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Gabriella Lionetto*, Laura Maggino, Filippo M. Martelli, Giulia Savegnago, Fabio Casciani, Salvatore Paiella, Antonio Pea, Alessandro Esposito, Claudio Bassi, Aldo Scarpa, Roberto Salvia, Giuseppe Malleo, Claudio Luchini
Universita degli Studi di Verona, Verona, Veneto, Italy

Pancreatic ductal adenocarcinoma (PDAC) exists in several morphological subtypes differing in prognostic significance. However, to date, a clinico-morphological correlation of these subtypes in the context of neoadjuvant therapy (NAT) has not been performed. The aim of this study was 1) to investigate the frequency of the different PDAC morphologies in patients undergoing radical intent pancreatectomy after NAT; and 2) to determine the prognostic impact of the presence of a secondary morphology in the primary tumor.

All patients who underwent pancreatic resection after NAT for PDAC (2013-2019) at one academic institution were enrolled. All pathological samples were included in toto and reviewed by experienced pathologists. The presence of a secondary morphology in the primary tumor specimen was determined according to a morphological cut-off ≥10%. Tumor regression grade (TRG) was classified according to the MDACC Scoring system. The clinico-pathological characteristics and the survival of the cohort were studied by means of conventional statistical analyses.

Among the 401 included patients 205 (51,5%) received Folfirinox, 134 (33,7%) gemcitabine/nab-paclitaxel. The median follow-up was 28.0 months, and the median disease specific survival (DSS) was 29.7 months. The median DSS associated to the principal tumor morphologies and their relative frequencies is shown in the Table. Gland forming PDAC with conventional morphology (n=167, 41,6%) was the most frequent subtype. Overall, no significant difference in DSS was observed. After pairwise comparison, the papillary morphology shown a significant higher survival rate compared to other less frequent subtypes (cribiform, p<0.019; gyriform, p<0.008; micropapillary, p<0.048; and adenosquamous, p<0.006). Overall, 247 (61,1%) displayed only a single principal tumor morphology, while 154 (38,4%) presented an additional secondary morphology in the primary tumor. PDACs harboring a secondary tumor morphology shown a significantly more advanced pathological profile and a higher TRG, as well as significantly shorter DSS and recurrence free survival (RFS) (Figure). At multivariable Cox regression, the presence of a secondary tumor morphology was independently associated with worse DSS (HR 1.881, 95% CI 1.384-2.557, p<0.001) and RFS (HR 1.635, 95% CI 1.230-2.175, p<0.001).

In patients receiving pancreatectomy after NAT, the presence of a secondary morphology in the primary tumor is frequent, occurring in over one third of the cases. This feature is associated with a less favorable pathological profile and a higher TRG, and represents an independent predictor of shorter DSS and RFS. Based on these findings, including a detailed morphological description in pancreatectomy pathology reports might provide valuable prognostic information and possibly help post-surgical decision-making.

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