Cancer emerging from the recurrence of sessile serrated adenoma/polyp resected endoscopically 5 years ago

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1 Japanese Journal of Clinical Oncology, 2016, 46(1) doi: /jjco/hyv154 Advance Access Publication Date: 3 November 2015 Case Report Case Report Cancer emerging from the recurrence of sessile serrated adenoma/polyp resected endoscopically 5 years ago A. Chino 1, *, S. Nagayama 2, H. Ishikawa 1, K. Morishige 1, T. Kishihara 1, M. Arai 3, Y. Sugiura 4, N. Motoi 4, N. Yamamoto 4, Y. Tamegai 1, and M. Igarashi 1 1 Digestive of Gastroenterology Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 2 Digestive of Surgery Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, 3 Clinical Genetic Oncology Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, and 4 Pathology Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan *For reprints and all correspondence: A. Chino, Digestive of Gastroenterology Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan. akiko.chino@jfcr.or.jp Received 5 May 2015; Accepted 17 September 2015 Abstract Since the serrated neoplastic pathway has been regarded as an important pathway of colorectal carcinogenesis, few reports have been published on clinical cases of cancer derived from sessile serrated adenoma/polyp, especially on recurrence after resected sessile serrated adenoma/polyp. An elderly woman underwent endoscopic mucosal resection of a flat elevated lesion, 30 mm in diameter, in the ascending colon; the histopathological diagnosis at that time was a hyperplastic polyp, now known as sessile serrated adenoma/polyp. Five years later, cancer due to the malignant transformation of the sessile serrated adenoma/polyp was detected at the same site. The endoscopic diagnosis was a deep invasive carcinoma with a remnant sessile serrated adenoma/polyp component. The carcinoma was surgically removed, and the pathological diagnosis was an adenocarcinoma with sessile serrated adenoma/polyp, which invaded the muscularis propria. The surgically removed lesion did not have a B-RAF mutation in either the sessile serrated adenoma/polyp or the carcinoma; moreover, the initial endoscopically resected lesion also did not have a B-RAF mutation. Immunohistochemistry confirmed negative MLH1 protein expression in only the cancer cells. Lynch syndrome was not detected on genomic examination. The lesion was considered to be a cancer derived from sessile serrated adenoma/polyp recurrence after endoscopic resection, because both the surgically and endoscopically resected lesions were detected at the same location and had similar pathological characteristics, with a serrated structure and low-grade atypia. Furthermore, both lesions had a rare diagnosis of a sessile serrated adenoma/polyp without B-RAF mutation. This report highlights the need for the follow-up colonoscopy after endoscopic resection and rethinking our resection procedures to improve treatment. Key words: sessile serrated adenoma/ polyp, cancer derived from sessile serrated adenoma/polyp, B-RAF mutation The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 89

