High Incidence of Appendiceal Neoplasms in the Elderly: A Critical Concern for Non-Surgical Treatment

Appendiceal neoplasms (ANs) are rare tumors accounting for less than 1% of all gastrointestinal malignancies [1]. These neoplasms include a wide variety of growths, including neuroendocrine neoplasms (NENs), low-grade appendiceal mucinous neoplasms (LAMN), high-grade appendiceal mucinous neoplasms (HAMN), as well as primary adenocarcinomas [2, 3]. In addition to these neoplasms, the appendix can also be infiltrated by secondary tumors, such as lymphomas, genital tract malignancies, and metastatic carcinomas, among others [2, 3].

Despite the diverse spectrum of ANs, they often present with appendicitis-like symptoms and are often discovered incidentally during histopathological examination [4, 5]. Imaging modalities such as ultrasonography and computed tomography (CT) are helpful in identifying features of ANs, such as an enlarged or thickened appendix, calcifications, or nodules [5, 6]. However, these findings are not specific to neoplasms and may also be seen in benign conditions. On the other hand, imaging features of ANs may be subtle or resemble those of appendicitis [5, 6].

Surgery is the gold standard of treatment for acute appendicitis (AA). However, studies suggest that medical therapy may be a safe alternative to surgery [7]. Avoiding the potential risks of surgery is a major advantage of medical treatment. However, non-surgical treatment options may lead to tumors getting missed. Recent studies have shown that the prevalence of ANs can be as high as 28% in patients treated with non-surgical methods who subsequently underwent interval appendectomy [7‒11]. These findings highlight the need for caution when considering non-surgical management of AA, particularly in patients who may be at higher risk of ANs. Therefore, defining the clinical, imaging, and histopathological features of ANs and their distribution by age may be helpful in selecting patients for medical treatment. In this study, we documented temporal trend analyses of appendectomies performed over 12 years and evaluated the prevalence, clinical presentation, imaging, and histopathological features of ANs.

This was a multicenter retrospective observational cohort study. The digital health records of four tertiary referral hospitals (Erzincan Binali Yildirim University, Mengücek Gazi Training and Research Hospital [TARH], Umraniye TARH, Sultan II. Abdulhamid Han TARH, and Eskisehir City Hospital) were examined, and patients who underwent appendectomy for presumed AA from 2011 to 2022 were identified. Histopathological and imaging features, demographics, and clinical data of the cases were collected. Cases with missing medical records, laboratory, or imaging results were excluded. The slides of cases whose histopathological features were not clearly described in the pathology report were re-evaluated. Among these cases, those whose slides or blocks were not available in the pathology archive were also excluded. Six cases were excluded from the study due to missing data.

Approval for this study was granted by the Local Ethics Committee (approval number: 2023–04/02 dated February 16, 2023), and the research was carried out following the guidelines outlined in the Declaration of Helsinki. Patients provided informed consent for their participation and the publication of their clinical information.

Data were extracted from the electronic health records, including demographic data (age, gender), clinical presentation, laboratory results (white blood cell [WBC] level), imaging findings, macroscopic features, histopathological features, and diagnosis. Information on the diameter of the appendix (distance between the outer walls of the appendix measured on gross examination) was extracted from pathology reports.

The cases were classified into four groups according to their histopathological features. Cases without evidence of inflammation (neutrophilic infiltration, mucosal ulceration, and fibrinopurulent exudate in the appendix lumen) were classified in a negative appendectomy group [12]. Cases with neutrophilic inflammatory infiltrates were classified in the appendicitis group [12]. Cases with a primary or metastatic tumor were classified in the ANs group [3]. Cases with other abnormalities, such as parasites, diverticular disease, endometriosis, polyps, etc., were classified in the unusual findings group.

Afterward, the ANs group was divided into four subgroups according to diagnosis. Subgroup I: LAMN/HAMN; subgroup II: NENs; subgroup III: primary adenocarcinoma; and subgroup IV: secondary tumor infiltration.

Cases were also grouped according to age at diagnosis, and a total of six age groups were created (0–15 years, 16–39 years, 40–49 years, 50–59 years, 60–69 years, and over 70 years). Cases within the age range of 0–15 years were evaluated in the pediatric group, while the remaining cases were evaluated in the adult group. A diagram illustrating the selection of study participants and the classification of cases is provided in Figure 1.

