling of the juxtatumoral stroma to the infiltrative tumor growth, might be indicative for a highly dissociative tumor growth and is correlated to poorly differentiated tumors. Loss of CD 34 stromal staining in association with the upregulation of SMA is a parameter of peritumoral stromal remodelling in squamous cell carcinoma of the uterine cervix

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