Introduction

Appendix neoplasms are rarely seen, and are identified in pathological examinations of patients who are operated on with a diagnosis of acute appendicitis, with a ratio of 1% [1]. Neuroendocrine tumors (NETs), described by Oberndorfer in 1907, are seen in the gastrointestinal and bronchopulmonary system. Appendiceal NETs (ANETs) originate from the appendix lamina propria and the neuroendocrine progenitor cells, located in the submucosa. Most ANETs (75%) are located in the distal part of the appendix, which can be explained by the subepithelial neuroendocrine cells; they are predominantly situated in these areas of the organ [2]. ANETs rank third for gastrointestinal location after the small intestine (44.7%) and rectum (16.7%); it is the most common tumor of the appendix, accounting for 60% of all appendicular tumors [3]. ANETs can secrete serotonin and other vasoactive substances, causing carcinoid syndrome-like NETS in the gastrointestinal tract [4]. Annual incidence of ANETs is reported at 0.4–0.6/100,000 [5]. They are most commonly seen in patients between ages 30 and 40 but are detected in patients younger than average for malignant appendiceal neoplasms [2].

In our study, we examined patients who underwent appendectomy, with a diagnosis of acute appendicitis, who were diagnosed with ANETs via histopathological examination, while also having ANET characteristics.

Material and methods

A retrospective analysis was done on patients who underwent emergency appendectomy for suspicion of acute appendicitis between January 2011 and January 2020 at the Istanbul Bakirkoy Dr. Sadi Konuk Education and Research Hospital. Data were collected from the hospital’s electronic database. The study was approved by the hospital’s local ethics committee. Patients diagnosed with ANETs in histopathological examinations were included in the study. Age, gender, clinical appearance, preoperative diagnosis, inflammatory markers, and surgical findings were collected, while information of histopathological details was recorded. Location, size, grade, and differentiation of the tumor, histopathological staging, and resection margins were included.

Inclusion criteria of the study: (1) patients whose histopathological examination of appendectomy material was a result of ANETs; (2) patients over the age of 15 and under 80.

Exclusion criteria of the study: (1) patients with suspicion of a mass via abdominal imaging methods (USG, CT, or MRI); (2) patients under the age of 15 or over 80 years old.

Appendectomy specimens are prepared according to a hospital-defined protocol, which includes immediate fixation in formalin prior to transport to the pathology laboratory. Specimens are cut at the tip, trunk, and base and examined by a senior pathologist. Available appendectomy specimens, tissues fixed with phosphate-buffered 10% formaldehyde, were put in blocks after macroscopic examination in accordance with the procedure, and were subjected to a tissue follow-up procedure. Materials embedded in paraffin blocks were cut with a microtome device at a thickness of 4 μm, with tissue examined on the microscope slide and routinely stained with hematoxylin and eosin (H&E), then assessed under a light microscope. Immunohistochemical examination was performed with synaptophysin, chromogranin-A, and Ki-67 for NETs. Details of macroscopic and microscopic findings appear in the final report. Samples from unexpected abnormal cases and pathology request forms with surgical notes were reviewed by the surgeon for evidence of suspected pathologies during an intraoperative examination of the appendix. Statistical analysis was performed using SPSS version 20.0 R (IBM Corporation, Armonk, NY, USA). Categorical variables were presented as actual numbers and percentages (%), while continuous variables were represented as the mean.

Results

From January 2009 to May 2014, 5720 patients underwent emergency appendectomies to treat clinically suspicious appendicitis at our institution. The distribution of histopathological results for these patients was assessed in 5312 patients as acute appendicitis, along with 23 patients without neoplastic issues (endometriosis, parasites, and granulomatous disease), 329 patients as negative appendectomy, and 44 patients as neoplastic disease. Twenty-four cases of neoplastic disease were ANETs, and 20 were epithelial tumors (Fig. 1). The average age of patients with ANET was 30 (18–67), with gender distribution found to be 10 males and 14 females (Table 1). The main complaint of all patients was right lower quadrant pain. Twelve patients experienced loss of appetite, nausea, and vomiting. Average time between onset of complaints and admission to the hospital was 2 days [1,2,3,4].

