Superficial Serrated Adenoma (SuSA): A New Subtype of Serrated Lesions ()
1. Introduction
Colorectal cancer (colorectal cancer, CRC) is one of the most common malignant tumors in the world, ranking the third in the incidence of all cancers, the second in mortality, and the first in all cancers of the digestive system [1] . In recent years, with the improvement of people’s health awareness and the increasing popularity of colonoscopy, digestive endoscopy doctors pay more and more attention to the diagnosis and treatment of early CRC. The premonitory signs of colorectal cancer include two pathways: conventional adenomas and serrated lesions. The classical approach of “adenoma-adenocarcinoma” put forward in the 1970s [2] . It is generally believed that adenomatous polyps are precancerous lesions of CRC. Although traditional adenoma is the main precursor of CRC carcinogenesis, another pathway, serrated lesion pathway, has been paid more and more attention in recent years. According to the literature, up to about 30% of colorectal cancer is thought to be caused by serrated lesions [3] .
Colorectal serrated lesions are a group of heterogeneous lesions different from common polyps/adenomas. Their histological features are serrated structures in the colonic recess, which is the result of decreased apoptosis and increased senescence of epithelial cells in the recess [4] . According to the latest classification of digestive tumors in the 5th edition of the World Health Organization, serrated lesions include hyperplastic polyps (HP), sessile serrated lesion (SSL), sessile serrated lesion with dysplasia (SSL-D), traditional serrated adenomas (TSA) and serrated adenoma-unclassified [5] . At present, it is not clear which lesion type SuSA belongs to, but as a new subtype of serrated lesions, a case of adenocarcinoma originating from SuSA has been reported in the literature, indicating that SuSA has the nature of precancerous lesions [6] . In this paper, the research progress of SuSA at home and abroad is summarized as follows.
2. The Origin of SuSA
Superficial serrated adenoma (SuSA) is a new subtype of serrated lesion proposed by Hashimoto et al. in 2018. Most SuSA are located in the sigmoid colon or rectum of the left colon, showing typical mixed adenoma and serrated features, including straight adenoma glands, serrated only in the superficial part [6] [7] . According to related literature reports, SuSA has two subtypes: TSA-associated SuSA and isolated SuSA [8] . TSA-associated SuSA is easily detected when associated with TSA, so when we find it, it can be removed by us together with TSA [8] . On the contrary, if it is an isolated SuSA, the endoscopic manifestation is usually very small and is often indistinguishable from hyperplastic polyps, which may lead to some confusion [8] and mistake it for HP, resulting in recognition and ignorance. Therefore, it is necessary to understand the common endoscopic features of SuSA.
3. Endoscopic Features
The shape of SuSA shown by endoscopy is diverse, depending on the size of the lesion itself. The study of Mizuguchi et al. [9] shows that most SuSA are white in color, with clear boundaries, and lobulated structures are also common, especially in large lesions.
According to the size of endoscopic SuSA, it can be divided into three groups: diminutive (1 - 5 mm), small (6 - 9 mm), large (≥10 mm) [9] .
Diminutive (1 - 5 mm): Endoscopic appearance is mostly round, often accompanied by slight eminence, indicating smooth, clear but irregular boundary; under magnifying pigment endoscope, the vascular morphology is not clear, and the JNET classification is type 1.
Small (6 - 9 mm): Endoscopy often showed faded tone, slight uplift without pedicle, uneven surface and lobulated structure; irregular surface structure could be seen under indigo staining, but the boundary was clear, and the blood vessels were not obvious under magnifying pigment endoscope, and the JNET classification was type 1.
Large (≥10 mm): The larger lesions showed flat eminence with lobulated structure (different iated from TA and SSL). Lengthening and branching could be seen on part of the surface, and the boundary was clear but irregular. The blood vessels seen under magnifying pigment endoscope are not obvious or very few can be shown as reticular vessels [9] . The irregular lobulated surface structure can be seen after indigo staining, and the pitting type II or IIIH can be observed by magnifying endoscopy, indicating that SuSA has a consistent serrated surface microstructure [9] . However, in all the SuSA we found, endoscopy did not show mucus cap coverage [9] .
