Extent of Resection and Long-Term Outcomes for Appendiceal Adenocarcinoma: a SEER Database Analysis of Mucinous and non-Mucinous Histologies

Background Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. Patients and Methods Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000–2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan–Meier estimates and examined using Cox proportional hazards modeling. Results Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81–1.22]. Conclusions Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-024-15233-9.

low grade, negative resection margins, no lymphovascular invasion).Patients with high-risk T1 tumors or invasion beyond the submucosa (> T2) are considered for a right hemicolectomy for pathologic assessment of the ileocolic lymph nodes. 6,7he clinical behavior of appendiceal adenocarcinomas varies on the basis of disease stage and the presence of a mucinous subtype. 8Mucinous appendiceal adenocarcinoma (MAA) is distinguished from non-mucinous appendiceal adenocarcinoma (NMAA) by the criterion of having > 50% of the cross-sectional area histologically comprised of mucin. 3MAA have distinct patterns of metastatic spread, with mucinous seeding of the peritoneal cavity and a lower rate of lymphatic and hematogenous dissemination. 9,10hile the rate of isolated lymph node metastases in the absence of other metastatic disease is lower for MAA compared with NMAA, the presence of nodal metastases is nevertheless prognostic of survival for both subtypes. 11,12till, the role of routine colectomy for therapeutic removal of involved lymph nodes may not improve survival, particularly for MAAs.4][15][16] To clarify the association between extent of resection and disease-specific survival (DSS), a preferrable study endpoint for a cancer with a generally favorably prognosis, the Surveillance, Epidemiology, and End Results (SEER) database was queried to evaluate the oncologic value of the extent of surgical resection for both mucinous and non-mucinous subtypes.

Patient selection
After institutional review board approval, data (2000-2020) were extracted from the SEER database (https:// seer.cancer.gov/).Patients ≥ 18 years of age who underwent resection of appendiceal adenocarcinoma were identified.Patients were selected using appendix site code (ICD-O-3 topography code C18.1) and corresponding ICD-O-3 morphology codes for MAA and NMAA (Supplemental Table 1).Patients were excluded if they had metastatic disease at the time of surgical resection or unknown diseasespecific survival.

Variables
The demographic and clinical SEER variables utilized in this study included age (< 60, 60-69, 70-79, and > 80 years), sex, race/ethnicity, median income, population density (metropolitan areas, adjacent or non-adjacent nonmetropolitan areas), primary tumor (pT)-stage, regional lymph node metastasis (pN)-stage, tumor grade, and administration of adjuvant chemotherapy.Extent of resection was defined by either appendectomy versus hemicolectomy.The primary outcome, DSS, was defined as the interval between date of diagnosis and date of death from disease, with censoring at last contact or death from another cause.

Statistical Analyses
Descriptive statistics are presented as frequencies for categorical variables and median [interquartile range (IQR)] for continuous variables.Pearson's χ2 and Wilcoxon ranksum tests were used to analyze categorical and continuous variables, respectively.Variables associated with colectomy on univariate analysis were entered into a stepwise logistic regression model (p ≤ 0.05 for entry; p > 0.10 for removal) to identify independent predictors of colectomy utilization.The influence of colectomy on DSS was analyzed using Kaplan-Meier estimates and Cox proportional hazards modeling with backwards stepwise selection (p ≤ 0.05 for entry; p > 0.10 for removal) including all the aforementioned demographic and clinical SEER variables.Multivariable Cox regression was performed both for the overall cohorts and within each T-stage category.Propensity score matching between ''control'' (i.e., appendectomy) and ''case'' (i.e., colectomy) was attempted but abandoned owing to significance imbalance between the two groups, highlighting the marked and nonrandom differences in treatment approaches in this national subset. 17,18Thus, only multivariable regressions were utilized.p-Values ≤ 0.05 were considered statistically significant; all tests were two-sided.Analyses were carried out using SPSS version 29.0 (IBM Corp., Armonk, NY).

Rates and Predictors of Colectomy
A total of 7549 patients with appendiceal adenocarcinoma who underwent appendectomy or colectomy were identified in the SEER database.Serial exclusion of patients with metastatic disease at time of initial resection (n = 2843) and those without known disease-specific Extent of Resection and Long-Term … survival (n = 32) yielded a final cohort of 4674 patients.The majority (n = 3169; 67.8%) underwent colectomy; the remaining patients underwent appendectomy (n = 1505; 32.2%).Regarding histologic subtype, 2684 (57.4%) were NMAAs, and 1990 (42.6%) were MAAs.
In both the non-mucinous and mucinous subsets, significant clinicopathologic differences existed between the appendectomy and colectomy-treated groups (Table 1).For both histologies, colectomy was increasingly used for younger patients and was associated with higher T-stages.Notably, no disparities were observed by treatment strategy according to sex, median income, population density, and tumor grade.
Preoperative carcinoembryonic antigen (CEA) values were available for 25.6% of the overall cohort (non-mucinous: n = 670; mucinous: n = 525); in both subsets, elevated CEA was not associated with rates of colectomy (p = 0.400 and p = 0.605, respectively).In a multivariable logistic regression model, age, T-stage, and N-stage were independently associated with colectomy use (Supplemental Table 2).
Since tumor grade has been previously reported to be associated with risk of lymph node disease, rates of lymph node metastases in NMAA and MAA were analyzed in our cohort, stratified by tumor grade. 11,19For both histologies, grade was significantly associated with N+ disease (p < 0.001), with poorly differentiated tumors exhibiting the highest rates of lymph node metastasis (NMAA: 44.4%, MAA: 31.3%, p = 0.002; Supplemental Table 3).Patients with well-differentiated and moderately differentiated tumors had lower rates of lymph node metastases, with no significant difference between NMAA and MAA tumors (well differentiated: 9.0% versus 7.7%, p = 0.450; poorly differentiated: 20.5% versus 19.2%, p = 0.490, respectively).

