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SHOULD WE BE DOING CYTOREDUCTIVE SURGERY WITH HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY FOR SIGNET RING CELL APPENDICEAL ADENOCARCINOMA? A STUDY FROM THE US HIPEC COLLABORATIVE
Nick C. Levinsky*1, Mackenzie C. Morris1, Koffi Wima2, Jeffrey Sussman2, Syed Ahmad2, Jordan Cloyd3, Charles Kimbrough3, Keith Fournier4, Andrew Lee4, Sean Dineen5, Sophie Dessureault5, Jula Veerapong6, Joel Baumgartner6, Callisia N. Clarke7, Charles A. Staley8, Shishir K. Maithel8, Jennifer Leiting9, Travis e. Grotz9, Laura Lambert10, Ryan J. Hendrix10, Sean Ronnekleiv-Kelly11, Courtney Pokrzywa11, Mustafa Raoof12, Oliver S. Eng12, Fabian M. Johnston13, Jonathan B. Greer13, Sameer Patel2
1Department of Surgery, University of Cincinnati, Cincinnati, OH; 2Division of Surgical Oncology, University of Cincinnati College of Medicine, Cincinnati, OH; 3Division of Surgical Oncology, Department of Surgery, The Ohio State University Medical Center, Columbus, OH; 4Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX; 5Department of Gastrointestinal Oncology, Moffitt Cancer Center, Department of Oncological Sciences, Morsani College of Medicine, Tampa, FL; 6Division of Surgical Oncology, Department of Surgery, University of California, San Diego, CA; 7Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI; 8Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA; 9Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN; 10Division of Surgical Oncology, Department of Surgery, University of Massachusetts Medical School, Worcester, MA; 11Division of Surgical Oncology, Department of Surgery, University of Wisconsin, Madison, WI; 12Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA; 13Department of Surgery, Johns Hopkins University, Baltimore, MD

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly utilized for peritoneal surface malignancies. The optimal patient selection for this procedure remains poorly defined. Appendiceal adenocarcinoma with signet ring cells (SCA) is associated with worse overall survival (OS), and it is unclear if CRS-HIPEC should be pursued in this patient population. We assessed the prognostic implications of signet ring cell features in patients with appendiceal adenocarcinoma and peritoneal carcinomatosis undergoing CRS-HIPEC using the largest multi-institutional HIPEC database in the United States.
Methods: The US HIPEC Collaborative, a 12 center, multi-institutional database of patients undergoing CRS-HIPEC, was reviewed for patients with SCA. Univariate analysis of demographic and pathologic factors was performed. OS and recurrence free survival (RFS) was determined by Kaplan-Meier analysis.
Results: Of 894 patients with appendiceal adenocarcinoma that underwent CRS-HIPEC, 125 had SCA (13.9%). The two groups were similar regarding age, sex, race, and ASA status. There were no differences in primary tumor size (p=0.99), lymph nodes examined (p=0.75), peritoneal carcinomatosis index (PCI) (15.6 9.4 vs 16.7 9.1, p=0.33), or completeness of cytoreduction (CCR) (CC0 47.9% vs 51.2%; CC1 21.9% vs 24.5%, p=0.25). Patients with SCA had a higher prevalence of positive lymph nodes (34.4% vs 11.1%, p<0.01), greater incidence of lymphovascular invasion (LVI) (47.2% vs 5.0%, p<0.01), perineural invasion (PNI) (40.0% vs 3.6%, p<0.01), and were more likely to have poor differentiation (70.8% vs 8.2%, p<0.01). These patients were also more likely to receive neoadjuvant (45.6% vs 19.3%, p<0.01) or adjuvant (52.0% vs 15.8%, p<0.01) chemotherapy. Signet ring cells conferred a worse median OS (32.0 vs 91.4 months, p<0.01) and RFS (17.7 vs 32.4 months, p<0.01). On subgroup analysis, improved OS was seen in patients with well/moderately differentiated SCA (49.9 vs 24.0 months, p=0.03), PCI <20 (49.3 vs 20.1 months, p<0.01), and ability to achieve CC0/1 (49.3 vs 15.1 months, p<0.01). However, receipt of neoadjuvant therapy in patients with signet ring cell cancers (n=57) was not associated with improved median OS (26.0 vs 32.0 months, p=0.99) or RFS (18.5 vs 15.2 months, p=0.82) despite similar PCI, CCR, LVI, PNI, presence of positive lymph nodes, and ASA status.
Conclusion: Herein, we present the largest multi-institutional HIPEC series evaluating the prognostic implications of SCA after CRS-HIPEC. We recommend using this procedure selectively in patients with poorly differentiated tumors, PCI >20, and when a complete cytoreduction cannot be achieved. However, while this is a negative prognostic feature, SCA with peritoneal involvement should not be a contraindication to CRS-HIPEC in the appropriately selected patient.


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