Pathologic features of aggressive vulvar carcinoma are associated with epithelial-mesenchymal transition

Abstract

Factors contributing to aggressive behavior in vulvar squamous cell carcinoma (vSCC) are poorly defined; however, a recent study has shown that vSCCs with an infiltrative pattern of invasion and fibromyxoid stroma are associated with worse outcomes than tumors with a pushing or nested pattern of invasion and lymphoplasmacytic stroma. Epithelial-mesenchymal transition (EMT) has been associated with tumor progression in a number of malignancies, and this study proposes that EMT contributes to tumor aggressiveness in this subset of vSCC. Immunohistochemistry was used to detect nuclear localization of β-catenin, loss of E-cadherin, and presence of vimentin in 58 cases of vSCC. The association of these phenotypic changes with pathologic features and clinical outcomes was tested using Fisher’s exact and χ2 analyses (significance at p ≤0.05). EMT-associated features were identified in 45 of 58 cases (78%) with 28 cases exhibiting more than one feature. Nuclear β-catenin and presence of vimentin were significantly more likely to occur in tumors with an infiltrative pattern of invasion or a fibromyxoid stromal response. Loss of E-cadherin was significantly associated with an infiltrative pattern, but not a fibromyxoid stroma. Risk for tumor recurrence was significantly increased in tumors with nuclear localization of β-catenin alone or in tumors displaying multiple EMT-associated features. These results suggest that the development of an EMT may be a mechanism by which infiltrative vulvar tumors with a fibromyxoid stromal response behave more aggressively and convey worse outcomes than tumors that do not exhibit these pathologic features.

Vulvar squamous cell carcinoma aggressiveness is associated with differential expression of collagen and STAT1

“…Morphologic variants of vSCC have been described and correlated with tumor aggressiveness [ 4 – 6 ]. As depicted in Fig.…”

“…Approval for research using archived human samples was obtained from the Institutional Review Board of the University of Arkansas for Medical Sciences (UAMS). We previously identified 143 cases of vSCC in UAMS case archives [ 4 – 6 ] and classified variants of these vSCCs as containing “pushing tumor” with lymphoplasmacytic stroma (LPC) or “infiltrative tumor” with fibromyxoid stroma (FMX) [ 5 ]. Due to the close association of nodal metastases and tumor recurrence with these morphologic variants [ 5 ], the current study used 10 cases of Push/LPC tumors and 8 cases of Inf/FMX tumors for proteomic analysis (Table 1 ).…”

“…Treatment of vSCC patients based on the use of this staging system for prognostic stratification is associated with recurrence rates as high as 50–70% [ 2 , 3 ]. Therefore, we opted to focus case selection based on our previously published findings which indicate that specific morphologic features reflective of differences in the tumor microenvironment are superior predictors of recurrence and tumor aggressiveness [ 4 – 6 ]. Specifically, tumors with an infiltrative tumor morphology and a fibromyxoid stroma (Inf/FMX) behaved more aggressively with a higher prevalence of tumor recurrence, perineural invasion (PNI), and nodal metastasis when compared to more indolent tumors having a pushing morphology with a lymphoplasmacytic stroma (Push/LPC) [ 4 – 6 ].…”

“…Therefore, we opted to focus case selection based on our previously published findings which indicate that specific morphologic features reflective of differences in the tumor microenvironment are superior predictors of recurrence and tumor aggressiveness [ 4 – 6 ]. Specifically, tumors with an infiltrative tumor morphology and a fibromyxoid stroma (Inf/FMX) behaved more aggressively with a higher prevalence of tumor recurrence, perineural invasion (PNI), and nodal metastasis when compared to more indolent tumors having a pushing morphology with a lymphoplasmacytic stroma (Push/LPC) [ 4 – 6 ]. The association of these pathognomonic features with clinical outcomes indicates a fundamental difference in tumor–stroma interactions underlying the development of these vSCC variants.…”

Vulvar cancer recurrence — an analysis of prognostic factors in tumour-free pathological margins patients group

“…Therefore, it is necessary to focus on new histopathological, genetic and epigenetic factors. Actual sources state the increased risk of recurrence based on increased tumour aggression in association with the presence of perineural invasion or epithelial-mesenchymal transition [31,32]. Increased risk of local recurrence is also characterized by HPV tumour negativity in conjunction with differentiated VIN, lichen sclerosus and genetic alterations such as TP53 mutations [33,34].…”