The statistical analysis was performed using SPSS (version 25) software. Differences in age, gender, WBC, and appendiceal diameter among groups were assessed using the χ² or Kruskal-Wallis tests, depending on the data characteristics. The statistical confidence level was set at 0.95 (alpha = 0.05). Odds ratios (ORs) were calculated to evaluate the risk of developing ANs in different age groups. A logistic regression analysis was performed, and ORs along with their corresponding 95% CIs were determined. A receiver operating characteristic (ROC) analysis was conducted to evaluate the diagnostic performance of age and appendiceal diameter for predicting ANs. The sensitivity, specificity, and area under the ROC curve (AUC) were calculated. The optimal cutoff value was determined based on the maximum Youden Index. The Youden Index, a measure of the test’s overall performance across all possible cutoff values, was calculated as follows: Youden Index = Sensitivity, + Specificity – 1.

A Joinpoint Regression Analysis was conducted to determine the time trend of AN incidence from January 2011 to December 2022. The study period was divided into segments based on changes in the trend of AN incidence. The slope of the trend line between Joinpoints was used to calculate the annual percentage change (APC) of AN incidence during that period. In the model, years (2011–2022) were considered independent variables, while the ratio of ANs to all appendectomy cases was included as the dependent variable. A logarithmic transformation was applied to the AN rate during modeling. The optimal model was designed using the least squares method, and the regression parameters were generated using Grid Search methods.

A total of 22,310 patients who underwent an appendectomy between 2011 and 2022 were identified. Six cases were excluded from the study due to missing data. Of the 22,304 cases included in the final analysis, 13,181 (59%) were males and 9.123 (41%) were females, with a mean age of 26 years (range: 0–97 years, SD 16). The distribution of cases based on histopathological features was as follows: 3,473 (16%) cases in the negative appendectomy group, 18,169 (81%) cases in the appendicitis group, 332 (1.5%) cases in the unusual findings group, and 330 (1.5%) cases in the neoplasm group. The baseline demographic and histopathological features of the study population are presented in Table 1.

The overall rate of ANs in the cohort was 1.5% (one neoplasm per 67 appendectomies). Joinpoint analysis showed a significant change in the ANs rate during the study period. The AN rate increased more rapidly in 2011–2014, followed by a slower increase from 2014 to 2020, and a possible decrease from 2020 to 2023. Changes in the incidence of ANs over time are presented in Table 2 and Figure 2.

In the pediatric group, the incidence of ANs was relatively low, with one neoplasm per 238 appendectomies (0.42%). NENs were the most common type, accounting for approximately 67% of all cases of ANs. LAMNs were the second most common type, accounting for 20% of the cases. Metastatic tumors were extremely rare, and only 2 cases showed infiltration of hematological malignancies in the subserosal area of the appendix. Representative examples of ANs are presented in Figure 3.

In the adult group, the most common types of neoplasms are LAMN/HAMN (44.8%), followed by NEN (43.5%), secondary tumor infiltration (8.1%), and primary adenocarcinoma (3.6%). We observed that the distribution of subtypes of ANs was strongly related to the age of patients (Table 3). Increasing patient age was correlated with a higher rate of adenocarcinoma and a lower rate of NENs. The majority (90%) of adenocarcinoma cases were detected in individuals over 40 years of age, whereas a significant proportion (75%) of NENs cases were detected in individuals under 40 years of age.

We also found that the age of the patients was strongly related to the rate of ANs. There was a significant increase in the rate of ANs with age, from 0.93 for those aged 16–29 years to 9.05 for those aged 70 years or older (shown in Fig. 4a). The mean age of patients in the ANs group was 46 years. There was a significant difference in the mean age at presentation between the ANs group and the other groups (p < 0.001) (shown in Fig. 4b). We also found that the odds of having an AN were significantly higher in patients aged 30 years and older compared to those younger than 30 years, with an OR of 1.36 (95% CI: 1.04–1.78) for patients aged 30–39 years, an OR of 1.92 (95% CI: 1.43–2.58) for those aged 40–49 years, an OR of 2.42 (95% CI: 1.72–3.41) for those aged 50–59 years, an OR of 4.47 (95% CI: 3.09–6.47) for those aged 60–69 years, and an OR of 7.31 (95% CI: 5.09–10.49) for patients aged 70 years or older. Furthermore, ROC analysis showed that age was a significant predictor of ANs, with an AUC of 0.734 (95% CI: 0.706–0.761, p < 0.001). The optimal cut-off point was found to be 28.5, with a sensitivity of 72% and a specificity of 64% (Fig. 4c).

In 90% of cases with ANs, the presenting complaint was right lower quadrant abdominal pain, and physical examination revealed tenderness or rebound tenderness. Ultrasonography and CT scans were performed in 40% and 60% of the cases, respectively. Preoperative imaging findings favored neoplasms or raised suspicion of neoplasms in only 16% of cases (n = 52). Among these cases, 1 had primary adenocarcinoma, 2 involved hematological malignancies, and 49 had LAMN or HAMN morphology. None of the NENs were detected by the preoperative imaging modality.