2 90 Cancer emerging from the recurrence of sessile serrated adenoma/polyp Background In 2003, Torlakovic et al. (1) showed that some hyperplastic polyps (HPs) are neoplastic and proposed the disease entity of sessile serrated adenoma/polyp (SSAP). Following their proposal, serrated polyps (SPs) were classified as classical HPs, SSAPs or traditional serrated adenomas (TSAs) (2) based on detailed pathological analyses. The adenoma carcinoma sequence proposed by Vogelstein (3) is still the canonical pathway of colorectal carcinogenesis, accounting for 80% of all cases of colorectal cancer. Recently, the serrated neoplastic pathway has been thought to play an important role in the carcinogenesis of proximal colorectal cancer (4). Specifically, B-RAF mutation is observed in the majority of SSAPs, but is almost never observed in conventional adenomas (5). In addition, SSAP-derived cancers are characterized by a high microsatellite instability (MSI) status. These findings lend support to the existence of the serrated neoplastic pathway and SSAPs being the main precursors of MSI-high colon cancers (6). The presence of SSAPs should be considered seriously, especially in terms of the treatment indications for SSAPs, and surveillance after endoscopic resection is important as well. We encountered a thought-provoking case of a cancer coexisting with SSAP in the proximal colon, possibly derived from a residual SSAP with low-to-high grade atypia after endoscopic resection of a lesion diagnosed as an atypical HP 5 years previously. Case presentation A 77-year-old woman was referred to our hospital for further management of a flat lesion, 30 mm in diameter, in the ascending colon in The color pattern, transparency and mucinous deposition of the lesion were identical to those of the surrounding mucosa, and HP was diagnosed on the basis of endoscopic findings. Because the lesion was large and located in the proximal colon, we decided to treat the lesion with endoscopic resection. Endoscopic piecemeal mucosal resection (EPMR) was performed, and therefore, the horizontal margin status on histopathology was unclear. A final diagnosis of a HP with a metaplastic component was made on the basis of the histopathological criteria at that time (Fig. 1). Of note, reliable pathological diagnostic criteria regarding sessile serrated adenomas, including atypical HPs, were not established before the implementation of the new World Health Organization classification in After treatment, the patient was followed up at a private hospital. At the 1-year follow up after EPMR, no neoplastic lesions were detected. Therefore, the next follow-up examination had been scheduled for 3 years later. In 2012, 5 years after the initial EPMR, a recurrent lesion was suspected on examination at the same private hospital. It was a flat, elevated lesion with a diameter of 30 mm, located in the ascending colon. The patient was referred again to our hospital for treatment. Conventional endoscopy with indigo carmine dye spraying revealedalargesuperficialelevatedlesionwithanelevatedarea andadepressiononthe rightedgeof thelesion (Fig. 2). The previous lesion was located in the ascending colon as determined by a common marking of the anal site with 2-folds from cecum (Fig. 3a; white arrow at cecum). The trace after initially resection in 2007 was showed Fig. 3b, the recurrent lesion was showed at the same position, (Fig. 3c; white arrow at cecum). Moreover, we detected right side convulsions that were considered due to the initial EPMR (Fig. 3d; yellow arrow at convulsions). Figure 1. (a) Endoscopic findings of the initial lesion resected in 2007 a flat elevated lesion. (b) Indigo carmine spraying showing no irregular elevation or depression within the lesion. (c and d) Pathological findings of the initial resected lesion.

3 Jpn J Clin Oncol, 2016, Vol. 46, No Figure 2. (a and b) Dye-spraying endoscopic views. (a) The oral-side and (b) anal-side of the recurrent lesion in (c) The elevated area shown in (a) with a glandular structure on magnified endoscopy. (d) The absence of the glandular structure in the depressed region inside the elevated area shown in (b). For further examination, narrow-band imaging with magnification was employed to visualize the entire area of the superficial elevated lesion, including the depressed portion (Fig. 4). The intervening area between the superficial and elevated portions showed unclear vessel patterns and expanded crypt openings with magnifying surface patterns, which are frequently seen in SSAPs (7) (Fig. 4b). In the depressed portion had irregular vessels characterized by disordered capillary networks, which are commonly seen in carcinomas (Fig. 4c). According to the classification proposed by Kimura et al. (8), the pit pattern in the flat area was classified as Type II open that is specific to SSAPs. In contrast, III L -like pits of various sizes with patchy fragmentation (V I -pit pattern) were distributed irregularly in the depressed region inside the elevated area. Considering all these endoscopic findings, the lesion was considered to be a cancer derived from SSAP that invaded the submucosal layer. Therefore, surgical resection with lymph node dissection was recommended. A laparoscopic right hemi-colectomy was performed without any sequelae, and the final pathological diagnosis was a well-to-moderately differentiated adenocarcinoma with an SSAP component that invaded the muscular layer, T2N0M0, Stage I. The resected specimen had a peculiar gross appearance. The lesion was composed of three different organizations, a flat, elevated and intervening region, which were pathologically examined individually (Fig. 5a); the pathological diagnoses of the each region were SSAP with low-grade atypia (Fig. 5b), adenocarcinoma (Fig. 5c and e) and SSAP with high-grade atypia, respectively (Fig. 5d). The loss of MLH1 protein expression was evident by immunohistochemical analysis only in the cancer cells (Fig. 6), with the SSAP with low-grade atypia and SSAP with high-grade atypia components showing MLH1 protein expression. We re-examined the initial endoscopic resection specimen obtained 5 years previously. The histopathological diagnosis was SSAP with low-grade atypia, with MLH1 protein expression in those parts. The MSI status and K-RAS/B-RAF mutation status were analyzed using DNA samples extracted from microdissected tumor cells in each region. In the surgical resected specimen, the cancer derived from SSAP showed positive expression of four of the five MSI markers, indicating an MSI-high status. K-RAS or B-RAF mutations were not identified in any of the regions (Fig. 7). Similarly, the specimen that was endoscopically resected 5 years previously did not show B-RAF mutation. On the basis of genomic examination performed after obtaining informed consent, the absence of Lynch syndrome was confirmed. Discussion Since carcinogenesis from SPs via the serrated neoplastic pathway has been reported (5), it has become necessary to distinguish the features of classical HP, SSAP and TSA. Furthermore, it is important to standardize the endoscopic and histopathological diagnostic criteria for these lesions to accurately evaluate the malignant potential of each subtype. In previous studies, the B-RAF mutation has been detected in 65 90% of SSAPs, which is a significantly higher

