According to the 2019WHO, colorectal SPs may be classified as HP, sessil serrated lesions (SSL), sessil serrated lesions with dysplasia (SSLD), TSA, and serrated adenoma, unclassified polyps [2]. SSL and HP account for about 10% and 30% of all colorectal polyps [6]. Approximately 30% of all colorectal carcinomas arise via the serrated neoplasia pathway [7]. However, the appendix is the terminal organ of the cecum, it is inaccessible by endoscopy. Thus, there is currently minimal information regarding the biologic potential and evolution of mucosal alterations in the appendix [8]. Pathologists have traditionally chosen to apply terms used in pathological diagnosis of the colon to similar lesions found in the appendix. Investigators of appendiceal pathology have mainly focused on how these lesions differ from similar colonic neoplasms. Pai et al. [9] and Choi et al. [10] described differences in these lesions; they reported that appendiceal lesions harbor KRAS codon 12 and 13 mutations in over half of the cases with only a small subset harboring the BRAF V600E mutation. The frequent KRAS mutations seem to be more likely in LAMN [11], suggesting that colorectal diagnostic terminology may not apply to appendiceal serrated lesions. Until 2019, the WHO divided the appendix SPs into HP, SL, and SLD. In the appendix, HP and SL lesions are similar to HP and SSL lesions in colonic neoplasms, although in appendiceal SLD, dysplasia can take the form of conventional adenoma-like dysplasia, serrated dysplasia, or TSA-like dysplasia [1].
The mucosal epithelium of the SPs in the appendix can become flattened and undulating or scalloped focal, and can be accompanied by diverticulum and acute inflammation. Acellular mucin infiltrating the appendiceal wall can also be found in SPs. These conditions make the pathomorphological evaluation more complex and easily confused with LAMN. LAMN has a potential risk of peritoneal dissemination. It is important to distinguish SPs and LAMN.
Appendiceal SPs have also been described. However, except for rare case reports and a few case series [4,12,13], the true incidence is unknown. Yuyucu Karabulut et al. [14] described 960 appendix specimens, 71 cases (7.39%) were diagnosed as SPs, including 36 (50.7%) HP, 33 (46.48%) SSA/Ps (now called SL), and 2 (2.81%) TSAs (now called SLD). Most guidelines recommend including a longitudinal section or cross-section of the appendiceal tip and 2 additional cross-sections. Few institutions routinely sample the entire resected appendix, except when neoplasms are detected on examination of the initial sections[8]. Renshaw et al. [15] compared the incidence of SSA/Ps in 100 in toto appendix resections submitted for histological examination and 100 routinely submitted appendices (partial sampling), and found that among the appendices sampled in toto, 11 cases of SSA/Ps were identified, compared with 1 case in the routinely sampled group. In our study, the total incidence rate of SPs was 2.5% (66/2603). As one of China's single-center research centers for PMP, our institution began routinely sampling the entire appendix after April 2019. Since then, 516 appendices have been submitted. The incidence rate of SPs was 6.2% (32/516), which is higher than obtained in the traditionally sampled group (1.6%, 34/2088), which indicates that partial sampling may cause missed diagnosis. Sampling the entire appendix may provide more comprehensive data, which also challenges traditional diagnostic approaches.
As the most common element of the SP family in colorectal neoplasm, HP, comprises 80%–90% of all serrated polyps [16-17]. In our study sample, there were only 2 cases of HP among the SPs. Even in the in toto sampling group, the incidence rate was 1/66. This may be related to the fact that patients with HP present no overt clinical symptoms, besides the focal hyperplasia of the mucosa on histological observation. HPs were similar in appearance to the normal mucosa, and tended to be smaller than SL (previously called SSA/P lesions), and the latter were often circumferential [18]. In our study, none of HPs presented attractive diverticulum and mucin extravasation, which may be another reason for missed diagnosis.
The diameters of LAMN (mean 27.2 mm) were significantly larger than that of SPs (mean 9.6 mm) (P<0.01), and in some cases these could reach up to 60 mm. Imaging studies can identify such expanded structures and allow a diagnosis of appendix tumors or cysts, and prompt the patient to undergo appendectomy. In our sample population, 13 (59.1%) cases in the LAMN group underwent appendectomy owing to the presence of appendix tumors or cysts. Instead, all cases of SPs could be attributed to appendicitis.