The preoperative mean of the WBC count was 11.5 × 10³/μL (range: 3.51–32.0) in cases of ANs, and 14.31 × 10³/μL (range: 4–29.3) in non-neoplastic cases, while a standard WBC count in our laboratory ranges from 4,500 to 11,000 × 10³/μL. We found a statistically significant difference in the pre-operative WBC count between ANs and non-neoplastic cases (p < 0.001). Concurrent neutrophilic inflammatory infiltrates were detected in 68% of cases of ANs, and perforation was noted in 8% of cases.

The mean appendix diameter was 12.4 mm (5–36 mm) in ANs, and 8.4 mm (4–30 mm) in non-neoplastic cases. The mean appendix diameter was significantly larger in ANs (p = 0.002). A ROC analysis was performed to evaluate the effect of appendix lumen diameter on the prediction of ANs. The optimal cut-off value was determined to be 0.95 cm, generating an AUC of 0.746 (95% CI: 0.709–0.783, p < 0.001), with a sensitivity of 0.77 and a specificity of 0.56 for distinguishing ANs from non-neoplastic cases (shown in Fig. 5).

In the current study, we analyzed the clinical, imaging, and histopathological features of ANs. The overall rate of ANs in our cohort was 1.5%, and the rate increased from 0.53 to 1.81 over the past 12 years. A similar pattern has also been observed in population-based studies, which have reported an increase in the incidence of ANs in different age groups, genders, and histological types [1, 12‒15]. Various hypotheses have been proposed to explain the reasons; however, the reasons are not fully understood yet.

The increase in the incidence of ANs has been attributed mainly to the change in the rate of appendectomy. Johansson et al. [14] suggested that the increasing incidence of ANs may be related to the decreasing incidence of appendectomy, based on their hypothesis that the removal of the appendix could potentially protect against the development of ANs. However, Singh et al. [13] reported an increase in the incidence of ANs despite a lack of decrease in the rate of appendectomies.

Another proposed explanation for this situation is that the increased rate of appendectomy may have played a role. As ANs are often discovered as incidental findings during appendectomies, the increased number of these procedures could be associated with an increase in the detection of tumors. However, Orchard et al. [15] noted a small increase in the rate of appendectomies and stated that “the much larger increase in the incidence of ANs cannot be explained by the increase in appendectomies alone”.

Our results highlight a different perspective. We observed that the increase in the ANs rate may be associated with the decrease in the rate of negative appendectomies. Over the course of our study, the rate of negative appendectomy decreased steadily, starting at 17.1% in 2011 and reaching 10.7% in 2022 (Fig. 6). Thus, a reduction in the number of negative appendectomies could lead to a proportional increase in the rate of ANs. This situation has also been highlighted by Singh et al. [13]. Furthermore, according to Johansson et al. [14], the reduction in the rate of negative appendectomy ensures the preservation of the appendix, which allows the possibility of observing any tumor development.

Another potential explanation for the increasing incidence of ANs may be related to changes in techniques for pathological assessment. Studies suggest that a more extensive examination of specimens, with a greater representation of sections submitted for each case, may be influential in the detection of tumors [4, 16]. In our daily practice, we often submit the entire appendix for pathological examination. Among the subjects included in the study, there were cases where tumors were 2–3 mm in diameter; these tumors were not easily detected through macroscopic examination. However, due to the limited number of studies on this subject and their retrospective nature, it is not possible to make a definitive interpretation regarding the effect of pathological sampling on the incidence of ANs.

On the other hand, the aging population may have contributed to the increase in the incidence of ANs. As the incidence of primary adenocarcinoma and metastatic tumors is higher in the elderly, it seems likely that the incidence of ANs will increase as the population ages. Our results showed that the potential for detecting neoplasm increases with the age of the patient, with one neoplasm found in every 12 appendectomies over the age of 60. Our findings also showed that age is a good predictor of the risk of ANs. Patients over 28 years of age had an increased risk of ANs (4.4–fold), and 90% of primary adenocarcinomas were detected in patients over 40 years of age. In line with our findings, studies have reported that the age of the patient is associated with the risk of ANs. The incidence of ANs was reported to be higher in older patients [17] and increasing age has been found to be a risk factor for ANs in non-elective appendectomy [5, 18]. Patients over 40 years of age who underwent appendectomy were more likely to be diagnosed with ANs [19, 20]. Age over 50 years was identified as an independent risk factor for ANs with an OR of 6.6 (95% CI: 3.0–14.7) and an OR of 3.6 [1.1–11.4] respectively [21, 22].

