Appendiceal neoplasms in Saudi Arabia: prevalence and clinicopathological profile.

The appendix, though considered functionless, remains a focal point in the realm of surgery across various hospital settings. 1 , 2 Primary appendiceal neoplasms (ANs) encompass epithelial tumors (such as adenoma, simple mucocele, low-grade appendiceal mucinous neoplasms (LAMNs), high-grade appendiceal mucinous neoplasms, mucinous adenocarcinoma, colonic-type adenocarcinoma, and goblet cell carcinoma), neuroendocrine tumors (NETs) (classic and tubular), alongside others like lymphoma, mesenchymal tumors, sarcomas, neuroectodermal, and nerve sheath tumors. 3 – 5 ANs are infrequent, accounting for approximately 1% of appendectomy specimens, yet their prevalence is progressively rising globally. 6 – 8 To date, no significant increase in the prevalence of ANs has been reported in the Arabian Gulf States. However, an upsurge in appendectomies does not necessarily correlate with increased ANs within a population. 7 From 1973 to 2001, individual incidence rates of ANs worldwide ranged from 0.15 signet ring adenocarcinomas to 1.3 mucinous tumors per 1 000 000 people annually, while the incidence of appendiceal adenocarcinoma, ‘carcinoid’ tumors, and goblet cell carcinoma fell within this range. 9 , 10 Conversely, Shaib et al reported an average increase of 3.1% per 1 000 000 person-years, indicating a significant decline in the age at diagnosis, predominantly among females. 6 ANs typically manifest with nonspecific symptoms, commonly mimicking acute appendicitis, and are predominantly discovered during surgery, colonoscopy, 11 or in postoperative pathological evaluations, posing challenges in their management. 1 , 2 , 7 Additionally, the widespread use of computed tomography in abdominal investigations may enhance AN detection. Signet-ring cell adenocarcinomas and mucinous ascites, known as pseudomyxoma peritonei, reported in over 50% of initial diagnoses, correlating with a poorer prognosis. However, the prognostic factors remain poorly elucidated. 12 , 13 The management of ANs varies based on multiple factors, ranging from appendectomy to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. 14 , 15 Recent studies indicate an escalating trend of different cancers in Saudi Arabia, paralleled by an increase in mortality rates from 5% to 12% in less than two decades. 16 , 17 Moreover, insufficient studies exist to determine the apparent prevalence and clinicopathological characteristics of any ANs in Saudi Arabia. Hence, this study aimed to evaluate the Saudi population and compare findings with reports from other Gulf States and worldwide datasets.

The study included 25 out of 1110 patients who underwent appendectomies and had ANs; 13 were female. The mean (SD) age was 54.6 (10.04) ( Table 1 ). Most of the patients presented with different comorbidities (64%). Most patients showed a clinical presentation of acute appendicitis and a mass in the right iliac fossa. The majority were diagnosed preoperatively and underwent a semi-elective procedure. Laparoscopic exploration was undergone by 72%. Appendectomy alone was performed in 40% ( Table 2 ). The median (25th–75th percentile) hospital length of stay was 6.0 (3.0–12.0) days. However, around 80% of participants had no complications, and the median (minimum-maximum duration of stay in the ICU postoperatively was 0 (0–25), indicating that most patients did not require ICU care after surgery. The preoperative CT of the abdomen report suggested that only 64% of the patients had appendicular mass, as most of these patients were suspected of having malignancy preoperatively. The demographic characteristics of the patients (n=25). Data are mean (standard deviation) for age or and number (percentage) for categorical data. The characteristics of the intervention/complications (n=25). Data are mean (standard deviation) or median (25th-75th percentile), minmax for hospital stay and length of postoperative ICU admission days) for continuous data and number (percentage) for categorical data. The histopathological characteristics are shown in Table 3 , with 76% of the cases diagnosed as low-grade appendiceal mucinous neoplasms (LAMN). One middle-aged female patient had double neoplasms (LAMN and NET). Three patients had appendicular perforation, and all margins were negative for malignant cells. Both the lymphovascular and perineural invasions were present in three different patients, two and three, respectively. The median postoperative follow-up was 71 months, ranging from 13-102 months ( Table 4 ). Two patients (8%) experienced local recurrence. However, re-exploration was a necessity for four patients. One patient had re-exploration after six days of the initial procedure, while another needed the procedure after more than 180 days. Distal metastasis was identified, as was the adenocarcinoma case. However, the 5-year overall and disease-free survival rates were 88% and 80%, respectively. The histopathological characteristics. Data are number (percentage). Follow up and surveillance. Data are median (25th-75th percentile) for follow-up period and number (percentage) for categorical data. CRS: Cytoreductive Surgery, HIPEC: Hyperthermic intraperitoneal chemotherapy, LA: Laparoscopic appendectomy, LAMN: Low grade appendiceal mucinous neoplasm, NET: Neuroendocrine tumor