4 92 Cancer emerging from the recurrence of sessile serrated adenoma/polyp Figure 3. (a and b) The location of the initial resected lesion, with markings such as the anal site with 2-folds from the cecum (white arrow). (c and d) Findings of the recurrent lesion at the same site. (d) Right side convulsions after endoscopic piecemeal mucosal resection (yellow arrow). rate than that for other SPs (5,9,10). In addition, the B-RAF mutation was detected more often in SSAPs located in the proximal colon, suggesting an effect of location on tumor development (9,11). In the present case of cancer coexisting with SSAP located in the proximal colon, B-RAF mutations were not detected in any of the specimens examined. Pathological examination showed continuous gradation of the SSAP area to the cancerous portions, without any traditional adenomatous components. Furthermore, the grading of the serrated structure, such as low-grade atypia, of the initially resected lesion was similar to that of the surgically resected lesion. Loss of MLH1 protein expression was observed in only the cancer cells. Moreover, a MSI-high status was confirmed for the cancer. B-RAF mutation status in sporadic and familial MSI-high colorectal cancers has been shown to differ. Familial MSI-high lesions such as Lynch syndrome are associated with an earlier age of onset and histopathological characteristics that reflect an origin in traditional adenoma (12). Moreover, some reports state that familial MSI-high colorectal cancers do not show B-RAF mutation (13). In the present case, B-RAF mutation was not detected in the MSI-high colorectal cancer in the proximal colon, but cancer was diagnosed at an advanced age. Finally, on the basis of genetic sequencing results, Lynch syndrome was ruled out. In conclusion, we consider that the lesion in this case is a sporadic MSI-high colorectal cancer. Thus, the SSAP in this case was rare. The sporadic MSI-high cancer developed from a recurrent SSAP without B-RAF mutation, which arose from a SSAP without B-RAF mutation that was endoscopically resected with microscopic residual organs. We hypothesize that the SSAP without B-RAF mutation was localized for a long period; transformation occurred in the recurrent lesion, seen on the right edge of the presented lesion; and carcinoma then developed rapidly from the SSAP. Our resection procedures need to be re-thought to improve treatment and decrease the rate of SSAP recurrence. Currently, the treatment strategy for SSAPs with a diameter of >20 mm is not established. Furthermore, the recurrence rate of SSAPs after endoscopic resection has not been reported. For colorectal neoplastic lesions, including adenomatous lesions of all pathological types, the recurrence rate after piecemeal resection such as EPMR has been reported to be higher than that after en bloc resection (14,15). Pohl et al. (16) reported that the rate of incomplete resection was significantly associated with tumor size and SSAP histology, as margins of very large SSAPs are often not distinct. To decrease the recurrence rate, we recommend resected margin examination with magnifying endoscopy; however, the resected margin immediately after EPMR is often not clearly observed. Therefore, a special process should be considered

5 Jpn J Clin Oncol, 2016, Vol. 46, No Figure 4. (a) Conventional endoscopic findings of the lesion shown in Fig. 2b. (b and c) Narrow-band imaging magnifying endoscopic findings of the area marked in yellow in (a) showing characteristics of SSAPs (b) and a depressed area with an irregular vascular pattern (c). (d and e) The pit pattern of the flat elevated lesion (yellow square in a) sowing a type-ii open pit pattern (d), with a V I -pit pattern evident in the depressed part (red square in a) (e). Figure 5. (a) The total resected lesion showing thin sections of the blue, green, and yellow line. (b) The blue section diagnosed as sessile serrated adenoma with low-grade atypia, and the (c) green and (e) red sections diagnosed as adenocarcinoma. (d) The intervening region (the yellow line) evaluated as a sessile serrated adenoma with high-grade atypia.

