Traditional serrated adenoma with superficially serrated adenoma: A case treated with endoscopic submucosal dissection with detailed endoscopic observation and pathological study

Abstract A new subtype of serrated lesions, superficially serrated adenoma (SuSA), has been proposed as a lesion that histopathologically exhibits the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one. SuSA has been elucidated to be a precursor lesion of KRAS‐type traditional serrated adenoma. It has also been reported that SuSA may have malignant potential. We report a case treated with endoscopic submucosal dissection and detailed observation. Endoscopy revealed a raised lesion with a two‐tier raised appearance in the sigmoid colon: a tall pinecone‐like reddish structure and flattened whitish elevation on white light imaging. Magnifying narrow‐band imaging revealed conspicuous blood vessels in the pinecone‐like structure and slightly dilated reticular vessels in the flattened area. Crystal violet staining showed that the pinecone‐like structure had a type IVH pit pattern and the flattened area had a stellate to slightly elongated type IIIH pit pattern diagnosed based on Kudo's classification and other pit pattern classification systems. Ki67‐positive cells were distributed in the basal and middle layers of the gland in the flattened elevated area. Genetic analysis results were positive for KRAS mutation and negative for BRAF mutation. Histopathological examination revealed a traditional serrated adenoma in the pinecone‐like structure and SuSA in the adjacent flattened elevated area.


INTRODUCTION
Superficially serrated adenoma (SuSA) was proposed as a new subtype of serrated lesions by Hashimoto et al. 1  ical features of both conventional-type adenomas and serrated lesions, making it difficult to classify the lesions as either one. Since SuSA has been elucidated to be a precursor lesion of KRAS-subtype traditional serrated adenoma (TSA), it may have malignant potential. 2 However, in today's colonoscopy practice, SuSA may be F I G U R E 1 Endoscopic findings of traditional serrated adenoma (TSA) with superficially serrated adenomas (SuSA). (a) Colonoscopy shows a raised lesion with a two-tier raised appearance in the sigmoid colon, consisting of a tall pinecone structure and flattened elevation. Indigo carmine dye spray highlights the nodular surface. (b) The yellow box indicates the boundary between the TSA and SuSA components, which is magnified in Figure 1c. The red box indicates a typical part of the SuSA component, which is magnified in Figure 1d To date, there are still few reports on the clinicopathologic features and detailed endoscopic findings of SuSA. Herein, we report a case of TSA with SuSA carefully detected by colonoscopy and treated with endoscopic submucosal dissection, wherein an immunohistochemistry analysis was performed.

CASE REPORT
A 74-year-old woman was referred to our hospital for endoscopic resection of a polyp in the sigmoid colon. Colonoscopy showed a raised lesion, approximately 25 mm in size, with a two-tier raised appearance in the sigmoid colon, consisting of a tall pinecone-like structure and a flattened elevation (Figure 1a). The pinecone-like structure appeared reddish (Figure 1c), and the flattened area was white to the same color as the surrounding background mucosa (Figure 1d) on white-light imaging.
Magnifying narrow-band imaging (NBI) revealed conspicuous blood vessels in the pinecone-like structure ( Figure 2a) and slightly dilated reticular vessels in the flattened areas ( Figure 2b). Crystal violet staining showed that the pinecone-like structure had an IV H -type pit pattern, diagnosed based on Kudo's classification 3 and other pit pattern classification systems 4-6 ( Figure 2c). The flattened area showed a stellate to slightly elongated III H -type pit pattern ( Figure 2d).
Based on these findings, endoscopic submucosal dissection was performed, considering the TSA in the pinecone-like structure and adenoma or SuSA in the adjacent flattened structure. The patient underwent an en-bloc resection without any adverse events.
Histopathological examination revealed a dense proliferation of the glandular ducts with pseudostratified nuclei and a serrated surface around the TSA lesion, forming tall ridges (Figure 3a).
Immunohistochemical staining showed that CK20 was expressed in the upper layer of the flattened structure adjacent to the TSA lesion (Figure 4a).   Ki-67 and MYC expressions were distributed in the basal and middle layers of the flattened structure (Figure 4b,c). Additionally, β-catenin, suggesting the activation of the Wnt pathway, was found in some nuclei (Figure 4d). These are specific features of the SuSA.
Genetic analysis revealed positive results for KRAS mutation and negative for BRAF mutation. No tests could be performed for RSPO fusions. The histopathological findings and KRAS mutation strongly suggested the possibility of TSA with SuSA.

DISCUSSION
In 2018, a new subtype of serrated lesions, SuSA, has been proposed as a new subtype of serrated lesions that manifests the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one. 1 It is known that some types of SuSA are associated with TSA.
In a report examining 21 cases of TSA with SuSA by Mizuguchi et al., the median age was 67 years, of which the majority was female. All lesions were located in the sigmoid colon or rectum and had a median diameter of 15 mm. Genetic analysis results showed RSPO mutation/overexpression in 95% of both TSA and SuSA components and KRAS mutations in all patients. 7 Endoscopic findings revealed a two-tier raised elevation, with a flat portion (SuSA) and a taller elevated portion (TSA). The SuSA portion appeared white, whereas the TSA portion appeared reddish on white-light imaging.
Although the NBI findings clearly showed blood vessels in the TSA area, none were observed in most SuSA areas. Chromoendoscopy revealed a type III H pit pattern in the SuSA areas.
Tanaka et al.studied the histopathology of TSA and its associated lesions according to KRAS and BRAF mutations. They found that all TSA with associated lesions showing KRAS mutations were located in the distal colon. These lesions were considered SuSA-like lesions and reported to show a type II L pit pattern in the associated portion without endoscopic mucus signs or II-Open pit pattern. 8 Chino et al. reported a group of lesions with serrated, adenomatous structures with TSA that were difficult to classify based on the criteria for conventional diagnosis as tubuloserrated adenomas.
All lesions in previous reports were located in the distal colon and had sessile-elevated central components resembling mixed adenomatous morphology and included various pit patterns such as typeIV with serration, type II, and type III L . All these lesions had KRAS mutations without BRAF ones and were reported to be similar to SuSAs. 9 Since genetic analysis showed RSPO fusion/overexpression at a high rate in both TSA and SuSAs in these reports,TSA presenting with a two-stage elevation in the distal colon with KRAS mutations may be considered associated with SuSAs.
In our case, the flattened component of the two-stage elevated lesion, the SuSA, showed a type II pit pattern, a stellate cap with an elongated type II pit pattern, and a partially branching pit pattern. In addition, the flattened component showed a network pattern of vessels on NBI.
Although vascular structures have not been reportedly recognized in approximately 80% of SuSA lesions, vessels could be seen in our case, and the caliber of the vessels in the flattened component was similar to that in the surrounding normal mucosa. Therefore, this lesion was diagnosed as similar to type I according to the Japan NBI Expert Team classification. 10 Genetic analysis showed KRAS mutations in both lesions, without performing analysis for RSPO fusions, as the RSPO gene fusion test could only be performed in a limited number of facilities.
Since the SuSA may not only be a precursor lesion of TSA but also have malignant potential, 2 colonoscopy should be carefully performed for detecting spreading tumors around TSA lesions, particularly when these TSA lesions are noticed in the distal colon. Further studies are required to determine the clinical features of this condition.

C O N F L I C T O F I N T E R E S T S TAT E M E N T None.
O R C I D Momoka Sato https://orcid.org/0000-0002-1251-8515