Journal of Gastrointestinal Surgery https://doi.org/10.1007/s11605-019-04336-4 2019 SSAT PLENARY PRESENTATION Should We Be Doing Cytoreductive Surgery with HIPEC for Signet Ring Cell Appendiceal Adenocarcinoma? A Study from the US HIPEC Collaborative Nick C. Levinsky1 & Mackenzie C. Morris1 & Koffi Wima1 & Jeffrey J. Sussman1 & Syed A. Ahmad1 & Jordan M. Cloyd2 & Charles Kimbrough2 & Keith Fournier3 & Andrew Lee3 & Sean Dineen4 & Sophie Dessureault4 & Jula Veerapong5 & Joel M. Baumgartner5 & Callisia Clarke6 & Mohammad Y. Zaidi7 & Charles A. Staley7 & Shishir K. Maithel7 & Jennifer Leiting8 & Travis Grotz8 & Laura Lambert 9 & Ryan J. Hendrix9 & Sean Ronnekleiv-Kelly10 & Courtney Pokrzywa10 & Mustafa Raoof11 & Oliver S. Eng11 & Fabian M. Johnston12 & Jonathan Greer12 & Sameer H. Patel1 Received: 17 May 2019 /Accepted: 19 July 2019 # 2019 The Society for Surgery of the Alimentary Tract Abstract Background Appendiceal adenocarcinoma with signet ring cells (SCA) is associated with worse overall survival (OS), and it is unclear whether cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) should be pursued in this patient population. We assessed the prognostic implications of signet ring cells in patients with appendiceal adenocarcinoma and peritoneal carcinomatosis undergoing CRS-HIPEC. Methods The US HIPEC Collaborative, a 12-center, multi-institutional database of patients undergoing CRS-HIPEC, was reviewed for patients with SCA. Univariate and multivariate analyses were performed. Results Of 514 patients undergoing CRS-HIPEC for appendiceal adenocarcinoma, 125 (24%) had SCA. The SCA and non-SCA groups had similar baseline characteristics. SCA had worse OS compared with non-SCA (32.0 vs 91.4 months, p <0.001).In univariate analysis for only SCA cases, there was worse OS in patients with poorly differentiated tumors, positive lymph nodes, LVI, PCI > 20, or incomplete cytoreduction (CC-2/3). However, multivariate analysis showed only positive lymph nodes (HR 1.14 [95% CI 1.00–1.31], p = 0.04), poor differentiation (5.60 [1.29–24.39], p = 0.02), and incomplete cytoreduction (4.90 [1.11– 12.70], p = 0.03) were independently associated with decreased OS for SCA. Conclusion While signet cells are a negative prognostic feature, they should not be a contraindication to CRS-HIPEC in patients with well-moderately differentiated tumors with negative lymph nodes, where complete cytoreduction can be achieved. Keywords Appendiceal adenocarcinoma . Signet ring cells . Cytoreductive surgery . Hyperthermic intraperitoneal chemotherapy * Sameer H. Patel 6 Division of Surgical Oncology, Department of Surgery, Medical [email protected] College of Wisconsin, Milwaukee, WI, USA 7 1 Division of Surgical Oncology, Winship Cancer Institute, Emory Division of Surgical Oncology, Department of Surgery, University of University, Atlanta, GA, USA Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, 8 Cincinnati, OH 45267-0558, USA Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA 2 Division of Surgical Oncology, Department of Surgery, The Ohio 9 State University Wexner Medical Center, Columbus, OH, USA Division of Surgical Oncology, Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA 3 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Division of Surgical Oncology, Department of Surgery, University of Wisconsin, Madison, WI, USA 4 Department of Gastrointestinal Oncology, Moffitt Cancer Center, Department of Oncologic Sciences, Morsani College of Medicine, 11 Division of Surgical Oncology, Department of Surgery, City of Hope Tampa, FL, USA National Medical Center, Duarte, CA, USA 5 Division of Surgical Oncology, Department of Surgery, University of 12 Department of Surgery, Johns Hopkins University, Baltimore, MD, California, San Diego, CA, USA USA JGastrointestSurg Introduction of patients with signet ring cell pathology were identified. Clinicopathologic factors evaluated were demographic in- Appendiceal adenocarcinoma is a rare tumor that accounts for formation, cancer-specific factors, perioperative parame- < 1% of all gastrointestinal cancers.1,2 Auniquecharacteristic ters, pathologic factors, postoperative factors, systemic of this tumor is that approximately one-fifth of patients present chemotherapy administration, and survival outcomes. with peritoneal mucinous dissemination, resulting in the clin- Preoperative tumor markers were evaluated with CEA > ical syndrome of pseudomyxoma peritonei.3 Treatment for 5 ng/mL, CA 19-9 > 37 U/mL, and CA 125 > 35 U/mL patients with peritoneal carcinomatosis secondary to deemed as positive values. appendiceal neoplasms typically consists of cytoreductive sur- gery with hyperthermic intraperitoneal chemotherapy (CRS- Statistical Analysis HIPEC).4,5 Outcomes following CRS-HIPEC remain highly variable and are influenced by not only both appropriate pa- Categorical variables were compared using the chi-square test, tient selection, but also center experience.6 while continuous variables were compared using the Despite being a rare tumor, it