AD has been described more than a century ago but remains to be an underdiagnosed and poorly understood pathological entity [1]. A higher incidence rate of AD in autopsy studies has been reported compared to appendectomies ranging from 0,014 to 2%. Hospital records for a 15,5-year period revealed a high number of appendectomies in our study. However, the incidence rate of AD among these specimens was only 2% proving the rarity of AD. This rate is on the higher end compared to other studies in the literature that were conducted with appendectomies.
Male gender, age over 30 years, Hirschsprung’s disease, and cystic fibrosis are reported as risk factors for the development of AD [6, 13, 14]. In the study by Marcacuzco et al, which is one of the studies with the highest number of AD cases in the literature, 42 cases of AD in 7044 appendectomies were reported with an F/M ratio of 15/27 and a mean age of 46 [15]. Chia et al. reported a median age of 29 years and a 55% male incidence [13]. The mean age was 54,1 years in our study and in contrast to the literature, there was a female predominance of 53%. The high mean age can be explained by the absence of children in our population as our hospital does not have a pediatric surgery department.
Two types of AD have been identified as congenital (including all four layers of the bowel wall) and acquired (including the mucosa and submucosa of the bowel wall without the muscular layer) which is also known as a pseudo-diverticulum. Congenital diverticula are much rarer than acquired ones and are known to be more resistant to perforation because of the muscular layer that they comprise [6, 13]. All the cases in our study were acquired AD. An increased intraluminal pressure plays role in the formation of AD. The anatomical structure of the appendix enables the lumen to be obstructed easily and the obstruction may be caused by a tumor, fecalith, or voluminous mucus deposition [8]. The diagnosis of AD is usually made when there is an obstruction of the appendiceal lumen. Mucin accumulation is one of the main reasons for the obstruction and may be a result of many pathologies. It is also described with the term “mucocele” based on the macroscopic appearance by the clinicians [16]. In our study, 33,8% of the cases showed mucin accumulation with almost half of them having diverticulitis. The causes of mucin accumulation also include benign and/or malignant epithelial proliferations such as appendiceal mucinous neoplasia and adenocarcinoma and other neoplastic lesions of the appendix such as NET or SSAs. Seven cases with mucin accumulation within the appendiceal lumen had LAMN in our study with 3 of them having concurrent diverticulitis.
Diverticulitis occurs as a common complication of AD, is difficult to distinguish from acute appendicitis clinically and radiologically, and is usually diagnosed histopathologically [17]. The literature indicates that acute or chronic diverticulitis will eventually develop in almost two-thirds of AD cases. Perforation is more prevalent than cases of acute appendicitis without AD owing to the absence of a muscular layer. In most cases, the mesoappendix surrounds the perforation and the AD is mesenteric which results in localized peritonitis [6]. Yardimci et al. reported a 70% perforation rate in their study with 24 cases of acute appendiceal diverticulitis [18]. Among 68 cases of AD, 44 of them had diverticulitis (64,7%) and 37 (54,5%) of these cases showed perforation and localized peritonitis. The rate of diverticulitis was found to be consistent with the literature findings.
The coexistence of neoplastic lesions and AD has not been fully evaluated in the literature, only a couple of studies pointed out this association to date with varying incidence rates from 17,5–48% [8, 11, 12, 19, 20, 21]. Dupre et al. reported a 48% rate of appendiceal neoplasia in cases with AD. They found that the most common appendiceal neoplasia associated with AD was NET followed by mucinous adenomas and adenocarcinomas [8]. Similarly, Medlicott et al. reported the most common neoplasm associated with AD to be NET [21]. In another study, this rate was found to be 18,1% with the majority of them being LAMNs followed by SSA and NET [11]. Kallenbach et al. reported a 43,6% rate of coexistent neoplasms and stated the LAMN to be the most common AD-associated mass lesion [12]. This rate was 35,2% in our study with 24 neoplastic lesions. Consistent with the literature, the most common was LAMN (n = 13), followed by NET (n = 3), SSA (n = 3), adenocarcinoma (n = 2), granular cell tumor (n = 1), hyperplastic polyp accompanied by an IFP (n = 1) and a collision tumor of LAMN and NET within multiple AD which we reported recently [22].
Although the most common neoplasm of the appendix is known to be a NET, because of their typical localization in the distal tip of the appendix they do not always cause luminal obstruction [23]. LAMN on the other hand is characterized by abundant mucin production and acellular mucin dissection in the appendiceal wall. The development of LAMN within an AD may be explained by the thinning of the muscularis propria by the increased intraluminal pressure and prolapse of the mucinous epithelium from the weak points of the wall. The mucin accumulation in 7 cases of 13 LAMNs in our study supports this theory. This also indicates the role of AD in the pathogenesis of pseudomyxoma peritonei.
Appendiceal endometriosis is very rare and constitutes 1% of all endometriotic lesions [24]. The only reported case of the combination of AD and endometriosis in the literature belongs to our institution [25]. In the following years, 3 more cases of endometriosis were diagnosed as accompanying lesions to the AD. With a total of 4 cases, the incidence of endometriosis with AD was 5,8% in this study.
IFPs are rare, benign, mesenchymal submucosal lesions of the gastrointestinal tract. Appendiceal IFPs accont for < 1% of all [26]. Even though there are a couple of case studies about appendiceal IFPs in the literature, our AD case that harbors both an IFP and a hyperplastic polyp is unique with the coexistence of both lesions.
A thorough sampling of the appendectomy specimen and a careful macroscopic microscopic evaluation is crucial to overcome the underdiagnosis of AD and the accompanying lesions. As described in the study by Li et al. some important neoplastic lesions of the appendix including AD, SSA, and LAMN may be underestimated because of insufficient macroscopic sampling [27]. Sampling the entire appendix does not seem cost-effective and will more likely increase the workload, however, underdiagnosing or misdiagnosing a neoplastic entity will also bring its own problems. A thoughtful histopathological approach to suspicious cases might be a good solution.
This study represents a high number of detected ADs in the literature with 68 cases. Other strengths include the detailed demographic features and histopathological evaluation of the cases. One limitation of our study was the absence of pediatric cases since the hospital does not specialize in pediatric surgery. Because the study was designed from a histopathological approach, the clinical signs and symptoms of the cases before undergoing operation were not included.
In conclusion, the real incidence rates of AD may be higher than reported in the literature and this can be achieved by a detailed macroscopic and microscopic examination. Our study results revealed that ADs are accompanied by neoplastic lesions at a rate of 35,2%.
Thus, it is important for surgeons and pathologists to be aware of AD and the coexisting pathologies they may harbor. When processing the appendectomy specimen in the pathology laboratory, if there is a pre-diagnosis or suspicion of AD and/or if there is apparent mucin accumulation it may be important to take more samples than usual not to miss any underlying neoplasms. The close association between LAMN and AD should be kept in mind when assessing the appendix.