4. Histopathological Features
Histopathologically, SuSA mainly showed typical mixed adenoma and serrated features [8] . It mainly includes the straight adenomatous gland and the superficial part of the serrated structure, the middle and lower layer of non-serrated glands, the cells are columnar, the bottom of the cell nuclear base is slender and uniform [7] , showing a typical “second floor”. Under the microscope, a clear boundary can be seen in the pathological section, there is a sudden transition between the neoplastic gland and the normal mucosa around the lesion, and the superficial layer of the lesion can be seen with serrated process + middle-deep adenomatoid glandular hyperplasia. Immunohistochemistry showed that CK20 was expressed in the upper layer of SuSA, similar to that in normal mucosa, Ki 67 and MYC were expressed in the middle and lower layer of SuSA, and SuSA showed not only membranous β-catenin expression, but also moderate nuclear β-catenin expression [7] .
5. Molecular Biological Characteristics
Up to now, simultaneous KRAS mutation and RSPO fusion/overexpression are often found in most SuSA [9] . RSPO fusion and overexpression that lead to activation of WNT signal transduction are common and specific for SuSA and TSA [10] . Another remarkable feature of SuSA is its frequent coexistence with TSA. Previous studies have shown that there are the same KRAS mutations and RSPO fusion or overexpression in the related components of SuSA and TSA, which confirmed their tissue relationship, but the mere existence of KRAS mutation and RSPO fusion or overexpression is not enough to promote the development of SuSA into TSA, and other unknown factors are needed [7] [11] . SuSA is mostly sessile lesions, lacking the pedicled or subpedicled morphology and typical cytology, ectopic recess formation and fissure serrated characteristics of TSA, so it is difficult to determine the morphological relationship between isolated SuSA and TSA, and only about 30% of TSA have KRAS mutations and RSPO fusion or overexpression, indicating that not all TSA originate from SuSA, but part of them originate from SuSA [7] [8] . Compared with TSA, the lesion size of SuSA is smaller.
6. Differential Diagnosis
SuSA usually needs to be differentiated from SSL, SSLD, and TA in endoscopic morphology and histology, but tiny SuSA is more likely to be confused with proliferative polyps. Therefore, the main identification points of SuSA, HP, SSL and so on are mainly given here.
7. Under Endoscope
The most common site of SuSA is located in the sigmoid colon or rectum. The color is white and has a clear boundary. The lobulated structure is especially prominent in large lesions. The mucus cap is often invisible, and bright blue ridge (LBC) and white opaque substance (WOS) are often seen in white light and narrow band imaging (NBI). Under magnifying pigment endoscope, most of the openings of glandular duct showed II, II-L and III-H [7] .
About 70% of HP is located in the left colon, usually <5 mm in diameter [12] . Under white light endoscope, HP is transparent or pale, usually similar to the surrounding mucosa, round or oval, and the shape is flat [13] [14] . Brown reticular capillaries could not be observed under magnifying pigment endoscope, and the opening of glandular duct was type II [15] . The most common site of SSL is located in the right colon. Endoscopic screening shows that mucus cap is an important “clue” to find SSL. LBC is often not visible under white light and NBI, while WOS is only sometimes visible. Pale, flat or sessile shape can be seen under white light endoscope, with the characteristics of cloud-like appearance, irregular surface, mucous cap and blurred edges [16] . The black spot sign was observed in NBI mode [17] . Under magnifying pigment endoscope, most of the openings of glandular duct were II-O and II.
8. Histologically
SuSA is mainly composed of vertical adenomatous glands. The transformation between superficial serrated glands in the outer layer and non-serrated glands in the middle and lower layers can be seen. The cells are columnar and the base of the nucleus is slender and uniform. The base of the recess is usually straight and does not have the characteristics of SSL, but larger lesions have some dilated glands, and all lesions are not accompanied by other types of polyps, such as HP or SSL [7] .
In the new WHO classification, HP is divided into microvesicular type (MVHP) and goblet cell-rich type (GCHP). MVHP is common in the right colon, and its zigzag structure is limited to the crypt. The cells in the crypt are composed of microbubble cells and goblet cells, of which MVHP is dominant, while GCHP is often located in the left colon, with few serrated structures and abundant goblet cells in the crypt [18] .
