Abstract
Introduction
Conversion from low-grade to high-grade disease is known to occur following repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC); however, the incidence rate, risk factors, and outcomes have not been studied.
Methods
We conducted a retrospective review of multiple CRS/HIPEC cases for patients originally diagnosed with low-grade appendiceal neoplasms, and compared converted cases with non-converters. Primary outcomes were the incidence rate and risk factors for conversion, while secondary outcomes were effect on cytoreduction, overall survival (OS), and disease-free survival (DFS).
Results
Overall, 65 patients undergoing 134 cases of repeat CRS/HIPEC were identified; 11 patients converted to high-grade disease, an incidence rate of 16.92%. Converted cases averaged 4.4 years between CRS/HIPEC, versus 3.7 years for non-converters. Elevated baseline carcinoembryonic antigen (CEA) level, splenectomy at index CRS/HIPEC, and adjuvant chemotherapy utilization were statistically significant with conversion. Conversion had no impact on specific cytoreductive scores at repeat CRS/HIPEC (p = 0.435). Evaluating the effect on OS from the index CRS/HIPEC conversion had no impact. Mean OS was 9.5 and 8.8 years for cases that remained low-grade compared with those that converted, respectively (p = 0.668); however, when comparing OS from the time of conversion at repeat CRS/HIPEC, patients who progressed to high-grade disease had decreased survival at 4.4 versus 5.8 years (p = 0.0317). There was no difference in DFS between non-converters and converters at 4.1 and 3.6 years, respectively (p = 0.671).
Conclusion
Conversion had no impact on OS from the index CRS/HIPEC but resulted in inferior survival from repeat surgery. Conversion was insignificant in regard to DFS, and should not be considered a contraindication to repeat CRS/HIPEC. Adjuvant chemotherapy should be avoided.
Similar content being viewed by others
References
Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol. 2007;14(2):484–92.
Huang CQ, Min Y, Wang SY, Yang XJ, Liu Y, Xiong B, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival for peritoneal carcinomatosis from colorectal cancer: a systematic review and meta-analysis of current evidence. Oncotarget. 2017;8(33):55657.
Chua TC, Moran BJ, Sugarbaker PH, Levine EA, Glehen O, Gilly FN, et al. Early-and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30(20):2449–56.
Levine EA, Stewart JH 4th, Shen P, Russell GB, Loggie BL, Votanopoulos KI. Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. J Am College Surg. 2014;218(4):573–85.
Ahmed S, Stewart JH, Shen P, Votanopoulos KI, Levine EA. Outcomes with cytoreductive surgery and HIPEC for peritoneal metastasis. J Surg Oncol. 2014;110(5):575–84.
Marmor S, Portschy PR, Tuttle TM, Virnig BA. The rise in appendiceal cancer incidence: 2000–2009. J Gastrointest Surg. 2015;19(4):743–50.
Carr NJ, Cecil TD, Mohamed F, Sobin LH, Sugarbaker PH, González-Moreno S, et al. A consensus for classification and pathologic reporting of pseudomyxoma peritonei and associated appendiceal neoplasia. Am J Surg Pathol. 2016;40(1):14–26.
Sugarbaker PH. The natural history, gross pathology, and histopathology of appendiceal epithelial neoplasms. Eur J Surg Oncol. 2006;32(6):644–7.
Guaglio M, Sinukumar S, Kusamura S, Milione M, Pietrantonio F, Battaglia L, et al. Clinical surveillance after macroscopically complete surgery for low-grade appendiceal mucinous neoplasms (LAMN) with or without limited peritoneal spread: long-term results in a prospective series. Ann Surg Oncol. 2018;25(4):878–84.
El Halabi H, Gushchin V, Francis J, Athas N, MacDonald R, Nieroda C, et al. The role of cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) in patients with high-grade appendiceal carcinoma and extensive peritoneal carcinomatosis. Ann Surg Oncol. 2012;19(1):110–4.
Van Sweringen HL, Hanseman DJ, Ahmad SA, Edwards MJ, Sussman JJ. Predictors of survival in patients with high-grade peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Surgery. 2012;152(4):617–25.
Sardi A, Jimenez WA, Nieroda C, Sittig M, Macdonald R, Gushchin V. Repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from appendiceal cancer: analysis of survival outcomes. Eur J Surg Oncol. 2013;39(11):1207–13.
Mogal H, Chouliaras K, Levine EA, Shen P, Votanopoulos KI. Repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: review of indications and outcomes. J Gastrointest Oncol. 2016;7(1):129.
Bekhor E, Carr J, Hofstedt M, Sullivan B, Solomon D, Leigh N, et al. The safety of iterative cytoreductive surgery and HIPEC for peritoneal carcinomatosis: a high volume center prospectively maintained database analysis. Ann Surg Oncol. 2020;27(5):1448–55.
Dindo D. The Clavien–Dindo classification of surgical complications. In: Cuesta MAngel, Bonjer J (eds). Treatment of postoperative complications after digestive surgery. London: Springer; 2014. pp. 13–17.
Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Yung RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003;27(8):1089–103.
Levine EA, Blazer DG 3rd, Kim MK, Shen P, Stewart JH 4th, Guy C, et al. Gene expression profiling of peritoneal metastases from appendiceal and colon cancer demonstrates unique biologic signatures and predicts patient outcomes. J Am College Surg. 2012;214(4):599–606.
Singhi AD, Davison JM, Choudry HA, Pingpank JF, Ahrendt SA, Holtzman MP, et al. GNAS is frequently mutated in both low-grade and high-grade disseminated appendiceal mucinous neoplasms but does not affect survival. Hum Pathol. 2014;45(8):1737–43.
Liao X, Vavinskaya V, Sun K, Hao Y, Li X, Valasek M, et al. Mutation profile of high-grade appendiceal mucinous neoplasm. Histopathology. 2020;76(3):461–9.
Hara K, Saito T, Hayashi T, Yimit A, Takahashi M, Mitani K, et al. A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix. Pathol-Res Practice. 2015;211(9):657–64.
Carr NJ, Bibeau F, Bradley RF, Dartigues P, Feakins RM, Geisinger KR, et al. The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei. Histopathology. 2017;71(6):847–58.
Turaga KK, Pappas SG, Gamblin TC. Importance of histologic subtype in the staging of appendiceal tumors. Ann Surg Oncol. 2012;19(5):1379–85.
Overman MJ, Fournier K, Hu CY, Eng C, Taggart M, Royal R, et al. Improving the AJCC/TNM staging for adenocarcinomas of the appendix: the prognostic impact of histological grade. Ann Surg. 2013;257(6):1072–8.
Choudry HA, Bednar F, Shuai Y, Jones HL, Pai RK, Pingpank JF, et al. Repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion is feasible and offers survival benefit in select patients with peritoneal metastases. Ann Surg Oncol. 2019;26(5):1445–53.
Powers BD, Felder S, Veerapong J, Baumgartner JM, Clarke C, Mogal H, et al. Repeat cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is not associated with prohibitive complications: results of a multiinstitutional retrospective study. Ann Surg Oncol. 2020;27(13):4883–991.
Votanopoulos KI, Ihemelandu C, Shen P, Stewart JH, Russell GB, Levine EA. Outcomes of repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal surface malignancy. J Am College Surg. 2012;215(3):412–7.
Konstantinidis IT, Levine EA, Chouliaras K, Russell G, Shen P, Votanopoulos KI. Interval between cytoreductions as a marker of tumor biology in selecting patients for repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2017;116(6):741–5.
Chua TC, Chong CH, Liauw W, Zhao J, Morris DL. Inflammatory markers in blood and serum tumor markers predict survival in patients with epithelial appendiceal neoplasms undergoing surgical cytoreduction and intraperitoneal chemotherapy. Ann Surg. 2012;256(2):342–9.
Reghunathan M, Kelly KJ, Valasek MA, Lowy AM, Baumgartner JM. Histologic predictors of recurrence in mucinous appendiceal tumors with peritoneal dissemination after HIPEC. Ann Surg Oncol. 2018;25(3):702–8.
Mellemkjøer L, Olsen JRH, Linet MS, Gridley G, McLaughlin JK. Cancer risk after splenectomy. Cancer. 1995;75(2):577–83.
Sun LM, Chen HJ, Jeng LB, Li TC, Wu SC, Kao CH. Splenectomy and increased subsequent cancer risk: a nationwide population-based cohort study. Am J Surg. 2015;210(2):243–51.
Holohan C, van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug resistance in cancer: an overview. Cancers. 2014;6(3):1769–92.
Blackham AU, Swett K, Eng C, Sirintrapun J, Bergman S, Geisinger KR, et al. Perioperative systemic chemotherapy for appendiceal mucinous carcinoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Surg Oncol. 2014;109(7):740–5.
Kolla BC, Petersen A, Chengappa M, Gummadi T, Ganesan C, Gaertner WB, et al. Impact of adjuvant chemotherapy on outcomes in appendiceal cancer. Cancer Med. 2020;9(10):3400–6.
Lu P, Fields AC, Meyerhardt JA, Davids JS, Shabat G, Bleday R, et al. Systemic chemotherapy and survival in patients with metastatic low-grade appendiceal mucinous adenocarcinoma. J Surg Oncol. 2019;120(3):446–51.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosure
There are no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Mangieri, C.W., Valenzuela, C.D., Erali, R.A. et al. Incidence, Risk Factors, and Outcomes from Conversion of Low-Grade to High-Grade Appendiceal Neoplasms for Patients Undergoing Multiple Cytoreductive Surgeries with Hyperthermic Intraperitoneal Chemotherapy. Ann Surg Oncol 29, 205–211 (2022). https://doi.org/10.1245/s10434-021-10660-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-021-10660-4