Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade

Abstract

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with Po0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (Po0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P ¼ 0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P ¼ 0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix

“…These findings suggest the possible involvement of p53 during the progression of LAMN to MAC. Collectively, these findings are the first evidence that confirmed co-existence of genetically distinct low-grade and high-grade components within AMTs and possible transformations of MAC from LAMN within a single tumor, different from those that occurred during the recurrent process of the tumor [30].…”

A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia

“…Davison et al 14 found that any of the following confer a worse prognosis in PMP of appendiceal origin: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells. These features were used to classify lesions into 3 grades: G1 lacks all of these features; G2…”

“…[1][2][3][4][5][6][7][8][13][14][15][16][17]22,34 With the development of curative treatment for PMP based on cytoreductive surgery and perioperative intraperitoneal chemotherapy, it is essential to harmonize terminology and diagnostic criteria, not only for the management of individual patients but also to allow comparison between institutions and different surgical techniques which can profoundly affect outcomes. 16,22,35 Cytoreductive surgery and perioperative intraperitoneal chemotherapy are now considered a standard of care for PMP, 36 and prognostic assessments from histopathology performed at institutions not using this technique must be approached with caution.…”

“…Several participants stated they were unhappy with the term DPAM and felt it should be dropped, consistent with the controversy this term has caused in the literature. [13][14][15]17 However, it is widely used and the majority preferred to retain it as a synonym.…”

“…Unfortunately, the end result has been a variety of different proposed classifications [1][2][3][4][5][6]13 that can lead to confusion among treating clinicians. 14,15 Some of the terms used are contentious. For example, "adenomucinosis" for low-grade lesions is favored by some, but others believe it is unsuitable terminology.…”