According to the classification of WHO in 2019, SSL can be diagnosed with only one “characteristic” recess, that is, more than one developed horizontally along the mucosal muscle, bottom dilatation, zigzag changes reaching the bottom, asymmetric proliferation and so on [5] . Its remarkable feature is that the recess is twisted and usually expands toward the base, showing a boot-shaped, L-shaped or inverted T-shaped [15] [19] , and the jagged change is most obvious at the base.
9. Therapy
At present, a case of adenocarcinoma originating from SuSA has been reported in the literature, which shows that SuSA has the nature of precancerous lesion [6] , so endoscopic resection is recommended as soon as it is found. The common methods of endoscopic surgery are as follows:
Cold snare polypectomy(CSP) has high complete resection rate and low delayed bleeding rate. It is very suitable for serrated lesions of lt; 10 mm [20] . Some studies have confirmed that the complete resection rate of CSP is significantly better than that of cold forceps polypectomy in terms of the integrity of small polyps [21] . The principle of CSP is to ensure the removal of the normal edge of the surrounding 1/2 mm [20] , which not only ensures the complete resection rate and low delayed bleeding, but also avoids the thermal injury caused by thermal resection of polyps (hot snare polypectomy, HSP).
Endoscopic mucosal resection (EMR) is the first choice for lesions ≥10 mm [22] . According to related studies, for serrated lesions ≥10 mm, EMR can not only ensure the safety of lesion resection, but also ensure a low recurrence rate [23] .
For some lesions ≥20 mm, or TSA-related SuSA, we need to use endoscopic submucosal dissection (ESD) as a resection method. Of course, some studies have shown that piecewise EMR resection can be used to treat serrated lesions ≥20 mm, but it still has a significant recurrence rate [24] , so it is generally not recommended as a treatment.
For some lesions that cannot be removed under endoscope, such as 50 mm, 60 mm or larger, there may be severe submucosal fibrosis, endoscopic treatment with perforation and a high risk of perioperative bleeding; or some lesions with submucosal invasive cancer, endoscopic treatment will increase the risk of incomplete resection, for these lesions can be treated by surgery.
10. Summary and Prospect
The morbidity and mortality of CRC are on the rise in China, and the malignant transformation pathways of different pathological types of colorectal polyps are different. At present, we know that about 30% of colorectal cancer originates from “serrated lesion-cancer pathway”. Although we have a certain understanding of the morphology, pathological tissue and molecular characteristics of colorectal serrated lesions, however, the pathogenesis of cancerization through the serrated pathway still needs further study. In the understanding of SuSA, it is feasible to diagnose isolated SuSA with large correlation between SuSA and TSA under endoscope. In recent years, it has also been found that some subtypes of HP can develop into some precursors of colorectal cancer through zigzag pathways [25] . For example, MVHP may be the precursor of sessile serrated adenoma, and GCHP may be the precursor of TSA [26] [27] , but it still needs to be confirmed. At present, a case of adenocarcinoma originating from SuSA has been reported in the literature, and it has also been found that some subtypes of HP can also develop into precursors of colorectal cancer, so improving the understanding and differentiation of SuSA and HP is helpful to better understand the occurrence and development of colorectal tumors.
In the future, it is still challenging to identify isolated tiny SuSA and HP, because their morphological characteristics are similar and we need to constantly accumulate and explore. As for SuSA, a new subtype of serrated lesions, how should we understand whether it is only a precursor of TSA or may be divided into a new subtype independently, we need to further understand the differences in clinicopathology and molecular characteristics. The identification of new pathways in colorectal cancer could give researchers and clinicians the opportunity to address this challenge by optimizing screening to further prevent the onset and progression of colorectal cancer. In the future, more clinical case analysis is needed to clarify the characteristics of this novel serrated lesion and epigenetic characteristics, so as to further improve the development of colorectal cancer serrated pathway, which will help to stratify the risk of patients.
NOTES
*Corresponding author.