6 94 Cancer emerging from the recurrence of sessile serrated adenoma/polyp Figure 6. Immunohistochemical analysis of MLH1 expression in the area of sessile serrated adenoma/polyp with low-grade atypia and the cancer part, also serial sections (high-grade atypia), respectively. Note that the loss of MLH1 protein expression was evident only in the cancer cells. Figure 7. K-RAS and B-RAF mutation status with MLH1 expression patterns in each region of the resected lesion. for SSAP resection, which could involve marking the edge of the SSAP before resection, coagulating the margin after resection or confirming scar formation over a short-term follow-up after resection, with additional treatment as needed (17,18). If these measures are difficult to implement, we ought to select en bloc resection with procedures such as endoscopic submucosal dissection and, rather important thing is to detect the SSAP should be complete resection. During surveillance after SSAP resection, if resection is found to be incomplete or the status cannot be determined, follow-up colonoscopy could be recommend once within a year (19). The appropriate intervals for surveillance are still debated, as the growth process of SSAPs is uncertain whether SSAPs spread laterally over time or have clear borders and appear rapidly is still not established. According to the study by Holme et al. (20) large SPs left in situ do not frequently progress to colorectal cancer over their natural course and large serrated polyps are an independent risk factor for colorectal cancer. The rate of growth of SSAP may be slow, but this is not related with its malignant potential. We should pay careful attention to the possibility that SSAP recurrence from residual lesion is also undergo malignant transformation similar to those of conventional adenoma. Consent statement Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal. Authors contributions A.C. designed and drafted the manuscript. S.N. and M.A conceived and revised the manuscript, and did supervision. N.Y, N.M and Y.S did pathological diagnosis. T.K., K.M., H.I., Y.T. and M.I. did endoscopic diagnosis. S.M. did surgical treatment. All authors read and approved the final manuscript.

7 Jpn J Clin Oncol, 2016, Vol. 46, No Acknowledgements We thank Drs Nobuhiko Okawa, Shigehiro Katakura and Yoshiharu Satake for helpful discussions about establishing the diagnosis. Conflict of interest statement None declared. References 1. Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003;27: Snover DC, Ahnen DJ, Burt RW, Odze RD. Tumor of the colon and rectum; serrated polyps of the colon and rectum and serrated polyposis. WHO; 2010; Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61: Melo FDSE, Wang X, Fessler E, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 2013;19: Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010;138: O Brien MJ. Hyperplastic and serrated polyps of colorectum. Gastroenterol Clin N Am 2007;36: Yamashina T, Takeuchi Y, Uedo N, et al. Diagnostic feature of sessile serrated adenoma/ polyps on magnifying narrow band imaging: A prospective study of diagnostic accuracy. J Gastroenterol Hepatol 2015;20: Kimura T, Yamamoto E, Yamano H, et al. A Novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma. Am J Gastroenterol 2012;107: Spring KJ, Zhao ZZ, Karamatic R, et al. Height prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroentorol 2006;131: Carr NJ, Mahajan H, Tan KL, Hawkins NJ, Ward RL. Serrated and nonserrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. J Clin Pathol 2009;62: Patil DT, Shadrach BL, Rybicki LA, Leach BH, Pai RK. Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status. Mod Pathol 2012;25: Iino H, Simms L, Young J, et al. DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary nonpolyposis colorectal cancer. Gut 2000;47: McGivern A, Wynter CVA, Whitehall VLJ, et al. Promoter hypermethylation frequency and B-RAF mutation distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 2004;3: Oka S, Tanaka S, Saito Y, et al. Local recurrence after endoscopic resection for large colorectal neoplasia: a multicenter prospective study in japan. Am J Gastroenterol 2015;110: Arleen MO, Patham B, Marc JZ, et al. Endoscopic mucosal resection recurrence rate for colorectal lesions. South Med J 2014;107: Pohl H, Srivastava A, Bensen SP, et al. Incomplete polyp resection during colonoscopy- result of the complete adenoma resection (CARE) study. Gastroenterol 2013;144: Livio C, Maria AB, Maria LG, et al. Can magnification endoscopy detect residual adenoma after piecemeal resection of large sessile colorectal lesion to guide subsequent treatment? A prospective single-center study. Dis Colon Rectum 2009;52: Regula J, Wronska E, Polkowski M, et al. Argon plasma coagulation after piecemeal polypectomy of sessile colorectal adenomas: Long-term followup study. Endsc 2003;35: Bauer VP, Papaconstantinou HT. Management of serrated adenomas and hyperplastic polyps. Clin Colon Rectal Surg 2008;21: Holme Ø, Bretthauer M, Eide TJ, et al. Long-term risk of colorectal cancer in individuals with serrated polyps. Gut 2015;64: