The definition of tumor deposits (TD) in colonic adenocarcinoma has been modified in different editions of AJCC/TNM staging system. Studies have shown that the presence of TD is associated with advanced tumor growth and poor prognosis. Most of these data were obtained in patients with simultaneous lymph node (LN) metastases. Reports focusing on the impact of TD in patients without LN metastasis are limited. We retrospectively restaged all right-sided colonic adenocarcinoma over a 10-year period using criteria from the 5th, 6th, and 7th AJCC edition. We compared the number of tumor nodule interpreted as LN and TD in each edition, and evaluated the stage migration caused by TD definition change. We then assessed clinical significance of TD in AJCC 7th edition by comparing 5-year overall survival of N1c patients vs. other N category (N0, N1, N2) patients with similar T and M status. We showed that average number of tumor nodule interpreted as LN per case and number of cases with positive LN were significantly decreased with 7th edition compared to 5th/6th; however, numbers of cases with TD and <12 LN were significantly increased with 7th edition compared to 5th/6th. These changes, however, resulted in minimal effects on the final stage grouping. Our survival analysis showed that N1c patients had significantly worse survival compared to N0 patients. Although not statistically significant, the hazard ratios indicated that N1c group might have worse survival than N1 group and better survival than N2 group. Therefore, we conclude that TD predict patient outcome at least similarly to positive LN.
Context The AJCC 7th Ed defines pericolonic tumor deposits (TD) as discrete tumor foci in pericolic fat showing no evidence of residual lymph node (LN). This definition relies on subjective features rather than size (5th) or shape (6th) and introduced the category N1c. While typically straightforward, metastases are encountered where distinction between LN and TD is unclear. For data to be meaningful, agreement on distinguishing features between positive LN and TD is needed. Objective We evaluated the agreement between GI pathologists on difficult metastases and report a list of distinguishing features they found helpful. Design Tumor metastases (25) from right-sided colonic adenocarcinomas were selected where distinction between positive LN and TD was challenging. Virtual slides were reviewed by 7 GI pathologists. A list of features potentially helpful in differentiating positive LN and TD was ranked for usefulness by each pathologist. Every metastasis was diagnosed as positive LN or TD. For each case diagnosed as positive LN, reviewers listed every feature used in diagnosis. Results Complete agreement was found in 11/25 metastases, 5 positive LN and 6 TD (kappa statistic, 0.4; 95% CI, 0.28, 0.67). Top ranked features included round shape, peripheral lymphocyte rim, peripheral lymphoid follicles, possible subcapsular sinus, LN in surrounding fat and thick capsule. Top utilized features were similar. Conclusions Significant agreement between evaluators existed, but inconsistency remains. We found that round shape, lymphoid follicles, peripheral lymphocyte rim, LN in surrounding fat, possible subcapsular sinus and thick capsule were most often used to aid in LN diagnosis.
PurposeAppendiceal tumors are a heterogeneous group of diseases that include typical neuroendocrine tumors (TNET), goblet cell carcinoids (GCC), and atypical GCC. Atypical GCC are classified into signet-ring cell cancers (SRCC) and poorly differentiated appendiceal adenocarcinoids. The prognosis and management of these diseases is unclear because there are no prospective studies. The aim of this study is to assess the characteristics and outcome of appendiceal TNET, GCC, and SRCC patients.Materials and MethodsAppendiceal TNET, GCC, and SRCC patients diagnosed between 1973 and 2011 were identified in the Surveillance Epidemiology and End Results (SEER) database. Demographics, type of surgery, and clinicopathologic characteristics were collected. Survival functions were estimated by the Kaplan-Meier method, and log-rank test was used to assess the difference in overall survival (OS) among the three histologies.ResultsThe SEER database yielded 1,021 TNET patients, 1,582 with GCC, and 534 SRCC patients. TNET presented at a younger age (p < 0.001). Patients with SRCC presented with advanced stage disease (p < 0.001). The median OS (mOS) for GCC and TNET patients was not reached; mOS for SRCC was 24 months. Multivariate analysis stratified for stage revealed significantly longer survival for TNET and GCC than SRCC (p < 0.001).ConclusionThis is the largest report to date for appendiceal neuroendocrine tumor patients, suggesting a spectrum of diseases with different characteristics and outcomes. In this report, we present a treatment approach for this complex spectrum of disease, based on the experience of Ohio State and Emory Universities investigators.
Background Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathologic diagnosis recently defined by the World Health Organization in 2010. Due to poor understanding of MANEC as a clinical entity, there is significant variation in the management of these patients. The purpose of our study was to characterize MANEC to develop evidence-based treatment strategies. Methods The Ohio State University patient database was queried for the diagnosis of MANEC and 46 patients were identified. For comparison, the database also was queried for goblet cell carcinoid (GCC) of the appendix, signet ring cell carcinoma, and carcinoid/neuroendocrine tumor of the appendix. Charts were then retrospectively reviewed for clinicopathologic characteristics, patient treatment, and survival data. Results The mean age of diagnosis of MANEC was 54 years. Eighty-seven percent of MANEC arose from the appendix, with 28 % of patients undergoing appendectomy and 35 % undergoing right hemicolectomy as their index operation. Immunohistochemical staining was positive for chromogranin (82 %), synaptophysin (97 %), and CD56 (67 %). Sixty-seven percent of patients presented with stage IV disease and 41 % had nodal metastases. Overall survival was 4.1 years, which was statistically significantly different (p ≤ 0.05) compared with carcinoid tumors (13.4 years), GCC (15.4 years), and signet ring carcinoma (2.2 years). Conclusions MANEC is a more aggressive clinical entity than both GCC of the appendix and carcinoid/neuroendocrine tumors of the appendix. Based on these findings, we recommend patients with MANEC tumors undergo aggressive multidisciplinary cancer management and close surveillance.
Fhit protein is lost or reduced in a large fraction of human tumors, and its restoration triggers apoptosis and suppresses tumor formation or progression in preclinical models. Here, we describe the identification of candidate Fhit-interacting proteins with cytosolic and plasma membrane localization. Among these, Annexin 4 (ANXA4) was validated by co-immunoprecipitation and confocal microscopy as a partner of this novel Fhit protein complex. Here we report that overexpression of Fhit prevents Annexin A4 translocation from cytosol to plasma membrane in A549 lung cancer cells treated with paclitaxel. Moreover, paclitaxel administration in combination with AdFHIT acts synergistically to increase the apoptotic rate of tumor cells both in vitro and in vivo experiments.
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