Integrating Peritoneal Histological Growth Patterns Into Preoperative Decision-Making for Colorectal Peritoneal Metastses

Colorectal cancer (CRC) remains the third most commonly diagnosed malignancy worldwide and the second leading cause of cancer-related death, with approximately 15% of patients presenting with synchronous liver metastases (LM) and 7% with peritoneal metastases (PM) at diagnosis. Despite curative-intent resection of the primary tumor, 16-20% of patients subsequently develop metachronous LM and up to 19% develop PM within three years [1-5].

Surgery remains the only potentially curative treatment for patients with colorectal peritoneal metastases (CRPM), offering long-term (>10years) disease-free survival (DFS) in a subset of highly selected patients [6,7]. However, selecting candidates for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) remains challenging and requires balancing the potential oncologic benefit of complete cytoreduction against perioperative risks and postoperative morbidity [6-8].

Consequently, strong prognostic markers-clinical, biological, or genetic-are crucial to refine surgical decision-making. Currently, the two most consistent clinical determinants of outcome are the extent of disease (Peritoneal Cancer Index, PCI) and the completeness of cytoreduction (CC-score) [6-8]. Over the last decade, surgical selection has become more restrictive (e.g., PCI threshold moving from 25 to 17), and molecular profiles such as BRAF mutations have been associated with poor outcomes, potentially guiding against aggressive surgery in selected cases [8,9]. Yet, these markers are insufficient to fully capture inter-patient heterogeneity and do not reliably individualize surgical benefit [8,9].

In colorectal liver metastases (CRLM), the histological growth pattern (HGP) at the tumor-liver interface has emerged as a robust prognostic biomarker, with the desmoplastic HGP (d-HGP) associated with superior survival compared with replacement or pushing patterns [10,11]. International consensus guidelines have standardized HGP scoring for CRLM, enabling reproducible assessment and cross-study comparison [12]. Large multicentric cohorts also suggest possible modulation of HGP by systemic chemotherapy, supporting its value as a marker of intrinsic tumor biology and treatment response [13,14].

Transposing this concept to the peritoneum, our group identified two reproducible peritoneal HGP in colorectal peritoneal metastases: the pushing pattern (P-HGP) and the infiltrating pattern (I-HGP). Across two monocentric studies, a dominant P-HGP (>50-60% of the tumor-peritoneum interface) was strongly associated with prolonged disease-free and overall survival (OS) [15,16].

Taken together, these findings support HGP of PM as a potential histological biomarker to refine patient selection for CRS ± HIPEC beyond current clinical and molecular criteria.

However, existing data derive exclusively from retrospective single-center cohorts, underscoring the need for prospective validation to:

Confirm the independent prognostic value of HGP of PM (for overall and disease-free survival) in contemporary clinical practice; Standardize sampling and pathological assessment (standard operating procedures, central review, and interobserver reproducibility studies); Develop and validate a histo-prognostic scoring system integrating PM HGP with relevant clinicopathological variables, aimed at predicting patient outcomes and supporting preoperative decision-making for CRS ± HIPEC candidacy.

This prospective cohort study is designed to address these objectives without modifying standard care. By collecting clinicopathological and survival data prospectively, it will provide robust evidence for the integration of HGP into a multivariable prognostic model capable of stratifying surgical candidates and guiding individualized treatment strategies.

Inclusion criteria

• Age ≥ 18 years
• Histologically confirmed colorectal adenocarcinoma
• Suspected or confirmed peritoneal metastases from colorectal cancer based on imaging or prior clinical evaluation
• Patients undergoing staging laparoscopy and/or cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) as part of standard clinical care
• Availability of peritoneal metastasis tissue samples suitable for histopathological analysis
• Written informed consent provided for participation in the study

Exclusion criteria

• Age < 18 years
• Peritoneal metastases originating from non-colorectal primary tumors
• Absence of available or adequate peritoneal metastasis tissue samples for histological growth pattern analysis
• Patients who decline or withdraw informed consent
• Patients unable to provide informed consent