can manifest with several Wilcoxon rank-sum test, and results are reported as n (%) or unique histologies which carry distinct biologic behaviors. median (inter-quartile range) as appropriate. If data were un- Several studies have demonstrated that histologic subtype is available or incomplete for a case entry, that case was exclud- prognostic of overall survival (OS), with high-grade lesions ed from the specific analysis for which data were unavailable. carrying the worst prognosis.7–9 Among the high-grade le- Median OS and recurrence-free survival (RFS) between co- sions, signet ring cells have been shown to be the most ag- horts were compared using the Kaplan-Meier method with the gressive, with SEER data reporting median OS of approxi- log-rank test. OS was calculated as the time from the date of mately 24 months.10–12 Signet ring cells are a histopathologic surgery until the date of reported death or last documented feature demonstrating intra-cellular mucinous vacuoles that patient follow-up. Cox proportional hazard regression was push the nuclei toward the cell periphery, giving the appear- performed to identify clinically relevant factors independently ance of a medieval signet ring.2 associated with OS. Covariates are as shown in Tables 3 and 4. Although CRS-HIPEC is uniformly accepted as a treat- Statistical analyses were performed with SAS (SAS Institute, ment for patients with low-grade appendiceal lesions, there Cary, NC). remains controversy in patients with high-grade lesions. Several studies have advised careful patient selection when dealing with signet ring cell appendiceal cancers.8,11 Despite Results these studies highlighting various factors associated with de- creased OS after CRS-HIPEC, many are limited to smaller Cohort Demographics single-institution series or having limited numbers of patients with signet cell tumors.2,8,10,11 Therefore, we sought to eval- A total of 514 patients with appendiceal adenocarcinoma uate outcomes in patients with signet ring cell appendiceal underwent CRS-HIPEC from 1999 to 2018. Group demo- adenocarcinoma and identify adverse prognostic factors that graphics are in Table 1. The median patient age was may serve as guidelines to select patients who would benefit 55 years, 55.8% were female, and 86.3% were white. A from CRS-HIPEC. total of 125 patients (24.3%) had signet ring cells present on pathologic examination while 389 patients (75.7%) did not. There were no significant differences in age, sex, Materials and Methods race, or ASA class among those with or without signet ring cells. Patients with signet ring cells were more likely Data Source to be uninsured (8.8% vs 1.3%, p < 0.001), current smokers (10.2% vs 1.8%, p < 0.001), or current drinkers The US HIPEC Collaborative is a multi-institutional group (8.5% vs 2.8%, p <0.001). comprised of 12 high volume academic institutions across the USA which routinely performs CRS-HIPEC. Clinicopathologic and Treatment Characteristics Following appropriate Institutional Review Board approv- al, a retrospective chart review of all CRS-HIPEC cases at The clinicopathologic and treatment characteristics are each institution from 1999 to 2018 was performed, and the displayed in Table 2. Compared with patients without signet data were subsequently compiled. This database consisted ring cells, patients with signet ring cell lesions were more of 2372 cases with malignancies of varying primary ori- likely to receive neoadjuvant chemotherapy (45.6% vs gins. The database was queried for all patients with prima- 19.3%, p < 0.001) or adjuvant chemotherapy (52.0% vs ry appendiceal adenocarcinoma (n = 514), and the subset 15.8%, p < 0.001) without regard to receipt of the other J Gastrointest Surg Table 1 Characteristics of patients undergoing CRS-HIPEC for appendiceal adenocarcinoma Characteristics Whole cohort (n =514), Non-signet ring cells (n =389), Signet ring cells (n =125), p median (IQR), n (%) median (IQR), n (%) median (IQR), n (%) Age, years 55 (48–65) 56 (48–65) 53 (47.5–62) 0.14 Sex, female 287 (55.8%) 214 (55.0%) 73 (58.4%) 0.51 Race 0.52 White 441 (86.3%) 331 (85.8%) 110 (88.0%) Black 13 (2.5%) 8 (2.1%) 5 (4.0%) Asian 25 (4.9%) 21 (5.4%) 4 (3.2%) Hispanic 18 (3.5%) 14 (3.6%) 4 (3.2%) Other 14 (2.7%) 12 (3.1%) 2 (1.6%) ASA Class 0.99 I 4 (0.96%) 3 (1.0%) 1 (0.9%) II 107 (25.72%) 78 (25.5%) 29 (26.4%) III 287 (68.99%) 212 (69.3%) 75 (68.2%) IV 18 (4.33%) 13 (4.2%) 5 (4.5%) Insurance status <0.001 Private 328 (67.08%) 251 (66.9%) 77 (67.5%) Government 146 (29.86%) 119 (31.7%) 27 (23.7%) Uninsured 15 (3.07%) 5 (1.3%) 10 (8.8%) Current smoker 19 (3.75%) 7 (1.8%) 12 (10.2%) < 0.001 Current drinker 21 (4.15%) 11 (2.8%) 10 (8.5%) < 0.001 modality. There was no difference in past surgical history with Survival Outcomes Following CRS-HIPEC regard to prior appendectomy or previous CRS-HIPEC; how- ever, those with signet cells were more likely to undergo a Kaplan-Meier analysis was performed to estimate median staging diagnostic laparoscopy (42.7% vs 21.3%, p <0.001).