Abstract
In recent years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have substantially improved the clinical outcome of pseudomyxoma peritonei (PMP) originating from mucinous appendiceal cancer. However, current histopathological grading of appendiceal PMP frequently fails in predicting disease outcome. We recently observed that the integration of cancer cell transcriptional traits with those of cancer-associated fibroblasts (CAFs) improves prognostic prediction for tumors of the large intestine. We therefore generated global expression profiles on a consecutive series of 24 PMP patients treated with CRS plus HIPEC. Multiple lesions were profiled for nine patients. We then used expression data to stratify the samples by a previously published “high-risk appendiceal cancer” (HRAC) signature and by a CAF signature that we previously developed for colorectal cancer, or by a combination of both. The prognostic value of the HRAC signature was confirmed in our cohort and further improved by integration of the CAF signature. Classification of cases profiled for multiple lesions revealed the existence of outlier samples and highlighted the need of profiling multiple PMP lesions to select representative samples for optimal performances. The integrated predictor was subsequently validated in an independent PMP cohort. These results provide new insights into PMP biology, revealing a previously unrecognized prognostic role of the stromal component and supporting integration of standard pathological grade with the HRAC and CAF transcriptional signatures to better predict disease outcome.
Highlights
The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is nowadays recognized as the “gold standard” treatment for pseudomyxoma peritonei (PMP)originated from mucinous appendiceal tumors [1–9], due to favorable biologic behavior characterizedCancers 2020, 12, 1495; doi:10.3390/cancers12061495 www.mdpi.com/journal/cancersCancers 2020, 12, 1495 by a pattern of late or non-invasive multifocal spread into tissues, with low risk of hematogenous dissemination
In primary colorectal cancer (CRC), we have shown that a transcriptional signature reflecting cancer-associated fibroblast (CAF) abundance and function
From August 1997 to December 2018, 177 patients diagnosed with PMP underwent CRS + HIPEC
Summary
The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is nowadays recognized as the “gold standard” treatment for pseudomyxoma peritonei (PMP)originated from mucinous appendiceal tumors [1–9], due to favorable biologic behavior characterizedCancers 2020, 12, 1495; doi:10.3390/cancers12061495 www.mdpi.com/journal/cancersCancers 2020, 12, 1495 by a pattern of late or non-invasive multifocal spread into tissues, with low risk of hematogenous dissemination. The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is nowadays recognized as the “gold standard” treatment for pseudomyxoma peritonei (PMP). Originated from mucinous appendiceal tumors [1–9], due to favorable biologic behavior characterized. PMP has been described in association with mucinous tumors from other sites, including colon, ovary, gallbladder, pancreas, and urachus [10]. CRS plus HIPEC has been extensively used to increase the five- and ten-year overall survival (OS) of patients with PMP of appendiceal origin [11–19]. Disease-free survival (DFS) shows a significant and often unpredictable variability, with a non-negligible relapse rate in treated patients [20–27]. The relapse is sometimes re-treatable by CRS associated or not with. HIPEC, but in many cases this is not feasible due to the carcinomatosis features, not amenable with a complete surgical cytoreduction [4]
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