This study is the first to assess the prevalence and clinicopathological characteristics of ANs within our institution. The observed incidence of appendiceal tumors marginally exceeds those incidences previously reported in the literature. 8 , 19 - 22 Bastiaenen et al documented an incidence of appendiceal neoplasms (ANs) at 0.71% in their systematic review. 22 In their study, which analyzed 4545 appendectomy samples, Lohsiriwat et al 23 reported a tumor occurrence rate of 0.97%. Meanwhile, other studies have documented neoplasm incidences of up to 2.5%, a range that aligns with the results we have observed in our research. 24 , 25 Recent research has revealed a heightened incidence of appendiceal neoplasms (ANs), measured at 3.2%. 8 Our observations contribute to the body of literature indicating an increase in the incidence of appendiceal tumors by up to 54% in recent decades. 11 Our study included 25 patients (13 female and 12 male participants with a mean (SD) age of 54.6 (14.04) who had ANs out of a total of 1110 patients who underwent procedures for appendectomies. In a retrospective investigation carried out by Aleter et al at Hamad Medical Corporation (HMC), Qatar, a cohort of 12 454 patients underwent appendectomy. Within this group, 50 individuals (0.4%) had appendicular mucinous neoplasms (AMN) upon histopathological examination, with an mean (SD) age of 47.2 (13.1) years. The study observed a slight male predominance over female patients at a ratio of 1.2:1. 26 The elevated male prevalence observed might be linked to the specific sociodemographic configuration in Qatar, characterized by a disproportionately high male to female ratio. This disparity is primarily due to the immigrant worker demographic, which accounts for 94% of the nation's workforce and represents 70% of the total population. 27 During a study undertaken at our institution in 2005, a total of 1547 appendectomies were carried out, with 9 cases (0.6%) reported to have carcinoid tumors originating in the appendix. 28 Khan et al, in another study in Abha, Saudi Arabia, examined 3374 appendectomy specimens from 2578 Saudi and 796 non-Saudi nationals. They found a 74.7% diagnosis rate for inflamed appendix, with 7.8% to 22.5% being normal appendix cases, more prevalent in females. Notably, the study highlighted occurrences of 1 cyst adenoma, 2 mucocele cases, and 3 NETs in the appendix. 29 The age of our patients in our study was slightly younger than the age range of 50–60 years reported in Misdraji et al's study. This may be attributed to the larger sample they studied (107 cases). Also, the gender distribution in their study was intriguing, as they suggested a female predominance (4.1:1). 30 Several research findings have indicated that being over the age of 50 is a risk factor for the development of appendiceal tumors. 24 , 31 An American study analyzing a sample size of up to 3293 patients revealed that the risk of AN, along with an appendiceal diameter greater than 10 mm as detected by CT scans, increased up to threefold in patients older than 40 years. 32 An Asian research study that encompassed 17 patients (10 men and 7 women) that ranged in age from 36 to 86 years with a mean age of 77.0 years. Predominantly, ANs were detected in patients aged 60 years and older (14 out of 17, 82.3%), demonstrating a significant disparity in incidence rates between individuals aged ≥60 years compared to those under 60 years ( P <.001). 25 While multiple studies have recognized advanced age as a risk factor for appendiceal cancer, the application of patient age as a predictor is hindered by its low sensitivity and specificity. The comparative significance of additional risk factors is yet to be clearly defined, though various factors have been proposed, including female gender, Crohn's disease, 33 appendiceal perforation, 34 the presence of anemia upon admission 31 and prolonged duration of symptoms. In terms of comorbidities, a study reported that 35 (70%) patients did not have comorbidities, unlike our study, where 9 (36%) did. This difference might be explained by the higher age range in our study. 26 The majority of our cases were diagnosed preoperatively. In Aleter et al's study, 26 cases were diagnosed intraoperatively or through post-surgery histological examination, aligning with other studies where a preoperative diagnosis was impossible in over 50% of patients. This discrepancy may be attributed to the prevalence of appendiceal mucinous neoplasms among the cases. 30 , 35 Accurately identifying an AN through pre-surgical imaging findings can be notably difficult. Two studies underscored this difficulty. Bolmers et al 36 reported only 3 out of 30 cases where intraoperative identification of ANs was correct. A similar retrospective analysis of 3554 appendectomies revealed that only 2 out of 20 patients were correctly suspected of having an appendiceal neoplasm prior to surgery. 4 As a result, the pathological examination of the resected appendix becomes pivotal. It determines the lesion's nature, whether benign or malignant, and also assesses factors like depth of invasion and vascular involvement. Consequently, a comprehensive and meticulous examination is imperative, including a thoughtful evaluation of the need for potential additional resection. 37 The heightened use of advanced imaging technologies in recent times for diagnostic purposes and health screenings could be responsible for the more frequent detection of asymptomatic ANs. 14 Most patients presented with a clinical presentation of acute appendicitis and a mass in the right iliac fossa. Similarly, Kehagias et al reported a 72-year-old woman with an acute abdomen. Her CT scan revealed an 8.3×5.2×4.1 cm cystic lesion in the right iliac fossa. 38 Saleem and coworkers described a case of a pregnant lady who was diagnosed with acute appendicitis and had a LAMN on histopathology. She exhibited leukocytosis, and although the ultrasound results were inconclusive, and minimal fluid was observed in the right iliac fossa. 39 In our study, almost half of patients were treated using laparoscopic intervention, while 28% used open procedures, with appendectomy being the most common (40%). A Spanish study reported that appendectomy was a sufficient treatment for tumors in more than 80% of neoplasia cases. 8 In another study, the primary surgical procedures mainly involved appendectomies, with an open-to-laparoscopic ratio of approximately 1:2.5. 26 In our study, all had preoperative intravenous contrast CT scans of the abdomen. The preoperative CT of the abdomen report suggested that only 64% of the patients had an appendicular mass, as most of the patient were suspected of having malignancy preoperatively. CT abdomen was the most used imaging method for appendiceal mucinous neoplasms diagnosis (79.54%), as reported by Aleter and colleagues. 26 However, a Finnish study indicated that CT scanning is not reliable to exclude neoplastic causes underlying acute appendicitis. 40 In our study's histologic classification of neoplasms, epithelial neoplasms, with LAMNs making up 76% of these cases, were predominant over neuroendocrine tumors (NETs). This finding validates the epidemiological shift witnessed in recent years, where NETs, previously referred to as carcinoids, no longer represent the most prevalent cases. 41 El-Esawy et al conducted a retrospective study at King Abdul-Aziz Specialist Hospital, Taif City, Saudi Arabia, focusing on mucinous appendiceal tumors. Their findings revealed that these tumors accounted for 0.36% (9 cases) of all appendectomies (2476). Notably, 66.7% of the cases were classified as LAMNs, while the remaining 33.3% were identified as mucinous adenocarcinomas. 42 A study conducted by Guraya and Almaramahny at Taibah University reported that among 9323 patients who underwent appendectomies, 10 cases (0.1%: 8 men and 2 women with a mean age of 53.1 years) were diagnosed with primary adenocarcinoma of the appendix. 43 Naar et al, 32 in their research with a cohort of over 3000 patients, verified a shift towards a higher prevalence of epithelial neoplasms. Marmor et al 11 observed an escalation in the frequency of epithelial tumors, without a corresponding reduction in neuroendocrine tumor incidences. In addition, Gómez-Báez et al highlighted that LAMN and neuroendocrine tumors (NETs) emerged as the predominant neoplasms with malignant potential. 8 LAMN was the most common histological type (n=41, 82%), as reported by Aleter et al. 26 Out of 107 cases in the Misdraji et al study, 88 (82.24%) cases were classified as LAMN. 30 However, Kangaspunta et al found that 84 patients were diagnosed with an appendiceal tumor. The most common tumors were NETs (n=33), followed by LAMNs (n=14) and adenocarcinomas (n=11). This variation may be attributed to the larger sample of the population they studied as they screened a total of 5224 patients who underwent appendectomy, of whom 4766 had histopathologically confirmed acute appendicitis. 40 In a study conducted in the Netherlands, the predominant malignant neoplasms identified were grade 1 NETs, comprising 65% (13 out of 20 cases). 4 The study by Tajima et al highlighted intramucosal neoplasms as the most frequently occurring type of appendiceal neoplasm, comprising 23.5% of the cases, with a total of 4 instances noted. 25 Only three patients in our study had appendicular perforation, and all the margins were negative for malignant cells. In their case report, Kehagias et al revealed a histopathological examination indicating LAMN with negative regional lymph nodes. 38 Moreover, our study revealed a particularly rare case of dual pathology within a single patient, presenting both NET and LAMN. This instance of coexisting neoplasms in the appendix, while exceedingly uncommon, adds a layer of complexity to the understanding of appendiceal pathologies. The identified case involved a 41-year-old female presenting with a well-differentiated Grade 1 (G1) NET accompanied by LAMN, which further shows the variability and heterogeneity observed in ANs. The rarity of encountering such dual pathologies worldwide is noteworthy. The NET, in conjunction with LAMN, not only shows the diverse spectrum of appendiceal tumors but also reveals the diagnostic and therapeutic challenges faced in clinical practice. The patient's case detailed a NET located in the proximal half of the appendix, perforating the visceral peritoneum/serosa with a size of 2.4 cm and exhibiting a low mitotic rate of 3 per 2 mm 2 , accompanied by a Ki67 index of 5%. The primary procedure involved a laparoscopic appendectomy, followed by subsequent interventions, including laparoscopic single port omentectomy, excision of pelvic peritoneal deposits, and hyperthermic intraperitoneal chemotherapy. This study adds a picture of ANs in a major tertiary hospital in Saudi Arabia. However, there are several limitations to address: it is retrospective and confined to a single institution (requiring a sizable multicenter study); and it is based on a small population derived from pathology and colorectal unit data. This study showed that the incidence of ANs is increasing with a high prevalence of LAMN. The pathological examination of the resected appendix plays a pivotal role in the diagnosis of ANs, as it is compared to preoperative and intraoperative diagnosis. Furthermore, this study encourages local researchers to perform more and perhaps prospective studies with a larger population from different centers in the country.

This study was performed at King Khalid University Hospital, a tertiary care hospital in Riyadh, Saudi Arabia, spanning from May 2015 to June 2020. The study focused on assessing the prevalence and clinicopathological characteristics of ANs. The study concluded in March 2024, marking the end date for calculating follow-up periods of patients, which commenced from the date of diagnosis. The investigation utilized data from the pathology database of the department (specifically, histopathological analysis of surgical specimens) and the electronic filing system (E-SIHI). Ethical approval (Ref. No. E-20/4575) was obtained from the institutional ethical committee before commencing the study. The study included patients who underwent appendectomy, with their specimens submitted for histopathological evaluation. A total of 1110 pathological reports were reviewed, identifying 32 patients with ANs. Subsequently, seven patients were excluded—six with metastatic deposits from ovarian origins and one with endometriosis deposits with no primary ANs—resulting in a final eligible cohort of 25 patients. This group comprised various conditions, including simple mucoceles, appendiceal NETs, appendiceal adenocarcinomas, mixed ANs, and mucinous neoplasms. All cases underwent review by a pathologist specializing in abdominal malignancies. Similar to the protocol followed in well-developed hospitals worldwide, all patients had preoperative intravenous contrast computerized tomography (CT) scans of the abdomen. 18 , 19 Inclusion criteria included cases with a histopathologically confirmed diagnosis of primary ANs, patients who completed postoperative follow-ups (based on the type of ANs), and charts documenting necessary study data like patient demographics, presentations, imaging studies, laboratory investigations, histopathological reports, and procedure notes. Exclusion criteria involved cases with non-primary ANs (like metastatic deposits from ovarian origins), patients lacking regular postoperative follow-ups (based on the type of ANs), or charts lacking necessary study data. The investigators meticulously collected demographic and clinicopathological characteristics, including age, gender, clinical presentation, leukocyte count, radiological findings, histopathologic analysis, initial and subsequent surgical procedures, operative findings, hospital length of stay, intensive care unit admission, follow-ups, recurrence, severity of postoperative complications (categorized according to the Clavien–Dindo classification) 20 colonoscopy reports, and adherence to the Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines. 21 The study concluded in March 2024, marking the end date for calculating follow-up periods of the patients, which commenced from the date of diagnosis. The collected data were recorded, and subsequent processing was done using IBM SPSS version 28.0 for Windows (Armonk, NY, USA: IBM Corp). Descriptive statistical methods were applied to present frequencies and percentages, characterizing the attributes of the study participants for categorical variables like gender and outcomes of surgeries. Continuous variables, such as the age of patients and the duration of hospital stay (measured in days), were summarized using mean or median values.