SPs were often associated with acute appendicitis (35/66, 53.0%). It has previously been suggested that the intestinal mucosa can develop hyperplastic and architectural changes mimicking serrated polyps as a response to inflammatory stimuli [19]. Serrated epithelial lesions have also been described for inflammatory bowel disease (IBD) as a reactive response to inflammatory stimuli [20]. Similarly, in the acute appendicitis, the appendiceal mucosa may present with hyperplastic serrated lesions [15]. We also identified 5 additional cases of reactive serrated lesions in our review. In fact, reactive serrated lesions are not real SPs. The key differences were reactive serrated changes that were mostly limited to the surface of the mucosa, while the inflammatory and reactive serrated lesions alterations were always mixed. In real SPs, we can distinctly separate the surrounding inflamed mucosa from serrated lesions, and can observe branching, basal dilation, inverted T-shaped or L-shaped crypts in the background. We also found that SLD (20/32,62.5%) were more likely to be associated with acute inflammation than SL (13/32,40.6%). It can also be said that acute inflammation may more likely to lead to mucosal atypia. When SLD are not accompanied by acute inflammation, it may resemble a conventional adenoma with pseudostratified elongated hyperchromatic nuclei or display enlarged, vesicular nuclei with prominent nucleoli, that can easily be identified. Nevertheless, when accompanied with acute inflammation, the discrete distinction and categorization of dysplasia from reparative changes were challenged, which was the most noteworthy diagnostic puzzle we encountered in the review. Conversely, LAMN was less likely to be associated with acute inflammation (4/22,18.2%), although, there was no statistical significance between SPs and LAMN (P=0.009).
The mucosal epithelial structures of SL and SLD were complex, showing serrated, filiform, flatted, or scalloped changes. There were no differences in the proportion of epithelial structural changes between the groups. All SL and SLD cases had typical crypt architectural features, including serration, dilatation, horizontal orientation, L-shape or inverted T-forms. This morphology should be distinguished from crypt changes caused by lymphatic follicles. In the normal appendix, the extensive follicular architecture distorts the crypts in many regions and leads to variable crypt lengths, distribution, and architecture [8]. In the normal appendix, these changes were confined to the clearly identifiable follicular area, and no additional serrated structures were found in the surrounding mucosa.
Serrated and filiform structures were more likely to appear in SPs, while flat and clustered structures were present in LAMN. In the background of flattened or clustered lesions, only 4 cases of LAMN presented focal filiform villous structures, which was not consistent with the literature [1,5]. We speculated that LAMN with an extensive filiform villous structure is more likely to be associated with PMP, but these cases were excluded from the study. Whether this is the result of a selection bias requires further observation.
SPs can also present a flattened mucosa and acellular mucin in the appendiceal wall, which are more likely to be confused with LAMN, and which make the diagnosis more challenging. To improve the differential diagnosis, it is important to sample the entire appendix. In cases with the presence of acellular mucin in the wall, we should focus on whether there is concomitant diverticulum. Diverticula of the appendix can be either acquired or congenital. Congenital diverticula are rarer, and generally consist of the mucosa, submucosa, serosa, and muscular layers, while acquired diverticula disease (ADD) are usually “false” and lack the muscular layers [21]. Increased intraluminal pressure is most commonly due to obstruction (benign or malignant) or inflammation and may predispose to ADD formation in weak areas of the appendiceal vascular walls [22-23]. In our SPs group, 12 cases were accompanied by ADD. Among these, there were 11 cases with mucin accumulation in the appendiceal wall, and all were characterized as acellular mucin. Diverticulum or inflammation leads to increased pressure in the appendix cavity, and then causes mucosal atrophy and flattened mucosa, the lamina propria becomes thinner or even disappears, which can easily be mistaken it for the occurrence of push infiltration and diagnosed as LAMN. In our group, 11 cases of appendiceal SPs appeared with atrophied and flattened mucosa. The lamina propria was notably thinned, but a small amount of residue could still be detected after careful observation. In retrospect, 8 cases of SPs were mis-diagnosed as LAMN, of which 4 cases presented flattened mucosa with diverticula and intramural mucin, 2 cases presented flat mucosa, and the 2 remaining cases presented intramural mucin. Fortunately, no additional surgical procedures were required for these patients. Thus, in such cases, the effective diagnostic points to consider include: observing the existence of muscularis mucosa and the presence of fibrosis in the appendiceal wall. SMA immunohistochemistry can be used to assist in more dubious cases. In the LAMN group, focal/complete disappearance of muscularis mucosa and fibrosis in the appendiceal wall were identified; in 9 cases, these were limited to submucosa fibrosis and 13 cases there was evidence of full thickness fibrosis. Among these, 4 cases exhibited local fibrosis with a background of SPs. We tend to classify such cases as LAMN, which indicates the potential risk of PMP. Calcification (10/22, 45.5%) was also a good indicator of LAMN diagnosis. It can be recognized by imaging studies prior to surgical procedures.
It is clear that LAMN presents the potential risk of peritoneal dissemination [15]. The pathomorphology of SPs and LAMN are partly overlapped., it is a challenge to distinguish them. And molecular biological differences between LAMN and SPs are required to further our understanding of this disease.