Influence of Colectomy on Disease-Specific Survival in the Overall Cohort
Median follow-up was 74 (IQR 33-131) months and 87 (IQR 41-150) months for the non-mucinous and mucinous adenocarcinoma subsets, respectively.A total of 1214 (26.0%) disease-specific deaths were observed.The long-term survival impact of extent of surgical resection was examined using Cox proportional hazards modeling, including those variables significantly associated with DSS by univariate analysis (

Survival Analysis of Extent of Resection, Stratified by T-stage
Given that T-stage and N-stage were each associated with disease-specific survival, and that nodal positivity was increasingly observed for higher T-stage, the impact of extent of surgery was analyzed for each T-stage.For nonmucinous appendiceal adenocarcinoma, there was no difference in DSS observed for appendectomy versus colectomy for patients with T1 tumors (log rank p = 0.298; Fig. 1).In contrast, utilization of colectomy was associated with improved DSS for patients with T3 (log rank p = 0.018) tumors and a trend toward improved DSS was observed in patients with T2 tumors (log rank p = 0.095).Patients with T4 non-mucinous tumors managed with appendectomy or colectomy evidenced similar DSS (log rank p = 0.912).In a multivariable cox regression accounting for age, N-stage, grade, and use of adjuvant chemotherapy, colectomy in patients with T3 tumors was associated with reduced risk of disease-specific death (HR 0.75, 95% CI 0.58-0.98,p = 0.032).Extent of surgery was not independently associated with DSS for other T categories (p = 0.495, p = 0.100, and p = 0.259 for T1, T2, and T4 lesions, respectively).

Survival Analysis of Extent of Resection, Stratified by Grade
The association of the extent of surgical resection and DSS was subsequently analyzed for each tumor type and stratified by tumor grade.For patients with moderately differentiated NMAA, hemicolectomy was associated with improved DSS compared with appendectomy (log rank p = 0.006; Fig. 3).In contrast, colectomy was not associated with DSS in well-differentiated (log rank p = 0.992) and poorly Extent of Resection and Long-Term … differentiated (log rank p = 0.762) NMAA.For patients with MAA, extent of resection was not associated with DSS for any tumor grade (well differentiated: p = 0.948, moderately differentiated: p = 0.289, poorly differentiated: p = 0.744).

