Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer

Abstract

Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter. PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients. Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAC = 21.93 months vs. PDAC = 12.7 months; log-rank < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker ( = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine ( = -0.84; CI, -0.90- -0.75) and human ( = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADC = 41.7 months; ADC = 14.77 months; log rank, = 0.040) in PDAC patients. This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. .

A prospectively validated machine learning model for the prediction of survival and tumor subtype in pancreatic ductal adenocarcinoma

“…Post mortem analyses of terminal stage PDAC specimens have shown higher tumor cellularity compared to resectable PDAC specimens, which likely represent earlier tumor development stages (14). In line with this observation we previously demonstrated that higher regional tumor cellularity identified in PDAC resection specimens was associated with a significantly worse overall survival and that the pre-operative DW-MRI-derived ADC parameter could serve as a non-invasive marker thereof (15,16). Upholding these findings, the current analysis identified (12).…”

Modifications of pancreatic diffusion MRI by tissue characteristics: what are we weighting for?

“…The fact that high ADC values in PDAC with lower cellularity were associated with a better outcome is in agreement with earlier reports of favorable outcome for PDAC with lower cellularity, which appears iso‐attenuated in dynamic‐enhanced computed tomography . Still, this report on the negative relationship between ADC values and cellularity of PDAC warrants more confirmation by radiological‐pathological correlation evidence, primarily since the normal pancreas, which is composed of highly packed exocrine tissue of serous acinar cells, appears to have higher cell density than PDAC (see Figure a). Yet, it is widely accepted that ADC values in the normal pancreas are higher.…”

“…Among the reviewed studies, one pancreatic study was included, by Wang et al, who also reported on negative correlation between pathological characteristics such as tumor cellularity and Ki‐67 labeling index, and the ADC values of neuro‐endocrine tumors (NETs) . More recently, the first evidence for a negative correlation between murine and human pancreatic ductal adeno‐carcinoma (PDAC) cellularity and ADC measurements was reported by Heid et al Their results also suggest a possible role for ADC as prognostic indicator and stratification tool, since preoperative ADC values correlated positively with survival. The fact that high ADC values in PDAC with lower cellularity were associated with a better outcome is in agreement with earlier reports of favorable outcome for PDAC with lower cellularity, which appears iso‐attenuated in dynamic‐enhanced computed tomography .…”

Tumor Heterogeneity in Pancreatic Adenocarcinoma

“…Erkan et al [38] proposed an activated stroma index that relies on the area occupied by αSMA+ stromal cells/ the area occupied by collagen. While considerable variations could be seen between tumors, those with a low collagen abundance and a heavy αSMA+ stromal cell infiltration had a worse prognosis, a finding confirmed by others [39]. In addition to the raw number of activated fibroblasts, their functional heterogeneity and distribution may dramatically impact the tumor outcome.…”