In our cohort, the presenting symptom of most cases of ANs was right lower abdominal pain, accompanied by defense and/or rebound tenderness. Numerous studies have shown that ANs rarely have distinct clinical features and often present appendicitis-like symptoms [4, 5]. We observed that the mean preoperative WBC count in AN cases was 11.5 × 10³/μL, whereas the accepted standard WBC count in our laboratory ranges from 4,500 to 11,000 × 10³/μL. The mean WBC count showed a significant difference between AN and non-neoplastic cases (11.5 vs. 14.31 × 10³/μL). In agreement with our results, Koç and Çelik [23] showed that the preoperative WBC count of ANs was significantly lower than that of non-neoplastic cases (9.3 vs. 12.8 × 103/μL). Despite the higher WBC count in non-neoplastic cases compared to ANs, studies have shown that the WBC count cannot serve as a reliable diagnostic marker for appendicitis [24]. In our opinion, the reliability of using WBC as a single measure to determine neoplasm risk is not acceptable, as 68% of our cases with ANs show concurrent neutrophilic infiltration, and cases of AA may exhibit normal WBC counts [25].

Studies indicate that imaging methods provide only limited assistance in diagnosing ANs [5, 6]. However, consideration of the diameter of the appendix may serve as a warning sign for ANs. Studies reported that the mean normal appendix diameter can range from 5.6 ± 1.3 mm to 8.19 ± 1.6 mm in CT [26, 27]. Traditionally, an appendix diameter greater than 6 mm has been considered the cut–off point for diagnosing appendicitis [28]. In our cohort, the mean appendix diameter was significantly larger in ANs; the mean was 12.4 mm for ANs and 8.4 mm for non-neoplastic cases. Increased appendix diameter has been reported to be an independent risk factor for ANs, with an OR for greater than 10 mm of 1.06 (95% CI: 1.01–1.12) and an OR for 13 mm and greater of 3.2 (95% CI: 1.0–10.3) respectively [21, 23]. Furthermore, isolated dilatation in the distal segment of the appendix with a regular proximal segment has been shown to be highly associated with mucinous neoplasms [29].

Non-surgical treatment options have become more popular for AA in recent years. However, there is a concern that non-surgical treatments may lead to the tumors getting missed. The incidence of tumors was observed to be significantly higher in patients who underwent interval appendectomy than in those who underwent emergency appendectomy (12.6 vs. 1.2%) [11]. A high rate of tumors was detected in patients who did not undergo interval appendectomy when closely followed up with imaging [10]. Therefore, assessment of risk factors for ANs may be useful in identifying patients for interval appendectomy or follow-up. The findings of this study suggest that surgeons should carefully consider the possibility of ANs in patients over 40 years of age with an appendix diameter of 0.95 cm or greater. Failure to diagnose ANs in these patients may result in tumor growth, stage migration, or adverse patient outcomes. Therefore, it is important for clinicians to be aware of the risk factors associated with ANs and to consider them in their diagnostic approach to appendicitis. Future research should aim to develop effective screening tools and diagnostic algorithms to improve the preoperative detection of ANs.

Our study has some limitations that may have affected the results. First, the retrospective nature of the study and the cohort, which included only patients who underwent an appendectomy for possible appendicitis, may limit the generalizability of our findings. In addition, our data may have been influenced by both the patient population and the treatment choices of surgeons at the study centers. Furthermore, our findings only include data from patients who underwent an appendectomy. Long-term follow-up of patients who received medical treatment might provide more comprehensive information on the risk of missed ANs.

The current analysis of the clinical, imaging, and histopathological features of ANs revealed that the rate of ANs has increased over the past decade. Our findings indicate a significant association between age and the rate of ANs. The high rate of ANs in elderly patients underlines the importance of considering ANs in the differential diagnosis of appendicitis, especially in older age groups. Furthermore, our research revealed that the diameter of the appendix was greater in ANs compared to non-neoplastic cases. Notably, an appendix diameter exceeding 9.5 mm serves as a crucial warning sign. These findings may have substantial implications for treatment management and the follow-up of patients.

This protocol for this study was reviewed and approved by Erzincan Binali Yildirim University, Medical School Ethics Committee, approval number #16/02/2023, 2023-04/02.

The authors have no conflicts of interest to declare.

The authors did not receive any funding for this study.

Gizem Issin: design of work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, and final approval of the manuscript. Fatih Demir, Irem Guvendir Bakkaloglu, Diren Vuslat Cagatay, Hasan Aktug Simsek, Ismail Yilmaz, Ebru Zemheri: data collection, critical revision of the article, and final approval of the manuscript.

The data that support the findings of this study are available on request from the corresponding author.