DISCUSSION
The current study comprises the largest population-based study evaluating disease-specific survival by extent of resection for patients with mucinous and non-mucinous subtypes of appendiceal adenocarcinoma.In our analysis, non-mucinous histologies were associated with significant rates of lymph node metastases (26-44% for T3-4 lesions).In support of expert guidelines, surgical clearance of such lymph nodes with colectomy was associated with improvements in cancer-related deaths, particularly for T3 and moderately differentiated tumors.In contrast, mucinous histologies had lower rates of lymph node metastases, and use of colectomy was not associated with improved disease-specific survival for any MAA patients.Such data confirm the divergent biologic characteristics of mucinous versus non-mucinous AA and highlight the importance of consideration of histologic subtype in their surgical management.
Previous SEER-based propensity-score-matched analysis found that mucinous histology was not independently associated with long-term survival in stage I-III AA patients. 20he authors subsequently conclude that the same treatment strategies can be applied regardless of histologic subtype.However, similar risk-adjusted prognosis does not necessarily equate to similar surgical treatment.Here, by segregating the NMAA and MAA patients in all statistical analyses, a histology-dependent association between extent of resection and disease-specific survival was identified.For patients with NMAA, absolute improvements in DSS were observed for T2 and T3 lesions as well as moderately differentiated tumors.A DSS advantage was not observed in patients with T1 tumors.In support, previous studies have not demonstrated a survival benefit of an extensive lymphadenectomy for low risk T1 tumors, likely given the low rates of nodal disease. 14,15Patients with T1 tumors exhibited lymph node positivity rates of only 6.8% when undergoing colectomy.The lack of association between extent of surgery and survival for NMAA T4 tumors was an interesting finding, possibly driven by the higher risk of metastatic failure that would render extensive lymphadenectomy alone an ineffective way to achieve cure.Oncologic tenets from the surgical management of colorectal cancer-namely, the use of colectomy for surgical staging of the draining lymph node basin-may not be relevant for the mucinous subtype of AA.In support, genomic analyses have revealed differences in the mutational landscape of AA and CRC as well as between MAA and NMAA. 21Compared with NMAA, MAA are more likely to harbor mutations in KRAS and GNAS, with fewer mutations in TP53. 22,23These genomic differences provide biologic support for consideration of distinct clinical entities requiring individualized treatment approaches.In these data, disease-specific survival was independent of type of resection for all MAA patients in a multivariable model adjusting for T-stage, grade, and use of adjuvant chemotherapy.Likewise, a previous analysis of MAA using the SEER dataset found that extent of resection was not associated with disease-specific survival, although this prior analysis involved a more heterogeneous cohort inclusive of patients with metastatic disease and data dating primarily from the twentieth century. 24Still, the current results were surprising, given the significant risk of nodal involvement for certain patients (17-22% in T3 and T4 MAA; 18-29% for moderately and poorly differentiated MAA).
One possible explanation could be the unique biologic behavior of mucinous tumors.These tumors have a propensity to recur within the peritoneum, which may not be prevented by more extensive lymphadenectomy.Mucin 2 (MUC2) is the most abundant, gel-forming, mucus protein primarily secreted in the small bowel and colon. 25MUC2 and MUC5A have been found to be overexpressed in MAA, with MUC2 being more profoundly expressed in pseudomyxoma peritonei of appendiceal origin. 26,279][30][31] Under normal conditions, secreted mucin serves to protect the intestinal epithelium and subsequently undergoes degradation.However, when peritoneal seeding occurs, the produced mucin fails to degrade within the peritoneal cavity, leading to accumulation and development of pseudomyxoma peritonei.This mucin can shield cancer cells from the host's immune system as well as prevent the delivery of chemotherapy agents, leading to treatment failure. 32,33Additionally, the mucin can facilitate the spread of tumor cells within the peritoneal cavity and create a favorable microenvironment that enhances tumor growth. 33,34his unique biologic behavior potentially renders an extensive lymphadenectomy alone an ineffective way to achieve cure for localized MAA.Relatedly, in a study examining outcomes in patients with metastatic MAA and peritoneal seeding who underwent cytoreductive surgery and intraperitoneal chemotherapy, the addition of right hemicolectomy did not provide a survival advantage over those who underwent appendectomy alone.Additionally, when the cohort was stratified by lymph node status, no difference in survival was observed between node-negative patients, node-positive patients, and patients with unknown nodal status. 35ithout the prospect of randomized data given the rarity of this entity, these multivariable-adjusted registry-based data may be the best quality data available to guide clinical management.Still, these findings need to be interpreted with caution, and several limitations warrant emphasis.][38][39] Nevertheless, significant differences were observed between the appendectomy and the colectomy cohorts.An attempt to build propensity-score-matched cohorts failed, which points to the likely impact of treatment bias present in these nonrandomized data.Still, SEER reporting of disease-specific (versus overall) survival allowed for more precise understanding of the impact of surgical extent on long-term outcomes while minimizing the bias of patient comorbidity on both surgical treatment and the rate of non-disease-related deaths.A second major limitation is the lack of data on resection margin status following appendectomy as well as information on specific histologic characteristics, such as lymphovascular invasion (LVI).These two variables are important determinants in surgical management of T1 tumors; without these data, our findings may only be applicable for T1 tumors without positive resection margins or LVI.Third, the analyses of tumor grade are limited by institutional differences in pathologic grading as well as changes in the grade classification (i.e., two-versus three-versus four-tier system) that occurred over the study period.Thus, the results of the grade-stratified analyses need to be validated in additional contemporary series.Fourth, serum biomarkers (e.g., Ca 19-9 and CA 125) may be elevated in patients with appendiceal adenocarcinoma and have been associated with survival.Unfortunately, such data were not available to be included in these analyses.Lastly, limitations particular to SEER include certain database inadequacies, such as (a) specific chemotherapy regimens utilized, (b) completion of prescribed treatment schedules, (c) rates and types of recurrences, and (d) all clinical details that may have informed decisions regarding extent of surgery.In this regard, we observed a small number of patients who underwent appendectomy alone for node-positive disease that could not be explained by differences in their social determinants of health.It is possible that patient comorbidity may have contributed to some of these treatment decisions.

CONCLUSIONS
In this contemporary, population-based analysis of the use of colectomy for nonmetastatic mucinous and non-mucinous appendiceal adenocarcinoma, the survival impact of surgical strategies varied by histologic subtype.No improvement in disease-free survival was observed for the subset of patients with mucinous AA regardless of T-stage and histologic grade.These data support consideration of histologic subtype in the surgical treatment of localized AA.In the absence of randomized data, these results raise doubts regarding the need for colectomy for localized MAA.

TABLE 1
Clinicodemographics of NMAA and MAA patients in the overall study cohort

TABLE 2
Cox regression model for independent predictors of disease-specific survival