Fig. 1
figure 1

Flowchart of the study

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Table 1 Demographic, presentation, and operative findings
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None of the patients had additional signs or symptoms suggestive of carcinoid syndrome, such as flushing, diarrhea, asthma, and cyanosis. All patients had clinical features supported by inflammatory markers, also suggestive of acute appendicitis. Preoperative leukocytosis was detected in 10 patients. The diagnosis of acute appendicitis was made in 11 patients by abdominal ultrasonography (USG): they were confirmed by abdominal computed tomography (CT). The other 13 patients were not diagnosed with appendicitis via USG, even though CT was used as an additional imaging method. Patients with a suspected appendix mass were excluded from the study, or those who underwent CT scan. There was no suspicion of a neoplastic lesion in any patient during the operation. One patient was operated on under spinal anesthesia and 23 under general anesthesia. Open appendectomy was performed in one patient and laparoscopic appendectomy was performed in 23 patients. Perforated appendicitis was present in two patients. The classic McBurney incision was preferred in patients having an open appendectomy. Histology confirmed concomitant acute appendix inflammation in 14 cases, tumor-distant appendix perforation in two cases, and gangrenous appendix in four cases; however, two cases showed normal appendix with ANETs (Table 1). During histological examination, the size of the tumor was less than 10 mm in 14 patients (58.33%), between 10–20 mm in nine patients (37.50%), and greater than 2 cm in one patient (Table 2). The majority (62.50%) were at the tip of the appendix (Table 2). While complete resection was successfully achieved in 23 patients, a perforated appendix was detected during surgery in two patients, although its site was distant from the tumor during pathological examination, with tumor diameters of 5 and 7 mm; therefore, it was not possible to precisely determine the resection margin. Serosal–subserosal invasion in nine patients (two showed mesoappendix invasion) was also reported. According to the National Comprehensive Cancer Network (NCCN) guidelines and tumor, nodes, and metastases (TNM) classification of appendicular carcinoids (Table 2), 11 patients (45.83%) were graded as T1, one patient (4.16%) as T2, 11 (41.83%) as T3, and one (4.16%) as T4. All patients were successfully treated with simple appendectomy. Grade 1 well-differentiated ANETs were detected in 22 cases without lymphovascular and perineural (LVI and PNI) invasion. Right hemicolectomy was performed 3 months later in a grade 1 well-differentiated case with a tumor diameter of 23 mm, located distally with LVI and PNI. Grade 2 well-differentiated ANETs were detected in two cases (Table 2). LVI was detected in 17 mm grade 2 well-differentiated cases, with right hemicolectomy performed on day 92. Right hemicolectomy was recommended for 11 patients, whose histopathological was found as T3. Right hemicolectomy was performed in four patients, while seven patients did not accept the surgery (Fig. 1). With a mean follow-up of 43 months, none of the operated patients developed evidence of metastasis or recurrence (range 17–108). Follow-up measures included laboratory testing of chromogranin A and B. One patient was found not to have elevated levels in these tests. In addition, 13 patients were followed-up with laboratory tests, including a 24-h urinary 5-hydroxyindolacetic acid (5-HIAA). These levels increased in two patients, more than 9 weeks postoperatively at follow-up appointments, but returned to normal levels with subsequent analysis. All patients who underwent right hemicolectomy during follow-up were asymptomatic, while imaging was performed annually with abdominopelvic CT. All operated patients were followed, and remained tumor-free during the study period, with no evidence of recurrence or metastatic disease. Patients who did not accept surgery were followed by checking 68 Ga-Dotatate PET-CT and 24-h urine 5-HIAA in the first year and then every 2 years. One patient had surgery in 2013, with complaints of sweating and flushing in the 7th year, which was T3 with subserosal invasion: local recurrence was detected by 68 Ga-Dotatate PET-CT. Right hemicolectomy was recommended to the patient, who wanted time to consider the surgery.

Table 2 Histopathological characteristics for the resected appendicular ANET specimens
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Discussion

ANETs are usually diagnosed incidentally in the histopathological evaluation of the appendectomy specimen [7, 10], found between 0.008% and 1.6% in various studies [6,7,8,9]. In our series, incidental ANETs were 0.42%. ANETs usually have a silent course without tumor-specific characteristics to make a preoperative diagnosis, unless they yield symptoms of carcinoid syndrome. Thus, these tumors are usually undetectable and often found in histopathological examinations of patients operated on for acute appendicitis [3,4,5].

In a study by Coursey et al., a retrospective evaluation of ANETs were detected in appendectomy specimens, while CT was performed in 10 patients, but the tumor was not detected when they were examined again [10]. In this study, the mean tumor diameter was 6.1 mm. Kangaspunta et al. emphasized that CT could not be used to exclude neoplastic etiology underlying acute appendicitis [11]. In our study, preoperative ANETs were not suspected in patients clinically diagnosed with acute appendicitis, along with having surgery. In a retrospective evaluation of patients with ANETs in our study, abdominal CT was performed in 15 patients, but detected only in two cases, with tumor diameters of 15 mm and 23 mm. The mean tumor diameter was found at 7.66 mm in male patients and 6.84 mm in female patients, which was similar to other studies. We suspect that abdominal CT will not provide sufficient data for diagnosis of ANETs. None of the patients in our cohort had suspicious neoplastic lesions during open or laparoscopic approach for appendectomy. Davenport et al. emphasized routine enbloc removal of the mesoappendix rather than skeletonizing it during laparoscopic application in acute appendicitis. They emphasized it would be beneficial to ANET staging while avoiding additional surgical interventions [12]. As suggested in this study, the appendix was removed en bloc with the mesoappendix, without skeletonizing the appendix in all cases. Pawa et al. stated that more than 90% of ANETs are located in the distal part of the appendix. In a review published in 2018, the frequency of such tumors at the tip of the appendix was found to be 60–75% in the most common location [13]. In our study, 62.5% of case tumors were at tip of the appendix and found to be correlated with other studies. We followed international guidelines for ANETs’ treatment, which depends on tumor size, location, mesoappendix invasion, lymph node involvement, LVI, PNI, proliferation rate, and tumor differentiation. The Eurupean Neuroendocrine Tumor Society (ENETS) guidelines indicate that appendectomy is sufficient for well-differentiated ANETs of < 1 cm at the tip and body of the appendix, while for tumors larger than 2 cm, or those 1–2 cm with mesoappendix invasion, positive resection margins, angioinvasion, a Ki-67 labeling index > 2%, were advised to undergo oncologic right hemicolectomy [13,14,15]. In the guidelines published by the NCCN in 2015, appendectomy would be sufficient for ANETs of 2 cm or less, but tumors larger than 2 cm, or those with lymph nodes ( +) with positive resection margins, the recommendation was right hemicolectomy [16]. In our series, there were nine patients with a grade 1 well-differentiated tumor, including proper biology and size, which is why an index appendectomy was done. Two patients had locally advanced disease, so underwent oncologic right hemicolectomy at a later date.

Conclusion

Preoperative diagnosis of ANETs is difficult. Histopathological examination of appendectomy material is important for tumor management. Some tumors smaller than 1 cm can invade the subserosa or mesoappendix, which led to changes in treatment management. Follow-up and management is still a matter of serious debate.